Abstract
Kappa free light chain (KFLC) index, a measure for intrathecal production of free kappa chains, has been increasingly recognized for its diagnostic potential in multiple sclerosis (MS) as a quantitative alternative to IgG oligoclonal bands (OCBs). Our objective was to investigate the sensitivity, specificity, and overall diagnostic accuracy of KFLC index in MS. KFLC index was prospectively determined as part of the diagnostic workup in patients with suspected MS (n=327) between May 2013 and February 2020. Patients with clinically isolated syndrome (CIS), radiologically isolated syndrome (RIS), and MS had markedly higher KFLC index (44.6, IQR 16-128) compared with subjects with other neuro-inflammatory disorders (ONID) and symptomatic controls (SC) (2.19, IQR 1.68-2.98, p<0.001). KFLC index had a sensitivity of 0.93 (95% CI 0.88-0.95) and specificity of 0.87 (95% CI 0.8-0.92) to discriminate CIS/RIS/MS from ONID and SC (AUC 0.94, 95% CI 0.91-0.97, p<0.001). KFLC index and intrathecal fraction (IF) KFLC had similar accuracies to detect MS. Treatment with disease-modifying therapy (DMT) did not influence the level of KFLC index and it was not affected by demographic factors or associated with degenerative or inflammatory biomarkers in cerebrospinal fluid (CSF). KFLC index in MS diagnostics has methodological advantages compared to OCB and is independent to subjective interpretation. Moreover, it is an attractive diagnostic tool since the diagnostic specificity and sensitivity of KFLC index are similar with that of OCBs and KFLCIF and better than for IgG index. We show that KFLC index was influenced neither by DMT nor by demographic factors or other inflammatory or degenerative processes in MS as determined by biomarkers in CSF.
Highlights
Cerebrospinal fluid (CSF) analysis is an important part of the diagnostic work-up of multiple sclerosis (MS) (Arrambide & Tintore 2016)
In accordance with previous reports, our findings suggest that Kappa free light chain (KFLC)-index has higher sensitivity than immunoglobulin G (IgG) oligoclonal bands (OCB) to discriminate clinically isolated syndrome (CIS)/radiologically isolated syndrome (RIS)/MS patients from controls and comparable specificity (Desplat-Jégo et al 2005; Presslauer et al 2008; Duranti et al 2013; Passerini et al 2016; Pieri et al 2017; Leurs et al 2020; Duell et al 2020; Christiansen et al 2018)
We confirm that KFLC-index has high diagnostic accuracy to predict intrathecal immunoglobulin synthesis via isoelectric focusing (IEF) (Süße et al 2018) and that KFLC-index may contribute to the identification of OCB-negative MS patients (Ferraro et al 2020)
Summary
Cerebrospinal fluid (CSF) analysis is an important part of the diagnostic work-up of multiple sclerosis (MS) (Arrambide & Tintore 2016). These include time-consuming manual handling and the potential for subjective interpretation (Hassan-Smith et al 2014). To previous work regarding immunoglobulin intrathecal fraction (Reiber 1998), an alternative method was recently proposed based on a nonlinear quotient diagram with a hyperbolic reference range (Reiber et al 2019). This nonlinear method aimed at reducing the risk of false positive and false negative interpretations associated with the linear index and depending on the patients’ individual albumin quotient (QAlb) value (Reiber & Peter 2001). We aimed to utilize the nonlinear hyperbolic reference range and compare its performance to that of KFLC-index in MS diagnostics
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