Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9–64), and the median interval from attack to biopsy was 1 month (range 0.5–96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

To clarify the clinical, neuropathological, and molecular characteristics of spinocerebellar ataxia type 6 (SCA6), two unrelated Japanese families with SCA6 were studied. A clinical feature of the two families was late onset "pure" cerebellar ataxia. Pathologically, three SCA6 brains consistently showed Purkinje cell dominant cortical cerebellar degeneration. Morphometric analysis showed that loss of the cerebellar granule cells and inferior olivary neurons were very mild compared with the severity of Purkinje cell loss. There was no obvious ubiquitin immunoreactive nuclear inclusions. All aVected patients had identical expanded alleles, and the expansion was also homogeneously distributed throughout the brain without mosaicism. The present study showed that SCA6 is characterised by Purkinje cell dominant cortical cerebellar degeneration, highly stable transmission of the CAG repeat expansion, and lack of ubiquitin immunoreactive nuclear inclusions. (J Neurol Neurosurg Psychiatry 1999;67:86-89)

Purpose: To elucidate the clinical and epidemiologic characteristics of optic neuritis in Japan. Design: Multicenter cross-sectional, observational cohort study. Participants: A total of 531 cases of unilateral or bilateral noninfectious optic neuritis identified in 33 institutions nationwide in Japan. Methods: Serum samples from patients with optic neuritis were tested for antieaquaporin-4 antibodies (AQP4-Abs) and antiemyelin oligodendrocyte glycoprotein antibodies (MOG-Abs) using a cell-based assay and were correlated with the clinical findings. Main Outcome Measures: Antibody positivity, clinical and radiologic characteristics, and visual outcome. Results: Among 531 cases of optic neuritis, 12% were AQP4-Ab positive, 10% were MOG-Ab positive, 77% were negative for both antibodies (double-negative), and 1 case was positive for both antibodies. Pretreatment visual acuity (VA) worsened to more than a median 1.0 logarithm of the minimum angle of resolution (logMAR) in all groups. After steroid pulse therapy (combined with plasmapheresis in 32% of patients in AQP4-Abepositive group), median VA improved to 0.4 logMAR in the AQP4-Abepositive group, 0 logMAR in the MOG-Abepositive group, and 0.1 logMAR in the double-negative group. The AQP4-Abepositive group showed a high proportion of females, exhibited diverse visual field abnormalities, and demonstrated concurrent spinal cord lesions on magnetic resonance imaging (MRI) in 22% of the patients. In the MOG-Abepositive group, although posttreatment visual outcome was good, the rates of optic disc swelling and pain with eye movement were significantly higher than those in the AQP4-Abepositive and double-negative groups. However, most cases showed isolated optic neuritis lesions on MRI. In the double-negative group, 4% of the patients had multiple sclerosis. Multivariate logistic regression analysis of all participants identified age and presence of antibodies (MOG-Ab and AQP4-Ab) as significant factors affecting visual outcome. Conclusions: The present large-scale cohort study revealed the clinicoepidemiologic features of noninfectious optic neuritis in Japan. Antieaquaporin-4 antibodyepositive optic neuritis has poor visual outcome. In contrast, MOG-Ab positive cases manifested severe clinical findings of optic neuritis before treatment, but few showed concurrent lesions in sites other than the optic nerve and generally showed good treatment response with favorable visual outcome. These findings indicate that autoantibody measurement is useful for prompt diagnosis and proper management of optic neuritis that tends to become refractory.