scholarly journals Reiber’s Diagram for Kappa Free Light Chains: The New Standard for Assessing Intrathecal Synthesis?

Diagnostics ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 194 ◽  
Author(s):  
Philipp Schwenkenbecher ◽  
Franz Felix Konen ◽  
Ulrich Wurster ◽  
Torsten Witte ◽  
Stefan Gingele ◽  
...  
Keyword(s):  
Linear Function ◽  
Oligoclonal Bands ◽  
Light Chains ◽  
Hyperbolic Function ◽  
Free Light Chains ◽  
Mcdonald Criteria ◽  
Relapsing Multiple Sclerosis ◽  
Automated Determination

Oligoclonal bands are the gold standard for determination of an intrathecal immunoglobulin G synthesis and were recently included in the McDonald criteria of 2017 to diagnose relapsing multiple sclerosis (MS) as a substitute for dissemination in time. Intrathecally produced kappa free light chains (KFLC) are a novel promising biomarker with similar characteristics and the advantage for automated determination. However, different approaches exist to determine the intrathecal KFLC fraction. The most common method is to calculate the CSF/serum KFLC quotient with reference to the albumin CSF/serum quotient (QKappa/QAlb) the so-called KFLC index. Recently, Reiber developed a theoretically and empirically founded hyperbolic function similar to his traditional hyperbolic function for the immunoglobulins A, G, M. Our study included a total of 168 patients with either MS according to the McDonald criteria of 2017, clinically isolated syndrome (CIS) with conversion to MS during follow-up, or stable CIS. Positive oligoclonal bands were compared with the KFLC index, Reiber’s KFLC diagram, Presslauer’s KFLC exponential curve, and Senel’s linear curve for KFLC. Reiber’s diagram detected an intrathecal production of KFLC in 98/100 patients with MS, only one patient fewer than oligoclonal bands positivity (99/100). By using the KFLC index ≥ 5.9, Presslauer’s KFLC exponential function, and Senel’s linear curve two more patients would not have been identified (96/100). For the group of patients who converted from CIS to MS similar results were obtained for both the oligoclonal bands and the Reiber graph (21/24, 88%). The KFLC index ≥ 5.9, Presslauer’s method, and Senel’s linear function each identified two patients fewer (19/24, 79%). In patients with stable CIS, 11/44 patients (25%) displayed oligoclonal bands in contrast to 9/44 patients (20%) with elevated KFLC by using Reiber’s diagram and Presslauer’s method, 8/44 patients (18%) with elevated KFLC as detected by Senel’s linear function, and 7/44 patients (16%) with KFLC index ≥ 5.9. In conclusion, Reiber’s KFLC diagram shows a great diagnostic performance to detect an intrathecal KFLC production in patients with MS.

scholarly journals The Persisting Significance of Oligoclonal Bands in the Dawning Era of Kappa Free Light Chains for the Diagnosis of Multiple Sclerosis

2018 ◽  
Vol 19 (12) ◽  
pp. 3796 ◽  
Author(s):  
Philipp Schwenkenbecher ◽  
Franz Konen ◽  
Ulrich Wurster ◽  
Konstantin Jendretzky ◽  
Stefan Gingele ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Light Chain ◽  
Clinically Isolated Syndrome ◽  
Free Light Chain ◽  
Oligoclonal Bands ◽  
Light Chains ◽  
Oligoclonal Band ◽  
Free Light Chains ◽  
Mcdonald Criteria

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.

New-Onset Gait Difficulty With Kappa Free Light Chains in Cerebrospinal Fluid

2021 ◽  
pp. 42-43
Author(s):  
Maria Alice V. Willrich ◽  
Ruba S. Saadeh
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Magnetic Resonance ◽  
Oligoclonal Bands ◽  
Light Chains ◽  
Resonance Imaging ◽  
Free Light Chains ◽  
Mcdonald Criteria ◽  
T2 Hyperintensity

