Kappa Free Light Chain for Diagnosis and Neurofilament Light Chain for Prognosis in Autoimmune Encephalitis

Abstract

Background and Objectives Reliable biomarkers for autoimmune encephalitis (AE) are limited, and emerging CSF markers are not incorporated into current diagnostic criteria. Prognostic tools remain insufficient, highlighting the need for biomarkers that support both early diagnosis and assessment of disease severity and prognosis. Methods In this multicenter prospective cohort study, we analyzed clinical data and paired CSF-serum samples from adults with definite AE enrolled in the German Network for Research on Autoimmune Encephalitis registry and the CSF biobank of Hannover Medical School. Of 2,330 screened individuals, 92 patients with anti–N-methyl-d-aspartate receptor (NMDAR, n = 53), anti–leucine-rich glioma-inactivated 1 (LGI1, n = 20), or anti–contactin-associated protein-like 2 (CASPR2, n = 19) encephalitis were included and followed longitudinally for a median of 38 months. Control groups comprised patients with relapsing multiple sclerosis, varicella-zoster virus encephalitis, and noninflammatory neurologic conditions (each n = 30), as well as antibody-positive patients without AE (n = 15), with the groups frequency-matched for age and sex. Kappa free light chain (KFLC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokines were measured in paired CSF-serum samples obtained at baseline and during follow-up. Disease severity and disability were assessed using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score and the modified Rankin Scale (mRS). Results Intrathecal synthesis of KFLC was detected in 94% of anti-NMDAR, 50% of anti-LGI1, and 53% of anti-CASPR2 encephalitis cases, demonstrating higher diagnostic sensitivity than CSF-restricted oligoclonal bands or pleocytosis. Diagnostic specificity across pooled control groups was moderate at 44% but reached 90% when compared with noninflammatory neurologic controls. CSF NfL z-score levels were strongly associated with baseline disease severity, with each 1-standard deviation increase corresponding to an approximately 10-point higher CASE score, independent of clinical covariates (β = 0.61). Longitudinal changes in NfL concentrations in CSF and serum were associated with disease severity and neurologic disability at follow-up (CASE score: adjusted R2 = 0.401; mRS score: adjusted R2 = 0.203). GFAP and cytokines showed limited diagnostic or prognostic utility. Discussion Intrathecal KFLC synthesis represents a highly sensitive CSF marker that supports early suspicion of autoimmune encephalitis and prompts antibody testing. NfL provides robust biochemical information on baseline disease severity and longitudinal changes that may aid prognostic assessment across AE subtypes.