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Cerebrospinal fluid testing has been used for many years in the diagnosis of multiple sclerosis. Today, classic oligoclonal bands are complemented by quantitative markers of intrathecal immune activity, while highly sensitive laboratory methods can measure selected nervous-system proteins not only in CSF but also in blood.
Different biomarkers answer different clinical questions. Oligoclonal bands and kappa free light chains are used primarily for diagnosis. Neurofilament light chain helps assess neuroaxonal injury, whereas glial fibrillary acidic protein is being actively studied as a potential marker of gradual progression.
CSF is in direct contact with the central nervous system, so it can reveal processes occurring within the CNS: intrathecal immunoglobulin synthesis, changes in cellular composition and selected signs of neuroinflammation.
Its main limitation is the need for lumbar puncture. For this reason, CSF is not suitable for frequent routine monitoring.
Blood sampling can be repeated easily, making blood biomarkers especially attractive for long-term monitoring and assessment of disease dynamics.
Modern high-sensitivity assays can measure very low concentrations of proteins that originate in the nervous system and enter the circulation.
| Biomarker | Sample | What it reflects | Main role | Use |
|---|---|---|---|---|
| Oligoclonal IgG bands (OCB) | CSF and serum | Intrathecal IgG synthesis | Diagnosis | Routine |
| Kappa free light chains (κ-FLC) | CSF and serum | Intrathecal immunoglobulin synthesis | Diagnosis | Included in the 2024 McDonald criteria |
| IgG index | CSF and serum | Quantitative assessment of intrathecal IgG synthesis | Additional diagnostic information | Used clinically |
| Neurofilament light chain (NfL) | Blood or CSF | Neuroaxonal injury | Activity assessment and monitoring | The best-studied blood biomarker in MS |
| Glial fibrillary acidic protein (GFAP) | Blood or CSF | Astroglial activation | Research on progression | Promising, not yet routine |
| CXCL13 | Mainly CSF | Intrathecal B-cell activity | Research on inflammatory activity | Mainly research |
| Chitinase-3-like protein 1 (CHI3L1 / YKL-40) | CSF and blood | Glial and innate immune activation | Research on chronic tissue injury | Mainly research |
| MSDA test | Serum | Multi-protein disease activity profile | Additional assessment of disease activity | Specialized commercial test |
Lumbar puncture is not necessary in every patient with an obvious clinical and MRI picture, but it remains important when the diagnosis needs additional support or when other inflammatory, infectious or systemic disorders must be excluded.
Demonstrate local IgG synthesis within the central nervous system and have major diagnostic value in MS.
A quantitative marker of the intrathecal immunoglobulin response that may be used, within the 2024 McDonald criteria, as an alternative to CSF-specific OCB in appropriate diagnostic settings.
These basic CSF measures help determine whether the CSF profile is compatible with MS or whether findings point toward another disease.
Oligoclonal IgG bands are detected by isoelectric focusing with simultaneous analysis of CSF and serum.
For MS diagnosis, bands that are present in CSF but absent from serum are particularly important. This pattern indicates immunoglobulin synthesis within the central nervous system.
Primarily to document an intrathecal immune response during diagnostic work-up.
OCB cannot tell whether new lesions have appeared, whether the disease is active today, or how well a DMT is working.
Once the diagnosis is firmly established, repeating OCB for routine monitoring is usually unnecessary.
When immunoglobulins are produced, B cells and plasma cells also generate free light chains. With active intrathecal immunoglobulin synthesis, CSF kappa free light chain concentrations may increase.
Assessment of intrathecal synthesis requires more than the absolute CSF κ-FLC concentration. The CSF result is interpreted relative to serum κ-FLC and to blood–CSF barrier permeability.
A commonly used approach is the κ-FLC index, which combines the CSF-to-serum κ-FLC ratio with the albumin quotient.
| Oligoclonal bands | Kappa free light chains | |
|---|---|---|
| Type of result | Qualitative or semi-quantitative | Quantitative |
| Main method | Isoelectric focusing | Immunochemical assay |
| Automation | Limited | Higher |
| Clinical experience | Very extensive | Less extensive, but rapidly growing |
| 2024 McDonald criteria | Yes | Yes |
| Routine activity monitoring | No | No |
A mild lymphocytic pleocytosis can occur in MS. Marked pleocytosis or an unusual cellular profile should prompt consideration of another diagnosis.
Markedly elevated protein is not typical of uncomplicated MS and should be interpreted in the context of alternative disorders.
Assesses blood–CSF barrier function and is required for calculation of some intrathecal indices.
Provides a quantitative measure of intrathecal IgG synthesis. It has a long clinical history but does not replace modern assessment with OCB or κ-FLC.
Markedly low CSF glucose is not typical of MS and may point toward infection, granulomatous disease or another process.
Microbiological, cytological, immunological and other studies may be added when needed for differential diagnosis.
