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

在日本，多发性硬化症(MS)被分为两种亚型：1)常规多发性硬化症(CMS)，脱髓鞘病变播散于中枢神经系统；2)视神经脊髓型多发性硬化症(OSM)，其特征是选择性累及视神经和脊髓。OSMS和视神经脊髓炎(NMO)有许多共同特征。我们探讨了OSMS的发病机制和治疗：1.NMO-Ig G阳性病例的特点2004年，我们报道了一种NMO-OSMS特异性自身抗体NMO-Ig G。纵向延伸的。脊髓损害和失明常见于NMO-Ig G阳性患者。此外，其中一些有独特的脑部病变，如纵向广泛的病变和中脑导水管周围病变。抗水通道蛋白4(AQP4)抗体检测方法的建立2005年，NMO-Ig G的靶抗原被鉴定为AQP4。我们建立了一种敏感的抗AQP4抗体检测方法，发现约90%的NMO患者和高危综合征患者血清阳性，而MS和其他疾病患者中该自身抗体均为阴性，提示NMO与抗AQP4抗体有关。AQP4在NMO病变中的丢失我们对NMO和CMS的脊髓病变进行了比较神经病理学研究。结果，我们发现在NMO中，AQP4在储存免疫球蛋白和活化补体的血管周围区域完全丢失。髓鞘碱性蛋白的免疫反应性保留较好。相反，AQP4在MS的脱髓鞘病变中表达上调。这些结果表明，AQP4在NMO中是以星形胶质细胞足突上密集表达为靶点的，NMO是与MS不同的临床实体。NMO的治疗我们发现，对大剂量静脉注射甲基强的松龙无效的NMO患者中有一半对血浆置换有反应。我们还发现长期低剂量的皮质类固醇可以有效地减少NMO的复发

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