Known as the great imitator because of its protean manifestations, syphilis results from infection by the spirochete Treponema pallidum. Although the incidence of infection has decreased dramatically since advent of penicillin in the the mid-20th century,1 syphilis still represents a large global problem, especially in developing countries. The World Health Organization estimated that 12 million new cases of syphilis occurred worldwide in 1999. Despite a program instituted in the 1990s to eliminate syphilis from the United States, the incidence of infection here has risen by more than 75 percent since 2000, when it was at a low of 2.1 per 100,000 people. According to statistics from the 2008 National STD Prevention Conference ( 2008/media/ release-12march 2008.htm), 2007 marked the seventh consecutive year that the rate of syphilis rose in the United States—a year when nearly two-thirds of acquired syphilis infections occurred in men who have sex with men, a group in which the rate of HIV co-infection is also high. Although responsible for less than 5 percent of all cases of uveitis,2,3 syphilis should always be considered in the differential diagnosis of ocular inflammation, both because it is often curable and because accurate diagnosis and treatment prevents further spread of the infection.

Systemic Disease

Syphilis can be acquired transplacentally or in the postnatal period. Congenital syphilis can present during childhood with a number of systemic features, including Hutchinson's teeth, saddle nose deformity and deafness, and can also cause ocular complications, most notably interstitial keratitis (See Figure 1) and ectopia lentis.4 Acquired syphilis is divided conventionally into four stages.4 Primary syphilis is characterized by the formation of a painless chancre, which typically appears two to six weeks after infection at the site of inoculation. Secondary syphilis occurs four to 10 weeks following infection and is characterized by non-specific symptoms, such as fever and malaise, as well as the formation of a generalized rash, which often involves the palms and soles.5 Latent syphilis, in which disease is clinically undetectable, can persist for many years. Tertiary syphilis, characterized by neurologic and cardiovascular manifestations, occurs months to years following infection and may produce significant morbidity. 

Ocular Manifestations

Complications of syphilis infection can involve virtually all ocular structures. Regarding the ocular surface, syphilis can cause conjunctivitis,6 episcleritis or scleritis.7,8 Interstitial keratitis (See Figure 1), often associated with conjunctival injection and anterior chamber inflammation, is a well-recognized manifestation of congenital syphilis that typically presents between 5 and 20 years of age.9,10 Dislocation of the crystalline lens may also occur following congenital infection.11

Uveitis, which may be unilateral or bilateral, is one of the most frequent ocular manifestations of syphilis.2,3,9 Granulomatous features, including large keratic precipitates (See Figure 2) and iris nodules, may occur in syphilitic uveitis, but are by no means the norm.10 Dilated iris vessels, known as iris roseolae (See Figure 3), occur rarely, but are relatively specific for syphilis.10 Along with all forms of herpes virus infection, sarcoidosis and toxoplasmosis, syphilis is a common cause of elevated intraocular pressure associated with uveitis, or so-called Inflammatory Ocular Hypertension Syndrome.12

Posterior segment involvement, including chorioretinitis, retinitis, vasculitis, vitritis and panuveitis, can also occur.7,13-15 Chorioretinitis, one of the most frequent manifestations, is typically multifocal and associated with a significant degree of vitreous inflammation.15-17 A "ground glass" retinitis, often associated with retinal vasculitis, is said to be characteristic of syphilis (See Figure 6).18

Originally described by J. Donald M. Gass, MD, acute syphilitic posterior placoid chorioretinopathy (ASPPC) results from syphilitic infection of the retinal pigment epithelium in the macula or peripapillary region.13,19 As the name suggests, lesions are typically large and placoid (See Figure 5). Following resolution, involved areas of RPE often show a leopard-spot appearance on fluorescein angiography.20 Serous retinal detachment with macular pseudohypopyon formation may accompany ASPPC.21 Patients with ASPPC are often, but not necessarily, immunocompromised.13,22,23 Although thought by some to be a finding specific to syphilis, ASPPC can be difficult to distinguish from acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroidopathy, necrotizing herpetic retinitis, outer toxoplasmic retinochoroiditis or intraocular lymphoma. 

