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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.)

Tick-borne encephalitis (TBE) is an acute disease caused by the tick-borne encephalitis virus. Due to the viral nature of the condition, there is no effective causal treatment for full-blown disease. Current and nonspecific TBE treatments only relieve symptoms. Unfortunately, the first phase of TBE is characterized by flu-like symptoms, making diagnosis difficult during this period. The second phase is referred to as the neurological phase as it involves structures in the central nervous system-most commonly the meninges and, in more severe cases, the brain and the spinal cord. Therefore, it is important that early markers of TBE that will guide clinical decision-making and the choice of treatment are established. In this review, we performed an extensive search of literature reports relevant to biomarkers associated with TBE using the MEDLINE/PubMed database. We observed that apart from routinely determined specific immunoglobulins, free light chains may also be useful in the evaluation of intrathecal synthesis in the central nervous system (CNS) during TBEV infection. Moreover, selected metalloproteinases, chemokines, or cytokines appear to play an important role in the pathogenesis of TBE as a consequence of inflammatory reactions and recruitment of white blood cells into the CNS. Furthermore, we reported promising findings on tau protein or Toll-like receptors. It was also observed that some people may be predisposed to TBE. Therefore, to understand the role of selected tick-borne encephalitis biomarkers, we categorized these factors and discussed their potential application in the diagnosis, prognosis, monitoring, or management of TBE.

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.

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.

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.)

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: 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.

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: Cerebrospinal fluid (CSF) immunoglobulin free light chains (FLC) have been suggested as quantitative alternative to oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS). However, little is known on their role in predicting clinical and paraclinical disease progression, particularly in early stages., Objective: To assess the prognostic value of FLC in OCB-positive patients with clinically isolated syndrome (CIS) suggestive of MS and early MS., Methods: We determined FLC kappa (KFLC) and lambda (LFLC) in CSF and serum by nephelometry in 61 patients (CIS ( n = 48), relapsing-remitting multiple sclerosis ( n = 13)) and 60 non-inflammatory neurological controls. Median clinical follow-up time in CIS was 4.8 years (interquartile range (IQR), 1.5-6.5 years). Patients underwent 3T magnetic resonance imaging (MRI) at baseline and follow-up (median time interval, 2.2 years; IQR, 1.0-3.7 years) to determine T2 lesion load (T2LL) and percent brain volume change (PBVC)., Results: CSF FLC were significantly increased in CIS/MS compared to controls (all p < 0.001). A lower KFLC/LFLC CSF ratio was associated with CIS-clinically definite multiple sclerosis (CDMS) conversion (hazard ratio (HR) = 2.89; 95% confidence interval (CI) = 1.17-7.14; p < 0.05). No correlations were found for FLC variables with T2LL or PBVC., Conclusion: Our study confirms increased intrathecal synthesis of FLC in CIS/MS which supports their diagnostic contribution. The KFLC/LFLC CSF ratio appears to have a prognostic value in CIS beyond OCB.

Over the past five years, a number of papers have appeared describing the assay of free immunoglobulin light chains in cerebrospinal fluid to assist in the diagnosis of multiple sclerosis. The assay of kappa free immunoglobulin chains is being advocated as a technically simpler and cheaper quantitative alternative to the qualitative detection of oligoclonal bands. This article reviews the analytical and clinical characteristics of these immunoglobulin free light chain assays and places them in their historical context and possible future developments.

IgG kappa and IgG lambda concentrations were quantified in 96 paired CSF and sera using Hevylite™ antibodies in an in-house developed sandwich ELISA method. In 56 of these samples, the results were compared with a qualitative isoelectric focusing/affinity-mediated immunoblotting assay for oligoclonal IgG kappa and IgG lambda. Normal IgG kappa/lambda ratio in the CSF was the same as in serum. In 19/33 patients with intrathecal oligoclonal IgG synthesis, skewed IgG kappa/lambda ratio was observed (increased in 16 and decreased in 3 cases). The analysis of light chain composition of intrathecally synthesised immunoglobulins could contribute to our understanding of intrathecal humoral immune response, although its diagnostic utility is limited.

