The kappa free light chains index is an accurate diagnostic biomarker for paediatric multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) may occur before the age of 18. Differentiation between paediatric MS (PedMS) and other demyelinating syndromes (ODSs) is challenging. In adult with MS, the kappa free light chain (KFLC) index has proven to be a reliable marker of intrathecal Ig synthesis. OBJECTIVE: To assess the diagnostic value of the KFLC index in a cohort of patients with paediatric-onset, inflammatory disorders of the CNS. METHODS: We included 73 patients and divided them into four groups: PedMS (n = 16), ODS (n = 17), encephalitis and/or inflammatory epilepsy (EE, n = 15), and controls without inflammatory CNS diseases (n = 25). The KFLC index was calculated and compared with the results of the oligoclonal bands determination. RESULTS: The KFLC index was higher in the PedMS group (median (interquartile range (IQR)): 150.9 (41.02-310.6)) than in the ODS (3.37 (2.22-8.11)), the EE (5.53 (2.31-25.81)) and the control group (3.41 (2.27-5.08)), respectively. The best KFLC index cut-off for differentiating between patients with PedMS and controls was 6.83 (sensitivity: 100%; specificity: 92%). A KFLC index over 93.77 indicated that the patient is very likely to have PedMS (sensitivity: 68%; specificity: 100%). CONCLUSION: The KFLC index is a reliable tool for the diagnosis of MS in a paediatric population.

Inter-assay diagnostic accuracy of cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis.

Background: Cerebrospinal fluid (CSF) kappa free light chain (κFLC) measures gained increasing interest as diagnostic markers in multiple sclerosis (MS). However, the lack of studies comparing assay-dependent diagnostic cutoff values hinders their use in clinical practice. Additionally, the optimal κFLC parameter for identifying MS remains a subject of ongoing debate. Objectives: The aim of this study was to compare same-sample diagnostic accuracies of the κFLC index, κIgG index, CSF κFLC/IgG ratio, and isolated CSF κFLC (iCSF-κFLC) between two reference centers using different methods. Methods: Paired serum and CSF samples were analyzed for κFLC and albumin concentrations by Freelite®-Optilite (Sint-Jan Bruges hospital) and N Latex®-BNII (Ghent University hospital). Diagnostic performance to differentiate MS from controls was assessed using ROC curve analysis. Results: A total of 263 participants were included (MS, n = 80). Optimal diagnostic cutoff values for the κFLC index (Freelite®-Optilite: 7.7; N Latex®-BNII: 4.71), κIgG index (Freelite®-Optilite: 14.15, N Latex®-BNII: 12.19), and CSF κFLC/IgG ratio (Freelite®-Optilite: 2.27; N Latex®-BNII: 1.44) differed between the two methods. Sensitivities related to optimal cutoff values were 89.9% (Freelite®-Optilite) versus 94.6% (N Latex®-BNII) for the κFLC index, 91% (Freelite®-Optilite) versus 92.2% (N Latex®-BNII) for the κIgG index, and 81.3% (Freelite®-Optilite) versus 91.4% (N Latex®-BNII) for the CSF κFLC/IgG ratio. However, for iCSF-κFLC, optimal diagnostic cutoff values (0.36 mg/L) and related specificities (81.8%) were identical with a related diagnostic sensitivity of 89.9% for Freelite®-Optilite and 90.5% for N Latex®-BNII. The diagnostic performance of the κFLC index [area under the curve (AUC) Freelite®-Optilite: 0.924; N Latex®-BNII: 0.962] and κIgG index (AUC Freelite®-Optilite: 0.929; N Latex®-BNII: 0.961) was superior compared to CSF oligoclonal bands (AUC: 0.898, sensitivity: 83.8%, specificity: 95.9%). Conclusions: The κFLC index and the κIgG index seem to be excellent markers for identifying MS, irrespective of the method used for κFLC quantification. Based on the AUC, they appear to be the measures of choice. For all measures, optimal cutoff values differed between methods except for iCSF-κFLC. iCSF-κFLC might therefore serve as a method-independent, more cost-efficient, initial screening measure for MS. These findings are particularly relevant for clinical practice given the potential future implementation of intrathecal κFLC synthesis in MS diagnostic criteria and for future multicentre studies pooling data on κFLC measures.

Multiple Sclerosis: From the Application of Oligoclonal Bands to Novel Potential Biomarkers.

Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system with a high heterogeneity among patients. In the clinical setting, one of the main challenges is a proper and early diagnosis for the prediction of disease activity. Current diagnosis is based on the integration of clinical, imaging, and laboratory results, with the latter based on the presence of intrathecal IgG oligoclonal bands in the cerebrospinal fluid whose detection via isoelectric focusing followed by immunoblotting represents the gold standard. Intrathecal synthesis can also be evidenced by the measurement of kappa free light chains in the cerebrospinal fluid, which has reached similar diagnostic accuracy compared to that of oligoclonal bands in the identification of patients with multiple sclerosis; moreover, recent studies have also highlighted its value for early disease activity prediction. This strategy has significant advantages as compared to using oligoclonal band detection, even though some issues remain open. Here, we discuss the current methods applied for cerebrospinal fluid analysis to achieve the most accurate diagnosis and for follow-up and prognosis evaluation. In addition, we describe new promising biomarkers, currently under investigation, that could contribute both to a better diagnosis of multiple sclerosis and to its monitoring of the therapeutic treatment response.

A comparison of measles-rubella-zoster reaction, oligoclonal IgG bands, oligoclonal kappa free light chains and kappa index in multiple sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the diagnostic performance of the measles-rubella-zoster reaction (MRZR) in a large real-world multiple sclerosis (MS) cohort. Second, to compare MRZR with the determination of oligoclonal IgG bands (OCB), oligoclonal kappa free light chain bands (oKFLC), and the KFLC index. METHODS: A single-center retrospective study was conducted at the University Hospital Ostrava (Czech Republic). Patients were eligible if aged ≥18 years with a determined clinical diagnosis. IgG antibodies against measles (M), rubella (R), and varicella zoster (Z) viruses were determined in paired CSF and serum using ELISA and MRZR indicated as positive if at least two components had an antibody index >1.4. OCB and oKFLC were detected by means of isoelectric focusing, and KFLC CSF and serum concentrations for calculation of the KFLC index were determined immunochemically. RESULTS: A total of 1,751 patients were included in the analyzed data set, which comprised 379 MS patients and 1,372 non-MS controls. The frequency of positive MRZR was higher in MS than in non-MS cases (MS 32.2 % vs non-MS 2.8 %; p < 0.001). This corresponded to a specificity of 97.2 % (95 % CI 96.1-98.0) and sensitivity of 32.2 % (95 % CI 27.5-37.2) and overall accuracy of 83.1 % (95 % CI 81.3-84.8). In comparison, the highest sensitivity of 95.6% (95 % CI 93.0-97.5) was for OCB with specificity of 86.9 % (95 % CI 84.9-88.7), followed by oKFLC with sensitivity and specificity of 94.7 % (95 % CI 91.5-96.9) and 78.4% (95 % CI 75.7-80.8), respectively, and the KFLC index with sensitivity of 92.5 % (95 % CI 86.6-96.3) and specificity of 93.5 % (95 % CI 90.5-95.9). DISCUSSION: MRZR remains a very specific test for the diagnosis of MS but has low sensitivity, which disallows its independent use. In contrast, OCB showed the highest sensitivity and thus remains the gold standard for the diagnosis of MS.

Prognostic value of cerebrospinal fluid biomarkers in multiple sclerosis: The key role of kappa free light chains and a multivariate predictor for disease progression.

OBJECTIVE: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system with varying progression rates among individuals. The ability to predict disease progression is crucial for treatment decisions with disease-modifying therapies (DMTs). A few cerebrospinal fluid (CSF) biomarkers have been investigated in relation to disease progression, but few have been effectively translated into clinical practice. The aim of this study was to evaluate the diagnostic and prognostic value of known CSF markers, to compare their sensitivity and specificity, and to develop a prognostic model using a combination of markers to predict disease progression. METHODS: This retrospective cohort study included 82 patients with a first episode of inflammatory demyelinating symptoms suggestive of MS between January 2018 and January 2021. Patients underwent diagnostic lumbar puncture and other investigations according to the multiple sclerosis (MS) protocol. They were divided into three groups according to MRI findings, relapse rate and EDSS score. CSF marker concentrations were determined by laser nephelometry and electrochemiluminescence immunoassay. RESULTS: The results showed that the number of oligoclonal bands could discriminate the progression-free group from the other groups, but had a lower discriminatory power compared to CSF marker concentrations. Among CSF markers, FLC kappa showed the best discriminatory performance. By combining FLC kappa with gender and lesion localization information, a simple predictor of progression-free group membership was proposed. This predictor showed good sensitivity (91 %) and specificity (65 %). CONCLUSION: In conclusion, CSF FLC kappa concentration, together with gender and lesion localization, may be a valuable predictor of disease progression in MS patients. This study highlights the potential of using CSF biomarkers for prognostic purposes and offers a simple approach to predicting disease progression.

