1、进行性多灶性白质脑病 由由JC(John Cunningham)JC(John Cunningham)病毒感染少病毒感染少突胶质细胞为主要特征的致命性中枢神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。经系统脱髓鞘性疾病。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。器官移植者5%；He was treated with dexamethasone 6 mg three times a day,tapered over 2 weeks,and cART was discontinued for two weeks.MRI perfor
2、med at our hospital 3 week after the initial one showed lesions in FLAIR(A,arrows)and contrast enhancement in T1-weighted image post gadolinium injection(B,arrowheads).Enlarged nuclei containing viral inclusions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。treatment of opportunistic infections in HIV-i
3、nfected adults and adolescents:recommendationsHis aphasia improved progressively with addition of ritonavir to his cART(combined antiretrovial therapy)regimen.MRI performed 2 and a half month after onset of initial symptoms showed enlargement of the lesions in the left hemispheric white matter and t
4、he corpus callosum in FLAIR(C,arrows)which displayed intense contrast enhancement in T1-weighted images(D,arrowheads)as well as mass effect,right to left shift and subfalcine herniation.中枢神经系统 JC 病毒感染Lancet Neurol.HIV使宿主陷入免疫抑制状态，JC病毒特异性CD4+T细胞减少,使病毒的复制不受限制；Classic PML:demyelinating lesion of the whi
5、te matter(arrow)surrounded by multipleAll neurological symptoms progressively improved and 2 and a half year later,he has no residual weakness and only minor word finding difficulties.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；1 神经系统以外的JC病毒的潜伏PCR was positive for JCV in the CSF peripheral CD4 count wa
6、s 468 cells/ul.treatment with dimethyl fumarate.PML相关免疫重建炎性综合征 进行性多灶性自质脑病主要累及免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：疫抑制或接受免疫调节治疗的人群：艾滋病患者艾滋病患者,约占约占79%79%；恶性血液系统疾病者恶性血液系统疾病者13%13%；器官移植者器官移植者5%5%；合并自身免疫性疾病者合并自身免疫性疾病者,尤其是系统尤其是系统性红斑狼疮和类风湿性关节炎，性红斑狼疮和类风湿性关节炎，3%3%。JCJC病毒病毒JCJC病毒可穿过病毒可穿过1515种不同细胞的胞膜到达种不同细胞的胞膜到达胞核胞
7、核,然而却只能在人类神经母细胞瘤细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。胞内复制产生子代病毒。JCJC病毒介导细胞死亡的机制尚不清楚病毒介导细胞死亡的机制尚不清楚,推推测被该病毒感染的细胞可能会发生凋亡测被该病毒感染的细胞可能会发生凋亡。但体外实验显示。但体外实验显示,病毒也可介导星形胶病毒也可介导星形胶质细胞发生坏死而非凋亡。质细胞发生坏死而非凋亡。PMLPML病因学病因学血清流行病学研究发现血清流行病学研究发现,约约80%80%正常成人正常成人体内存在体内存在JCJC病毒抗体。病毒抗体。JCJC病毒主要潜伏于骨髓、脾、扁桃体及病毒主要潜伏于骨髓、脾、扁桃体及肾脏等部位借助外周
8、淋巴细胞、单核细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。胞甚至无细胞血浆在体内循环。从从JCJC病毒潜伏感染至发生进行性多灶性自病毒潜伏感染至发生进行性多灶性自质脑病质脑病,共需经历共需经历5 5个关键步骤：个关键步骤：1 1 神经系统以外的神经系统以外的JCJC病毒的潜伏病毒的潜伏 2 2 感染非编码控制区序列发生重排使病毒颗粒从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原型转变为嗜神经型 3 JC 3 JC病毒重新激活导致病毒血症病毒重新激活导致病毒血症,使中枢神经系使中枢神经系统受累统受累 4 4 人体免疫监视功能失效人体免疫监视功能失效 5 5 少
9、突胶质细胞被病毒感染少突胶质细胞被病毒感染His aphasia improved progressively with addition of ritonavir to his cART(combined antiretrovial therapy)regimen.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。His aphasia improved progressively with addition of ritonavir to his cART(combined antiretrovial therapy)regimen.trea
10、tment of opportunistic infections in HIV-infected adults and adolescents:recommendationsPML相关免疫重建炎性综合征PCR was positive for JCV in the CSF peripheral CD4 count was 468 cells/ul.Beyond progressive multifocal leukoencephalopathy:expanded pathogenesis of JC virus infection in the central nervous system.
