NMO-IgG is a disease-specific autoantibody for neuromyelitis optica (NMO) and its target antigen is aquaporin-4 (AQP4) water channel. Recently, we established a sensitive anti-AQP4 antibody assay using human AQP4-transfected cells, which appeared more sensitive than the original NMO-IgG assay. So far, there has been no large-scale study on anti-AQP4 antibody titre in NMO and related disorders. We tested 148 sera of patients with NMO, high-risk syndrome of NMO, multiple sclerosis (MS), clinically isolated syndrome suggestive of MS and miscellaneous diseases. We analysed the relation of anti-AQP4 antibody titres and clinical and laboratory parameters. The sensitivity of anti-AQP4 antibody assay was 91% (95% CI 79-100) for NMO and 85% (65-100) for high-risk syndrome, and the specificity was 100% (91-100) for NMO and high-risk syndrome, that is, none with the other disorders was positive. Among 21 anti-AQP4 antibody-positive cases whose NMO-IgG were tested, 15 were NMO-IgG-positive and 6 were NMO-IgG-negative. Higher anti-AQP4 antibody titres were associated with complete blindness and extensive or large cerebral lesions on MRI. The lengths of spinal cord lesions on MRI were positively correlated with the titres of anti-AQP4 antibody at the nadir of exacerbations. A few patients who had short (approx. one to two vertebral segments) spinal cord lesions on MRI were also seropositive with low anti-AQP4 antibody titres, but did have other clinical and MRI features of NMO. Anti-AQP4 antibody titres became lower after high-dose methylprednisolone, and a follow-up showed anti-AQP4 antibody titres remained low in relapse-free periods under immunosuppression. Cerebrospinal fluid (CSF)-anti-AQP4 antibody was detected when the serum-antibody titres exceeded 512x, at the ratio of 1 (CSF) to 500 (serum). Using a sensitive assay, the results of the present study suggest that NMO and high-risk syndrome may be essentially anti-AQP4 antibody-associated disorders, and that the anti-AQP4 antibody titres have significant clinical and immunological implications in NMO.

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Neuromyelitis optica (NMO) is characterized by severe optic neuritis and transverse myelitis. The relationship of NMO to multiple sclerosis (MS) has long been debated, but NMO has been classified as a demyelinating disease. Since the discovery of an NMO‐specific autoantibody to aquaporin 4 (AQP4), a dominant water channel in the central nervous system densely expressed on end‐feet of astrocytes, the clinical, magnetic resonance imaging and laboratory findings to distinguish NMO from MS have been clarified. Furthermore, pathological studies showed an extensive loss of immunoreactivities to astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), and perivascular deposition of immunoglobulins and activated complements with a relative preservation of the staining of myelin basic protein (MBP) in acute NMO lesions, but not in MS. In support of these pathological findings, the GFAP levels in the cerebrospinal fluid (CSF) during acute exacerbation of NMO are remarkably elevated compared with MBP and neurofilament, whereas the CSF‐GFAP in MS is not different from those in controls. Additionally, recent experimental studies have convincingly shown that AQP4 antibody is pathogenic in causing astorocytic destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that damage of astrocytes is far more severe than those of myelin and neurons, and that autoimmune astrocytopathy is the primary pathology in NMO. Based on these accumulated data, we propose that NMO should be classified as an astrocytopathic disease rather than a demyelinating disease.

ObjectiveTo elucidate the differences in the source and in the level of intrathecal synthesis between anti-aquaporin-4 antibodies (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).MethodsThirty-eight patients with MOG-IgG-associated disease and 36 with AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD) were studied for the antibody titers in the sera and cerebrospinal fluids (CSF) simultaneously collected in the acute attacks. The quotients between CSF and serum levels of albumin, total IgG, and each disease-specific antibody were calculated. Intrathecal production level in each disease-specific antibody was evaluated by calculating antibody index from these quotients.ResultsEleven of the 38 patients with MOG-IgG were positive for the antibody only in the CSF, while no patient with AQP4-IgG showed CSF-restricted AQP4-IgG. Blood-brain barrier compromise as shown by raised albumin quotients was seen in 75.0% of MOG-IgG-positive cases and 43.8% of AQP4-IgG-positive cases. Moreover, MOG-IgG quotients were more than 10 times higher than AQP4-IgG quotients (effect size r = 0.659, p < 0.0001). Elevated antibody index (>4.0) was confirmed in 12 of 21 with MOG-IgG, whereas it was seen only in one of 16 with AQP4-IgG (φ = 0.528, p < 0.0001). The CSF MOG-IgG titers (rho = +0.519, p = 0.001) and antibody indexes for MOG-IgG (rho = +0.472, p = 0.036) correlated with the CSF cell counts but not with clinical disability.ConclusionsIntrathecal production of MOG-IgG may occur more frequently than that of AQP4-IgG. This finding implies the different properties of B-cell trafficking and antibody production between MOG-IgG-associated disease and AQP4-IgG-positive NMOSD.