Iberian Registry of Ocular Syphilis (IBERSOS) report 1: epidemiology, clinical spectrum and treatment outcomes of ocular syphilis in the Iberian Peninsula

Abstract

Purpose

The Iberian Registry of Ocular Syphilis aims to describe the epidemiology, clinical manifestations and treatment outcomes of ocular syphilis in Spain and Portugal. This re-emerging condition, associated with rising global syphilis rates and HIV coinfection, presents with diverse ocular and systemic features. The study seeks to fill knowledge gaps regarding incidence, presentation and therapeutic response.

Methods

This multicentre, observational cohort study includes patients aged ≥18 years with newly diagnosed ocular syphilis confirmed by treponemal and nontreponemal serological tests. Conducted across 23 centres, data collection followed routine clinical practice and included demographics, ocular/systemic findings, treatment regimens and outcomes at 3–6 months post-treatment.

Results

In the first year, 41 patients met the inclusion criteria, of whom 39 consented to participate in the registry, with an incidence of 0.57 cases per 100 000 persons/year. Most were male (94.9%), especially men who have sex with men (66.7%) and HIV coinfection (20.5%). Bilateral ocular involvement was observed in 64.1% of patients, with anterior segment inflammation in 64.1%, vitritis in 53.8%, retinal or choroidal involvement in 69.2% and optic nerve involvement in 59.0%. Systemic syphilis stage included primary (7.7%), secondary (25.6%) and tertiary or quaternary (15.4%). Treatment was initiated after a mean of 6.2±9.3 weeks after the onset of symptoms, and 2.6±6.0 weeks after the initial presentation at the hospital. Intravenous penicillin G was used in 65.8%, and 61.3% achieved a four-fold titre reduction in the reaginic test at the final visit (3 to 6 months after antibiotic therapy). Final visual acuity improved to 0.17 LogMAR (p<0.001), with 56% of eyes gaining ≥0.1 LogMAR.

Conclusions

Ocular syphilis in the Iberian Peninsula shows a wide clinical spectrum and frequent posterior segment involvement. Most patients achieved favourable serological and visual outcomes. These findings support the effectiveness of standard therapies and highlight the need for early diagnosis, especially in high-risk populations.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Ocular syphilis is a rare but potentially blinding manifestation of systemic syphilis. Evidence is limited to small, single-centre cohorts, with scarce multicentre data from Europe despite rising syphilis incidence and HIV co-infection.

WHAT THIS STUDY ADDS

• The Iberian Registry of Ocular Syphilis provides the first multicentre, prospective data on ocular syphilis in Spain and Portugal, demonstrating diverse clinical presentations, high rates of posterior involvement and favourable serological and visual outcomes even when treatment initiation was delayed.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• These findings underscore the need for heightened clinical suspicion in high-risk populations, support current penicillin-based treatment strategies and establish a foundation for future analytical studies and public health planning as the registry expands.

Introduction

Syphilis is a systemic infectious disease caused by a bacterial spirochaete named Treponema pallidum which is transmitted during sexual relations or from mother to fetus via placenta¹. It primarily affects individuals who engage in high-risk sexual behaviours, among other risk factors, and can affect immunocompetent healthy patients.² Its incidence has been increasing since 1998 in higher-income countries³ including Spain^{4 5} and Portugal. Despite the availability of effective antibiotic treatments, syphilis, and ocular syphilis in particular, is not always easily suspected due to its wide range of clinical manifestations.⁶ This is especially significant because failing to treat syphilis with adequate antibiotics, and to treat it uniquely with corticosteroids and/or immunomodulators in its initial stages may result in severe long-term complications.⁶

To increase the evidence base for this re-emerging condition, the Iberian Registry of Ocular Syphilis (IBERSOS) aims to provide a comprehensive description of the epidemiology, clinical manifestations and treatment responses of ocular syphilis in Spain and Portugal. The registry collects standardised data to address knowledge gaps regarding incidence, risk factors that influence both the serological and functional responses to treatment, clinical presentation and treatment outcomes as its primary objective.

