Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), whereas neuromyelitis optica (NMO) is an inflammatory disease of the CNS selectively affecting the optic nerves and spinal cord. The pathological hallmark in MS is sharply demarcated demyelinating plaque with axons relatively preserved, whereas in NMO both axons and myelin are involved, resulting in necrotic cavitation. The nosological position of NMO has long been a matter of debate. In Asians, MS is rare; however, when it appears, the selective but severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal MS (OSMS), has similar features to those of the relapsing form of NMO in Western populations. Recent discovery of a specific immunoglobulin G (IgG) against NMO, designated NMO-IgG, suggests that NMO is a distinct disease entity with a fundamentally different etiology from that of MS. Because NMO-IgG has been reported to be present in about 50%-60% of OSMS patients with longitudinally extensive spinal cord lesions (LESCLs), OSMS in Asians has been suggested to be the same entity as NMO. About half of the patients with the anti-aquaporin 4 (AQP4) antibody demonstrate brain lesions fulfilling the Barkhof criteria, whereas OSMS patients without the anti-AQP4 antibody show significantly fewer brain lesions. These findings indicate that the mechanism of LESCLs in Asians is heterogeneous, both related and unrelated to anti-AQP4 antibody, and that the disease condition with anti-AQP4 antibody does not completely overlap OSMS in Asians. This review discusses possible mechanisms for OSMS and anti-AQP4 autoimmune syndrome of the CNS.