Search

Background: Cerebrospinal fluid (CSF) kappa-free light chains (KFLC) are becoming a diagnostic biomarker for multiple sclerosis (MS)., Objectives: We aimed to compare the diagnostic performance of intrathecal synthesis biomarkers to that of oligoclonal bands (OB) in diagnosing MS, radiological and clinical isolated syndromes (RIS-CIS) on a large cohort of patients collected over 10 years., Methods: We collected 1124 patients (58% females) in 10 years who underwent CSF analysis for intrathecal synthesis in the diagnostic work-up, and they were classified according to their diagnosis as 417 MS, 287 with other neurological inflammatory disorders (including 76 RIS-CIS), and 420 non-inflammatory diseases (excluding lymphoproliferative and infective diagnosis)., Results: MS patients significantly differ from all other groups (including if considering the RIS-CIS cohort) for CSF KFLC, KFLC intrathecal fraction (IF), Kappa index, and OB. Evaluating the diagnostic performance, the Kappa index cut-off was 6.4 for diagnosing MS and 5.7 for predicting OB. A diagnostic algorithm could avoid IEF if the Kappa index is higher than 20., Conclusions: The KFLC index confirmed its accuracy for MS diagnosis in this large Italian cohort, adding information also in the RIS-CIS population., Competing Interests: Declarations. Conflicts of interest: None for all authors for this work. Ethics approval: Local Ethical Committee approvals (Comitato Etico Interaziendale AOU “Maggiore della Carità” di Novara, ASL BI, ASL NO, ASL VCO): CE 060/2022 and 260/2022). Consent to participate/consent for publication: written consent obtained from all participants., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Multiple sclerosis (MS) diagnosis includes the presence of restricted oligoclonal bands (OCB) in cerebrospinal fluid (CSF), but it has several limitations, as it is an observer-dependent time-consuming technique and offers a dichotomous result. Thus kappa free light chains (KFLC) have emerged as a quantitative alternative. However, the cut-off values for KFLC have not been well established yet and it is not clear if differences between sexes exist. We aim to evaluate these and to compare the diagnostic accuracy of KFLC concentrations and their related indexes versus OCB. For that purpose, paired CSF and serum samples were collected and immediately processed for albumin, total protein, immunoglobulins and OCB, then frozen at -20°C. KFLC was measured in a BN II (Siemens Healthineers, Germany). KFLC-derived indexes were calculated. Diagnostic accuracy was evaluated by the area under the curve (AUC), Youden's index and odds ratio. From the 193 patients included, 56 were classified as MS according to the 2017 McDonald criteria. K-index, Q KFLC and Reiber's diagram showed good accuracy in MS diagnosis when studied distinguishing between sexes, similar to OCB. Cut-offs for K-index and Q KFLC change substantially between sex having the highest AUC similar than OCB. A sex-dependent algorithm combining the use of K-index, Q KFLC and OCB yields the highest diagnostic accuracy. In conclusion, CSF KFLC measurement is a rapid, quantitative and easy-to-standardize tool that used through the proposed sex-dependent algorithm may reduce the number of manual OCB tests performed., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Background: The presence of inflammatory changes in the cerebrospinal fluid (CSF), including immunoglobulin intrathecal synthesis (IS), can support the diagnosis of autoimmune encephalitis (AE) and allow prompt treatment. The main aim of our study was to calculate the Kappa index as a marker of IS, in patients with AE., Methods: Charts of patients undergoing a diagnostic work-up for suspected AE between 2009 and 2023 were reviewed and the Graus criteria applied. CSF and serum kappa free light chains were determined using the Freelite assay (The Binding Site Group) and the turbidimetric Optilite analyzer., Results: We identified 34 patients with "definite" AE (9 anti-NMDAR AE and 25 limbic AE) and nine patients with "possible" AE. Five patients (15%) with definite AE had pleocytosis and twelve (34%) showed CSF-restricted oligoclonal bands (OCB) at isoelectric focusing. The Kappa index was >6 in 29.4% and > 3 in 50% of the definite AE patients. It was elevated (>3) in 36.4% of patients with definite AE who resulted negative to OCB testing and was the only altered parameter suggestive of an ongoing inflammatory process in the CNS in three definite AE patients with otherwise normal CSF findings (i.e. normal cell count and protein levels, no OCBs). In the possible AE group, one patient had a Kappa index >3 in the absence of OCB., Conclusions: The Kappa index could be useful, as a more sensitive marker of IS and as a supportive marker of neuroinflammation, in the diagnostic work-up of suspected AE., Competing Interests: Declaration of competing interest DF's institution has received kappa free light chain assays (Freelite) for research purposes from Binding Site (Birmingham). GDN, MG, PN, RB, SM, AMS, MS, FV, KS, MC and SM have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Oligoclonal bands (OCB) analysis is the reference standard for detecting an intrathecal IgG synthesis. Alongside OCB, free light chains kappa (FLCκ) are considered an additional sensitive biomarker for determining patterns 2 or 3, indicating intrathecal Ig synthesis. However, kFLC IF is not suitable for detecting a monoclonal pattern 5. The primary aim of this study was to evaluate the impact of incorporating FLCκ analysis into routine cerebrospinal fluid (CSF) diagnostics instead of OCB testing on the rate of missed monoclonal IgG detection., Methods: A two-center retrospective biomarker study was conducted. OCB were identified using isoelectric focusing in polyacrylamide gels followed by silver staining or in agarose gels followed by immunofixation. FLCκ were quantified using nephelometry and FLCκ assay (Siemens)., Results: Out of a combined total of 17,755 OCB analyses conducted between 2011 and 2021, a subset of 269 cases (1.5 %) exhibited pattern 5. 98 samples (36 %), which included 18 samples with intrathecal inflammation as determined by additional OCB pattern 2 were included in the FLCκ analysis. Of those, 16 (89 %) had intrathecal FLCκ synthesis., Conclusions: While FLCκ offers a promising avenue for detecting an intrathecal inflammation, the pattern 5, though rare, remains a valuable additional finding of OCB analysis. A combined approach of FLCκ and OCB analysis is recommended for a comprehensive assessment of the humoral intrathecal immune response., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

