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December 05, 2025
8 min read
A 55-year-old white man with a medical history of well-controlled type 2 diabetes, rheumatoid arthritis and fibromyalgia presented with progressively worsening, painless decline in vision of both eyes.
His ocular history was notable for keratoconus in both eyes, managed with contact lenses.
Two weeks earlier, he noticed darkening of his vision, “like looking through a dark curtain.” He also noted onset of vesicular lesions at the corner of both eyes, along with one vesicular lesion on the left upper eyelid, prompting presentation to a local eye doctor. After evaluation, he was suspected of having herpetic eye disease and started on valacyclovir three times daily (dose unclear), prednisolone eye drops two times daily in both eyes and erythromycin ointment three times daily in both eyes. However, his symptoms continued to worsen, prompting repeat presentation 4 days later to an outside retina specialist who noted 2+ anterior chamber and vitreous cells in both eyes, areas of peripheral retinal whitening in the right eye and mild disc swelling in the left eye, concerning for bilateral panuveitis. Acute retinal necrosis was suspected, and oral valacyclovir was increased to 2 g three times daily. The patient was urgently referred to our retina service for further evaluation.
Examination
On initial examination, the patient’s uncorrected visual acuity was hand motion in the right eye and 20/250 in the left eye without improvement with pinhole. IOP was 15 mm Hg in the right eye and 10 mm Hg in the left eye. His pupils were equal, round and sluggishly reactive to light without evidence of a relative afferent pupillary defect in both eyes. Confrontation visual fields were globally constricted in the right eye and near complete constriction with temporal field sparing in the left eye. Extraocular motility was normal in both eyes. External exam revealed crusted ulcer/vesicles adjacent to the lateral canthus of both eyes, with a left upper lid lesion deroofed vesicle along the eyelid crease. Anterior segment exam was notable for trace stellate keratic precipitates inferiorly, 3+ anterior chamber flare with trace cell, and 2+ anterior vitreous cell in both eyes. Posterior segment exam through hazy media was notable for mild disc edema and blurred margins in both eyes, a flame hemorrhage in the left eye within the macula, and scattered peripheral and midperipheral retinal whitening greater in the right eye than the left eye sparing the maculae.
Ancillary testing
OCT of the macula of both eyes demonstrated hyperreflective debris in the vitreous, photoreceptor/outer retinal layer disruption and hyperreflective pyramidal retinal pigment epithelium (RPE) irregularities (Figure 1). Fundus photos were obtained, notable for hazy media and multifocal patches of retinal whitening in the right eye (Figure 2a) and a flame-shaped heme in the macula, vessel sheathing nasally and scattered peripheral retinal whitening in the periphery in the left eye (Figure 2b). Fundus autofluorescence showed well-demarcated hyperautofluorescence in the posterior pole involving the maculae, more discernable in the left eye than the right (Figure 3). Finally, fluorescein angiography demonstrated significant media haze, hyperfluorescence of both optic discs and nasal vessel delay in the right eye, with prominent choroidal vasculature suggestive of RPE atrophy in both eyes (images not shown).
Source: Omar AbuQamar, MD, and Arjun Sharma, MD
Additional history
Uveitis-centered review of systems and physical examination were performed. The patient endorsed additional systemic ailments he had been dealing with over the past several weeks. Most notably, he reported a palmar rash and cold sores in the mouth that developed at the time of the eyelid lesions and decreased vision, along with a painful genital rash present for the past 3 weeks. He also noted an umbilical skin infection for which he was started on doxycycline by his primary care physician 3 days prior to our clinic visit. He had several tattoos, of which one on his arm was raised on our examination. He had a cat at home. He had chronic joint pain and was started on a short course of oral prednisone 20 mg 2 weeks earlier.
What is your diagnosis?
See answer below.
