Research progress on laboratory detection of neurosyphilis_West China Medical Journal

Authors：

WEI Yinhao ¹ , SHI Mingqiao ^1,2 , TENG Li ^1,3 ,  TAO Chuanmin ¹

1. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Laboratory Medicine, Shenzhen Maternity & Child Healthcare Hosptial, Shenzhen, Guangdong 518028, P. R. China;
3. Department of Public Health Management, the Second People’s Hospital of Karamay, Karamay, Xinjiang 834000, P. R. China;

Corresponding author：

TAO Chuanmin, Email: taocm@scu.edu.cn

Keywords：

Neurosyphilis; laboratory test; serological test; chemokine CXC ligand 13

DOI：

10.7507/1002-0179.202111005

Video：

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Neurosyphilis is a group of clinical syndromes in which Treponema pallidum invades the nervous system and causes damage to the meninges, blood vessels, brain parenchyma or spinal cord. At present, there is no highly specific and sensitive method for the diagnosis of neurosyphilis, and its diagnosis mainly depends on clinical manifestations, abnormal cerebrospinal fluid and the comprehensive judgment of clinicians. Current studies show that some cytokines and chemokines are promising for laboratory detection of neurosyphilis. This article reviews the research progress of neurosyphilis from the aspects of traditional laboratory testing, polymerase chain reaction testing, cytokine and chemokine testing, and existing diagnostic criteria for neurosyphilis, in order to provide a reference for clinical testing and follow-up research.

Citation： WEI Yinhao, SHI Mingqiao, TENG Li, TAO Chuanmin. Research progress on laboratory detection of neurosyphilis. West China Medical Journal, 2022, 37(8): 1243-1247. doi: 10.7507/1002-0179.202111005 Copy

