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Variations in Clinical Presentation of Ocular Syphilis: Case Series Reported From a Growing Epidemic in the United States

Marx, Grace E. MD, MPH; Dhanireddy, Shireesha MD; Marrazzo, Jeanne M. MD, MPH; Tuddenham, Susan A. MD, MPH; Rompalo, Anne M. MD, ScM; Leone, Peter A. MD; Gaydos, Charlotte A. DrPh; Rietmeijer, Cornelis A. MD, PhD

doi: 10.1097/OLQ.0000000000000477
The Real World of STD Prevention
Free

Ocular syphilis, a form of neurosyphilis, has been increasingly diagnosed in the United States. This case series summarizes the course of 6 patients recently diagnosed with ocular syphilis, emphasizing the varied sociodemographic factors and the wide range of symptoms and outcomes that are seen in patients with this disease.

Recent cases of ocular syphilis in the United States are described, highlighting the diversity of sociodemographic factors, symptom presentations, disease course, and physical outcomes of this syndrome.

From the *Denver Public Health Department, Denver Prevention Training Center, Denver, CO; †Division of Infectious Diseases, Department of Medicine, University of Colorado, Aurora, CO; ‡Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA; §Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL; ¶Division of Infectious Diseases, Department of Medicine, Bayview Medical Center, Johns Hopkins University, Baltimore, MD; ∥Division of Infectious Disease, Department of Medicine, University of North Carolina, Chapel Hill, NC; **Division of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, MD; and ††Colorado School of Public Health, Aurora, CO

Conflict of interest: None declared.

The authors would like to thank Dr. Daniel Corbett and Dr. Thuy Doan, respectively, of the Departments of Ophthalmology at the University of Colorado and University of Washington, who provided and described the ocular images.

Correspondence: Cornelis A Rietmeijer, MD, PhD, Colorado School of Public Health.

Received for publication January 19, 2016, and accepted April 14, 2016.

Ocular syphilis, a form of neurosyphilis defined as symptoms or signs of ocular disease (eg, vision loss or uveitis) in a person with laboratory-confirmed syphilis of any stage, has been detected with increased frequency in the United States in the last 2 years.1 This trend is perhaps not surprising given the notable increase in early syphilis during this time.2 Given that reported incidence is based on passive surveillance, which relies on clinicians reporting to the local, state, or federal health departments, these numbers are almost certainly an underestimate of the true burden of disease. We present herein a small case series of patients with ocular syphilis diagnosed in 2015 in diverse geographical areas of the United States. Our goal is to increase awareness of the disease's diverse demographic factors and variable clinical presentations (summarized in Table 1) in an effort to emphasize the importance of heightened clinical vigilance and rigorous reporting.

TABLE 1

TABLE 1

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CASE 1: NEGATIVE CEREBROSPINAL FLUID VENEREAL DISEASE RESEARCH LABORATORY AFTER TREATMENT IN A HUMAN IMMUNODEFICIENCY VIRUS–NEGATIVE PATIENT

A 41-year-old man was referred to a county sexually transmitted diseases (STD) clinic for treatment of syphilis after his primary provider identified a rapid plasma reagin (RPR) titer of 1:256 on routine screening. At the STD clinic, the patient's only complaints were of a mild rash about 1 month prior that had resolved, and several weeks of bilateral visual haziness, white halos around the periphery of his vision, occasional flashing lights, and vertigo. He reported condomless sexual activity with both women and men, including with 2 new anonymous male partners within the prior 3 months. On examination, vital signs were normal, and the patient was without rash or genital lesion. Rapid RPR was reactive with a titer of >1:16 at the STD clinic and reflex testing at the reference laboratory revealed a reactive Treponema pallidum particle agglutination assay (TPPA) and RPR titer of 1:64. Gonorrhea and chlamydia testing by nucleic acid amplification test in urine and pharyngeal samples and an antibody/antigen human immunodeficiency virus (HIV) test were negative. He was referred to the infectious diseases (ID) clinic for concern of ocular syphilis; however, due to work restraints, he declined to be seen that day. He was given 2.4 million units intramuscular (IM) benzathine penicillin and was instructed to return to the clinic in 1 week. At the follow-up visit, he received a second dose of IM penicillin and was again referred to the ID clinic, where he reported persistent but improving visual changes and resolution of his vertigo. He was referred immediately to the ophthalmology clinic where examination revealed bilateral posterior uveitis (see Figs. 1 and 2). With the clinical diagnosis of ocular syphilis, he was admitted to the hospital for additional evaluation and treatment. Lumbar puncture revealed cerebrospinal fluid (CSF) with 0 red blood cells (RBC)/μL, 0 white blood cells (WBC)/μL, glucose 59 mg/dL and protein 33 mg/dL. The CSF Venereal Disease Research Laboratory (VDRL) test was nonreactive. He received aqueous crystalline penicillin G intravenous (IV) 24 million units/day for 14 days with complete symptomatic resolution.

