Higher baseline levels of serum neurofilament-light chain (sNfL) are prognostic of disease activity in patients with clinically isolated syndrome, according to a retrospective analysis of 181 individuals presenting with CIS at two MS centres in Spain during the period 2004-2022 (Comabella et al. Neurol Neuroimmunol Neuroinflamm 2025;12:e200370).

Baseline sNfL Z-scores were highest in patients who met criteria for dissemination in space (DIS) and time (DIT), somewhat lower in those with DIS but no DIT, and lowest in those without DIS or DIT. Epstein-Barr nuclear antigen (EBNA)-1-specific IgG levels were also elevated in patients with DIS and DIT compared to those without DIS or DIT.

Obtaining baseline sNfL was especially useful in the group with no DIS or DIT. A total of 40% of this subgroup developed MS after a median 8.1 years. A baseline sNfL Z-score >1.64 discriminated between patients who later developed disease activity compared to those who did not (positive and negative predictive values of 87.5%). The PPV of this cut-off value was higher (100%) in the subgroup presenting with optic neuritis. Baseline serum glial fibrillary acidic protein (sGFAP) was not predictive of disease activity in the no DIS/no DIT group.

Baseline sNfL also identified CIS patients with DIS but no DIT who later developed disease activity. The PPV was 97.3% using a baseline sNfL Z-score >1.28 as a cut-off value. A baseline sGFAP >66.42 pg/mL also discriminated CIS patients with DIS/no DIT who developed disease activity from those without disease activity (PPV 95.1%). The PPV was 100% for patients with sNfL Z-scores >1.28 and sGFAP >66.42 pg/mL.

Baseline sNfL alone was not prognostic of disease activity in the small group of OCB-negative patients. Using a higher sGFAP cut-off value of 68.69 pg/mL did predict disease activity (PPV 83.3%). The combination of sNfL Z-score >1.28 and the sGFAP >66.42 pg/mL was predictive of disease activity (PPV 100%).

The authors noted that CIS patients with DIS/no DIT who are OCB-negative are not diagnosed with MS according to the current diagnostic criteria, although 71.4% in this study were subsequently diagnosed with MS after a median 6.5 years. Fluid biomarkers can be obtained less invasively than OCBs and appear to be adequate surrogates of DIT, enabling earlier diagnosis of MS in patients presenting with CIS.