醫(yī)學課件-進行性多灶性白質腦病課件

1、Progressive Multifocal Leukoencephalopathy1Progressive Multifocal Leukoen 由JC (John Cunningham) 病毒感染少突膠質細胞為主要特征的致命性中樞神經系統(tǒng)脫髓鞘性疾病。2 由JC (John Cunningham) 進行性多灶性自質腦病主要累及免疫抑制或接受免疫調節(jié)治療的人群： 艾滋病患者,約占79%； 惡性血液系統(tǒng)疾病者13%； 器官移植者5%； 合并自身免疫性疾病者, 尤其是系統(tǒng)性紅斑狼瘡和類風濕性關節(jié)炎，3%。3 進行性多灶性自質腦病主要累及免疫抑制或接JC病毒JC病毒可穿過15種不同細胞的胞膜到達胞

2、核, 然而卻只能在人類神經母細胞瘤細胞內復制產生子代病毒。JC病毒介導細胞死亡的機制尚不清楚,推測被該病毒感染的細胞可能會發(fā)生凋亡。但體外實驗顯示, 病毒也可介導星形膠質細胞發(fā)生壞死而非凋亡。4JC病毒JC病毒可穿過15種不同細胞的胞膜到達胞核, 然而卻PML病因學血清流行病學研究發(fā)現(xiàn),約80%正常成人體內存在JC病毒抗體。JC病毒主要潛伏于骨髓、脾、扁桃體及腎臟等部位借助外周淋巴細胞、單核細胞甚至無細胞血漿在體內循環(huán)。5PML病因學血清流行病學研究發(fā)現(xiàn),約80%正常成人體內存在J從JC病毒潛伏感染至發(fā)生進行性多灶性自質腦病, 共需經歷5個關鍵步驟： 1 神經系統(tǒng)以外的JC病毒的潛伏 2 感染

3、非編碼控制區(qū)序列發(fā)生重排使病毒顆粒從原型轉變?yōu)槭壬窠浶?3 JC病毒重新激活導致病毒血癥, 使中樞神經系統(tǒng)受累 4 人體免疫監(jiān)視功能失效 5 少突膠質細胞被病毒感染6從JC病毒潛伏感染至發(fā)生進行性多灶性自質腦病, 共需經歷5個HIV與JCV感染之間的關系：HIV使宿主陷入免疫抑制狀態(tài)，JC病毒特異性CD4+T細胞減少,使病毒的復制不受限制；HIV感染直接破壞血一腦脊液屏障，使?jié)摲《镜募毎M人腦組織；HIV感染誘導產生的細胞因子在內的信號轉導通路, 導致病毒啟動子被激活；HIV反式激活蛋白（Tat 蛋白）可以在體外作用于病毒啟動子,最終啟動病毒基因的表達。7HIV與JCV感染之間的關系：7中樞

4、神經系統(tǒng) JC 病毒感染經典型PML炎癥型PMLPML相關免疫重建炎性綜合征JC病毒小腦顆粒細胞神經元神經病JC病毒腦膜炎JC病毒腦病8中樞神經系統(tǒng) JC 病毒感染經典型PML8經典型PML臨床表現(xiàn)： 亞急性出現(xiàn)的偏癱、偏身感覺障礙、視覺受累、失語、共濟失調、意識模糊乃至癡呆一般不伴發(fā)熱癥狀開始可出現(xiàn)部分癥狀, 隨著病灶的不斷擴大,癥狀加劇并增多。另有約18%的患者由于病灶鄰近皮質可伴發(fā)癲病發(fā)作。9經典型PML臨床表現(xiàn)：9病理學特征： 少突膠質細胞的裂解性感染, HE染色可見腫脹的少突膠質細胞胞核內存在嗜雙色包涵體，免疫組織化學或原位雜交染色可見少突膠質細胞胞質及胞核內表達病蛋自或核酸, 少突

5、膠質細胞的上述病理改變以進展性病灶的邊緣部位最為常見。10病理學特征：10Enlarged nuclei containing viral inclusionsHematoxylin and eosinCase report of a patient with progressivemultifocal leukoencephalopathy undertreatment with dimethyl fumarate. Dammeier et al. BMC Neurology (2015) 15:10811Enlarged nuclei containing virClassic PML:

6、demyelinating lesion of the white matter (arrow) surrounded by multipleJCV-infected glial cells (arrowheads).12Classic PML: demyelinating lesJCV GCN: JCV infection of granule cell neurons(arrows).13JCV GCN: JCV infection of granJCV encephalopathy: JCV infected (arrow) hemispheric cortical neurons (a

7、rrowhead).14JCV encephalopathy: JCV infect影像學改變： 累及雙側大腦半球,呈多發(fā)非對稱性融合分布, 但也可表現(xiàn)為單側甚至孤立性病灶、幕上病灶常源于血流最豐富的皮質下自質,狀似貝殼,頂葉最常受累,其次是額葉, 較少波及內囊、外囊及胼胝體幕下白質病灶則主要位于小腦中腳鄰近的腦橋和小腦, 有時腦橋病變會蔓延至中腦和或延髓。15影像學改變：15 病變多局限于皮質下U形纖維區(qū)域, 不累及U形纖維, 深部及腦室周圍自質較少受累是經典型進行性多灶性白質腦病的特征性表現(xiàn), 常被用來與艾滋病腦病及其他白質病變相鑒別。16 病變多局限于皮質下U形纖維區(qū)域, 不累1717

8、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 peripheral CD4 count was 468 cells/ul. MRI performed at another hospital reported a 3 cm focus

9、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 corona radiata, the corpus callosum and the right frontal white matter. MRI performed a

10、t 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 ritonavir to his cART (combined antiretrovial therapy) regimen. His CD4 count i

11、ncreased 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 hemispheric white matter and the corpus callosum in FLAIR (C, arrows) whic

12、h 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 cART was discontinued for two weeks. All neurological symptoms prog

13、ressively 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, arrows) and absence of contrast enhancement in T1-weighted im

14、age (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. 2010 April ; 9(4): 42543718 A 40 yo man with HIV i診斷： PML的明確

15、診斷有賴于組織病理學證實，對于不能施行腦組織活檢者, 明確診斷PML需具備以下三點： 1 持續(xù)存在的PML典型臨床癥狀 2 腦脊液病毒檢測陽性 3 具有PML的典型影像學表現(xiàn)血液或尿液病毒陽性無診斷價值19診斷：19Kaplan 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, t

16、he National Institutes of Health, and the HIV Medicine Association of the InfectiousDiseases Society of America. MMWR Recomm Rep 2009;58:1207. quiz CE1-4.20Kaplan JE, Benson C, Holmes KH治療：西多福韋及阿糖胞苷的療效尚有諸多爭議；5-HTC2A受體阻斷藥米氮平和利培酮具有潛在的治療價值, 已在一些醫(yī)療單位于臨床；抗瘧疾藥物甲氟喹在體外也有抗病毒能力, 且能透過血-腦脊液屏障,部分病例治療有效；對合并HIV感染的患者,高效抗逆轉錄病毒療法為最佳選擇, 可穩(wěn)定50-60%患者的病情。21治療：21不伴HIV感染且臨床狀況允許的患者,應避免應用免疫抑制藥如激素、那他珠單抗等；器官移植者, 由于不應用免疫抑制藥可加重機體排