Seronegative NMOSD: Emerging Mechanisms, Diagnostic Boundaries, and Therapeutic Opportunities

Recent advances in neuroimmunology have revolutionized the classification and understanding of
central nervous system inflammatory disorders, particularly with the identification of aquaporin-4
(AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies in demyelinating diseases.
Neuromyelitis optica spectrum disorder (NMOSD) remains a key diagnosis in this landscape;
however, a clinically significant subset of patients with NMOSD-like syndromes are seronegative for
both AQP4-IgG and MOG-IgG. These antibody-negative cases pose persistent challenges due to
their biological heterogeneity, overlapping clinical features with other neuroinflammatory diseases,
and the absence of standardized diagnostic and therapeutic frameworks. The pathogenesis of
seronegative NMOSD is still poorly understood, with current evidence pointing to potential novel
immune pathways, autoantibodies, or distinct endophenotypes. The lack of evidence-based
guidelines leaves these patients at risk for under-recognition or suboptimal care, underscoring an
urgent need for research to clarify their place within the neuroimmunological spectrum.

This Research Topic aims to advance the scientific and clinical understanding of seronegative
NMOSD as a distinct and unresolved neuroimmunological entity. Our objective is to address critical
gaps by exploring the underlying mechanisms, clinical and radiological phenotypes, novel
biomarkers, and therapeutic strategies specific to this antibody-negative group. We invite
contributions that dissect mechanistic processes beyond current antibody paradigms, define
emerging diagnostic boundaries, and chart precision approaches for disease stratification and
management. In particular, we seek studies that critically examine the limitations of conventional
diagnostic frameworks, highlight the nuanced diversity of clinical presentations, and propose
innovative approaches to therapeutic decision-making for these patients, who are often excluded
from pivotal clinical trials.

This Research Topic will focus exclusively on seronegative NMOSD and closely related antibody
negative inflammatory demyelinating syndromes. Submissions should emphasize the unique
biological, clinical, or therapeutic aspects of antibody-negative disease, but comparative studies that
help differentiate seronegative NMOSD from AQP4-positive NMOSD, MOGAD, multiple sclerosis,
and idiopathic transverse myelitis are also encouraged. We welcome original research, reviews,
perspectives, case reports, and experimental or clinical methodology articles. To further delineate the
field, we particularly invite manuscripts addressing, but not limited to, the following themes:

• Pathogenic mechanisms and novel immune targets in AQP4-/MOG-negative NMOSD
• Discovery and validation of new biomarkers, autoantibodies, and immune signatures
• Clinical, neuroimaging, and disease course phenotypes across the seronegative NMOSD
spectrum
• Diagnostic barriers, classification challenges, and disease boundaries
• Therapeutic responsiveness, treatment strategies, and innovation for antibody-negative
patients
• Precision medicine and personalized clinical approaches for seronegative NMOSD

Articles may also address methodological advances in immunoprofiling, neuroimaging, or
biomarker development relevant to this population. We accept a wide range of article types,
including Original Research, Review, Mini-Review, Systematic Review, Methods, Hypothesis &
Theory, Perspective, Clinical Trial, Study Protocol, Case Report, Brief Research Report, Data
Report, General Commentary, and Opinion manuscripts.

Topic Editor Shahd Hamid declares the following conflicts of interest: receipt of honoraria for speaker and advisory board roles from Novartis, Roche, Merck, KSP, and Amgen.

Topic Editor Azza Ismail declares the following conflicts of interest: receipt of honoraria for speaker and advisory board roles from Merck, Novartis, Roche, and Julphar.