Methods

The IBERSOS registry is a multicentre, observational cohort study conducted across 23 centres in Spain and Portugal, with a total reference population of 7 247 788 persons. The reference population was calculated from the combined catchment populations reported by the regional health services of the respective autonomous communities in Spain and the Portuguese national health system, based on official census data for year 2024. All cases included in this study were recruited between June 2023 and December 2024. Although this period exceeds one calendar year, it reflects the staggered enrolment of participating centres, as not all received institutional approval to join the registry simultaneously. Therefore, each centre had its own specific start and end dates for data collection. Importantly, the results presented here represent the first year of participation for each centre in the registry.

All consecutive patients aged 18 years or over with intraocular inflammation related to ocular syphilis, as confirmed by positive treponemal test with supporting non-treponemal serology, who had expressly agreed to participate in the registry, were prospectively included. Patients with previously treated syphilis were included if reinfection was confirmed by a fourfold increase in the non-treponemal test result. Patients with suspected syphilis without serological test confirmation and those with previously treated syphilis without confirmed serological reinfection on nontreponemal tests were excluded. Patients who met the inclusion criteria but did not agree to be included in the registry were counted in the incidence measurement. However, none of their clinical data was added to the registry.

Patients with long-term diagnosed syphilis (prevalent cases) were excluded.

Data collection adhered to routine clinical practice and included the following:

1. Demographics: age, sex, ethnicity and risk factors for sexually transmitted infections.

2. Clinical presentation: visual acuity, intraocular pressure, anterior and posterior segment findings and systemic manifestations, including syphilis stage according to Centers for Disease Control and Prevention (CDC) guidelines.⁷

3. Treatment details: antibiotic regimens, use of adjunctive therapies and treatment timelines.

4. Outcomes: changes in serological markers, visual acuity and intraocular inflammation 3–6 months after treatment. A period of 3 to 6 months after treatment was selected for the final follow-up, with the aim of allowing complete clinical resolution of cases and, at the same time, providing sufficient time for serological response, particularly in patients with HIV infection, who may require more time than non-HIV patients to achieve negativisation or a significant decrease in titres.

Mean incidence with Agresti-Coull 95% CIs⁸ was calculated for a mid-period reference population.

Although the study was not population-based, the Spanish and Portuguese regional health service provides free healthcare for all the referral population, and most infectious uveitis cases will attend their referral public hospital. It is uncommon for infectious and sight-threatening uveitis cases to be exclusively cared for in private clinics. Thus, our data will provide a useful approximation to the real, population-based statistics.

Qualitative variables were expressed as percentages. Quantitative variables were expressed as mean values (± SD) if they followed a normal distribution using the Shapiro–Wilk test,⁹ or as median values (range) if they did not. Generalised estimating equations were used to assess differences in visual acuity between baseline and final visit, accounting for intra-subject correlation as some participants contributed data from one eye and others from both. A p value of <0.05 was considered statistically significant. Data was analysed using JASP V.0.19.3 (JASP Team, the Netherlands).

Results

Patient enrolment and baseline characteristics: during the first year, 41 patients met the inclusion criteria (figure 1). Of these, 2 declined to participate in the registry. The observed incidence rate was 0.57 cases per 100 000 persons/year. Table 1 and figure 2 represent the observed incidence of ocular syphilis by region.

Figure 1. Patient flowchart.

Table 1. Incidence of ocular syphilis by region.