Objectives: We aimed to compare various methods for free light chain (fLC) quantitation in cerebrospinal fluid (CSF) and serum and to determine whether quantitative CSF measurements could reliably predict intrathecal fLC synthesis. In addition, we wished to determine the relationship between free kappa and free lambda light chain concentrations in CSF and serum in various disease groups., Methods: We analysed 166 paired CSF and serum samples by at least one of the following methods: turbidimetry (Freelite™, SPAPLUS), nephelometry (N Latex FLC™, BN ProSpec), and two different (commercially available and in-house developed) sandwich ELISAs. The results were compared with oligoclonal fLC detected by affinity-mediated immunoblotting after isoelectric focusing., Results: Although the correlations between quantitative methods were good, both proportional and systematic differences were discerned. However, no major differences were observed in the prediction of positive oligoclonal fLC test. Surprisingly, CSF free kappa/free lambda light chain ratios were lower than those in serum in about 75% of samples with negative oligoclonal fLC test. In about a half of patients with multiple sclerosis and clinically isolated syndrome, profoundly increased free kappa/free lambda light chain ratios were found in the CSF., Conclusions: Our results show that using appropriate method-specific cut-offs, different methods of CSF fLC quantitation can be used for the prediction of intrathecal fLC synthesis. The reason for unexpectedly low free kappa/free lambda light chain ratios in normal CSFs remains to be elucidated. Whereas CSF free kappa light chain concentration is increased in most patients with multiple sclerosis and clinically isolated syndrome, CSF free lambda light chain values show large interindividual variability in these patients and should be investigated further for possible immunopathological and prognostic significance., Competing Interests: Competing Interests: I have read the journal´s policy and the authors of this manuscript have the following competing interests: The Binding Site Company provided Hevylite antibodies and Hevylite diagnostic kits free of charge to the University Hospital Ostrava for research use. These reagents, however, were not used in this study and the provision of these antibodies has no impact on the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All reagents used in this study were purchased under standard pricing conditions. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Recently, serum free light chain (FLC) assays incorporating anti-kappa (κ) and anti-lambda (λ) FLC monoclonal antibodies have become available: N Latex FLC assay (Siemens) and Seralite® (Abingdon Health). The purpose of this review is to provide an overview of these two new monoclonal antibody-based methods. In doing so, the review will outline the performance characteristics of each method, including a summary of: assay principles, antibody specificity, analytical performance and assay performance in disease. Additionally, the review will describe the potential user benefits of adopting these new generation FLC assays, which are designed to overcome the established limitations of existing polyclonal antibody based FLC assays.

Objectives: Clinical trials of IV-rituximab have proved successful. It is unclear whether intrathecal (IT)-rituximab is more efficacious at lower doses. We examine its effects on B-cell biomarkers., Methods: MS patients received IT-rituximab at 3 time-points. CSF and serum samples were obtained at up to 5 time-points (days 0, 7, 14, 56 and 112). Serum and CSF BAFF and CXCL13, and CSF kappa and lambda free light chains (FLC) were measured. Flow cytometry was performed, examining effects on lymphocytes, CD3-19+ and CD3-20+ cells., Results: CSF BAFF fell following rituximab (p=0.0091 absolute values, p=0.0284 change from baseline) whilst serum BAFF increased across time-points 1-4 (p=0.0005 absolute values, p=0.0017 change from baseline). There were significant reductions in CD20+ and CD19+ cells in blood from baseline (p<0.0001) but not in CSF. CSF kappa FLC levels significantly increased (p=0.0480)., Conclusions: BAFF levels fall in CSF but increase in serum following IT-rituximab. Rituximab appears to act peripherally with dramatic decreases in peripheral CD20+ and CD19+ cells. It is likely that CSF B-cell counts were too low to enable differences to be seen. The rapid reduction in B-cells suggests rituximab has immediate effects. The profound depletion of B-cells, despite low doses of rituximab, underlines rituximab's efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The results of free light chains quantitation in the cerebrospinal fluid were recently compared with the presence of cerebrospinal fluid-restricted oligoclonal IgG, but not oligoclonal free kappa light chains and oligoclonal free lambda light chains. We therefore aimed to compare the performance of the quantitative tests with the qualitative one for the same molecule., Methods: Seventy-five paired cerebrospinal fluid and serum samples were analysed for oligoclonal IgG, oligoclonal free kappa light chains and oligoclonal free lambda light chains. Cerebrospinal fluid and serum free kappa and lambda light chains were quantified using Freelite™ kits on SPA Plus analyzer. ROC curves were analysed for the prediction of intrathecal synthesis and compared for cerebrospinal fluid concentration, cerebrospinal fluid/serum quotient (QfLC) and index (QfLC/QAlbumin). The presence of cerebrospinal fluid-restricted oligoclonal free kappa light chains and oligoclonal free lambda light chains bands was used as reference., Results: No statistically significant differences were observed among cerebrospinal fluid concentration, QfLC and index for the prediction of free light chain intrathecal synthesis. Each parameter was able to predict the occurrence of cerebrospinal fluid-restricted oligoclonal free light chain bands (AUCs 0.932-0.999). However, we noted elevated cerebrospinal fluid free light chain concentrations in the absence of cerebrospinal fluid-restricted oligoclonal free light chain bands in two patients with very high serum free light chain values., Conclusions: Quantitation of cerebrospinal fluid free light chains reliably predicts their intrathecal synthesis. Yet, cerebrospinal fluid/serum quotient may still be preferred to correct for high serum free light chain concentrations. An appropriate formula should be sought to correct for blood-cerebrospinal fluid barrier status., (© The Author(s) 2015.)

