Syphilis: Clinical Manifestations and Treatment
Clinical Manifestations by Stage
Syphilis progresses through distinct stages with characteristic symptoms that guide diagnosis and treatment decisions.
Primary Syphilis
- Painless ulcer (chancre) at the infection site with regional lymphadenopathy is the hallmark presentation 1
- The chancre typically appears 10-90 days after exposure and heals spontaneously within 3-6 weeks even without treatment 1
- HIV-infected individuals may present with multiple or atypical chancres, and primary lesions might be absent or overlooked 1
- The lesion is highly infectious and contains numerous spirochetes visible on darkfield microscopy 2, 1
Secondary Syphilis
- Diffuse maculopapular rash that characteristically involves the palms and soles, often accompanied by constitutional symptoms (fever, malaise, headache) 3, 4
- Generalized lymphadenopathy occurs in most cases 3, 4
- Mucocutaneous lesions including condyloma latum (broad, flat, wart-like lesions in moist areas) 4
- Can mimic acute primary HIV infection with similar constitutional symptoms and CSF abnormalities 1
- Symptoms typically appear 4-10 weeks after the chancre and resolve spontaneously within weeks to months 4
Latent Syphilis
- Completely asymptomatic with positive serologic tests as the only evidence of infection 1, 5
- Early latent: infection acquired within the preceding year (documented seroconversion, fourfold titer increase, recent symptoms, or partner with early syphilis) 5
- Late latent: infection of unknown duration or acquired more than one year ago 5
Tertiary Syphilis
- Occurs in approximately 25% of untreated patients after 3-12 years of latency 1
- Gummatous lesions: destructive granulomatous lesions affecting skin, bones, and internal organs 1
- Cardiovascular syphilis: aortitis, aortic regurgitation, coronary ostial stenosis 1
- Late neurologic involvement: tabes dorsalis, general paresis 1
Neurosyphilis
- Can occur at any stage of infection, not just tertiary disease 3, 4
- Manifestations include meningitis, stroke, cranial nerve palsies (especially CN VIII causing hearing loss), uveitis, and cognitive impairment 3
- Psychiatric symptoms including psychosis, mania, depression, anxiety, and personality changes can be the primary presentation 6
- Diagnosis requires CSF examination showing elevated WBC count (>5 cells/mm³), elevated protein, or reactive VDRL-CSF 2
Diagnostic Approach
Direct Detection Methods
- Darkfield microscopy or direct fluorescent antibody testing of lesion exudate is definitive for diagnosing early syphilis when lesions are present 1
- These methods are most useful for primary and secondary syphilis with active mucocutaneous lesions 2, 1
Serologic Testing
- Two-step approach: nontreponemal screening (VDRL or RPR) followed by treponemal confirmation (FTA-ABS or MHA-TP) 1
- Nontreponemal tests (VDRL, RPR) are quantitative and used for screening and monitoring treatment response 2, 1
- A fourfold change in nontreponemal titer is clinically significant for diagnosis or treatment monitoring 1
- Treponemal tests remain positive for life and should not be used to assess treatment response 5
- Use the same test method (VDRL or RPR) and preferably the same laboratory for serial monitoring, as RPR titers are often slightly higher than VDRL and cannot be directly compared 2, 5
Special Diagnostic Considerations
- HIV-infected patients may have abnormal serologic results (unusually high, low, or fluctuating titers), requiring consideration of biopsy or direct microscopy in clinically suggestive cases 2
- For neurosyphilis diagnosis, CSF VDRL is highly specific but less sensitive; a negative CSF FTA-ABS essentially excludes neurosyphilis 2
- All patients diagnosed with syphilis should be tested for HIV 1
Treatment Regimens
Primary and Secondary Syphilis
Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment 1, 5
- For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days 5, 7
- A fourfold decline in nontreponemal titers is expected within 6 months after successful treatment 1, 5
Early Latent Syphilis
- Benzathine penicillin G 2.4 million units IM as a single dose 5
- For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days 5
Late Latent Syphilis or Latent Syphilis of Unknown Duration
Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 1, 5
- For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 28 days 5, 7
- A fourfold decline in titers is expected within 12-24 months 5
Tertiary Syphilis (Non-Neurosyphilis)
- Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 5
Neurosyphilis
Aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours or continuous infusion for 10-14 days 1, 8
- Alternative regimen: procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days 8
- Penicillin-allergic patients must undergo desensitization, as penicillin is the only proven effective therapy for neurosyphilis 5, 8
Special Populations
Pregnant Women
Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission and congenital syphilis 2, 5
- All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 5
- Screen at first prenatal visit, during third trimester, and at delivery 5
- Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress; this concern should not delay therapy 2, 5
HIV-Infected Patients
- Use the same treatment regimens as non-HIV-infected patients 5
- Closer follow-up is mandatory to detect potential treatment failure or disease progression 5
- Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis compared to single dose 5
Follow-Up and Treatment Monitoring
Quantitative nontreponemal tests (VDRL or RPR) should be repeated at 3,6,12, and 24 months 1, 5
- For primary/secondary syphilis: expect fourfold decline within 6 months 1, 5
- For late syphilis: expect fourfold decline within 12-24 months 5
- Treatment failure is defined as failure of nontreponemal titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 5
Management of Treatment Failure
- Re-evaluate for HIV infection 5
- Perform CSF examination to rule out neurosyphilis 5
- Consider retreatment with weekly benzathine penicillin for 3 weeks 5
Management of Sexual Partners
Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative 2, 5
- Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 5
- Sexual transmission occurs only when mucocutaneous lesions are present, which is uncommon after the first year of infection 2
Critical Pitfalls to Avoid
- Never use oral penicillin preparations for syphilis treatment—they are ineffective 5
- Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 5
- Do not switch between VDRL and RPR when monitoring treatment response, as quantitative results cannot be directly compared 2, 5
- Do not rely on treponemal test titers to assess treatment response—they correlate poorly with disease activity and remain positive for life 5
- Never substitute alternatives for penicillin in pregnancy—only penicillin prevents congenital syphilis 5
Important Clinical Considerations
The Jarisch-Herxheimer reaction is an acute febrile reaction with headache and myalgia that may occur within 24 hours after any syphilis therapy, particularly in early syphilis 2, 5, 8