Reiber’s Diagram for Kappa Free Light Chains: The New Standard for Assessing Intrathecal Synthesis?

Abstract

Oligoclonal bands are the gold standard for determination of an intrathecal immunoglobulin G synthesis and were recently included in the McDonald criteria of 2017 to diagnose relapsing multiple sclerosis (MS) as a substitute for dissemination in time. Intrathecally produced kappa free light chains (KFLC) are a novel promising biomarker with similar characteristics and the advantage for automated determination. However, different approaches exist to determine the intrathecal KFLC fraction. The most common method is to calculate the CSF/serum KFLC quotient with reference to the albumin CSF/serum quotient (QKappa/QAlb) the so-called KFLC index. Recently, Reiber developed a theoretically and empirically founded hyperbolic function similar to his traditional hyperbolic function for the immunoglobulins A, G, M. Our study included a total of 168 patients with either MS according to the McDonald criteria of 2017, clinically isolated syndrome (CIS) with conversion to MS during follow-up, or stable CIS. Positive oligoclonal bands were compared with the KFLC index, Reiber’s KFLC diagram, Presslauer’s KFLC exponential curve, and Senel’s linear curve for KFLC. Reiber’s diagram detected an intrathecal production of KFLC in 98/100 patients with MS, only one patient fewer than oligoclonal bands positivity (99/100). By using the KFLC index ≥ 5.9, Presslauer’s KFLC exponential function, and Senel’s linear curve two more patients would not have been identified (96/100). For the group of patients who converted from CIS to MS similar results were obtained for both the oligoclonal bands and the Reiber graph (21/24, 88%). The KFLC index ≥ 5.9, Presslauer’s method, and Senel’s linear function each identified two patients fewer (19/24, 79%). In patients with stable CIS, 11/44 patients (25%) displayed oligoclonal bands in contrast to 9/44 patients (20%) with elevated KFLC by using Reiber’s diagram and Presslauer’s method, 8/44 patients (18%) with elevated KFLC as detected by Senel’s linear function, and 7/44 patients (16%) with KFLC index ≥ 5.9. In conclusion, Reiber’s KFLC diagram shows a great diagnostic performance to detect an intrathecal KFLC production in patients with MS.

Intrathecal kappa free light chains as markers for multiple sclerosis

“…Of note, in our study the specificity of OB was similar to that of KFLC index (85%). If comparing different approaches to calculate KFLC intrathecal fraction in our cohort, sensitivity towards MS diagnosis was 98% for Reiber’s KFLC diagram 9 , in face of 53% specificity. Thus, concerning MS diagnosis, KFCL index performances resulted more similar to that of OB in our population.…”

“…This value showed the greatest combination of sensitivity and specificity in our population 2 , 3 . Regarding KFLC, other approaches have been studied to calculate the intrathecal fraction including different cut-offs of the index, Reiber's diagram, Presslauer's exponential curve, and Senel's linear curve 9 . As concerns MS diagnosis according to McDonald criteria 2017 10 in our cohort, we then compared our cut-off for KFLC index 2 to Reiber’s KFLC diagram 8 , since this latter approach presented the greater sensitivity in previous studies 9 .…”

“…All these markers are corrected for blood-CSF barrier permeability: by comparison to serum for OB and by albumin ratio (serum/CSF albumin) for indexes 7 . Recently, the great sensitivity of intrathecal KFLC fraction towards MS diagnosis has been confirmed even using different approaches 8 , 9 . In this study we also considered measures for the excess of kappa and lambda FLC only in the CSF, called CSF ratios, that are not albumin and serum-corrected.…”

The Impact of Immunomodulatory Treatment on Kappa Free Light Chains as Biomarker in Neuroinflammation

“…Since the CSF concentration of KFLC was similar between untreated patients and patients under infusion of methylprednisolone and our findings indicate a significant reduction of serum KFLC concentrations, the ratio of CSF and serum KFLC (Q KFLC) might be falsely elevated. In methods to evaluate the origin of KFLC in CSF such as KFLC index or diagrams, falsely elevated Q KFLC might falsify the results and, therefore, pretend an intrathecal inflammation [18,27]. This might be of relevance in patients with borderline results with close proximity to the Q albumin-depending threshold value.…”

“…Patients were included when they were either newly diagnosed with MS according to the 2017 McDonald criteria or converted to MS during follow-up. Some of these patients were previously investigated with a focus on different other aspects [14][15][16][17][18]. A total of 107 patients were included.…”