Treponema pallidum pallidum

Etiology

• Infection by Treponema pallidum subspecies pallidum

Stages

graph LR

Syphilis --2 to 6 weeks--> Primary[Primary syphilis]
Syphilis --3 weeks to<br/>3 months--> Secondary[Secondary syphilis]
Syphilis --years to<br/>decades--> Tertiary[Tertiary syphilis]

Tertiary --> Cardiovascular
Tertiary --> Gummatous
Tertiary --> Neurosyphilis

subgraph Neurosyphilis
Neurosyphilis --> Meningovascular
Neurosyphilis --> Parenchymatous
Neurosyphilis --> Tabes[Tabes dorsalis]
end

Primary syphilis

• Incubation period is about 3 weeks
• Chancre
• Ulcerative lesion
  • Clean borders
  • Indurated
  • Not painful unless secondarily infected
  • Lasts 2 to 6 weeks
• May present with regional lymphadenopathy
• Diagnosis with darkfield microscopy, fluorescent antibody smear, or (most commonly) serology
• Serology often negative in early syphilis

Secondary syphilis

• Incubation period 3 weeks to 3 months
• Often no history of chancre
• Diffuse maculopapular rash that involves palms and soles
  • Can have extremely variable presentation
• Generalized lymphadenopathy
• Fever, chills, arthralgias
• Less common: condyloma lata, aseptic meningitis, iritis, mucosal white patches, glomerulonephritis, paroxysmal nocturnal hemoglobinuria, hepatitis

Neurosyphilis

• Most common tertiary syphilis (75%)
• Incubation period is 7-15 years
• Three major presentations: meningovascular syphilis, parenchymous syphilis, and tabse dorsalis

Meningovascular

• Most common neurosyphilis
• Subdivided into cerebromeningeal (diffuse or focal) and cerebrovascular
• Stroke-like symptoms, especially MCA or basilar territory
• Can present as a sudden change, as syphilitic apoplexy
• Can present following a prodrome of weeks to months of non-specific headaches, vertigo, irritability, insomnia, and personality changes

Parenchymatous

• Previously known as "generalized paresis of the insane"
• Commonly found on psychiatric wards
• Causes psychosis and dementia
• Later, coarse tremors, Argyll-Robinson pupil, paresis

Tabes dorsalis

• Least common neurosyphilis
• Isolated posterior cord degeneration leading to a loss of proprioception in the lower extremities
• Stomp the ground when walking to use intact pain/pressure sensation
• Can present with Charcot foot and, rarely, recurrent abdominal pain
• Diagnosed by serum CMIA, but RPR may be negative

Others

• Isolated ocular neurosyphilis
• Meningitis: can present at any time during the course of disease
• Others

Cardiovascular syphilis

• Incubation period is 20-25 years
• Aortic root involvement leading to aortitis and dilatation
• May result in aneurysm, aortic insufficiency, or angina secondary to stenosis at the aortic root
• Diagnosed by RPR +/- CMIA

Gummatous syphilis

• Least common (10-15%) tertiary syphilis
• Incubation period 6-8 years
• Gummas may appear anywhere, in any organ
• CNS lesions look like toxo, so beware in HIV patients

Other presentations

• Isolated auditory syphilis
• Isolated optic syphilis

Latent syphilis

• Most common form of syphilis is latent, at any stage

Diagnosis

• Often done as non-treponemal test to screen, followed by treponemal test to confirm
• In Ontario, we do a treponemal test to screen (CMIA), then repeat it with a more specific treponemal test (TPPA) alongside RPR

Direct visualization

• Darkfield microscopy
  • Chancre cleaned and smear obtained
  • Smear must be visualized immediately
  • Sensitivity decreases with duration
• Smear for fluorescent monoclonal antibody
  • Best to use in primary syphilis

Non-treponemal tests (VDRL/RPR)

• Veneral Diseases Research Laboratory (VDRL) has been replaced by the rapid plasma reagin (RPR) test
  • Quantitative tests for a non-specific anti-cardiolipin antibody that is produced in syphilitic (and other) infections
• False positives in pregnancy, autoimmune disorders (lupus, APLA), and chronic infections (leishmaniasis, leprosy, ...)
• 50% sensitive in primary, 100% sensitive in secondary
• Tests will eventually become nonreactive

Treponemal tests

• More specific and sensitive, but more expensive
• False positive in lupus and Lyme disease
• Remain positive for life
• Four main tests:
  • Fluorescent treponemal antibody absorption (FTA-Abs): Essentially the gold standard
  • Chemoluminescnence microparticle immunoassay (CMIA or CLIA): the screening test used in Ontario. Often used as a screening test as it is an easily-automated immunoassay and is more sensitive and specific than RPR.
  • Treponema pallidum Particulate Agglutination assay (TPPA): a modification of the TPHA. Used as the confirmatory test (alongside RPR) used in Ontario.
  • T. pallidum hemagglutination assay (TPHA): very old test.
  • T. pallidum enzyme immunassay (TP-EIA)

Interpretation of serology

CMIA screen	RPR	TPPA	Interpretation
Non-reactive	—	—	Negative result; or early syphilis (consider repeat in 4 weeks)
Reactive	Reactive	Reactive	Recent or prior syphilis infection
Reactive	Non-reactive	Reactive	Recent or prior syphilis infection
Reactive	Non-reactive	Non-reactive	False positive; or early syphilis, previously treated, or late latent (repeat in 4 weeks)
Reactive	Non-reactive	Indeterminate	Inconclusive result; false positive, early syphilis, old treated syphilis, or old untreated syphilis (repeat in 4 weeks)
Reactive	Reactive	Non-reactive	Inconclusive result; false positive, early syphilis, old treated syphilis, or untreated syphilis (repeat in 4 weeks)
Reactive	Reactive	Indeterminate	Recent or prior syphilis infection

Treatment

Primary and secondary

• Benzethine penicillin G 2.4 million units IM once, divided between two buttocks
• Alternative (penicillin allergy): doxycycline 100mg BID for 2 weeks
• Alternative (penicillin allergy and pregnancy): penicillin desensitization or azithromycin

Tertiary

• Benzethine penicillin G 2.4 million units IM q1week for 3 weeks
• Alternative (penicillin allergy): doxycycline for 30 days
• Monitor response with RPR titres, which should drop 4-fold within 6 months

Tertiary (Neurosyphilis)

• Penicillin G 4 million units IV q4h for 10 to 14 days
• Often followed by at least one dose of IM benzethine penicillin, sometimes weekly for 2-3 weeks