Background and Objective: In this study, we evaluated the diagnostic and prognostic significance of cerebrospinal fluid free light chains (CSF FLC) at the time of clinically isolated syndrome (CIS)., Methods: We compared FLC-parameters at the moment of CIS in patients with conversion to multiple sclerosis (MS) after 2 years (CIS-MS), patients who remained stable both clinically and radiologically after 2 years (CIS-nonMS), patients with non-inflammatory neurologic diseases (NIND) as a comparison group and patients with other inflammatory neurologic diseases (IND) with intrathecal oligoclonal bands (OCB) synthesis. ROC-analysis was conducted to define FLC-assay characteristics and cut-off values. We also compared FLC-concentrations in CIS patients to determine their OCB-status. A correlation analysis was performed between FLC-concentrations and the expanded disability scale score (EDSS), annualized relapse rate (ARR) and MRI-activity (i.e., number of new and gadolinium-enhancing (Gd+) lesions) in patients., Results: The levels of kappa-FLC (k-FLCCSF) and lambda-FLC (λ-FLCCSF) as well as kappa- and lambda-quotients (Q-k and Q-λ) were elevated in CIS-MS compared to the CIS-nonMS and NIND groups. These levels did not differ significantly when compared with the IND group. We identified several patients with high k-FLCCSF and λ-FLCCSF in OCB-negative CIS and IND groups. The level of k-FLCCSF production was significantly higher in OCB-positive patients in the CIS-MS group compared to the CIS-nonMS group. The concentrations of k-FLCCSF and Q-k in the CIS-MS group showed significant correlation with the level of EDSS after 2 years (k-FLC: r = 0.4477,p = 0.0016; Q-k: r = 0.4621, p = 0.0016). λ-FLCCSF and Q-λ inversely correlated with the number of Gd+ lesions (CSF λ-FLC: r = -0.3698, p = 0.0223; Q-λ: r = -0.4527, p = 0.0056)., Conclusion: The concentration of CSF FLC predicts conversion to MS within 2 years following CIS. OCB-positive patients with an early conversion have a higher concentration of CSF-FLC. We have also shown a prognostic significance of k-FLCCSF for future EDSS-progression.

Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so-called novel anti-MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0.02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted., (© 2013 John Wiley & Sons Ltd.)

In our search of new biomarkers for multiple sclerosis (MS), we aimed to characterize the immunoglobulin (Ig) free light chains (FLC) in patients' cerebrospinal fluid (CSF) and serum, and to evaluate the diagnostic utility of FLC monomer-dimer patterns for MS. FLC were analyzed by Western blotting and mass spectroscopy. CSF and serum samples were examined for the presence of oligoclonal Ig bands by a conventional laboratory test for MS. Three distinct pathological FLC monomer-dimer patterns, typical of MS but not of other neurological diseases, were revealed. In 31 out 56 MS patients the highly increased CSF levels of κ monomers and dimers were demonstrated. In 18 MS patients, the increased κ-FLC levels were accompanied by highly elevated λ dimers. Five MS cases showed no significant elevation in κ-FLC, but they displayed abnormally high λ dimer levels. The intensity of the immunoreactive FLC bands was measured to account for κ and λ monomer and dimer levels and their ratios in the CSF and serum. Combined usage of different FLC parameters allowed the determination of the appropriate FLC threshold values to diagnose MS. The developed method showed higher sensitivity and specificity (96% and 90%, respectively), as compared to those of the conventional OCB test (82% and 70%, respectively). Our study highlights the role of the differential analysis of monomeric and dimeric κ- and λ-FLC for the precise diagnosis of MS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Diagnosis of central nervous system (CNS) lymphoma depends on histopathology of brain biopsies, because no reliable disease marker in the cerebrospinal fluid (CSF) has been identified yet. B-cell lymphomas such as CNS lymphomas are clonally restricted and express either kappa or lambda immunoglobulin light chains. The aim of this study was to find out a potential diagnostic value of free immunoglobulin light chains released into the CSF of CNS lymphoma patients. Kappa (kappa) and lambda (lambda) free immunoglobulin light chains (FLC) were measured in CSF and serum samples collected from 21 patients with primary and secondary CNS lymphomas and 14 control patients with different neurologic disorders. FLC concentrations and ratios were compared between patient groups and were further analyzed in correlation with clinical, cytopathological, and radiological findings. FLC concentrations for all patients were lower in CSF when compared to serum. In patients with CNS lymphoma, the FLC ratios in CSF were higher (range 392-0.3) compared to control patients (range 3.0-0.3). Irrespective of cytopathological proven lymphomatous meningitis, in 11/21 lymphoma CSF samples the FLC ratios were markedly above 3.0 indicating a clonally restricted B-cell population. Increased FLC ratios in CSF were found in those patients showing subependymal lymphoma contact as detected in magnetic resonance imaging. In summary, this is the first report demonstrating that a significant proportion of patients with CNS lymphomas display a markedly increased FLC ratio in the CSF.

Background: So far, an inflammation of the central nervous system (CNS) is diagnosed by immunoglobulin measurement in cerebrospinal fluid (CSF) and serum as well as by determination of the oligoclonal bands. With the free kappa and lambda light chains, new markers to diagnose intrathecal synthesis are available., Methods: In addition to routine diagnostic tests and the assessment of standard parameters, free immunoglobulin light chains were measured in the CSF of patients with neurological disorders., Results: A significant agreement was found between an increase in free kappa light chain CSF serum quotients and results of the currently widely applied method of oligoclonal band measurement for the detection of intrathecal immunoglobulin synthesis. A sensitivity of 95% and 100% specificity for free kappa light chain concentrations at a cut-off of 0.41 mg/l was determined for free kappa light chains compared with oligoclonal bands. However, the free lambda light chains in 20 out of the 110 investigated samples were characterized by inconsistent behaviour. These otherwise unremarkable samples yielded increased CSF quotients, leading to the assumption that free lambda light chains represent a highly sensitive measure of intrathecal immunologlobulin synthesis. Thirteen of the 20 samples described above were obtained from patients with cerebral infarction, 4 samples derived from patients with cerebral paresis (primarily facial paresis), one sample was from a patient with multisystem atrophy and two were obtained from patients with migraine and neuralgia., Conclusion: These findings suggest that the high sensitivity of lambda light chains for the detection intrathecal immunoglobulin synthesis may be of benefit in establishing clinical diagnoses.

