User:Julinka Auta Fernandes/sandbox MS laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D. Julinka Auta Fernandes

Overview

Cerebrospinal fluid (CSF) analysis provides laboratory evidence that can support the diagnosis of multiple sclerosis (MS), contribute to the 2024 McDonald diagnostic criteria, and assist in excluding alternative diagnoses. Evidence of intrathecal immunoglobulin synthesis is demonstrated by either CSF-restricted oligoclonal bands (OCBs) or the kappa free light chain (κ-FLC) index. These findings are not specific for MS and must be interpreted together with the clinical and MRI findings.

Laboratory Findings

CSF analysis:

• CSF analysis is useful in patients with suspected multiple sclerosis when the clinical or MRI findings do not by themselves establish the diagnosis, when CSF evidence is required by the 2024 McDonald criteria, or when an alternative diagnosis must be excluded. CSF analysis may not be necessary when the clinical presentation and MRI findings are characteristic and already fulfill the diagnostic criteria, provided there are no features suggesting a mimic.

• Routine CSF evaluation in suspected MS should consider white blood cell count, differential cell profile, albumin quotient, and assessment of intrathecal immunoglobulin synthesis. Additional CSF studies, including glucose, lactate, microbiological testing, cytology, or other targeted investigations, should be guided by the clinical presentation and suspected alternative diagnoses.

• CSF-restricted oligoclonal bands (OCBs) are evidence of intrathecal IgG synthesis and remain an established laboratory biomarker in MS. OCBs are not specific for MS and may also occur in other inflammatory, infectious, autoimmune, and neoplastic disorders.

• OCB patterns 2 and 3 demonstrate intrathecal IgG synthesis. A positive OCB result generally requires at least 2 bands in CSF that are absent from the paired serum sample. OCB testing is conventionally performed by isoelectric focusing followed by IgG-specific immunodetection using paired CSF and serum samples.

• OCBs are detected in more than 90% of patients with clinically definite MS, but they may also occur in important mimics. OCBs are detected in approximately 25% or fewer of patients with neuromyelitis optica spectrum disorder and in approximately 10% of patients with MOG antibody-associated disease. Therefore, a positive OCB result should not be regarded as diagnostic of MS in isolation.

• The kappa free light chain (κ-FLC) index is accepted as an alternative to OCBs for demonstrating intrathecal immunoglobulin synthesis under the 2024 McDonald criteria. A κ-FLC index of ≥6.1 is the recommended consensus decision threshold. The index should be calculated from paired CSF and serum κ-FLC and albumin measurements, and each laboratory should verify the cutoff for its validated assay.

• κ-FLC has diagnostic performance comparable with OCB. The 2025 consensus reported equivalent diagnostic accuracy at the 95% confidence level, with approximately 90% concordance between the two methods. In uncommon discordant cases, measurement of both κ-FLC and OCB may be considered.

• Validated turbidimetric or nephelometric assays should be used for κ-FLC testing. External proficiency-testing programs are available, and laboratories should use assays validated for CSF and serum and perform appropriate local verification before clinical implementation.

• Higher κ-FLC index values may have prognostic associations with increased disease activity; however, this prognostic application should be distinguished from its established diagnostic role in demonstrating intrathecal immunoglobulin synthesis.

• The IgG index is a quantitative measure of intrathecal IgG synthesis but has substantially lower diagnostic sensitivity than OCBs and is no longer recommended as the quantitative alternative to OCB for demonstrating intrathecal immunoglobulin synthesis. κ-FLC is the preferred quantitative alternative.

• A negative OCB or κ-FLC result does not by itself exclude MS. Conversely, a positive OCB or κ-FLC result does not by itself establish MS. Laboratory findings must be interpreted together with the clinical presentation and MRI findings, and alternative diagnoses should be appropriately excluded.

• CSF findings may assist in excluding alternative diagnoses that can mimic MS, including central nervous system infection, neuromyelitis optica spectrum disorder, MOG antibody-associated disease, vasculitis, other autoimmune or inflammatory disorders, and neoplastic disease. Additional CSF and serum investigations should be selected according to the clinical context and relevant diagnostic red flags.

• The 2024 McDonald criteria and CSF consensus recommendations apply to pediatric and adult patients with both relapsing and progressive-onset MS. CSF findings should therefore be interpreted within the same overall diagnostic framework in these populations.

• Neurofilament light chain (NfL) is not recommended as a diagnostic biomarker for MS. CSF and blood/serum NfL may have prognostic and disease-monitoring applications, including assessment of inflammatory activity, new MRI lesions, treatment response, and risk of progression, but NfL should not be used as a substitute for OCB or κ-FLC when diagnostic intrathecal immunoglobulin evidence is required.

• Glial fibrillary acidic protein (GFAP) is an emerging biomarker of astrocytic injury and is associated particularly with progressive forms of MS and progression independent of relapse activity. GFAP may have prognostic and disease-monitoring applications but is not an established diagnostic biomarker under the 2024 McDonald criteria.

• Chitinase-3-like protein 1 (CHI3L1) is an emerging biomarker associated with progression independent of relapse activity and selected MRI lesion characteristics. CHI3L1 is not an established diagnostic biomarker for MS.

• CXCL13 and other proposed fluid biomarkers remain emerging or investigational biomarkers. Their potential prognostic or disease-monitoring roles are being studied, but they are not established diagnostic criteria for MS and should not replace OCB or κ-FLC.

• The 2024 McDonald criteria should be applied when the clinical likelihood of MS is sufficiently high; CSF biomarkers should not be used in isolation to make an MS diagnosis. Careful clinical assessment, MRI interpretation, and exclusion of a better alternative diagnosis remain essential.