Neuromyelitis Optica Antibody in the Diagnosis of Neuromyelitis Optica
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. Lancet. 2004;364(9451):2106–2112
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that affects the spinal cord and optic nerves. Historically, it was often misdiagnosed as MS; however, the two diseases differ in their natural history, pathophysiology, treatment, and prognosis. Until this publication, there were no unique biomarkers to distinguish the two diseases.
To assess the capacity of NMO-IgG to distinguish NMO and related disorders from MS.
Cross-sectional study of serum from patients with the appropriate clinical criteria from 1998 to 2003.
Serum was obtained and tested from 102 North American patients with clinically defined NMO or syndromes that suggested a high-risk NMO such as optic–spinal disease. In addition, 12 Japanese patients with optic–spinal MS were included. Control patients had
MS, other myelopathies, optic neuropathies, and miscellaneous disorders. In addition, 14 patients were included who were incidentally shown to have NMO-IgG among 85,000 patients tested for suspected paraneoplastic autoimmune conditions.
Interventions Serum samples were obtained from all study subjects and were tested by an indirect immunofluorescence assay, which identified a distinctive NMO-IgG staining pattern. Selected positive and negative serum samples were also tested on sections of mouse midbrain, spinal cord, and liver in order to localize the regions where the patients’ IgG bound.
The primary outcome of this study was to establish the sensitivity and specificity for NMO-IgG in NMO.
The sensitivity and specificity for NMO-IgG were 73% (95% CI = 60–86) and 91% (95% CI = 79–100) for NMO and 58% (95% CI = 30–86) and 100% (95% CI = 66–100) for those identified as optic–spinal MS (which is now considered to be the same as NMO).
- NMO-IgG was detected in half of patients with high-risk syndromes.
- Of 14 seropositive cases identified incidentally, 12 had NMO or a high-risk syndrome for the disease.
- In mice, NMO-IgG immunofluorescence was in a distribution suggestive of an antigen at the blood–brain barrier.
NMO-IgG is a specific autoantibody of NMO and binds at or near the blood–brain barrier. It distinguishes NMO from MS. Asian optic–spinal MS seems to be the same condition as NMO.
The authors described an IgG autoantibody (NMO-IgG) that is highly specific for NMO, and the presence of this specific serum autoantibody can differentiate NMO from MS. No biomarker had previously been described. Because of this discovery, NMO became the first inflammatory demyelinating disorder of the CNS to have a defined autoantigen. This discovery has enabled physicians to use a serologic test to help support the diagnosis of the disease and has helped to define an NMO spectrum of disorders. Further refinements in the quality of the assay have been made, further increasing the sensitivity and specificity. This study also paved the way for the discovery that NMO-IgG is actually directed against aquaporin-4 (AQP-4), a water channel that is highly expressed in optic nerves, spinal cord, and certain areas of the brain stem.