Ocular syphilis Janet L. Davis

Purpose of review Review current literature relevant to syphilitic uveitis utilizing Medline search and online governmental resources relevant to the diagnosis and management of syphilis presenting with ocular manifestations. Recent findings There is a trend for increasing frequency of primary and secondary syphilis in developed countries, especially in young men. Ocular manifestations of syphilis are rare, occurring in less than one in 1 million persons in the United Kingdom. Distinctive patterns of syphilitic uveitis include white, focal preretinal opacities, and acute posterior placoid uveitis. Enhanced imaging can facilitate clinical diagnosis. Definitive diagnosis remains serologic. The Centers for Disease Control currently recommends reverse sequence testing with initial treponemal antibodies, followed by a quantitative nontreponemal test, which, if negative, triggers a confirmatory treponemal pallidum agglutination test. Persons testing positive for syphilis should also be tested for HIV. Recommendations of the Centers for Disease Control for treatment are unchanged: all ocular syphilis should be treated according to neurosyphilis regimens and should receive cerebrospinal fluid testing. Summary Increased case numbers of syphilitic uveitis have stimulated interest in this old disease. This locally destructive ocular inflammation with the potential for severe systemic complications is curable with treatment and should have the highest priority for prompt recognition and treatment. Keywords epidemiology of ocular syphilis, syphilis serology, syphilitic uveitis, treatment of ocular syphilis


in 2013 was more than double than in 2000: 5.3 cases vs. 2.1 per 100 000 population [5 ]. Men accounted for 91.1% of reported early syphilis cases in 2013. Young men were disproportionately affected, and those who were 20–24 years old in 2005–2009 and 25–29 years old in 2009–2013 had the greatest percentage increases, especially among men having sex with men [5 ]. Primary and secondary syphilis accounts for only 31.4% of all cases, however, and latent and congenital infections may also be associated with syphilitic uveitis. Primary and secondary syphilis reported by health authorities is also the most likely to be treated and, therefore, not progress to syphilitic uveitis. The total number of cases of syphilis in any stage reported to the CDC was 49 903 cases &

Syphilitic uveitis remains an important clinical problem in ophthalmology. It is both immediately sight threatening and associated with the risk of both systemic and ocular long-term complications that may result in severe loss of function. Nonetheless, with prompt diagnosis, it is curable with a relatively short course of antibiotic treatment, making its recognition a priority. The last general review of ocular syphilis was published in this journal in 2006 [1]. This review covers recent trends in the epidemiology of syphilis and reports the most recent recommendations of the Centers for Disease Control (CDC) for diagnosis and management. Clinical series and new observations reported in the last 3 years are also summarized.

EPIDEMIOLOGY Syphilitic uveitis is increasing in the developed world [2,3 ], a trend potentially linked to unprotected sex in the era of effective HIV treatment [4]. In the USA, the rate of primary and secondary syphilis &


Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA Correspondence to Janet L. Davis, MD, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 900 NW 17th ST, Miami, FL 33136, USA. Tel: +1 305 326 6377; e-mail: [email protected] Curr Opin Ophthalmol 2014, 25:513–518 DOI:10.1097/ICU.0000000000000099

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Ocular manifestations of systemic disease


KEY POINTS  Preretinal opacities or acute posterior placoid chorioretinitis can be key diagnostic signs of syphilitic uveitis.  Enhanced imaging with OCT and ICG angiography can facilitate ophthalmological diagnosis.  Serologic diagnosis is imperative and has been revised to reserve sequence testing by the CDC.  All patients with ocular syphilis should receive cerebrospinal fluid testing and HIV testing.  All ophthalmic manifestations of syphilis should be treated with a CDC-approved neurosyphilis regimen.

