Never forget ocular syphilis: A case series from a single tertiary centre

Introduction

Syphilis can affect many organs including the skin, heart, blood vessels, bones, nervous system, and the eye. ¹ Ocular syphilis (OS) can present at any stage of syphilis and ophthalmic manifestations of syphilis often pose a diagnostic challenge for clinicians, as it is the great imitator.^2–4

In recent years, syphilis is markedly on the rise.^5,6 This is also our observation and here, we share and analyze the clinical data of cases with OS.

Methods

Serologically confirmed consecutive OS cases diagnosed between June 2020 and February 2023 at our ophthalmology department were retrospectively analyzed. Ocular syphilis was defined by the presence of any ocular involvement together with a positive syphilis serology. Besides standard ophthalmic examination, fluorescein angiography and optical coherence tomography were also performed where appropriate. Full laboratory investigations including serology for infectious diseases and cranial magnetic resonance were carried out. The patients were fully informed about the examinations and written consent was obtained.

All of the cases were notified to Turkish Health Authorities and relevant systemic antibiotic therapy was given. The study was approved by the Ethics Committee of Dokuz Eylul University (2023/08-18).

Results

Sixteen eyes of 10 patients (seven males and three females) were enrolled. Mean age was 44.50 ± 10.19 years (range, 29-60 years). Characteristics of the patients and their clinical features at the time of diagnosis and our treatment strategies are summarized in Table 1. Two patients (Case 1 and Case 6) were misdiagnosed as non-infectious panuveitis/posterior uveitis elsewhere and unfortunately were treated with oral methylprednisolone. Best-corrected visual acuity (BCVA) was only light perception in three eyes of two patients at the first eye examination. In contrast, two patients with unilateral involvement presented with a good Snellen visual acuity, 0.8 or more at the admission. Final BCVA was the worst in patients presenting with exudative retinal detachment and associated optic neuropathy. Posterior segment involvement was found in 15 of 16 eyes. Five eyes were diagnosed to have placoid chorioretinitis (Figure 1), three eyes as posterior uveitis (Figure 2), three eyes as panuveitis, one eye as necrotizing retinitis (Figure 3), one eye as exudative retinal detachment, two eyes as optic neuropathy, and the remaining eye as sclerouveitis. One patient had marked ciliary injection and hypopyon in both eyes (Figure 4). Features of the ocular involvement, baseline and final BCVA, and follow-up time can be seen in detail in Table 2.

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Table 1.

Patient characteristics, clinical features at the time of diagnosis, and treatment strategies.

Case Number	Age/Sex	Stage	RPR Titer	HIV Status	Treatment Regimen	Clinical Onset	Control RPR Titer
Case 1	34/M	Primary syphilis (Two months after the genital chancre)	1/1024	Positive CD4+ T cell: 409 cell/mm3 Viral load: >100.000 copy/ml	Ceftriaxone 2x2 g IV (2 weeks) and Bilateral intravitreal ceftazidime (once) and 24 mg PO methylprednisolone (with rapid taper)	Right eye: Exudative retinal detachment Left eye: Syphilitic necrotizing retinitis	In the third month of diagnosis 1/512
Case 2	44/M	Latent syphilis unknown duration (no history of chancre or mucocutaneous lesions)	1/16	Negative	7.2 MU IM penicillin G (3 equal doses at one-week interval)	Posterior uveitis	N/A
Case 3	60/M	Latent syphilis unknown duration (no history of chancre or mucocutaneous lesions)	1/16	Negative	7.2 MU IM penicillin G (3 equal doses at one-week interval)	Bilateral optic neuropathy	In the third month of diagnosis 1/16
Case 4	44/F	Latent syphilis unknown duration (no history of chancre or mucocutaneous lesions)	1/16	Negative	Ceftriaxone 1 gm IM (20 days)	Posterior uveitis	N/A
Case 5	40/M	Secondary syphilis (had mucocutaneous lesions at the diagnosis)	1/256	Positive CD4+ T cell: 400/mm3 Viral load: 1.280.000 copy/ml	7.2 MU IM penicillin G (3 equal doses at one-week interval)	Panuveitis	N/A
Case 6	42/M	Secondary syphilis (had mucocutaneous lesions at the diagnosis)	1/64	Negative	6x4 MU IV penicillin G (2 weeks) and 32 mg PO methylprednisolone (with rapid taper)	Placoid chorioretinitis	In the sixth month of diagnosis 1/64
Case 7	29/F	Secondary syphilis (no history of chancre or mucocutaneous lesions, having multiple lymphadenopathies for two months)	1/16	Negative	Penicillin allergy Ceftriaxone 1x2 g (2 weeks) and 32 mg PO methylprednisolone (with rapid taper)	Multiple cervical and axillary lymph adenopathies Posterior uveitis	In the fifth month of diagnosis and RPR was negative
Case 8	40/M	Secondary syphilis (had mucocutaneous lesions at the diagnosis and a history of chancre three months before)	1/64	Negative	6x4 MU IV penicillin G (1 week) and Denied further treatment (oral doxycycline (200 mg/day) for 2 weeks)	Right eye: Panuveitis Left eye: Placoid chorioretinitis	N/A
Case 9	52/M	Latent syphilis unknown duration (no history of chancre or mucocutaneous lesions)	1/64	Negative	Ceftriaxone 1 g IV (4 weeks)	Placoid chorioretinitis	In the first month of diagnosis 1/32
Case 10	60/F	Latent syphilis unknown duration (no history of chancre or mucocutaneous lesions)	N/A	Negative	7.2 MU IM penicillin G (3 equal doses at one-week interval)	Sclerouveitis	N/A

