Department of Neurology and Geriatrics (Y.S., N.K., Y.H., M.Y., Y. Takata, O.W., J.Y., Y. Tashiro, R.S., S.N., A.Y., K.I., K.S., H.A., K.M., K.H., A.H., Y.O., R.H., T.S., E.M., R.O., I.H., T.I., H.T.), Center for Chronic Viral Diseases (S.A., S.I.), Department of Neurosurgery (H.H.), and Department of Psychiatry (A.S.), Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Center for Genomic Medicine (H.W., F.M.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Neurology (Y. Tashiro, R.S.), Fujimoto Hayasuzu Hospital, Miyazaki, Japan; and National Sanatorium Hoshizuka Keiaien (M.G.), Kagoshima, Japan.
Neurol Neuroimmunol Neuroinflamm. 2015 Aug 13;2(5):e143. doi: 10.1212/NXI.0000000000000143. eCollection 2015 Oct.
To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent.
From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin.
All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff-positive macrophages and 2-7 μm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy.
We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis.
确定一种新型不明病原体脑炎的病原体，并探讨有效的治疗方法，报告该病原体的初步超微结构和基因组特征。
2005 年至 2012 年，我们治疗了 4 例具有地理聚集性和相似临床特征、血清/CSF 细胞学和影像学表现的日本患者。所有患者均进行了脑活检，通过组织学分析神经病理学变化，应用电子显微镜揭示潜在病原体的特征。从受影响的脑组织和 CSF 中获得基因组 DNA，并采用无偏高通量测序方法筛选指示病原体来源的特定基因组序列。
所有患者均表现为进行性痴呆伴不自主舌运动。CSF 细胞学检查显示单核细胞升高。颞叶、皮质下白质和脊髓可见异常 MRI 信号。活检脑组织显示聚集的过碘酸希夫阳性巨噬细胞和 2-7μm 直径的圆形/椭圆形无核或无细胞壁的小体散布在血管周围。无偏高通量测序鉴定出 100 多个古菌特异性 DNA 片段。所有患者对甲氧苄啶/磺胺甲噁唑（TMP-SMX）加皮质类固醇治疗均有反应。
我们报告了 4 例由不明病原体引起的脑炎病例。基于超微结构和基因组研究，我们提出了一种新的疾病实体，由具有古菌特征的病原体引起。TMP-SMX 治疗对这种新型脑炎有效。
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