Background: Numerous studies have demonstrated elevated kappa free light chains (KFLCs) in CSF of multiple sclerosis (MS) patients. However, so far only small cohorts have been examined, and generally only through qualitative KFLCs analysis. Using a recently developed free light chain (FLC) immunoassay, it is now possible to quantitatively measure KFLCs by automated nephelometry. Our objective was to determine the extent to which KFLC levels in CSF correlated with the diagnosis of MS and CISSMS (clinically isolated syndrome suggestive of MS) compared to oligoclonal banding (OCB) and the immunoglobulin G (IgG) index., Methods: CSF and serum samples from 438 unselected patients, including a MS group of 70 patients (41 MS, 29 CISSMS), were analysed using nephelometry and isoelectric focusing. We then retrospectively correlated results with patients' diagnoses., Results: Of the MS group (n = 70), 67 patients had elevated KFLCs using the KFLC index (> or = 5.9), 64 patients showed OCB and 56 patients presented with an elevated IgG index (> or = 0.6). Sensitivities were 0.96 for the KFLC index, 0.91 for OCB and 0.80 for the IgG index. The specificity of the KFLC index for the MS group (0.86) was lower than that of OCB (0.92) but distinctly higher compared to the IgG index (0.77)., Conclusion: In this study, an elevated KFLC-index represented the most sensitive and specific quantitative diagnostic parameter for MS. As it is measured by automated, routinely available laboratory methods, KFLC quantitation can provide a rapid and reproduceable indication of intrathecal immunological processes supporting current MS diagnostic criteria.

Background: Lymphomatous meningitis (LM) represents a severe complication of malignant lymphomas. While clinical suspicion is raised by symptoms ranging from mild disturbances of sensation to severe pain or impaired consciousness, the definite diagnosis of LM is often difficult to obtain. Since B-cell lymphomas are clonally restricted to express either kappa or lambda immunoglobulin light chain, we hypothesised that analysis of free light chain (FLC) ratios might facilitate the diagnosis of LM., Methods: Kappa and lambda FLC were measured using a novel nephelometric assay in cerebrospinal fluid (CSF) and serum from 17 patients. 5/17 suffered from LM as demonstrated by cytology, immunocytology, and/or imaging procedures., Results: Measurement of FLC concentrations in CSF was achieved for all 17 patients. FLC levels in CSF were lower than serum FLC levels in samples for the same patient obtained at the same time (p < 0.01). CSF and serum FLC concentrations correlated weakly in all patients irrespective of LM status. Significantly more patients with cytopathologically and immunohistochemically proven LM displayed abnormal kappa/lambda FLC ratios in CSF compared to individuals with no LM (p < 0.01)., Conclusion: This is the first report demonstrating that a significant proportion of LM patients display an abnormal kappa/lambda FLC ratio in the CSF.

Oligoclonal free light chains (FLC) banding has been described in multiple sclerosis (MS) and should be correlated with disease activity. However, discrepancies between studies have been reported because of differences in methods. A new quantitative, rapid, and automated method using nephelometry is now available. Our objective was to investigate the interest of this method for the diagnosis and prognosis of MS. For this purpose, FLC index was determined in paired samples of CSF and serum from consecutive and unselected patients from the same department of neurology. We enrolled 89 patients (33 MS, 15 "possible MS", and 41 controls) and correlated with IgG index, IgG oligoclonal banding, and clinical MS progression criteria. The main results were (1) FLC kappa index was more sensitive but less specific than IgG index for the diagnosis of MS, (2) two MS patients were negative for oligoclonal banding but exhibited a positive kappa index, (3) no relation between FLC kappa indices, MS clinical criteria, and disease progression was found. In conclusion, FLC kappa index should be considered as a useful complementary test for MS diagnosis. Its pronostic interest remains to be determined on a larger cohort of possible MS patients.

Although the presence of oligoclonal IgG with abnormal kappa/lambda light-chain ratio in multiple sclerosis (MS) has been known for many years, this finding has not been put to diagnostic use in most routine clinical laboratories. In a retrospective study we report differences in the oligoclonal banding patterns between multiple sclerosis and non-MS patients. We had sufficient cerebrospinal fluid (CSF) on 36 from 71 patients with oligoclonal bands for immunofixation for kappa and lambda light chains, and for free kappa and free lambda. Thirteen out of 14 patients with clinically confirmed MS had predominantly IgG (kappa) banding. In contrast, in seven out of eight patients with diagnoses other than MS the IgG was linked to both kappa and lambda light chains in approximately equal proportions. Nine out of 14 patients with probable/possible/suspected MS showed predominantly IgG (kappa) banding; five others in this group had both IgG (kappa) and IgG (lambda) and free lambda light chains. The finding of IgG (kappa) bands in CSF samples with oligoclonal bands supports a diagnosis of MS.