The diagnosis of MS relies on a combination of imaging, clinical examinations, and biological analyses, including blood and cerebrospinal fluid (CSF) assessments. G-Oligoclonal bands (OCBs) are considered a "gold standard" for MS diagnosis due to their high sensitivity and specificity. Recent advancements have involved the introduced of kappa free light chain (k-FLC) assay into cerebrospinal fluid (CSF) and serum (S), along with the albumin quotient, leading to the development of a novel biomarker known as the "K-index" or "k-FLC index". The use of the K-index has been recommended to decrease costs, increase laboratory efficiency, and to skip potential subjective operator-dependent risk that could happen during the identification of OCBs profiles. This review aims to provide a comprehensive overview and analysis of recent scientific articles, focusing on updated methods for MS diagnosis with an emphasis on the utility of the K-index. Numerous studies indicate that the K-index demonstrates high sensitivity and specificity, often comparable to or surpassing the diagnostic accuracy of OCBs evaluation. The integration of the measure of the K-index with OCBs assessment emerges as a more precise method for MS diagnosis. This combined approach not only enhances diagnostic accuracy, but also offers a more efficient and cost-effective alternative.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dekeyser, De Kesel, Cambron, Vanopdenbosch, Van Hijfte, Vercammen and Laureys.)

Objectives: To study intrathecal kappa free light chain (KFLC) synthesis in people living with HIV (PLWH) in comparison with multiple sclerosis (MS)., Methods: Cross-sectional analysis including 56 untreated and 150 well treated PLWH, and compared with 58 controls, and 223 MS patients., Results: Elevated serum/cerebrospinal fluid (CSF) IgG and KFLC indices were observed in untreated PLWH. Seventy percent of untreated PLWH had KFLC index above 6.1, a threshold associated with clinically isolated syndrome/MS diagnosis. No association was found between KFCL index and CSF markers of neuronal injury in either PLWH or MS patients., Conclusions: HIV-related immune system dysfunction is often associated with an elevated KFLC index akin to those observed in MS. HIV infection should be considered as a differential diagnosis for patients presenting with neurological symptoms and increased intrathecal immunoglobulin synthesis., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Kappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS)., Objective: To investigate whether κ-FLC index has similar diagnostic value in patients with primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB)., Methods: Patients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation., Results: A total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients., Conclusion: κ-FLC index shows similar diagnostic sensitivity than OCB in PPMS., Competing Interests: HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Siemens, Teva, and received honoraria for acting as consultant for Biogen, Celgene, Novartis and Teva. He is associate editor of Frontiers in Neurology. KB has participated in meetings sponsored by and received travel funding or speaker honoraria from Roche, Teva, Merck, Biogen, Sanofi. PC has received research funding and speaker fees from Merck Serono, Roche, Novartis, Biogen, Sanofi. AE has participated in meetings sponsored by Novartis. MDF participated on advisory boards for and received speaker or writing honoraria, funding for travelling and research support from Alexion, Bayer, Biogen Idec, Sanofi, Siemens Healthineers, Merck, Mylan, Novartis, Roche, Teva and Viatris. LG participated on advisory boards for, and received writing honoraria and travel grants from Almirall, Biogen, Euroimmun, Fujirebio, Merck, Mylan, Novartis, Roche, Sanofi, Siemens Healthineers, and Teva. DM has participated in meetings sponsored by Siemens. VVP has received travel grants from Merck, Biogen, Sanofi and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck, Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma. TP has received research grant support and travel support from Biogen Idec, Merck Serono, Novartis, Bayer Schering, Sanofi-Aventis, Roche, and Genzyme. SP had received travel funding and speaker honoraria from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, The Binding Site. IR has received compensation for lectures from Biogen. UR has participated in meetings sponsored by or received honoraria for advisor/speaker for Bayer, Biogen, Janssen, Lek, Merck, Novartis, Roche, Sanofi-Genzyme, Teva. His institution has received research support from Biogen and Novartis. CS has participated in meetings sponsored by Siemens. CT has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Biogen, Bioorchstra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Novo Nordisk, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. Research of CET is supported by the European Commission Marie Curie International Training Network, grant agreement No 860197 MIRIADE, Innovative Medicines Initiatives 3TR Horizon 2020, grant no 831434and JPND bPRIDE, National MS Society Progressive MS alliance and Health Holland, the Dutch Research Council ZonMW, Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW #73305095007 and Health~Holland, Topsector Life Sciences & Health PPP-allowance; #LSHM20106. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. DV received travel grants from Merck, Sanofi-Genzyme, Almirall and Novartis and research grants from Merck. MV has received research funding and speaker fees from Merck Serono, Roche, Novartis, Biogen, Sanofi. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene-BMS, Genzyme-Sanofi, Horizon, Merck, Novartis Pharma, Roche, and Teva. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal Multiple Sclerosis and Related Disorders and review editor of Frontiers Neurology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hegen, Berek, Cavalla, Christiansen, Emeršič, Di Filippo, Gaetani, Hassler, Leurs, Milosavljevic, van Pesch, Petersen, Presslauer, Rosenstein, Rot, Schnabl, Teunissen, Vecchio, Vercellino and Deisenhammer.)