Kappa free light chains index in multiple sclerosis very long-term prognosis.

Introduction: The role of the kappa-free light chain (kFLC) in the diagnosis of multiple sclerosis (MS) and, to a lesser extent, its role as a medium-term prognostic marker have been extensively studied. This study aimed to explore its potential as a long-term prognostic marker for MS. Methods: We performed an exploratory retrospective observational study by selecting patients systemically followed up in our MS unit with available cerebrospinal fluid and serum samples at the time of initial evaluation. Two groups were defined: benign MS (bMS), defined as patients with Expanded Disability Status Scale (EDSS) ≤ 3 at 10 years of follow-up, and aggressive MS (aMS), defined as patients with EDSS ≥ 6 at 15 years of follow-up. Clinical variables were collected, and the immunoglobulin G (IgG) index, kFLC index, and oligoclonal bands (OCB) were determined for all patients and compared between the groups. Results: Twenty bMS and 15 aMS patients were included in this study. Sixty percent (21/35) were female, and the mean age at the time of the first symptom was 31.5 ± 9.45 years, with no statistical differences between groups. Median follow-up time was 19.8 years (Interquartile range, IQR 15.9-24.6). The median EDSS scores at the last follow-up were 1.5 and 7.5 in the bMS and the aMS group, respectively. No statistically significant differences were found in the kFLC index between the two groups (136.6 vs. 140.27, p=0.59). The IgG index was positive in 62.9% of patients (55% bMS vs. 73.3% aMS, p>0.05), and OCB was positive in 88.6% (90% bMS vs. 86.7% aMS, p>0.05). A significant positive correlation was found between IgG and kFLC indices (rs = 0.85, p<0.001). Conclusion: Given the absence of differences between the two groups with opposite disease courses, it is unlikely that the kFLC index is a reliable and powerful marker of long-term prognosis in MS.

Clinically isolated syndrome: Diagnosis and risk of developing clinically definite multiple sclerosis.

INTRODUCTION: In most cases, multiple sclerosis (MS) initially presents as clinically isolated syndrome (CIS). Differentiating CIS from other acute or subacute neurological diseases and estimating the risk of progression to clinically definite MS is essential since presenting a second episode in a short time is associated with poorer long-term prognosis. DEVELOPMENT: We conducted a literature review to evaluate the usefulness of different variables in improving diagnostic accuracy and predicting progression from CIS to MS, including magnetic resonance imaging (MRI) and such biofluid markers as oligoclonal IgG and IgM bands, lipid-specific oligoclonal IgM bands in the CSF, CSF kappa free light-chain (KFLC) index, neurofilament light chain (NfL) in the CSF and serum, and chitinase 3-like protein 1 (CHI3L1) in the CSF and serum. CONCLUSIONS: Codetection of oligoclonal IgG bands and MRI lesions reduces diagnostic delays and suggests a high risk of CIS progression to MS. A KFLC index > 10.6 and CSF NfL concentrations > 1150 ng/L indicate that CIS is more likely to progress to MS within one year (40%-50%); 90% of patients with CIS and serum CHI3L1 levels > 33 ng/mL and 100% of those with lipid-specific oligoclonal IgM bands present MS within one year of CIS onset.

Biochemical biomarkers for multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system. Although there is currently no definite cure for MS, new therapies have recently been developed based on a continuous search for new biomarkers. DEVELOPMENT: MS diagnosis relies on the integration of clinical, imaging and laboratory findings as there is still no singlepathognomonicclinical feature or diagnostic laboratory biomarker. The most commonly laboratory test used is the presence of immunoglobulin G oligoclonal bands (OCB) in cerebrospinal fluid of MS patients. This test is now included in the 2017 McDonald criteria as a biomarker of dissemination in time. Nevertheless, there are other biomarkers currently in use such as kappa free light chain, which has shown higher sensitivity and specificity for MS diagnosis than OCB. In addition, other potential laboratory tests involved in neuronal damage, demyelination and/or inflammation could be used for detecting MS. CONCLUSIONS: CSF and serum biomarkers have been reviewed for their use in MS diagnosis and prognosis to stablish an accurate and prompt MS diagnosis, crucial to implement an adequate treatment and to optimize clinical outcomes over time.