1.	中国疾病预防控制中心性病控制中心, 中华医学会皮肤性病学分会性病学组, 中国医师协会皮肤科医师分会性病亚专业委员会. 梅毒、淋病和生殖道沙眼衣原体感染诊疗指南(2020 年). 中华皮肤科杂志, 2020, 53(3): 168-179.
2.	Miklossy J. Chronic or late lyme neuroborreliosis: analysis of evidence compared to chronic or late neurosyphilis. Open Neurol J, 2012, 6: 146-157.
3.	Liu LL, Zheng WH, Tong ML, et al. Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients. J Neurol Sci, 2012, 317(1/2): 35-39.
4.	Boog GHP, Lopes JVZ, Mahler JV, et al. Diagnostic tools for neurosyphilis: a systematic review. BMC Infect Dis, 2021, 21(1): 568.
5.	疾病预防控制局. 2020 年全国法定传染病疫情概况. (2021-03-12)[2021-08-03]. http://www.nhc.gov.cn/jkj/s3578/202103/f1a448b7df7d4760976fea6d55834966.shtml.
6.	Dombrowski JC, Pedersen R, Marra CM, et al. Prevalence estimates of complicated syphilis. Sex Transm Dis, 2015, 42(12): 702-704.
7.	de Voux A, Kidd S, Torrone EA. Reported cases of neurosyphilis among early syphilis cases-United States, 2009 to 2015. Sex Transm Dis, 2018, 45(1): 39-41.
8.	Tang W, Huang S, Chen L, et al. Late neurosyphilis and tertiary syphilis in Guangdong province, China: results from a cross-sectional study. Sci Rep, 2017, 7: 45339.
9.	Tan X, Zhang J, Li J, et al. The prevalence of asymptomatic neurosyphilis among HIV-negative serofast patients in China: a meta-analysis. PLoS One, 2020, 15(11): e0241572.
10.	Du FZ, Wang QQ, Zheng ZJ, et al. The challenge of diagnosis and treatment of neurosyphilis in China: results from a nationwide survey. Sex Health, 2021, 18(4): 333-339.
11.	Tuddenham S, Katz SS, Ghanem KG. Syphilis laboratory guidelines: performance characteristics of nontreponemal antibody tests. Clin Infect Dis, 2020, 71(Suppl 1): S21-S42.
12.	Marra CM. Alternatives to the cerebrospinal fluid venereal disease research laboratory test for neurosyphilis diagnosis. Sex Transm Dis, 2021, 48(8S): S54-S57.
13.	Versiani I, Cabral-Castro MJ, Puccioni-Sohler M. A comparison of nontreponemal tests in cerebrospinal fluid for neurosyphilis diagnosis: equivalent detection of specific antibodies. Arq Neuropsiquiatr, 2019, 77(2): 91-95.
14.	Li D, Huang X, Shi M, et al. Diagnostic role of CXCL13 and CSF serology in patients with neurosyphilis. Sex Transm Infect, 2021, 97(7): 485-489.
15.	栾兴宝, 翁文佳, 张明, 等. 快速血浆反应素滴度与神经梅毒相关性的 Meta 分析. 传染病信息, 2021, 34(5): 402-405, 410.
16.	Yu J, Shi J, Wan H, et al. Clinical characteristics, diagnosis, and predictors of neurosyphilis patients with human immunodeficiency virus co-infection: a retrospective study at infectious diseases hospitals in two cities of China. Medicine (Baltimore), 2021, 100(42): e27430.
17.	Martínez-Ayala P, Quiñonez-Flores A, González-Hernández LA, et al. Clinical features associated with neurosyphilis in people living with HIV and late latent syphilis. Int J STD AIDS, 2022, 33(4): 330-336.
18.	陈怀忠, 谢俭, 李伟, 等. 梅毒血清固定患者神经梅毒发生情况及相关因素分析. 中国麻风皮肤病杂志, 2022, 38(4): 214-216.
19.	华云晖, 李子海, 于晓云, 等. 神经梅毒患者 121 例回顾性分析. 临床皮肤科杂志, 2021, 50(11): 648-650.
20.	Marra CM, Maxwell CL, Tantalo LC, et al. Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis. Clin Infect Dis, 2008, 47(7): 893-899.
21.	肖瑶, 游含宇, 沈旭, 等. 神经梅毒患者血清治疗有效的影响因素分析. 皮肤性病诊疗学杂志, 2021, 28(5): 376-381.
22.	Lu Y, Ke W, Yang L, et al. Clinical prediction and diagnosis of neurosyphilis in HIV-negative patients: a case-control study. BMC Infect Dis, 2019, 19(1): 1017.
