Reclassification of acute inflammatory myelopathies in the antibody era: from AQP4-IgG and MOG-IgG to double-seronegative disease

Acute inflammatory myelopathy refers to a heterogeneous group of acute or subacute spinal cord syndromes characterized by clinical features suggestive of inflammatory involvement. Although these diseases have overlapping clinical manifestations, their underlying mechanisms, disease progression, and classification systems remain heterogeneous. The discovery of AQP4-IgG and MOG-IgG has driven a shift from a “syndrome-based nomenclature” to a “disease-specific classification,” allowing some patients previously classified as transverse myelitis or seronegative NMOSD to be reclassified as more specific disease entities. However, AQP4-IgG/MOG-IgG double-negative cases remain highly heterogeneous, including double-negative NMOSD, multiple sclerosis (MS), other immune-mediated myelopathies, and non-inflammatory mimics. Additionally, testing conditions may also affect whether a patient is classified as seronegative. This narrative review examines the roles of antibody stratification, MRI, and cerebrospinal fluid in the classification of acute inflammatory myelopathy, focusing on the disease composition of double-negative cases and longitudinal reclassification. Existing evidence supports interpreting double-seronegative status as a serological classification state rather than an independent disease entity. Some patients initially unclassified may be reclassified into specific disease categories during longitudinal follow-up.