Cerebrospinal fluid (CSF) free light chains of kappa or lambda (FLC kappa/lambda) type were investigated by affinity mediated blotting technique (AMI) and ELISA in 28 patients of which nine with AIDS and Toxoplasma gondii encephalitis (AIDS, TE), 11 with AIDS with or without other CNS AIDS-related opportunistic infections (non-TE AIDS) and eight control patients with or without inflammatory neurological disorders (control group). CSF restricted oligoclonal FLC bands either of k or lambda isotype or both were found by AMI in 18 (90%) out of 20 AIDS patients, while a CSF pattern predominantly characterized by FkappaLC rather than FlambdaLC was observed in eight (88.8%) out of nine TE patients. No FLC components were detected in the matched sera of TE or non-TE AIDS patients or in the CSF and sera from control group. The anti-parasite-specific FkappaLC CSF/serum mean levels and the T. gondii-specific FkappaLC index values were found by ELISA to be significantly more elevated in TE patients when compared to non-TE AIDS or control group. These findings suggest that the increased production of T. gondii-specific FkappaLC could provide insights into pathogenesis of reactivated TE in immunocompromised patients and may have important diagnostic usefulness.

We report here the case of a patient with the Shy-Drager syndrome and multiple myeloma who had evidence consistent with a central neural autoimmune basis for sympathetic autonomic failure. Autonomic function testing showed no recordable peroneal skeletal muscle sympathoneural traffic, normal arterial norepinephrine (NE) spillover during supine rest and no increment in NE spillover during exposure to lower body negative pressure. The patient's cerebrospinal fluid and serum contained an immunoglobulin G that bound to rat locus ceruleus (LC) in an in vitro test system. The myeloma protein was of the lambda subtype and bound in the rat LC, without binding in the substantia nigra, as demonstrated with anti-lambda antiserum. Since in this case the monoclonal antibody produced by the myeloma bound specifically to LC cells, the results are consistent with the hypothesis that in this patient the Shy-Drager syndrome may have had an immune-mediated basis.

Objectives: To determine the relationship between baseline CSF immunologic abnormalities and MS disease progression; To determine progression rates in an untreated, recently-diagnosed MS sample using several validated clinical measures., Background: CSF immune abnormalities are common in MS but have not been linked to disease progression., Design Methods: Thirty-six patients with definite (n = 28), probable (n = 2), or possible (n = 6) MS were studied prospectively. Baseline CSF was analyzed for free kappa and lambda light chains, myelin basic protein, IgG synthesis rate, and IgG index. MS patients were entered into the study within 5 years of symptom onset and examined semiannually for as long as 53.4 months (median length of follow up 38.9 months). MS progression was defined as sustained worsening on the following clinical measurement instruments: the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI), the 9 Hole Peg Test (9HT) and the Box and Blocks test (BBT). Kaplan-Meier estimates of disease progression were calculated and the relationship between baseline CSF values and disease progression was determined using Cox proportional hazards regression models., Results: By 36 months, 33% (95% CI = 10.3, 55.7) of patients had progressed on EDSS and 49.7% (95% CI = 27.7, 71.7) had progressed on at least one of the outcome measures. Patients with CSF free kappa chain levels in the upper quartile had a significantly higher risk of progression on EDSS (Hazard Ratio 3.78; p = 0.04) and 9HT (Hazard Ratio 10.77, p = 0.04)., Conclusions: In this study, CSF free kappa light chains predicted subsequent physical deterioration in prospectively evaluated MS patients. If this is confirmed by larger studies, then CSF free kappa light chains could serve as a target for intervention in therapeutic trials.

The serum and liquor of 70 patients with multiple sclerosis (MS), 54 patients with other neurological diseases and 20 controls were examined for free light chains (FLC) of immunoglobulins type chi and lambda. The findings were compared to blood-brain barrier competence, liquor pleocytosis, IgG intrathecal synthesis 86% MS patients exhibited high levels of liquor chi-type FLC which appeared early in the disease course irrespectively of MS phase and pattern. Simultaneous high content of lambda-type FLC was reported in 52% of the cases. Patients in need of differential diagnosis were characterized by normal or reduced (in spinocerebellar ataxia) concentrations of FLC except for the conditions with impaired blood-brain barrier.

The first case of a primary and solitary IgA (lambda) producing tumour (possibly a non-Hodgkin's lymphoma) in the CNS is reported. Clinical and neuroimaging findings are described. Early diagnosis without brain biopsy and successful therapy were possible by CSF and serum immunoglobulin analysis which proved local paraprotein production restricted to the CNS.

An unusual complication of chronic lymphocytic leukemia (CLL) is reported. The patient, a 79-year-old man, had a long standing history of CLL, that had been complicated by the development of a Guillain-Barré-like syndrome and a peripheral biclonal gammopathy. The biclonal immunoglobulins identified in the serum were IgM lambda and IgG lambda. The patient's condition progressed and he eventually developed ophthalmologic complications. Cerebrospinal fluid (CSF) obtained during evaluation of his visual dysfunction contained numerous small, mature lymphocytes consistent with the presence of CLL cells in the central nervous system (CNS); immunoperoxidase staining of these cells revealed a monoclonal population. Protein electrophoretic evaluation of the patient's CSF showed a single monoclonal band and immunofixation electrophoresis of the CSF revealed that the immunoglobulin present was IgG lambda. No evidence for the monoclonal IgM paraprotein identified in serum could be appreciated in the CSF by immunofixation. Taken together, these findings strongly implied that there was CNS involvement by the leukemia and this process caused the patient's neurologic symptoms. Furthermore, this study demonstrates that chronic lymphocytic leukemia should also be considered as one of the hematopoietic malignancies associated with monoclonal gammopathies involving the CNS.