23.	Marra CM, Maxwell CL, Dunaway SB, et al. Cerebrospinal fluid Treponema pallidum particle agglutination assay for neurosyphilis diagnosis. J Clin Microbiol, 2017, 55(6): 1865-1870.
24.	Shiva F, Goldmeier D, Lane P, et al. Cerebrospinal fluid TPPA titres in the diagnosis of neurosyphilis. Sex Transm Infect, 2020, 96(5): 389-390.
25.	Dumaresq J, Langevin S, Gagnon S, et al. Clinical prediction and diagnosis of neurosyphilis in HIV-infected patients with early Syphilis. J Clin Microbiol, 2013, 51(12): 4060-4066.
26.	应姗珊, 罗岚, 邓杰伦, 等. 脑脊液 ECLIA 与 FTA-ABS 检测在 NS 诊断中的应用价值研究. 国际检验医学杂志, 2021, 42(11): 1291-1294.
27.	Marks M, Lawrence D, Kositz C, et al. Diagnostic performance of PCR assays for the diagnosis of neurosyphilis: a systematic review. Sex Transm Infect, 2018, 94(8): 585-588.
28.	Castro R, Águas MJ, Batista T, et al. Detection of Treponema pallidum Sp. pallidum DNA in cerebrospinal fluid (CSF) by two PCR techniques. J Clin Lab Anal, 2016, 30(5): 628-632.
29.	Vanhaecke C, Grange P, Benhaddou N, et al. Clinical and biological characteristics of 40 patients with neurosyphilis and evaluation of Treponema pallidum nested polymerase chain reaction in cerebrospinal fluid samples. Clin Infect Dis, 2016, 63(9): 1180-1186.
30.	Gudowska-Sawczuk M, Mroczko B. Chemokine ligand 13 (CXCL13) in neuroborreliosis and neurosyphilis as selected spirochetal neurological diseases: a review of its diagnostic significance. Int J Mol Sci, 2020, 21(8): 2927.
31.	Zhang Y, Wang J, Wei Y, et al. CXCL13 concentration in latent syphilis patients with treatment failure. Open Med (Wars), 2020, 15(1): 635-643.
32.	Masouris I, Klein M, Ködel U. The potential for CXCL13 in CSF as a differential diagnostic tool in central nervous system infection. Expert Rev Anti Infect Ther, 2020, 18(9): 875-885.
33.	Magliozzi R, Mazziotti V, Montibeller L, et al. Cerebrospinal fluid IgM levels in association with inflammatory pathways in multiple sclerosis patients. Front Cell Neurosci, 2020, 14: 569827.
34.	Zeng YL, Lin YQ, Zhang NN, et al. CXCL13 chemokine as a promising biomarker to diagnose neurosyphilis in HIV-negative patients. Springerplus, 2016, 5(1): 743.
35.	Wang C, Wu K, Yu Q, et al. CXCL13, CXCL10 and CXCL8 as potential biomarkers for the diagnosis of neurosyphilis patients. Sci Rep, 2016, 6: 33569.
36.	于晓云, 闫宁, 李子海, 等. CXCL8, CXCL10 和 Th1/Th2 细胞因子在神经梅毒患者的血清和脑脊液中的表达情况研究. 中华男科学杂志, 2020, 26(4): 335-340.
37.	Li W, Wu W, Chang H, et al. Cerebrospinal fluid cytokines in patients with neurosyphilis: the significance of interleukin-10 for the disease. Biomed Res Int, 2020, 2020: 3812671.
38.	Wang C, Zhu L, Gao Z, et al. Increased interleukin-17 in peripheral blood and cerebrospinal fluid of neurosyphilis patients. PLoS Negl Trop Dis, 2014, 8(7): e3004.
39.	Li XX, Zhang J, Wang ZY, et al. Increased CCL24 and CXCL7 levels in the cerebrospinal fluid of patients with neurosyphilis. J Clin Lab Anal, 2020, 34(9): e23366.
40.	Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep, 2015, 64(RR-03): 1-137.
41.	Janier M, Unemo M, Dupin N, et al. 2020 European guideline on the management of syphilis. J Eur Acad Dermatol Venereol, 2021, 35(3): 574-588.

