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

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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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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Kappa Index versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders

Diagnostics ◽

10.3390/diagnostics10100856 ◽

2020 ◽

Vol 10 (10) ◽

pp. 856

Author(s):

Diana Ferraro ◽

Roberta Bedin ◽

Patrizia Natali ◽

Diego Franciotta ◽

Krzysztof Smolik ◽

...

Keyword(s):

Multiple Sclerosis ◽

Oligoclonal Bands ◽

Inflammatory Disorder ◽

Kappa Index ◽

Free Light Chains ◽

Complementary Information ◽

Albumin Ratio ◽

Oligoclonal Igg ◽

Csf Oligoclonal Bands ◽

Oligoclonal Igg Bands

Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID). Methods: We enrolled patients who underwent a diagnostic spinal tap throughout two years. KFLC levels were determined using a Freelite assay (Binding Site) and the turbidimetric Optilite analyzer. Results: Of 540 included patients, 223 had a CNSID, and 84 had MS. The kappa index was more sensitive (0.89 versus 0.85) and less specific (0.84 versus 0.89), with the same AUC (0.87) as OCB for MS diagnosis (optimal cut-off: 6.2). Adding patients with a single CSF IgG band to the OCB-positive group slightly increased the AUC (0.88). Likewise, the kappa index (cut-off: 3.9) was more sensitive (0.67 versus 0.50) and less specific (0.81 versus 0.97), with the same AUC (0.74) as OCB, for a CNSID diagnosis. Conclusion: The kappa index and CSF OCB have comparable diagnostic accuracies for a MS or CNSID diagnosis and supply the clinician with useful, complementary information.

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Utility of isoelectric focusing of cerebrospinal fluid and serum on agarose evaluated for neurological patients.

Clinical Chemistry ◽

10.1093/clinchem/29.5.810 ◽

1983 ◽

Vol 29 (5) ◽

pp. 810-815 ◽

Cited By ~ 58

Author(s):

H Link ◽

V Kostulas

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Cerebral Infarction ◽

Isoelectric Focusing ◽

Neurological Diseases ◽

Oligoclonal Bands ◽

Good Reproducibility ◽

Routine Examination ◽

Neurological Patients ◽

Agarose Electrophoresis

Abstract Agarose isoelectric focusing was used to demonstrate oligoclonal bands in cerebrospinal fluid (CSF) and serum from 998 consecutive neurological patients. Compared with agarose electrophoresis, agarose isoelectric focusing was slightly more sensitive, showing more (and more easily discernible) oligoclonal bands. Agarose isoelectric focusing, which has good reproducibility, revealed oligoclonal bands in CSF in 95% of 43 patients with multiple sclerosis, 44% of 39 with aseptic meningoencephalitis, and 14% of 906 with other neurological diseases. Interestingly, oligoclonal bands were found in CSF from 12% of 162 patients with acute cerebral infarction and 23% of 53 with polyneuropathy, and also in 29% of 17 with dementia, while only 4% of 206 patients with headache, vertigo, or psychoneurosis had this CSF abnormality. We recommend this procedure for the routine examination of paired CSF and serum specimens for the presence of oligoclonal bands.

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

Laboratory Medicine ◽

10.1093/labmed/lmz073 ◽

2020 ◽

Vol 51 (4) ◽

pp. 402-407 ◽

Cited By ~ 2

Author(s):

Luisa Agnello ◽

Bruna Lo Sasso ◽

Giuseppe Salemi ◽

Patrizia Altavilla ◽

Emanuela Maria Pappalardo ◽

...

Keyword(s):

Multiple Sclerosis ◽

Screening Test ◽

Neurological Diseases ◽

Oligoclonal Bands ◽

Confirmatory Test ◽

Light Chains ◽

Clinical Use ◽

Free Light Chains ◽

Cutoff Value ◽

Turbidimetric Assay

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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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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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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Neurology (Neuromuscular)

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2015.156 ◽

2015 ◽

Vol 42 (S1) ◽

pp. S33-S33

Author(s):

Y Wang ◽

Y Zhu ◽

W Zhang ◽

M Liu ◽

G Li ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Neurological Disorders ◽

Neurological Diseases ◽

Autonomic Nerve ◽

Paired Samples ◽

Nerve Dysfunction ◽

The Mean ◽

Mean Concentration

Background: IL-27 acts as a ‘master regulator’ in modulating inflammation and was responsible for a number of autoimmune diseases. However, the role of IL-27 was not addressed in Guillain-Barré syndrome (GBS). Methods: Sixty-five subjects including 19 with GBS, 7 with encephalitis or meningitis, 23 with multiple sclerosis or neuromyelitis optica as well as 11 with other non-inflammatory neurological disorders were enrolled. ELISA was used to detect the concentrations of IL-27 in paired samples of cerebrospinal fluid and plasma. Results: The mean concentration of IL-27 in GBS patients was significantly lower than in other neurological disorders both in CSF and in plasma (all p<0.05). GBS patients with cranial involvement, decreased reflexes, hypaesthesia, autonomic nerve dysfunction, MRC score <30 are inclined to have a lower CSF IL-27 level than patients without these symptoms (182 pg/ml, 181 pg/ml, 185 pg/ml, 185 pg/ml, 194 pg/ml vs 211 pg/ml, 205 pg/ml, 202 pg/ml, 198 pg/ml, 199 pg/ml, respectively). Similar results were noted in plasma except for cranial involvement. Conclusions: Production of IL-27 was disparate between GBS and other neurological diseases and a significantly lower level of IL-27 was observed in GBS patients, indicative of an anti-inflammatory role of IL-27 in GBS.

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