As “the great masquerader,” syphilis can mimic many other diseases, which makes its identification and diagnosis a challenge. Unfortunately, a delay in diagnosis can have detrimental effects on patients’ lives and vision; therefore, it is crucial that syphilis be on the differential for all patients who present with uveitis even without other signs or symptoms of syphilis.

According to the Centers for Disease Control and Prevention, in recent years, syphilis rates have been on the rise across the United States at a higher rate than other sexually transmitted infections.¹ This includes congenital syphilis, which has had an even larger increase in incidence than acquired syphilis, and in the population with human immunodeficiency virus (HIV), which has had a significant increase in syphilis diagnoses over the past 10 years.^1-4 Although ocular syphilis is present in only around 0.6% to 2.0% of patients with syphilis, the increasing prevalence means ocular syphilis cases are also on the rise.⁵

Syphilis is caused by a spirochete bacterium, Treponema pallidum, and is transmitted directly through sexual contact or indirectly through vertical transmission from an infected mother to the fetus. It has 4 stages, and ocular symptoms can present at any point in the disease progression.

Stages

Primary syphilis occurs about 3 weeks after exposure and is characterized by chancres (painless ulcerative lesions), which often occur on the genitals and heal spontaneously over about 12 weeks. These lesions are infectious and can transmit the bacteria through direct contact. Secondary syphilis occurs 2 to 24 weeks after resolution of chancres and is characterized by a rash on the trunk, palms, and soles, as well as condyloma lata (smooth, wart-like lesions) on the genitals/rectum. 

Tertiary syphilis occurs years after secondary syphilis symptoms resolve, but many patients do not go on to develop this stage. This stage is characterized by cardiac syphilis (aneurysms or stenosis of cardiac vessels), gummas (granulomatous growths within tissues), and neurosyphilis (including tabes dorsalis and paresis); however, neurosyphilis can occur at any stage of the disease. Latent syphilis occurs between stages where there are no symptoms present and can last for years.

Ocular symptoms most often occur in the secondary and tertiary stages but can occur in any stage and are considered signs of neurosyphilis. Manifestations of ocular syphilis include anterior, intermediate, or panuveitis, retinal vasculitis, and optic nerve edema.^3,6,7

Prevalence

A study looking at the incidence of ocular syphilis over a 10-year period in West Virginia found an almost 300% increase in incidence of syphilis between 2010 and 2020 and an increase in ocular syphilis of almost 900%.³ This trend has been seen worldwide, with studies showing similar increases in the United Kingdom, France, and Canada over the same time period.^5,8,9 Between 2011 and 2019, the nationwide incidence of syphilitic uveitis in the United States roughly tripled from 0.08 per 100,000 to 0.25 per 100,000.⁴

Analyses of populations at risk show that men, men who have sex with men, African Americans, and those of low socioeconomic status are disproportionately impacted by syphilis.⁴ A regional disparity within the United States was also demonstrated, which shows a higher prevalence in the Western, followed by Southern, Northeast, and lowest prevalence in the Midwest states.³

Diagnosis

Physical exam

Many patients with syphilitic uveitis can be diagnosed even before they sit in the exam chair. It is important to take a good look at patients’ hands to examine them for the characteristic palmar rash associated with secondary syphilis and ask about other systemic rashes or lesions they may have noticed, which may steer diagnosis.

Ocular exam

Patients with ocular syphilis can demonstrate infection in almost any ocular tissue but most commonly the uvea, retina, and optic nerve are involved. Anterior uveitis, chorioretinitis, retinal vasculitis, panuveitis, and papillitis are the most common presentations and occur bilaterally in about half of patients.³ Patients with ocular syphilis may present with retinal lesions such as punctate inner retinitis, syphilitic posterior placoid chorioretinitis, and exudative retinal detachment. Less common manifestations include Kyrieleis plaques and retinal necrosis (Figure 1).