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 (r s = 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., Competing Interests: PA-P, LB, EM, IL, AM-V, LR-P, AM-Y and SM-Y received honoraria for participating on advisory boards and for collaborations as consultants and scientific communications; they also received research support as well as funding for travel and congress expenses from Roche, Biogen Idec, Novartis, TEVA, Merck, Genzyme, Sanofi, Bayer, Almirall, and Celgene. LG-S and VM received funding for travel and congress expenses from The Binding Site. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Arroyo-Pereiro, García-Serrano, Morandeira, Urban, Mas, Framil, León, Muñoz-Vendrell, Matas, Romero-Pinel, Martínez-Yélamos, Martínez-Yélamos and Bau.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To address the diagnostic performances of cerebrospinal fluid (CSF) free light chains (FLC) measurements compared to oligoclonal bands (OCB) to support multiple sclerosis (MS) diagnosis., Results: kFLC index showed the highest diagnostic accuracy to detect MS patients with the highest AUC compared to OCB, IgG index, IF kFLC R, kFLC H, λFLC index and IF λFLC., Conclusions: FLC indices are biomarkers of intrathecal Immunoglobulin synthesis and central nervous system (CNS) inflammation. kFLC index can discriminate between MS and other CNS inflammatory disorders, while λFLC index is less informative for MS but can play a role to support the diagnosis of other inflammatory CNS disorders., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest None of the authors report any conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Inter-individual courses of multiple sclerosis (MS) are extremely variable. The objective of this study was to investigate whether κ-free light chain (κ-FLC) index and serum neurofilament light (sNfL) have an additive predictive value for MS disease activity., Methods: Patients with early MS who had cerebrospinal fluid (CSF) and serum sampling at disease onset were followed for four years. At baseline, age, sex, disease duration, number of T2-hyperintense (T2L), and contrast-enhancing T1 lesions (CEL) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying treatment (DMT) were registered. κ-FLC was measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient. sNfL was determined by single-molecule array, and age- and body-mass-index adjusted Z scores were calculated., Findings: A total of 86 patients at a mean age of 33 ± 10 years and with a female predominance of 67% were included; 36 (42%) patients experienced a second clinical attack during follow-up. Cox regression analysis adjusted for age, sex, T2L, CEL, disease and follow-up duration, and DMT use during follow-up revealed that both κ-FLC index as well as sNfL Z score independently predict time to second clinical attack. The chance for freedom of relapse within 12 months was 2% in patients with high levels of κ-FLC index (>100) and high sNfL Z score (>3), 30% in patients with high κ-FLC index (>100) and lower sNfL Z score (≤3), 70% in patients with lower κ-FLC index (≤100) but high sNfL Z score (>3), and 90% in patients with lower levels of κ-FLC index (≤100) and sNfL Z score (≤3)., Interpretation: κ-FLC index and sNfL Z score have an additive predictive value for early MS disease activity that is independent of known predictors., Funding: This study was funded by a grant of the charitable foundation of the Austrian Multiple Sclerosis Society., Competing Interests: Declaration of interests HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Siemens, Teva, and received honoraria for acting as consultant for Biogen, Celgene, Novartis and Teva. He is associate editor of Frontiers in Neurology. KB has participated in meetings sponsored by and received travel funding or speaker honoraria from Roche, Teva, Merck, Biogen, Sanofi. GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Lilly, Merck, Novartis, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene, Merck, Novartis, Roche and Teva. MA received speaker honoraria and/or travel grants from Biogen, Novartis, Merck and Sanofi. PA has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Merck, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Sanofi-Genzyme, Roche, and Teva for a clinical study. FDP has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. AG has nothing to disclose. DM has participated in meetings sponsored by Siemens. MP has participated in meetings sponsored by, received speaker or consulting honoraria or travel funding from Amicus, Merck, Novartis and Sanofi-Genzyme. PP has nothing to disclose. CS has participated in meetings sponsored by Siemens. SW has participated in meetings sponsored by, received honoraria or travel funding from Allergan, Biogen, Ipsen Pharma, Merck, Novartis, Roche, Sanofi Genzyme, Teva and Bristol Myers Squibb. AZ has participated in meetings sponsored by, received speaking honoraria or travel funding from Biogen, Merck, Novartis, Sanofi-Genzyme and Teva. TB has participated in the last 2 years in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Biogen, Bionorica, BMS/Celgene, Eisai, Horizon, Jazz Pharmaceuticals, Janssen-Cilag, MedDay, Merck, Novartis, Roche, Sanofi Aventis/Genzyme, Sandoz, TG Therapeutics, TEVA and UCB. His institution has received financial support in the last 2 years by unrestricted research grants (Biogen, BMS/Celgene, Novartis, Sanofi Aventis/Genzyme, Roche, TEVA) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, BMS/Celegen, Merck, Novartis, Roche, Sanofi Aventis/Genzyme, TEVA. JW has nothing to disclose. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene-BMS, Genzyme-Sanofi, Horizon, Merck, Novartis Pharma, Roche, and Teva. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders) and review editor of Frontiers Neurology., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 (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.

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., Competing Interests: IR has received compensation for lectures from biogen. MA has received compensation for lectures and/or advisory boards from Biogen, Genzyme, and Novartis. LN has received lecture honoraria from Biogen, Novartis, Teva, Sanofi and has served on advisory boards for Merck, Janssen and Sanofi. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB BBS, which is a part of the GU Ventures Incubator Program, all unrelated to the work presented in this paper. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB BBS, which is a part of the GU Ventures Incubator Program outside submitted work. JL has received travel support and/or lecture honoraria and has served on scientific advisory boards for Alexion, Almirall, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator initiated study. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rosenstein, Axelsson, Novakova, Rasch, Blennow, Zetterberg and Lycke.)

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system that shows a high interindividual heterogeneity, which frequently poses challenges regarding diagnosis and prediction of disease activity. In this context, evidence of intrathecal inflammation provides an important information and might be captured by kappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF). In this review, we provide an overview on what is currently known about κ‑FLC, its historical development, the available assays and current evidence on its diagnostic and prognostic value in MS. Briefly, intrathecal κ‑FLC synthesis reaches similar diagnostic accuracy compared to the well-established CSF-restricted oligoclonal bands (OCB) to identify patients with MS, and recent studies even depict its value for prediction of early MS disease activity. Furthermore, detection of κ‑FLC has significant methodological advantages in comparison to OCB detection., (© 2022. The Author(s).)

