1、中中枢神经系枢神经系统螺统螺旋体病诊旋体病诊疗进疗进展展-脑脊液检查在合并感染脑脊液检查在合并感染HIV的神经梅毒患者诊断中的应用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 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，
2、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。The 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
3、 into early neurosyphilis and 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
4、regions of the brain.流行病学流行病学 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 neu
5、rosyphilis per year in HIV+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 wh
6、o have sex with men)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)神经梅神经梅毒的疾病进程毒的疾病进程Christina M.Marra University of Washington，Seattle,
7、Washington,USA临床症状临床症状(梅毒梅毒)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临床症状(梅毒梅毒)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。潜伏期过后就是三三期梅毒期梅毒，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
8、关闭不全，直至心力衰竭而死亡。初次性接触感染后的3天到3个月是一期梅一期梅毒毒，称为“硬下疳”，经过一段时间后会自愈；再经过4到10个星期发展为二二期梅毒期梅毒，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.临床症临床症状状(神神经梅经梅毒毒)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。临床症状临床症状(神经梅毒神经梅毒)无症状性神经梅无症状性神经梅毒毒占15-40%，病
9、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CSF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。I.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
10、well LP:10-100 WBC(lymphocyte predominance),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 neurosyphilisCDC-Neurosyphilis-Mandell:Principles and Practice of Infectious Disease,5Th ed,p
11、p 2476-2489.临床症状临床症状(神经梅毒神经梅毒)II.Acute syphilitic 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
12、demonstrate higher cell counts/protein and lower glucose Serum and CSF VDRL almost always positive急性梅毒性脑膜急性梅毒性脑膜炎炎占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 Infect
13、ious Disease,5Th ed,pp 2476-2489.临床症状临床症状(神经梅毒神经梅毒)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
14、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，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.临床症状临床症状(神经梅毒神经梅毒)IV.General paresis:Relatively rare;occurs 15-20 years after initial infection Syphilitic infection of the meninges and cortex causes per
15、sonality changes,paranoia,emotional 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
16、.A PCR has been developed but data on utility not known.麻痹痴呆麻痹痴呆少见，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 Diseas
17、e,5Th ed,pp 2476-2489.临床症状临床症状(神经梅毒神经梅毒)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 R
18、omberg;Argyll-Robertson pupils 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(Ch
19、arcot)关节(肿胀，无痛、关节内积液与活动过度)及内脏危象(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.临床症状临床症状(神经梅毒神经梅毒)VI.Pearls about neurosyphilis:Any inflammatory disease of the eye can be mimicked by neurosyp
20、hilis The cranial nerves most 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
21、always indicates neurosyphilis,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 pr
22、e-HIV era 神经梅毒的关键点：神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 Infecti
23、ous Disease,5Th ed,pp 2476-2489.影影像学检查像学检查头颅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脑脊液检查脑脊液检查Lus dos Ramos Machado et al.CSF:infectious diseases The CSF anal
24、ysis is abnormal in 70%of NS patients.The main results from CSF general analysis are described in Table 3:脑脊液检查脑脊液检查Lus dos Ramos Machado et al.CSF:infectious diseases选择腰穿的标准选择腰穿的标准As a lumbar puncture is not without risk,the decision to perform this procedure needs to be carefully considered.Patien
25、ts in any of 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
26、treatment response 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
27、differential diagnosis梅毒血清测定阳性患者具有下列情况梅毒血清测定阳性患者具有下列情况之一：之一：先先天性梅天性梅毒毒 神经系统或眼部表现的存神经系统或眼部表现的存在在 三期梅三期梅毒毒 患者对治疗反应患者对治疗反应差差 神经梅毒治疗反应的监神经梅毒治疗反应的监测测 在下列情况下对艾滋病人行腰穿在下列情况下对艾滋病人行腰穿检查：检查：o 快速血浆反应素试验（快速血浆反应素试验（RPR）滴度滴度1:32稀释；稀释；o CD4阳性细胞数阳性细胞数 20/ul but nonreactiveCSF-VDRL Consider ARV tx,CD4,HIV RNA,CSF FTA
28、-ABS,+CD19%Point of Care CSF Tests Immunochromatographic strip tests(ICTs)Detect IgG,IgM and IgA antibodies 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 mat
29、erial Not recommended for CSFChristina M.Marra University of Washington，Seattle,Washington,USA即时脑脊液检验即时脑脊液检验 胶体金免疫层析试纸条测试（ICT）I.测定重组密螺旋体蛋白的IgG,IgM和IgA抗体。II.想用作血液样本的测定。III.试验中获得高敏感性（85-97%）和高特异性（94-98%）IV.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）I.测定脂类物质的IgG和IgM抗体。I
30、I.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)Syphicheck-WB(India)Visitect(Scotland)Christina M.Marra University of Washington，Seattle,Washington,USA胶体金免疫层析胶体金免疫层析试试纸纸条测试（条测试（ICT）Syphicheck-WB,a modified TPHA,for the detection of Trepon
31、ema specific IgG and IgM antibodies in serum,plasma or whole blood.VISITECT SYPHILIS is a rapid,point-of-care,sandwich immunochromatographic test for the detection of Treponema pallidum in whole blood,serum or plasma.Christina M.Marra University of Washington，Seattle,Washington,USAChristina M.Marra
32、University of Washington，Seattle,Washington,USA 四种试剂盒测定梅毒患者的敏感性四种试剂盒测定梅毒患者的敏感性和特异性和特异性品牌品牌Abbott Determine Syphilis TP testSD BIOLINESyphilis 3.0 testVisitectSyphilis testSyphiche-ck WB test产地产地美国韩国英国印度注入孔中的标本需要注入孔中的标本需要量（量（l）50205050缓释液需要量缓释液需要量1滴3滴50L2滴显示结果需要时间显示结果需要时间（min）55201515血清敏感性（血清敏感性（%）10
33、095.594.067.4血清特异性（血清特异性（%）98.997.998.198.8血清阳性预测值（血清阳性预测值（%）95.492.491.893.8血清阴性预测值（血清阴性预测值（%）10098.898.691.7全血敏感性（全血敏感性（%）81.987.673.564.0全血特异性（全血特异性（%）99.499.499.799.7全血阳性预测值（全血阳性预测值（%）97.197.598.498.3全血阴性预测值（全血阴性预测值（%）96.096.794.391.0抗凝全血敏感性（抗凝全血敏感性（%）77.187.677.970.8抗凝全血特异性（抗凝全血特异性（%）10099.4100
34、99.7抗凝全血阳性预测值抗凝全血阳性预测值（%）10097.510098.4抗凝全血阴性预测值抗凝全血阴性预测值（%）95.096.794.892.6郑和义 北京协和医院 2008-1-20共感染HIV和梅毒的患者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
35、（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无无有有无反应无反应有反应有反应按神经梅毒治疗脑脊液蛋白量45g/L45g/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无反应有反应有反应排除神经梅毒Can J Infect Dis Med Microbiol Vol 26 Suppl A January/February 2015Canadian Public Health Laboratory Networkl
36、aboratory guidelines for the diagnosisof neurosyphilis in Canada神经梅毒诊神经梅毒诊断流程图断流程图B神经梅毒治疗方案神经梅毒治疗方案E.L.Ho and S.S.Spudich Journal compilation CSIRO 2015结束语当你尽了自己的最大努力时，失败也是伟大的，所以不要放弃，坚持就是正确的。When You Do Your Best,Failure Is Great,So DonT Give Up,Stick To The End感谢聆听不足之处请大家批评指导Please Criticize And Guide The Shortcomings演讲人：XXXXXX 时 间：XX年XX月XX日