Determination of sensitivities and specificities of cerebrospinal fluid free light chains to diagnose multiple sclerosis- a multicentric case-control study.

BACKGROUND: CSF free light chains help diagnose multiple sclerosis, but no data is available on the Asian population. Our objective was to study the diagnostic utility of CSF free light chains for diagnosing multiple sclerosis in Indian patients. METHODS: Prospective multicentric case-control study. Cases included those who were tested for oligoclonal bands and fulfilled the modified McDonald criteria 2017 for multiple sclerosis and clinically isolated syndromes. Those tested for oligoclonal bands (OCB) but with other diagnoses- inflammatory and non-inflammatory were included as controls. Clinical details were collected from electronic medical records. CSF and serum kappa and lambda free light chains were measured, apart from oligoclonal bands, immunoglobulin, and albumin in paired serum and CSF samples. RESULTS: There were 70 patients (31 cases and 39 controls). The mean age was 43.41(SD 16.073) years, and 43(61.4%) were females. CSF kappa showed highest specificity 97.4%, at a cut off 2.06 mg/L (sensitivity 71%) and highest sensitivity 90.3%, at a cut off 0.47 mg/L (specificity 79.5%). Best balance of sensitivity and specificity for CSF kappa was seen at a cut-off of ≥ 0.63 mg/L {sensitivity 87·1 (CI - 70.17-96.37), and specificity 87·18 (CI -72.57-95.70)}. The ratio of Kappa/lambda showed highest specificity of 100%(similar to OCB) with a sensitivity of 71% at a cut off of 1.72. The ratio of sum of kappa and lambda light chains, and Qalb (∑CSF FLC/Qalb), showed the highest specificity (94.87%)among the blood brain barrier corrected ratios. CONCLUSION: This study showed that the diagnostic utility of CSF kappa was comparable to OCB to diagnose multiple sclerosis in sensitivity, but not specificity, so can be a screening test before testing for OCB in our population.

High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis.

Background: Evolving evidence suggests that measurement of cerebrospinal fluid (CSF) kappa free light chain (KFLC) synthesis has high diagnostic sensitivity and specificity for multiple sclerosis (MS), but its prognostic ability is less investigated. The usefulness of KFLC in predicting cognitive impairment (CI) is still unknown. Methods: In a monocentric longitudinal retrospecitve cohort study, KFLC-index ([CSF KFLC/serum KFLC]/[CSF albumin/serum albumin]) measured by latex-enhanced immunonephelometry was prospectively determined as part of the diagnostic workup in patients with early relapsing-remitting MS (RRMS, n=77). The ability of KFLC-index to predict information processing speed (IPS) worsening as assessed with the symbol digit modalities test (SDMT) was investigated in univariable and multivariable models. Results: In patients with KFLC-index>100 (n=31), 11 subjects (35.5%) showed reduced SDMT scores by ≥8 points at follow-up (mean follow-up time 7.3 ± 2.6 years), compared with their baseline scores (p=0.01). Baseline KFLC-index>100 was strongly associated with a higher hazard of SDMT score reduction at follow-up (adjusted hazard ratio 10.5, 95% confidence interval 2.2-50.8, p=0.003; median time to SDMT reduction 7 years). Conclusion: Intrathecal KFLC synthesis has become an attractive diagnostic tool for MS. We show for the first time that in a real-world setting of early RRMS, KFLC-index predicted cognitive decline. Whether this predictive ability of KFLC-index also concerns other cognitive domains than IPS, warrants further investigations.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Intrathecal immunoglobulin-G synthesis is a hallmark of multiple sclerosis (MS), which can be detected by oligoclonal IgG bands (OCB) or by κ-free light chains (κ-FLC) in cerebrospinal fluid. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate whether κ-FLC index has similar diagnostic value to identify patients with clinically isolated syndrome (CIS) or MS compared to OCB, and to determine κ-FLC index cut-off. METHODS: PubMed was searched for studies that assessed diagnostic sensitivity and specificity of κ-FLC index and OCB to discriminate CIS/MS patients from control subjects. Two reviewers following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines performed study eligibility assessment and data extraction. Findings from studies were analyzed with bivariate mixed models. RESULTS: A total of 32 studies were included in the meta-analysis to evaluate diagnostic value of κ-FLC index. Sensitivity and specificity ranged from 52% to 100% (weighted average: 88%) and 69% to 100% (89%) for κ-FLC index and from 37% to 100% (85%) and 74% to 100% (92%) for OCB. Mean difference of sensitivity and specificity between κ-FLC index and OCB was 2 and -4 percentage points. Diagnostic accuracy determined by mixed models revealed no significant difference between κ-FLC index and OCB. A discriminatory cut-off for κ-FLC index was determined at 6.1. CONCLUSION: The findings indicate that κ-FLC index has similar diagnostic accuracy in MS as OCB.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement.