Background: Cerebrospinal fluid (CSF) free light chain (FLC) detection has been proposed as a tool for diagnosing primary central nervous system lymphoma (PCNSL), but there is no consensus on the appropriate reference range and its value for monitoring chemotherapy efficacy has not been investigated in Chinese PCNSL patients. We assessed the application potential of CSF FLC ratios for diagnosing PCNSL and monitoring associated treatment efficacy., Methods: Kappa (κ) and lambda (λ) FLC were measured by nephelometry in CSF samples of patients with PCNSL (n = 45), other neurological diseases (n = 30), and normal controls (n = 60). Results of κ/λ FLC ratios (FLCr) were correlated with patients' diagnoses and receiver operating characteristic analysis was used to determine accuracy. In PCNSL patients, FLCr analysis was compared between PCNSL before and after treatment., Results: κ FLC and FLCr concentrations in PCNSL were significantly higher than in patients without PCNSL (P < 0.05). The optimal cut-off for FLCr was 0.35, with diagnostic sensitivity and specificity of 78% and 72%, respectively. FLCr concentrations decreased after chemotherapy., Conclusion: CSF FLC is a novel biomarker for diagnosis and chemotherapy efficacy monitoring in PCNSL., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The kappa index (K-Index), calculated by dividing the cerebrospinal fluid (CSF)/serum kappa free light chain (KFLC) ratio by the CSF/serum albumin ratio, is gaining increasing interest as a marker of intrathecal immunoglobulin synthesis. However, data on inter-laboratory agreement of these measures is lacking. The aim was to assess the concordance of CSF and serum KFLC measurements, and of K-index values, across different laboratories. KFLC and albumin of 15 paired CSF and serum samples were analyzed by eight participating laboratories. Four centers used Binding Site instruments and assays (B), three used Siemens instruments and assays (S), and one center used a Siemens instrument with a Binding Site assay (mixed). Absolute individual agreement was calculated using a two-way mixed effects intraclass correlation coefficient (ICC). Cohen's kappa coefficient (k) was used to measure agreement on positive (≥5.8) K-index values. There was an excellent agreement in CSF KFLC measurements across all laboratories (ICC (95% confidence interval): 0.93 (0.87-0.97)) and of serum KFLC across B and S laboratories (ICC: 0.91 (0.73-0.97)), while ICC decreased (to 0.81 (0.53-0.93)) when including the mixed laboratory in the analysis. Concordance for a positive K-Index was substantial across all laboratories (k = 0.77) and within S laboratories (k = 0.71), and very good (k = 0.89) within B laboratories, meaning that patients rarely get discordant results on K-index positivity notwithstanding the testing in different laboratories and the use of different platforms/assays.

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)-1β, 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Levraut, Landes, Mondot, Cohen, Bresch, Brglez, Seitz-Polski and Lebrun-Frenay.)

Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes ( p < 0.0001/ p < 0.05) and IgG-oligoclonal bands (OCGBs) ( p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index ( p = 0.049). KFLC-index was higher in patients with LMCE ( p = 0.008) and correlated with CHI3L1 ( p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1-147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2-7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course., Competing Interests: Authors LC and AL were employed by The Binding Site Iberia. The Binding Site has ceded the turbidimetry kits to measure KFLC for the present study. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Castillo-Villalba, Gil-Perotín, Gasque-Rubio, Cubas-Nuñez, Carratalà-Boscà, Alcalá, Quintanilla-Bordás, Pérez-Miralles, Ferrer, Cañada Martínez, Tortosa, Solís-Tarazona, Campos, Leivas, Laíz Marro and Casanova.)

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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Free light chains (FLC) are a promising biomarker to detect intrathecal inflammation in patients with inflammatory central nervous system (CNS) diseases, including multiple sclerosis (MS). The diagnostic use of this biomarker, in particular the kappa isoform of FLC ("KFLC"), has been investigated for more than 40 years. Based on an extensive literature review, we found that an agreement on the correct method for evaluating KFLC concentrations has not yet been reached. KFLC indices with varying cut-off values and blood-CSF-barrier (Q Albumin ) related non-linear formulas for KFLC interpretation have been investigated in several studies. All approaches revealed high diagnostic sensitivity and specificity compared with the oligoclonal bands, which are considered the gold standard for the detection of intrathecally synthesized immunoglobulins. Measurement of KFLC is fully automated, rater-independent, and has been shown to be stable against most pre-analytic influencing factors. In conclusion, the determination of KFLC represents a promising diagnostic approach to show intrathecal inflammation in neuroinflammatory diseases. Multicenter studies are needed to show the diagnostic sensitivity and specificity of KFLC in MS by using the latest McDonald criteria and appropriate, as well as standardized, cut-off values for KFLC concentrations, preferably considering non-linear formulas such as Reiber's diagram.

The analysis of cerebrospinal fluid (CSF) is routinely used in the diagnostic work-up of a range of inflammatory, infective, and congenital neurological conditions. Many diagnostic tests used in this analysis have poor sensitivity; as such, we investigated the utility of CSF free light chain (FLC) analysis as an adjunct to currently used assays in a paediatric population with neurological disorders. Kappa (κ) and lambda (λ) FLC levels were quantitated in blinded CSF samples by two nephelometric platforms. Results were correlated to clinical diagnoses and classified according to inflammatory/infective or non-inflammatory pathogenesis. FLC results were also compared to currently used CSF diagnostic tests including oligoclonal bands (OCB), CSF IgG and albumin levels, and differential cell count. Of 70 samples analysed, 29 (41%) had an inflammatory or infective diagnosis and 41 (59%) presented with a range of non-inflammatory aetiologies. Thirteen patients had elevated κFLC or λFLC as detected on the IMMAGE 800, defined as greater than the detection limit of the assay (0.600 mg/L for CSF κFLC, and 0.490 mg/L for CSF λFLC), and of these 12 (92%) had an inflammatory disease (sensitivity 41.4%, specificity 97.6%). On the BN II using optimal cut-offs of 0.27 mg/L and 0.12 mg/L for CSF κFLC and λFLC respectively, 24 (34%) patients had elevated results, of which 21 (88%) had an inflammatory disease (sensitivity 72.4%, specificity 92.7%). Analysis of FLC correlated better with diagnostic classification of the diseases than OCB, cell counts and CSF IgG levels. The results of this study support the use of CSF FLC analysis in the diagnosis of paediatric neuroinflammatory conditions., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate whether κ-free light chain (κ-FLC) index predicts multiple sclerosis (MS) disease activity independent of demographics, clinical characteristics, and MRI findings., Methods: Patients with early MS who had CSF and serum sampling at disease onset were followed for 4 years. At baseline, age, sex, type of symptoms, corticosteroid treatment, and number of T2 hyperintense (T2L) and contrast-enhancing T1 lesions (CELs) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying therapy (DMT) were registered. κ-FLCs were measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient., Results: A total of 88 patients at a mean age of 33 ± 10 years and female predominance of 68% were included; 38 (43%) patients experienced a second clinical attack during follow-up. In multivariate Cox regression analysis adjusting for age, sex, T2L, CEL, disease and follow-up duration, administration of corticosteroids at baseline and DMT during follow-up revealed that κ-FLC index predicts time to second clinical attack. Patients with κ-FLC index >100 (median value 147) at baseline had a twice as high probability for a second clinical attack within 12 months than patients with low κ-FLC index (median 28); within 24 months, the chance in patients with high κ-FLC index was 4 times as high as in patients with low κ-FLC index. The median time to second attack was 11 months in patients with high κ-FLC index whereas 36 months in those with low κ-FLC index., Conclusion: High κ-FLC index predicts early MS disease activity., Classification of Evidence: This study provides Class II evidence that in patients with early MS, high κ-FLC index is an independent risk factor for early second clinical attack., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

