Intrathecal K free light chain synthesis in multiple sclerosis at clinical onset associates with local IgG production and improves the diagnostic value of cerebrospinal fluid examination

Puthenparampil, Marco; Altinier, Sara; Stropparo, Erica; Zywicki, Sofia; Poggiali, Davide; Cazzola, Chiara; Toffanin, Elisabetta; Ruggero, Susanna; Grassivaro, Francesca; Zaninotto, Martina; Plebani, Mario; Gallo, Paolo

doi:10.1016/j.msard.2018.08.002

Cited by 26 publications

(37 citation statements)

References 21 publications

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“…More than one-half of OCB-negative MS patients had an elevated kappa index, underlining the utility of the kappa index in this patient population, in accordance with previous studies [ 7 , 19 , 20 ]. The kappa index seems to be useful also in patients with a single IgG band since, in this patient population, an elevated kappa index showed a very high specificity (0.94) and a high PPV (0.86) for the prediction of an infectious/inflammatory CNS disorder, meaning that a positive kappa index in patients with a single IgG band helps to rule in a CNSID.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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

et al. 2020

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“…Several research groups have demonstrated increased kappa and, to a lesser extent, lambda FLC levels in the cerebrospinal fluid (CSF) of patients with MS [5][6][7][8][9][10]. In particular, FLCs were also detected in the CSF of the small proportion of patients diagnosed with MS without OCBs and in patients with CIS, suggesting that they may be a more sensitive marker of the disease [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis

Ferraro

Trovati

Bedin

et al. 2019

Euro J of Neurology

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Background and purpose Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB‐negative patients with suspected MS. Methods The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB‐negative patients with suspected/possible MS and in 54 OCB‐positive patients with MS. Results The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut‐off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB‐negative MS (23/92) and in 98% of OCB‐positive patients with MS. Using a qualitative approach and a kappa index cut‐off of 5.9, based on literature data, we likewise found that 24% of OCB‐negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB‐negative patients without MS (P < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples. Conclusions The kappa index could contribute to the identification of OCB‐negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index.

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“…Noteworthy, KFLC index proved to be increased in MS patients with no evidence of IgG OCB, amounting to almost 5% of cases [50,55,62] , showing a greater sensitivity but a less specificity by using a threshold of 5.9.…”

Section: Kappa Free Light Chains and Kappa Indexmentioning

confidence: 91%

“…Although different thresholds have been used in several studies, ranging from 4.25 [55] to 12.3 [53] , KFLC index extensively proved to have a higher sensitivity and a lower specificity with a similar diagnostic accuracy compared with IgG OCB in discriminating MS and controls [53,[55][56][57][58][59] . In a recent study by Gaetani and coworkers, KFLC index distinguished precisely as did IgG OCB between MS and non-inflammatory diseases using a cut-off value of 7.83 [56] .…”

Section: Kappa Free Light Chains and Kappa Indexmentioning

confidence: 99%

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CSF biomarkers in multiple sclerosis: beyond neuroinflammation

Toscano¹,

Patti²

2020

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For many years, quantifiable biomarkers in neurological diseases have represented a hot topic. In multiple sclerosis (MS), cerebrospinal fluid biomarkers have played a diagnostic role since the introduction of Poser's criteria in 1983, with IgG oligoclonal bands playing a supporting role in an epoch prior to magnetic resonance imaging and a complementary one after the introduction of McDonald criteria in 2001. Nowadays, that supporting role has turned into a main one in substituting for dissemination in time and defining the diagnosis of MS in patients with a first clinical event, according to the 2017 revised McDonald criteria. Possibly kappa free light chains, N-CAM, chitinase 3-like protein 1 and IgM oligoclonal bands, not yet implemented in clinical practice, could similarly gain importance in the near future. Furthermore, the increasing knowledge of molecular mechanisms leading to chronic inflammation has enhanced interest in looking for biomarkers of disease activity, better defining the MS phenotype and patients with highly active disease. Accordingly, myelin proteins, intermediate filaments, metalloproteinases and other molecules involved in the inflammatory cascade, are currently under investigation. Finally, it has long been known that axonal loss occurs from the early phases, leading to a progressive neurological deterioration. Since established criteria to assess treatment failure and transition to progressive forms are still lacking, both treatment response and prognostic biomarkers would be useful to predict MS course, and neurofilaments seem to have this potential. The purpose of this review article was to illustrate biomarkers that have been already validated or require further validation after proving to be useful in exploratory studies and potentially could prove useful in clinical practice in the coming years.

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Intrathecal K free light chain synthesis in multiple sclerosis at clinical onset associates with local IgG production and improves the diagnostic value of cerebrospinal fluid examination

Cited by 26 publications

References 21 publications

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

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

Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis

CSF biomarkers in multiple sclerosis: beyond neuroinflammation

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