Syphilitic Uveitis: Clinical Features, Treatment, and Outcome

Introduction

Syphilis is a sexually transmitted chronic disease caused by the spirochete Treponema pallidum. Its regional prevalence worldwide ranges from 0.2% to 1.8% [1]. In Bulgaria, the average incidence is 5.5 cases per 100 000 inhabitants [2]. Ocular complications occur in 0.6% to 15% of cases; panuveitis and posterior uveitis are the most common ocular findings [3]. In Bulgaria, ocular syphilis is rare. A 5-year study conducted in Sofia revealed 6 cases with diverse manifestations, including posterior placoid chorioretinitis, panuveitis, and neuroretinitis [4]. Patients with ocular syphilis typically exhibit reduced visual acuity [5]. However, visual outcomes are generally favorable, and complete visual recovery may occur after appropriate treatment [6]. Timely diagnosis through serological testing and proper therapeutic management plays a crucial role in achieving favorable outcomes [7].

A wide spectrum of ocular involvement in syphilis has been described in the literature, along with variations in therapeutic approaches. Syphilitic uveitis represents a rare manifestation of the disease. This report presents the clinical features of 1 case and the treatment strategy selected for this patient. The objective was to assess the degree of visual recovery at the end of the follow-up period. The clinical relevance lies in selecting an appropriate therapeutic regimen for patients who present with similar features of syphilitic uveitis.

Case Report

A 52-year-old man with a history of sexual promiscuity involving prostituted women was diagnosed with secondary syphilis. He reported habits of tobacco smoking and limited alcohol consumption but denied any substance abuse. One month before presentation to the Dermatology Department of University Hospital in Pleven, Bulgaria, the patient reported a genital rash accompanied by burning and itching. During the same period, he noted a gradual decrease in visual acuity, first in the right eye and subsequently in the left. His bilateral vision progressively deteriorated over 1 month. Because of concern about a possible sexually transmitted infection, he sought dermatologic consultation for the genital rash.

On July 3, 2024, the patient was hospitalized in the Dermatology Department of University Hospital in Pleven, Bulgaria. Dermatologic examination revealed pathological skin changes on the scalp and anogenital region, characterized by erythematous papules and pustules covered with yellowish crusts. Erythematous macules with fine desquamation were also observed on the torso. The patient reported decreased vision. A diagnosis of syphilis was confirmed by positive rapid plasma reagin (RPR) and T. pallidum particle agglutination assay results. The patient displayed human immunodeficiency virus (HIV) negativity. Treatment consisted of intravenous aqueous penicillin G, 12 million international units (MIU) (administered as 4×3 MIU) daily for 7 days, along with methylprednisolone 40 mg tapered over the same period. Therapy was subsequently continued with 5 weekly intramuscular injections of benzathine penicillin G, 2.4 MIU each. The therapeutic regimen and dosage were determined by dermatologists in accordance with standard clinical guidelines. The source of infection was unknown, and the woman presumed to have transmitted the disease had not received treatment. At the time of presentation, the patient did not have a sexual partner; if he had, syphilis treatment would have been recommended for her as well.

On July 4, 2024, an ophthalmologic examination was conducted by an eye specialist from the Ophthalmology Department of the same hospital. The patient was diagnosed with bilateral panuveitis secondary to syphilis. Visual acuity was measured using the Snellen chart at a distance of 6 m, and the results were converted to United States equivalents (e.g., from 6/6 metric system to 20/20 United States equivalent) for presentation in this report. At the initial examination, visual acuity was visual acuity oculus dexter (VOD; visual acuity of the right eye)=light perception and projection (LPP) and visual acuity oculus sinister (VOS; visual acuity of the left eye)=20/630. Refraction without cycloplegia revealed physiological astigmatism in both eyes. The patient had not worn corrective lenses before the illness. Intraocular pressure measured by Goldmann tonometry was within normal limits: 13 mmHg in the right eye and 16 mmHg in the left eye. Color photographs of the anterior and posterior eye segments were obtained after mydriasis. Slit-lamp examination showed bilateral anterior non-granulomatous uveitis with scattered fine keratic precipitates on the corneal endothelium, a positive Tyndall effect, and posterior synechiae after mydriasis in the right eye only (Figure 1). Indirect ophthalmoscopy revealed vitritis with dense, floating vitreous opacities, confluent and pigmented in areas, more pronounced in the right eye, and papillitis in the left eye (Figure 2). The right optic disc could not be visualized due to media opacity. Fundus fluorescein angiography was not performed because of poor media transparency and inadequate mydriasis. Optical coherence tomography (OCT) and indocyanine green angiography were not performed because the clinic lacked necessary equipment.

