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Severe attacks of neuromyelitis optica spectrum disorder (NMO-SD) are improved by plasma exchange (PLEX) given as an adjunctive therapy. Initial studies failed to demonstrate a delay of PLEX treatment influenced clinical outcome; however PLEX was always used late. We examine the clinical consequences of delay in PLEX initiation on severe optic neuritis and spinal cord attacks in NMO-SD.All of our patients who suffered attacks of NMO-SD, treated in our centre by PLEX, were retrospectively considered for inclusion. Primary outcome was defined as complete improvement. Secondary poor/good outcomes were respectively defined to be the higher/lower third of Delta-Expanded Disability Status Scale (EDSS) (late minus baseline EDSS). Delays from clinical onset to PLEX initiation were categorised for multivariate analysis.Of the 60 patients included, NMO-SD criteria (2015) were fulfilled in 92%. One hundred and fifteen attacks were included and received PLEX with a median of 7 days (0–54) after clinical onset. The probability to regain complete improvement continuously decreased from 50% for PLEX given at day 0 to 1%–5% after day 20. Through multivariate analysis, the baseline impairment and PLEX delay were associated with the probability to complete improvement (OR 5.3; 95% CI 1.8 to 15.9). Reducing the PLEX delay also influenced the good secondary outcome but not the poor secondary outcome.These results confirm an improved clinical benefit of early initiation of PLEX during severe attacks of NMO-SD. Perceiving PLEX as a rescue therapy only after steroid failure could be deleterious.