	Incident cases	Referral population	Incidence (new cases per 100 000 persons/year)	95% CIincidence (new cases per 100 000 persons/year)
SPAIN	40	6 982 788	0.57	0.42	0.79
Madrid	13	2 101 637	0.62	0.35	1.07
Catalonia	8	1 555 964	0.51	0.24	1.03
Valencia	4	741 250	0.54	0.16	1.44
Basque Country	0	570 000	0	0	0.81
Andalucía	3	470 000	0.64	0.12	1.97
Aragon	8	377 967	2.12	0.99	4.26
Extremadura	4	268 973	1.49	0.43	3.97
Castille-La Mancha	0	265 000	0	0	1.75
Murcia	0	250 000	0	0	1.86
PORTUGAL	1	345 000	0.29	0	1.82
Lisbon	1	345 000	0.29	0	1.82
TOTAL	41	7 247 788	0.57	0.42	0.77

Figure 2. Ocular syphilis incidence by region in Spain and Portugal. Grey: no data.

The mean age at diagnosis was 46.9±13.6 years, 37 patients were men (94.9%) and 26 (66.7%) reported being men who have sex with men (MSM). Eight patients (20.5%) were HIV positive at the time of ocular syphilis diagnosis. No cases of primary HIV diagnosis were detected at the same time as syphilis.

Clinical presentations: twenty-five patients (64.1%) had bilateral involvement, 8 (20.5%) had only left eye involvement and 6 (15.4%) only right eye involvement. The mean best corrected visual acuity at presentation was 0.58±0.69 LogMAR. At presentation, 31 of 64 eyes (48.4%) with ocular syphilis had a best corrected visual acuity worse than 0.3 LogMAR. Anterior segment inflammation was present in 25 patients (64.1%). The median anterior chamber cell score was 0.5+ (range 0.5 to 3+). Vitritis was present in 21 patients (53.8%). Four patients (10.2%) presented with scleritis. Retinal and/or choroidal involvement was present in 27 patients (69.2%), and optic nerve involvement in 23 patients (59.0%).

Following SUN criteria, 2 patients (5.1%) had anterior uveitis (one of which had sclerouveitis), 2 (5.1%) had intermediate uveitis, 20 (51.3%) had posterior uveitis and 10 (25,6%) panuveitis (one of which had sclerouveitis). Additionally, there were 2 cases (5.1%) of isolated scleritis and 3 cases (7.7%) of isolated optic neuritis.

Systemic manifestations included primary syphilis with a chancre in 3 patients (7.7%), secondary syphilis with a palmoplantar rash and/or roseola in 10 (25.6%), and tertiary or quaternary symptomatic neurosyphilis in 6 (15.4%). Twenty patients (51.3%) were in a latent stage of systemic syphilis, except for ocular involvement.

Treatment and outcomes: treatment data was present in 38 cases, and the final follow-up visit was completed in 31 patients (50 eyes). Treatment regimens were intravenous penicillin G in 25 (65.8%), intramuscular penicillin G in 11 (28.9%) and doxycycline and ceftriaxone in one patient each (2.6%). The mean time from symptom onset to treatment initiation was 6.2±9.3 weeks. The mean time from first hospital presentation to treatment initiation was 2.6±6.0 weeks. Three patients developed a Jarisch-Herxheimer reaction after treatment initiation, which was successfully treated with paracetamol in one case and with systemic steroids in two.

Finally, the mean time between treatment and final follow-up visit was 20.6±5.5 weeks. No false negatives were observed due to the prozone effect. Serological response 6 months after treatment (four-fold Rapid Plasma Reagin -RPR- or Venereal Disease Research Laboratory -VDRL- titre decrease) was documented in 19 patients (61.3%). Intraocular inflammation persisted more than 3 months after treatment in 2 patients (6.5%). Final visual acuity after treatment was 0.17±0.4 LogMAR (p<0.001). Figure 3 shows visual acuity change after treatment for ocular syphilis. Twenty-eight eyes (56%) gained at least 0.1 LogMAR after treatment. Only 4 out of 50 eyes (8.0%) had a final vision worse than 0.3 at the final follow-up (3 cases of optic neuritis and one case of panuveitis with retinal vasculitis).