Figure 1

Figure 1

Figure 2

Figure 2

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CASE 2: HIV-POSITIVE MAN WITH BILATERAL BLINDNESS AFTER DELAYED TREATMENT

A 34-year-old man with a history of well-controlled HIV infection (752 CD4 cells/mm3; HIV viral load of <20 copies/mm3) developed subjective irritation in both eyes. About 2 weeks after symptom onset, he presented to a local emergency room where he was treated with gatifloxacin eye drops for presumed conjunctivitis. He experienced initial symptomatic improvement, but 1 week later developed a blind spot in the left eye that progressively enlarged over the course of several days to the point of total unilateral vision loss. Two days after complete left-sided vision loss, he developed rapidly progressive right-sided vision loss over several hours, prompting him to present again to the emergency room where he was urgently referred to an ophthalmologist. Fundoscopic examination revealed dense vitritis bilaterally, with a confluent area of whitening in the superonasal quadrant extending to the optic disc in the right eye, and possible peripheral retinal whitening in the left eye. He was diagnosed with bilateral necrotizing retinitis and panuveitis. The initial differential diagnosis included syphilis, herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), and toxoplasma infections. An anterior chamber vitreous tap for viral polymerase chain reaction (PCR) was performed and the patient was given empiric intravitreal foscarnet and IV acyclovir. Viral PCR studies from the vitreous fluid and toxoplasma IgG were negative. The treponemal-specific LIAISON chemiluminescence immunoassay test was positive and the RPR titer was 1:256. An RPR obtained 9 months prior had been negative. He reported sexual activity with men with a last sexual encounter about 2 months before presentation. The patient was diagnosed with syphilitic uveitis; the acyclovir was discontinued and IV penicillin G was administered for 14 days along with an oral prednisone taper and atropine eye drops. The patient's vision dramatically improved with treatment initially; however, after about 14 days of treatment, he developed a sudden decline in visual acuity. He was admitted to the hospital where a lumbar puncture revealed 1 WBC/μL, 0 RBC/μL, glucose 54 mg/dL, protein 32 mg/dL, negative VDRL, and negative PCR for enterovirus, VZV, CMV, and HSV. Fundoscopic examination revealed bilateral retinal detachments. He underwent a series of minimally invasive ocular interventions approximately 36 days after starting systemic therapy. Unfortunately, the right eye developed proliferative vitreoretinopathy and surgical revision was recommended. Repair of the retinal detachment in the left eye was scheduled, but the patient was lost to follow-up.

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CASE 3: MONOGAMOUS HETEROSEXUAL WOMAN PRESENTING WITH MILD OCULAR COMPLAINTS