Darkening vision, vesicular lesions
The differential of panuveitis includes infectious etiologies such as tuberculosis, toxoplasmosis, herpes simplex virus (HSV), varicella-zoster virus (VZV), Lyme and Bartonella and inflammatory causes such as sarcoidosis, HLA-B27-associated uveitis, rheumatoid arthritis, lupus, granulomatosis with polyangiitis, Vogt-Koyanagi-Harada disease, tattoo-associated uveitis and Behçet’s disease. Lymphoproliferative conditions are also on the differential although less likely in this patient given the acute onset of his symptoms. While he is not known to be immunosuppressed, his presentation is also confounded by the relative immunosuppression with diabetes and recent oral steroid and antibiotics course.
Clinical course
An anterior chamber tap was performed in our clinic at presentation to obtain fluid for HSV, VZV, toxoplasmosis and cytomegalovirus PCR. He was started on prednisolone acetate 1% four times daily in both eyes and cyclopentolate 1% three times daily in both eyes. Given the profound and bilateral vision loss from suspected syphilitic disease, the patient was admitted to the hospital for expedited workup, including consultation with neurology, infectious disease and rheumatology specialists. Laboratory studies were recommended to reflect the above differential, along with a chest X-ray to evaluate for hilar/mediastinal lymphadenopathy suggestive of sarcoidosis. Because the clinical index of suspicion was high for syphilis, the patient was empirically started on treatment for neurosyphilis with 24 million units of IV penicillin G every 24 hours, in addition to continuing antiviral therapy (switched to IV formulation) until laboratory studies resulted to narrow the broader differential.
While admitted, syphilis labs returned with an elevated RPR titer to 1:256, Treponema pallidum antibody positivity and CSF-VDRL positive demonstrating active neurosyphilis. In addition, Lyme antibody serum testing returned IgM positive and IgG negative, but cerebrospinal fluid testing was negative, indicating a possible acute infection but no central nervous system involvement. The remainder of the immunologic and infectious workup was negative, including HIV and anterior chamber fluid tap conducted in clinic.
After 5 days of IV penicillin, with the remainder of infectious testing negative and confirmation of ocular syphilis (neurosyphilis), antiviral therapy was stopped, and oral prednisone was added to help manage against inflammatory reaction. One week after IV penicillin, the patient subjectively reported improvement in visual acuity and contrast sensitivity. Objectively, his near visual acuity was 20/200 in the right eye and 20/100 in the left eye improving to 20/60 with pinhole. He was ultimately discharged with plans for a 14-day course of 24 million units of IV penicillin G daily.
Discussion
Syphilis is an infectious disease most commonly spread via sexual transmission of the spirochete Treponema pallidum. Appropriately labeled as the “great imitator,” syphilis has a plethora of systemic manifestations. Syphilis infection is classically divided into four sequential stages: primary, secondary, latent and tertiary. Primary syphilis is characterized by a single, painless chancre that develops at the site of initial infection. Secondary syphilis develops if left untreated, resulting in several disease manifestations, including diffuse maculopapular rash on the palms/soles and painful genital lesions. Latent syphilis most commonly refers to the resolution of the rash and other symptoms but continued seropositivity for T. pallidum. Finally, tertiary syphilis occurs years after primary infection and can affect nearly every organ system, classically causing gummas and the late-stage complication of cardiovascular syphilis involving the aortic root, which can be fatal. Ocular syphilis, considered a form of neurosyphilis, can occur at any stage of the disease and involve any part of the eye, with syphilitic uveitis being the most common sign, even as soon as 6 weeks after primary infection (Kiss et al.). Syphilis can present as posterior uveitis, either as acute syphilitic posterior placoid chorioretinitis or as small, creamy yellow superficial retinal precipitates, termed syphilitic punctate inner retinitis (Furtado et al.). OCT and fundus autofluorescence imaging are particularly useful in identifying cases of syphilis. Characteristic OCT findings of syphilis include hyperreflective lesions or deposits at the level of the RPE and outer retina and can be present in eyes without placoid lesions on examination (Hu et al.).
