Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis

Background and objectives: Determinants of disease activity and prognosis are limited in anti-NMDAR encephalitis. Neurofilament light chains (NfL) are markers of axonal damage and have been identified as valuable biomarkers for neurodegenerative and other neuroinflammatory disorders. We aimed to investigate serum NfL levels in patients with anti-NMDAR encephalitis as a biomarker for disease severity and outcome. Methods: In this retrospective study, NfL values were measured in all available pre-treatment serum and paired CSF samples of the nationwide anti-NMDAR encephalitis cohort. The values were analyzed in duplicate using Single Molecule Array (SIMOA) and compared to measurements in healthy references. Follow-up sera were tested to analyze longitudinal responsiveness, if at least available from two time points after diagnosis. Serum NfL levels were compared to data on disease activity (seizures, MRI and CSF findings), severity (mRS, admission days, ICU admission) and outcome (mRS and relapses), using regression analysis. Results: We have included 71 patients (75% female; mean age 31.4, range 0-85 years). Paired CSF samples were available of 33 patients, follow-up samples of 20 patients. Serum NfL levels at diagnosis were higher in patients (mean 19.5 pg/mL, 95%-CI 13.7-27.7) than in references (mean 6.4 pg/mL, 95%-CI 5.8-7.2, p<0.0001). We observed a good correlation between serum and CSF NfL values (R=0.84, p<0.0001). Serum NfL levels and age correlated in patients (Pearson's R=0.57, p<0.0001) and references (R=0.62, p<0.0001). Increased NfL values were detected in patients post-HSV1 encephalitis (mean 248.8 vs 14.1 pg/mL, p <0.0001) and in patients with brain MRI lesions (mean 27.3 vs 11.1 pg/mL, p=0.019). NfL levels did relate to the long-term follow-up (mRS at 12 months; βNfL=0.55, p=0.013), although largely explained by the effect of age on NfL levels and prognosis. In serial samples, NfL values did roughly follow clinical disease activity, albeit with delay. Discussion/conclusions: Increased serum NfL levels reflect neuro-axonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, while the association with outcome was confounded by age. The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic marker.