A 45-year-old woman developed a left “red eye” with no other associated symptoms. She did not seek evaluation initially, but later developed photosensitivity in the eye, prompting her to see an ophthalmologist who diagnosed her with uveitis and prescribed steroid eye drops. Her symptoms temporarily improved with the drops, but approximately 1 month later her symptoms recurred; this time her ophthalmologist diagnosed unilateral scleritis. Autoimmune analysis revealed positive antinuclear antibodies and rheumatoid factor, and negative antineutrophil cytoplasmic antibodies, and HLA-B27. Infectious disease work-up revealed a negative HIV test, negative Lyme antibody, and a positive TPPA with an RPR titer of 1:512. She reported a negative screen for syphilis 15 years prior. She reported sexual relations only with her husband, who admitted having sexual contact with several other partners. She did recall having a flaking rash on her palms about 2 years before her presentation but no genital lesions or other symptoms. She was treated at her local health department with 3 doses of weekly IM penicillin with resolution of her ocular symptoms. Her RPR declined to 1:128 approximately 1 month after treatment. At that time, she was seen in the ID clinic, where ophthalmologic and neurological examination was noted to be normal except that her left eye accommodated slightly slower than her right. The CSF evaluation showed 2 WBC/μL, 0 RBC/μL, protein 49 mg/dL, glucose 51 mg/dL, and a positive VDRL at a titer of 1:1. Given strong patient preference, she was treated with IV ceftriaxone 2 g daily for 14 days instead of the treatment of choice, IV penicillin. Her RPR declined further to 1:32 4 months after treatment completion without symptom recurrence.

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CASE 4: MONOGAMOUS MAN WITH UNCONTROLLED HIV; MALE SEXUAL PARTNER ALSO WITH OCULAR SYPHILIS

A 29-year-old man with HIV infection (214 CD4 cells/mm3 and HIV viral load of 41,000 copies/mm3, last recorded 4 years before presentation), not on treatment and out of care, presented to an ID clinic with complaints of progressive bilateral vision loss, worse on the left. His ocular symptoms had begun about 4 months prior in the left eye with floaters and paracentral scotoma. He recalled a diffuse pruritic erythematous rash about 9 months before presentation, predominantly on the torso, which resolved without treatment. He also noted paresthesias for several months as well as desquamation of the palms and soles. He reported several weeks of diarrhea, weight loss of 18 kg, and progressive generalized weakness resulting in a nonambulatory state about 7 weeks before presentation. He reported sexual activity only with his husband (case 5). Physical examination revealed a cachectic man with a body mass index of 15 and tachycardia at 115 beats/minute. Examination was notable for innumerable scattered raised violaceous nodules diffusely distributed over the torso as well as palmar and plantar erythema. No genital lesions were noted. Visual acuity was limited to basic shapes and colors. He was referred urgently to an ophthalmologist who diagnosed chronic bilateral anterior uveitis, intermediate uveitis and panuveitis, focal tractional retinal detachment on right, nasal and temporal retinal detachment on left, and 360 degree posterior synechiae in both eyes with iris bombe. He was admitted to the hospital and underwent lumbar puncture, which revealed 318 WBC/μL (30% neutrophils, 58% lymphocytes, 12% monocytes), 0 RBC/μL, glucose 13 mg/dL, and protein 124 mg/dL. The CSF bacterial PCR was positive for T. pallidum, CSF fluorescent treponemal antibody absorption was reactive, and CSF VDRL was positive at a titer of 1:4. Serum RPR titer was 1:1024 with positive syphilis IgG and TPPA. Plasma analyses revealed an HIV viral load of 107,800 copies/mm3 and 64 CD4 cells/mm3. He was treated with penicillin G IV for 14 days; he developed systemic inflammatory response syndrome, presumed secondary to a Jarisch-Herxheimer reaction. He was started on antiretroviral therapy to treat his HIV infection and was discharged from the hospital. At a follow-up clinic visit 3 months later, the patient reported significant improvement in his vision; laboratory studies revealed an HIV viral load of <20 copies/mm3 and 130 CD4 cells/mm3. Eight months after initial presentation, his RPR titer had decreased to 1:64. Ten months after initial presentation, he was referred back to the ID clinic as a contact to a person with secondary syphilis. He again denied any sexual contacts besides his husband and denied any new neurological or ophthalmologic symptoms. Physical examination revealed a new, scaly, erythematous rash on his torso, palms, and soles as well as painful sores on his tongue. His RPR titer was 1:512. He was treated with benzathine penicillin 2.4 million IM. An ophthalmologic examination 1 week after retreatment revealed no evidence of active ocular pathology.