There are two broad categories of serologic testing: nontreponemal (VDRL and RPR) and treponemal (FTA-ABS or EIA). Generally speaking, nontreponemal tests are used for screening and monitoring therapeutic response. Treponemal tests detect antibodies specifically against T. pallidum antigens. These tests are used in tandem with each other, either within the “traditional” algorithm or “reverse sequence” algorithm. In the traditional algorithm, RPR and VDRL are used to screen for the disease followed by confirmatory testing with a treponemal test. The reverse sequence algorithm starts with a screen with a treponemal test followed by confirmatory test with RPR and VDRL. Because ocular syphilis is managed as neurosyphilis, a lumbar puncture is typically performed to confirm central nervous system involvement with positive CSF-VDRL.
After its discovery in 1928 by Alexander Fleming and its initial use in syphilis in 1943, penicillin has remained the standard of care for treatment of syphilis, resulting in a precipitous decline in disease burden (Tampa et al.). However, the United States is currently in the midst of a syphilis epidemic. The number of reported cases has increased more than 2,000% from 5,979 cases in 2000 to 133,945 cases in 2020 (Papp et al.). This alarming statistic underscores the importance of keeping syphilis on the differential of any patient with intraocular inflammation, asking specific uveitis-related questions and performing a focused physical examination, which may ultimately reveal symptoms and signs that were not offered initially, similar to the patient in this case.
Once the diagnosis of ocular syphilis has been established, the patient should immediately be started on the neurosyphilis treatment regimen of IV penicillin G for 10 to 14 days. If a patient has a documented penicillin allergy, ceftriaxone may be considered as an alternative; however, most clinicians will opt for skin testing to confirm an allergy. If an allergy is confirmed, penicillin desensitization is required in collaboration with an allergist because the mainstay of treatment in neurosyphilis remains penicillin. Serum RPR titers can be used to monitor response to treatment and as a proxy for cerebrospinal fluid normalization. When promptly treated, the prognosis of ocular syphilis is good, with one prospective study reporting 92% of patients achieving a visual acuity of 20/40 or greater at final follow-up (Mathew et al.).
Follow-up
At the patient’s most recent follow-up visit, 1 month after initial presentation, best corrected visual acuity was 20/70 in the right eye and 20/40 improving to 20/30 with pinhole in the left eye. Ophthalmic examination demonstrated residual 1 to 2+ anterior chamber cell, 1+ flare and 1 to 2+ mostly pigmented anterior vitreous cell. There was trace disc edema, and the previous areas of retinal whitening were replaced with pigmentary changes in the posterior segment of both eyes. He is currently tapering off systemic and topical steroids, with a plan for follow-up in 2 months for formal manifest refraction and visual acuity testing with contact lenses on. Repeat RPR titers will be obtained in 6 months to assess treatment response.
- For more information:
- Omar AbuQamar, MD, is from Department of Ophthalmology, Lahey Hospital and Medical Center, Burlington, Massachusetts.
- Arjun Sharma, MD, is from New England Eye Center, Tufts Medical Center, Boston, and Department of Ophthalmology, Lahey Hospital and Medical Center, Burlington, Massachusetts.
- Edited by James T. Kwan, MD, and Heba Mahjoub, MD, of New England Eye Center, Tufts University School of Medicine. They can be reached at james.kwan.ophthalmology@gmail.com and hmahjoub@tuftsmedicalcenter.org.
Sources/Disclosures
Source:
Expert Submission
References:
Furtado JM, et al. Surv Ophthalmol. 2022;doi:10.1016/j.survophthal.2021.06.003.
Hu KS, et al. Ophthalmol Retina. 2022;doi:10.1016/j.oret.2021.06.011.
Kiss S, et al. Semin Ophthalmol. 2005;doi:10.1080/08820530500232092.
Mathew RG, et al. Invest Ophthalmol Vis Sci. 2014;doi:10.1167/iovs.14-14559.
Neurosyphilis, ocular syphilis, and otosyphilis. https://www.cdc.gov/std/treatment-guidelines/neurosyphilis.htm. Updated July 22, 2021. Accessed Nov. 10, 2025.
Papp JR, et al. MMWR Recomm Rep. 2024;doi:10.15585/mmwr.rr7301a1.
Tampa M, et al. J Med Life. 2014;15;7(1):4-10.
Disclosures:
The authors report no relevant financial disclosures.
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