Intrathecal immunoglobulin synthesis: The potential value of an adjunct test

Emeršič, Andreja; Anadolli, Vanesa; Krsnik, Mladen; Rot, Uroš

doi:10.1016/j.cca.2018.12.006

Cited by 22 publications

(32 citation statements)

References 30 publications

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“…In our study, we considered another approach to evaluated the excess of intrathecal KFLC only in CSF, and not corrected for blood-CSF barrier permeability. This CSF KFLC/IgG ratio also resulted sensitive (and specific) in discriminating MS from other neurological conditions, as previously described 13 . Not only this marker could be used to search for intrathecal IgG synthesis in suspect MS if serum is not available, but also supported the hypothesis that MS patients have an “excess” of KFLC production limited to the CSF 14 .…”

Section: Discussionsupporting

confidence: 81%

Intrathecal kappa free light chains as markers for multiple sclerosis

Vecchio

Bellomo

Serino

et al. 2020

Sci Rep

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Cerebrospinal fluid (CSF) kappa free light chain (KFLC) index has been described as a reliable marker of intrathecal IgG synthesis to diagnose multiple sclerosis (MS). Our aims were: (1) to compare the efficiency of KFLC through different interpretation approaches in diagnosing MS. (2) to evaluate the prognostic value of KFLC in radiologically and clinically isolated syndromes (RIS-CIS). We enrolled 133 MS patients and 240 with other neurological diseases (93 inflammatory including 18 RIS-CIS, 147 non-inflammatory). Albumin, lambda free light chain (LFLC) and KFLC were measured in the CSF and serum by nephelometry. We included two groups of markers: (a) corrected for blood-CSF barrier permeability: immunoglobulin G (IgG), KFLC and LFLC indexes. (b) CSF ratios (not including albumin and serum-correction): CSF KFLC/LFLC, CSF KFLC/IgG, CSF LFLC/IgG. KFLC were significantly higher in MS patients compared to those with other diseases (both inflammatory or not). KFLC index and CSF KFLC/IgG ratio showed high sensitivity (93% and 86.5%) and moderate specificity (85% and 88%) in diagnosing MS. RIS-CIS patients who converted to MS showed greater KFLC index and CSF KFLC/IgG. Despite OB are confirmed to be the gold-standard to detect intrathecal IgG synthesis, the KFLC confirmed their accuracy in MS diagnosis. A “kappa-oriented” response characterizes MS and has a prognostic impact in the RIS-CIS population.

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Section: Discussionsupporting

confidence: 81%

Intrathecal kappa free light chains as markers for multiple sclerosis

Vecchio

Bellomo

Serino

et al. 2020

Sci Rep

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“…Currently, oligoclonal bands (OCB) constitute the gold standard for detection of an intrathecal inflammation, which are isoelectrically focused and subsequently stained immunoglobulin G (IgG) antibodies in CSF [17]. KFLC are promising additional biomarkers to detect intrathecal inflammation with a similar performance in comparison with OCB analytics [18][19][20][21][22][23]. The determination of KFLC in CSF and serum has been performed fully automated for several years and the most common measurement methods are nephelometric, turbidimetric, and ELISA-assays [18,19].…”

Section: Introductionmentioning

confidence: 99%

“…The determination of KFLC in CSF and serum has been performed fully automated for several years and the most common measurement methods are nephelometric, turbidimetric, and ELISA-assays [18,19]. The advantages of automated measurements are rapid results, less expensive diagnostics, and rater-independency [20][21][22][23]. However, various challenges, including the lack of standard reference values, have prevented KFLC from being implemented into daily clinical routine so far.…”

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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“…0.012), with the highest albumin quotient found on a patient with suspected ependymoma (0.023). The K-Index linear function includes the albumin quotient, yet other reports have further evaluated non-linear functions to correct for possible alterations on the BCB by relating the kappa CSF/serum ratios to CSF/serum albumin ratio's dependent reference curves (17,21,28), obtaining excellent diagnostic accuracy but not proving to improve upon the easier-to-calculate K-Index (29)(30)(31). Moreover, we applied the recently defined hyperbolic function described by Reiber et al (32) to estimate the K-FLC intrathecal fraction (IF) in our cohort of patients (data not shown), finding an almost absolute agreement with our algorithm results.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Kappa Index as a Tool in the Diagnosis of Multiple Sclerosis: Implementation in Routine Screening Procedure

et al. 2021

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Previous studies have shown that cerebrospinal fluid (CSF) kappa free light chains (K-FLCs) may have a role in MS diagnosis. In this regard, the kappa index (K-Index) has demonstrated higher sensitivity, and slightly lower specificity than oligoclonal bands (OCBs), the gold standard for the detection of intrathecal immunoglobulin synthesis, a feature of MS. Here, we evaluated the performance of the K-Index (K-Index = CSF/serum K-FLC divided by CSF/serum albumin) for the differential diagnosis of MS in a cohort of patients with suspected MS. K-FLCs were quantitatively measured in parallel serum and CSF samples by turbidimetry (Freelite Mx reagent on an Optilite system, The Binding Site Group Ltd). From 160 (63.4%) of a total of 252 patients who had K-FLC in CSF <0.03 mg/dl, below the sensitivity limit of the technique, only one had a diagnosis of MS. However, the absence of OCB in this same patient suggested no synthesis of intrathecal immunoglobulin. Globally, MS patients presented significantly higher K-Index levels than patients without an MS diagnosis (66.96 vs. 0.025, respectively; p < 0.0001). In agreement, patients with positive OCB testing also exhibited higher K-Index levels than patients negative for OCB (65.02 vs. 0.024, respectively; p < 0.0001). An optimal K-Index cutoff of 3.045 was defined by receiver operating characteristic (ROC) analysis for screening suspected MS, achieving a higher diagnostic sensitivity and slightly lower specificity than OCB (Sens. 0.9778 and Spec. 0.8629 vs. Sens. 0.8889 and Spec. 0.9086, respectively). A previously reported K-Index cutoff of 6.6 also showed good diagnostic performance (Sens. 0.9333; Spec. 0.8731), validating its power as a diagnostic biomarker for MS. Finally, a time- and cost-effective algorithm for MS screening is proposed that would offer an initial rapid evaluation of the intrathecal immunoglobulin synthesis through the K-FLC in CSF and K-Index analysis, followed by reflexing OCB testing that may be ordered more selectively.

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Intrathecal immunoglobulin synthesis: The potential value of an adjunct test

Cited by 22 publications

References 30 publications

Intrathecal kappa free light chains as markers for multiple sclerosis

Intrathecal kappa free light chains as markers for multiple sclerosis

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

Evaluation of Kappa Index as a Tool in the Diagnosis of Multiple Sclerosis: Implementation in Routine Screening Procedure

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