Clinical Use of κ Free Light Chains Index as a Screening Test for Multiple Sclerosis

Luisa Agnello, PhD; Bruna Lo Sasso, PhD; Giuseppe Salemi, MD; Patrizia Altavilla, BS; Emanuela Maria Pappalardo, BS; Rosalia Caldarella, BS; Francesco Meli, BS; Concetta Scazzone, BS; Giulia Bivona, MD; Marcello Ciaccio, MD, PhD

Disclosures

Lab Med. 2020;51(4):402-407. 

In This Article

Abstract and Introduction

Abstract

Objective: To assess the usefulness of the κ free light chain index (κFLCi) as a screening test to identify patients with suspected MS.

Methods: The study included 56 patients with a request to test for oligoclonal bands (OCBs). OCBs were detected by isoelectric focusing, followed by immunofixation. Cerebrospinal fluid (CSF) and serum κFLC were measured by a turbidimetric assay. Also, the κFLC index (κFLCi) was calculated.

Results: CSF κFLC levels and κFLCi were significantly higher in patients with multiple sclerosis (MS) than in patients with other neurological diseases (NDs; P < .001 and P < .001, respectively). At the cutoff value of 2.9, the κFLCi detected MS with sensitivity of 97% and specificity of 65%. Overall, 92% patients with κFLCi of 2.9 or greater and who had tested positive for OCBs were diagnosed as having MS.

Conclusion: Our findings support the use of κFLCi as a screening test when MS is suspected, followed by OCB detection as a confirmatory test for the diagnosis of MS.

Introduction

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system (CNS) characterized by progressive demyelination leading to neurological disability.[1–3] It has been considered a T cell–mediated disorder for a long time.[4–6] However, within the past decade, accumulating evidence[7] has supported a pathogenic role of B cells, with a persistence of clonally expanded plasma cells generating intracerebral immunoglobulins (Igs). Detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) using isoelectric focusing (IEF) followed by immunofixation is considered a hallmark of MS testing. This modality is helpful especially when diagnosis remains challenging due to aspecific symptoms and uninformative imaging test results.[8] Indeed, the diagnosis of MS relies on the integration of medical history, clinical examination, magnetic resonance imaging (MRI) findings, and CSF examination, according to the most recent version of the McDonald criteria for MS diagnosis.[8] CSF analysis has strong potential as a source of emerging biomarkers for neurodegenerative diseases because it offers the opportunity to evaluate specific CNS inflammatory processes.[9,10]

Although OCB detection is characterized by high sensitivity and specificity, it is time-consuming; it gives qualitative, but not quantitative, information; it is a laborious manual technique; its interpretation is operator-dependent and susceptible to investigator bias; it has a long turnaround time (4 to 5 hours); and it is difficult to standardize. Thus, we advocate for the identification of a reliable biomarker that can overcome these limits. Among promising CSF biomarkers, kappa free light chain (κFLC) has gained strong attention in recent years. Physiologically, plasmacells secrete intact Igs and free light chains (FLCs) of the kappa (κ) and lambda (λ) varieties, which are produced in excess with respect to the total amount of intact Ig. Thus, κFLC analysis reflects B-cell activity in serum and in CSF. The presence of κFLC and lambda free light chain (λFLC) in CSF has been known since the early 1980s.[11] Generally, FLC concentration is low in the serum and in CSF of healthy individuals, but it increases in inflammatory diseases involving the CNS, including MS.[12] The recent availability of automated turbidimetric or nephelometric assays for the detection of CSF κFLC has promoted the introduction of such testing in clinical practice.

Although the role of clinical use of λFLC quantification is still controversial, accumulating evidence supports κFLC introduction for the evaluation of patients with suspected MS.[13] We consider it noteworthy that serum Ig and FLC can passively cross the blood-brain barrier. Thus, Ig and FLC in CSF can originate from circulating and intratechal synthesis. The estimation of CSF/serum Ig or FLC ratio, normalized by the CSF/serum albumin ratio, can discriminate between the origins of Ig and FLC, reducing false-positive results. The aim of the current study was to assess the diagnostic accuracy of κFLC measured by turbidimetry, combined with OCB detection, in MS diagnosis.

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