Syphilitic retinitis can be patchy early, becoming more confluent over time.24 Such changes can be difficult to distinguish from acute retinal necrosis (ARN) and toxoplasmic retinochoroiditis, especially when heavy vitritis is present,25 but unlike ARN and toxoplasmosis, syphilitic retinitis responds promptly to penicillin.13,15,22 Syphilitic retinitis can cause serous retinal detachment, which resolves promptly with penicillin treatment (See Figure 6).26 Neuroretinitis, sometimes associated with vasculitis or vitritis, may occur in syphilis as well (See Figure 7).15,27

Isolated retinal vasculitis can affect either arteries or veins and, if occlusive, may cause lasting retinal damage.15,28,29 Although more typical of toxoplasmic retinochoroiditis, nodular arteritis, known as Kyrieleis plaques, can also occur in syphilitic uveitis.30 Syphilitic intermediate uveitis may occur as well, although pars plana exudates are said to be infrequent.7,27 A host of neuro-ophthalmic manifestations, including the Argyll Robertson pupil, optic neuritis and optic neuropathy have also been described.10,31


The diagnosis of ocular syphilis depends largely on serologic testing. Despite the stigma of infection and the generally low prevalence of syphilis in the population at large, clinicians should have a low threshold for performing serologic analysis in patients with uveitis.5,32 Strong indications to test include a history of other sexually transmitted diseases or of high-risk sexual behavior, inflammation refractory to treatment with corticosteroids, or the finding of one or more suggestive clinical features described above, such as granulomatous features, iris roseola, ground glass retinitis, focal inflammatory accumulations or findings consistent with ASPPC. A recent case series found non-granulomatous anterior uveitis to be the most common manifestation of syphilitic uveitis, however, suggesting that syphilis testing is indicated even in the absence of suggestive clinical findings.33

Two types of antibody-based serum tests are employed in the diagnosis of syphilis—non-treponemal and treponemal.4 Non-treponemal tests, which include the Rapid Plasma Reagin (RPR) and the Venereal Disease Research Laboratory (VDRL) tests, detect antibodies directed against host antigens, such as cardiolipin, which are released following tissue damage induced by T. pallidum. Non-treponemal tests offer the advantage of quantifiability, reflect both disease activity and response to therapy, and can be used to test for reinfection. RPR and VDRL suffer, however, from limited sensitivity—which has been suggested to be as low as 70 percent.2,34 In contrast, treponemal tests, which include the Fluorescent Treponemal Antibody Absorption (FTA-ABS) and the Microhemagglutination Treponema pallidum (MHA-TP) tests, measure serum antibodies directed specifically against the T. Pallidum, and are highly sensitive. Titers of specific treponemal tests are generally not reliable in gauging response to treatment, however.35 While both treponemal and non-treponemal tests are quite specific, false positive results may occur, for example, in the setting of collagen vascular disease, advanced age and HIV infection. We therefore recommend that both a non-specific and specific test be obtained when considering the diagnosis of ocular syphilis.

Per Centers for Disease Control and Prevention guidelines, analysis of cerebrospinal fluid (CSF) should be performed in all patients with ocular syphilis,15,36,37,38 particularly since the presence of neurologic involvement, which is associated with greater morbidity and mortality, can not be accurately determined clinically. Findings suggestive of neurologic involvement include: greater than five white blood cells per microliter; elevated protein levels; or the presence of either treponemal or non-treponemal antibodies in the CSF. Non-treponemal testing, specifically VDRL or RPR, is performed most commonly on CSF and offers the same advantages and disadvantages relative to specific treponemal testing as described above for serologic testing.39

Direct visualization of treponemes by darkfield microscopy or silver staining aspirated fluids or excised tissues is also possible. Samples can be obtained from a chancre in primary syphilis, from an open pustule or regional lymph node in secondary disease, or from aqueous humor or vitreous in patients with uveitis.40 Polymerase chain reaction-based analysis of intraocular fluids may also be performed, particularly when serologic testing is unreliable, as in patients with collagen vascular disease, advanced age or HIV infection.39 In practice, however, such fluid- and tissue-based tests are rarely done in patients suspected of having ocular syphilis.

All patients with syphilis should be tested for HIV infection, both because risk factors for acquisition of syphilis and HIV are similar and because the presence of a chancre greatly increases the risk of HIV transmission.36 Many cases of HIV/AIDS have been diagnosed in patients presenting initially with ocular syphilis.2,13,18,22,27,29,41,42

Penicillin is the treatment of choice for all stages of syphilis. Acquired syphilis with ocular involvement should be treated as neurosyphilis with intravenous penicillin G, 18 to 24 million units (MU) daily for 10 to 14 days, followed by intramuscular procaine penicillin, 2.4 MU weekly for three weeks.36,37 T. pallidum replicates once every 30 hours, so sustained elevated intraocular levels of penicillin are required to achieve a bactericidal effect. Treatment failure may occur in patients treated solely with intramuscular penicillin, which does not achieve adequate, sustained intraocular concentrations.3,14,18,22 The overall failure rate of penicillin treatment in immunocompetent patients is approximately 1 percent,43 although persistent or recurrent disease may, in some cases, be attributed to noncompliance or insufficient therapy.3,18,43,44

