Syphilis is a predominantly sexually transmitted bacterial infection caused by the spirochete Treponema pallidum. The disease presentation consists of 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 appears on the palms and soles. The first two stages are followed by an asymptomatic phase (latent syphilis), which may last indefinitely 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 (e.g., syphilitic aortic aneurysm). Neurosyphilis, ocular syphilis, and otosyphilis are serious manifestations that can occur at any stage of infection. Treponemal or nontreponemal serological studies are used for screening, and diagnosis is typically made based on clinical assessment and the interpretation of the syphilis serologies. Alternatively, the diagnosis can be made using tests that directly detect T. pallidum (e.g., darkfield microscopy, PCR) if a specimen of infected tissue is obtainable. First-line treatment for syphilis is penicillin G; allergen sensitization should be initiated in patients with a penicillin allergy.
- 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. 2–12 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
- Early latent: acquired within the last year
- Late latent: acquired > 1 year ago
- Chronic, destructive granulomatous lesions with a necrotic center that tend to ulcerate
- May affect any organ, e.g., skin, internal organs, bones
Subtypes and variants
- Definition: Neurosyphilis is an infection with treponemal invasion of the CNS (e.g., meninges, cerebral vasculature and/or parenchyma). The diagnosis is based on characteristic clinical features in conjunction with supportive CSF findings.
- Epidemiology: can occur at any stage of infection
Clinical features: highly variable
- Acute syphilitic meningitis (e.g., neck stiffness, nausea)
- Subacute stroke, , and/or
- 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
- Diagnostics: CSF studies must be interpreted in the clinical context. Supportive findings are listed.
- Treatment: penicillin; See “Treatment of syphilis” for details.
- Otosyphilis: infection affecting the cochleovestibular system
- Ocular syphilis: infection affecting the eye
- Syphilis during pregnancy: See “Congenital syphilis.”
- Perform a focused clinical evaluation that includes exposure history.
Order both nontreponemal tests and treponemal tests for:
- Patients with
- Individuals with 
- Pregnant individuals at the first prenatal visit 
- Order direct detection in patients with suitable skin lesions, e.g., exudative chancre, condyloma.
- Consider additional studies (e.g., lumbar puncture) based on the clinical assessment.
Clinical evaluation 
- All patients
- Patients with visual or hearing symptoms
- Patients with neurological deficits : complete neurologic examination
A detailed assessment of exposure history is essential for distinguishing early latent syphilis (infected ≤ 1 year) versus late latent syphilis (infected > 1 year) in asymptomatic seropositive patients. 
Serological studies 
Nontreponemal tests (NTT) 
- Initial screening
- Monitoring response to treatment, i.e., with titer level
- Assessing for syphilis reinfection 
- Mechanism: quantitative detection of antibodies against lipoidal antigens, e.g., cardiolipin
- Types: both have comparable performance, are widely available, and cost-efficient
Accuracy: highly sensitive but nonspecific; positive in ∼ 62–78% of patients with primary syphilis 
- False-negative NTT:
- False-positive NTT: due to cross-reacting antibodies 
- Important considerations: : After infection, NTT titers can undergo seroreversion and convert to negative even if syphilis is not treated.
Treponemal tests (TT) 
- Initial screening
- Confirmatory test in the standard testing algorithm
- Mechanism: : qualitative detection of antibodies to treponemal antigens
- Types: Many TTs exist; examples of common types are listed here.
- Important considerations: After infection, TT titer typically stays positive indefinitely.
Testing algorithms 
- Standard algorithm
Reverse algorithm 
- TT first
- If positive, perform an NTT
- If NTT is negative, perform a second TT.
- Interpret serology results based on the clinical context (i.e., clinical features, risk factors, treatment history).
- Consider consulting an infectious disease specialist for assistance with interpreting serology results.
Interpretation of syphilis serologies for diagnosis
Serologic tests may be negative in early syphilis. If there is high clinical suspicion, repeat serologic testing after 2–4 weeks. Alternatively, if a suitable lesion exists, order a direct pathogen test (e.g., darkfield microscopy, PCR) to establish the diagnosis. 
Direct detection 
- Indication: the presence of a rash or lesions consistent with syphilis, e.g., exudative chancre, condyloma 
- Methods: Detection requires specialized laboratory equipment since T. pallidum cannot be cultivated in vitro or visualized with light microscopy. 
- Accuracy: gold standard to detect primary and secondary syphilis; high specificity but nonsensitive
Additional studies 
After confirming syphilis infection, order the following studies based on the clinical scenario.
- All patients: (e.g., HIV, gonorrhea, chlamydia)
- Patients of childbearing age: pregnancy test
- Suspected neurosyphilis
- Suspected ocular syphilis or otosyphilis: functional sensory testing (e.g., audiogram, )
No single finding can establish a diagnosis of neurosyphilis, ocular syphilis, or otosyphilis. These diagnoses can occur at any stage of infection and, if suspected, require prompt evaluation by a specialist. 
- Indication: concern for cardiovascular syphilis (e.g., reports of chest pain, dyspnea)
- Findings 
General principles 
Initiate antibiotic treatment in patients with:
- Confirmed syphilis infection
- Suspected early infection (prior to seroconversion, history of sexual contact with an infected person)
- Inform patients about the possibility of a to treatment.
- Assess for treatment response with NTT titer.
- Consult infectious disease for assistance with complex cases , and specialists for affected organs (e.g., ophthalmology for ocular syphilis).
All sexual contacts of a patient with syphilis should be identified, evaluated, and treated.
- Penicillin G is the first-line therapy for all patients.
- Patients with confirmed penicillin allergy
|Antibiotic therapy for syphilis infection |
|Stage or subtype||Penicillin regimens (first-line)||Alternative regimens (if nonpregnant)|
|Primary, secondary, or early latent syphilis|| |
|Tertiary or late latent syphilis|| || |
|Neurosyphilis, ocular syphilis, or otosyphilis|
Posttreatment assessment 
- Perform a clinical evaluation and measure NTT titers at 6 and 12 months after treatment. 
- Compare NTT titers to pretreatment results.
Either type of NTT (i.e., RPR or VDRL) may be used to assess treatment response, but do not compare across types when assessing the trend in titers. For example, a titer for RPR can only be compared to prior titers of RPR.
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.