11、PCR was positive for JCV in the CSF peripheral CD4 count was 468 cells/ul.中枢神经系统 JC 病毒感染PCR was positive for JCV in the CSF peripheral CD4 count was 468 cells/ul.器官移植者,由于不应用免疫抑制药可加重机体排斥反应,应试用树突细胞疫苗；treatment of opportunistic infections in HIV-infected adults and adolescents:recommendationstreatment
12、with dimethyl fumarate.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。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。HIVHIV与与JCVJCV感染之间的关系：感染之间的关系：nHIVHIV使宿主陷入免疫抑制状态，使宿主陷入免疫抑制状态，JCJC病毒特异性病毒特异性CD4+TCD4+T细胞减少细胞减少,使病毒的复制不受限制；使病毒的复制不受限制；nHIVHIV感染直接破坏血一脑脊液屏障，使潜伏病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；毒的细胞进人脑组织；nHIVHIV感染诱导产生的细胞
13、因子在内的信号转导感染诱导产生的细胞因子在内的信号转导通路通路,导致病毒启动子被激活；导致病毒启动子被激活；nHIVHIV反式激活蛋白（反式激活蛋白（Tat Tat 蛋白）可以在体外作蛋白）可以在体外作用于病毒启动子用于病毒启动子,最终启动病毒基因的表达。最终启动病毒基因的表达。中枢神经系统中枢神经系统 JC JC 病毒感染病毒感染经典型经典型PMLPML炎症型炎症型PMLPMLPMLPML相关免疫重建炎性综合征相关免疫重建炎性综合征JCJC病毒小脑颗粒细胞神经元神经病病毒小脑颗粒细胞神经元神经病JCJC病毒脑膜炎病毒脑膜炎JCJC病毒脑病病毒脑病经典型经典型PMLPML临床表现：临床表现：亚
14、急性出现的偏瘫、偏身感觉障碍、视觉亚急性出现的偏瘫、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般不伴发热症状开始可出现部分症状,随着病随着病灶的不断扩大灶的不断扩大,症状加剧并增多。另有约症状加剧并增多。另有约18%18%的的患者由于病灶邻近皮质可伴发癫病发作。患者由于病灶邻近皮质可伴发癫病发作。病理学特征：病理学特征：少突胶质细胞的裂解性感染少突胶质细胞的裂解性感染,HE,HE染色可见染色可见肿胀的少突胶质细胞胞核内存在嗜双色包涵体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
15、突胶质，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细胞胞质及胞核内表达病蛋自或核酸,少突胶少突胶质细胞的上述病理改变以进展性病灶的边缘部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。位最为常见。Enlarged nuclei containing viral inclusionsHematoxylin and eosinCase report of a patient with progressivemultifocal leukoencephalopathy undertreatment with dimethyl fumarate.Dammeier et
16、al.BMC Neurology()15:108Classic PML:demyelinating lesion of the white matter(arrow)surrounded by multipleJCV-infected glial cells(arrowheads).JCV GCN:JCV infection of granule cell neurons(arrows).JCV encephalopathy:JCV infected(arrow)hemispheric cortical neurons(arrowhead).影像学改变：影像学改变：累及双侧大脑半球累及双侧大脑
17、半球,呈多发非对称性融合分呈多发非对称性融合分布布,但也可表现为单侧甚至孤立性病灶、幕上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病灶常源于血流最丰富的皮质下自质,状似贝壳状似贝壳,顶叶最常受累顶叶最常受累,其次是额叶其次是额叶,较少波及内囊、外较少波及内囊、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邻近的脑桥和小脑,有时脑桥病变会蔓延至中有时脑桥病变会蔓延至中脑和或延髓。脑和或延髓。病变多局限于皮质下病变多局限于皮质下U U形纤维区域形纤维区域,不累及不累及U U形纤维形纤维,深部及脑室周围自质较少受累是经典深
18、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型进行性多灶性白质脑病的特征性表现,常被常被用来与艾滋病脑病及其他白质病变相鉴别。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 onset of word finding difficulties and right hemiparesis followed by seizure,4 days after starting cART.PCR was positive for JCV in the CSF periph
19、eral 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 frontal subcortical white matter,surrounded by linear and punctate foci of enhancement at the margins of the lesion.This lesion extended into the left c
