1、中枢神经系统螺旋体病诊疗进展-脑脊液检查在合并感染HIV的神经梅毒患者诊断中的应用,江苏省人民医院神经内科金庆文,梅毒,梅毒是由苍白（梅毒）螺旋体引起的慢性、系统性性传播疾病。主要通过性途径传播，临床上可表现为一期梅毒、二期梅毒、三期梅毒、潜伏梅毒和先天梅毒（胎传梅毒）等。与结核、麻风并称世界三大慢性传染病。是中华人民共和国传染病防治法中，列为乙类防治管理的病种。,神经梅毒,神经梅毒(neurosyphilis) 是由苍白密螺旋体侵犯神经系统出现脑膜、大脑、血管或脊髓等损害的一组临床综合征，可发生于梅毒病程的各个阶段，往往是因为早期梅毒未经彻底治疗，常为晚期（期）梅毒全身性损害的重要表现。Th
2、e term “neurosyphilis” is frequently misunderstood to be synonymous with “tertiary syphilis” by health care personnel.,Neurosyphilis is simply involvement of the central nervous system (CNS) with syphilis infection. The manifestations vary, though, and are usually divided into early neurosyphilis an
3、d late neurosyphilis. The late neurosyphilis manifestations usually manifest during the tertiary stage of syphilis and classically include dementia, general paresis, and tabes dorsalis, and are a result of extensive damage to the parynchema in the spinal cord or the cortical regions of the brain.,流行
4、病学,梅毒在全世界流行，据WHO估计，全球每年约有1200万新发病例，主要集中在南亚、东南亚和次撒哈拉非洲。近年来梅毒在我国增长迅速，已成为报告病例数最多的性病。所报告的梅毒中，潜伏梅毒占多数，一、二期梅毒也较为常见，先天梅毒报告病例数也在增加。,流行病学,10-50% of syphilis patients are HIV+ 15-20% of HIV+ syphilis patients have symptomatic neurosyphilis。 180,000-1.2 million cases of symptomatic neurosyphilis per year in HI
5、V+ individuals。The United States Centers for Disease Control and Prevention (CDC) reported that the incidence rate of syphilis in HIV-infected persons was 77-fold greater than that in the general population.,Syphilis is a common co-morbidity with HIV, especially in the MSM (men who have sex with men
6、) community. MSM make up approximately 2/3 of cases of syphilis nationwide and HIV co-infection rates range from 34% in Houston to 51% in Chicago to 60% in Los Angeles and San Francisco.,Flood et al. JID 1998;177 (April),神经梅毒的疾病进程,Christina M. Marra University of Washington，Seattle, Washington, USA,
7、临床症状(梅毒),1.获得性显性梅毒（1）一期梅毒 （2）二期梅毒 （3）三期梅毒 2.获得性隐性梅毒3.妊娠梅毒4.先天性显性梅毒（1）早期先天梅毒（2）晚期先天梅毒 5.先天潜伏梅毒,临床症状(梅毒),患者还会伴随发烧、喉咙痛、虚弱、消瘦、脱发及头痛等全身症状全部症状会在两个月之内消失，然后进入3到15年，最长可代46年的漫长潜伏期。潜伏期过后就是三期梅毒，有三种类型：梅毒瘤性梅毒患者全身的皮肤和脏器都会出现大小不一的树胶样肿瘤；神经性梅毒患者出现梅毒性脑膜炎，癫痫、瘫痪、痴呆接踵而至；心血管梅毒则会侵染主动脉，造成主动脉炎、动脉瘤、动脉瓣关闭不全，直至心力衰竭而死亡。,初次性接触感染后的
8、3天到3个月是一期梅毒，称为“硬下疳”，经过一段时间后会自愈；再经过4到10个星期发展为二期梅毒，症状多样，在躯干和四肢出现对称而不瘙痒的粉红色皮疹，随后演变成斑丘疹乃至溃疡，而口腔和咽喉黏膜上也会形成泛白的疣状病灶，接触传染性极强。,Am Fam Physician. 2012;86(5):433-440.,临床症状(神经梅毒),临床常见的几种神经梅毒为：无症状性神经梅毒;脑膜神经梅毒;血管神经梅毒;脊髓痨;麻痹性痴呆;先天性神经梅毒。,临床症状(神经梅毒),无症状性神经梅毒占15-40%，病人可有脑脊液的异常。诊断以CSF梅毒检验阳性，血清梅毒螺旋体和非梅毒螺旋体试验通常也为阳性；腰穿CS