Serologies

Once syphilis is suspected as the cause of a patient’s symptoms, diagnosis is confirmed based on antibody testing of serum or cerebrospinal fluid, or dark field microscopy with visualization of the spirochetes. Which test to order depends on which stage is suspected, because the different antibody titers fluctuate throughout the course of the disease and treatment (Figure 2). There are 2 groups of serologic testing: treponemal and nontreponemal.

The traditional algorithm for syphilis screening begins with nontreponemal serologic testing. These tests include the rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests and identify antibody-antigen complexes. These complexes are present during early infection but drop off and can become falsely negative later in the disease course. 

In patients with HIV, there is a phenomenon known as the prozone effect, which can result in a false negative result of nontreponemal studies despite active infection. Patients with HIV have excessive numbers of antibodies, which results in poor agglutination and therefore false negative results.¹⁰ This can be overcome by diluting the serum to decrease the antibody concentration. This is helpful to inform the receiving laboratory about when there is a high suspicion for syphilis despite a negative nontreponemal test.

Treponemal studies are typically used to confirm nontreponemal studies or when syphilis is suspected but nontreponemal studies are negative, such as early in the disease course. Tests which detect antibodies to syphilis include the Treponema pallidum particle agglutination assay, the fluorescent treponemal antibody absorption test, and Treponema pallidum IgG/IgM. The antibodies typically persist in the serum despite treatment and are present throughout life.

The reverse algorithm starts with treponemal serologic testing first, followed by nontreponemal serologic testing if the treponemal test is positive. The 2024 CDC guidelines state that either the traditional or the reverse algorithm are acceptable methods of screening. Clinicians must be aware that the traditional algorithm has a lower sensitivity in early and late latent syphilis.

Imaging

Imaging modalities helpful in the diagnosis and monitoring of ocular syphilis in the retina, choroid, and vitreous include optical coherence tomography (OCT), autofluorescence, fundus photographs, and fluorescein angiography. Lesions typical of syphilis that are present in the retina of patients with syphilitic uveitis include placoid lesions, pyramidal deposits, loss of ellipsoid zone, and vitreous cells (Figure 3).

On fundus examination, retinal findings of posterior-involving syphilitic uveitis include confluent areas of white or yellow-white placoid lesions involving the posterior pole, retinal arteriolitis, punctate inner retinitis, and retinal detachments.¹¹ Later findings may include bone spicule patterns resembling inherited retinal degenerations (Figure 4).

Fundus autofluorescence will show areas of hyperautofluorescence in the acute stage of disease but may show a trizonal pattern of autofluorescence with hyperfluorescence, hypofluorescence, and normal autofluorescence similar to that seen in acute zonal occult outer retinopathy when presenting as a chronic disease^.12

Optical coherence tomography findings include pyramidal deposits of subretinal fibrosis, subretinal fluid, and loss of the ellipsoid zone.¹¹  Fluorescein angiography will show hypofluorescence in the areas of placoid lesions as early blocking with late pooling and staining in a segmental distribution.¹¹

Treatment

The first-line treatment for ocular syphilis is 18 to 24 million units of intravenous penicillin per day for 10 to 14 days. Patients who are allergic to penicillin should undergo desensitization therapy to be able to receive the treatment without reaction, especially pregnant women with penicillin allergies who require treatment.

Alternative treatments include intramuscular penicillin 2.4 million units once daily combined with oral probenecid 500 mg orally 4 times per day for 10 to 14 days or intravenous ceftriaxone 1g to 2g daily for 10 to 14 days in patients with allergy to penicillin.¹³

Recently, there has been a shortage of intravenous penicillin G due to increased demand for the medication. In response, the FDA announced a different formulation of the medication can be used as a substitute for the injectable suspension.¹⁴

An acute febrile reaction following initiation of treatment, called the Jarisch-Herxheimer reaction, can occur within the first 24 hours of syphilis treatment. This represents an acute inflammatory reaction to the lysis of the bacteria and is not an allergic reaction to the medication.¹⁴

