Overview
- Definition
Systemic infection caused by the spirochete bacteria Treponema pallidum
Often transmitted through sexual activity, but may be congenital
The “Great Imitator” – may cause morbidity to any of the major body organs and can mimic a great variety of disease
- Symptoms
Blurring
Redness
Pain
Light sensitivity
Floaters
Scotoma
Usually present without systemic sign of syphilis
- Laterality
Bilateral 44–71%
- Course
Progressive
- Age of onset
Reproductive age but may present in childhood if congenital infection
- Gender/race
M > F; higher rates among men who have sex with men
- Systemic association
Multisystemic involvement presenting in stages when untreated
Considered neurosyphilis when uveitis is present
Exam: Ocular
Ocular syphilis may occur at any stage of syphilis
Anterior Segment
- More common
- Anterior uveitis
More commonly present with vitritis than isolated
Granulomatous or nongranulomatous
Interstitial keratitis
Posterior synechiae
Iris atrophy
- Less common
Lens dislocation
Chancre at conjunctiva or eyelid in primary syphilis
Iris engorgement – “roseola” – middle third iris involvement (rare)
Posterior Segment
- Chorioretinitis focal/diffuse
Most common posterior segment involvement
- Multifocal typically grayish-yellow lesions:
Typically posterior pole or near equator
Serous RD, disc edema, vasculitis, and vitritis are occasionally associated signs
- Acute syphilitic posterior placoid chorioretinitis (ASPPC) (rare, but characteristic)
One or more large, yellowish, circular, or oval placoid lesions at the level of RPE in or near macular
Retinitis without choroidal involvement/necrotizing retinitis
Vasculitis +/− vitritis
Intermediate uveitis
Panuveitis
Neuroretinitis
Benign tertiary syphilis (Gumma): in choroid and iris (rare)
Exam: Systemic
- Untreated syphilis may progress to four stages:
- 1.Primary syphilis: Chancre
Appears ~3 weeks after infection and resolves without treatment ~4 weeks after appearance
Painless indurated ulcer at genitalia/mouth/skin/conjunctiva or eyelid
- 2.Secondary syphilis: Generalized rash, mucocutaneous lesion, and lymphadenopathy
4–10 weeks after the initial manifestation
Maculopapular rash; prominent on the palms and soles
Flu-like symptoms, nausea, hair loss, mouth ulcers, and joint pains
Self-resolves in several weeks
- 3.Latent stage: No clinical manifestation is detectable
Noncontagious
- Can last in this stage for entire lifetime
- 3.1
Early latent (up to 1 year after initial infection)
- 3.2
Late latent (after 1 year)
- 3.1
- 4.Tertiary syphilis: represents an obliterative endarteritis
Can appear 10–30 years after infection
- Risk of severe morbidity and mortality
- 4.1
Benign tertiary syphilis (Gumma): in the skin and mucous membranes
- 4.2
Cardiovascular syphilis: aortitis, aortic aneurysm, aortic valve insufficiency
- 4.3
Late-stage neurosyphilis: general paresis and tabes dorsalis
- 4.1
- 1.
- Neurosyphilis
Can occur at any stage of syphilis
Cranial nerve dysfunction, stroke, meningitis, seizure, neuropsychiatric, general paresis, and tabes dorsalis
Imaging
- OCT
CME, retinal atrophy
ASPPC: subretinal fluid, ellipsoid zone disruption, and hyperreflective granular RPE changes
- FA
Nonspecific vasculitis: vascular and disc staining, pericapillary leakage
ASPPC: Hypofluorescent central lesion in the early phase with leopard spotting (scattered hypofluorescence) and progressive hyperfluorescence in mid-late phase; late leakage from the optic disc
- ICG
ASPPC: hypofluorescence corresponding to the macular lesion in both the early and late phases
Laboratory and Radiographic Testing
Syphilis testing is warranted in all patients with uveitis of unknown etiology (Table 26.1)
- Confirm diagnosis with multiple tests via at least one treponemal-specific and nonspecific method:
- 1.Nontreponemal tests
RPR/VDRL
Quantify amount of antibody against nontreponemal antigens, such as cardiolipin, which is released by host cells infected by T. pallidum
“Nonreactive ” or “reactive” at dilutions titer (e.g., 1:2, 1:4, 1:32)
Titers decrease and become negative after treatment → use to monitor response to therapy
VDRL false negative 30% in latent syphilis, while FTA-ABS only 1–2%
- 2.Treponemal tests
FTA-ABS
TP-PA/TPHA/MHA-TP
- Immunoassay (EIA/CIA): Treponemal IgG, IgM
Confirmatory test
Remains positive for lifetime, regardless of treatment status
More sensitive than nonspecific serologic test during latent stage
- 1.
