Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.


Christina M Marra, MD
Section Editors
Francisco González-Scarano, MD
John G Bartlett, MD
Deputy Editor
John F Dashe, MD, PhD


The term "neurosyphilis" refers to infection of the central nervous system (CNS) by Treponema pallidum, subspecies pallidum (hereafter termed T. pallidum). Neurosyphilis can occur at any time after initial infection.

Early in the course of syphilis, the most common forms of neurosyphilis involve the cerebrospinal fluid, meninges, and vasculature (asymptomatic meningitis, symptomatic meningitis, and meningovascular disease). Late in disease, the most common forms involve the brain and spinal cord parenchyma (general paralysis of the insane and tabes dorsalis). Each form has characteristic clinical findings, but in some cases there is overlap between these findings.

This topic will review the pathogenesis, epidemiology, clinical findings, diagnosis, and treatment of neurosyphilis. Other aspects of syphilis are discussed separately. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients" and "Syphilis: Treatment and monitoring".)


Neurosyphilis begins with invasion of the cerebrospinal fluid (CSF), a process that probably occurs shortly after acquisition of T. pallidum infection. The organism can be identified in the CSF from approximately one-quarter of untreated patients with early syphilis [1,2]. Specific strains of T. pallidum may be more likely to cause neurosyphilis [3].

Unlike other bacteria that can infect the CSF, invasion of CSF with T. pallidum does not always result in persistent infection, as spontaneous resolution may occur in some cases without an inflammatory response. In other cases, spontaneous resolution may occur after a transient meningitis (figure 1).

