Objectives: Free light chain kappa (FLC-k) in cerebrospinal fluid (CSF) is involved in intrathecal immune responses and is being investigated frequently for its diagnostic sensitivity. The objective of this study was the application and interpretation of FLC-k data in quotient diagrams with a hyperbolic reference range and to confirm the superior evaluation in comparison with another proposed reference method and cut-off values. Secondly, the performance of the FLC-k quotient diagram was analyzed in respect to MS and CIS patients and in relation to the polyspecific immune response., Materials and Methods: FLC-k was analyzed in a control cohort (n = 302) and in patients with MS/CIS (n = 98) using a nephelometric FLC-k kit. The intrathecal fraction of FLC-k based on the hyperbolic reference range was calculated in comparison to various linear FLC-k indices and routine CSF parameters [oligoclonal bands (OCB), polyspecific antiviral immune response]., Results: Using the new hyperbolic reference range, intrathecal FLC-k synthesis was found in 20 / 302 OCB negative controls. The sensitivity in the definitive MS cohort was 100%, compared to 93% positive OCB. The linear FLC-k Index interpretation with similar sensitivity for MS, however, bares the risk for the control samples,depending on the reference range, of false positive interpretations (up to 7 at low QAlb) or false negative interpretations (up to 17/20 FLC-k positives at high QAlb). The quantitative mean intrathecal FLC-k synthesis in the CIS cohort (later MS) was even slightly higher than in initially definitive MS questioning a pathophysiological difference. A positive MRZ reaction found in 53% percent of CIS patients with intrathecal FLC-k synthesis could have allowed diagnosis of MS immediately, i.e. earlier than with the Mc Donald criteria., Conclusions: The evaluation of FLC-k with hyperbolic reference range in quotient diagrams is superior to other analytical methods like the linear FLC-k index. We suggest a sequential CSF testing with FLC-k Reibergram evaluation, potentially followed by isoelectric focusing. With the MRZ reaction we obtain highest specificity for MS diagnosis., Competing Interests: Declaration of Competing Interest Dr. Nauck reports non-financial support by Siemens Healthineers, The Binding Site, Becton Dickinson, DZHK (German Centre for Cardiovascular Research, Partner Site Greifswald, University Medicine, Greifswald, Germany), DGKL (German federation of clinical chemistry and laboratory medicine), German federal medical association, Roche diagnostics Germany GmbH. He also received personal fees by Boehringer Ingelheim and Becton Dickinson; Grant by DZHK, LVL technologies, Bruker Biospin, Abbott, Radiometer, Tosoh and IDS Immunodiagnostic Systems Deutschland GmbH. Dr. Petersmann reports non-financial support and received personal fees by Radiometer, Nova Biomedical and Roche. The other authors report no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)