- Direct detection of pathogen from various bodily fluids
Dark-field microscopy
PCR
CSF analysis performed in every case of syphilitic uveitis
HIV checked in all syphilis patients
- Reliability of testing
- False positive
- RPR/VDRL
Transient (6 months or less) – malaria, mycobacterial disease, HIV, vaccination
Long-lasting (greater than 6 months) – SLE, RA, biliary cirrhosis, old age
- FTA-ABS
SLE, RA, biliary cirrhosis, old age
- False negative
Latent syphilis, VDRL false negative 30% while only 1–2% in FTA-ABS
- Prozone phenomenon
Results in negative or weakly positive nontreponemal test
No agglutination occurs due to antibody excess, mostly in primary and secondary syphilis → dilute and retest
- Serofast
Persistent nontreponemal titer after treatment
Consider persistent infection (? CNS)/retreating when nontreponemal titers do not decrease fourfold within 6 months after treatment
Interpretations of syphilis tests
Nontreponemal | Treponemal assays | Interpretation | Further action |
|---|---|---|---|
Reactive ≥ 1:8. | Reactive. | Current syphilis infection | Clinical evaluation should be performed to identify signs, symptoms, or past history of infection. |
Reactive at 1:1, 1:2, or 1:4. | Reactive. | Current or past infection, or due to serofast condition | |
Reactive ≥ 1:8. | Nonreactive. | Inconclusive for infection, biological false positive likely | Clinical evaluation should be performed to identify signs, symptoms, or past history of infection. If recent exposure is suspected, redraw sample in 2–4 weeks. |
Reactive at 1:1, 1:2, or 1:4. | Nonreactive. | Syphilis infection unlikely, biological false positive likely | |
Weakly reactive, Prozone has been ruled out. | Nonreactive. | Syphilis infection unlikely | |
Weakly reactive, Prozone has been ruled out. | Reactive. | Past or potential early syphilis infection | |
Nonreactive. | Reactive: False positive of treponemal assays has been ruled out by repeating with different methods. | Past or potential early syphilis infection | If past history of treatment is reported, no further management is needed unless recent exposure suspected → redraw sample in 2–4 weeks. |
Differential Diagnosis
Syphilis should be in the differential diagnosis for every uveitis patient
Treatment
- With uveitis, treat as neurosyphilis, regardless of CSF result
Intravenous penicillin G 18–24 million unit per day (3–4 million units IV q4h or continuous infusion) for 10–14 days
- Alternative – Procaine penicillin 2.4 million units IM once daily plus Probenecid 500 mg orally QID, both for 10–14 days
Ensure compliance
Follow nontreponemal titer q6 months
- Supplemental therapy, when needed
- IM benzathine penicillin G 2.4 million units weekly up to 3 weeks
To provide comparable total duration of therapy to late syphilis
- Penicillin-allergic patients
Ceftriaxone 2 g daily either IM or IV for 10–14 days (beware cross-reaction)
Tetracycline hydrochloride 500 mg PO QID for 30 days
Doxycycline 100 mg BID for 14 days
Macrolide (clarithromycin)
Consider penicillin desensitization
- Jarisch-Herxheimer reaction
Hypersensitivity reaction to treponemal antigens, released in large numbers as spirochetes are killed during therapy
Usually in the first 24 hours during the initial infusion treatment
Fever, myalgia, and headache ± increase ocular inflammation
Supportive treatment: antipyretics, NSAID
Local and systemic corticosteroid, with severe ocular inflammation
Referral/Comanagement
Infectious disease