20、orona radiata,the corpus callosum and the right frontal white matter.MRI performed at our hospital 3 week after the initial one showed lesions in FLAIR(A,arrows)and contrast enhancement in T1-weighted image post gadolinium injection(B,arrowheads).His aphasia improved progressively with addition of r
21、itonavir to his cART(combined antiretrovial therapy)regimen.His CD4 count increased to 558 cells/ul and his HIV plasma viral load was undetectable.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 h
22、emispheric white matter and the corpus callosum in FLAIR(C,arrows)which displayed intense contrast enhancement in T1-weighted images(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 cAR
23、T was discontinued for two weeks.All neurological symptoms progressively improved and 2 and a half year later,he has no residual 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,ar
24、rows)and absence of contrast enhancement in T1-weighted image(F,arrowheads).His CD4 count was 669/ul and HIVplasma viral load continue to be undetectable.Beyond progressive multifocal leukoencephalopathy:expanded pathogenesis of JC virus infection in the central nervous system.Lancet Neurol.April;9(
25、4):425437诊断：诊断：PML PML的明确诊断有赖于组织病理学证实，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对于不能施行脑组织活检者,明确诊断明确诊断PMLPML需需具备以下三点：具备以下三点：1 1 持续存在的持续存在的PMLPML典型临床症状典型临床症状 2 2 脑脊液病毒检测阳性脑脊液病毒检测阳性 3 3 具有具有PMLPML的典型影像学表现的典型影像学表现血液或尿液病毒阳性无诊断价值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 preventio
26、n andtreatment of opportunistic infections in HIV-infected adults and adolescents:recommendationsfrom CDC,the National Institutes of Health,and the HIV Medicine Association of the InfectiousDiseases Society of America.MMWR Recomm Rep ;58:1207.quiz CE1-4.治疗：治疗：n西多福韦及阿糖胞苷的疗效尚有诸多争议；西多福韦及阿糖胞苷的疗效尚有诸多争议；n
27、5-HTC2A5-HTC2A受体阻断药米氮平和利培酮具有潜在受体阻断药米氮平和利培酮具有潜在的治疗价值的治疗价值,已在一些医疗单位于临床；已在一些医疗单位于临床；n抗疟疾药物甲氟喹在体外也有抗病毒能力抗疟疾药物甲氟喹在体外也有抗病毒能力,且且能透过血能透过血-脑脊液屏障脑脊液屏障,部分病例治疗有效；部分病例治疗有效；n对合并对合并HIVHIV感染的患者感染的患者,高效抗逆转录病毒疗法高效抗逆转录病毒疗法为最佳选择为最佳选择,可稳定可稳定50-60%50-60%患者的病情。患者的病情。不伴不伴HIVHIV感染且临床状况允许的患者感染且临床状况允许的患者,应避免应应避免应用免疫抑制药如激素、那他珠
28、单抗等；用免疫抑制药如激素、那他珠单抗等；器官移植者器官移植者,由于不应用免疫抑制药可加重机由于不应用免疫抑制药可加重机体排斥反应体排斥反应,应试用树突细胞疫苗；应试用树突细胞疫苗；PMLPML相关免疫重建炎性综合征并临床症状呈渐相关免疫重建炎性综合征并临床症状呈渐进性加重者进性加重者,可以采用甲泼尼龙可以采用甲泼尼龙1g1g静脉冲击治静脉冲击治疗疗 然后口服糖皮质激素逐渐减量直至数月。然后口服糖皮质激素逐渐减量直至数月。预后：预后：n在高效抗逆转录病毒疗法普及之前在高效抗逆转录病毒疗法普及之前,艾滋病合并艾滋病合并PMLPML患者患者1 1年生存率仅为年生存率仅为10%,10%,目前业已升至目前业已升至50%50%；n 当患者外周血当患者外周血CD4+TCD4+T细胞增加并出现针对细胞增加并出现针对JCJC病毒的病毒的CD8+TCD8+T细胞细胞,以及以及MRIMRI显示病灶强化且显示病灶强化且神经功能恢复即提示患者生存期较长；神经功能恢复即提示患者生存期较长；n而脑脊液病毒拷贝数目与预后呈负相关。而脑脊液病毒拷贝数目与预后呈负相关。
