• Thomas Williams, Henrik Zetterberg, and Jeremy Chataway.
• Department of Neuroinflammation, Faculty of Brain Sciences, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK. Thomas.williams@nhs.net.
• J. Neurol. 2020 May 23.

BackgroundNeurofilament proteins have been extensively studied in relapsing-remitting multiple sclerosis, where they are promising biomarkers of disease activity and treatment response. Their role in progressive multiple sclerosis, where there is a particularly urgent need for improved biomarkers, is less clear. The objectives of this systematic review are to summarise the literature on neurofilament light and heavy in progressive multiple sclerosis, addressing key questions.MethodsA systematic search of PubMed, Embase, Web of Science and Scopus identified 355 potential sources. 76 relevant sources were qualitatively reviewed using QUADAS-2 criteria, and 17 were identified as at low risk of bias. We summarise the findings from all relevant sources, and separately from the 17 high-quality studies.ResultsDifferences in neurofilament light between relapsing-remitting and progressive multiple sclerosis appear to be explained by differences in covariates. Neurofilament light is consistently associated with current inflammatory activity and future brain atrophy in progressive multiple sclerosis, and is consistently shown to be a marker of treatment response with immunosuppressive disease-modifying therapies. Associations with current or future disability are inconsistent, and there is no evidence of NFL being a responsive marker of purportedly neuroprotective treatments. Evidence on neurofilament heavy is more limited and inconsistent.ConclusionsNeurofilament light has shown consistent utility as a biomarker of neuroinflammation, future brain atrophy and immunosuppressive treatment response at a group level. Neither neurofilament light or heavy has shown a consistent treatment response to neuroprotective disease-modifying therapies, which will require further data from successful randomised controlled trials.

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