Syphilis is a sexually transmitted infection caused by Treponema pallidum that can present with a wide variety of ocular manifestations such as uveitis, keratitis, retinal vasculitis, and optic neuropathy [1]. Ocular manifestations can arise at any stage of syphilis, and clinical presentation is highly variable and can mimic that of other ocular diseases. Posterior segment findings include syphilitic outer retinopathy (SOR), acute syphilitic posterior placoid chorioretinopathy (ASPPC), retinitis, chorioretinitis, and papillitis [2, 3]. Diagnosis is clinical with both treponemal and non-treponemal serological testing.

Penicillin has remained the gold standard of syphilis treatment since its first use in 1943. Ocular syphilis is treated identically to neurosyphilis with 10 to 14 days of intravenous (IV) penicillin G, 4 million units every 4 h [4], and often followed by 1–2 weeks of oral penicillin outpatient. T. pallidum can reside in sequestered sites such as ocular structures, so the use of parenteral rather than intramuscular penicillin G is critical [5]. Ocular syphilis can be treated effectively with penicillin, although delayed diagnosis and management may lead to poor visual outcomes [6].

To date, no cases of syphilitic resistance to penicillin have been reported, and the emergence of penicillin resistance is unlikely due to the mutational changes required [5]. However, there have been reports of persistent T. pallidum in syphilis patients following treatment, particularly in the aqueous humor [7,8,9]. Cases of neurosyphilis persisting despite penicillin therapy have also been reported [10, 11]. In addition, treatment failure with inadequate serologic response has been reported for primary and secondary syphilis [12]. Nevertheless, it is rare for complete treatment with penicillin to be ineffective, although chronic uveitis and persistent visual problems are still possible after treatment [13].

In this case series, we present three patients whose syphilitic posterior segment manifestations persisted despite treatment with parenteral penicillin, either due to chronic inflammation, incomplete treatment, or reinfection.

A 48-year-old female with a history of IV methamphetamine abuse presented with gradual vision loss for two months. Initial visual acuity (VA) was [20/40] in the right eye (OD) and [20/40] in the left eye (OS). Fundus autofluorescence (FAF) and pseudocolor imaging revealed SOR and papillitis in both eyes (OU) and ASPPC OS (Fig. 1A-D), which was confirmed with indirect ophthalmoscopy. On optical coherence tomography (OCT), cystoid macular edema (CME), retinal pigment epithelium (RPE) nodules, and disruption of the ellipsoid zone (EZ) and external limiting membrane (ELM) layers were noted OU (Fig. 2A-B). The patient tested positive for syphilis with both positive T. pallidum IgG antibody and rapid plasma reagin (RPR) at 1:16. She was admitted for neurosyphilis workup and was treated with IV penicillin for a total of 14 days. Oral prednisone 40 mg daily was added 48 h after initiation of penicillin therapy and continued for two weeks. The patient reported improvement in vision following the initiation of treatment.

One month later, she had persistent CME OU on examination. She received an intravitreal triamcinolone injection OS, after which there was some improvement. However, the patient still had persistent SOR on FAF and CME on OCT. Five months after the initial diagnosis, RPR was still positive at 1:8. Due to concern for inadequate initial treatment, penicillin therapy was restarted for three weeks. The patient’s SOR improved (Fig. 1E-H), but she had persistent CME OU (Fig. 2C-D) and was started on ketorolac drops OU. At her next visit, her CME was resolved OS but remained persistent OD, so she received another intravitreal triamcinolone injection OD. The patient’s VA consistently remained between [20/30] and [20/40] OU throughout her follow-up. She was eventually lost to follow-up.

Case 1 presentation imaging (A, C) pseudocolor and fundus autofluorescence imaging of the right eye with SOR and papillitis; (B, D) pseudocolor and fundus autofluorescence imaging of the left eye with SOR, papillitis, and ASPPC; Case 1 five months after presentation (E, G) pseudocolor and fundus autofluorescence imaging of the right eye with improved SOR; (F, H) pseudocolor and fundus autofluorescence imaging of the left eye with improved SOR

Case 1 presentation optical coherence tomography (OCT): cystoid macular edema (CME), retinal pigment epithelium (RPE) nodules, and disruption of the ellipsoid zone (EZ) and external limiting membrane (ELM) layers noted OU (A: right eye), (B: left eye); Case 1 five months after presentation on OCT: persistent CME noted OU (C: right eye), (D: left eye)

