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Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the effects of different disease-modifying therapies (DMT) on the humoral intrathecal immune response in the CSF of patients with multiple sclerosis (MS). FLCκ were analyzed in CSF and serum samples from MS patients taking DMT (n = 60) and those in a control cohort of treatment-naïve MS patients (n = 90). DMT was classified as moderately effective (including INFß-1a, INFß-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, triamcinolone); highly effective (including fingolimod, daclizumab) and very highly effective (alemtuzumab, natalizumab, rituximab/ocrelizumab, mitoxantrone). FLCκ were measured using a nephelometric FLCκ kit. Intrathecal FLCκ and IgG concentrations were assessed in relation to the hyperbolic reference range in quotient diagrams. Intrathecal FLCκ concentrations and IgG concentrations were significantly lower in samples from the cohort of MS patients taking very highly effective DMT than in samples from the cohort of MS patients taking highly effective DMT and in the treatment-naïve cohort (FLCκ: p = 0.004, p < 0.0001 respectively/IgG: p = 0.013; p = 0.021). The reduction in FLCκ could contribute to an anti-inflammatory effect in the CNS through this mechanism. There was no difference in the appearance of CSF-specific oligoclonal bands (p = 0.830). Longitudinal analyses are required to confirm these results.
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.
Background: The intrathecal humoral response is the characteristic diagnostic finding in the cerebrospinal fluid (CSF) analysis of patients with multiple sclerosis (MS). Although the average age of MS patients increases, little is known about the sensitivity of diagnostic markers in elderly MS patients. Methods: In this retrospective two-center study, intrathecal free light chains kappa fraction (FLCk IF) and oligoclonal bands (OCB) were studied in a large cohort of patients with early and late onset relapsing (RMS) and progressive (PMS) MS. Furthermore, the humoral immune profile in CSF was analyzed, including the polyspecific intrathecal immune response measured as the MRZ reaction. Results: While the frequency of CSF-specific OCB did not differ between early and late onset RMS and PMS, the sensitivity of positive FLCk IF and absolute FLCk IF values were lower in PMS. The positivity of the MRZ reaction was equally frequent in early and late onset RMS and PMS. PMS patients had higher local IgA concentrations than RMS patients (p = 0.0123). Conclusions: OCB are slightly superior to FLCk IF in progressive MS in terms of sensitivity for detecting intrathecal immunoglobulin synthesis. The MRZ reaction, as the most specific parameter for MS, is also applicable in patients with late onset and progressive MS.
In this retrospective, monocentric cohort study, we tested if an intrathecal free light chain kappa (FLC-k) synthesis reflects not only an IgG but also IgA and IgM synthesis. We also analysed if FLC-k can help to distinguish between an inflammatory process and a blood contamination of cerebrospinal fluid (CSF). A total of 296 patient samples were identified and acquired from patients of the department of Neurology, University Medicine Greifswald (Germany). FLC-k were analysed in paired CSF and serum samples using the Siemens FLC-k kit. To determine an intrathecal FLC-k and immunoglobulin (Ig) A/-M-synthesis we analysed CSF/serum quotients in quotient diagrams, according to Reiber et al. Patient samples were grouped into three cohorts: cohort I (n = 41), intrathecal IgA and/or IgM synthesis; cohort II (n = 16), artificial blood contamination; and the control group (n = 239), no intrathecal immunoglobulin synthesis. None of the samples had intrathecal IgG synthesis, as evaluated with quotient diagrams or oligoclonal band analysis. In cohort I, 98% of patient samples presented an intrathecal synthesis of FLC-k. In cohort II, all patients lacked intrathecal FLC-k synthesis. In the control group, 6.5% presented an intrathecal synthesis of FLC-k. The data support the concept that an intrathecal FLC-k synthesis is independent of the antibody class produced. In patients with an artificial intrathecal Ig synthesis due to blood contamination, FLC-k synthesis is lacking. Thus, additional determination of FLC-k in quotient diagrams helps to discriminate an inflammatory process from a blood contamination of CSF.
A New Laboratory Workflow Integrating the Free Light Chains Kappa Quotient into Routine CSF Analysis
(2022)
We performed this cohort study to test whether further analysis of intrathecal inflammation can be omitted if the free light chain kappa (FLCκ) quotient is within the reference range in the corresponding quotient diagram. FLCκ concentrations were measured in serum and cerebrospinal fluid (CSF) samples. The intrathecal fraction (IF) of FLCκ was calculated in relation to the hyperbolic reference range. 679 patient samples were used as a discovery cohort (DC). The sensitivity and negative predictive value (NPV) of the FLCκ-IF for the detection of an intrathecal humoral immune response (CSF-specific OCB and/or IF IgG/A/M > 0%) was determined. Based on these data, a diagnostic algorithm was developed and prospectively validated in an independent validation cohort (VC, n = 278). The sensitivity of the FLCκ-IF was 98% in the DC and 97% in the VC with a corresponding NPV of 99%. The use of the FLCκ-IF as a first line analysis would have reduced the Ig and OCB analysis by 62% in the DC and 74% in the VC. The absence of a FLCκ-IF predicts the absence of a humoral intrathecal immune response with a very high NPV of 99%. Thus, integration of our proposed algorithm into routine CSF laboratory analysis could help to reduce analytical efforts.