Intrathecal kappa free light chains as markers for multiple sclerosis

Abstract

Cerebrospinal fluid (CSF) kappa free light chain (KFLC) index has been described as a reliable marker of intrathecal IgG synthesis to diagnose multiple sclerosis (MS). Our aims were: (1) to compare the efficiency of KFLC through different interpretation approaches in diagnosing MS. (2) to evaluate the prognostic value of KFLC in radiologically and clinically isolated syndromes (RIS-CIS). We enrolled 133 MS patients and 240 with other neurological diseases (93 inflammatory including 18 RIS-CIS, 147 non-inflammatory). Albumin, lambda free light chain (LFLC) and KFLC were measured in the CSF and serum by nephelometry. We included two groups of markers: (a) corrected for blood-CSF barrier permeability: immunoglobulin G (IgG), KFLC and LFLC indexes. (b) CSF ratios (not including albumin and serum-correction): CSF KFLC/LFLC, CSF KFLC/IgG, CSF LFLC/IgG. KFLC were significantly higher in MS patients compared to those with other diseases (both inflammatory or not). KFLC index and CSF KFLC/IgG ratio showed high sensitivity (93% and 86.5%) and moderate specificity (85% and 88%) in diagnosing MS. RIS-CIS patients who converted to MS showed greater KFLC index and CSF KFLC/IgG. Despite OB are confirmed to be the gold-standard to detect intrathecal IgG synthesis, the KFLC confirmed their accuracy in MS diagnosis. A “kappa-oriented” response characterizes MS and has a prognostic impact in the RIS-CIS population.

The Increasing Role of Kappa Free Light Chains in the Diagnosis of Multiple Sclerosis

“…The cut-off for the CSF KFLC concentration varied between 0.103 µg/mL and 7 mg/L and a mean diagnostic sensitivity and specificity of 86% (95% confidence interval (80%, 92%)) and 91% (86%, 96%) was reached while the threshold for CSF LFLC concentration varied between 0.0175 µg/mL and 4.3 mg/L and a mean sensitivity and specificity of 67% (48%, 85%) and 82% (67%, 96%) was reported [4,19,20,23,33,47,48,50,[52][53][54][55][60][61][62][63][64][65][66][67][68]73,74,76,77,85,[88][89][90][91]130]. The cut-off for Q KFLC was set between 4.9 and 30 leading to a mean diagnostic sensitivity of 88% (79%, 96%) and specificity of 90% (77%, 100%) compared with the cut-off for Q LFLC (1.9 and 12.5), which reached a mean sensitivity of 33% (min-max: 21-45%) and specificity of 90% (minmax: 88-92%) [4,19,20,23,33,47,48 [4,68]. In the study of Rathbone et al, which investigated the KFLC/LFLC ratio in CSF too, an elevated ratio in MS patients was observed [52].…”

“…Some studies, which investigated the utility of FLC measurement in the diagnosis of MS, empirically created cut-off values either for the absolute KFLC or LFLC concentrations in CSF, CSF/serum KFLC, and LFLC quotients (Q KFLC , Q LFLC ), CSF KFLC/IgG, and LFLC/IgG ratios or KFLC/LFLC concentration ratios to determine KFLC or LFLC positivity [4,19,20,23,33,47,48,50,[52][53][54][55][60][61][62][63][64][65][66][67][68]73,74,76,77,85,[88][89][90][91]130]. The cut-off for the CSF KFLC concentration varied between 0.103 µg/mL and 7 mg/L and a mean diagnostic sensitivity and specificity of 86% (95% confidence interval (80%, 92%)) and 91% (86%, 96%) was reached while the threshold for CSF LFLC concentration varied between 0.0175 µg/mL and 4.3 mg/L and a mean sensitivity and specificity of 67% (48%, 85%) and 82% (67%, 96%) was reported [4,19,20,23,33,47,48,50,[52][53][54][55][60]…”

“…The index calculation may be employed for the evaluation of intrathecal synthesis of KFLC as well as for LFLC. Different studies applied KFLC indices varying between 0.92 and 20 and reached a mean diagnostic sensitivity of 87% (82%, 92%) and a mean diagnostic specificity of 87% in MS patients (83%, 91%) [19][20][21][22][23][24][27][28][29]33,42,[44][45][46][47][48][49][50][51]53,54,[56][57][58][59][60][61]64,65,[68][69][70][71][72][73][74][75][78][79][80][81][82]85,87,92]. It has to be considered that in some of these studies, the diagnostic utility of FLC in OCB-negative MS patients was investigated, leading to very low diagnostic sensitivity.…”

Adiponectin in Cerebrospinal Fluid from Patients Affected by Multiple Sclerosis Is Correlated with the Progression and Severity of Disease

“…However, although IgG levels and the Ig index are still valid parameters, CSF K free light chains and K index have higher accuracy and predictive value with respect to MS disability progression. Therefore, future validation studies will be needed to analyse the possible association between adiponectin and K indexes [ 37 , 38 ].…”

Cerebrospinal Tau Levels Predict Early Disability in Multiple Sclerosis

“…Oligoclonal bands were detected using isoelectrofocusing on agarose gel (Hydragel9 CSF Isofocusing; Sebia, Bagno a Ripoli, FI, Italia) followed by immuno xation with peroxidase, conjugated with anti-IgG antibodies on an electrophoresis system (Sebia Hydrasys). As part of the diagnostic MS procedure using nephelometry, we calculated albumin, IgG Index, and kappa free light chain index [36][37][38]. CSF total Tau and Abeta were measured using, respectively, two commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits.…”