Progression Independent of Relapse Activity in Aquaporin-4-IgG-Positive NMOSD: A Decade-Long Cohort Study

Disability in neuromyelitis optica spectrum disorder (NMOSD) is traditionally considered relapse-driven, but recent studies have suggested possible subclinical progression. Whether this translates into clinically meaningful disability worsening remains unclear, and quantitative data on progression independent of relapse activity (PIRA) in NMOSD are limited. We investigated the frequency and clinical relevance of PIRA in a large cohort with long-term follow-up.

We retrospectively analyzed 281 patients with AQP4-IgG-positive NMOSD with ≥2 years of follow-up. Significant Expanded Disability Status Scale (EDSS) worsening occurred following conventional thresholds, using a roving baseline. PIRA was defined as EDSS worsening without relapse between assessments, confirmed ≥6 months later, sustained, and not attributable to confounders. Relapse-associated worsening (RAW) was defined when the best EDSS score assessed ≥6 months after relapse still met the threshold.

The mean follow-up duration was 11.3 ± 5.1 years, and the mean relapse-free duration was 8.3 ± 5.2 years. A total of 1,662 EDSS assessments were performed, with a median of 5 per patient (interquartile range, 4-7). Seven patients (2.5%) met PIRA criteria. Despite no treatment escalation, none worsened further. Among 194 patients with relapses, 70 (36.1%) experienced RAW.

PIRA was rare, even with extended observation using a formal framework, reaffirming relapse as the principal driver of disability and supporting continued focus on relapse prevention.