Cerebrospinal fluid (CSF) analysis is of utmost importance for diagnosis and differential diagnosis of patients with suspected multiple sclerosis (MS). Evidence of intrathecal immunoglobulin G (IgG) synthesis proves the inflammatory nature of the disease, increases diagnostic certainty and substitutes for dissemination in time according to current diagnostic criteria. The gold standard to determine intrathecal IgG synthesis is the detection of CSF-restricted oligoclonal bands (OCBs). However, advances in laboratory methods brought up κ-free light chains (FLCs) as a new biomarker, which are produced in excess over intact immunoglobulins and accumulate in CSF in the case of central nervous system-derived inflammation. Overwhelming evidence showed a high diagnostic accuracy of intrathecal κ-FLC synthesis in MS with sensitivity and specificity of approximately 90% similar to OCB. κ-FLCs have advantages as its detection is fast, easy, cost-effective, reliable, rater-independent and returning quantitative results which might also improve the value of predicting MS disease activity. An international panel of experts in MS and CSF diagnostics developed a consensus of all participants. Six recommendations are given for establishing standard CSF evaluation in patients suspected of having MS. The panel recommended to include intrathecal κ-FLC synthesis in the next revision of MS diagnostic criteria as an additional tool to measure intrathecal immunoglobulin synthesis.

The Use of Kappa Free Light Chains to Diagnose Multiple Sclerosis.

Background: The positive implications of using free light chains in diagnosing multiple sclerosis have increasingly gained considerable interest in medical research and the scientific community. It is often presumed that free light chains, particularly kappa and lambda free light chains, are of practical use and are associated with a higher probability of obtaining positive results compared to oligoclonal bands. The primary purpose of the current paper was to conduct a systematic review to assess the up-to-date methods for diagnosing multiple sclerosis using kappa and lambda free light chains. Method: An organized literature search was performed across four electronic sources, including Google Scholar, Web of Science, Embase, and MEDLINE. The sources analyzed in this systematic review and meta-analysis comprise randomized clinical trials, prospective cohort studies, retrospective studies, controlled clinical trials, and systematic reviews. Results: The review contains 116 reports that includes 1204 participants. The final selection includes a vast array of preexisting literature concerning the study topic: 35 randomized clinical trials, 21 prospective cohort studies, 19 retrospective studies, 22 controlled clinical trials, and 13 systematic reviews. Discussion: The incorporated literature sources provided integral insights into the benefits of free light chain diagnostics for multiple sclerosis. It was also evident that the use of free light chains in the diagnosis of clinically isolated syndrome (CIS) and multiple sclerosis is relatively fast and inexpensive in comparison to other conventional state-of-the-art diagnostic methods, e.g., using oligoclonal bands (OCBs).

A simple scheme for large scale purification of urine - Derived Bence Jones Kappa protein.

We have investigated and optimized purification process, suitable for industrial scale, to obtain high purity grade Bence Jones Kappa Protein ('BJK-Protein'), while preserving its physiological properties and functions. BJK-Protein was obtained from a biological waste product i.e. human urine of renal failure patients. Isolated 'BJK-Protein' was analyzed by electrophoresis, western blotting, double immunodiffusion, SEC-HPLC assay and Mass Spectrometry (MS). The relative molecular mass of 'BJK-Protein' is 23054.2 Da. Moreover, dimer forms of 'BJK-Protein' were also detected in SDS-PAGE and mass spectrum corresponding to 46054.4 Da. The results of western blotting, immunoelectrophoresis, SEC-HPLC assay, and mass spectrometry analysis indicate a high purity (>99 %) of 'BJK-Protein'. Peptide mass fingerprint analysis of 'BJK-Protein' yielded peptides that partially matches the known database sequences of kappa variable region (KV139_HUMAN) of immunoglobulin. This protein was found to be stable up to 20 months at 2-8 °C temperature and also found negative for major undesirable viral markers as well as bacterial endotoxin. With this purification approach, the cost of purified 'BJK-Protein' is significantly reduced as compared to the current market price of Kappa light chain available in international market.

