Date Published: April 15, 2019
Publisher: Public Library of Science
Author(s): Harald Hegen, Anne Zinganell, Michael Auer, Florian Deisenhammer, Klemens Ruprecht.
The presence of ≥3 oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) without corresponding bands in serum represents a definite pathological pattern, whereas the clinical significance of 1–2 CSF bands (borderline pattern) is poorly investigated.
We screened 1986 consecutive CSF and serum samples which were collected over a four-year time period and had results of isoelectric focusing (IEF) available. Of patients with borderline OCB we reviewed individual medical charts for assessment of clinical diagnoses. Where feasible, IEF was replicated and results of follow-up samples were obtained. IEF was performed using polyacrylamide gel followed by immunoblotting and IgG-specific antibody staining. Additionally, we performed a systematic literature review of the diagnostic specificity of OCB using different cut-offs for CSF-restricted bands.
Out of 253 patients with borderline OCB, 21.7% had an inflammatory neurological disease (IND) of the central nervous system, comprising 4% multiple sclerosis patients, and 14.2% had a peripheral IND, whereas the remaining 64.1% of patients showed non-inflammatory diseases. Frequency of one or two CSF bands without corresponding serum bands did not differ between the disease groups. In a subgroup of 100 patients IEF was repeated. Of those, 73% were OCB negative, while no sample was positive. In 26 patients IEF results were available of a follow-up sample collected after a median of 27 months. Of those, 4 (15.4%) turned positive. Systematic literature review revealed a diagnostic specificity of OCB of 97% and 92% using a cut-off ≥3 and ≥2 CSF bands in patients with mainly non-inflammatory neurological diseases.
The clinical significance of one or two CSF-restricted bands is moderate and, hence, indicates a possible but not reliable proof of intrathecal B-cell activity. Sample re-testing, introduction of an additional diagnostic category, e.g. “possible intrathecal IgG synthesis”, and follow-up lumbar puncture might be possible options to address this scenario.
Detection of intrathecal IgG synthesis is part of the routine cerebrospinal fluid (CSF) work-up . Isoelectric focusing (IEF) and subsequent immunoblotting is the gold standard to visualize clonally restricted IgG known as oligoclonal bands (OCB) in CSF . Five different patterns of OCBs have been defined whereby the appearance of OCB in CSF without corresponding bands in serum constitute a local, intrathecal synthesis of IgG . The presence of OCB in CSF supports the diagnosis of a variety of inflammatory central nervous system (CNS) diseases extending from an autoimmune to infectious pathology . With regard to the cut-off defining OCB positivity, one might think that a consensus on ≥2 CSF bands has already been reached, as this threshold is recommended in the current MS diagnostic criteria  and suggested by recent review articles . However, this cut-off is still equivocal. There is no explicit threshold recommended by CSF guidelines [1–3] and several studies have been published that support ≥3 CSF bands to define OCB positivity [6–9]. Also, when approaching this topic from a different perspective, there a few studies that investigated the clinical significance of a single CSF band [10,11], whereas the value of double CSF bands has not been addressed so far.
The detection of OCB in CSF is the gold standard to prove intrathecal IgG synthesis indicating sustained inflammation within the CNS compartment supporting the diagnosis of a variety of neurological diseases, for example multiple sclerosis (MS) . However, the cut-off defining OCB positivity, that is the number of bands in the CSF without corresponding bands in serum, is still not unquestioned.