Neurofilaments are structural proteins of neurons, particularly axons. When nerve fibers are injured, neurofilament light chain is released into the extracellular space, then into CSF and, in smaller amounts, into blood.
High-sensitivity assays now allow reasonably reliable measurement of serum NfL, making it one of the best-studied blood biomarkers in multiple sclerosis.
NfL may rise after new inflammatory injury and a clinical relapse.
Higher NfL values are associated with a greater likelihood of new T2 lesions and gadolinium-enhancing lesions.
When inflammatory activity is effectively suppressed, elevated NfL often falls; serial measurements may therefore complement MRI.
An absolute NfL concentration cannot be interpreted using one universal threshold. The result depends on age, the patient’s condition, analytical method and several accompanying factors.
NfL concentrations increase with age, so the same result may mean something different in a young and an older patient.
Reduced renal function can be associated with higher serum NfL and should be considered during interpretation.
Body mass index and distribution volume may influence blood NfL concentrations.
Any significant injury to the nervous system may affect the result.
Results obtained on different analytical platforms are not always directly comparable.
Serial measurements performed with the same method are often more informative than a single isolated result.
GFAP is a structural protein of astrocytes. Whereas NfL primarily reflects neuroaxonal injury, GFAP is associated with the astrocytic response to injury and chronic changes within the central nervous system.
For this reason, GFAP is being studied particularly actively in progressive forms of MS and in disability accumulation that occurs independently of relapses.
In group-level studies, higher GFAP concentrations have been associated with progressive disease and subsequent worsening.
GFAP is being investigated as a possible biomarker of progression independent of relapse activity (PIRA).
Automated assays and age-specific reference databases may make GFAP more useful in future clinical practice.
In a large international analysis of people with primary and secondary progressive MS, higher serum GFAP was associated with subsequent confirmed disability worsening.
The association was particularly evident in patients with secondary progressive MS.
| NfL | GFAP | |
|---|---|---|
| Main cellular source | Neurons and axons | Astrocytes |
| What it reflects | Neuroaxonal injury | Astroglial activation |
| Acute inflammatory injury | Well studied | Less specific association |
| New MRI lesions | Well-established association | Weaker association |
| Progression | Has prognostic value | Being studied particularly actively |
| Readiness for routine practice | Higher | Lower |
CXCL13 is a signaling molecule involved in B-cell recruitment and organization of the humoral immune response.
In MS, CSF CXCL13 is of particular research interest because it may reflect the intensity of local B-cell activity within the central nervous system.
Higher levels have been associated in several studies with more pronounced inflammatory activity.
CXCL13 is being studied as a potential prognostic marker after a first demyelinating event and in early disease.
The marker is of interest for studying changes in humoral immune activity during treatment, but it is not a standard criterion for selecting therapy.
CHI3L1 is produced by several cell types, including astrocytes, microglia and cells of the monocyte–macrophage lineage.
In multiple sclerosis it is studied as a possible marker of chronic glial and innate immune activation.
In several studies, higher CHI3L1 levels have been associated with greater disability and progressive disease.
Possible associations with chronic active lesions and other manifestations of long-standing inflammatory injury are being investigated.
The protein is produced outside the CNS as well, and blood and CSF results do not always provide equivalent information.
The Multiple Sclerosis Disease Activity (MSDA) test is based not on a single biomarker, but on simultaneous measurement of 18 serum proteins processed by a machine-learning algorithm.
Additional quantitative information about disease activity that can be interpreted together with clinical findings and MRI.
MSDA does not establish an MS diagnosis, does not replace MRI and is not a stand-alone criterion for changing DMT.
Blood biomarkers may provide additional information about treatment response, but they should not be interpreted separately from the clinical course and MRI.
Relapses, new symptoms, neurological examination and functional changes are assessed.
New or enlarging lesions and, when needed, contrast activity are assessed.
Serial values may add information about new neuroaxonal injury.
GFAP, MSDA and emerging markers may add information, but their current clinical use is more limited.
In most cases, no. Once MS is firmly established, repeated testing of OCB, κ-FLC or routine CSF measures is not a standard way to monitor treatment effectiveness.
Oligoclonal bands, κ-FLC, routine CSF findings and MRI.
New lesions, relapses and neurofilament light chain.
Clinical course, GFAP, atrophy, PRL, SEL and other evolving markers.
MSDA and other proteomic approaches attempt to integrate several biological signals into one profile.
MRI, oligoclonal bands, κ-FLC, routine CSF findings and possible alternative diagnoses should be considered together.
Age, longitudinal trend, assay method, timing of previous relapses, MRI findings and comorbidities all matter.
PIRA, spinal cord involvement, functional change and other causes of deterioration should be assessed. GFAP may add information but does not replace clinical evaluation.
Laboratory biomarkers may complement clinical and MRI findings, but the decision should not depend on one test alone.