during 2011–2012, roughly three times the cases of early syphilis. The larger total included 322 cases of congenital syphilis in 2012 and 358 cases in 2011. There is no formal system for reporting ocular complications of syphilis or neurosyphilis in the United States or other jurisdictions. The British Ocular Syphilis Study utilized a national reporting system (the British Ocular Surveillance Unit) to collect 41 new cases of syphilitic uveitis from 2009 to 2011, for an annual incidence of 0.3 per 1 million persons in the United Kingdom [6 ]. This compares to approximately 50 per 1 million cases of syphilis diagnosed annually in the United Kingdom health clinics during the same period (http:// 953088000, accessed 8 February 2014). Ocular syphilis therefore appears to be 100 times less common than early syphilis. The frequency of ocular involvement may depend on stage of disease. Among 36 patients ill enough to be hospitalized for syphilis in Nantes, France, from 2000 to 2010, there was one case of unilateral anterior uveitis, five cases of unilateral or bilateral posterior uveitis, and five cases of bilateral panuveitis for a total of 11 out of 36 (30.6%) patients with syphilitic uveitis [7 ]. The patient group was almost entirely men having sex with men, but only 18 (50%) were HIV positive. In most uveitis clinics, syphilitic uveitis is still a rarity, requiring vigilance to diagnose. In Manchester, United Kingdom, a database search over 22 years yielded 22 cases of syphilitic uveitis among 3000 cases of new uveitis (0.7%) [3 ]. Eighteen of the cases (82%) presented in the last decade. A series of acute anterior uveitis in Sydney, Australia, recorded only two cases of syphilitic uveitis among 241 patients (0.8%) [8]. In a select population of 61 HIV-infected persons presenting with uveitis who had CD4þ T lymphocyte counts greater than 200 cells/ml, syphilitic uveitis accounted for 10 cases (16.4%). &&




Diagnosis begins with ophthalmologic examination but requires serologic testing for confirmation. Cases of ocular syphilis with unusual presentations, or presentations mimicking other diseases, can be identified by serologic screening of all uveitis patients.

Clinical diagnosis Syphilitic uveitis can present as a nonspecific anterior, intermediate, posterior, or panuveitis. Episcleritis/scleritis, [9] keratitis, and hypopyon are reported. Iris nodules, iridocyclitis, and posterior synechiae can occur. Posterior manifestations include vitreous inflammation, chorioretinitis, retinal vasculitis, branch vein occlusion, serous detachment, and rarely, necrotizing retinitis. Optic nerve manifestations include inflammatory disc edema, neuroretinitis, pallor and optic nerve gumma, a solid inflammatory lesion. The variability of findings among patients exceeds that of other infectious or noninfectious uveitis with defined causes, such as toxoplasmosis or herpetic retinitis. Risk factors for sexually transmitted diseases or HIV infection are important aspects of history taking. For most incident cases of uveitis, a strict rule of always placing syphilis in the differential diagnosis and including treponemal serological testing in any laboratory workup is wise. Distinctive clinical patterns can be recognized that assist rapid diagnosis. The first of these is the presence of superficial retinal precipitates in syphilitic panuveitis [10,11]. The precipitates are small, creamy white and can migrate over inflamed retina during the evolution of the infection and its treatment. Retinal involvement in syphilitic panuveitis has a mildly opacified appearance distinct from the typical white, necrotizing retinitis seen with herpetic retinitis (Fig. 1). One of the other features of syphilitic retinitis is that the areas of retinal involvement tend to heal with minimal disruption of the retinal pigment epithelium [10]. The other distinctive pattern is that of acute syphilitic posterior placoid chorioretinitis [12] (Fig. 2). A report of 16 new cases and a review of 44 previously reported cases concluded that the uniform distribution of outer retinal and inner choroidal inflammation in a discrete oval or circular area of the posterior pole was a distinctive pattern of ocular syphilis [13]. Patients were generally male, middle-aged, and one-third were HIV positive. Vision improvement was noted in most eyes regardless of the patient’s HIV status, except three eyes previously treated with intravitreal triamcinolone acetonide that developed retinal pigment epithelial (RPE) changes in the macula. Volume 25  Number 6  November 2014

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FIGURE 1. Fundus photograph, left eye, superonasal quadrant. Distinctive small, white preretinal opacities in an eye with syphilitic retinitis. Arteriolar sheathing is present superiorly and inferiorly in the frame. Such deposits have been observed to migrate across the retinal surface over the course of a few days; they are not intraretinal.

