教培用進(jìn)行性多灶性白質(zhì)腦病課件

1、進(jìn)行性多灶性白質(zhì)腦病進(jìn)行性多灶性白質(zhì)腦病 由JC (John Cunningham) 病毒感染少突膠質(zhì)細(xì)胞為主要特征的致命性中樞神經(jīng)系統(tǒng)脫髓鞘性疾病。 由JC (John Cunningham)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(xì)胞、單核細(xì)胞甚至無細(xì)胞血漿在體內(nèi)循環(huán)。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 performed at our hospi

2、tal 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對合并HIV感染的患者,高效抗逆轉(zhuǎn)錄病毒療法為最佳選擇, 可穩(wěn)定50-60%患者的病情。treatment of opportunistic infections in HIV-infected ad

3、ults 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 the corp

4、us 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.中樞神經(jīng)系統(tǒng) JC 病毒感染Lancet Neurol.HIV使宿主陷入免疫抑制狀態(tài)，JC病毒特異性CD4+T細(xì)胞減少,使病毒的復(fù)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；1 神經(jīng)系統(tǒng)以外的JC病毒的潛伏PCR was positive for JCV in the CSF peripheral CD4 coun

6、t was 468 cells/ul.treatment with dimethyl fumarate.PML相關(guān)免疫重建炎性綜合征 進(jìn)行性多灶性自質(zhì)腦病主要累及免疫抑制或接受免疫調(diào)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(fēng)濕性關(guān)節(jié)炎，3%。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(xì)JC病毒JC病毒可穿過15種不同細(xì)胞的胞膜到達(dá)胞核, 然而卻只能在人類神經(jīng)母細(xì)胞瘤細(xì)胞內(nèi)復(fù)制產(chǎn)生子代病毒。JC病毒介導(dǎo)細(xì)胞死亡的機(jī)制尚不清楚,推測被該病毒感染的細(xì)胞可能會發(fā)生凋亡。但體外實(shí)驗(yàn)顯示, 病毒

7、也可介導(dǎo)星形膠質(zhì)細(xì)胞發(fā)生壞死而非凋亡。JC病毒JC病毒可穿過15種不同細(xì)胞的胞膜到達(dá)胞核, 然而卻PML病因?qū)W血清流行病學(xué)研究發(fā)現(xiàn),約80%正常成人體內(nèi)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(xì)胞、單核細(xì)胞甚至無細(xì)胞血漿在體內(nèi)循環(huán)。PML病因?qū)W血清流行病學(xué)研究發(fā)現(xiàn),約80%正常成人體內(nèi)存在J從JC病毒潛伏感染至發(fā)生進(jìn)行性多灶性自質(zhì)腦病, 共需經(jīng)歷5個關(guān)鍵步驟： 1 神經(jīng)系統(tǒng)以外的JC病毒的潛伏 2 感染非編碼控制區(qū)序列發(fā)生重排使病毒顆粒從原型轉(zhuǎn)變?yōu)槭壬窠?jīng)型 3 JC病毒重新激活導(dǎo)致病毒血癥, 使中樞神經(jīng)系統(tǒng)受累 4 人體免疫監(jiān)視功能失效 5 少突膠質(zhì)細(xì)胞被病

8、毒感染從JC病毒潛伏感染至發(fā)生進(jìn)行性多灶性自質(zhì)腦病, 共需經(jīng)歷5個His aphasia improved progressively with addition of ritonavir to his cART (combined antiretrovial therapy) regimen.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(xì)胞、單核細(xì)胞甚至無細(xì)胞血漿在體內(nèi)循環(huán)。His aphasia improved progressively with addition of ritonavir to his cART (combined antiretrovial thera

9、py) regimen.treatment of opportunistic infections in HIV-infected adults and adolescents: recommendationsPML相關(guān)免疫重建炎性綜合征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 centr

10、al nervous system.PCR was positive for JCV in the CSF peripheral CD4 count was 468 cells/ul.中樞神經(jīng)系統(tǒng) 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, 由于不應(yīng)用免疫抑制藥可加重機(jī)體排斥反應(yīng), 應(yīng)試用樹突細(xì)胞疫苗；treatment of opportunistic infections in HIV-infected adults and adolescents: reco

