BACKGROUND: Free light chain kappa (FLCκ) have emerged as a sensitive biomarker to detect intrathecal immunoglobulin synthesis. To evaluate the role of FLCκ in routine cerebrospinal fluid laboratory diagnostics we conducted a prospective nationwide real world diagnostic study for evaluating the integration of kappa free light chain into clinical routine (ORCAS - prospective multicenter validation of a new laboratory workflow integrating the free light chains kappa in CSF analysis).

OBJECTIVES: To determine whether testing for intrathecal synthesis of FLCκ in cerebrospinal fluid (CSF) can predict intrathecal immunoglobulin (Ig) synthesis of total IgG, IgA, IgM or CSF-specific oligoclonal bands (OCB) with high sensitivity.

MATERIALS & METHODS: FLCκ were measured in 1052 paired CSF and serum samples according to local laboratory standards in six laboratories in Germany. Sensitivity and negative predictive value (NPV) of intrathecal FLCκ synthesis as first line detection of intrathecal Ig synthesis were assessed.

RESULTS: Of the 1052 samples, 624 fulfilled the inclusion criteria. The intrathecal fraction of FLCκ predicted intrathecal Ig synthesis with a sensitivity of 0.87 (CI 0.81-0.93) and a NPV of 0.97 (CI 0.95-0.98). The sensitivity for predicting CSF-specific OCB was 0.93 (CI 0.88-0.98).

CONCLUSIONS: In the real world setting this study analyzing FLCk for detecting intrathecal Ig synthesis did not reach its prespecified primary endpoint of sensitivity >0.95. Therefore, FLCκ should not yet be introduced as a stand-alone preselection marker for intrathecal Ig synthesis, but may provide additional value when combined with established diagnostic parameters.