Neurosyphilis results from infection of the central nervous system by the spirochete Treponema pallidum, subspecies pallidum. The disease has a heterogeneous spectrum of early and late manifestations.
For a general discussion, and for links to other system specific manifestations, please refer to the article on syphilis.
This disease is a rare entity in the current antibiotic era, but when present, tends to be seen in association with HIV or AIDS, affecting approximately 1.5% of that population demographic 1. Of all patients who are diagnosed with syphilis and are left untreated, between 5-10% of patients will have evidence of symptomatic neurosyphilis 1.
The clinical presentation is very varied and largely depends on the temporal stage of the disease and the corresponding area of the central nervous system that has been affected. In addition to features of neurosyphilis, signs and symptoms of secondary and other forms of tertiary syphilis may also be present 1-6.
However, in the modern era where this disease most often co-exists with HIV, late signs of neurosyphilis are rarely seen 5. This is because patients with HIV and neurosyphilis who do not receive treatment for either tend to develop fatal intercurrent infections and complications of AIDS before the late signs of neurosyphilis are able to manifest 5.
- asymptomatic neurosyphilis
- patients are asymptomatic and will only have evidence of neurosyphilis in CSF analysis 1,4
- occurs weeks to months after infection 3,4
- acute syphilitic meningitis
- clinical features identical to those of a bacterial leptomeningitis, such as headache, neck stiffness, seizures, cranial neuropathies, and raised intracranial pressure or hydrocephalus 1,4
- may be associated with the development of syphilitic gummas and focal pachymeningitis, similar to other granulomatous diseases such as tuberculosis or neurosarcoidosis, that can have clinical features of an intracranial mass (especially if they invade into the brain parenchyma) or spinal cord compression 1,2,4
- may be associated with myelitis (acute syphilitic meningomyelitis) resulting in upper motor neurone lesion signs on examination such as spastic paresis and hyperreflexia 7,8
- occurs months to years after infection 3,4
- meningovascular syphilis
- prodrome of mild clinical features of syphilitic meningitis 4,9
- this is followed by an arteritis of vessels in the subarachnoid space, ultimately leading to ischaemic stroke (which may be the presenting feature) of the brain and/or spinal cord 1,2,4,9
- there may also or alternatively be evidence of acute encephalitis presenting identically to herpes simplex encephalitis, a manifestation that is increasingly common in the HIV/AIDS demographic 10
- occurs months to years after infection 3,4
- ocular syphilis
- clinical features vary depending on the exact structures of the eye that are involved, but most commonly posterior uveitis (including posterior placoid chorioretinitis) or panuveitis are seen and present with progressively worsening visual acuity 4,11,12
- occurs months to years after infection 11,12
otosyphilis (or otitic syphilis)
- presenting with sensorineural hearing loss, tinnitus, and vertigo due to involvement of inner ear structures 4,13
- occurs months to years after infection 13
- general paresis (or general paralysis of the insane)
- characterised by dementia with marked personality changes 4
- occurs years to decades after infection 3,4
- presents with symptoms related to dorsal column and dorsal root involvement such as sensory ataxia (tabetic gait), lancinating neuropathic pains, and urinary incontinence 4
- many patients also have the classic Argyll Robertson pupil that responds to accommodation but not to light 4
- occurs decades after infection, often as the final manifestation 3,4
Characteristic lumbar puncture findings depend on the temporal stage of the disease, but generally include 1,5,6,10:
- a degree of lymphocytosis
- moderately elevated protein levels
- reactive CSF-VDRL or CSF FTA-ABS tests
It is thought that Treponema pallidum, subspecies pallidum, spreads to the central nervous system through invasion of the cerebrospinal fluid (CSF) 1,4. Thus, initial early manifestations of neurosyphilis include asymptomatic CSF infection before progressing to acute syphilitic meningitis that may have accompanying ocular disease (ocular syphilis) or inner ear disease (otosyphilis) 1,4. The disease then infiltrates the blood vessels of the subarachnoid space leading to arteritis in meningovascular syphilis 1,4. Finally, in late stages of the disease after many years or even decades, the brain parenchyma and spinal cord white matter tracts are then involved leading to general paresis and tabes dorsalis 1,4. The pathogenesis of acute encephalitis seen alongside meningovascular syphilis in HIV/AIDS patients remains unclear 10,14.
As with the clinical features, neurosyphilis can have a variety of radiographic presentations 1-3.