11、mmendationstreatment with dimethyl fumarate.由JC (John Cunningham) 病毒感染少突膠質(zhì)細(xì)胞為主要特征的致命性中樞神經(jīng)系統(tǒng)脫髓鞘性疾病。血清流行病學(xué)研究發(fā)現(xiàn),約80%正常成人體內(nèi)存在JC病毒抗體。HIV與JCV感染之間的關(guān)系：HIV使宿主陷入免疫抑制狀態(tài)，JC病毒特異性CD4+T細(xì)胞減少,使病毒的復(fù)制不受限制；HIV感染直接破壞血一腦脊液屏障，使?jié)摲《镜募?xì)胞進(jìn)人腦組織；HIV感染誘導(dǎo)產(chǎn)生的細(xì)胞因子在內(nèi)的信號轉(zhuǎn)導(dǎo)通路, 導(dǎo)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(dá)。His

12、aphasia improved progressi中樞神經(jīng)系統(tǒng) JC 病毒感染經(jīng)典型PML炎癥型PMLPML相關(guān)免疫重建炎性綜合征JC病毒小腦顆粒細(xì)胞神經(jīng)元神經(jīng)病JC病毒腦膜炎JC病毒腦病中樞神經(jīng)系統(tǒng) JC 病毒感染經(jīng)典型PML經(jīng)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(jì)失調(diào)、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(kuò)大,癥狀加劇并增多。另有約18%的患者由于病灶鄰近皮質(zhì)可伴發(fā)癲病發(fā)作。經(jīng)典型PML臨床表現(xiàn)：病理學(xué)特征： 少突膠質(zhì)細(xì)胞的裂解性感染, HE染色可見腫脹的少突膠質(zhì)細(xì)胞胞核內(nèi)存在嗜雙色包涵體，免疫組織化學(xué)或原位雜交染色可見

13、少突膠質(zhì)細(xì)胞胞質(zhì)及胞核內(nèi)表達(dá)病蛋自或核酸, 少突膠質(zhì)細(xì)胞的上述病理改變以進(jìn)展性病灶的邊緣部位最為常見。病理學(xué)特征：Enlarged nuclei containing viral inclusionsHematoxylin and eosinCase report of a patient with progressivemultifocal leukoencephalopathy undertreatment with dimethyl fumarate. Dammeier et al. BMC Neurology ( ) 15:108Enlarged nuclei containing v

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

15、 neurons (arrowhead).JCV encephalopathy: JCV infect影像學(xué)改變： 累及雙側(cè)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(cè)甚至孤立性病灶、幕上病灶常源于血流最豐富的皮質(zhì)下自質(zhì),狀似貝殼,頂葉最常受累,其次是額葉, 較少波及內(nèi)囊、外囊及胼胝體幕下白質(zhì)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。影像學(xué)改變： 病變多局限于皮質(zhì)下U形纖維區(qū)域, 不累及U形纖維, 深部及腦室周圍自質(zhì)較少受累是經(jīng)典型進(jìn)行性多灶性白質(zhì)腦病的特征性表現(xiàn), 常被用來與艾滋病腦病及其他白質(zhì)病變相鑒別。 病變多局限于皮質(zhì)下U形纖維區(qū)域, 不累教培

16、用進(jìn)行性多灶性白質(zhì)腦病課件 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

17、 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 corona radiata, the corpus callosum and the right frontal white matter. M

18、RI 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 ritonavir to his cART (combined antiretrovial therapy) regimen. H

19、is 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 hemispheric white matter and the corpus callosum in FLAIR (C

20、, 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 cART was discontinued for two weeks. All neurological

21、 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, arrows) and absence of contrast enhancement in

22、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(4): 425437 A 40 yo man with HIV i診斷： PML的明確診斷有賴于組織病理學(xué)證實(shí)，對于不能施行腦組織活檢者, 明確診斷PML需具備以下三點(diǎn)： 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(xué)表現(xiàn)血液或尿液病毒陽性無診斷價值診斷：Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention andtreat