Last revised by Daniel J Bell on 21 Feb 2024

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 (especially CN III, VI, VII and VIII), and raised intracranial pressure or hydrocephalus 1,4,18

    • 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 neuron 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 arteritis of vessels in the subarachnoid space, ultimately leading to ischemic stroke (which may be the presenting feature) of the brain and/or spinal cord (see spinal cord infarction) 1,2,4,9,18

    • 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 (a.k.a. otic/otitic syphilis)

  • general paresis (historically a.k.a. general paralysis of the insane)

    • characterized by dementia with marked personality changes 4

    • occurs years to decades after infection 3,4

  • tabes dorsalis

    • 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

    • the rare complication of Charcot joints may be present 19

    • 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 1,5,6,10,18:

  • a degree of lymphocytic pleocytosis

  • 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 (typically basilar) or diffuse 1,2

    • if cranial neuropathies are present then cranial nerve enhancement may be appreciated, most commonly of CN III, VI, VII and VIII 1,2,14,18

    • 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 edema 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 ischemic stroke for detailed temporal radiographical features) or of spinal cord infarction 1,2,7,9,18

    • 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 (a.k.a. otitic/otic 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

Treatment is with intravenous penicillin-based antibiotics such as benzathine penicillin G (benzylpenicillin) or ceftriaxone 1,10,18. 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/spinal infarction or atrophy 1,10.

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Cases and figures

  • Case 1: with syphilitic gummas
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  • Case 2: leptomeningeal enhancement
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  • Case 3: tabes dorsalis
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