Serum neurofilament light chain in multiple sclerosis: promise, pitfalls, and the path to clinical implementation.

BACKGROUND: Serum neurofilament light chain (sNfL) is an analytically robust blood biomarker of recent neuroaxonal injury in multiple sclerosis (MS), but its clinical role is constrained by biological confounding, assay and specimen variability, and limited evidence that sNfL-guided treatment decisions improve patient outcomes. AIM: To critically evaluate the evidence for blood NfL in MS across biological validity, disease-activity and prognostic associations, pharmacodynamic treatment responsiveness, and demonstrated clinical utility, with emphasis on practical interpretation. METHODS: This structured narrative review synthesized evidence identified through searches of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, completed on 31 July 2026, and supplemented by backward and forward citation tracking of key guidance documents, systematic reviews, meta-analyses, and pivotal studies. English-language human studies were prioritized when they directly informed analytical validity, disease activity, prognosis, treatment response, confounding, longitudinal interpretation, or clinical implementation. No quantitative pooling, formal risk-of-bias scoring, or certainty-of-evidence grading was performed. RESULTS: Evidence is strongest for biological validity, association with recent inflammatory activity, short-term prognostic enrichment, and pharmacodynamic responsiveness to effective disease-modifying therapy. These findings do not establish equivalent clinical utility. A 2026 diagnostic-accuracy meta-analysis found only modest standalone discrimination for inflammatory activity, and real-world implementation studies show that sNfL can alter clinician decisions without yet demonstrating improved patient outcomes. Interpretation is additionally affected by age, body size, renal function, acute central or peripheral neurological injury, specimen type, assay platform, and timing relative to relapse or treatment. CONCLUSION: Current evidence supports sNfL as an adjunctive decision-support biomarker in selected MS contexts, particularly when interpreted longitudinally alongside MRI and clinical assessment. It should not be used as a stand-alone diagnostic test, a universal treatment-switch threshold, or a validated management algorithm. Prospective studies are still required to show that sNfL-guided care improves clinical outcomes.