A Study on the Pathogenesis and Therapy of Optic-Spinal Multiple Sclerosis

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In Japan, multiple sclerosis (MS) has been classified into two subtypes, 1) conventional MS (CMS) in which demyelinating lesions are disseminated in the central nervous system and 2) optic-spinal MS (OSMS) characterized by the selective involvement of the optic nerves and spinal cord. OSMS and Neuromyelitis optica (NMO) have many features in common. We investigated the pathogeneses and therapy of OSMS :1. Features of NMO-IgG-positive casesIn 2004, we reported an NMO-OSMS-specific autoantibody, NMO-IgG. Longitudinally extensive. spinal cord lesions and blindness are commonly seen in NMO-IgG-positive patients. Also, some of them have unique brain lesions, such as longitudinally extensive lesions and periaqueductal lesions.2. Establishment of a sensitive assay of anti-aquaporin-4 (AQP4) antibodyThe target antigen of NMO-IgG was identified as AQP4 in 2005. We established a sensitive assay of anti-AQP4 antibody and found that about 90% of patients with NMO and the high-risk syndrome were seropositive, but none of the patients with MS and other diseases were positive for this autoantibody, suggesting that NMO is associated with anti-AQP4 antibody.3. Loss of AQP4 in NMO lesionsWe did a comparative neuropathological study of the spinal cord lesions of NMO and CMS. As a result, we found that in NMO AQP4 was completely lost in the perivascular regions where immunoglobulins and activated complements were deposited. The immunoreactivity of myelin basic protein was rather preserved. In contrast, AQP4 was upregulated in the demyelinating lesions of MS. These findings suggest that AQP4 densely expressed on the foot processes of astrocytes are targeted in NMO and that NMO is a distinct clinical entity from MS.4. Therapy of NMOWe found that half of NMO patients who were refractory to high-dose IV methylprednisolone did respond to plasma exchange. We also found that long-term low-dose corticosteroid was effective to reduce relapses in NMO