In this retrospective, monocentric cohort study, we tested if an intrathecal free light chain kappa (FLC-k) synthesis reflects not only an IgG but also IgA and IgM synthesis. We also analysed if FLC-k can help to distinguish between an inflammatory process and a blood contamination of cerebrospinal fluid (CSF). A total of 296 patient samples were identified and acquired from patients of the department of Neurology, University Medicine Greifswald (Germany). FLC-k were analysed in paired CSF and serum samples using the Siemens FLC-k kit. To determine an intrathecal FLC-k and immunoglobulin (Ig) A/-M-synthesis we analysed CSF/serum quotients in quotient diagrams, according to Reiber et al. Patient samples were grouped into three cohorts: cohort I ( n = 41), intrathecal IgA and/or IgM synthesis; cohort II ( n = 16), artificial blood contamination; and the control group ( n = 239), no intrathecal immunoglobulin synthesis. None of the samples had intrathecal IgG synthesis, as evaluated with quotient diagrams or oligoclonal band analysis. In cohort I, 98% of patient samples presented an intrathecal synthesis of FLC-k. In cohort II, all patients lacked intrathecal FLC-k synthesis. In the control group, 6.5% presented an intrathecal synthesis of FLC-k. The data support the concept that an intrathecal FLC-k synthesis is independent of the antibody class produced. In patients with an artificial intrathecal Ig synthesis due to blood contamination, FLC-k synthesis is lacking. Thus, additional determination of FLC-k in quotient diagrams helps to discriminate an inflammatory process from a blood contamination of CSF.

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.

Given its highly variable clinical course, an unmet need for objective prognostic assessment in Multiple Sclerosis (MS) persists. In this work, we suggest that CSF kappa free light chains (KFLC) determination at first relapse may provide insight into future disease activity and disability worsening. We quantified KFLC by nephelometry in paired CSF/serum samples of 28 patients, collected within one month of first-ever MS relapse, and explored correlations with clinical data on disease activity, retrospectively registered across a median follow-up time of 79 months. We documented KFLC ratio (CSF-FKLC/Serum-KFLC) as an independent predictor of second relapse occurrence and disability worsening at follow-up, in this cohort., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Manuel Salavisa has received support for scientific meetings from Genzyme, Roche and Merck Serono. Filipa Ladeira received speaking fees from Novartis, Biogen Idec and Merck Serono and support for scientific meetings from Biogen Idec, Novartis, Sanofi Genzyme and Teva. Ana Sofia Correia received an educational sponsorship from Merck Serono, consultant fees from Biogen Idec, Merck Serono, Novartis and Roche, as well as research support from Biogen Idec and support for scientific meetings from Bayer, Biogen Idec, Novartis, Roche, Sanofi Genzyme and Teva. Alexandra Mendes, Pedro Paixão, João Faro Viana e Miguel Viana-Baptista have no conflits of interest relevant to this manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To test the hypothesis that the intrathecal synthesis of free light chain kappa (FLC-k) can be used as a CSF biomarker to differentiate patients with myelitis due to multiple sclerosis (MS), myelitis due to neuromyelitis optica spectrum disease (NMOSD), and noninflammatory myelopathy, we analyzed FLC-k in 26 patients with MS myelitis, 9 patients with NMOSD myelitis, and 14 patients with myelopathy., Methods: This is a retrospective monocentric cohort study. FLC-k were analyzed using the nephelometric Siemens FLC-k kit in paired samples of CSF and sera. Intrathecal fraction (IF) of FLC-k was plotted in a FLC-k quotient diagram., Results: Ninety-six percent of patients with MS myelitis had an intrathecal synthesis of FLC-k in comparison with 55.6% for NMOSD and 14.3% of patients with noninflammatory myelopathy. The locally synthesized absolute amount of FLC-k was significantly higher in patients with myelitis due to MS than in patients with NMOSD ( p = 0.038) or noninflammatory myelopathy ( p < 0.0001). The sensitivity of FLC-k synthesis to detect inflammation in patients with myelitis is 85.7%. Using a receiver operating characteristic analysis, FLC-k IF >78% can discriminate patients with myelitis due to MS and NMOSD with a sensitivity of 88.5% and a specificity of 88.9% CONCLUSIONS: With the hyperbolic reference range in quotient diagrams for FLC-k, it is possible to distinguish inflammatory myelitis from noninflammatory myelopathies. An FLC-k IF >78% can be a hint to suspect myelitis due to MS rather than NMOSD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: Oligoclonal band (OCB) determination in cerebrospinal fluid (CSF) is the gold standard to detect intrathecal inflammation. However, there is uncertainty about the significance of one isolated band in CSF. Free light chains kappa (FLC-k) are gaining interest as a complementary method to detect intrathecal inflammation. The aim of this study was to investigate the performance of an additive measurement of FLC-k in patients with one isolated band in CSF., Materials & Methods: FLC-k were analyzed using the nephelometric Siemens FLC-k kit in paired samples of CSF and sera (n = 56) in patients with one isolated band in isoelectric focusing. According to medical diagnosis, samples were subdivided in inflammatory neurological disease, non-inflammatory neurological disease controls and symptomatic controls. Intrathecal fraction of FLC-k was plotted in a FLC-k quotient diagram. OCB interpretation was done blinded by three experienced raters., Results: Of 6695 OCB analyses, 91 (1.4%) had one isolated band in CSF. After exclusion of patient samples due to unclear OCB pattern after reevaluation and sample availability, 56 patient samples were included in the study. All patients with an inflammatory origin of disease (n = 13) had FLC-k values above the upper discrimination line (Qlim) in the FLC-k quotient diagram, resulting in a sensitivity of 100% with a positive predictive value of 52% and a negative predictive value of 100%. Fourteen patients (36%) with a non-inflammatory origin of disease (n = 39) had FLC-k values above Qlim., Conclusions: In patients with one isolated band in CSF, a lack of intrathecal fraction of FLC-k strongly favors a non-inflammatory orgin of disease. Implementation of FLC-k measurement can help the clinician in the diagnostic process of neurological diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS)., Methods: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes., Results: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p  < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p  < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB., Conclusion: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

