Free light chain kappa and the polyspecific immune response in MS and CIS – Application of the hyperbolic reference range for most reliable data interpretation

Süße, Marie; Reiber, Hansotto; Grothe, Matthias; Petersmann, Astrid; Nauck, Matthias; Dressel, Alexander; Hannich, Malte Johannes

doi:10.1016/j.jneuroim.2020.577287

Cited by 18 publications

(35 citation statements)

References 27 publications

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“…Between 2008 and 2016 samples were stored at −80°C. The samples acquired between 2016 and 2020 have been measured either as part of other study cohorts 7 – 9 or for the purpose of this study without being stored. Patients were grouped by the clinical diagnosis according to the corresponding criteria (MS: modified Mc Donald criteria 10 ; NMOSD: criteria proposed by Wingerchuk et al 5 ).…”

Section: Methodsmentioning

confidence: 99%

Free light chains kappa can differentiate between myelitis and noninflammatory myelopathy

Süße

Feistner

Grothe

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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

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Section: Methodsmentioning

confidence: 99%

Free light chains kappa can differentiate between myelitis and noninflammatory myelopathy

Süße

Feistner

Grothe

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…In 2019, Reiber and colleagues developed a quotient diagram based on a hyperbolic function to establish a reference range for KFLC in CSF similar to the hyperbolic function for the immunoglobulins A, G, and M [25]. This reference range has already been successfully applied in different studies and showed a superior performance in terms of diagnostic sensitivity for the detection of intrathecal inflammation as compared with other reference values for KFLC and the gold standard OCB [24][25][26][27][28][29]. However, the role of KFLC in other neurologic diseases than MS is not entirely clear.…”

Section: Introductionmentioning

confidence: 99%

The Increasing Role of Kappa Free Light Chains in the Diagnosis of Multiple Sclerosis

Konen

Schwenkenbecher

Jendretzky

et al. 2021

Cells

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

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“…It has been suggested to evaluate KFLC with hyperbolic reference range in quotient diagrams as this may reduce the rate of false-positive/-negative cases in the presence of low/high albumin quotients [ 18 ] and that the KFLC IF is a more accurate metric compared to OCB and kappa index [ 11 ]. In this study, a KFLC IF >0% turned out to be a very sensitive measure, which identified 92% of MS patients, but, due to its low specificity, it had a lower AUC in the prediction of MS, and a similar AUC for the prediction of a CNSID compared to the OCB/kappa index.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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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Free light chain kappa and the polyspecific immune response in MS and CIS – Application of the hyperbolic reference range for most reliable data interpretation

Cited by 18 publications

References 27 publications

Free light chains kappa can differentiate between myelitis and noninflammatory myelopathy

Free light chains kappa can differentiate between myelitis and noninflammatory myelopathy

The Increasing Role of Kappa Free Light Chains in the Diagnosis of Multiple Sclerosis

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

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