Beyond biomarker validation: defining when serum neurofilament light chain should influence management in multiple...

Serum neurofilament light chain (sNfL) is a well-established biomarker of neuroaxonal injury in multiple sclerosis (MS), associated with inflammatory disease activity, treatment response, and future clinical outcomes. As a downstream marker of tissue injury rather than a direct readout of a specific immune pathway, its increasing availability raises a more demanding question: when does sNfL provide enough additional information to improve management of an individual patient? This review examines sNfL from the perspective of clinical actionability and personalized decision support rather than biomarker validity alone. Reliable patient-level use requires analytical comparability, consideration of biological and clinical confounders, individualized normalization, temporal context, and longitudinal interpretation. Even when these conditions are met, clinical value depends on whether sNfL adds meaningful information beyond established clinical and magnetic resonance imaging monitoring. Current evidence best supports its role as a decision-support biomarker: unexpected or persistent abnormalities may justify verification, closer surveillance, or targeted reassessment, whereas normal values cannot reliably exclude clinically relevant MS biology, including relapse-independent disability accumulation. This asymmetry, together with the limited disease specificity of sNfL, argues against universal treatment thresholds and supports complementary biomarker and multimodal approaches. Evidence that sNfL predicts outcomes or influences intended management does not establish that acting on this information improves patient outcomes. Prospective studies are beginning to address this translational gap by evaluating sNfL-informed management strategies. The key remaining step is to demonstrate that acting on sNfL information-not merely measuring or interpreting it-improves clinically meaningful outcomes. Until then, sNfL is best positioned for biomarker-informed personalized monitoring rather than fully biomarker-guided care.