Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®


Christina M Marra, MD
Section Editors
Francisco Gonzalez-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. 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 (CSF), 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 "Pathophysiology, transmission, and natural history of syphilis" and "Pathogenesis, clinical manifestations, and treatment of early syphilis" and "Pathogenesis, clinical manifestations, and treatment of late syphilis" and "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infected patient".)


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]. Although investigators in the first half of the 20th century did not believe that there were "neurotropic strains" of T. pallidum, a study conducted in the antibiotic era suggested that strain variability may affect the characteristics of the infection [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.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2015. | This topic last updated: Jan 15, 2015.
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 ©2015 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. Tantalo LC, Lukehart SA, Marra CM. Treponema pallidum strain-specific differences in neuroinvasion and clinical phenotype in a rabbit model. J Infect Dis 2005; 191:75.
  4. Merritt HH, Adams RD, Solomon HC. Neurosyphilis, Oxford, 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. Kiss S, Damico FM, Young LH. Ocular manifestations and treatment of syphilis. Semin Ophthalmol 2005; 20:161.
  12. Gaudio PA. Update on ocular syphilis. Curr Opin Ophthalmol 2006; 17:562.
  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. Yimtae K, Srirompotong S, Lertsukprasert K. Otosyphilis: a review of 85 cases. Otolaryngol Head Neck Surg 2007; 136:67.
  15. Chiesi A, Vella S, Dally LG, et al. Epidemiology of AIDS dementia complex in Europe. AIDS in Europe Study Group. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 11:39.
  16. Hooshmand H, Escobar MR, Kopf SW. Neurosyphilis. A study of 241 patients. JAMA 1972; 219:726.
  17. Bash S, Hathout GM, Cohen S. Mesiotemporal T2-weighted hyperintensity: neurosyphilis mimicking herpes encephalitis. AJNR Am J Neuroradiol 2001; 22:314.
  18. Yao Y, Huang E, Xie B, Cheng Y. Neurosyphilis presenting with psychotic symptoms and status epilepticus. Neurol Sci 2012; 33:99.
  19. Hicdonmez T, Utku U, Turgut N, et al. Reversible postictal MRI change mimicking structural lesion. Clin Neurol Neurosurg 2003; 105:288.
  20. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1.
  21. 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.
  22. Libois A, De Wit S, Poll B, et al. HIV and syphilis: when to perform a lumbar puncture. Sex Transm Dis 2007; 34:141.
  23. Ghanem KG, Moore RD, Rompalo AM, et al. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS 2008; 22:1145.
  24. Ghanem KG, Moore RD, Rompalo AM, et al. Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms. Clin Infect Dis 2009; 48:816.
  25. Jaffe HW, Larsen SA, Peters M, et al. Tests for treponemal antibody in CSF. Arch Intern Med 1978; 138:252.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. Parkes R, Renton A, Meheus A, Laukamm-Josten U. Review of current evidence and comparison of guidelines for effective syphilis treatment in Europe. Int J STD AIDS 2004; 15:73.