The two faces of neuromyelitis optica

Over the past 15 years, it had seemed as if neuromyelitis optica (NMO) might be a distinct and homogeneous subtype of CNS demyelinating disease distinguishable from the heterogeneous assortment of patients captured by the umbrella diagnosis of multiple sclerosis (MS). NMO had distinctive clinical, radiologic, and pathologic characteristics and, in most cases, a highly specific biomarker, aquaporin-4 (AQP4) autoantibodies, was detectable.(1) However, recent observations might be interpreted as dashing hopes of NMO being a single disorder with uniform pathogenesis. The clinical presentation of NMO is increasingly recognized as heterogeneous. A variety of cerebral, diencephalic, and brainstem presentations(1,2) may occur as presenting features or over the course of the disease, which may have been previously considered inconsistent with the diagnosis. However, most of the manifestations of NMO seem to be explained by the distribution and level of expression of AQP4, so the heterogeneity of clinical manifestations does not seriously challenge the hypothesis of uniform pathogenesis.(3,4) A more vexing issue has been the 10%-30% of persons who are seronegative for the AQP4 autoantibody despite evaluation with the most sensitive cell-based assays available. Do they represent a distinct entity?