Diagnostic relevance of free light chains in cerebrospinal fluid - The hyperbolic reference range for reliable data interpretation in quotient diagrams

Background: Free light chains, type kappa (FLC-K), in cerebrospinal fluid (CSF) were compared to oligoclonal IgG in many studies for sensitive detection of immune reactions in brain. The missing consensus about CSF data interpretation prevents reliable conclusions. This can be overcome by a theory-based hyperbolic reference range in CSF/serum quotient diagrams. Methods: Mean Quotients for FLC-K, Q(kappa), and albumin, QAlb, of grouped, biochemically defined controls (N = 433) are fitted with the hyperbolic function Q(kappa)(mean) = a/b (QAlb(2) + b(2) )(0.5) - c by a generally applicable procedure excluding outliers. Results: With Q(kappa) (mean), the coefficient of variation CV (22.5%) and the reference range (Q(kappa) (mean) +/- 3 CV) we got the discrimination line Q(kappa) (lim) = (3.27(QAlb(2) + 33)(0.5)-8.2) x 10(-3) in a FLC-K Reibergram. Intrathecal FLC-K was found in 8% of another control group without OCB (N = 388) but was missed in 7% of patients with definite Multiple sclerosis (N = 95). In MS the mean intrathecal fraction was threefold larger for FLC-K (95%) compared to total IgG (36%). Similar mean quantities of intrathecal FLC-K contradict an immunological conversion between a Clinically isolated syndrome and MS. Discussion: The hyperbolic reference range is superior to linear FLC-K Index (10 to 15% false negatives) and exponential curves (30% false positive interpretations for controls) in the analytical range of MS data, with excellent data fit for up to ten-fold larger QAlb values. Dynamics of the small molecule FLC-K contribute to the understanding of molecular size dependent barrier functions.