Kappa Free Light Chain Index Demonstrates Utility in Differentiating NMOSD, MOGAD, and MS

A multicenter retrospective analysis published in Neurology suggests that kappa free light chain (KFLC) index may serve as a clinically useful biomarker to help distinguish myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), aquaporin-4–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and multiple sclerosis (MS), particularly in diagnostically challenging cases.¹ The findings indicate that while KFLC index performs similarly to cerebrospinal fluid (CSF) oligoclonal bands (OCBs), combining both measures may improve diagnostic accuracy.

Study Overview and Key Findings

The study, conducted across 18 centers in France using the NOMADMUS database, included 303 patients: 140 with MOGAD, 37 with AQP4-NMOSD, and 126 with relapsing-remitting MS. All patients underwent CSF evaluation for both KFLC index and OCB status.¹

In the study, senior author Romain Marignier, MD, PhD, professor of neurology at Claude Bernard University Lyon in France, and investigators observed a marked gradient in KFLC index values across the 3 diseases. Median KFLC index was highest in MS (49.90), intermediate in NMOSD (8.85), and lowest in MOGAD (0.60), with approximately 71% of MOGAD cases demonstrating undetectable CSF KFLC levels.¹

Diagnostic performance analyses showed:

• Excellent discrimination between MOGAD and MS (area under the curve [AUC], 0.93)
• Good discrimination between NMOSD and MS (AUC, 0.82)
• Moderate discrimination between MOGAD and NMOSD (AUC, 0.77)

Results showed that an optimal KFLC index threshold of 5.7 differentiated MOGAD from MS with 89% sensitivity and 89% specificity.¹ Higher thresholds were required for distinguishing NMOSD from MS (13.2), reflecting intermediate inflammatory activity.

OCBs demonstrated comparable diagnostic performance for distinguishing MS from MOGAD and NMOSD, with no statistically significant differences in AUC compared with KFLC index alone. However, combined use of KFLC index and OCBs significantly improved diagnostic accuracy across comparisons, with AUC increasing to 0.96 for MOGAD vs MS.¹

Clinical Context

MS, NMOSD, and MOGAD represent distinct immunopathologic entities within the spectrum of central nervous system demyelinating diseases. MS is characterized by intrathecal IgG synthesis and chronic inflammation, reflected in OCB positivity in approximately 90% to 95% of patients.^2,3 In contrast, OCBs are less frequently observed in NMOSD (15%–30%) and MOGAD (10%–15%), underscoring differences in underlying immune mechanisms.^4,5

KFLC index, calculated from CSF and serum free light chain levels normalized to albumin, has emerged as a quantitative biomarker of intrathecal immunoglobulin synthesis. Prior studies have demonstrated its diagnostic utility in MS and its potential prognostic value following a first demyelinating event. Compared with OCB testing, KFLC measurement is automated, less labor-intensive, and may offer faster turnaround times.⁶

Interpretation and Clinical Implications

The current findings support the use of KFLC index as an adjunctive diagnostic tool, particularly in cases where antibody testing or clinical presentation is inconclusive. This may be especially relevant given known limitations in antibody assays, including reduced specificity in low-titer MOG-IgG results and limited access to live cell-based assays in some centers.⁷

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Importantly, the study suggests that KFLC index retains diagnostic value regardless of OCB status, and vice versa, supporting a complementary rather than substitutive role. The authors propose that KFLC index thresholds—particularly around 6 for distinguishing MOGAD from MS—could potentially be incorporated into future diagnostic criteria as supportive evidence.¹

However, the clinical impact of these findings should be interpreted cautiously. Although KFLC index showed strong performance in distinguishing MS from MOGAD, its ability to differentiate NMOSD from other conditions was more limited, and confidence intervals were wider due to smaller sample sizes.¹

Limitations and Next Steps

The retrospective design and multicenter nature of the study introduce potential variability in sample handling and assay methodology. Additionally, the exclusion of pediatric patients and seronegative cases may limit generalizability to real-world populations.

Further prospective studies are needed to validate optimal KFLC index thresholds and assess performance in broader populations, including seronegative NMOSD and pediatric-onset disease. Standardization of KFLC measurement techniques will also be critical for widespread clinical adoption.

REFERENCES
1. Tournier A, Gavoille A, Pique J, et al. Diagnostic value of the kappa free light chain index to distinguish MOGAD, NMOSD, and MS. Neurology. 2026;106(8):e214806. Doi:10.1212/WNL.0000000000214806
2. Dobson R, Giovannoni G. Multiple sclerosis—a review. Eur J Neurol. 2019;26(1):27-40. Doi:10.1111/ene.13819
3. Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of CSF analysis in MS. Arch Neurol. 2005;62(6):865-870. Doi:10.1001/archneur.62.6.865
4. Jarius S, Wildemann B. The history of neuromyelitis optica. J Neuroinflammation. 2013;10:8. Doi:10.1186/1742-2094-10-8
5. Reindl M, Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat Rev Neurol. 2019;15(2):89-102. doi: 10.1038/s41582-018-0112-x
6. Presslauer S, Milosavljevic D, Huebl W, et al. Kappa free light chains: diagnostic and prognostic relevance in MS. PLoS One. 2014;9(2):e89945. doi: 10.1371/journal.pone.0089945
7. Waters PJ, McKeon A, Leite MI, et al. Serologic diagnosis of NMO: AQP4 antibody assays. Arch Neurol. 2012;69(8):1004-1008. Doi:10.1001/archneurol.2012.101