9、F细胞数：10-100个，蛋白50-100；极少的CSF梅毒检验阴性而血清试验阳性，如病人CSF与梅毒相似，则按神经梅毒治疗。,Asymptomatic neurosyphilis: 15-40% of patients with syphilis will have some CSF abnormalities. Diagnosed by positive CSF VDRL; serum treponemal and non-treponemal tests usually positive as well LP: 10-100 WBC (lymphocyte predominance),
10、protein 50-100 Rarely CSF VDRL will be negative with positive serum tests; in that case, if the patient has a CSFconsistent with syphilis, many people will treat for neurosyphilis,CDC-Neurosyphilis-Mandell: Principles and Practice of Infectious Disease, 5Th ed, pp 2476-2489.,临床症状(神经梅毒),II. Acute syp
11、hilitic meningitis: 6% of syphilis patients Typically the earliest manifestation of neurosyphilis Often associated with cranial nerve palsies, fever, HA, meningismus, and may have signs of corticalinvolvement CSF may be much like asymptomatic neurosyphilis or may demonstrate higher cell counts/prote
12、in and lower glucose Serum and CSF VDRL almost always positive,急性梅毒性脑膜炎占6%，常见的症状有脑神经麻痹、发热、头痛、颈强直、脑膜刺激征阳性、和癫痫发作等，脑脊液循环受阻可出现视盘水肿及颅内压增高。可有大脑皮层的症状。脑脊液与无症状性神经梅毒相似， 可能有更高的脑脊液细胞数和蛋白， 而糖含量低于正常；CSF和血清的梅毒检验均阳性。,CDC-Neurosyphilis-Mandell: Principles and Practice of Infectious Disease, 5Th ed, pp 2476-2489.,临床症
13、状(神经梅毒),III. Meningovascular syphilis: 10-12% of patients Syphilitic endarteritis causes infarction clinically similar to stroke, although may have a prodrome CSF: lymphocytosis, elevated protein; CSF VDRL usually positive,脑膜血管梅毒以脑膜或脑血管损害为主，占10-12%。梅毒性动脉炎可致梭状动脉瘤及脑血栓形成。常有前驱症状，临床表现与“中风”相似。脑脊液： 淋巴球增多 ，
14、蛋白升高；脑脊液梅毒检验阳性。,CDC-Neurosyphilis-Mandell: Principles and Practice of Infectious Disease, 5Th ed, pp 2476-2489.,临床症状(神经梅毒),IV. General paresis: Relatively rare; occurs 15-20 years after initial infection Syphilitic infection of the meninges and cortex causes personality changes, paranoia, emotional
15、lability, eventually progressing to memory loss and dementia CSF: elevated lymphs and/or protein; VDRL usually positive in pre-HIV era but current data suggests sensitivity of 27-92%. Treponemal tests may be more sensitive but often are not standardized for use on CSF. A PCR has been developed but d
16、ata on utility not known.,麻痹痴呆少见，首发感染15-20年后发病。梅毒感染脑膜和皮层导致人格改变、偏执狂、情绪不稳、记忆力、计算力、认知力减退日趋严重，时间及空间定向力障碍，及痴呆。脑脊液：淋巴细胞和蛋白升高；在艾滋病出现之前脑脊液梅毒检验阳性，但现在结果显示其敏感性仅为27-92%。密螺旋体试验更为敏感但在脑脊液测定中缺乏统一标准。PCR方法也被用于临床测定。,CDC-Neurosyphilis-Mandell: Principles and Practice of Infectious Disease, 5Th ed, pp 2476-2489.,临床症状(神经
17、梅毒),V. Tabes dorsalis: Now rare; disease of posterior columns of spinal cord that occurs 18-25 years after infection. Often coexists with general paresis. Manifestations: abnormal gait, paresthesias, lightning pains of extremities, loss of proprioception on exam, positive Romberg; Argyll-Robertson p
