Kappa Free Light Chains in the 2024 McDonald Criteria: What Neurologists Need to Know

A New Role for CSF Biomarkers

Diagnosis of multiple sclerosis (MS) has been supported by a triad of clinical presentation, imaging studies and laboratory biomarkers. Diagnostic stakes are high. A missed or delayed diagnosis can postpone disease-modifying therapy, whereas an incorrect diagnosis can expose patients to unnecessary treatment and delay recognition of an alternative disorder such as AQP4-IgG–positive NMOSD, MOGAD, infection, and other inflammatory or vascular mimics.¹

The McDonald criteria were updated in 2024,² and their new version incorporates additional imaging and laboratory biomarkers intended to improve diagnostic sensitivity while maintaining specificity.

Here we explain the new role of the CSF kappa free light chain (κFLC) index and, importantly, how clinicians and laboratories can implement and interpret this test in practice.

What Changed in the 2024 McDonald Criteria?

Since 2017, laboratory testing had been reintroduced to the criteria, since a positive result of 2 or more unique bands for oligoclonal banding analyzed by isoelectric focusing was an acceptable substitute for dissemination in time.³ The 2024 update added more specificity to the criteria with additional MRI imaging such as the central vein sign and paramagnetic rim lesions, and the optic nerve was added as a 5^th anatomical location for dissemination in space. For the clinical laboratory, the most consequential change is the recognition of intrathecal immunoglobulin κFLC synthesis as an alternative to CSF-restricted oligoclonal bands (OCBs) for establishing positive CSF.^2,4

The alternative diagnostic test to OCBs is the κFLC index, a calculation using measurement of κFLC in both CSF and serum, along with albumin measured in CSF and serum to correct for the blood-brain barrier (BBB) permeability. 

Oligoclonal Bands and κFLC: Same Clinical Question, Different Approaches

OCBs have been used in clinical laboratories for decades. The test is manual, labor-intensive, and in our institution, we can process 4 patient samples of CSF and serum on one gel, effectively limiting throughput. A positive OCB result demonstrates two or more CSF-restricted oligoclonal IgG bands that are absent from paired serum, providing evidence of intrathecal IgG synthesis by activated B cells and plasma cells in the CNS. During immunoglobulin assembly, light chains are produced in slight excess of heavy chains. OCB and κFLC-based testing therefore provide complementary approaches to detecting intrathecal humoral immune activation (Table 1).^5,6

CSF κFLC Concentration and the κFLC Index are Related but Distinct Laboratory Measurements.

Absolute CSF κFLC concentration requires only CSF and offers a simple quantitative measure that has demonstrated diagnostic utility for MS. However, the concentration can reflect both intrathecal κFLC production and κFLC entering the CSF from the circulation.⁷ The κFLC index additionally incorporates serum κFLC and the CSF/serum albumin quotient, helping distinguish passive transfer from blood from disproportionate κFLC production within the CNS. The 2024 McDonald criteria specifically recognize intrathecal κFLC synthesis assessed by the κFLC index rather than standalone CSF κFLC concentration (Table 1).

What Does the κFLC Index Measure?

The kappa index is analogous to the IgG index calculation, replacing the IgG concentration in CSF and serum for measurement of κFLC. 

• Index equation

κFLC index = (CSF κFLC/serum κFLC) ÷ (CSF albumin/serum albumin)

A large 2023 meta-analysis reviewed 32 studies and proposed a cutoff of 6.1 or greater to be the most sensitive for MS diagnosis, derived as a weighted mean from 32 studies which includes a total of ~3300 CIS and MS cases and ~5800 controls. Importantly, the meta-analysis included studies using different κFLC assays and platforms, yet an index cutoff of 6.1 emerged as the best overall discriminatory threshold⁵ between rMS and non-MS cases. This does not imply that κFLC assays are interchangeable; method-dependent differences remain important, particularly near clinical decision thresholds (Table 1).