Objective: To determine what kappa free light chain (KFLC) metric has the highest capacity to separate healthy patients from patients with MS, we evaluated the sensitivity, specificity, and the overall diagnostic accuracy of 4 different KFLC metrics. To assess the usefulness of KFLC in the diagnostics of MS, we compared the different KFLC metrics with oligoclonal bands (OCBs), the current gold standard biochemical method to demonstrate intrathecal antibody production., Methods: CSF and plasma were collected from patients with confirmed or suspected MS, other neurological diseases, as well as symptomatic and healthy controls between May 2017 and May 2018 (n = 335) at the Department of Neurology, Karolinska University Hospital, as part of routine diagnostic workup. KFLC analysis and isoelectric focusing for the detection of oligoclonal bands (OCB) were determined and correlated with diagnosis. Receiver operating characteristic (ROC) curve analysis was used to determine accuracy., Results: OCBs yielded a sensitivity of 87% and a specificity of 100%. All KFLC metrics showed a high sensitivity (89%-95%) and specificity (95%-100%). Using the optimal cutoff according to the Youden Index resulted for the KFLC intrathecal fraction in a cutoff of -0.41 with a sensitivity of 95% and a specificity of 97% and for CSF KFLC/CSF albumin with a cutoff of 1.93 × 10 -3 with a sensitivity of 94% and specificity of 100%., Conclusion: All evaluated KFLC metrics have excellent accuracy, and both KFLC intrathecal fraction and CSF KFLC/CSF albumin are at least as good as OCB in separating patients with MS from a control group., Classification of Evidence: This study provides Class III evidence that CSF KFLC accurately distinguishes patients with MS from healthy controls., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB-negative patients with suspected MS., Methods: The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB-negative patients with suspected/possible MS and in 54 OCB-positive patients with MS., Results: The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut-off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB-negative MS (23/92) and in 98% of OCB-positive patients with MS. Using a qualitative approach and a kappa index cut-off of 5.9, based on literature data, we likewise found that 24% of OCB-negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB-negative patients without MS (P < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples., Conclusions: The kappa index could contribute to the identification of OCB-negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index., (© 2019 European Academy of Neurology.)

The polyspecific B-lymphocyte response to neurotropic viruses such as measles (M), rubella (R) and varicella zoster (Z), known as MRZ reaction, is to-date the most specific neurochemical marker for multiple sclerosis (MS). The aim of this study was to investigate a possible association of immunoglobulin (Ig) kappa (κ-) and lambda (λ-) free light chains (FLC) with the presence of the MRZ reaction in multiple sclerosis. Immunoglobulin κ- and λ-FLC, MRZ reaction, oligoclonal IgG bands (OCB), and cerebrospinal fluid (CSF) routine parameters were measured in 65 MS patients. OCB were detected in 97% of MS patients, intrathecal IgG synthesis according to Reiber was detectable in 57%, an elevated IgG index (>0.7) in 66% and the MRZR was positive in 45%. All investigated κ-values (CSF κFLC, CSF-serum ratio of κFLCs (QκFLC), and κFLC index (κFLC/QAlbumin)) were significantly higher in patients with positive MRZ reaction as compared to MRZ negative MS patients. In contrast, λ-values showed no significant differences. Additionally to the putative diagnostic sensitivity and prognostic value of κFLC, the association of κFLC with a highly specific neurochemical marker for MS - the MRZ reaction, especially the determination of κFLCs is an informative tool to assess the B-cell response and determine its extent in MS patients., (Copyright © 2019. Published by Elsevier B.V.)

Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) have been suggested as quantitative alternative to oligoclonal bands (OB) in multiple sclerosis (MS) diagnosis. Despite OB have been associated to poor disease prognosis, little is known on KFLC in predicting MS early progression. Our aim is to evaluate the prognostic value of KFLC in a cohort of Italian MS patients., Methods: 100 patients (64 females) underwent CSF analysis during their diagnostic MS work-up. We collected clinical/paraclinical features (gender, age at onset, clinical course, early MS treatments (within 1 year), gadolinium-enhancing (Gd+) lesions), calculated K index (ratio CSF-serum KFLC and albumin), and MS severity score (MSSS) at last follow up (minimum 1 year). Statistical analysis included Mann-Whitney descriptive analysis, Spearman correlation for independent samples, and linear regression for significant predictors., Results: K index resulted a significant predictor for disability over time being higher in patients who developed greater MSSS. Accordingly, K index was also significantly increased in patients undergoing early versus delayed treatment (N = 50/100, p = 0.046). A similar role in predicting MS disability was confirmed for age at onset. No other factors were retained in our regression model. Of note, K index was not associated to known MS prognostic markers such as gender, age at onset, and Gd+ lesions (N = 31/96)., Conclusion: Our study suggests KFLC as a CSF quantitative marker to predict early disability in MS (despite not being a substitute for OB)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The importance of immunoglobulin G (IgG) oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS) was reaffirmed again in the recently revised MS diagnostic criteria. Since OCB testing is based on non-quantitative techniques and demands considerable methodological experience, measurement of CSF immunoglobulin free light chains (FLC) has been suggested as quantitative alternative to OCB. We aimed to establish reference values for FLC measures and evaluate their diagnostic accuracy with regard to the diagnosis of MS. Methods: Immunoglobulin kappa (KFLC) and lambda (LFLC) free light chains were prospectively measured by nephelometry in CSF and serum sample pairs in 1,224 patients. The analyzed cohort included patients with MS, other autoimmune or infectious inflammatory diseases of the nervous system as well as 989 patients without signs for nervous system inflammation. Results: Regarding diagnosis of MS, the diagnostic sensitivity and specificity of intrathecal KFLC ratio were 93.3 and 93.7% using the CSF-serum albumin ratio-dependent reference values, 92.0 and 95.9% for intrathecal KFLC ratio applying the ROC-curve determined cut-off levels, 62.7 and 98.3% for IgG index, 64.0 and 98.8% for intrathecal IgG synthesis according to Reiber diagrams, and 94.7 and 93.3% for OCB. Diagnostic sensitivity and specificity of intrathecal LFLC were clearly lower than KFLC. Conclusions: Intrathecal KFLC and OCB showed the highest diagnostic sensitivities for MS. However, specificity was slightly lower compared to other quantitative IgG parameters. Consequently, CSF FLC may not replace OCB, but it may support diagnosis in MS as a quantitative parameter.