1. 中国疾病预防控制中心性病控制中心, 中华医学会皮肤性病学分会性病学组, 中国医师协会皮肤科医师分会性病亚专业委员会. 梅毒、淋病和生殖道沙眼衣原体感染诊疗指南(2020 年). 中华皮肤科杂志, 2020, 53(3): 168-179.
2. Miklossy J. Chronic or late lyme neuroborreliosis: analysis of evidence compared to chronic or late neurosyphilis. Open Neurol J, 2012, 6: 146-157.
3. Liu LL, Zheng WH, Tong ML, et al. Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients. J Neurol Sci, 2012, 317(1/2): 35-39.
4. Boog GHP, Lopes JVZ, Mahler JV, et al. Diagnostic tools for neurosyphilis: a systematic review. BMC Infect Dis, 2021, 21(1): 568.
5. 疾病预防控制局. 2020 年全国法定传染病疫情概况. (2021-03-12)[2021-08-03]. http://www.nhc.gov.cn/jkj/s3578/202103/f1a448b7df7d4760976fea6d55834966.shtml.
6. Dombrowski JC, Pedersen R, Marra CM, et al. Prevalence estimates of complicated syphilis. Sex Transm Dis, 2015, 42(12): 702-704.
7. de Voux A, Kidd S, Torrone EA. Reported cases of neurosyphilis among early syphilis cases-United States, 2009 to 2015. Sex Transm Dis, 2018, 45(1): 39-41.
8. Tang W, Huang S, Chen L, et al. Late neurosyphilis and tertiary syphilis in Guangdong province, China: results from a cross-sectional study. Sci Rep, 2017, 7: 45339.
9. Tan X, Zhang J, Li J, et al. The prevalence of asymptomatic neurosyphilis among HIV-negative serofast patients in China: a meta-analysis. PLoS One, 2020, 15(11): e0241572.
10. Du FZ, Wang QQ, Zheng ZJ, et al. The challenge of diagnosis and treatment of neurosyphilis in China: results from a nationwide survey. Sex Health, 2021, 18(4): 333-339.
11. Tuddenham S, Katz SS, Ghanem KG. Syphilis laboratory guidelines: performance characteristics of nontreponemal antibody tests. Clin Infect Dis, 2020, 71(Suppl 1): S21-S42.
12. Marra CM. Alternatives to the cerebrospinal fluid venereal disease research laboratory test for neurosyphilis diagnosis. Sex Transm Dis, 2021, 48(8S): S54-S57.
13. Versiani I, Cabral-Castro MJ, Puccioni-Sohler M. A comparison of nontreponemal tests in cerebrospinal fluid for neurosyphilis diagnosis: equivalent detection of specific antibodies. Arq Neuropsiquiatr, 2019, 77(2): 91-95.
14. Li D, Huang X, Shi M, et al. Diagnostic role of CXCL13 and CSF serology in patients with neurosyphilis. Sex Transm Infect, 2021, 97(7): 485-489.
15. 栾兴宝, 翁文佳, 张明, 等. 快速血浆反应素滴度与神经梅毒相关性的 Meta 分析. 传染病信息, 2021, 34(5): 402-405, 410.
16. Yu J, Shi J, Wan H, et al. Clinical characteristics, diagnosis, and predictors of neurosyphilis patients with human immunodeficiency virus co-infection: a retrospective study at infectious diseases hospitals in two cities of China. Medicine (Baltimore), 2021, 100(42): e27430.
17. Martínez-Ayala P, Quiñonez-Flores A, González-Hernández LA, et al. Clinical features associated with neurosyphilis in people living with HIV and late latent syphilis. Int J STD AIDS, 2022, 33(4): 330-336.
18. 陈怀忠, 谢俭, 李伟, 等. 梅毒血清固定患者神经梅毒发生情况及相关因素分析. 中国麻风皮肤病杂志, 2022, 38(4): 214-216.
19. 华云晖, 李子海, 于晓云, 等. 神经梅毒患者 121 例回顾性分析. 临床皮肤科杂志, 2021, 50(11): 648-650.
20. Marra CM, Maxwell CL, Tantalo LC, et al. Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis. Clin Infect Dis, 2008, 47(7): 893-899.
21. 肖瑶, 游含宇, 沈旭, 等. 神经梅毒患者血清治疗有效的影响因素分析. 皮肤性病诊疗学杂志, 2021, 28(5): 376-381.
22. Lu Y, Ke W, Yang L, et al. Clinical prediction and diagnosis of neurosyphilis in HIV-negative patients: a case-control study. BMC Infect Dis, 2019, 19(1): 1017.
23. Marra CM, Maxwell CL, Dunaway SB, et al. Cerebrospinal fluid Treponema pallidum particle agglutination assay for neurosyphilis diagnosis. J Clin Microbiol, 2017, 55(6): 1865-1870.
24. Shiva F, Goldmeier D, Lane P, et al. Cerebrospinal fluid TPPA titres in the diagnosis of neurosyphilis. Sex Transm Infect, 2020, 96(5): 389-390.
25. Dumaresq J, Langevin S, Gagnon S, et al. Clinical prediction and diagnosis of neurosyphilis in HIV-infected patients with early Syphilis. J Clin Microbiol, 2013, 51(12): 4060-4066.
26. 应姗珊, 罗岚, 邓杰伦, 等. 脑脊液 ECLIA 与 FTA-ABS 检测在 NS 诊断中的应用价值研究. 国际检验医学杂志, 2021, 42(11): 1291-1294.
27. Marks M, Lawrence D, Kositz C, et al. Diagnostic performance of PCR assays for the diagnosis of neurosyphilis: a systematic review. Sex Transm Infect, 2018, 94(8): 585-588.
28. Castro R, Águas MJ, Batista T, et al. Detection of Treponema pallidum Sp. pallidum DNA in cerebrospinal fluid (CSF) by two PCR techniques. J Clin Lab Anal, 2016, 30(5): 628-632.
29. Vanhaecke C, Grange P, Benhaddou N, et al. Clinical and biological characteristics of 40 patients with neurosyphilis and evaluation of Treponema pallidum nested polymerase chain reaction in cerebrospinal fluid samples. Clin Infect Dis, 2016, 63(9): 1180-1186.
30. Gudowska-Sawczuk M, Mroczko B. Chemokine ligand 13 (CXCL13) in neuroborreliosis and neurosyphilis as selected spirochetal neurological diseases: a review of its diagnostic significance. Int J Mol Sci, 2020, 21(8): 2927.
31. Zhang Y, Wang J, Wei Y, et al. CXCL13 concentration in latent syphilis patients with treatment failure. Open Med (Wars), 2020, 15(1): 635-643.
32. Masouris I, Klein M, Ködel U. The potential for CXCL13 in CSF as a differential diagnostic tool in central nervous system infection. Expert Rev Anti Infect Ther, 2020, 18(9): 875-885.
33. Magliozzi R, Mazziotti V, Montibeller L, et al. Cerebrospinal fluid IgM levels in association with inflammatory pathways in multiple sclerosis patients. Front Cell Neurosci, 2020, 14: 569827.
34. Zeng YL, Lin YQ, Zhang NN, et al. CXCL13 chemokine as a promising biomarker to diagnose neurosyphilis in HIV-negative patients. Springerplus, 2016, 5(1): 743.
35. Wang C, Wu K, Yu Q, et al. CXCL13, CXCL10 and CXCL8 as potential biomarkers for the diagnosis of neurosyphilis patients. Sci Rep, 2016, 6: 33569.
36. 于晓云, 闫宁, 李子海, 等. CXCL8, CXCL10 和 Th1/Th2 细胞因子在神经梅毒患者的血清和脑脊液中的表达情况研究. 中华男科学杂志, 2020, 26(4): 335-340.
37. Li W, Wu W, Chang H, et al. Cerebrospinal fluid cytokines in patients with neurosyphilis: the significance of interleukin-10 for the disease. Biomed Res Int, 2020, 2020: 3812671.
38. Wang C, Zhu L, Gao Z, et al. Increased interleukin-17 in peripheral blood and cerebrospinal fluid of neurosyphilis patients. PLoS Negl Trop Dis, 2014, 8(7): e3004.
39. Li XX, Zhang J, Wang ZY, et al. Increased CCL24 and CXCL7 levels in the cerebrospinal fluid of patients with neurosyphilis. J Clin Lab Anal, 2020, 34(9): e23366.
40. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep, 2015, 64(RR-03): 1-137.
41. Janier M, Unemo M, Dupin N, et al. 2020 European guideline on the management of syphilis. J Eur Acad Dermatol Venereol, 2021, 35(3): 574-588.

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