Systemic syphilis therapy initiated at the Dermatology Department was also considered adequate for managing ocular inflammation. The ophthalmologist prescribed topical therapy consisting of antibiotic-corticosteroid eye drops (tobramycin/dexamethasone 3 mg/1 mg/mL) (5×daily) and atropine sulfate 1% eye drops (2× daily) for both eyes. The patient was scheduled for a follow-up ophthalmologic evaluation 1 week later. After the initial ophthalmology consultation, cerebrospinal fluid examination was performed due to the observed optic nerve changes. Based on the results, a diagnosis of neurosyphilis was excluded.

Following 1 week of treatment, visual acuity was VOD=20/2000 and VOS=20/200, with improved ocular media transparency. The retina was reimaged using color fundus photography. Vasculitic changes resembling perivascular sheathing of narrowed vessels were observed (Figure 3). Examination of the peripheral retina with a Goldmann 3-mirror lens revealed chorioretinitis in the left eye. Assessment of the right peripheral retina was limited by posterior synechiae and an irregularly shaped pupil. In the left eye, several small, well-defined, whitish inflammatory infiltrative foci were observed at the 7 o’clock position in the mid-peripheral region. No additional abnormalities were visualized in the remaining mid- or far-peripheral areas of the left eye. Importantly, these pathological findings were not photographed due to a lack of appropriate imaging equipment.

The patient was examined twice monthly for the following 3 months by an ophthalmologist. Visual acuity, clinical findings, and treatments during the 6 follow-up visits are summarized in Table 1. Pathological changes in the anterior segment, except for persistent synechiae in the right eye, resolved within 4 weeks of treatment initiation. The posterior segment was assessed by indirect ophthalmoscopy; repeat examination of the peripheral retina using a Goldmann 3-mirror lens was not performed. Vitreous opacities cleared by the eighth week, and the margins of the optic nerve head normalized by the tenth week. During the follow-up period, uveitis treatment was adjusted according to disease progression. Approximately 6 weeks after therapy began, topical bromfenac (0.9 mg/mL) was added twice daily in both eyes. Two months after treatment initiation, a periocular corticosteroid injection was administered to the more severely affected right eye. Topical corticosteroid therapy was continued until the end of the observation period.

The uveitis responded favorably to therapy, with gradual visual improvement from VOD=LPP and VOS=20/630 at baseline to VOD=20/25 and VOS=20/20 at the end of follow-up. The only adverse effect of treatment reported by the patient was residual moderate photophobia. Serologic tests for syphilis were not repeated during or after the follow-up period.

Discussion

Syphilis most frequently affects middle-aged men. Diagnosis of T. pallidum infection is based on clinical presentation and confirmed by serologic testing. Non-treponemal tests include the Venereal Disease Research Laboratory test and the RPR test; treponemal tests include the fluorescent treponemal antibody absorption test, the microhemagglutination T. pallidum test, and the T. pallidum particle agglutination test. Infection with T. pallidum is confirmed when both treponemal and non-treponemal test results are positive, or when 2 different treponemal tests yield positive findings [8]. Coinfection with HIV is also common, supporting the recommendation to screen all patients with syphilis for HIV [9]. Lumbar puncture and cerebrospinal fluid analysis are advised in patients with syphilis who display optic nerve involvement [7]. Ocular manifestations occur more often during the secondary and early latent stages of acquired syphilis [10]. Because nearly every form of ocular inflammation can occur, syphilis should be included in the differential diagnosis of all uveitis cases. Serologic testing is essential for accurate diagnosis [7–9]. This report describes a 52-year-old heterosexual, HIV-negative man with syphilitic uveitis secondary to acquired syphilis. His diagnosis was confirmed by positive RPR and T. pallidum particle agglutination assay results. Cerebrospinal fluid examination showed no abnormalities, excluding neurosyphilis. The diagnosis of syphilis was first established serologically by a dermatologist, providing the etiologic basis for the uveitis diagnosis. Syphilitic uveitis is rare. If this patient had initially presented to the Ophthalmology Department, appropriate antibiotic therapy might have been delayed. Therefore, it is essential that ophthalmologists perform serologic testing for syphilis in every case of uveitis to ensure timely diagnosis and treatment.

