Syphilis is a predominantly sexually transmitted bacterial infection with the spirochete Treponema pallidum. The disease presents with four distinct, successive clinical stages if left untreated. Primary syphilis manifests with a painless chancre (primary lesion), typically on the genitals. Secondary syphilis is characterized by a polymorphic, maculopapular rash that also appears on the palms and soles. The first two stages are followed by an asymptomatic phase (latent syphilis), in which the disease may resolve entirely or progress to tertiary syphilis. During the tertiary stage, characteristic granulomas (gumma) may appear, which can cause irreversible organ damage, particularly in the cardiovascular system (syphilitic aortic aneurysm) and the CNS (neurosyphilis). Diagnosis requires serologic analyses, including nontreponemal tests for screening purposes and treponemal tests for confirmation. Further tests may directly detect T. pallidum (darkfield microscopy, PCR) if a specimen of infected tissue or blood can be obtained. The first-line treatment for syphilis is penicillin, which should be administered after an infection has been confirmed. , a complication seen in children of women who have syphilis during pregnancy, is discussed in another article.
- 10–90 days
- On average 21 days
- Localized disease
- Primary lesion (chancre)
- Nontender regional lymphadenopathy (e.g., involvement of the inguinal lymph nodes in genital primary syphilis)
- Disseminated disease due to the systemic spread of the spirochetes, inducing an immunologic reaction
- Begins approx. 8–12 weeks after primary infection and typically lasts 2–6 weeks 
- Constitutional symptoms
- Polymorphic rash
- Condylomata lata
- Additional lesions
- Special variant of secondary syphilis: malignant syphilis
Remember that Secondary Syphilis causes Systemic Symptoms.
- No clinical symptoms, despite seropositivity
- May last months, years, or even for the entire life of the patient
- Disease may resolve, reactivate, or progress to tertiary syphilis
- Chronic, destructive granulomatous lesions with a necrotic center that tend to ulcerate
- May affect any organ, e.g., skin, internal organs, bones
- , ascending aortic aneurysm (thoracic aortic aneurysm), syphilitic mesaortitis, aortic root dilation and insufficiency
- Due to Treponema-induced vasculitis of the vasa vasorum of the large vessels (especially the aorta), resulting in vessel wall atrophy, and thereby, aneurysm formation
- Invasion of the CNS, causing an inflammatory reaction of the meninges and the surrounding vessels, as well as the cerebral parenchyma
- Acute meningeal syphilis: symptoms of acute meningitis (e.g., neck stiffness, nausea)
- Meningovascular syphilis : subacute stroke, cranial neuropathies
- Late (parenchymal) neurosyphilis
- Paretic neurosyphilis: chronic, progressive meningoencephalitis, resulting in widespread cerebral atrophy and major neurocognitive disorder
- Argyll Robertson pupil
- Tabes dorsalis (syphilitic myelopathy): demyelination of the dorsal columns and the dorsal root ganglia
Syphilis (also known as “the great imitator”) may have a very broad clinical presentation that mimics many other diseases!
- See “Congenital syphilis.”
- Use nontreponemal serological tests to screen for syphilis and treponemal tests and PCR to confirm the diagnosis.
- If skin or mucous membranes eruptions (chancre or condylomata) are present, the pathogen can be directly detected in the material with darkfield microscopy or PCR.
- If neurosyphilis is suspected: After serum screening and confirmation tests, perform CSF tests.
Serological testing 
Two separate serological tests are required to establish a diagnosis of syphilis: Nontreponemal tests are used for screening purposes, while treponemal tests confirm the diagnosis. In early primary syphilis, both types of tests may be nonreactive. Therefore, direct detection of the treponemes is usually preferred during this stage.
- Indications: screening, evaluation of disease activity , monitoring response to treatment
- Method: detection of anti-cardiolipin antibodies (high sensitivity but low specificity)
Commonly used tests: quantitative tests that are cost-efficient and widely available
- Rapid plasma reagin (RPR): generally the test of choice
Venereal Disease Research Laboratory (VDRL)
- Especially useful in the evaluation of neurologic involvement using cerebrospinal fluid
- Positive in ∼ 80% of patients with primary syphilis 
- False-positive results, caused by cross-reacting antibodies, can occur due to:
- A titer of ≥ 1:8 in combination with a typical rash in individuals without a history of syphilis is suggestive of syphilis; for individuals with a history of syphilis, the criteria is a fourfold rise in titer. 
- Special considerations: revert to negative after treatment
- Indication: confirmatory test after a positive or equivocal nontreponemal test (high positive predictive value)
- Method: detection of specific antibodies to treponemal antigens
- Interpretation: Positive results indicate active syphilis; or persistent antibodies from a prior infection.
- Commonly used tests
- Special considerations: remain positive after treatment
Direct detection of the pathogen 
- Indication: definite tests to detect primary and secondary syphilis when a specimen can be obtained (e.g., exudative chancre, condyloma)
- Interpretation: confirmation of diagnosis, but negative results do not rule out syphilis
- Available tests
- Angiography: aneurysms of the ascending aorta or aortic arch
- Chest CT
Treponema pallidum cannot be cultivated in vitro.
First-line therapy: benzathine penicillin G
- Primary, secondary, or early latent: IM, a single dose is sufficient
- Late latent, tertiary, or date of transmission unknown: weekly IM injections over a 3-week course
- Sexual contacts should also be treated
- Neurosyphilis: IV penicillin G for 10–14 days
- Alternatively: in the case of allergy to penicillin (confirmed with skin testing)
Penicillin is the drug of choice for treatment of syphilis.
Jarisch-Herxheimer reaction: acute, transient, systemic reaction to bacterial endotoxin-like substances and pyrogens that are released after initiation of antibiotic therapy ; 
- Clinical features
- NSAIDs for symptomatic treatment
- May consider meptazinol
- Chorioretinitis 
We list the most important complications. The selection is not exhaustive.