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

Abstract

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.

Evidence for an Intrathecal Immunoglobulin Synthesis by Kappa Free Light Chains in Neurological Patients with an Isolated Band in Isoelectric Focusing

“…Specificity was 100% because only patients with an IND were above the threshold for positive k-FLC. Similar sensitivity and specificity have been reported in past studies of patients with more than one band in IEF, where k-FLC were measured quantitatively [ 9 , 19 ]. In this regard, our results are also mainly consistent with the ones of a previous study on only one isolated band [ 14 ].…”

“…The evaluation of k-FLC in laboratory work-up has proven to be a useful additional parameter within the diagnosis of intrathecal immunoglobulin synthesis [ 8 , 9 , 10 , 11 , 12 ], which has also been determined to be robust against external influences such as storage, plasma exchange and common therapy in acute exacerbation in MS (depending on drug concentration) [ 9 ]. Furthermore, in the case of artificial blood contamination of the CSF, k-FLC does not increase artificially compared with the Ig indices [ 18 ].…”

“…As a relatively labour-intensive and costly procedure, IEF has a long turnaround time of 4–5 h. Furthermore, due to visual interpretation of the results, rater-dependent bias can occur, which has served as a motivational factor to search for easier to standardise and faster laboratory options [ 8 ]. An alternative to IEF is the quantification of kappa free light chains (k-FLC) in the CSF [ 9 , 10 , 11 , 12 ]. k-FLC are produced by B/plasma cells and are present in a free form in serum and CSF, resulting from excess production compared with the heavy chains.…”

“…Hence, these k-FLC are measurable similar to intact immunoglobulins despite their shorter half-life [ 13 ]. Measured turbido- or nephelometrically with low laboratory effort, k-FLC have shown comparable sensitivity and specificity in the detection of neuroimmunological diseases such as MS in recent studies [ 9 , 10 , 11 , 12 ].…”

Diagnostic Cerebrospinal Fluid Biomarker in Early and Late Onset Multiple Sclerosis

“…All FLCk negative samples revealed pathological OCB results in the silver staining method after isoelectric focusing on polyacrylamide gels. Studies using silver staining to detect OCB showed a better performance with higher rates of OCB-positive patients than other methods of OCB determination, even if the cause of this has not been conclusively clarified [ 30 ]. Therefore, we recommend that the OCB detection is performed by silver staining if a clinical suspicion of MS and negative FLCk levels are present.…”