Figure 3. Scatter plot representing the best corrected visual acuity in LogMAR change from presentation to 3–6 months after antibiotherapy for syphilis, in 50 eyes of 31 patients who completed at least 3 months of follow-up. Grey line: no change. LogMAR: logarithm of the Minimum Angle of Resolution. BCVA: Best corrected visual acuity.

Discussion

Our study aims to analyse data on patients diagnosed with ocular syphilis in Spain and Portugal, including epidemiology, risk factors, clinical manifestations, treatment and outcomes, in order to deeply understand this disease and prepare for a potential increase in its incidence and, subsequently, its ocular involvement. To our knowledge, all previous studies on this topic have involved small cohorts, and no ocular syphilis registry containing data from across the Iberian Peninsula has yet been published.

Since its discovery in the 15th century,² syphilis has always been a matter of public health concern. First, in the pre-antibiotic era, due to its severe consequences and morbidity burden, and subsequently during the HIV pandemic, due to the surge in AIDS-related cases.¹⁰ Currently, we are witnessing another increase in infection rates, according to reports from official health authorities in the European Union, the USA, England and China.^{1 11–14} The resurgence of syphilis observed since 2000 has been attributed to a diminished fear of HIV infection and a decline in the consistent use of barrier protection methods, following the AIDS pandemic of the 1980s and the introduction of highly active antiretroviral therapy in the 1990s.¹⁵ A second wave has been attributed to changes in sexual behaviour secondary to readily available pre-exposure prophylaxis¹⁶ and apps that facilitate sexual encounters^{13 17} since the second decade of the 21st century. However, estimation of syphilis has always been difficult due to variability in case reporting and knowledge based on small published cohorts; consequently, syphilis may be underestimated.^{11 18} It has been reported that <2% of patients diagnosed with syphilis have ocular involvement, although prevalence varies among studies,^{5 14 19} but not all recent studies agree on an equal increase in ocular syphilis rates alongside the overall increase in syphilis cases.^{11 20 21} Although ocular syphilis is reported to be a rare manifestation of the disease, its devastating consequences, including permanent visual disability,²² make raising awareness mandatory to ensure prompt detection and treatment.

In our registry, most patients affected by ocular syphilis were men (94.9%). Although this is consistent with most published studies,^{1 12 23} it does not confirm the findings of some recent articles regarding a change in the epidemiology of syphilis, which suggest an increase in infection rates among women. The number of cases among women doubled between 2014 and 2018.¹³ This may be due to differences in the incidence of ocular involvement between men and women with syphilis, which has been described previously.^{22 24 25} We will continue to assess this finding in the ongoing registry.

Regarding health risk factors associated with syphilis, we found the following to be the most important: MSM (66.7%), followed by HIV infection (20.5%), which is similar to what has been described in previous literature.⁵ Some studies have hypothesised that the lack of a correlation between rising syphilis incidence and ocular syphilis may be explained by the predominance of cases among MSM. This subgroup of patients is known to be deeply concerned about their health and to adhere to strict health controls, meaning that syphilis can be detected earlier and ocular syphilis can be avoided.²³ This could explain as well why, in recent registries, patients with ocular syphilis tend to be older than patients with syphilis: earlier diagnosis of syphilis in this subgroup may be related to more frequent health monitoring and access to regular screening, which could reduce the likelihood of progression to ocular involvement.¹⁴

Most studies on syphilis agree on the relationship between syphilis and HIV. On the one hand, syphilitic chancres can facilitate HIV transmission due to epithelial disruption.^{2 26} On the other hand, HIV is a known risk factor for sexually transmitted diseases such as syphilis. In some articles, 50% of patients with ocular syphilis were co-infected with HIV.¹⁶ HIV can alter the natural course of syphilis, making diagnosis more difficult in certain cases.² Whether HIV is related to a predisposition to neurosyphilis,^{2 3} different clinical presentations or poorer outcomes is a matter of ongoing discussion in different publications. Nonetheless, a large sample would be required to fulfil the purpose of illuminating this field of knowledge.