Background: Detection of cerebrospinal fluid (CSF) specific oligoclonal bands (OCB) supports the diagnosis of multiple sclerosis (MS), but the method is technically demanding and gives only qualitative information. Kappa free light chains (KFLC) quantification could represent a convenient alternative. We evaluated the diagnostic accuracy of OCB and KFLC in our cohort to further estimate the gain in diagnostic performance when combining both of them., Methods: KFLC were measured in paired serum and CSF samples of 80 patients with MS and 50 patients with non-inflammatory neurological disorders. OCB were detected using an in-house alkaline phosphatase assay. Likelihood ratio (LR) was used to explore the benefit of the combined KFLC and OCB test., Results: Sensitivity of KFLC index (≥5.3) and intrathecal KFLC fraction (≥10%) was 96% and 95% respectively, compared to 91% sensitivity of OCB assay. Specificity was 96% for intrathecal KFLC synthesis and 98% for OCB. Probability of MS in the absence of OCB was further reduced with concurrently normal KFLC index., Conclusions: Normal KFLC parameters allow confident exclusion of intrathecal inflammation, but probability of MS is greater with positive OCB. Use of KFLC as an adjunct test might be beneficial in specialized MS centers with larger pretest probability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The objective was to evaluate the precision of kappa and lambda free light chains (KFLC and LFLC) in CSF for the diagnosis of multiple sclerosis (MS) and prognosis of clinically isolated syndrome (CIS)., Methods: CSF and serum samples from CIS, MS and other neurological non-MS disease were collected between 2015 and 2017. FLC concentrations were measured using immunoassay Freelite™. Results were correlated with the patients' diagnoses and ROC curve analysis was used to determine accuracy. In CIS patients, analysis of FLC were compared in CIS converters vs. non-converter during follow-up., Results: In the MS group (n = 41), the optimal cut-off for KFLC determined was 7 mg/L, with a diagnostic sensitivity and specificity of 95% and 97%, respectively. The optimal cut-off for LFLC was 0.7 mg/L, with a diagnostic sensitivity and specificity of 71% and 81%, respectively. 36 CIS patients were included; mean follow-up time was 28 ± 9 months, and 22 (61.1%) patients converted to MS. The median concentration of CSF K and LFLCs at CIS diagnosis was slightly higher in CIS-converters compared to non-converters, but this did not reach statistical significance (KFLC: median 7 ± 5.3 mg/L vs. 5 ± 2.3 mg/L, p = 0.11; LFLC 0.7 ± 0.33 mg/L vs. 0.5 ± 0.23 mg/L p = 0.16). A strong correlation was observed between the concentration of K and L FLCs at diagnosis and the change in PBVC during follow-up (r = 0.72 and r = 0.65, respectively)., Conclusion: KFLCs have a high sensitivity and specificity for the diagnosis of MS. FLC concentrations at CIS diagnosis were not significantly higher in CIS-converters.

The latest revision of the McDonald criteria of 2017 considers the evidence of an intrathecal immunoglobulin (IgG) synthesis as a diagnostic criterion for dissemination in time in multiple sclerosis. While the detection of oligoclonal bands is considered as the gold standard, determination of kappa free light chains might be a promising tool as a less technically demanding and cost saving method. However, data on the direct comparison between kappa free light chains and oligoclonal bands are limited and no study to date has used the highly sensitive method of polyacrylamide gels with consecutive silver staining for the demonstration of oligoclonal bands. Furthermore, the impact of the revised McDonald criteria of 2017 on the role of kappa free light chains as a biomarker has not been investigated. Nephelometry was used to determine kappa free light chains in cerebrospinal fluid (CSF) and serum from 149 patients with their first demyelinating event between 2010 and 2015. Clinical data, kappa free light chains, and oligoclonal band status were compared at the time of initial diagnosis and after follow-up to identify converters from clinically isolated syndrome to multiple sclerosis. An elevated kappa free light chain index (>5.9) was found in 79/83 patients (95%) with multiple sclerosis diagnosed at baseline, slightly less frequent than oligoclonal bands (98.8%). 18/25 (72%) patients who converted from clinically isolated syndrome to multiple sclerosis showed an elevated kappa free light chain index compared to 20/25 (80%) patients with positive oligoclonal bands. In patients with stable clinically isolated syndrome 7/41 (17%) displayed an elevated kappa free light chain index against 11/41 (27%) oligoclonal band positive patients. Only two patients with stable clinically isolated syndrome showed an elevated kappa free light chain index but were oligoclonal bands negative. In conclusion, determination of the kappa free light chain index is a promising diagnostic approach to assess intrathecal immunoglobulin synthesis in multiple sclerosis. Nevertheless, oligoclonal bands are highly prevalent in multiple sclerosis and can detect an intrathecal synthesis of IgG even when the kappa free light chain index is below the threshold. We consider sequential use of both methods as reasonable.