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Figure 1.

Case 6, Consecutive color fundus pictures; Right fundus was normal at the first presentation (a) but an active, non-elevated, placoid yellowish lesion (red arrow) was visible at the left macula (b). Three weeks following the systemic methylprednisolone therapy with the misdiagnosis of non-infectious uveitis; a similar but wider lesion (red arrow) occurred in between the vascular arcades at the right macula (c) whereas the left macular lesion looked partly regressed (d). Two months after the correct diagnosis and intravenous penicillin therapy; both fundi looked normal (e), (f).

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Figure 2.

Case 7, Color fundus picture of the left eye depicting the optic nerve head hyperemia (yellow arrow) (a) and multiple hyperautofluorescent dots (red arrows) extending from macula to the midperipheral retina on fundus autofluorescence image of the left eye (b).

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Figure 3.

Case 1, Left eye. Color fundus picture (a) showing the yellowish whitish lesions (red arrows) with ill-defined margin at the posterior pole together with the yellowish retinal and preretinal nodules (red circles) and hemorrhages (blue arrowhead) at the temporal retina on our first examination. Optical coherence tomographic section (b) demonstrated the bacillary layer foveal detachment (white arrowhead) with serous retinal detachment. Two months after the intravenous penicillin therapy; color fundus picture (c) delineated the resolution of necrotizing retinitis with some residual pale-yellow retinal dots (orange arrowhead).

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Figure 4.

Case 1, (a) Slit-lamp picture of the right eye showing the marked hypopyon (red arrow) with severe fibrinous reaction (yellow arrow) and mild hypopyon (b) in the left anterior chamber (red arrow).

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Table 2.

Features of ocular involvement, baseline and final best corrected visual acuity, and follow-up time.

Case Number	Laterality	Anterior Segment Involvement	Posterior Segment Involvement	Initial Best Corrected Visual Acuity	Final Best Corrected Visual Acuity	Follow-up (Weeks)
Case 1	Right eye	+	+	Light perception	Counting fingers at 1 m	4
	Left eye	+	+	Counting fingers at 1 m	0.8
Case 2	Right eye	−	+	1.0	1.0	4
	Left eye	−	+	0.5	1.0
Case 3	Right eye	−	+	Counting fingers at 2 m	0.05	28
	Left eye	−	+	Counting fingers at ½ m	Counting fingers at ½ m
Case 4	Left eye	+	+	0.4	0.7	12
Case 5	Right eye	+	+	Light perception	1.0	8
	Left eye	+	+	Light perception	0.8
Case 6	Right eye	−	+	0.7	0.9	8
	Left eye	−	+	0.7	0.8
Case 7	Left eye	+	+	1.0	1.0	2
Case 8	Right eye	+	+	1.0	1.0	2
	Left eye	+	+	Counting fingers at ½ m	Counting fingers at 1 m
Case 9	Right eye	−	+	N/A	N/A	5
	Left eye	−	+	N/A	N/A
Case 10	Left eye	+	−	0.9	N/A	20

N/A: Not available.