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CASE 5: MAN WITH UNCONTROLLED HIV AND RECURRENT SYPHILIS; MALE SEXUAL PARTNER ALSO WITH OCULAR SYPHILIS

A 35-year-old man with untreated HIV (unknown baseline CD4 count and HIV viral load) presented to the ID clinic with progressive bilateral vision loss over the prior 9 months with floaters and bilateral visual field deficits, worse on the left. He reported a 31-kg weight loss over this time but denied other symptoms. He reported sexual activity only with his husband (case 4). Physical examination revealed hyperpigmented macules on his palms and soles as well as 2 painless ulcerations on the ventral penis. Visual acuity was limited to minimal light perception in the left eye; neurological examination was otherwise unremarkable. Fundoscopic examination by an ophthalmologist noted chronic bilateral anterior uveitis, intermediate versus panuveitis, as well as left macular retinal detachment and right retinal detachment (see Figs. 3–5). He was also noted to have a left dense cataract and left iris bombe with associated elevated intraocular pressure. The CSF examination revealed 78 WBC/μL (3% neutrophils, 90% lymphocytes), glucose 55 mg/dL, and protein 58 mg/dL. The CSF VDRL was positive at a titer of 1:4 and CSF fluorescent treponemal antibody was reactive. Serum RPR titer was 1:4096 and syphilis IgG and TPPA were reactive. Human immunodeficiency virus viral load was 34,740 copies/mm3, and CD4 count was 111 cells/mm3. He was treated with penicillin G IV for 14 days without complication and was started on antiretroviral therapy for his HIV infection. At a follow-up clinic visit, 3 months after initial presentation, laboratory studies revealed an HIV viral load of <20 copies/mm3 and 190 CD4 cells/mm3. His rash had resolved. Re-examination by the ophthalmologist revealed slight visual acuity improvement on the right but no change on the left. Seven months after presentation, he reported sexual activity with 3 new partners. The STD screening was performed; RPR titer had decreased to 1:256 and gonorrhea and chlamydia testing of samples from the urethra, pharynx, and rectum was negative. Nine months after initial presentation, he noted a new, nonpainful, nonpruritic rash on the penis, bilateral forearms, and right thigh. He denied new sexual partners since his last clinic visit. He was treated with a topical antifungal medication for presumed tinea corporis without improvement in the rash. A physical examination 10 months after initial presentation revealed erythematous papules on the bilateral arms and legs, scaly macules on the palms and a healing ulcer on the tip of his tongue as well as several erythematous papules on the penile shaft and scrotum. He denied any new changes to his vision. Laboratory studies revealed an RPR titer of 1:512; other STD testing was negative. A repeat CSF evaluation revealed 5 WBC/μL, 0 RBC/μL, glucose 62 mg/dL, protein 36 mg/dL, and a negative CSF VDRL. He was treated with benzathine penicillin 2.4 million units IM with subsequent improvement in his rash.

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5

Figure 5

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CASE 6: HETEROSEXUAL MAN WITH PERMANENT VISUAL DEFICITS AFTER DELAYED TREATMENT

A 33-year-old man with no significant medical history developed sore throat and tinnitus about 6 weeks before the initial presentation. He reported taking a week of antibiotics without symptom improvement. Two weeks before presentation, he developed blurred vision and photophobia. He presented to an emergency room where computed tomography of his head showed possible sinusitis. He was discharged with a course of trimethoprim-sulfamethoxazole and was instructed to see an ophthalmologist. However, due to financial and insurance barriers, he delayed seeking specialty care. Two days before presentation, his symptoms progressed to near complete vision loss, and he also developed a new periorbital and frontal headache. He again presented to the emergency room where examination revealed normal vital signs, white patches on his oropharyngeal mucosal membranes, and a hyperkeratotic scaly plaque on his torso, buttocks, palms, and soles. Visual acuity was to finger count only. Ocular examination revealed bilateral conjunctival injection as well as dilated pupils that reacted slowly to light exposure. A slit lamp examination revealed panuveitis and bilateral acute retinal necrosis. Laboratory testing revealed a negative HIV test, RPR titer of 1:512, and positive syphilis TPPA. The CSF examination showed 75 WBC/μL (78% lymphocytes, 3% neutrophils, 19% macrophages), 35 RBC/μL, protein 58 mg/dL, glucose 57 mg/dL, and a positive VDRL.

