Re-emergence of syphilis since approximately 2000 is well documented by national and international surveillance bodies1,2,3,5. The change in epidemiology has been attributed to factors that include high-risk sexual practices and global travel, immunomodulatory impacts of infection with HIV and highly active anti-retroviral therapy, and changes in antibiotic sensitivity of T. pallidum28,29,30. A recent plethora of case series of ocular syphilis11,18,19,20,21,23,24,25,26,27 has suggested a re-emergence of ocular syphilis, although studies using national databases in the US and UK22,31 have not supported an increase in incidence. As discussed by the authors of those studies, heightened awareness and early treatment of syphilis might be relevant; however, a temporal lag might also explain this discrepancy, with both studies including data collected up to 2011.

Our investigation was conducted between January 2013 and July 2015. Two pieces of evidence suggest the incidence of ocular syphilis is increasing in Brazil. The Escola Paulista de Medicina - Hospital São Paulo has published two surveys of consecutive patients presenting to the uveitis service. In the first survey15, conducted between 1975 and 1979, ocular syphilis was responsible for 1.8% of presentations; in the second survey32, conducted from 2012 to 2013, ocular syphilis was responsible for 6.1% of presentations. Separately, review of the cases of the ocular syphilis managed at Hospital das Clínicas de Ribeirão Preto, a referral center for this study and home to the only public inflammatory eye disease clinic in the region, indicated 10 cases between 2000 and 2012 (0.77 cases/year) and 25 cases between 2013 and 2015 (8.33/year); there were no changes in the referral system and no expansion of patient services that might otherwise explain this increase.

We report the largest series of ocular syphilis yet described, including 127 patients diagnosed by standard criteria including serological testing, CSF analysis and response to anti-microbial treatment. Just over three-quarters of our patients were men. Age at presentation ranged widely, but averaged in the fifth decade. Approximately one-third of the patients were HIV-positive. These demographics are consistent with those reported by three smaller case series of patients with syphilitic uveitis: a cohort of 85 persons from The Netherlands19, a cohort of 66 persons from France21, and a cohort of 50 persons from Spain20. In those studies, 62–92% of patients were men; mean age varied between 41 and 49 years; and 34–47% of patients were HIV-positive. In keeping with findings of British Ocular Syphilis Study22, which reported on 41 persons diagnosed between 2009 and 2011, uveitis was by far the most common presentation of ocular syphilis in our cohort, affecting 212 of 214 eyes. Posterior uveitis – typically characterized by retinal involvement – was the most common uveitis subtype, accounting for 77%, while anterior, intermediate and pan- uveitis each accounted for less than 10%.

There is debate regarding the optimum management of ocular syphilis, including indications for lumbar puncture, anti-microbial treatment, and use of adjunctive corticosteroid33. Lumbar puncture, performed in two-thirds of our patients, demonstrated abnormalities in almost 30% of these individuals. A new report from South Africa on the use of lumbar puncture in the management of ocular syphilis34 indicated 46% of 68 patients diagnosed with ocular syphilis were investigated with lumbar puncture, and one-quarter of those investigated had findings consistent with neurosyphilis, including positive FTA-ABS and/or lymphocytic pleocytosis. On the basis of their results, the authors concluded, “lumbar puncture should be a routine investigation for all patients diagnosed with ocular syphilis”. Over 90% of our patients were treated with IV aqueous penicillin G or ceftriaxone, following the CDC recommendations for treatment of ocular syphilis35, which are identical to those for neurosyphilis. These recommendations have been widely adopted, based on recent reports11,17,18,19,23,25,26,27. There are no guidelines for the use of corticosteroid medications in patients with ocular syphilis, although these drugs may be given in conjunction with antibiotics to limit inflammation;11,18,19,25,26,27 approximately 60% of our patients received locally injected or systemic corticosteroid. Interestingly, in the study of 66 French patients with syphilitic uveitis, persistence of inflammation one month after commencement of treatment was associated with use of intravenous or periocular, but not oral or topical, corticosteroid21.