A 49-year-old woman sought care for a 9-month history of gait difficulty. She was dragging her right foot when walking and could not walk more than 3 blocks because of right leg weakness. Physical examination showed right-sided weakness of hip flexion and foot dorsiflexion and symmetrical hyperreflexia at the knees and ankles. Magnetic resonance imaging of the brain showed multiple foci of T2 hyperintensity throughout the white matter in both cerebral and cerebellar hemispheres, predominantly in a periventricular distribution. Several small enhancing lesions and mild generalized cerebral volume loss were seen. The appearance and distribution were consistent with a demyelinating process such as multiple sclerosis. Magnetic resonance imaging of the cervical and thoracic spine showed multiple small T2 hyperintensities, including 1 enhancing lesion in the cervical spinal cord. Oligoclonal bands were positive, with 11 unique bands in the cerebrospinal fluid. The concentration of cerebrospinal fluid kappa free light chains was increased, at 0.314 mg/dL. The patient was diagnosed with relapsing-remitting multiple sclerosis. A 5-day course of intravenous corticosteroids was started, after which she noted clinical improvement. At her last follow-up 2 years after initial evaluation, the patient has been stable with no new clinical multiple sclerosis episodes and stable magnetic resonance imaging disease burden with no new lesions. The diagnosis of multiple sclerosis incorporates clinical, imaging, and laboratory evidence. The 2017 revised McDonald criteria state that a finding of cerebrospinal fluid -specific oligoclonal bands can replace the criterion for dissemination in time to make a diagnosis of definitive multiple sclerosis. The standard test for oligoclonal bands is performed using isoelectric focusing electrophoresis and takes more than 3 hours to complete. The case patient had 11 unique cerebrospinal fluid bands. The number of bands is not correlated with disease severity or prognosis.

Prognostic value of free light chains lambda and kappa in early multiple sclerosis

2016 ◽  
Vol 23 (11) ◽  
pp. 1496-1505 ◽  
Author(s):  
Margarete M Voortman ◽  
Tatjana Stojakovic ◽  
Lukas Pirpamer ◽  
Margit Jehna ◽  
Christian Langkammer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Prognostic Value ◽  
Oligoclonal Bands ◽  
Light Chains ◽  
Time Interval ◽  
Free Light Chains ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Remitting Multiple Sclerosis ◽  
In Cis

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.

Impact of Novel M-Component Based Biomarkers On to Progression Free Survival After Treatment in Intact Immunoglobulin Multiple Myeloma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2927-2927
Author(s):  
Efstathios Koulieris ◽  
Dimitrios Maltezas ◽  
Nikolaou Eytychia ◽  
Vassiliki Bartzis ◽  
Tatianna Tzenou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Binding Site ◽  
Progression Free Survival ◽  
Normal Serum ◽  
Light Chains ◽  
Free Light Chains ◽  
Serum Free ◽  
Depth Of Response ◽  
Serum Free Light Chains

Abstract Abstract 2927 Background and Aims: Multiple Myeloma (MM) is characterized by bone marrow (BM) plasma cell infiltration and the presence of serum/urine monoclonal immunoglobulin (Ig). The depth of response has been associated with longer PFS in MM causing subsequent prolonged survival. Recently novel M-based biomarker immunoassays have been developed (Freelite™, Hevylite™) and their significance in MM diagnosis and prognosis has been demonstrated.1,2 Furthermore serum Free Light Chains (sFLC) are used for better assessment of treatment response, thus patients are considered to achieve stringed Complete Response (sCR) by having CR criteria plus normal serum Free Light Chains Ratio (sFLCR) and absent clonal cells on BM.3 The significance of Hevylite™ on response has not been assessed so far. Patients in nCR or better do not automatically restore their ratio of intact monoclonal Ig/intact polyclonal Ig of the same class (Hevylite™ or HLCR). We therefore investigated the importance of sFLCR and HLCR normalisation at plateau on PFS, in a series of patients with intact Ig MM. Patients and Methods: 50 intact immunoglobulin MM patients were studied from diagnosis to last follow up. Immunofixation was IgG (26 -kappa and 12 –lamdba) and IgA (6 –kappa and 6 -lambda). All patients were symptomatic at diagnosis. Sera samples (n=312) were analyzed for sFLC-kappa and sFLC-lambda with Freelite™ and sFLCR were calculated, and for IgGkappa, IgGlambda IgAkappa, IgAlambda with Hevylite™ and ratios IgGkappa/IgGlambda, IgGlambda/IgGkappa, IgAkappa,/IgAlambda and IgAlambda/IgAkappa (HLCRs) were calculated. sFLCRs and HLCRs values above the 95%-ile of normal individuals were considered abnormal. Statistical analysis was performed using SPSS ver 15.0. File data were reviewed. Results: At diagnosis sFLCR was abnormal in 86% of patients while HLCR was abnormal in all. All treatment lines were initiated according to standard criteria and median lines of therapy were 2 (range 1–11). Median follow up was 33 months (7–145). During patients' cumulative follow-up, 145 lines of therapy were studied and the subsequent responses were estimated. Thirty eight percent of responses were sCR, CR and nCR, 20% PR, 18% MR and 24% refractory and progressive disease. HLCR normalized in 44% of patients with sCR, CR and nCR. The depth of response correlated to PFS and patients in sCR, CR and nCR had longer PFS than the others (p<0.001). Serum FLCR and HLCR normal values at response were both strong parameters of increased PFS after treatment at any line (p=0.035 and p=0.046 respectively). Conclusion: Serum HLCR normalization at plateau reflects prolonged responses in intact Ig MM. Disclosures: Harding: Binding Site: Employment. Bradwell:The Binding Site: shareholder Other.

