Diagnostic Maze: Navigating the complexity of isolated optic disc edema in syphilitic uveitis

(Image Credit: AdobeStock/Who is Danny)

A resurgence of syphilis has brought renewed attention to ocular syphilis, a condition with a broad range of manifestations that can mimic other ocular and systemic diseases. With cases of syphilitic uveitis on the rise, recognizing its varied presentations—including optic disc edema, which may appear without other significant eye inflammation—is increasingly important for timely diagnosis and treatment. Although optic disc edema is often accompanied by other ocular findings, isolated cases can lead to diagnostic challenges.

Given that cerebrospinal fluid analysis may not always yield positive results, clinicians should maintain a high index of suspicion for syphilis in patients with unexplained optic disc swelling, ensuring appropriate testing and prompt initiation of antibiotic therapy to improve visual outcomes.

Case

A 47-year-old woman with a history of recent bilateral ear infection requiring ongoing sulfamethoxazole/trimethoprim treatment presented to the emergency department at a tertiary care hospital with 3 weeks of progressive bilateral vision loss, flashes of lights, and concern for visual field deficits. The patient mentioned a presumed urinary tract infection with urinary burning a few months prior that had resolved without treatment. Upon further review of systems, she also noted pulsatile tinnitus, transient visual obscurations upon bending over, headache, neck pain and stiffness, weight loss, perioral cold sores, and pruritic vaginal lesions.

An ophthalmic examination revealed near visual acuity of 20/400 pinhole (PH), 20/150 OD and 20/50+2 PH, 20/40-2 OS, normal IOP, and no relative afferent pupillary defect. Her anterior segment was unremarkable on slit-lamp examination. However, her fundus examination was notable for trace vitreous cell in both eyes and diffuse optic disc edema in both eyes, more prominent in the left eye, with edema tracking into the macula. Differential diagnosis at this point was broad, including infectious optic neuritis, autoimmune optic neuritis, papilledema secondary to elevated intracranial pressure, papillophlebitis, diabetic or hypertensive papillopathy, and, less likely, compressive optic neuropathy, neuroretinitis, and ischemic optic neuropathy.

Figure 1. Fundus images of the optic nerve demonstrate disc edema in a patient

Figure 2. Fundus autofluorescence demonstrates hyperflourescent speckling throuhout the macula of the right eye.

Later that week, the patient was seen in the outpatient ophthalmology clinic for follow-up, where fundus photos and optical coherence tomography of the optic disc were obtained, demonstrating disc edema (Figure 1). Fundus autofluorescence (FAF) demonstrated hyperfluorescent speckling throughout the macula of the right eye (Figure 2), and fluorescein angiography demonstrated late disc leakage in both eyes, suggestive of active disc edema (Figure 3). No vasculitis, placoid lesions, or other chorioretinal lesions were apparent.

Given the concern of optic disc edema OU, the patient was recommended to undergo an MRI of the brain with and without contrast and magnetic resonance venography of the brain, which demonstrated an incidental meningioma without acute abnormalities. Subsequent lumbar puncture demonstrated a normal opening pressure and cell counts. Blood tests were performed, including those for complete blood count, antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies, and inflammatory markers erythrocyte sedimentation rate and C-reactive protein (CRP). Abnormal laboratory results included ANA positivity at 1:640 and elevated CRP (24.4 mg/L; reference, 0–5.0 mg/L).

Figure 3. Fluorescein angiography shows late disc leakage in both eyes, suggesting active disc edema. (Images courtesy of Sonya Besager, MD)

An extensive infectious workup was also performed, including a meningitis/encephalitis panel, QuantiFERON-TB Gold, treponemal IgG, Bartonella henselae, Borrelia polymerase chain reaction, Toxoplasma IgG and IgM, herpes simplex virus, and HIV testing. Ultimately, her labs demonstrated elevated reponemal IgG, which triggered a subsequent reflex rapid plasma reagin, also elevated at 1:128, suggestive of current infection.

Given both positive treponemal and nontreponemal testing, the patient was diagnosed with syphilitic optic disc edema and was treated with a 14-day course of intravenous penicillin G (initially during her hospitalization followed by administration through a peripherally inserted central catheter line upon discharge) as recommended by the Centers for Disease Control and Prevention (CDC) for the treatment of neurosyphilis.

Discussion

The recognition of syphilitic uveitis and other ocular manifestations of syphilis is increasingly relevant as the incidence of syphilis and syphilitic uveitis rises. The CDC has reported a 74% increase in syphilis cases from 2001 to 2017.¹ Similarly, a recent population-based analysis of more than 450,000 hospitalizations demonstrated a rise in syphilitic uveitis–related admissions from 0.08 per 100,000 in 2011 to 0.23 per 100,000 in 2019.¹

There exists a broad range of manifestations of ocular syphilis, including but not limited to, anterior segment findings such as iris roseola, gummata, papules or nodules, atrophy, Argyll Robertson pupils, interstitial keratitis, anterior uveitis (granulomatous and nongranulomatous), intermediate uveitis, and vitritis. Known posterior segment findings include chorioretinitis, posterior placoid chorioretinitis, serpiginous-like choroiditis, focal or multifocal retinitis, vasculitis, exudative retinal detachment, optic disc edema or papillitis, and neuroretinitis.

