An international panel of experts in conjunction with the Consortium of MS Centers (CMSC) has developed recommendations on the use of neurofilament-light chain (NfL) as a biomarker of disease activity in multiple sclerosis (Freedman et al. eBioMedicine 2024;101:104970).

NfL is a marker of neuroaxonal damage that occurs across a range of neurological conditions. In MS, a change from baseline in NfL in CSF or serum is indicative of recent neuroinflammatory damage and is prognostic of disease worsening. Higher sNfL levels are correlated with Gd+ lesions and new T2 lesions over the subsequent year and are associated with poorer disability outcomes at five years.

NfL levels generally decrease after initiation of a disease-modifying therapy (DMT). Lower sNfL levels have been shown to be associated with fewer lesions and less brain atrophy at year 2, and a lower risk of EDSS progression at year 4 (Kuhle et al. Neurology 2019;92:e1007-e1015).

The international panel recommended obtaining CSF and serum NfL at baseline. sNfL is sufficient if no lumbar puncture is planned and is less invasive than cNfL for subsequent follow-ups. NfL testing may be performed if new MRI lesions are observed; at 3-6 months after a disease activity event (relapse, Gd+ lesion); and at 3-6 month intervals after DMT initiation to evaluate treatment effectiveness. Recent studies have shown that higher sNfL levels during the course of treatment continue to be predictive of new lesion activity (Leist et al. AAN 2024;S42.003).

The panel noted that a treatment switch may be indicated if NfL levels do not decrease substantially with therapy. Normal variation in NfL may be 40%, so less substantial NfL changes may not be informative.

At present, there are several issues that limit the usefulness of NfL testing in routine clinical practice. The expert panel acknowledged that there is a need to establish reference ranges and to identify cutoff values indicative of disease worsening. There is also a need to better understand how to correct for confounders, such as body mass, age and other medical conditions. Moreover, it is unclear if NfL has prognostic value in progressive forms of MS.