Objectives: The detection of cerebrospinal fluid (CSF)-specific IgG oligoclonal bands (OCB) by isoelectric focusing (IEF) is widely used to help diagnose inflammatory neurological disorders (IND), including multiple sclerosis. However, the quantification of free light chains (FLC) is increasingly evaluated as a surrogate method to determine the presence of an intrathecal inflammatory process. The objective of this study was to evaluate the diagnostic performance of kappa (κ) FLC measurement in comparison with OCB detection by IEF., Material and Methods: We measured serum and CSF κFLCs by turbidimetry using the SPA plus automated analyser and calculated the κ index in 142 samples from OCB-positive and negative MS, as well as from patients with inflammatory and non-inflammatory neurological disorders (IND and NIND)., Results: The κFLC index was significantly increased in OCB-positive MS and IND patients versus OCB-negative patients. Its performance was relatively comparable to that of IEF for MS diagnosis. When using a κFLC index cutoff value of 6.29, sensitivity increased from 61.2% to 75.7% in comparison with IEF for diagnosing IND (P = .0051), with a slightly lower non-statistically significant specificity (82.1% vs 100%). When considering both OCB status positivity or a κFLC index superior to 6.29 to diagnose IND status, sensitivity raised to 80.6% (P < .05) with an equal specificity., Conclusion: Our results demonstrate that the κFLC index does not discriminate MS from other IND patients, but is a reliable technique to detect intrathecal inflammation. However, κFLC quantification should probably be considered as a complementary method, rather than a substitute, to OCB detection., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Purpose: The gold standard for detection of intrathecal immunoglobulin synthesis is the measurement of oligoclonal bands (OCB). In the diagnosis of multiple sclerosis, the kappa free light chains (KFLC) index has a similar sensitivity and specificity as OCB. This study investigated whether determination of the KFLC index could be used to predict the presence of OCB., Methods: The KFLC index was determined prospectively from 295 paired serum and cerebrospinal fluid samples. KFLC were determined by nephelometry using the N Latex FLC kappa kit (Siemens Healthcare Diagnostics Products GmbH) on the BN Prospec analyzer (Siemens Healthcare Diagnostics Products GmbH) (cohort I). A cut-off value was determined using receiver operating characteristic analysis in relation to OCB positivity. These results were validated prospectively in 96 samples (cohort II) as well as retrospectively in samples of 46 patients known to be OCB positive (cohort III). We also compared the agreement of two commercially available nephelometric KFLC assays., Results: In cohort I, a KFLC index of 3.61 yielded 100% sensitivity and 88% specificity. Prospective validation of this cut-off value in cohort II showed 92% sensitivity and 96% specificity. In cohort III, a sensitivity of 93% was achieved. Comparison of Siemens and Binding Site (Birmingham, UK) assays revealed good agreement (r 2  = 0.86)., Conclusions: The KFLC index with a cut-off value of 3.61 had high diagnostic accuracy to predict immunoglobulin G synthesis via OCB analysis. Determination of the KFLC index provided a quantitative parameter that could be used as an initial diagnostic step in inflammatory central nervous system disorders before measuring OCB., (© 2018 EAN.)

Background: Free light chains (FLC) have been proposed as diagnostic biomarker in patients with inflammatory central nervous system diseases. The objective of this study was to investigate the diagnostic utility of intrathecal κ- and λ-FLC synthesis in patients with neuroborreliosis., Methods: κ- and λ-FLC were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of 34 patients with neuroborreliosis and compared to a cohort of 420 control patients. κ-FLC index was calculated as [CSF κ-FLC/serum κ-FLC]/[CSF albumin/serum albumin], and λ-FLC index in analogy., Results: κ-FLC and λ-FLC index were significantly elevated in patients with neuroborreliosis compared to the control group. At a specificity level of 95%, κ-FLC and λ-FLC index showed a diagnostic sensitivity of 88.2% and 100%. In comparison, IgM and IgG synthesis according to Reiber formula, IgG index >0.7 and OCB status reached a sensitivity of 83.9%, 44.1%, 58.8% and 64.7%., Conclusion: These findings support the diagnostic value of intrathecal FLC synthesis in neuroborreliosis patients and demonstrate a valid, easy and rater-independent alternative for the detection of an intrathecal immunoglobulin production.

Background: Cerebrospinal fluid (CSF) used in immunoglobulin gamma (IgG) index testing and oligoclonal bands (OCBs) are common laboratory tests used in the diagnosis of multiple sclerosis. The measurement of CSF free light chains (FLC) could pose as an alternative to the labor-intensive isoelectric-focusing (IEF) gels used for OCBs., Methods: A total of 325 residual paired CSF and serum specimens were obtained after physician-ordered OCB IEF testing. CSF kappa (cKFLC) and lambda FLC (cLFLC), albumin and total IgG were measured. Calculations were performed based on combinations of analytes: CSF sum of kappa and lambda ([cKFLC+cLFLC]), kappa-index (K-index) ([cKFLC/sKFLC]/[CSF albumin/serum albumin]), kappa intrathecal fraction (KFLCIF) {([cKFLC/sKFLC]-[0.9358×CSF albumin/serum albumin]^[0.6687×sKFLC]/cKFLC)} and IgG-index ([CSF IgG/CSF albumin]/[serum IgG/serum albumin])., Results: Patients were categorized as: demyelination (n=67), autoimmunity (n=53), non-inflammatory (n=50), inflammation (n=38), degeneration (n=28), peripheral neuropathy (n=24), infection (n=13), cancer (n=11), neuromyelitis optica (n=10) and others (n=31). cKFLC measurement used alone at a cutoff of 0.0611 mg/dL showed >90% agreement to OCBs, similar or better performance than all other calculations, reducing the number of analytes and variables. When cases of demyelinating disease were reviewed, cKFLC measurements showed 86% clinical sensitivity/77% specificity., Conclusions: cKFLC alone demonstrates comparable performance to OCBs along with increased sensitivity for demyelinating diseases. Replacing OCB with cKFLC would alleviate the need for serum and CSF IgG and albumin and calculated conversions. cKFLC can overcome challenges associated with performance, interpretation, and cost of traditional OCBs, reducing costs and maintaining sensitivity and specificity supporting MS diagnosis.

Background: Identifying new biomarkers is needed to overcome the diagnostic difficulties of pediatric multiple sclerosis (MS). Recently, we developed a new technique including CSF analysis of free light chain (FLC) monomers and dimers, which can improve diagnosis of adult MS. The present study has been designed to evaluate the utility of our technique for MS diagnosis in children., Methods: Patients with MS (n=21) and non-MS demyelinating or inflammatory neurological disorders (n=35) participated in the study. MS diagnosis was based on clinical and magnetic resonance imaging (MRI) findings. Western blot analysis was applied to examine FLC in the patients' CSF and serum. FLC indices for FLC monomer and dimer levels and κ/λ ratios were estimated. The samples were also analyzed by oligoclonality test., Results: The study revealed abnormally elevated levels of κ-FLC monomers and dimers in the CSF of 10 MS patients ("κ-type MS"). Increased amounts of λ dimers were found in six MS cases ("λ-type MS"), while high levels of both κ and λ FLC ("mixed type MS") were documented in three MS cases. MRI and clinical assessment showed a more aggressive disease form for the "mixed" and "λ-type" cases. Our method demonstrated higher sensitivity (90.5%) and specificity (91.4%) for discrimination between MS and non-MS patients, as compared to oligoclonality test (81% and 65.7%, respectively)., Conclusions: The proposed method may significantly contribute to diagnosis and prognosis of pediatric MS.