Additionally, when treating a patient for syphilis, it is important to collaborate with infectious disease specialists to assist with treatment and diagnosis of other infections that often occur with syphilis, such as HIV and other sexually transmitted infections. HIV coinfection is present in 23% of cases of ocular syphilis.⁵

Screening Guidelines

The CDC recommends screening for syphilis⁸ as follows:

• Asymptomatic men and women with increased risk factors (transactional sex work, incarceration);
• Pregnant women at their first prenatal visit and again at 28 weeks if increased risk factors (substance use, STIs, multiple partners, new partners);
• Men who have sex with men annually while sexually active, every 3 to 6 months if increased risk factors (transactional sex work, incarceration);
• Transgender patients should be screened at least annually based on sexual behaviors and exposure risks; and
• Patients with HIV should be screened on initial HIV evaluation and at least annually unless increased risk factors.

Conclusion

Syphilis is a bacterial infection that can have serious systemic and visual consequences if not identified and treated appropriately. It can present with inflammation throughout the eye but most often as panuveitis. In recent years, both syphilis and syphilitic uveitis have shown trends of increasing incidence, and it is important for ophthalmologists to have a low threshold for testing in patients with uveitis to prevent both morbidity and blindness from undiagnosed infection. RP 

David M. Hinkle, MD, is the Oliver and Carrol Dabezies Endowed Chair in the Department of Ophthalmology at Tulane University School of Medicine in New Orleans, Louisiana. He reports no relevant disclosures. Reach him at dhinkle@tulane.edu.

Emily Laurent, MD, is an ophthalmology resident at Tulane University School of Medicine in New Orleans, Louisiana. She reports no relevant disclosures.

References

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3. Harvey J, Lee IJ, Lee CS, Hinkle D. Ocular syphilis on the rise: a 10-year analysis from 2010 to 2020. Int Ophthalmol. 2023;43(12):4419-4426. doi:10.1007/s10792-023-02759-2
4. Mir TA, Kim SJ, Fang W, Harvey J, Hinkle DM. Rising incidence of syphilitic uveitis-related hospitalizations in the US. JAMA Ophthalmol. 2024;142(1):7-14. doi:10.1001/jamaophthalmol.2023.5386
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8. Centers for Disease Control and Prevention. Screening recommendations and considerations referenced in treatment guidelines and original sources. August 12, 2021. Accessed April 24, 2024. https://www.cdc.gov/std/treatment-guidelines/screening-recommendations.htm 
9. Wells J, Wood C, Sukthankar A, Jones NP. Ocular syphilis: the re-establishment of an old disease. Eye. 2017;32(1):99-103. doi:https://doi.org/10.1038/eye.2017.155
10. Awake P, Angadi K, Sen S, Bhadange P. Prozone phenomenon in secondary syphilis with HIV co-infection: Two cases. Indian J Sex Transm Dis AIDS. 2022;43(2):183-185. doi:10.4103/ijstd.ijstd_43_22 
11. DeVience EX, Schechet SA, Carney M, et al. Syphilitic retinitis presentations: punctate inner retinitis and posterior placoid chorioretinitis. Int Ophthalmol. 2021;41(1):211-219. doi:10.1007/s10792-020-01569-0
12. Saleh MG, Campbell JP, Yang P, Lin P. Ultra-wide-field fundus autofluorescence and spectral-domain optical coherence tomography findings in syphilitic outer retinitis. Ophthalmic Surg Lasers Imaging Retina. 2017;48(3):208-215. doi:10.3928/23258160-20170301-03
13. Centers for Disease Control and Prevention. Neurosyphilis, ocular syphilis, and otosyphilis - STI treatment guidelines. July 22, 2021. Accessed April 24, 2024. https://www.cdc.gov/std/treatment-guidelines/neurosyphilis.htm
14. Centers for Disease Control and Prevention. Syphilis - STI treatment guidelines. www.cdc.gov. 2021. Accessed April 24, 2024. https://www.cdc.gov/std/treatment-guidelines/syphilis.htm