In keeping with the diverse clinical involvements, we documented a wide range of complications in the eyes with ocular syphilis, on presentation and/or during follow-up. Cataract was the most common anterior segment complication, seen initially in 9% of affected eyes and having an incidence rate of 0.18 per eye-year. Ocular hypertension or glaucoma occurred with an incidence rate of 0.10 per eye-year. Regarding posterior segment complications, cystoid macular edema was first observed only at presentation and in 5% of involved eyes, while epiretinal membrane was seen initially in 3% of affected eyes, but also appeared during follow-up with an incidence rate of 0.09 per eye-year. Although retinal vasculitis was noted in more than one-quarter of eyes with ocular syphilis, occlusions of major retinal vessels did not result. The most comprehensive published report of complications in ocular syphilis prior to our report describes 35 US patients managed at John Hopkins School of Medicine11. A similar range of complications was observed in these patients, albeit with different initial frequencies and incidence rates, probably reflecting different cohort demographics (i.e. two-thirds African-American and 54% HIV-positive), in addition to the shorter interval between onset of uveitis and presentation.

We recorded reduced visual acuities at presentation for a majority of eyes with ocular syphilis: 39% of eyes registered visual acuities of 20/200 or worse, and another 27% of eyes had visual acuities between 20/50 and 20/100. Although approximately one-half of eyes had a 2-line or more improvement of best-corrected Snellen visual acuity during follow-up, 17% of eyes remained 20/200 or worse and another 25% of eyes were between 20/50 and 20/100 at the 4–8 week evaluation. The incidence rate for vision loss to 20/50 or worse was 0.10 per eye-year and for vision loss to 20/200 or worse was 0.06 per eye-year. Differences in reporting of visual acuity make it difficult to compare our findings with those of studies from The Netherlands, France and Spain19,20,21. However, each of those studies reported improvement in visual acuity after treatment in the majority, but with some patients having persistent vision loss. That approximately 40% of our patients were left with reduced visual acuity might reflect the mean 3-month time interval for diagnosis of ocular syphilis. In a cohort of 20 HIV-positive Japanese patients27, presence of ocular symptoms for more than one month prior to diagnosis was associated with poor final visual acuity.

Given the strong link between HIV infection and ocular syphilis, it is relevant to compare presentation and course in HIV-negative versus HIV-positive individuals. There were no differences in drug treatments and time to treatment in our HIV-positive and HIV-negative patients. We observed a younger age and higher number of males in the HIV-positive group. We also observed more posterior and pan- uveitis, and less anterior and intermediate uveitis, in HIV-positive persons in comparison to HIV-negative persons. This distribution of uveitis by HIV infection status is supported by independent analyses of the literature36,37. Incidence rates of complications reflected the anatomic location of the uveitis – lower for anterior segment complications and higher for posterior segment complications in HIV-positive eyes – and incidence rates for visual acuity loss were higher in HIV-positive persons. However, rates of vision loss, as well as changes in visual acuity in follow-up, were equivalent to those seen in HIV-negative individuals. In the cohorts of 50 Spanish patients20 and 41 UK patients22, visual acuity outcomes between HIV-negative and HIV-positive patients were also similar.

We have reported a large observational case series of ocular syphilis, including patients diagnosed during a 2.5-year period that ended July 2015, in four tertiary referral inflammatory eye disease clinics in Brazil. Strengths of our research include substantial sample size, recent and relatively short time interval of enrollment, and the process of standardized data collection on consecutive cases. Limitations of the work reflect its retrospective nature, including in particular, availability of some information, such HIV infection status and results of CSF analysis, for a limited subset of subjects. Although our clinics receive tertiary referrals, they are based at public hospitals; since at least 75% of the Brazilian population uses the public health system38, our data are likely to be reflective of ocular syphilis as it occurs in the general population. Our results indicate that today ocular syphilis most commonly manifests as posterior uveitis, and frequently results in complications that may compromise vision, despite treatment with appropriate antibiotics. Medical practitioners should consider the possibility of, and investigate for, syphilis in all cases of uveitis.