Autoimmune work-up revealed a positive antinuclear antibodies at a titer of 1:160 (speckled pattern) and HLA-B27, normal angiotensin converting enzyme levels, and negative antineutrophil cytoplasmic antibodies, Borrelia burgdorferi serologies, and gonorrhea and chlamydia testing. Viral PCR of the aqueous humor for HSV, CMV, VZV, and toxoplasma was negative. He reported sexual activity with only 2 women in the prior year. He recalled having a painless genital lesion in the recent past. He was admitted to the hospital where he was empirically started on IV acyclovir. After the elevated RPR titer was reported, the acyclovir was replaced with IV penicillin G 24 million units daily for 10 days along with oral methylprednisolone and steroid eye drops. One week after admission, his vision had not improved and visual prognosis was considered to be poor.

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DISCUSSION

These 6 cases of ocular syphilis highlight the diversity of clinical presentations and potentially devastating sequelae of this syndrome. Although the majority of recently published cases have been seen in HIV-infected men who have sex with men3 which describes 3 of our 6 cases, we also present cases in a heterosexual woman and man as well as in an HIV-negative man reporting sex with both women and men. This syndrome can be challenging to diagnose because patients usually present with visual symptoms to their primary care provider or emergency/urgent care center, where STDs are not often highest on the differential diagnosis. Limited access to medical care, whether due to lack of knowledge or financial resources, also contributes to delays in diagnosis and treatment, which may result in poor visual outcomes as demonstrated in several of our cases. Increased awareness of this syndrome in all clinical care settings, paired with a low threshold for syphilis screening, could lead to improved care for patients. Ocular symptoms in the setting of laboratory evidence of active syphilis infection (ie, an elevated RPR titer) should be treated as an ophthalmologic emergency with a low threshold to treat empirically if fundoscopic and CSF examination is not available or refused.4

There are a number of limitations to our study. Given the absence of comprehensive or systematic reporting, we cannot draw conclusions about disease tends. We assume that the anecdotal increase in ocular syphilis cases in the United States reflects a true epidemic; however, other possibilities could explain these trends. For example, heightened awareness of syphilis and syphilitic complications in the context of a broader syphilis epidemic could result in reporting bias. Another possibility is that presence of an oculotropic syphilitic strain in circulation could be causing a disproportionate amount of ocular disease.

Nonetheless, it is critical that STD specialists consider a possible ocular syphilis epidemic as an opportunity to reinforce CDC's call for expanded epidemiologic surveillance of syphilis and its varied complications. Noting that most patients with ocular syphilis present in early syphilis, it is also important to call for increased vigilance for ocular disease in patients who present with symptoms or signs of primary or secondary syphilis.

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Institutional Review

The Colorado Multiple Institution Review Board (COMIRB) is the institution review board of record for this multisite report with the understanding, but not requiring proof, that all individual case studies also adhere to the regulations of the individual institutions of report. According to COMIRB regulations, case series including more than 1 case report, are considered a “systematic” review and subject to COMIRB oversight. Because the case reports in this article do not contain identifiable information in terms of protected health information, COMIRB exempt status for this report was requested and obtained, including a waiver of informed consent.

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REFERENCES

1. Woolston S, Cohen SE, Fanfair RN, et al. A Cluster of Ocular Syphilis Cases—Seattle, Washington, and San Francisco, California, 2014–2015. MMWR Morb Mortal Wkly Rep 2015; 64:1150–1151.
2. Patton ME, Su JR, Nelson R, et al. Primary and secondary syphilis—United States, 2005–2013. MMWR Morb Mortal Wkly Rep 2014; 63:402–406.
3. CDC. Clinical advisory: Ocular syphilis in the United States. Atlanta, GA: US Department of Health and Human Services, CDC; 2015. Available at http://www.cdc.gov/std/syphilis/clinicaladvisoryos2015.htm.
4. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015 (No. RR-3).
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