The presence of free immunoglobulin light chains (FLCs) in the cerebrospinal fluid (CSF) and sera of patients with human immunodeficiency virus-1 (HIV-1) infection, multiple sclerosis (MS), and neurologically healthy control individuals was investigated by paying special attention to ensure that only truly free light chains would be detected. The FLCs were extracted by specifically binding them to Sepharose-coupled anti-FLC monoclonal antibodies, and thereafter they were electrophoresed and immunoblotted with monoclonal antibodies to both light chain (LC) isotypes. A frequent occurrence of kappa and lambda FLCs was found in both CSF and sera of HIV-1 infected patients. In HIV-1 infection and in MS, the frequency of FLCs of the CSF was equal. In healthy controls, only occasional weak FLCs were observed in either CSF or serum. FLC bands of the CSF from patients with HIV-1 infection tended to be more intensive than those of the appropriately diluted sera. Both intrathecal synthesis of FLCs and their transudation from sera through the impaired blood-brain barrier (BBB) may contribute to this. Increasing severity of general HIV-1 infection was accompanied by an increase of FLC intensity in sera. A qualitative demonstration of FLC in the CSF may be meaningful only in the absence of altered BBB function.

We describe an affinity-mediated capillary blotting technique for the detection of free kappa or lambda light chains in native cerebrospinal fluid (CSF) after isoelectric focusing in agarose gel. Interferences by light chains bound to immunoglobulins were carefully excluded. An absolute amount of 20-50 ng of free kappa or lambda Bence-Jones proteins were detectable by this method, under the form of several discrete bands with isoelectric points between 5 and 8.5. No free light chains were observed in CSF and sera from patients without neurological disorders (n = 26). Such bands were present in most CSF samples in the case of central nervous system (CNS) infections, except in aseptic meningitis. In a group of 48 multiple sclerosis (MS) patients, 44 (92%) displayed oligoclonal free kappa bands restricted to the CSF; oligoclonal IgG bands were observed in 40 cases, and oligoclonal free lambda bands in 33. In this group, the presence of CSF free light chain bands was highly correlated with their absolute levels (p less than 0.001). In other neurological diseases (n = 44), oligoclonal free kappa and free lambda bands were detected much more rarely, in seven (16%) and four (9%) cases respectively. Surprisingly, the CSF from three unrelated patients with Huntington's disease (out of five tested) contained both oligoclonal IgG and free kappa bands.

We measured kappa/lambda light chain ratios of Ig and IgG in 41 serum and 34 cerebrospinal fluid (CSF) samples from 47 patients at different clinical stages of human immunodeficiency virus type 1 (HIV-1) infection and in serum and CSF samples from control subjects. Both ratios were more elevated in HIV-1 seropositive subjects than controls. The elevation was more evident in samples from asymptomatic seropositive patients (ASP) than those from patients with acquired immunodeficiency syndrome (AIDS). In addition, there was a statistically significant elevation of Ig kappa/lambda ratios in ASP CSF compared to serum. We also delineated the light chain composition of oligoclonal IgG bands (OCB) by isoelectric focusing followed by immunofixation in CSF and serum samples from selected ASP and patients with AIDS who had neurological involvement. Five of six AIDS and all seven ASP samples had IgG OCB exclusively or predominantly of the kappa type. Four IgG OCB of the lambda type and one free lambda chain band were seen in CSF from a pediatric AIDS patient. The presence of an abnormally elevated kappa/lambda ratio correlated with the presence of IgG kappa OCB (p less than 0.02). We conclude that HIV-1 infection is associated with a kappa light chain predominance and with OCB mainly composed of kappa light chains.

The kappa/lambda (kappa/lambda) ratios of IgG, IgA and IgM in the cerebrospinal fluid (CSF) and in the sera of 10 patients with Guillain-Barré syndrome were analyzed. The kappa/lambda ratios of IgG, IgA and IgM in the CSF and in the serum were not significantly different between the acute and the late stages of Guillain-Barré syndrome nor between Guillain-Barré syndrome and the normal controls. In the CSF, however, the concentration of albumin, IgG, IgA and IgM in the acute phases of Guillain-Barré syndrome were significantly higher than in the normal controls. These results suggest that in Guillain-Barré syndrome, the increase of immunoglobulins may not be due to intrathecal synthesis and therefore there are no significant changes in the kappa/lambda ratios in the CSF.