All patients had positive serology confirming the diagnosis of syphilis and examination for neurosyphilis were carried out. All patients were tested for human immunodeficiency virus (HIV) serology and HIV co-infection was diagnosed in two patients. Tests for hepatitis B/C virus and hepatitis A were also performed. Unfortunately, we cannot perform nucleic acid amplification tests for chlamydia, gonorrhea, and other sexually transmitted infections due to reimbursement issues with the test kits. Cranial and orbital MRI revealed no abnormal findings in any patient. Lumbar puncture was performed in one patient and cerebrospinal fluid analysis was normal.

Four patients were treated with intramuscular benzyl-penicillin G 2.4 million units (MU) weekly for three weeks, one patient received a 14-day course of intravenous (IV) penicillin G (24 MU daily), and one patient could receive only one week of penicillin G course (24 MU daily) as he denied further treatment and was discharged with two weeks of oral doxycycline (200 mg/day) treatment. Four patients were treated with IV ceftriaxone sodium (1 g/d for two patients, 2 g/d for one patient, and 4 g/d for one patient) for at least 14 days. One of these four patients had a known penicillin allergy. Among the HIV-positive patients; Case 1 was treated with fixed-dose single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and Case 5 was treated with the oral once-daily, fixed-dose single-tablet regimen of abacavir/dolutegravir/lamivudine. Three patients were put on a regimen of oral methylprednisolone with rapid a taper (with IV antibiotic therapy, in order to alleviate the intensity of the inflammation). Case 1 received intravitreal ceftazidime (2.25 mg/0.1 mL) for both eyes besides the ongoing IV therapy and significant clinical improvement was noted the next day. Topical steroids with cycloplegic eyedrops were administered in all eyes.

Discussion

While ocular involvement is rare in syphilis, ⁷ all of the study patients were diagnosed with the ocular involvement. Delay in diagnosis and improper treatment can lead to irreversible visual loss. ⁷ Kaya et al. ⁸ reported a case of syphilis admitted with optic neuritis and then multiple retinitis foci and treated with intravenous pulse steroids without antibiotics. Also, two of our patients were treated with systemic corticosteroid therapy elsewhere due to misdiagnosis.

In our study, all cases received the diagnosis based on ocular findings. We observed a wide variation in visual acuity among the patients, ranging from normal to as low as light perception vision and most of the patients presented with posterior segment findings (15 of 16 eyes). Human immunodeficiency virus co-infection was newly diagnosed in two patients. Testing for HIV co-infection is recommended for all individuals who have recently been diagnosed with syphilis.^9,10

In the treatment of syphilis, penicillin G is the recommended drug of choice, administered via the parenteral route.^11,12 Alternative antibiotics are ceftriaxone and doxycycline/tetracycline. ⁵ Based on the 2020 European guideline on syphilis management, individuals with penicillin allergy and early syphilis (primary, secondary, and early latent) should be treated with oral doxycycline 200 mg daily for 14 days. For cases with late latent syphilis (acquired ≥1 year previously or of unknown duration), as well as cardiovascular and gummatous syphilis in patients with penicillin allergy, the recommended treatment is oral doxycycline 200 mg daily for 21-28 days. ¹⁰

Ceftriaxone is also an alternative to benzyl-penicillin for the treatment of neurosyphilis for patients allergic to penicillin (1 or 2 g administered daily, either intramuscularly or intravenously, for 10 days).^11,13 One of our patients had a penicillin allergy and was treated with IV ceftriaxone at a dose of 2 g for two weeks. Although penicillin is the first-choice treatment for all stages of syphilis, we couldn’t use it due to the shortage of the drug in our country at that time. Therefore, some of the patients were treated with IV ceftriaxone. There is no consensus in the guidelines regarding the treatment of OS with ceftriaxone, and our four patients were treated with different doses of ceftriaxone by the Infectious Diseases Department.^10,11

The role of adjunctive intravitreal ceftazidime therapy in the treatment of OS was highlighted by Lim et al. ¹⁴ Intravitreal ceftazidime therapy can be considered in patients with poor vision at the presentation, retinitis, severe panuveitis, optic nerve involvement, and inadequate clinical response after systemic antibiotics. ¹⁴

We believe that our case series will increase awareness among the clinicians about the OS as the delay in diagnosis and improper treatment can lead to irreversible visual loss.^7,15