A separate report of spectral domain optical coherence tomography (OCT) in 30 eyes of 19 syphilitic placoid patients documented small amounts of subretinal fluid and disruption of the ellipsoid zones at diagnosis [14 ]. After 1 week of treatment, the fluid resolved with persistent disruption of the outer retina and deposits at the level of the RPE, which then ultimately resolved in 28 eyes. Eyes that remained anatomically abnormal had poor final acuity. Imaging studies can be helpful in distinguishing placoid syphilis from other entities, such as sarcoidosis, Vogt–Koyanagi–Harada, posterior scleritis, viral retinitis, and lymphoma. For example, indocyanine green (ICG) angiography typically shows both early and late hypofluorescence of the lesion, whereas fluorescein angiography shows a progressive, diffuse leak [13]. This confluent ICG hypofluorescence was noted in another study to be found only in syphilitic uveitis compared to other types of infectious retinitis [15]. This distinctive pattern contrasts with the nonspecific findings on angiography in ocular syphilis other than the posterior placoid variant [16]. Hyperautofluorescence is present in the placoid lesion [17]. &&

Serologic diagnosis Regardless of clinical clues to syphilitic uveitis, serological testing remains the way in which most diagnoses are made. Serologically negative patients are rare and reported only among HIV-infected patients

FIGURE 2. (a) Fundus photograph, right eye, temporal macula. The fellow eye of the same patient as in Fig. 1 also demonstrated features of acute syphilitic placoid posterior uveitis, with retinal opacification in a round or oval area of the posterior pole. (b) Mid-venous phase fluorescein angiography of the same area shows diffuse retinal leakage corresponding to the ovoid area of opacification. The RPE mottling indicates chronic damage and will persist after healing of the active inflammation.

[18]. Ophthalmology has a long history of concurrently requesting treponemal and nontreponemal tests for syphilis, an order sometimes ignored by laboratories that do not perform treponemal testing if the nontreponemal test is negative. The CDC currently recommends enzyme immunoassays (EIAs) and chemiluminescent immunoassays (CIAs) to detect antibodies to treponemal antigens as the best screening tests for syphilis followed by reflex testing of positive specimens with the

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Ocular manifestations of systemic disease

nontreponemal test, rapid plasma reagin (RPR). ( htm, accessed 8 March 2014). The rationale for reverse-sequence testing is that there are a significant number of patients with either very early syphilis (immunoglobulin M antibodies) or late syphilis (immunoglobulin G antibodies), such as those with neurosyphilis with ocular manifestations, who will be positive by treponemal-specific tests and negative by RPR. Because sensitivity of the EIA or CIA tests is higher than RPR and specificity is lower, discordant results are expected. Specimens positive by EIA or CIA and negative on RPR are submitted for a confirmatory treponema pallidum particle agglutination test (TP-PA), and if that test is positive, a diagnosis of syphilis is considered confirmed. A negative EIA is considered definitive that syphilis is not present (Fig. 3). Screening with EIA and CIA in this manner was adopted by the European Union in 2008. Morbidity and mortality weekly report reported the results of reverse sequence syphilis screening at three sites with low population prevalence and two sites with high population prevalence. In the low prevalence areas, 40.8% of patients with positive syphilis antibody by EIA and negative RPR were not confirmed by TP-PA to have syphilis vs. 4.1% in the high prevalence area. Application of this new screening paradigm in ocular syphilis has not been performed. Because the RPR or venereal disease research laboratory (VDRL) is associated with active infection, in practical terms, most patients with active syphilitic uveitis will be RPR positive. The prozone effect may render some tests negative unless the specimen is initially diluted. The RPR is also useful as a quantitative measure of response to treatment. Patient suspected of ocular syphilis should currently be screened with EIA or CIA with reflex to RPR, and confirmatory TP-PA for discordant results. Fluorescent treponemal antibody (FTA) is no longer recommended, as TP-PA has the best combination of sensitivity and specificity relative to the initial screening tests (http://www., accessed 8 March 2014). Repeat testing of discordant results is recommended. VDRL and RPR are considered equally valid, but are not interchangeable when following patients for response. Syphilitic uveitis can also be diagnosed with direct detection methods. Early attempts with dark-field microscopy of aqueous humor have been replaced by polymerase chain reaction (PCR) [19]. This is not likely to be a total solution as some cases might still be missed. A limited form of posterior syphilitic uveitis mimicking acute zonal occult outer retinopathy was reported in two patients [20]. Initial 516





RPR + Syphilis (past or present)

TP - PA + Syphilis (past or present)