Simple, sensitive, and fully standardized solid-phase enzyme-linked competitive binding immunoassays to quantify free kappa and lambda immunoglobulin light chains are described. The assays were developed to measure the concentration of free light chains in cerebrospinal fluid (CSF), in part because elevated levels of free kappa light chains have utility as a diagnostic marker for multiple sclerosis (MS). Polyclonal rabbit antibodies raised against pooled Bence Jones proteins are bound to solid-phase Staphylococcal protein A and used as the primary antisera in this assay. A pool of Bence Jones proteins isolated from the urine of 10 individuals with multiple myeloma are used as a biotin-labeled ligand and to develop a standard curve. The assays as described are sensitive to the low nanogram range and are specific for free kappa or lambda light chains. The assays were found to have acceptable precision, and results correlated highly with concentrations determined using competitive-binding radioimmunoassays previously described.

Using a sensitive new method for detecting oligoclonal immunoglobulin M (IgM) in unconcentrated cerebrospinal fluid (CSF), the intrathecal synthesis of IgM was correlated with that of free light chains in patients with multiple sclerosis, infections of the central nervous system and other neurological conditions. A strong correlation was found between the presence of oligoclonal IgM and that of free light chains in the CSF from patients with multiple sclerosis and infections of the central nervous system. No oligoclonal IgM response was observed in patients with non-inflammatory or non-infectious neurological conditions. This implies that oligoclonal IgM has the same diagnostic significance as free light chains.

Assessment of the presence of immunoglobulin (Ig) of restricted heterogeneity i.e. oligoclonal Ig in cerebrospinal fluid subjected to isoelectric focusing (IEF) may be difficult because of the tendency of the technique to subdivide even normal polyclonal IgG into bands and zones. Focused Ig stained by the immunoperoxidase technique for kappa and lambda light chains shows correspondence between the two patterns in the case of normal polyclonal Ig, but a marked discrepancy between kappa and lambda patterns in disorders associated with oligoclonal Ig, and kappa and lambda immunofixation makes assessment of agarose IEF separations of IgG more reliable.

One hundred thirty-two patients were separated into clinically defined groups of definite, probable and possible multiple sclerosis (MS), the spinal cord variant of MS (SCV), and non MS neurologic disease. HLA antigens A3 and B7 occurred at increased frequencies in definite and probably MS patients when compared with neurologic controls and healthy adults. CSF elevations of either kappa/lambda ratio, IgG/total protein ratio, or IgG were seen in 65% of the definite, probable and SCV groups. Patients with HLA A3 and B7 antigens had a higher than predicted incidence of elevated kappa/lambda ratio, suggesting that there may be immunogenetic control mechanisms which influence this CSF parameter. Neither HLA antigens nor CSF protein abnormalities correlated with the age of onset, progression, or degree of disability of disease, thus limiting their prognostic usefulness.

Several immunological parameters, of which the most important are the kappa-lambda ratios, the presence of free light chains and the double ring formation for kappa-chains in single radial immunodiffusion, were investigated in the cerebrospinal fluid and serum of patients affected with different neurological diseases. Parallels were run either with multiple sclerosis or subacute sclerosing panencephalitis. There seems to be a correlation between the frequency of the presence of free light chains and the degree of severity of the immunological process.

22 MS CSFs and 20 control CSFs were studied using an electroimmunofixation (EIF) technique on Cellulose Acetate strips. The oligoclonal gammaglobulin bands on MS CSFs were composed almost exclusively of complete IgG molecules. In a few MS CSFs bands composed of free heavy chains and of free light chains were observed. The bands were very often (93 percent) found to be homogeneous as far as the light chain type was concerned. In such homogeneous bands the light chain type most frequently observed was Kappa (59 percent). In 5 MS cases only Kappa type bands were detected, while a CSF with Lambda type bands only was never observed. On control CSFs, clear cut IgG oligoclonal bands were observed only in a case of subacute sclerosing panencephalitis (SSPE).

The light (L) chain types (kappa and lambda) of oligoclonal IgG bands of matching CSF and serum from 10 MS patients were identified in immunofixation after isoelectric focusing in polyacrylamide gel. Each specimen showed 10-15 oligoclonal bands in pH region of 7.5-9.3. In 7 MS CSF and 5 sera a greater number of oligoclonal IgG bands were of kappa (kappa)-type whereas in 3 CSF and 2 sera the majority was of lambda (lambda)-type. In 3 sera a clearcut correlation of bands with either type of L chain was not observed due to diffuse staining background. Only a small number of oligoclonal IgG bands in 7 of 10 CSF and serum pairs had identical isoelectric points and the same type of L chain. The results show that the individual MS patient had oligoclonal IgG bands in serum, differ with respect to number, isoelectric point and L chain type from the oligoclonal IgG profile seen in the patient's CSF.

The presence of free lambda chain dimers in the CSF of selected patients suffering from subacute sclerosing panencephalitis was proved by use of agar double diffusion and immunoelectrophoresis. The significance of this finding is discussed.

