1、Progressive Multifocal Progressive Multifocal LeukoencephalopathyLeukoencephalopathy进行性多灶性白质脑病 由由JC(John Cunningham)JC(John Cunningham)病毒感染少突胶质细胞为主要特征的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。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：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
2、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,尤其是系统性红斑狼疮和类风湿性尤其是系统性红斑狼疮和类风湿性关节炎，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胞核种不同细胞的胞膜到达胞核,然而却只能在人类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。神经母细胞瘤细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,推测被该病毒感染的细胞推测被该病毒感染的细胞可能会发生凋亡。但体外实验显示可能会发生凋亡。但体外实验显示,病毒也可介导星形胶质细胞病毒也可介导星形胶质
3、细胞发生坏死而非凋亡。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%正常成人体内存在正常成人体内存在JCJC病毒抗体。病毒抗体。JCJC病毒主要潜伏于骨髓、脾、扁桃体及肾脏等部位借助外周淋巴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。细胞、单核细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质脑病病毒潜伏感染至发生进行性多灶性自质脑病,共需经历共需经历5 5个关个关键步骤：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
4、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,使中枢神经系统使中枢神经系统受累受累 4 4 人体免疫监视功能失效人体免疫监视功能失效 5 5 少突胶质细胞被病毒感染少突胶质细胞被病毒感染HIVHIV与与JCVJCV感染之间的关系：感染之间的关系：HIVHIV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；HIVHIV感染直接破坏血一脑脊液屏障，使潜伏病毒感染直
5、接破坏血一脑脊液屏障，使潜伏病毒的细胞进人脑组织；的细胞进人脑组织；HIVHIV感染诱导产生的细胞因子在内的信号转导通感染诱导产生的细胞因子在内的信号转导通路路,导致病毒启动子被激活；导致病毒启动子被激活；HIVHIV反式激活蛋白（反式激活蛋白（Tat Tat 蛋白）可以在体外作用蛋白）可以在体外作用于病毒启动子于病毒启动子,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J
6、CJC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：亚急性出现的偏瘫、偏身感觉障碍、视觉受亚急性出现的偏瘫、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伴发热症状开始可出现部分症状,随着病灶的不随着病灶的不断扩大断扩大,症状加剧并增多。另有约症状加剧并增多。另有约18%18%的患者由于的患者由于病灶邻近皮质可伴发癫病发作。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
7、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突胶质细胞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胞质及胞核内表达病蛋自或核酸,少突胶质细胞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的上述病理改变以进展性病灶的边缘部位最为常见。见。Enlarged nuclei containing viral inclusionsHematoxylin and eosinCase report of a patient with progressivemultifocal leukoencephalopathy un
8、dertreatment with dimethyl fumarate.Dammeier et al.BMC Neurology(2015)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 co
9、rtical 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、幕上病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灶常源于血流最丰富的皮质下自质,状似贝壳状似贝壳,顶顶叶最常受累叶最常受累,其次是额叶其次是额叶,较少波及内囊、外囊及较少波及内囊、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脑桥和小脑,有时脑桥病变会蔓延至中脑和或延有时脑桥病变会蔓延至中脑和或延髓。髓。病变多局限于皮质下病变多局
10、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,常被用常被用来与艾滋病脑病及其他白质病变相鉴别。来与艾滋病脑病及其他白质病变相鉴别。A 40 A 40 yoyo man with HIV infection,who presented with progressive man with HIV infection,who presented with progressive onset of word finding difficultie
11、s and right onset of word finding difficulties and right hemiparesishemiparesis followed by followed by seizure,4 days after starting seizure,4 days after starting cARTcART.PCR was positive for JCV in the.PCR was positive for JCV in the CSF peripheral CD4 count was 468 cells/CSF peripheral CD4 count
12、 was 468 cells/ul ul.MRI performed at.MRI performed at another hospital reported a 3 cm focus of abnormal increased another hospital reported a 3 cm focus of abnormal increased signal on FLAIR sequences in the left frontal signal on FLAIR sequences in the left frontal subcorticalsubcortical white wh
13、ite matter,surrounded by linear and matter,surrounded by linear and punctatepunctate foci of enhancement at foci of enhancement at the margins of the lesion.This lesion extended into the left corona the margins of the lesion.This lesion extended into the left corona radiataradiata,the corpus,the cor
14、pus callosumcallosum and the right frontal white matter.and the right frontal white matter.MRI performed at our hospital 3 week after the initial one showed MRI performed at our hospital 3 week after the initial one showed lesions in FLAIR(A,arrows)and contrast enhancement in T1-lesions in FLAIR(A,a
15、rrows)and contrast enhancement in T1-weighted image post gadolinium injection(B,arrowheads).His weighted image post gadolinium injection(B,arrowheads).His aphasia improved progressively with addition of aphasia improved progressively with addition of ritonavirritonavir to his to his cARTcART(combine
16、d (combined antiretrovialantiretrovial therapy)regimen.His CD4 count therapy)regimen.His CD4 count increased to 558 cells/increased to 558 cells/ul ul and his HIV plasma viral load was and his HIV plasma viral load was undetectable.He then presented with worsening aphasia.MRI undetectable.He then pr
17、esented with worsening aphasia.MRI performed 2 and a half month after onset of initial symptoms performed 2 and a half month after onset of initial symptoms showed enlargement of the lesions in the left hemispheric white showed enlargement of the lesions in the left hemispheric white matter and the
18、corpus matter and the corpus callosumcallosum in FLAIR(C,arrows)which in FLAIR(C,arrows)which displayed intense contrast enhancement in T1-weighted images(D,displayed intense contrast enhancement in T1-weighted images(D,arrowheads)as well as mass arrowheads)as well as mass effect,righteffect,right t
19、o left shift and to left shift and subfalcinesubfalcine herniationherniation.He was treated with.He was treated with dexamethasonedexamethasone 6 mg three times 6 mg three times a day,tapered over 2 weeks,and a day,tapered over 2 weeks,and cARTcART was discontinued for two was discontinued for two w
20、eeks.All neurological symptoms progressively improved and 2 weeks.All neurological symptoms progressively improved and 2 and a half year later,he has no residual weakness and only minor and a half year later,he has no residual weakness and only minor word finding difficulties.MRI showed word finding
21、 difficulties.MRI showed leukomalacialeukomalacia and atrophy of and atrophy of the left frontal lobe with dilatation of the left lateral the left frontal lobe with dilatation of the left lateral ventriculeventricule in in FLAIR(E,arrows)and absence of contrast enhancement in T1-FLAIR(E,arrows)and a
22、bsence of contrast enhancement in T1-weighted image(F,arrowheads).His CD4 count was 669/weighted image(F,arrowheads).His CD4 count was 669/ul ul and and HIVplasmaHIVplasma viral load continue to be undetectable.viral load continue to be undetectable.Beyond progressive multifocal leukoencephalopathy:
23、expanded pathogenesis of JC virus infection in the central nervous system.Lancet Neurol.2010 April;9(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需具需具备以下三点：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
24、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 prevention 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
25、Society of America.MMWR Recomm Rep 2009;58:1207.quiz CE1-4.治疗：治疗：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；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；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,且能且能透过血透过血-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；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
26、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体由于不应用免疫抑制药可加重机体排斥反应排斥反应,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静脉冲击治疗静脉冲击治疗 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：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%；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病病毒的毒的CD8+TCD8+T细胞细胞,以及以及MRIMRI显示病灶强化且神经显示病灶强化且神经功能恢复即提示患者生存期较长；功能恢复即提示患者生存期较长；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。