TP - PA − Syphilis unlikely

FIGURE 3. Centers for Disease Control recommended algorithm for reverse sequence serologic testing for syphilis. The testing sequence begins with a sensitive but nonspecific high throughput immunoassay for treponemal antibodies. If the test is negative, syphilis is ruled out. If it is positive, it is followed by a nontreponemal quantitative test. A positive nontreponemal test is considered diagnostic of syphilis, past or present. A negative RPR is confirmed by a sensitive and specific treponemal test, the TP-PA. CIA, chemiluminescence immunoassay; EIA, enzyme immunoassay; RPR, rapid plasma reagin; TP-PA, treponemal pallidum particle agglutination. Adapted from the Centers for Disease Control webinar on reverse sequence testing. ( std/syphilis/Syphilis-Webinar.htm, accessed 8 March 2014).

response to corticosteroids in one patient, who also had cardiolipin antibodies, led to speculation that some of the posterior manifestations of syphilis may be immunologically mediated rather than direct infection, and therefore PCR would be predicted to have been negative if performed. If positive syphilis serology is found, then HIV testing is also indicated [21]. Patients in any stage of syphilis who have unexplained ophthalmic abnormalities warrant further investigation with examination of the cerebrospinal fluid [22]. Patients with Volume 25  Number 6  November 2014

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Ocular syphilis Davis

confirmed syphilitic uveitis should also have examination of the cerebrospinal fluid. VDRL is less sensitive than FTA in the cerebrospinal fluid; at times, only leukocytosis or elevated protein is present.

TREATMENT Ocular syphilis with active clinical manifestations is considered a secondary syphilis and also a neurologic syphilis. It is treated in the same manner as neurosyphilis, according to CDC guidelines [22]. Subsequent four-fold decrease in titer by the same nontreponemal test is taken as evidence of a response to treatment. Congenital, latent, or late latent syphilis can produce ophthalmic abnormalities such as optic neuropathies or pseudoretinitis pigmentosa [17], but may not have active evidence of clinical disease and should be considered in patients with unexplained vision loss. Treatment in those cases would be expected to prevent further damage, but unlike treatment for syphilitic uveitis, not restore function. Parenteral penicillin is the drug of choice for ocular syphilis. The recommended adult regimen is aqueous crystalline penicillin G 18–24 million units per day administered as 3–4 million units intravenously every 4 h or by continuous infusion for 10–14 days. The alternative adult regimen, if access to therapy can be ensured (e.g., over weekends), is procaine penicillin 2.4 million units intramuscularly once daily plus probenecid 500 mg orally four times a day, both for 10–14 days. An extended course of benzathine penicillin, 2.4 million units intramuscularly once per week for up to 3 weeks, can be considered to provide a longer duration of therapy. The use of corticosteroids to modulate the degree of inflammation is undefined. Topical corticosteroids can be used liberally, and intravitreal injections of triamcinolone appear to be harmful [13]. Oral corticosteroids and periocular steroid injections are generally not used, but could be considered for inflammatory complications such as macular edema. Generally, the inflammation subsides with penicillin treatment with visual improvement within 1 month [14 ]. &&

CONCLUSION Syphilis is a rare but important cause of uveitis. Increasing frequency of early syphilis cases is the likely cause of increasing numbers of cases of syphilitic uveitis, even though the incidence of ocular syphilis is less than 1% of the number of new cases per year. Clinical diagnosis is improved by recognition of two classic patterns: preretinal focal

