Proportion and Clinical Characteristics of Double‐Seronegative
NMOSD
in a Multicenter Real‐World Cohort
Jae‐Won Hyun, Ki Hoon Kim, Seung Woo Kim, Ha Young Shin, You‐Ri Kang, Tai‐Seung Nam, Woojun Kim, Su‐Hyun Kim, Ho Jin Kim ABSTRACT
Background
Recent 2025 neuromyelitis optica spectrum disorder (NMOSD) criteria distinguish AQP4‐IgG‐positive disease from seronegative‐syndromic groups, into which double‐seronegative‐NMOSD (DN‐NMOSD) may be reclassified, suggesting the need to better characterize DN‐NMOSD within prior diagnostic frameworks.
Objective
To determine the proportion and clinical characteristics of DN‐NMOSD using rigorously applied 2015 NMOSD criteria with cell‐based assays (CBAs).
Methods
In this multicenter retrospective cohort study across four Korean referral centers, 634 individuals fulfilling the 2015 criteria were identified. AQP4‐IgG and MOG‐IgG were assessed using CBAs, with repeated testing in initially seronegative individuals.
Results
DN‐NMOSD accounted for 8.4% (53/634). Median onset age was 36 years, with mild female predominance (59%). At disease onset, classical NMO phenotype (simultaneous optic neuritis and myelitis) was rare (2%), and isolated brain involvement without myelitis, optic neuritis, or area postrema syndrome was uncommon (13%). Over a median 9‐year follow‐up, 93% showed a relapsing course, and maintenance immunosuppressive therapy was used in 91% with reduction in relapse rate after treatment ( p < 0.001).
Conclusions
In a large multicenter cohort, DN‐NMOSD represents a small proportion of NMOSD when stringent diagnostic criteria and repeated CBA testing are applied. These findings may provide data relevant to ongoing discussions on classification of the seronegative‐syndromic group within evolving diagnostic frameworks.