In patients with penicillin allergy, several therapeutic alternatives are available, including tetracycline, doxycycline, chloramphenicol, ceftriaxone and the macrolide antibiotics.22,45 No antibiotic other than penicillin, however, has been proven to be effective for the treatment of syphilis. Therefore, penicillin desensitization, in which increasing doses of the penicillin are administered with careful monitoring, is sometimes recommended, particularly in patients with neurologic involvement.13

Systemic corticosteroids also have a role in the treatment of syphilitic eye disease, but only in the setting of appropriate antibiotic therapy.46 Topical corticosteroids are effective in the treatment of anterior uveitis. While systemic cyclosporine and oral corticosteroids have been used to treat refractory interstitial keratitis, the benefit of such agents has to be weighed against the potential for side effects and should only be used once the underlying infection has been treated with penicillin.47

In assessing the efficacy of therapy, either RPR or VDRL titers should be obtained at six, 12 and 24 months following treatment, and more frequently in patients with HIV.37 If a fourfold decrease in non-treponemal antibody titers is not achieved following six months of treatment in patients with primary or secondary syphilis, or 12 months after treatment in patients with latent or tertiary disease, reanalysis of the CSF, reassessment of HIV status and re-treatment should be considered. In patients with positive CSF abnormalities, lumbar puncture should be performed every six months following treatment until the abnormalities have normalized.37 Retreatment should be considered if the CSF white blood cell count has not decreased by six months after therapy or if CSF abnormalities persist past two years following treatment.

Long-Term Ocular Complications

Common long-term complications of syphilitic uveitis include glaucoma, cataract, epiretinal membrane and macular edema. Choroidal neovascularization, while uncommon, has been described and may resolve following treatment with penicillin.44 The Jarisch-Herxheimer reaction, which results from the release of treponemal antigens from spirochetes killed following initiation of antibiotic therapy, may result in fever, malaise and headache, as well as a worsening of ocular manifestations48 and may be prevented by administration of systemic corticosteroids concurrent with antibiotic treatment. Widespread chorioretinal scarring can occur in some patients.
Syphilis and HIV

A high index of suspicion for ocular syphilis should be maintained in all HIV-infected patients, regardless of CD4 count.22,49 Unusual ocular manifestations, including ASPPC (See Figure 7) and preretinal focal inflammatory accumulations (See Figure 8), have been observed more commonly in HIV-positive patients.50,51 HIV-positive individuals are also more likely to have a severe, atypical clinical course;14,52-54 uveitis is more frequently posterior and bilateral; central nervous system involvement is more common; and serologic testing is less reliable in patients with HIV.22,55 Of note, the sensitivity of treponemal tests (FTA-ABS, MHA-TP) has been reported to be as low as 62 percent in symptomatic HIV-positive patients.10,29,56

Patients with HIV are also at increased risk for serologic treatment failure, with slower normalization of antibody titers or CSF abnormalities.57,58 Cases of actual treatment failure despite high-dose intravenous penicillin treatment have prompted some experts to recommend a prolonged treatment course and possibly maintenance therapy in patients with HIV infection.22,54

Syphilis remains a common infection worldwide. Despite initially successful attempts to lower the incidence of syphilis in the United States in the 1990s, a steady increase in the rate of infection has been noted since 2000, especially among men who have sex with men and in those infected with HIV. Syphilis should be considered in all patients with uveitis, and in particular those who are known to be HIV-positive or who engage in high-risk sexual activities. Serologic testing is required both to confirm the diagnosis and to monitor response to therapy. Patients with ocular syphilis should undergo CSF testing and, regardless of findings, be treated as neurosyphilis with 10 to 14 days of high-dose intravenous followed by three weekly injections of IM penicillin. All patients found to have syphilis should be reported to the local health authority so that sexual partners can be contacted and tested.

Dr. Wender is a resident in ophthalmology at California Pacific Medical Center in San Francisco. Dr. Eliott is a professor of ophthalmology and director of the Retina Service at Doheny Eye Institute, University of Southern California, Los Angeles. Dr. Jumper is the CPMC Retina Service chief and in private practice at the West Coast Retina Medical Group. Dr. Cunningham is director of the Uveitis Service at CPMC, an adjunct clinical professor of ophthalmology at Stanford University School of Medicine, and in private practice at West Coast Retina Medical Group. Contact Dr. Cunningham at West Coast Retina, 185 Berry St, San Francisco, Calif. 94107. Phone: (415) 972 4600; fax: (415) 975 0999; e-mail: emmett_cunning This work was supported by the San Francisco Retinal Foundation and the Pacific Vision Foundation.

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