Syphilis is known as “the great imitator” because it can mimic a wide spectrum of ocular disorders, most often affecting the uveal tract [10]. Histologically, syphilitic uveitis is classified as granulomatous or non-granulomatous [11]. Although granulomatous inflammation was once considered typical of syphilis, the non-granulomatous form has become more common in recent years. Classic but rare clinical features of granulomatous uveitis include mutton fat-like precipitates on the cornea or posterior vitreous membrane and the presence of iris granulomas in the anterior chamber. In contrast, characteristic pathological findings of the non-granulomatous form of ocular syphilis include fine keratic precipitates, diffuse anterior scleritis, vitreous opacities, diffuse retinitis, retinal or macular edema, retinal vasculitis, and papillitis [12]. According to the Standardization of Uveitis Nomenclature, uveitis is categorized as anterior, intermediate, posterior, or panuveitis [13]. The most common clinical feature of ocular syphilis is bilateral uveitis; posterior uveitis and panuveitis occur far more often than anterior uveitis [5,7,10,14,15]. The optic disc is also affected in ocular syphilis; such instances manifest as papillitis, optic neuritis, or neuroretinitis [10]. The clinical features observed in our patient were consistent with previously described patterns of syphilitic uveitis. He presented with bilateral non-granulomatous panuveitis characterized by fine keratic precipitates, posterior synechiae, vitreous opacities, chorioretinitis, retinal vasculitis, and papillitis. In 2021, Jabs and colleagues proposed classification criteria for syphilitic uveitis, which include inflammation of any part of the uveal tract along with a positive serologic test result indicating T. pallidum infection. In cases of posterior uveitis or panuveitis, one of the following findings must also be present: placoid inflammation of the retinal pigment epithelium, multifocal inflammation of the retina or retinal pigment epithelium, necrotizing retinitis, or retinal vasculitis [16]. The present case met these diagnostic criteria. The inflammatory infiltrative foci observed in the mid-peripheral retina of the patient’s left eye are of particular clinical interest. Similar multiple, small, well-defined, whitish lesions have been reported in Chinese patients by other authors [12,14]. Yang and coworkers suggested that such punctate precipitates are pathognomonic for ocular syphilis. According to their hypothesis, these lesions could contain treponemal organisms and inflammatory cells within or upon the retina; they also might represent granulomatous formations [12]. Unfortunately, in our case, these pathological findings were not photographed or followed longitudinally. In future similar cases, particular attention should be given to documenting such lesions. It is essential to determine whether their shape, number, color, and size change during and after antisyphilitic therapy, and to clarify their precise localization in the retina or choroid using advanced imaging modalities such as wide-field OCT.

The “gold standard” treatment for syphilitic uveitis is intravenous benzylpenicillin, administered at a total daily dose of 12 to 24 MIU in divided doses of 3 to 4 MIU every 4 h for 10 to 21 days [17–19]. Antibacterial agents may be used as monotherapy or combined with systemic corticosteroids [15]. Zhang et al. reported that antibacterial monotherapy alone may be sufficient to improve both uveitis and visual function [9]. The use of corticosteroids remains a subject of debate. Bollemeijer et al. found no statistically significant difference in visual outcomes between patients treated with additional oral or injected corticosteroids and those who did not receive such treatment. They observed no improvement in visual acuity during follow-up and concluded that adjunctive corticosteroid therapy may be ineffective [5]. Hoogewoud and colleagues suggested that the timing between antimicrobial and anti-inflammatory treatments is a critical factor. In their study, periocular dexamethasone injections administered before or within 6 days of antibiotic initiation had a negative effect on recovery [20]. However, corticosteroids are frequently prescribed in clinical practice, particularly for patients with severe ocular inflammation or chronic macular edema [15,21,22]. Most members of the International Ocular Syphilis Study Group recommended adjunctive corticosteroid therapy for selected patients, favoring systemic or topical administration and, less commonly, local injections [7]. Some authors have advised local corticosteroid administration in cases of interstitial keratitis or anterior uveitis, and systemic administration in cases of profound vision loss, posterior uveitis, scleritis, or optic neuritis [23].