- asymptomatic neurosyphilis: no radiographic features
- acute syphilitic meningitis:
- leptomeningeal enhancement that may be either focal or diffuse 1,2
- if cranial neuropathies are present then cranial nerve enhancement may be appreciated, most commonly of CN VII and CN VIII 1,2,14
- syphilitic gummas, if present, appear as small focal nodules adjacent to the meninges that are isodense on CT, hypointense on T1-weighted MRI, hyperintense on T2-weighted MRI, have high diffusion signal on DWI, and exhibit homogeneous contrast-enhancement on T1-weighted MRI or on contrast-enhanced CT; they may additionally have a dural tail sign, evidence of focal pachymeningitis, and surrounding cerebral oedema 1,2,15
- syphilitic meningomyelitis, if present, is associated with T2-weighted long-segment intrinsic spinal cord hyperintensities, most commonly in the thoracic cord, which may or may not involve the dorsal columns 7
- meningovascular syphilis:
- radiographic features of syphilitic meningitis such as leptomeningeal enhancement and presence of syphilitic gummas 1,2,7,9
- focal segmental vascular narrowing and ‘beading’ may be seen on angiographic studies 1,2,7,9
- regions of cortical or subcortical infarction in any vascular territory (see ischaemic stroke for detailed temporal radiographical features) 1,2,7,9
- if acute encephalitis is present, the radiographical features of mesiotemporal T2-weighted hyperintensities seen are indistinguishable from herpes simplex encephalitis 10,14; there may also be residual atrophic cerebral changes seen once the acute phase has resolved 8
- ocular syphilis: often no radiographic features 12
- otosyphilis (or otitic syphilis):
- gummas may be seen in the internal auditory canal 16
- there may be radiographic evidence of osteitis and osteolysis of the adjacent temporal bone 16
- general paresis (or general paralysis of the insane): cerebral atrophy, both central and cortical atrophy may be present 1,2,7
- tabes dorsalis: MRI may reveal cord atrophy and longitudinal T2-weighted hyperintensities in the dorsal columns of the spinal cord, mimicking the radiographical appearance of subacute combined degeneration of the cord 17
Treatment and prognosis
Treatment is with intravenous penicillin-based antibiotics such as benzathine penicillin G 1,10. Management should also be initiated for HIV if concomitantly present 1,10. Prognosis is generally good unless there are established non-reversible changes such as cerebral infarction or atrophy 1,10.
- 1. Smith AB, Smirniotopoulos JG, Rushing EJ. From the archives of the AFIP: central nervous system infections associated with human immunodeficiency virus infection: radiologic-pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 28 (7): 2033-58. doi:10.1148/rg.287085135 - Pubmed
- 2. Brightbill TC, Ihmeidan IH, Post MJ, Berger JR, Katz DA. Neurosyphilis in HIV-positive and HIV-negative patients: neuroimaging findings. AJNR. American journal of neuroradiology. 16 (4): 703-11. Pubmed
- 3. Shih RY, Koeller KK. Bacterial, Fungal, and Parasitic Infections of the Central Nervous System: Radiologic-Pathologic Correlation and Historical Perspectives. Radiographics : a review publication of the Radiological Society of North America, Inc. 35 (4): 1141-69. doi:10.1148/rg.2015140317 - Pubmed
- 4. Hooshmand H, Escobar MR, Kopf SW. Neurosyphilis. A study of 241 patients. JAMA. 219 (6): 726-9. Pubmed
- 5. Khamaysi Z, Bergman R, Telman G, Goldsher D. Clinical and imaging findings in patients with neurosyphilis: a study of a cohort and review of the literature. International journal of dermatology. 53 (7): 812-9. doi:10.1111/ijd.12095 - Pubmed
- 6. Johns DR, Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. The New England journal of medicine. 316 (25): 1569-72. doi:10.1056/NEJM198706183162503 - Pubmed
- 7. Nagappa M, Sinha S, Taly AB, Rao SL, Nagarathna S, Bindu PS, Bharath RD, Murthy P. Neurosyphilis: MRI features and their phenotypic correlation in a cohort of 35 patients from a tertiary care university hospital. Neuroradiology. 55 (4): 379-88. doi:10.1007/s00234-012-1017-9 - Pubmed
- 8. 3. Berger JR. Neurosyphilis and the spinal cord: then and now. J. Nerv. Ment. Dis. 2011;199 (12): 912-3. doi:10.1097/NMD.0b013e31823928e8 - Pubmed citation
- 9. Behrouz R, Malek AR, Chichkova RI. Meningo-Vascular Syphilis: Revisiting An Old Adversary. Practical Neurology. 2011 Jul:32-7.
- 10. Karsan N, Barker R, O'Dwyer JP. Clinical reasoning: the "great imitator". Neurology. 83 (22): e188-96. doi:10.1212/WNL.0000000000001033 - Pubmed
- 11. Chen J, Lee L. Posterior placoid chorioretinitis: An unusual ocular manifestation of syphilis. Clin Ophthalmol. 2011;2 (3): 669-73. Free text at pubmed - Pubmed citation
- 12. Smith GT, Goldmeier D, Migdal C. Neurosyphilis with optic neuritis: an update. Postgraduate medical journal. 82 (963): 36-9. doi:10.1136/pgmj.2004.020875 - Pubmed
- 13. Pasricha JM, Read TR, Street AC. Otosyphilis: a cause of hearing loss in adults with HIV. The Medical journal of Australia. 193 (7): 421-2. Pubmed
- 14. Bash S, Hathout GM, Cohen S. Mesiotemporal T2-Weighted Hyperintensity: Neurosyphilis Mimicking Herpes Encephalitis. American Journal of Neuroradiology. 22 (2): 314. Pubmed
- 15. Jeong YM, Hwang HY, Kim HS. MRI of neurosyphilis presenting as mesiotemporal abnormalities: a case report. Korean journal of radiology. 10 (3): 310-2. doi:10.3348/kjr.2009.10.3.310 - Pubmed
- 16. Kivekäs I, Vasama JP, Hakomäki J. Bilateral Temporal Bone Otosyphilis. Otology & Neurotology. 2014 Feb 1;35(2):e90-1.
- 17. Pandey S. Magnetic resonance imaging of the spinal cord in a man with tabes dorsalis. J Spinal Cord Med. 2011;34 (6): 609-11. doi:10.1179/2045772311Y.0000000041 - Free text at pubmed - Pubmed citation