scholarly journals Free Light Chains and Intrathecal B Cells Activity in Multiple Sclerosis: A Prospective Study and Meta-Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Gabriella Passerini ◽  
Gloria Dalla Costa ◽  
Francesca Sangalli ◽  
Lucia Moiola ◽  
Bruno Colombo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Inflammatory Diseases ◽  
Meta Analysis ◽  
Area Under The Curve ◽  
The Other ◽  
Oligoclonal Bands ◽  
Light Chains ◽  
Free Light Chains ◽  
A Prospective Study

Background. The presence of CSF oligoclonal bands (OBs) is an independent prognostic factor for multiple sclerosis (MS), but the difficulties in the standardization of the test and the interlaboratory variation in reporting have contributed to its limited use in the diagnosis of the disease. Standard nephelometric assays to measure free light chains (FLC) levels have been recently developed and the test may improve the detection of intrathecal B cells activity.Methods. The presence of OBs, kappa and lambda FLC levels, and standard indices of intrathecal inflammation were assessed in 100 consecutive patients, including patients with MS, clinically isolated syndromes (CIS), other inflammatory diseases of the CNS, and other noninflammatory diseases.Results. Both KFLC and LFLC correlated strongly with the presence of OCBs and with all common tests for intrathecal inflammation (p<0.001for all comparisons). KFLC and LFLC were significantly different in patients with MS and CIS compared to the other groups (p<0.001andp<0.001, resp.) and had a better diagnostic accuracy than all the other tests (area under the curve 82.3 % for KFLC index and 79.3 % for LFLC index).Conclusion. Nephelometric assays for KFLC in CSF reliably detect intrathecal immunoglobulin synthesis and discriminate MS patients.

scholarly journals Kappa Free Light Chains and IgG Combined in a Novel Algorithm for the Detection of Multiple Sclerosis

2020 ◽  
Vol 10 (6) ◽  
pp. 324
Author(s):  
Monika Gudowska-Sawczuk ◽  
Joanna Tarasiuk ◽  
Alina Kułakowska ◽  
Jan Kochanowicz ◽  
Barbara Mroczko
Keyword(s):  
Multiple Sclerosis ◽  
Oligoclonal Bands ◽  
Light Chains ◽  
Control Group ◽  
Free Light Chains ◽  
Pattern Type ◽  
Multiple Sclerosis Patients ◽  
Type 3