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 24, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Lukehart SA, Hook EW 3rd, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 1988; 109:855.
  2. Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. N Engl J Med 1997; 337:307.
  3. Marra C, Sahi S, Tantalo L, et al. Enhanced molecular typing of treponema pallidum: geographical distribution of strain types and association with neurosyphilis. J Infect Dis 2010; 202:1380.
  4. Merritt HH, Adams RD, Solomon HC. Neurosyphilis, Oxford University Press, New York 1946.
  5. Moore JE, Hopkins H. Asymptomatic neurosyphilis. The prognosis of early and late asymptomatic neurosyphilis. JAMA 1930; 95:1637.
  6. Marra CM, Castro CD, Kuller L, et al. Mechanisms of clearance of Treponema pallidum from the CSF in a nonhuman primate model. Neurology 1998; 51:957.
  7. Stokes JH, Beerman H, Ingraham NR. Modern Clinical Syphilology: Diagnosis, Treatment, Case Study, 3rd ed, WB Saunders, Philadelphia 1944.
  8. Taylor MM, Aynalem G, Olea LM, et al. A consequence of the syphilis epidemic among men who have sex with men (MSM): neurosyphilis in Los Angeles, 2001-2004. Sex Transm Dis 2008; 35:430.
  9. Poliseli R, Vidal JE, Penalva De Oliveira AC, Hernandez AV. Neurosyphilis in HIV-infected patients: clinical manifestations, serum venereal disease research laboratory titers, and associated factors to symptomatic neurosyphilis. Sex Transm Dis 2008; 35:425.
  10. Wolters EC. Neurosyphilis: a changing diagnostic problem? Eur Neurol 1987; 26:23.
  11. Conde-Sendín MA, Amela-Peris R, Aladro-Benito Y, Maroto AA. Current clinical spectrum of neurosyphilis in immunocompetent patients. Eur Neurol 2004; 52:29.
  12. Fargen KM, Alvernia JE, Lin CS, Melgar M. Cerebral syphilitic gummata: a case presentation and analysis of 156 reported cases. Neurosurgery 2009; 64:568.
  13. Moradi A, Salek S, Daniel E, et al. Clinical features and incidence rates of ocular complications in patients with ocular syphilis. Am J Ophthalmol 2015; 159:334.
  14. Rescigno RJ, Glatman M, Patel SN. A complicated case of sarcoidosis. Neurosyphilis. JAMA Ophthalmol 2014; 132:649.
  15. Oliver SE, Aubin M, Atwell L, et al. Ocular Syphilis - Eight Jurisdictions, United States, 2014-2015. MMWR Morb Mortal Wkly Rep 2016; 65:1185.
  16. Centers for Disease Control and Prevention (CDC). Clinical advisory: ocular syphilis in the United States. www.cdc.gov/std/syphilis/clinicaladvisoryos2015.htm (Accessed on November 08, 2016).
  17. Oliver S, Sahi SK, Tantalo LC, et al. Molecular Typing of Treponema pallidum in Ocular Syphilis. Sex Transm Dis 2016; 43:524.
  18. Yimtae K, Srirompotong S, Lertsukprasert K. Otosyphilis: a review of 85 cases. Otolaryngol Head Neck Surg 2007; 136:67.
  19. Phillips JS, Gaunt A, Phillips DR. Otosyphilis: a neglected diagnosis? Otol Neurotol 2014; 35:1011.
  20. Zheng D, Zhou D, Zhao Z, et al. The clinical presentation and imaging manifestation of psychosis and dementia in general paresis: a retrospective study of 116 cases. J Neuropsychiatry Clin Neurosci 2011; 23:300.
  21. Lee JW, Wilck M, Venna N. Dementia due to neurosyphilis with persistently negative CSF VDRL. Neurology 2005; 65:1838.
  22. Hooshmand H, Escobar MR, Kopf SW. Neurosyphilis. A study of 241 patients. JAMA 1972; 219:726.
  23. Karsan N, Barker R, O'Dwyer JP. Clinical reasoning: the "great imitator". Neurology 2014; 83:e188.
  24. Budhram A, Silverman M, Burneo JG. Neurosyphilis mimicking autoimmune encephalitis in a 52-year-old man. CMAJ 2017; 189:E962.
  25. Yao Y, Huang E, Xie B, Cheng Y. Neurosyphilis presenting with psychotic symptoms and status epilepticus. Neurol Sci 2012; 33:99.
  26. Hicdonmez T, Utku U, Turgut N, et al. Reversible postictal MRI change mimicking structural lesion. Clin Neurol Neurosurg 2003; 105:288.
  27. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1.
  28. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004; 189:369.
  29. Libois A, De Wit S, Poll B, et al. HIV and syphilis: when to perform a lumbar puncture. Sex Transm Dis 2007; 34:141.
  30. Ghanem KG, Moore RD, Rompalo AM, et al. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS 2008; 22:1145.
  31. Marra CM, Sahi SK, Tantalo LC, et al. Toll-like receptor polymorphisms are associated with increased neurosyphilis risk. Sex Transm Dis 2014; 41:440.
  32. Janier M, Hegyi V, Dupin N, et al. 2014 European guideline on the management of syphilis. J Eur Acad Dermatol Venereol 2014; 28:1581.
  33. Larsen SA, Hambie EA, Wobig GH, Kennedy EJ. Cerebrospinal fluid serologic test for syphilis: treponemal and nontreponemal tests. In: Advances in sexually transmitted diseases, Morisset R, Kurstak E (Eds), VNU Science Press, Utrecht 1986. p.157-162.
  34. Izzat NN, Bartruff JK, Glicksman JM, et al. Validity of the VDRL test on cerebrospinal fluid contaminated by blood. Br J Vener Dis 1971; 47:162.
  35. Marra CM, Tantalo LC, Maxwell CL, et al. The rapid plasma reagin test cannot replace the venereal disease research laboratory test for neurosyphilis diagnosis. Sex Transm Dis 2012; 39:453.
  36. Harding AS, Ghanem KG. The performance of cerebrospinal fluid treponemal-specific antibody tests in neurosyphilis: a systematic review. Sex Transm Dis 2012; 39:291.
  37. Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 2004; 38:1001.
  38. 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; 47:893.
  39. Marra CM, Maxwell CL, Collier AC, et al. Interpreting cerebrospinal fluid pleocytosis in HIV in the era of potent antiretroviral therapy. BMC Infect Dis 2007; 7:37.
  40. Marra CM, Tantalo LC, Sahi SK, et al. CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis. Sex Transm Dis 2010; 37:283.
  41. Mothapo KM, Verbeek MM, van der Velden LB, et al. Has CXCL13 an added value in diagnosis of neurosyphilis? J Clin Microbiol 2015; 53:1693.
  42. Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals. Clin Infect Dis 2000; 30:540.
  43. Yim CW, Flynn NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis. Antimicrob Agents Chemother 1985; 28:347.
  44. Punia V, Rayi A, Sivaraju A. Stroke after Initiating IV Penicillin for Neurosyphilis: A Possible Jarisch-Herxheimer Reaction. Case Rep Neurol Med 2014; 2014:548179.
  45. Davis LE, Oyer R, Beckham JD, Tyler KL. Elevated CSF cytokines in the Jarisch-Herxheimer reaction of general paresis. JAMA Neurol 2013; 70:1060.