An Update on Laboratory-Based Diagnostic Biomarkers for Multiple Sclerosis and Beyond.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disease in which analysis of clinical presentation, imaging studies, and laboratory tests aid in diagnosis. CONTENT: This review discusses laboratory tests ordered to rule out and rule in MS, such as the traditional measurement of cerebrospinal fluid (CSF) IgG index and oligoclonal bands. Biomarkers discovered in the past 2 decades, such as aquaporin-4 (AQP4) antibodies and myelin oligodendrocyte glycoprotein (MOG) antibodies, have been incorporated into clinical practice in the diagnosis of disorders referred to as MS mimics. The importance of test selection, assay methodology, optimal sample for testing, and diagnostic utility of these biomarkers is reviewed. Other laboratory testing that can aid in the differentiation between MS and these biomarker-defined CNS demyelinating diseases is described. There is a focus on emerging biomarkers such as the use of kappa immunoglobulin free light chain concentration in CSF and kappa CSF index measurement as an alternative to oligoclonal bands which has a potential for an improvement in laboratory workflows. Finally, the role of biomarkers of disease activity and prognosis are discussed, including neurofilament light chain, glial fibrillary acidic protein, and myelin basic protein. Future perspectives with improved laboratory testing tools and discovery of additional biomarkers are provided. SUMMARY: Laboratory testing for demyelinating disorders using CSF and serum are routine practices that can benefit from an update, as novel biomarker-defined entities have reduced the potential for MS misdiagnosis, and CSF/serum biomarkers reinstated in the diagnostic criteria of MS.

Kappa Free Light Chains in Cerebrospinal Fluid in Inflammatory and Non-Inflammatory Neurological Diseases.

BACKGROUND: Oligoclonal bands represent intrathecal immunoglobulin G (IgG) synthesis and play an important role in the diagnosis of multiple sclerosis (MS). Kappa free light chains (KFLC) are increasingly recognized as an additional biomarker for intrathecal Ig synthesis. However, there are limited data on KFLC in neurological diseases other than MS. METHODS: This study, conducted at two centers, retrospectively enrolled 346 non-MS patients. A total of 182 patients were diagnosed with non-inflammatory and 84 with inflammatory neurological diseases other than MS. A further 80 patients were classified as symptomatic controls. Intrathecal KFLC production was determined using different approaches: KFLC index, Reiber's diagram, Presslauer's exponential curve, and Senel's linear curve. RESULTS: Matching results of oligoclonal bands and KFLC (Reiber's diagram) were frequently observed (93%). The Reiber's diagram for KFLC detected intrathecal KFLC synthesis in an additional 7% of the patient samples investigated (4% non-inflammatory; 3% inflammatory), which was not found by oligoclonal band detection. CONCLUSIONS: The determination of both biomarkers (KFLC and oligoclonal bands) is recommended for routine diagnosis and differentiation of non-inflammatory and inflammatory neurological diseases. Due to the high sensitivity and physiological considerations, the assessment of KFLC in the Reiber's diagram should be preferred to other evaluation methods.

Kappa Free Light Chains, Soluble Interleukin-2 Receptor, and Interleukin-6 Help Explore Patients Presenting With Brain White Matter Hyperintensities.

