Clinical Use of κ Free Light Chains Index as a Screening Test for Multiple Sclerosis

Abstract Objective To assess the usefulness of the κ free light chain index (κFLCi) as a screening test to identify patients with suspected MS. Methods The study included 56 patients with a request to test for oligoclonal bands (OCBs). OCBs were detected by isoelectric focusing, followed by immunofixation. Cerebrospinal fluid (CSF) and serum κFLC were measured by a turbidimetric assay. Also, the κFLC index (κFLCi) was calculated. Results CSF κFLC levels and κFLCi were significantly higher in patients with multiple sclerosis (MS) than in patients with other neurological diseases (NDs; P < .001 and P < .001, respectively). At the cutoff value of 2.9, the κFLCi detected MS with sensitivity of 97% and specificity of 65%. Overall, 92% patients with κFLCi of 2.9 or greater and who had tested positive for OCBs were diagnosed as having MS. Conclusion Our findings support the use of κFLCi as a screening test when MS is suspected, followed by OCB detection as a confirmatory test for the diagnosis of MS.

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Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: A multicenter study

Multiple Sclerosis Journal ◽

10.1177/1352458515594044 ◽

2015 ◽

Vol 22 (4) ◽

pp. 502-510 ◽

Cited By ~ 46

Author(s):

Stefan Presslauer ◽

Dejan Milosavljevic ◽

Wolfgang Huebl ◽

Fahmy Aboulenein-Djamshidian ◽

Walter Krugluger ◽

...

Keyword(s):

Multiple Sclerosis ◽

Multicenter Study ◽

Neurological Diseases ◽

Diagnostic Value ◽

Clinically Isolated Syndrome ◽

Oligoclonal Bands ◽

Light Chains ◽

Diagnostic Biomarker ◽

Free Light Chains ◽

Igg Synthesis

Background: Kappa free light chains (KFLCs) have been proposed as a diagnostic biomarker in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). Objective: The objective of this paper is to validate the diagnostic accuracy of intrathecal KFLC synthesis in a multicenter study. Methods: KFLCs were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of patients with CIS ( n = 60), MS ( n = 60) and other neurological diseases ( n = 60) from four different MS centers. The upper normal limit for intrathecal KFLC concentrations depending on blood-CSF barrier function was previously calculated in a cohort of 420 control patients. Results: Diagnostic sensitivity of intrathecal KFLC synthesis, IgG synthesis according to Reiber, IgG index and oligoclonal bands (OCBs) was 95%, 72%, 73% and 93% in patients with MS and 82%, 47%, 43% and 72% in patients with CIS. Specificity of intrathecal KFLC synthesis was 95% and 98% for all other measures. Conclusion: These findings further support the diagnostic value of intrathecal KFLC synthesis in CIS and MS patients and demonstrate a valid, easier and rater-independent alternative to OCB detection.

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The contribute of cerebrospinal fluid free light-chain assay in the diagnosis of multiple sclerosis and other neurological diseases in an Italian multicenter study

Multiple Sclerosis Journal ◽

10.1177/13524585211064121 ◽

2021 ◽

pp. 135245852110641

Author(s):

Gaetano Bernardi ◽

Tiziana Biagioli ◽

Paola Malpassi ◽

Teresa De Michele ◽

Domizia Vecchio ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Neurological Disorders ◽

Operating Characteristic ◽

Neurological Diseases ◽

Characteristic Curve ◽

Oligoclonal Bands ◽

Free Light Chains ◽

Complementary Information ◽

Combined Use

Background: Cerebrospinal fluid (CSF) free light chains (FLCs) can be an alternative assay to oligoclonal bands (OCBs) in inflammatory neurological disorders, but threshold has no consensus. Objective: To assess the diagnostic accuracy of CSF FLCs in multiple sclerosis (MS) and other neurological diseases. Methods: A total of 406 patients from five Italian centers. FLCs were measured in CSF and serum using Freelite MX assays on Optilite. Results: A total of 171 patients were diagnosed as MS, 154 non-inflammatory neurological diseases, 48 inflammatory central nervous system (CNS) diseases, and 33 peripheral neurological diseases. Both kFLC and λFLC indices were significantly higher in patients with MS compared to other groups ( p < 0.0001). The kFLC index ⩾ 6.4 is comparable to OCB for MS diagnosis (area under the receiver operating characteristic curve (AUC) = 0.876; sensitivity 83.6% vs 84.2%; specificity 88.5% vs 90.6%). λFLC index ⩾ 5 showed an AUC of 0.616, sensitivity of 33.3% and specificity of 90.6%. In all, 12/27 (44.4%) MS patients with negative OCB had kFLC index ⩾ 6.4. Interestingly, 37.5% of 24 patients with a single CSF IgG band showed high kFLC index and 12.5% positive λFLC index. Conclusion: Our findings support the diagnostic utility of FLC indices in MS and other CNS inflammatory disorders, suggesting a combined use of FLC and OCB to help clinicians with complementary information.

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

Multiple Sclerosis International ◽

10.1155/2016/2303857 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 4

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.

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

Brain Sciences ◽

10.3390/brainsci10060324 ◽

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.

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

10.1093/med/9780197583425.003.0013 ◽

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.