18、upils may be seen with this and/or general paresis Abnormal CSF is less common in this setting, and CSF VDRL was normal in up to 1/3 of cases in pre-HIV era,脊髓痨病变以脊髓后索和后根为主。首发感染18-25年后发病。常与麻痹痴呆并发。表现为感觉性共济失调、跨阈步态、睫反射消失、充溢性尿失禁等症状体征，多数患者有阿-罗瞳孔、肢体闪击性剧烈疼痛，男性患者阳萎常见，部分患者可有夏科(Charcot)关节(肿胀，无痛、关节内积液与活动过度)及内脏
19、危象(以胃危象为多见，表现为阵发性腹剧痛、持续性呕吐，需与急腹症鉴别)脑脊液异常较少见。在艾滋病出现之前三分之一患者脑脊液梅毒检验正常。,CDC-Neurosyphilis-Mandell: Principles and Practice of Infectious Disease, 5Th ed, pp 2476-2489.,临床症状(神经梅毒),VI. Pearls about neurosyphilis: Any inflammatory disease of the eye can be mimicked by neurosyphilis The cranial nerves most
20、 commonly involved in neurosyphilis are VII and VIII Syphilitic otitis causes tinnitus and may be the only symptom at presentation In non-HIV+ patients, those with neurosyphilis should have a positive serum treponemal test (MHATP/FTA) In non-HIV+ patients, a positive CSF VDRL always indicates neuros
21、yphilis, whereas a positive CSF PCR for syphilis simply indicates that CSF invasion has occurred HIV+ patients may have titers discordant from their true disease state and therefore probably warrant more aggressive treatment; they may also progress more quickly than pts in the pre-HIV era,神经梅毒的关键点：神
22、经梅毒可被误诊为眼部的炎性疾病；神经梅毒最常累及的颅神经是面神经和位听神经；梅毒性耳炎可导致耳鸣，且是唯一的临床症状；在HIV阴性的病人中，神经梅毒患者的血清梅毒测定阳性；在HIV阴性的病人中，脑脊液血清性病研究实验室试验（VDRL)阳性提示神经梅毒，而梅毒螺旋体的PCR阳性螺旋体的脑脊液侵人。在HIV阳性的病人中，脑脊液血清性病研究实验室试验的滴度与疾病的状态不符，提示病人需要更为有效的治疗，相比HIV阴性患者，疾病的临床进展更快速。,CDC-Neurosyphilis-Mandell: Principles and Practice of Infectious Disease, 5Th e
23、d, pp 2476-2489.,影像学检查,头颅CT和MRI可见脑萎缩，以额叶和颞叶为主。部分病例MRI可见额叶，颞叶，海马等部位的高信号。合并脑膜血管梅毒的病人可见相应血管供应区的脑梗死病灶。部分病例可见脑膜强化。脑血管检查可见脑血管弥漫性不规则狭窄，狭窄动脉近端瘤样扩张，传转转或腊肠状，狭窄远端小动脉梗死。,Psychiatria Danubina, 2013; Vol. 25, Suppl. 2, pp 153157,脑脊液检查,Lus dos Ramos Machado et al. CSF: infectious diseases, The CSF analysis is abno
24、rmal in 70% of NS patients. The main results from CSF general analysis are described in Table 3 :,脑脊液检查,Lus dos Ramos Machado et al. CSF: infectious diseases,选择腰穿的标准,As a lumbar puncture is not without risk, the decision to perform this procedure needs to be carefully considered. Patients in any of
25、the following categories with positive syphilis serology should be strongly considered for a lumbar puncture : Congenital syphilis Presence of neurologic or ophthalmic manifestations Tertiary syphilis Patients who fail to achieve an adequate response to treatment Monitoring neurosyphilis treatment r