There are multiple different reagents available on the market to measure free light chains, and despite similar reference intervals in serum, the assays are not fully harmonized. κFLC can be measured using validated ELISAs, turbidimetric or nephelometric immunoassays. Reagents may employ rabbit or sheep polyclonal antibodies or monoclonal antibodies against hidden epitopes of light chains only exposed when light chains are free.  Because CSF κFLC concentrations are substantially lower than those encountered in serum, low-end analytical sensitivity, precision, and reproducibility are important considerations for the assays. Nephelometry measures light scattered by antigen–antibody complexes and is well suited to measurement of low-concentration proteins, while providing random access to testing samples and effective throughput with gains in turn-around-time. Regardless of platform, laboratories should verify analytical performance and the clinical decision threshold on the method they use.

How Should Clinicians Use κFLC Testing in Practice?

For patient-facing neurologists, consider this clinical workflow:

• Begin with an appropriate clinical context: The patient should have a presentation in which MS is genuinely being considered; κFLC should not be used as a general screening test for nonspecific neurologic symptoms. 
• Order the appropriate specimens: Obtain paired CSF and serum κFLC measurements and paired CSF and serum albumin measurements so that the κFLC index can be calculated. Ideally, CSF and serum should be obtained on the same day. 
• Interpret the results: A κFLC index ≥6.1 defines positive CSF under the accompanying recommendations for the 2024 criteria when validated assays are used. In the United States, κFLC assays may not have manufacturer-cleared CSF applications for MS diagnosis, requiring laboratories offering CSF testing to establish and validate performance under applicable laboratory-developed test requirements. 
• Integrate the result into the criteria: A positive result supports intrathecal immunoglobulin synthesis in the same diagnostic role as CSF-restricted OCBs. It does not, by itself, establish MS. Results should be interpreted with the clinical presentation, MRI findings, and exclusion of alternative diagnoses.
• Address negative or discordant findings: Concordance between κFLC and OCB testing is approximately 90%. When clinical and MRI findings strongly suggest MS but κFLC is negative, OCB testing may be useful; conversely, κFLC may help when OCB findings are negative, equivocal, or technically difficult to interpret. 
• Avoid overinterpretation: A negative κFLC index does not independently exclude MS, and a positive index may occur in other inflammatory disorders of the central nervous system. 

Implementation Considerations for Laboratories

• Laboratories should use validated ELISA, turbidimetric or nephelometric assays with appropriate quality assurance and local verification of cutoffs. Laboratories should verify the recommended 6.1 decision threshold on their own analytical system rather than derive a new local cutoff from a small cohort of patients. Validation should include comparison with an orthogonal method such as OCB and access to patients diagnostic clinical history for clinical sensitivity and specificity calculations.  
• Reports should clearly identify the calculation, decision threshold, assay, and interpretive limitations. 
• Although higher κFLC values may have prognostic associations, the immediate role established by the McDonald criteria is diagnostic evidence of intrathecal immunoglobulin synthesis.  

The  addition of the κFLC index modernizes the laboratory component of MS diagnosis by providing an automated and quantitative alternative to OCB testing. It may simplify access to positive-CSF assessment without changing the central principle of the McDonald criteria: MS remains an integrated clinical, imaging, and laboratory diagnosis requiring careful exclusion of mimics.

Key Take-Away Messages

1. “Kappa free light chains” are not one universal, single laboratory result. Raw κFLC CSF concentration and κFLC index are related but not the same. 
2. The index requires four measurements and correctly paired specimens of CSF and serum. 
3. A universal-looking cutoff does not mean κFLC assays are analytically interchangeable. 
4. Positive CSF is not positive MS. Other inflammatory CNS diseases can yield evidence of intrathecal immunoglobulin synthesis.
5. OCBs have not become obsolete. Routine duplicate testing is unnecessary, but OCB remains valuable in selected discordant or clinically atypical cases.
6. Implementation at local laboratories needs careful review. Analytical sensitivity at low CSF concentrations, assay validation, reporting, and interpretation are part of translating the new criteria into actual patient care.