A 24-year-old previously healthy male presented to the clinic with sudden vision loss OD for two days, in addition to floaters and flashes for several months. VA was counting fingers (CF) at 5 feet OD and [20/25] OS. FAF and pseudocolor imaging revealed ASPPC and papillitis OU and SOR OS (Fig. 3A-D). On OCT, RPE nodules and disruption of the EZ and ELM layers were noted OD (Fig. 4A-B). The patient tested positive for syphilis with positive T. pallidum IgG antibody and RPR at 1:64. He was admitted and completed a 10-day course of IV penicillin and oral prednisone with significant improvement.

Five months later, the patient’s VA was [20/20] OD and [20/25] OS, and he had persistent SOR OD and resolved retinitis OS (Fig. 3E-H). OCT macula findings normalized at the five-month visit (Fig. 4C-D). He was additionally treated with oral doxycycline 100 mg twice daily for one month. Oral prednisone 40 mg daily was restarted for two weeks. Two weeks later, no signs of active retinitis or uveitis were noted, so prednisone was tapered. One month later, FAF showed resolution of the SOR. Repeat RPR was non-reactive. After one year, the patient’s VA was [20/20] OU, and fundus findings and imaging were all normal.

Case 2 presentation imaging (A, C) pseudocolor and fundus autofluorescence imaging of the right eye with ASPPC and papillitis; (B, D) pseudocolor and fundus autofluorescence imaging of the left eye with ASPPC, SOR, and papillitis; Case 2 five months after presentation (E, G) pseudocolor and fundus autofluorescence imaging of the right eye with persistent SOR and areas of perivasculitis; (F, H) pseudocolor and fundus autofluorescence imaging of the left eye with resolved retinitis

Case 2 presentation optical coherence tomography (OCT): retinal pigment epithelium (RPE) nodules, and disruption of the ellipsoid zone (EZ) and external limiting membrane (ELM) layers noted OU (A: right eye), (B: left eye); Case 2 five months after presentation on OCT: normalized macula findings OU (C: right eye), (D: left eye)

A 52-year-old male with a history of human immunodeficiency virus (HIV) untreated for over a year, tobacco use, and methamphetamine abuse presented with eye pain and visual loss OD for over a week. VA was hand motion (HM) OD and [20/25] OS. T. pallidum IgG antibody was positive and RPR was reactive at > 1:128. Lumbar puncture was deferred, and MRI of the brain and orbits was normal. The patient was started on a 14-day course of penicillin, in addition to oral prednisone, prednisolone drops, and atropine drops.

At clinic follow-up one week after presentation, the patient’s VA was HM OD and [20/40] OS. There was no clear view of the retina OD due to obstruction by dense vitritis (Fig. 5A). FAF and pseudocolor imaging showed evidence of ASPPC and papillitis OS (Fig. 5B-C), which were confirmed on indirect biomicroscopy. At the one-month visit after completing treatment, the patient’s VA improved to [20/30] OD and [20/25] OS, but he had persistent papillitis OD (Fig. 5D-F) and was subsequently restarted on oral prednisone. RPR titer was 1:16. One year later, his VA worsened again to HM OD and [20/30] OS. On imaging, he had ASPPC OU. RPR had increased to 1:128, suggesting reinfection with syphilis. Inpatient treatment with 14 days of IV penicillin and oral prednisone was started. After treatment, the patient’s VA improved to [20/60] OD and [20/25] OS. There was mild CME noted OD. The patient received a triamcinolone injection OD to mitigate the continued inflammation; however, the patient was lost to follow-up before convalescence was confirmed.

Case 3 presentation imaging (A) pseudocolor imaging of the right eye with dense vitritis obstructing view of the retina; (B, C) pseudocolor and fundus autofluorescence imaging of the left eye with ASPPC and papillitis; Case 3 one month after presentation (D, F) pseudocolor and fundus autofluorescence imaging of the right eye with persistent papillitis and abnormal vessels temporally; (E, G) pseudocolor and fundus autofluorescence imaging of the left eye

Table 1 summarizes the relevant findings for each patient, including past medical history, presenting symptoms, initial exam findings, treatment course, and patient outcome. Table 2 summarizes the progression of RPR titers following initiation of treatment for each patient in our study.