Free light chains in cerebrospinal fluid of multiple sclerosis patients negative for IgG oligoclonal bands

Altinier, Sara; Puthenparampil, Marco; Zaninotto, Martina; Toffanin, Elisabetta; Ruggero, Susanna; Gallo, Paolo; Plebani, Mario

doi:10.1016/j.cca.2019.06.016

Cited by 14 publications

(22 citation statements)

References 13 publications

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“…The cut-off for the CSF KFLC concentration varied between 0.103 µg/mL and 7 mg/L and a mean diagnostic sensitivity and specificity of 86% (95% confidence interval (80%, 92%)) and 91% (86%, 96%) was reached while the threshold for CSF LFLC concentration varied between 0.0175 µg/mL and 4.3 mg/L and a mean sensitivity and specificity of 67% (48%, 85%) and 82% (67%, 96%) was reported [4,19,20,23,33,47,48,50,[52][53][54][55][60][61][62][63][64][65][66][67][68]73,74,76,77,85,[88][89][90][91]130]. The cut-off for Q KFLC was set between 4.9 and 30 leading to a mean diagnostic sensitivity of 88% (79%, 96%) and specificity of 90% (77%, 100%) compared with the cut-off for Q LFLC (1.9 and 12.5), which reached a mean sensitivity of 33% (min-max: 21-45%) and specificity of 90% (minmax: 88-92%) [4,19,20,23,33,47,48 [4,68]. In the study of Rathbone et al, which investigated the KFLC/LFLC ratio in CSF too, an elevated ratio in MS patients was observed [52].…”

Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 97%

“…Some studies, which investigated the utility of FLC measurement in the diagnosis of MS, empirically created cut-off values either for the absolute KFLC or LFLC concentrations in CSF, CSF/serum KFLC, and LFLC quotients (Q KFLC , Q LFLC ), CSF KFLC/IgG, and LFLC/IgG ratios or KFLC/LFLC concentration ratios to determine KFLC or LFLC positivity [4,19,20,23,33,47,48,50,[52][53][54][55][60][61][62][63][64][65][66][67][68]73,74,76,77,85,[88][89][90][91]130]. The cut-off for the CSF KFLC concentration varied between 0.103 µg/mL and 7 mg/L and a mean diagnostic sensitivity and specificity of 86% (95% confidence interval (80%, 92%)) and 91% (86%, 96%) was reached while the threshold for CSF LFLC concentration varied between 0.0175 µg/mL and 4.3 mg/L and a mean sensitivity and specificity of 67% (48%, 85%) and 82% (67%, 96%) was reported [4,19,20,23,33,47,48,50,[52][53][54][55][60]…”

Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 99%

“…The index calculation may be employed for the evaluation of intrathecal synthesis of KFLC as well as for LFLC. Different studies applied KFLC indices varying between 0.92 and 20 and reached a mean diagnostic sensitivity of 87% (82%, 92%) and a mean diagnostic specificity of 87% in MS patients (83%, 91%) [19][20][21][22][23][24][27][28][29]33,42,[44][45][46][47][48][49][50][51]53,54,[56][57][58][59][60][61]64,65,[68][69][70][71][72][73][74][75][78][79][80][81][82]85,87,92]. It has to be considered that in some of these studies, the diagnostic utility of FLC in OCB-negative MS patients was investigated, leading to very low diagnostic sensitivity.…”

Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 99%

“…It has to be considered that in some of these studies, the diagnostic utility of FLC in OCB-negative MS patients was investigated, leading to very low diagnostic sensitivity. Some studies also investigated LFLC indices (cut-off 0.29-21.45) leading to lower mean sensitivity (64% (46%, 81%)) and specificity (83% (74%, 93%)) [19][20][21][22][23][24][27][28][29]33,42,[44][45][46][47][48][49][50][51]53,54,[56][57][58][59][60][61]64,65,[68][69][70][71][72][73][74][75][78][79][80][81][82]85,87,92]. FLC indices implement Q Albumin and therefore are more accurate in detecting the intrathecally synthesized portion and differentiating it from FLC, which diffused from blood into CSF.…”

Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 99%

See 3 more Smart Citations

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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Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 97%

Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 99%

Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 99%

Section: Kflc Threshold Values In the Diagnosis Of Msmentioning

confidence: 99%

See 2 more Smart Citations

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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show abstract

“…Diagnosis of MS relies on the so-called McDonald criteria, latest updated in 2017 (5). These criteria include detection of active inflammatory foci in the CNS as seen by positron emission tomography (PET) and magnetic resonance imaging (MRI) and intrathecal production of immunoglobulins (Igs), measured as an elevated cerebrospinal fluid (CSF)/serum IgG index, as a free light chain index or as the occurrence of oligoclonal bands (OCBs) of IgG in CSF (6)(7)(8)(9)(10). Each oligoclonal band is a result of intrathecal antibody (Ab) synthesis by single B cell clones and therefore, specific CSF/ serum Ab indices (AIs) may also be elevated, e.g., Abs to various viruses, corresponding to the specificity of some of the OCBs (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus and Multiple Sclerosis

2020

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Multiple sclerosis (MS) is a neurologic disease affecting myelinated nerves in the central nervous system (CNS). The disease often debuts as a clinically isolated syndrome, e.g., optic neuritis (ON), which later develops into relapsing-remitting (RR) MS, with temporal attacks or primary progressive (PP) MS. Characteristic features of MS are inflammatory foci in the CNS and intrathecal synthesis of immunoglobulins (Igs), measured as an IgG index, oligoclonal bands (OCBs), or specific antibody indexes. Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). Many of the clinical signs of MS described above can be explained by chronic/recurrent EBV infection and current models of EBV involvement suggest that RRMS may be caused by repeated entry of EBV-transformed B cells to the CNS in connection with attacks, while PPMS may be caused by more chronic activity of EBV-transformed B cells in the CNS. In line with the model of EBV’s role in MS, new treatments based on monoclonal antibodies (MAbs) targeting B cells have shown good efficacy in clinical trials both for RRMS and PPMS, while MAbs inhibiting B cell mobilization and entry to the CNS have shown efficacy in RRMS. Thus, these agents, which are now first line therapy in many patients, may be hypothesized to function by counteracting a chronic EBV infection.

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Cerebrospinal fluid kappa free light chains as biomarker in multiple sclerosis—from diagnosis to prediction of disease activity

Hegen

Berek

Deisenhammer

2022

Wien Med Wochenschr

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SummaryMultiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system that shows a high interindividual heterogeneity, which frequently poses challenges regarding diagnosis and prediction of disease activity. In this context, evidence of intrathecal inflammation provides an important information and might be captured by kappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF). In this review, we provide an overview on what is currently known about κ‑FLC, its historical development, the available assays and current evidence on its diagnostic and prognostic value in MS. Briefly, intrathecal κ‑FLC synthesis reaches similar diagnostic accuracy compared to the well-established CSF-restricted oligoclonal bands (OCB) to identify patients with MS, and recent studies even depict its value for prediction of early MS disease activity. Furthermore, detection of κ‑FLC has significant methodological advantages in comparison to OCB detection.

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Free light chains in cerebrospinal fluid of multiple sclerosis patients negative for IgG oligoclonal bands

Cited by 14 publications

References 13 publications

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

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

Epstein-Barr Virus and Multiple Sclerosis

Cerebrospinal fluid kappa free light chains as biomarker in multiple sclerosis—from diagnosis to prediction of disease activity

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