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Application of κ free light chains in cerebrospinal fluid as a biomarker in multiple sclerosis diagnosis: development of a diagnosis algorithm

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0285 ◽

2018 ◽

Vol 56 (4) ◽

pp. 609-613 ◽

Cited By ~ 13

Author(s):

Estefania Valencia-Vera ◽

Ana Martinez-Escribano Garcia-Ripoll ◽

Alfredo Enguix ◽

Carmen Abalos-Garcia ◽

Maria Jesus Segovia-Cuevas

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

High Sensitivity ◽

Demyelinating Diseases ◽

Oligoclonal Bands ◽

Light Chains ◽

Moderate Increase ◽

Free Light Chains ◽

Cross Sectional ◽

Significant Difference

Abstract Background: The determination of κ free light chains (KFLC) in cerebrospinal fluid (CSF) by nephelometry is a feasible alternative to immunoglobulin G oligoclonal bands (OCB) in the evaluation of intrathecal synthesis of immunoglobulin in multiple sclerosis (MS) and other demyelinating diseases. The aim of this study was to assess the diagnostic value of KFLC and its inclusion in a procedure algorithm along with OCB interpretation. Methods: A cross-sectional study, which included 123 patients with a CSF OCB request, was carried out. Isoelectric focusing followed by immunofixation was used to detect OCB, and nephelometry was used to analyze KFLC. The KFLC index was calculated using CSF/serum quotient of KFLC and albumin. The KFLC index was compared with MS diagnosis to find the optimal cutoff. It was obtained from the receiver operating characteristic (ROC) curves and the Youden method. Results: The CSF KFLC median was 1.66 mg/L in the MS group, whereas in other central nervous system diseases, KFLC showed generally no or only moderate increase in CSF (median 0.10 mg/L). KFLC index showed a significant difference between groups. ROC analysis for CSF KFLC concentration, and KFLC indexes were 91.88% and 93.94%, respectively. The best cutoff for the KFLC index was 2.91 for MS diagnosis (sensitivity: 83.78%; specificity: 85.88%). The proposed algorithm showed high sensitivity (89.19%) and specificity (84.71%). Conclusions: KFLC determination is rapid and automatized, but it has no higher sensitivity and specificity than OCB in MS diagnosis. Nevertheless, when used in screening, it could reduce the number of manual OCB tests.

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Cerebrospinal fluid free light chains determination in oligoclonal bands negative patients with suspected multiple sclerosis

Clinica Chimica Acta ◽

10.1016/j.cca.2019.03.1291 ◽

2019 ◽

Vol 493 ◽

pp. S616-S617

Author(s):

D. Ferraro ◽

P. Natali ◽

A. Trovati ◽

R. Bedin ◽

F. Vitetta ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Oligoclonal Bands ◽

Light Chains ◽

Free Light Chains

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Cerebrospinal fluid free light chains compared to oligoclonal bands as biomarkers in multiple sclerosis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2019.577108 ◽

2020 ◽

Vol 339 ◽

pp. 577108 ◽

Cited By ~ 4

Author(s):

Lorenzo Gaetani ◽

Marinella Di Carlo ◽

Giovanni Brachelente ◽

Federico Valletta ◽

Paolo Eusebi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Oligoclonal Bands ◽

Light Chains ◽

Free Light Chains

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

International Journal of Molecular Sciences ◽

10.3390/ijms19123796 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3796 ◽

Cited By ~ 12

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.

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Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-1300 ◽

2019 ◽

Vol 57 (10) ◽

pp. 1574-1586

Author(s):

Harald Hegen ◽

Janette Walde ◽

Dejan Milosavljevic ◽

Fahmy Aboulenein-Djamshidian ◽

Makbule Senel ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Diagnostic Performance ◽

Neurological Diseases ◽

Diagnostic Value ◽

Oligoclonal Bands ◽

Light Chains ◽

Control Group ◽

Free Light Chains ◽

Diagnostic Biomarkers ◽

Reference Limit

Abstract Background Free light chains (FLC) have been proposed as diagnostic biomarkers in the cerebrospinal fluid (CSF) of patients with inflammatory central nervous system (CNS) diseases. However, which method to use for determining an intrathecal FLC synthesis has not yet been clarified. The objective of this study was to compare the diagnostic performance of CSF FLC concentration, FLC quotient (QFLC), FLC index and FLC intrathecal fraction (FLCIF). Methods κ- and λ-FLC were measured by nephelometry under blinded conditions in CSF and serum sample pairs of patients with clinically isolated syndrome (CIS; n = 60), multiple sclerosis (MS; n = 60) and other neurological diseases (n = 60) from four different MS centers. QFLC was calculated as the ratio of CSF/serum FLC concentration, the FLC index as QFLC/albumin quotient and the percentage FLCIF by comparing QFLC to a previously empirically determined, albumin quotient-dependent reference limit. Results CSF FLC concentration, QFLC, FLC index and FLCIF of both the κ- and λ-isotype were significantly higher in patients with CIS and MS than in the control group, as well as in oligoclonal bands (OCB) positive than in OCB negative patients. Each parameter was able to identify MS/CIS patients and OCB positivity, however, diagnostic performance determined by receiver operating characteristic (ROC) analyses differed and revealed superiority of FLC index and FLCIF. Conclusions These findings support the diagnostic value of FLC measures that correct for serum FLC levels and albumin quotient, i.e. blood-CSF barrier function.

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