Background: It is well known that the cerebrospinal fluid (CSF) concentrations of free light chains (FLC) and immunoglobulin G (IgG) are elevated in multiple sclerosis patients (MS). Therefore, in this study we aimed to develop a model based on the concentrations of free light chains and IgG to predict multiple sclerosis. We tried to evaluate the diagnostic usefulness of the novel κIgG index and λIgG index, here presented for the first time, and compare them with the κFLC index and the λFLC index in multiple sclerosis patients. Methods: CSF and serum samples were obtained from 76 subjects who underwent lumbar puncture for diagnostic purposes and, as a result, were divided into two groups: patients with multiple sclerosis (n = 34) and patients with other neurological disorders (control group; n = 42). The samples were analyzed using turbidimetry and isoelectric focusing. The κIgG index, λIgG index, κFLC index, and λFLC index were calculated using specific formulas. Results: The concentrations of CSF κFLC, CSF λFLC, and serum κFLC and the values of κFLC index, λFLC index, and κIgG index were significantly higher in patients with multiple sclerosis compared to controls. CSF κFLC concentration and the values of κFLC index, λFLC index, and κIgG index differed in patients depending on their pattern type of oligoclonal bands. κFLC concentration was significantly higher in patients with pattern type 2 and type 3 in comparison to those with pattern type 1 and type 4. The κFLC index, λFLC index, and κIgG index were significantly higher in patients with pattern type 2 in comparison to those with pattern type 4. The κFLC index and κIgG index were significantly higher in patients with pattern type 2 in comparison to those with pattern type 1, and in patients with pattern type 3 compared to those with pattern type 4. The κIgG index was markedly elevated in patients with pattern type 3 compared to those with pattern type 1. In the total study group, κFLC, λFLC, κFLC index, λFLC index, κIgG index, and λIgG index correlated with each other. The κIgG index showed the highest diagnostic power (area under the curve, AUC) in the detection of multiple sclerosis. The κFLC index and κIgG index showed the highest diagnostic sensitivity, and the κIgG index presented the highest ability to exclude multiple sclerosis. Conclusion: This study provides novel information about the diagnostic significance of four markers combined in the κIgG index. More investigations in larger study groups are needed to confirm that the κIgG index can reflect the intrathecal synthesis of immunoglobulins and may improve the diagnosis of multiple sclerosis.

Free light chains and heavy/light chains pairs assay in diagnostics of multiple myeloma and other diseases related to plasmatic cells dyscrasias

2017 ◽  
Vol 53 (1) ◽  
pp. 41-46
Author(s):  
Ewelina Kudyba ◽  
Tomasz Wróbel
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Protein Electrophoresis ◽  
Light Chains ◽  
Free Light Chains ◽  
Heavy Chains ◽  
Plasma Cell Neoplasms ◽  
Single Clone ◽  
Minimal Residual

Plasma cell neoplasms constitute a large group of diseases characterized by uncontrolled proliferation of a single clone of plasmocytes and production of monoclonal protein which may be present in patient’s serum in the form of intact immunoglobulins, free light immunoglobulin chains, or both of these molecules simultaneously. In addition to the methods commonly used for years for the determination of the protein such as protein electrophoresis or immunofixation, clinical standards in the last decade included the test for determining the concentration of κ and λ free light chains in serum. The test profile mentioned above has been complemented by a new method for identifying and determining the concentration of immunoglobulins with the possibility of recognizing the binding between pairs of heavy chains γ, α, μ and κ or λ light chains of immunoglobulins. It gives the opportunity to differentiate separately Ig’κ and Ig’λ molecules in each immunoglobulin class. Quantification of these sensitive and specific markers is used for the early diagnosis of the disease and it also provides the ability to accurately monitor the treatment, evaluate minimal residual disease and detect early the recurrence of monoclonal gammopathy like multiple myeloma.

Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2900-2902 ◽  
Author(s):  
Mark Drayson ◽  
Lian X. Tang ◽  
Roger Drew ◽  
Graham P. Mead ◽  
Hugh Carr-Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Activity ◽  
Light Chain ◽  
Free Light Chain ◽  
Light Chains ◽  
Free Light Chains ◽  
Serum Free ◽  
Serum Free Light Chain

Abstract Using sensitive, automated immunoassays, increased concentrations of either κ or λ free light chains (and abnormal κ/λ ratios) were detected in the sera of 19 of 28 patients with nonsecretory multiple myeloma. Four other patients had suppression of one or both light chains, and the remaining 5 sera had normal or raised free light-chain concentrations with substantially normal κ/λ ratios. Six of the patients with an elevated single free light chain, who were studied during follow-up, had changes in disease activity that were reflected by the changes in free light-chain concentrations. It is concluded that quantification of free light chains in serum should prove useful for the diagnosis and monitoring of many patients with nonsecretory myeloma.

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