The patient in this case received initial systemic therapy with intravenous aqueous penicillin G and methylprednisolone, as well as topical treatment comprising antibiotic-corticosteroid and atropine sulfate eye drops in both eyes. Based on a review of the literature, this regimen was considered appropriate for managing syphilitic uveitis. Antibiotic therapy was essential due to the infectious nature of the etiologic agent. Systemic corticosteroids were administered because of substantially reduced visual acuity, posterior uveitis, and papillitis. The systemic treatment lasted 7 days and was followed by intramuscular benzathine penicillin G administered once weekly for 5 weeks. Topical antibiotic-corticosteroid and cycloplegic agents were prescribed due to involvement of the anterior uvea. Antibiotic-corticosteroid eye drops were continued throughout the follow-up period. Given that the ophthalmologic findings remained largely unchanged despite slight visual improvement, additional therapy was introduced. Six weeks after treatment initiation, topical bromfenac was added in both eyes. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce intraocular inflammation and tend to improve visual acuity in anterior uveitis by decreasing uveitic cystoid macular edema [24]. However, there are limited data regarding the use of NSAIDs in syphilitic uveitis. Suelves and colleagues reported the benefits of systemic NSAID administration in a case of recurrent sclerouveitis after syphilitic panuveitis [25]. Four weeks after topical bromfenac initiation, gradual recovery of ophthalmologic findings was noted in our patient. Further research is needed to determine whether topical NSAIDs, in combination with antibiotic-corticosteroid agents, provide additional benefit concerning disease progression and visual recovery after treatment of syphilitic uveitis. A periocular corticosteroid injection was administered to the right eye, 8 weeks after therapy began. This eye had not previously shown clinically significant improvement. The extended interval between antibiotic therapy and the periocular corticosteroid injection was consistent with current treatment recommendations [20].

Treatment outcomes among patients with syphilitic uveitis have considerable clinical significance. The disease typically follows a course of onset, progression, and resolution [8]. At presentation, Snellen visual acuity is often reduced to between 20/40 and 20/200 [5]. In many cases, the final visual outcome is favorable; systemic penicillin therapy restores visual acuity to 20/25 or better in most patients [15]. Some studies have identified potential risk factors for poor visual prognosis. These include a delay of more than 12 weeks between uveitis onset and treatment initiation, ocular symptoms lasting longer than 28 days, the presence of macular edema or chronic optic neuropathy, HIV coinfection, poor initial visual acuity, bilateral involvement, initial misdiagnosis, and retinal pathology [7,9]. In contrast, favorable prognostic indicators include higher baseline visual acuity, early initiation of antibiotic therapy, presence of intermediate uveitis, and absence of neurosyphilis or HIV infection [15]. In the present case, the patient demonstrated substantial visual improvement after treatment, from VOD=LPP and VOS=20/630 at presentation to VOD=20/25 and VOS=20/20 at the end of the follow-up period. Early etiologic diagnosis, the specific pattern of ocular involvement, appropriate systemic therapy, and delayed administration of peribulbar dexamethasone contributed to the favorable outcome in this case. However, visual recovery was gradual, occurring approximately 3.5 months after treatment began. This delayed improvement may be attributable to unrecognized conditions such as macular edema, acute syphilitic posterior placoid chorioretinopathy, necrotizing retinitis, or serous retinal detachment. Diagnostic imaging modalities such as OCT or fluorescein angiography would have been valuable for the detection of such lesions, but these modalities were not utilized in the present case.

To estimate the patient’s response to therapy, repeat serologic testing for syphilis was proposed. Non-treponemal titers are interpreted according to the follow-up interval; a fourfold decline is expected by 6 months after treatment, although titers may remain high at 3 months in some patients. Thus, ocular inflammation activity does not always correspond to serologic results [12]. In the present study, therapeutic effectiveness was assessed on the basis of clinical features and visual acuity. A control serologic test at 6 months would have been preferable, as recommended, but the patient did not attend ophthalmologic follow-up after visual recovery.

Conclusions

Ocular syphilis is rare and exhibits wide clinical variability. In this case, it manifested as bilateral non-granulomatous panuveitis with vitreous opacities, retinal vasculitis, and papillitis. Early detection and appropriate treatment usually preserve visual acuity and ocular function. Serologic tests are essential for diagnosis. In our patient, 7 days of systemic aqueous penicillin G and methylprednisolone, followed by 5 weeks of intramuscular benzathine penicillin G administered once weekly, together with topical antibiotic-corticosteroid agents, cycloplegics, and bromfenac, restored visual acuity to 20/25 or better by the end of an approximately 14-week follow-up period. The final visual outcome was satisfactory. Systemic and topical antibiotic-corticosteroid agents did not worsen prognosis. If periocular corticosteroid injections are required, they should be administered at least 2 months after initiation of antibiotics. The use of topical NSAIDs in syphilitic panuveitis warrants further study. Our therapeutic strategy is proposed as a consideration, recognizing that each case requires individualized assessment. Despite improvement, our patient’s recovery was slow. Additional investigations such as OCT and angiography would help document retinal and vascular changes that could delay visual recovery.