Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis

Background: Free light chains (FLC) have been proposed as diagnostic biomarkers in the cerebrospinal fluid (CSF) of patients with inflammatory central nervous system (CNS) diseases. However, which method to use for determining an intrathecal FLC synthesis has not yet been clarified. The objective of this study was to compare the diagnostic performance of CSF FLC concentration, FLC quotient (Q(FLC)), FLC index and FLC intrathecal fraction (FLCIF). Methods: kappa- and lambda-FLC were measured by nephelometry under blinded conditions in CSF and serum sample pairs of patients with clinically isolated syndrome (CIS; n = 60), multiple sclerosis (MS; n = 60) and other neurological diseases (n = 60) from four different MS centers. Q(FLC) was calculated as the ratio of CSF/serum FLC concentration, the FLC index as Q(FLC)/albumin quotient and the percentage FLCIF by comparing Q(FLC) to a previously empirically determined, albumin quotient-dependent reference limit. Results: CSF FLC concentration, Q(FLC), FLC index and FLC IF of both the kappa- and lambda-isotype were significantly higher in patients with CIS and MS than in the control group, as well as in oligoclonal bands (OCB) positive than in OCB negative patients. Each parameter was able to identify MS/CIS patients and OCB positivity, however, diagnostic performance determined by receiver operating characteristic (ROC) analyses differed and revealed superiority of FLC index and FLCIF. Conclusions: These findings support the diagnostic value of FLC measures that correct for serum FLC levels and albumin quotient, i.e. blood-CSF barrier function.