In our registry, we found a preponderance of bilateral involvement (64.1%), which is common in uveitis secondary to systemic infections. Ocular syphilis is a complication of a systemic disease that can access the eye via the blood. Certain articles suggest that, in line with previous findings, when ocular syphilis is unilateral, the left eye is more frequently affected, as it receives more direct blood supply.²³ However, although left eyes were also more affected than right eyes in our series, no statistically significant difference between right and left eye involvement was observed. Consistent with previous publications,¹⁴ we found retinal and/or choroidal involvement to be the most common clinical manifestation of ocular syphilis (69.2%), followed by anterior segment involvement (64.1%), optic nerve involvement (59%) and vitritis (53.8%). Scleritis was observed in 10.2% of cases in our cohort, which is higher than the rate typically reported in most published series of ocular syphilis (0.9% to 2%).^{25 27} This difference may be due to the prospective design of the IBERSOS registry, which enabled the detailed documentation of all inflammatory phenotypes. This includes cases of scleral involvement that may have been overlooked in retrospective studies or underrepresented in specialist uveitis clinics.

Contrary to previous beliefs, ocular syphilis can occur during the primary and secondary stages of the disease, as well as in the early and late latent, tertiary or classic quaternary stage.¹⁹ Considering this, systemic manifestations are usually concurrently or recently present in patients with ocular syphilis. In our study, we found that 7.7% of cases presented with primary-stage manifestations (chancre), 25.6% presented with palmoplantar rash (a characteristic sign of secondary syphilis) and 15.4% presented with signs of symptomatic neurosyphilis in the tertiary/quaternary stage. Our data coincide with findings from other articles where nearly half of patients affected with ocular syphilis have systemic manifestations.¹⁴

As established,⁶ the majority of patients included in our registry received a standard course of intravenous aqueous crystalline penicillin G 4 million units IV every 4 hours during 14 days (65.8%). Twenty-eight point nine per cent received three weekly doses of 24 million units intramuscular benzathine penicillin G, and only two patients did not receive penicillin: one received doxycycline (100 mg every 12 hours for 30 days), and the other received ceftriaxone (2 g daily for 14 days). Due to the small sample size of the group not receiving penicillin, we cannot conduct a comparative study of the results of the different therapeutic regimens at this time. Following treatment, only two patients experienced persistent intraocular inflammation. Both of them have received a full course of intravenous penicillin and were HIV negative, and had a confirmed fourfold decrease in the titre of the reaginic test.

Despite being one of the largest ocular syphilis registries, our study has limitations, primarily due to its small sample size, characteristic of a rare disease. This prevented us from performing inferential statistics or comparisons between groups.

Furthermore, our study may underestimate the real incidence of ocular syphilis. The study included participants from both tertiary and secondary centres, as well as from public and private institutions, in order to capture the variability of the population and healthcare systems across the Iberian Peninsula. Nonetheless, it remains possible, though unlikely, that some patients from a given health area may have been managed in small private practices and therefore not captured in our dataset. Consequently, the incidence figures reported here should be regarded as a lower limit for this disease incidence in the Iberian Peninsula.

In conclusion, the first-year results of the IBERSOS registry reveal the diverse and often severe clinical spectrum of ocular syphilis, including high rates of bilateral involvement, significant retinal/choroidal and optic nerve complications and systemic manifestations such as neurosyphilis. Over half of the patients achieved a satisfactory serological response, and visual outcomes generally improved following treatment. Persistent inflammation was rare, suggesting effective control with standard therapies. The study underscores the need for heightened awareness, timely diagnosis and prompt treatment, particularly in high-risk populations like individuals with HIV. Continued data collection will enhance understanding of prognostic factors and guide management strategies in this re-emerging infectious disease.

Data availability statement

Data are available upon reasonable request.