进行性多灶性白质脑病

1、Progressive Multifocal Leukoencephalopathy,由JC (John Cunningham) 病毒感染少突胶质细胞为主要特征的致命性中枢神经系统脱髓鞘性疾病。,进行性多灶性自质脑病主要累及免疫抑制或接受免疫调节治疗的人群： 艾滋病患者,约占79%； 恶性血液系统疾病者13%； 器官移植者5%； 合并自身免疫性疾病者, 尤其是系统性红斑狼疮和类风湿性关节炎，3%。,JC病毒,JC病毒可穿过15种不同细胞的胞膜到达胞核, 然而却只能在人类神经母细胞瘤细胞内复制产生子代病毒。 JC病毒介导细胞死亡的机制尚不清楚,推测被该病毒感染的细胞可能会发生凋亡。但体外实验显示

2、, 病毒也可介导星形胶质细胞发生坏死而非凋亡。,PML病因学,血清流行病学研究发现,约80%正常成人体内存在JC病毒抗体。 JC病毒主要潜伏于骨髓、脾、扁桃体及肾脏等部位借助外周淋巴细胞、单核细胞甚至无细胞血浆在体内循环。,从JC病毒潜伏感染至发生进行性多灶性自质脑病, 共需经历5个关键步骤： 1 神经系统以外的JC病毒的潜伏 2 感染非编码控制区序列发生重排使病毒颗粒从原型转变为嗜神经型 3 JC病毒重新激活导致病毒血症, 使中枢神经系统受累 4 人体免疫监视功能失效 5 少突胶质细胞被病毒感染,HIV与JCV感染之间的关系： HIV使宿主陷入免疫抑制状态，JC病毒特异性CD4+T细胞减少,

3、使病毒的复制不受限制； HIV感染直接破坏血一脑脊液屏障，使潜伏病毒的细胞进人脑组织； HIV感染诱导产生的细胞因子在内的信号转导通路, 导致病毒启动子被激活； HIV反式激活蛋白（Tat 蛋白）可以在体外作用于病毒启动子,最终启动病毒基因的表达。,中枢神经系统 JC 病毒感染,经典型PML 炎症型PML PML相关免疫重建炎性综合征 JC病毒小脑颗粒细胞神经元神经病 JC病毒脑膜炎 JC病毒脑病,经典型PML,临床表现： 亚急性出现的偏瘫、偏身感觉障碍、视觉受累、失语、共济失调、意识模糊乃至痴呆一般不伴发热症状开始可出现部分症状, 随着病灶的不断扩大,症状加剧并增多。另有约18%的患者由于病

4、灶邻近皮质可伴发癫病发作。,病理学特征： 少突胶质细胞的裂解性感染, HE染色可见肿胀的少突胶质细胞胞核内存在嗜双色包涵体，免疫组织化学或原位杂交染色可见少突胶质细胞胞质及胞核内表达病蛋自或核酸, 少突胶质细胞的上述病理改变以进展性病灶的边缘部位最为常见。,Enlarged nuclei containing viral inclusions Hematoxylin and eosin,Case report of a patient with progressivemultifocal leukoencephalopathy under treatment with dimethyl fum

5、arate. Dammeier et al. BMC Neurology (2015) 15:108,Classic PML: demyelinating lesion of the white matter (arrow) surrounded by multiple JCV-infected glial cells (arrowheads).,JCV GCN: JCV infection of granule cell neurons (arrows).,JCV encephalopathy: JCV infected (arrow) hemispheric cortical neuron

6、s (arrowhead).,影像学改变： 累及双侧大脑半球,呈多发非对称性融合分布, 但也可表现为单侧甚至孤立性病灶、幕上病灶常源于血流最丰富的皮质下自质,状似贝壳,顶叶最常受累,其次是额叶, 较少波及内囊、外囊及胼胝体幕下白质病灶则主要位于小脑中脚邻近的脑桥和小脑, 有时脑桥病变会蔓延至中脑和或延髓。,病变多局限于皮质下U形纤维区域, 不累及U形纤维, 深部及脑室周围自质较少受累是经典型进行性多灶性白质脑病的特征性表现, 常被用来与艾滋病脑病及其他白质病变相鉴别。,A 40 yo man with HIV infection, who presented with progressive

7、onset of word finding difficulties and right hemiparesis followed by seizure, 4 days after starting cART. PCR was positive for JCV in the CSF peripheral CD4 count was 468 cells/ul. MRI performed at another hospital reported a 3 cm focus of abnormal increased signal on FLAIR sequences in the left fro

8、ntal subcortical white matter, surrounded by linear and punctate foci of enhancement at the margins of the lesion. This lesion extended into the left corona radiata, the corpus callosum and the right frontal white matter. MRI performed at our hospital 3 week after the initial one showed lesions in F

9、LAIR (A, arrows) and contrast enhancement in T1-weighted image post gadolinium injection (B, arrowheads). His aphasia improved progressively with addition of ritonavir to his cART (combined antiretrovial therapy) regimen. His CD4 count increased to 558 cells/ul and his HIV plasma viral load was unde

10、tectable. He then presented with worsening aphasia. MRI performed 2 and a half month after onset of initial symptoms showed enlargement of the lesions in the left hemispheric white matter and the corpus callosum in FLAIR (C, arrows) which displayed intense contrast enhancement in T1-weighted images

11、(D, arrowheads) as well as mass effect,right to left shift and subfalcine herniation. He was treated with dexamethasone 6 mg three times a day, tapered over 2 weeks, and cART was discontinued for two weeks. All neurological symptoms progressively improved and 2 and a half year later, he has no resid

12、ual weakness and only minor word finding difficulties. MRI showed leukomalacia and atrophy of the left frontal lobe with dilatation of the left lateral ventricule in FLAIR (E, arrows) and absence of contrast enhancement in T1-weighted image (F, arrowheads). His CD4 count was 669/ul and HIVplasma vir

13、al load continue to be undetectable.,Beyond progressive multifocal leukoencephalopathy: expanded pathogenesis of JC virus infection in the central nervous system. Lancet Neurol. 2010 April ; 9(4): 425437,诊断： PML的明确诊断有赖于组织病理学证实，对于不能施行脑组织活检者, 明确诊断PML需具备以下三点： 1 持续存在的PML典型临床症状 2 脑脊液病毒检测阳性 3 具有PML的典型影像学表

14、现 血液或尿液病毒阳性无诊断价值,Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58:1207. quiz CE1-4.,治疗： 西多福韦及阿糖胞苷的疗效尚有诸多争议； 5-HTC2A受体阻断药米氮平和利培酮具有潜在的治疗价值, 已在一些医疗单位于临床； 抗疟疾药物甲氟喹在体外也有抗病毒能力, 且能透过血-脑脊液屏障,部分病例治疗有效； 对合并HIV感染的患者,高效抗逆转录病毒疗法为最佳选择, 可稳定50-60%患者的病情。,不伴HIV感染且临床状况允许的患者,应避免应用免疫抑制药如激素、那他珠单抗等； 器官移植者,