While optic disc edema is a well-documented manifestation of syphilis in conjunction with other ocular manifestations, it is rarely seen as an isolated sign of syphilitic uveitis or nearly isolated, accompanied only by mild vitritis, as in the case of the patient reported here. More commonly, optic disc edema is seen in conjunction with retinal vasculitis, chorioretinal lesions, or more significant vitritis. A retrospective study in Tel Aviv, Israel, of patients hospitalized for systemic syphilis between 2009 and 2017 reported a 19% prevalence of optic disc edema; however, only 8% of the patients had isolated disc edema.² Similar findings are reiterated in other studies of the manifestations of ocular syphilis.^3,4

Bilateral optic disc edema is even rarer as an isolated or apparently isolated manifestation. In the same study in Tel Aviv, it was seen in only 3% of the cohort, and there exist only a few other reports of bilateral syphilitic optic disc edema in the literature.^2,5,6 One case series by Klimova et al describes bilateral optic disc edema in 9 patients, all of whom had either concurrent panuveitis or other manifestations of posterior uveitis.⁵ A case series by Kabanovski demonstrates apparently isolated bilateral optic disc edema.

However, on further examination and imaging, all patients were found to have subtle chorioretinitis presenting as punctate hyperautofluorescent lesions throughout the posterior pole, similar to those seen in the case reported here, thus revealing another subtle sign in what may initially appear to be isolated disc edema.⁶

Of note, only 71% of patients ultimately determined to have ocular syphilis had an initially positive cerebrospinal fluid (CSF) analysis, as defined in the Tel Aviv study as elevated protein or leukocyte count, or positive venereal disease research laboratory test or Treponema pallidum hemagglutination assay.² Although this may raise the potential for misdiagnosis in this cohort, it is worth mentioning that patients with ocular syphilis may not demonstrate positive testing on CSF analysis. Therefore, a high suspicion of syphilis should be maintained in cases of unilateral or bilateral disc edema.

Conclusions

Given the increased incidence of both syphilis and syphilitic uveitis, the rare manifestation of ocular syphilis as unilateral or bilateral disc edema may be increasingly encountered, including in a seemingly unaffected and uninflamed eye. A high suspicion for syphilis should be maintained in patients presenting with disc edema, and other testing, such as FAF that may demonstrate more subtle findings, should be considered. CSF analysis may or may not demonstrate positive findings, but patients should still undergo treatment as tertiary syphilis per the CDC with a 14-day course of intravenous penicillin. The timely use of oral corticosteroids, following the initiation of systemic antibiotics, likely improves final visual outcomes given the inflammatory nature of the disease,⁷ although further studies are needed.

References

1. Mir TA, Kim SJ, Fang W, Harvey J, Hinkle DM. Rising incidence of syphilitic uveitis-related hospitalizations in the US. JAMA Ophthalmol. 2024;142(1):7-14. doi:10.1001/jamaophthalmol.2023.5386

2. Klein A, Fischer N, Goldstein M, Shulman S, Habot-Wilner Z. The great imitator on the rise: ocular and optic nerve manifestations in patients with newly diagnosed syphilis. Acta Ophthalmol. 2019;97(4):e641-e647. doi:10.1111/aos.13963

3. Puech C, Gennai S, Pavese P, et al. Ocular manifestations of syphilis: recent cases over a 2.5-year period. Graefes Arch Clin Exp Ophthalmol. 2010;248(11):1623-1629. doi:10.1007/s00417-010-1481-z

4. McNally MA, Murira A, Dillard CM, Aisenberg G. The great masquerader: syphilis mimicking papilledema and traction alopecia. Cureus. 2020;12(3):e7391. doi:10.7759/cureus.7391

5. Klimova A, Brichova M, Heissigerova J, Rihova E, Svozilkova P. Trends in management of ocular syphilis in tertiary uveitis centre in Prague, Czech
   Republic. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2023;167(3):281-287. doi:10.5507/bp.2022.038

6. Kabanovski A, Donaldson L, Jeeva-Patel T, Margolin EA. Optic disc edema in syphilis. J Neuroophthalmol. 2022;42(1):e173-e180. doi:10.1097/WNO.0000000000001302

7. Ishihara R, Buscho S, Yu HJ, Gupta PK. Assessment of visual acuity outcomes in ocular syphilis treated with adjunctive topical or oral steroids. Cureus. 2023;15(7):e41395. doi:10.7759/cureus.41395