26、esponse In addition to the above, CSF exam should be considered in HIV-infected patients with: Serum RPR titre 1:32 dilutions OR CD4 350 cells/L OR Some experts recommend CSF examination in all HIV-infected individuals with any stage of syphilis OR Late latent syphilis OR To rule out other different
27、ial diagnosis,梅毒血清测定阳性患者具有下列情况之一：先天性梅毒神经系统或眼部表现的存在三期梅毒患者对治疗反应差神经梅毒治疗反应的监测在下列情况下对艾滋病人行腰穿检查：快速血浆反应素试验（RPR）滴度1:32稀释；CD4阳性细胞数 20/ul but nonreactiveCSF-VDRL Consider ARV tx, CD4, HIV RNA, CSF FTA-ABS, + CD19%,Point of Care CSF Tests Immunochromatographic strip tests (ICTs) Detect IgG, IgM and IgA antibod
28、ies to recombinanttreponemal proteins Intended for use on blood Sensitive (85-97%) and specific (94-98%) in field trials Goal is specificity over sensitivity RPR/TRUST Detect IgG and IgM to lipoid material Not recommended for CSF,Christina M. Marra University of Washington，Seattle, Washington, USA,即
29、时脑脊液检验胶体金免疫层析试纸条测试（ICT） 测定重组密螺旋体蛋白的IgG, IgM和IgA抗体。想用作血液样本的测定。试验中获得高敏感性（85-97%）和高特异性（94-98%）检测的主要目标是特异性诊断。快速血浆反应素试验/甲苯胺红不加热血清试验（tolulized red unheated serum test, TRUST） 测定脂类物质的IgG和IgM抗体。不推荐用于脑脊液测定。,ICTs Tested Optimized and assessed readability on a test CSF panel SD Bioline Syphilis 3.0 (Korea) Syp
30、hicheck-WB (India) Visitect (Scotland),Christina M. Marra University of Washington，Seattle, Washington, USA,胶体金免疫层析试纸条测试（ICT）,Syphicheck-WB, a modified TPHA, for the detection of Treponema specific IgG and IgM antibodies in serum, plasma or whole blood.,VISITECT SYPHILIS is a rapid, point-of-care, s
31、andwich immunochromatographic test for the detection of Treponema pallidum in whole blood, serum or plasma.,Christina M. Marra University of Washington，Seattle, Washington, USA,Christina M. Marra University of Washington，Seattle, Washington, USA,四种试剂盒测定梅毒患者的敏感性和特异性,郑和义 北京协和医院 2008-1-20,共感染HIV和梅毒的患者,
32、检查是否具有神经系统感染梅毒的症状和体征,快速血浆反应素试验（RPR）1:32或CD4细胞数350个/ul,腰椎穿刺术,脑脊液血清性病研究实验室试验（VDRL）,考虑腰穿,脑脊液细胞数,按神经梅毒治疗,20个/视野,6-20个/视野,5个/视野,按神经梅毒治疗,CD4细胞数200或HIV RNA50c/ml或服用抗逆转录病毒药物治疗,排除神经梅毒,脑脊液荧光密螺旋体抗体吸收试验（FTA-ABS）,排除神经梅毒（需除外仅累及眼或听力系统的梅毒）,按神经梅毒治疗,无症状但快速血浆反应素试验（RPR）1:32或CD4细胞数5个/视野,无症状但快速血浆反应素试验（RPR）1:32,无,有,无反应,有反
33、应,按神经梅毒治疗,脑脊液蛋白量,45g/L,45g/L,脑脊液荧光密螺旋体抗体吸收试验（FTA-ABS）,排除神经梅毒（需除外仅累及眼或听力系统的梅毒）,按神经梅毒治疗,无反应,有反应,排除神经梅毒,Can J Infect Dis Med Microbiol Vol 26 Suppl A January/February 2015,Canadian Public Health Laboratory Networklaboratory guidelines for the diagnosisof neurosyphilis in Canada,神经梅毒诊断流程图B,神经梅毒治疗方案,E. L. Ho and S. S. Spudich Journal compilation CSIRO 2015,谢谢！,
