Free light chain kappa and the polyspecific immune response in MS and CIS - Application of the hyperbolic reference range for most reliable data interpretation

Marie Süße; Hansotto Reiber; Matthias Grothe; Astrid Petersmann; Matthias Nauck; Alexander Dressel; Malte Johannes Hannich

doi:10.1016/j.jneuroim.2020.577287

Free light chain kappa and the polyspecific immune response in MS and CIS - Application of the hyperbolic reference range for most reliable data interpretation

J Neuroimmunol. 2020 Jun 12:346:577287. doi: 10.1016/j.jneuroim.2020.577287. Online ahead of print.

Authors

Marie Süße¹, Hansotto Reiber², Matthias Grothe¹, Astrid Petersmann³, Matthias Nauck⁴, Alexander Dressel⁵, Malte Johannes Hannich⁶

Affiliations

¹ Departement of Neurology, University Medicine Greifswald, Greifswald, Germany.
² CSF and Complexity Studies, Göttingen and University Göttingen, Germany.
³ Institute of Clinical Chemistry, University Göttingen, Germany.
⁴ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁵ Departement of Neurology, Carl-Thiem Klinikum Cottbus, Germany.
⁶ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. Electronic address: malte.hannich@med.uni-greifswald.de.

PMID: 32599341
DOI: 10.1016/j.jneuroim.2020.577287

Abstract

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.

Keywords: Cerebrospinal fluid; Clinically isolated syndrome; Free light chain kappa; MRZ antibody reaction; Multiple sclerosis; Oligoclonal IgG.