Introduction: Many patients are referred to multiple sclerosis (MS) tertiary centers to manage brain white matter hyperintensities (WMH). Multiple diagnoses can match in such situations, and we lack proper tools to diagnose complex cases. Objective: This study aimed to prospectively analyze and correlate with the final diagnosis, cerebrospinal fluid (CSF) interleukin (IL)-1ß, soluble IL-2 receptor (CD25), IL-6, IL-10, and kappa free light chains (KFLC) concentrations in patients presenting with brain WMH. Methods: All patients over 18 years addressed to our MS tertiary center for the diagnostic workup of brain WMH were included from June 1, 2020, to June 1, 2021. Patients were separated into three groups-MS and related disorder (MSARD), other inflammatory neurological disorder (OIND), and non-inflammatory neurological disorder (NIND) groups-according to clinical presentation, MRI characteristics, and biological workup. Results: A total of 176 patients (129 women, mean age 45.8 ± 14.7 years) were included. The diagnosis was MSARD (n = 88), OIND (n = 35), and NIND (n = 53). Median CSF KFLC index and KFLC intrathecal fraction (IF) were higher in MSARD than in the OIND and NIND groups; p < 0.001 for all comparisons. CSF CD25 and IL-6 concentrations were higher in the OIND group than in both the MSARD and NIND groups; p < 0.001 for all comparisons. KFLC index could rule in MSARD when compared to NIND (sensitivity, 0.76; specificity, 0.91) or OIND (sensitivity, 0.73; specificity, 0.76). These results were similar to those with oligoclonal bands (sensitivity, 0.59; specificity, 0.98 compared to NIND; sensitivity, 0.59; specificity, 0.88 compared to OIND). In contrast, elevated CSF CD25 and IL-6 could rule out MSARD when compared to OIND (sensitivity, 0.58 and 0.88; specificity, 0.95 and 0.74, respectively). Discussion: Our results show that, as OCBs, KFLC biomarkers are helpful tools to rule in MSARD, whereas elevated CSF CD25 and IL-6 rule out MSARD. Interestingly, CSF IL-6 concentration could help identify neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and central nervous system (CNS) vasculitis. These results need to be confirmed within more extensive and multicentric studies. Still, they sustain that KFLC, CSF CD25, and CSF IL-6 could be reliable biomarkers in brain WMH diagnostic workup for differentiating MSARD from other brain inflammatory MS mimickers.

Kappa free light chains: Diagnostic performance in multiple sclerosis and utility in a clinical laboratory.

BACKGROUND: Automated, technically simple analytical methods offering objective results are highly valued in clinical laboratories. Kappa free light chains (KFLC) in cerebrospinal fluid (CSF) are promising multiple sclerosis (MS) biomarkers, particularly kappa (K) index. METHODS: KFLC were determined in CSF and serum samples of patients diagnosed with MS, clinically/radiologically isolated syndrome (N, 39), and controls (N, 152; inflammatory and non-inflammatory neurological disorders). Diagnostic performance of several KFLC parameters, previously determined oligoclonal band (OCB) testing, and IgG index, was assessed. A K index decision threshold for sample screening was identified and reduction in performed OCB analyses estimated accordingly. RESULTS: Higher KFLC parameters were detected in the MS group and K index performed best among them (AUC 0.92). At a 7.25 cut-off it showed better sensitivity (85% vs. 77%) though less specificity (88% vs. 91%) than OCBs. Comparatively, IgG index's performance was inferior (AUC 0.83). A decision K index threshold of 2.55 (97% sensitivity) would reduce OCB testing by 52% in the studied population. CONCLUSIONS: The proposed 7.25 cut-off could assist MS diagnostics and identify some false negative cases from OCB studies. Sequential algorithms using K index for the decision to perform OCB detection would improve laboratory efficiency and substantially reduce costs.

The Influence of Renal Function Impairment on Kappa Free Light Chains in Cerebrospinal Fluid.

BACKGROUND: The determination of kappa free light chains (KFLC) in cerebrospinal fluid (CSF) is an upcoming biomarker for the detection of an intrathecal immunoglobulin synthesis. Since renal function impairment leads to altered serum KFLC and albumin concentrations, interpretation of KFLC in CSF may be influenced by these parameters. METHODS: In this two-center study, the influence of renal function (according to the CKD-EPI creatinine equation) on KFLC and albumin concentrations was investigated in patients with "physiological" (n = 139), "non-inflammatory" (n = 146), and "inflammatory" (n = 172) CSF profiles in respect to the KFLC index and the evaluation in quotient diagrams in reference to the hyperbolic reference range (KFLC IF). RESULTS: All sample groups displayed declining KFLC indices and KFLC IF values with decreasing renal function (P-values between <.0001 and .0209). In "inflammatory" CSF profile samples, 15% of the patients presented a KFLC index <5.9 while 10% showed an intrathecal KFLC fraction below QKappa(lim), suggesting possible false negative KFLC results. CONCLUSIONS: The influence of renal function should be considered while interpreting KFLC results in patients with neuroinflammatory diseases. The interpretation of KFLC in quotient diagrams is less susceptible to renal function impairment than the KFLC index and should be preferentially used.