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

在日本，多发性硬化症（MS）分为两种亚型，1）常规MS（CMS），其中脱髓鞘病变散布在中枢神经系统中，2）视脊髓MS（OSMS），其特征在于视神经和脊髓的选择性受累。OSMS和视神经肌萎缩症（NMO）有许多共同的特征。我们探讨了OSMS的发病机制和治疗方法：1. NMO-IgG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-IgG。纵向广泛。脊髓损伤和失明在NMO-IgG阳性患者中常见。此外，他们中的一些人有独特的脑病变，如纵向广泛病变和导水管周围病变。水通道蛋白4（AQP 4）抗体检测方法的建立2005年发现的NMO-IgG的靶抗原为AQP 4。我们建立了一种敏感的抗AQP 4抗体检测方法，发现约90%的NMO和高危综合征患者血清学阳性，而MS和其他疾病患者均无该抗体阳性，提示NMO与抗AQP 4抗体有关. NMO病变中AQP 4的丢失我们对NMO和CMS的脊髓病变进行了神经病理学的比较研究。结果，我们发现在NMO中，AQP 4在免疫球蛋白和活化补体沉积的血管周围区域完全丢失。髓鞘碱性蛋白的免疫反应性相当保存。相反，AQP 4在MS的脱髓鞘病变中上调。这些发现表明，在星形胶质细胞的足突上密集表达的AQP 4在NMO中被靶向，并且NMO是与MS不同的临床实体。NMO的治疗我们发现，大剂量甲泼尼龙静脉注射难治的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皮质类固醇对减少NMO复发有效

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