inflammatory deposits and posterior placoid chorioretinitis. Imaging with spectral domain OCT, autofluorescent photography, and ICG angiography also augment clinical diagnostic skills. Reverse sequence serological testing has unknown advantages for the diagnosis of uveitis. Case numbers are likely too few to perform clinical studies to compare the merits of one testing strategy over another. Aqueous humor PCR for syphilis may provide the unique advantage of direct detection of the spirochete, but so far has been reported only for a few cases. Treatment for syphilitic uveitis always follows the treatment regimens used for neurosyphilis and requires an examination of the cerebrospinal fluid. Acknowledgements Supported by NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Department of Defense (DOD-Grant#W81XWH-09-10675). Conflicts of interest The author has no conflicts of interest to declare.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Gaudio PA. Update on ocular syphilis. Curr Opin Ophthalmol 2006; 17:562– 566. 2. Fonollosa A, Giralt J, Pelegrin L, et al. Ocular syphilis–back again: understanding recent increases in the incidence of ocular syphilitic disease. Ocul Immunol Inflamm 2009; 17:207–212. 3. Jones NP. The Manchester Uveitis Clinic: The first 3000 patients-epidemiol& ogy and Casemix. Ocul Immunol Inflamm 2013. [Epub ahead of print] A 22-year survey of incident uveitis cases that reports a less than 1% frequency of syphilitic uveitis but notes a marked increase in cases in the last decade of the study. 4. Butler NJ, Thorne JE. Current status of HIV infection and ocular disease. Curr Opin Ophthalmol 2012; 23:517–522. 5. Patton ME, Su JR, Nelson R, Weinstock H. Primary and secondary syphilis & United States, 2005–2013. MMWR Morb Mortal Wkly Rep 2014; 63:402– 406. Basic epidemiologic information on the incidence of early syphilis in the USA. 6. Mathew RG, Goh BT, Westcott MC. British Ocular Syphilis Study (BOSS): && 2-year National Surveillance Study of Intraocular Inflammation Secondary to Ocular Syphilis. Invest Ophthalmol Vis Sci 2014; 55:5394–5400. A prospective survey of ocular syphilis in the United Kingdom, enabling an estimate of the population incidence in the post-penicillin era. Also provides valuable information regarding clinical course i HIV-positive and HIV-negative patients. 7. Lefebvre M, Biron C, Guillouzouic A, et al. [Syphilis in Nantes tertiary care & hospital between 2000 and 2010: a case series of 36 hospitalized patients]. Rev Med Interne 2013; 34:522–527. Enumerates the frequency of uveitis among this population of hospitalized patients with syphilis. 8. Karaconji T, Maconochie Z, McCluskey P. Acute anterior uveitis in Sydney. Ocul Immunol Inflamm 2013; 21:108–114. 9. Fenolland JR, Bonnel S, Rambaud C, et al. Syphilitic scleritis. Ocul Immunol Inflamm 2014; 1–3. 10. Fu EX, Geraets RL, Dodds EM, et al. Superficial retinal precipitates in patients with syphilitic retinitis. Retina 2010; 30:1135–1143. 11. Wickremasinghe S, Ling C, Stawell R, et al. Syphilitic punctate inner retinitis in immunocompetent gay men. Ophthalmology 2009; 116:1195– 1200.

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Ocular manifestations of systemic disease 12. Gorovoy IR, Desai S. Syphilitic posterior placoid chorioretinitis. Sex Transm Dis 2013; 40:852–853. 13. Eandi CM, Neri P, Adelman RA, et al. Acute syphilitic posterior placoid chorioretinitis: report of a case series and comprehensive review of the literature. Retina 2012; 32:1915–1941. 14. Pichi F, Ciardella AP, Cunningham ET Jr, et al. Spectral domain optical && coherence tomography findings in patients with acute syphilitic posterior placoid chorioretinopathy. Retina 2014; 34:373–384. Depictions of the OCT appearance of syphilitic uveitis with clinical correlations to course and visual acuity outcomes. 15. Knecht PB, Papadia M, Herbort CP. Secondary choriocapillaritis in infectious chorioretinitis. Acta Ophthalmol 2013; 91:e550–e555. 16. Balaskas K, Sergentanis TN, Giulieri S, Guex-Crosier Y. Fluorescein and indocyanine-green angiography in ocular syphilis: an exploratory study. Graef Arch Clin Exp Ophthalmol 2012; 250:721–730.


17. Jumper JM, Randhawa S. Imaging syphilis uveitis. Int Ophthalmol Clin 2012; 52:121–129. 18. Tucker JD, Li JZ, Robbins GK, et al. Ocular syphilis among HIV-infected patients: a systematic analysis of the literature. Sex Transm Infect 2011; 87:4–8. 19. Cornut PL, Sobas CR, Perard L, et al. Detection of Treponema pallidum in aqueous humor by real-time polymerase chain reaction. Ocul Immunol Inflamm 2011; 19:127–128. 20. Lima BR, Mandelcorn ED, Bakshi N, et al. Syphilitic outer retinopathy. Ocul Immunol Inflamm 2014; 22:4–8. 21. Restivo L, Abbouda A, Nardella C, et al. Uveitis heralding previously unknown luetic and HIV infection. Syphilitic uveitis in an Italian referral center. Ann Ist Super Sanita 2013; 49:133–137. 22. Centers for Disease Control Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR Morb Mortal Wkly Rep 2010; 59:1–116.

Volume 25  Number 6  November 2014

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Ocular syphilis.

Review current literature relevant to syphilitic uveitis utilizing Medline search and online governmental resources relevant to the diagnosis and mana...
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