Free kappa and lambda light chains were assayed by particle-counting immunoassay in cerebrospinal fluid (CSF) from patients with various neurological disorders. Detection limits were 25 and 50 ng/ml, respectively. Values of free kappa chain were higher than 50 ng/ml (upper reference limit) in 155 of 191 (81%) multiple sclerosis (MS) patients, in 100 of 168 (60%) patients with central nervous system (CNS) infections but in 41 of 217 (19%) patients with other neurological disorders. Free kappa chains were also assayed in 273 matched sera. The mean concentration in the control group (1.58 micrograms/ml; SD: 0.41) did not differ significantly from those in MS sera (1.63 micrograms/ml; SD: 0.43). The free kappa chain index was increased in 86% of MS patients and in 40% of patients with CNS infections. Regarding free lambda chains, CSF values were higher than 240 ng/ml (upper reference limit) in most neurological disorders (50-100%). However, the use of a lambda chain index increased the specificity of the assay as this index was higher than the upper reference value in 86% of MS patients and in only 23% of patients with infectious diseases. In MS, high levels of free kappa and lambda indices correlated significantly (P less than 0.01) with either the presence of oligoclonal bands or a high IgG index. Local synthesis of free light chains is an additional marker of an ongoing immune response within the CNS, especially in MS.

We investigated the oligoclonal bands (OB) in CSF of patients with multiple sclerosis (MS), Guillain-Barré syndrome (GBS) and aseptic meningitis (AS) using polyacryamide or agarose isoelectric focusing following electroblotting and immunostaining for IgG, IgA, IgM and light chains. OB staining for IgG was detected in 80% of patients with MS, 25% with GBS and 13% with AS. OB staining for IgA and IgM was not detected in any disease. In MS, OB were stained only for the kappa or lambda light chains, which was compatible with OB staining for IgG. These results suggest that in MS, OB are monoclonal because they can be stained for gamma heavy chains and for only one light chains.

The distribution of the kappa and lambda light chains within the cerebrospinal fluid (CSF) IgG oligoclonal bands of 15 multiple sclerosis (MS) and 3 subacute sclerosing panencephalitis (SSPE) patients has been studied by isoelectric focusing (IF) followed by direct immunofixation. The oligoclonal bands demonstrated by IF were both homogeneous and heterogeneous with regard to the light chain type; in the MS patients there was a prevalence of heterogeneous bands and of homogeneous bands of lambda type, while in SSPE a slight prevalence of kappa homogeneous bands was found. The kappa homogeneous bands were preferentially disposed in a more cathodal position in respect to lambda IgG bands; in some cases bands probably constituted only of free light chains of lambda type were found. Finally, in some cases, the oligoclonal IgG pattern was more distinct after immunofixation than after basal IF.

Based on prior reports of free light chains of immunoglobulin G (IgG) in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), we quantitated free kappa and lambda chains and whole IgG concentrations using sensitive and specific radioimmunoassays (RIAs). The RIA for free kappa chains had a sensitivity of 0.25 micrograms/ml and was capable of specifically measuring free kappa chains in whole CSF or serum even in the presence of a 4-log excess of whole IgG. By RIA, free kappa chains were detected in CSF samples from 33 (84%) of 39 MS patients but in only 1 (2.4%) of 42 controls. The control patients included 10 with noninfectious inflammatory diseases and 9 with central nervous system infections. The concentration of free kappa chains in the CSF of the MS patients was 1.40 +/- 1.21 micrograms/ml. Free kappa chains were concentrated in the CSF 71- to 120-fold relative to reference proteins. In contrast, increased levels of free lambda chains or of whole IgG were nonspecific; abnormalities were seen in controls with infections or inflammatory diseases as often as in MS patients. These studies suggest that the measurement of free kappa light chains may have important diagnostic usefulness, since the specificity of the finding for MS appears to be high.

Using antisera against Bence-Jones protein, the concentration of light chains type k and l can be determined in CSF. The calculation of the ratio of type k to type I light chains in CSF represents a sensitive measure for the evaluation of immunological processes involving the CNS. Our results demonstrate that an increase k/l ratio is encountered in 48% of CSF specimen from multiple sclerosis (MS) patients, but also in 50% from patients with other inflammatory diseases involving the CNS, in contrast to only 18% from other neurological diseases. In none of the MS or inflammatory cases is the altered k/l ratio the only indicator of a CNS inflammation, most commonly it is accompanied by an overproportional CSF-IgG elevation (increased QG ratio), an increased cell count or both. For these reasons determination of CSF k/l ratios is helpful in the differentiation of MS and other neurological diseases, but not for the differentiation of other inflammatory CNS diseases from MS.

Based on previous data on free immunoglobulin light chains in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), we evaluated free kappa and lambda light chains in the CSF from 3 patients groups: (a) 42 with MS, (b) 16 with other neurological inflammatory diseases (ONID) and (c) 42 with non inflammatory neurological diseases (NIND) used as control. The kappa and lambda light chains contents were evaluated using a specific and sensitive (0.5 mcg/ml) enzyme linked immunosorbent assay (ELISA). Whole CSF immunoglobulins G (CSF-IgG) concentrations were determined by an immuno-nephelometric method and CSF oligoclonal banding was assessed by agarose gel electrophoresis. Elevated free kappa light chains levels were found in 36 of the 42 (85.7%) MS-CSF, and only in 2 of the 16 (12.5%) ONID-CSF. Moreover, all MS-CSF with oligoclonal banding (21/42) exhibited detectable free kappa light chains. In contrast, elevated free lambda light chains or whole CSF-IgG concentrations were found not so specific. These results suggest that free kappa light chains measurement in MS-CSF may have an important diagnostic usefulness. This assay offers a reliable alternative to other available procedures and may constitute complementary technique in routine investigation of MS-CSF.