North Carolina providers are required by law to report all newly diagnosed cases of syphilis to local health departments. Once reported, health department staff verify treatment, collect syphilis-related signs and symptoms from the reporting provider, and attempt to interview each case to identify risk behaviors and sex partners at risk of transmitting syphilis. Health department staff enter all case report data into the North Carolina Electronic Disease Surveillance System (NC EDSS).

We reviewed cases in all stages of syphilis entered into NC EDSS; a patient meeting the syphilis surveillance case definition [16] with ocular symptoms not explained by another etiology was considered a case of ocular syphilis.

We identified 83 potential cases of ocular syphilis from 1 January 2014 to 31 December 2015 using 2 ascertainment methods (Figure 1). First, we identified cases where a checkbox indicated “eye/conjunctiva” was a site of infection. Second, we searched free-text fields from syphilis case investigation notes, using key words (eg, eye, vision, sight, or blind). The “eye/conjunctiva” checkbox was a standard component of the syphilis case report form before this investigation, but disease investigation specialists (DIS) were encouraged to ask all investigated syphilis cases about eye symptoms and utilize the checkbox in early 2015.

For all identified ocular syphilis cases, we reviewed data in NC EDSS and abstracted demographic information, syphilis testing, symptoms and treatment, sexual behavior, partner information, and other risk factor information. We also requested medical records from reporting providers and reviewed records for clinical visits associated with the ocular syphilis diagnosis to document additional symptoms, risk, treatment, and comorbidities. We characterized ocular syphilis cases and compared symptoms by human immunodeficiency virus (HIV) status. We estimated ocular syphilis prevalence among all syphilis cases reported to NC EDSS by demographic, behavioral, and clinical characteristics.

In North Carolina, syphilis cases diagnosed in any stage increased 35%, from 1799 cases in 2014 to 2433 cases in 2015. A total of 63 ocular syphilis cases were identified: 21 in 2014 and 42 in 2015, a 100% increase. Ocular syphilis cases represented 1.5% of all reported syphilis cases in North Carolina during 2014–2015, and were distributed among 33 of 100 counties. No patients with ocular syphilis named another ocular syphilis patient as a sexual partner, and no other epidemiologic links were found between cases, such as travel or an institutionalized setting.

Most ocular syphilis patients were male (n = 59 [94%]); of those, 42 (71%) stated they had male sex partners (Table 1). The mean age was 45 years (range, 21–79 years). Primary or secondary syphilis was diagnosed in 24 (38%). Median RPR was 1:128 and varied slightly by stage of disease (primary or secondary syphilis = 1:256; all latent syphilis [early, late, and latent of unknown duration] = 1:128). A variety of syphilis symptoms were reported; a recent skin rash was most common. However, 25 (40%) patients reported no recent syphilis symptoms other than ocular symptoms. Forty-two patients (67%) received the recommended treatment for ocular syphilis, and 13 (21%) patients received intramuscular (IM) benzathine penicillin only. Among 38 ocular syphilis patients who had a lumbar puncture with cerebrospinal fluid (CSF) analysis, 24 (63%) had a reactive CSF Venereal Disease Research Laboratory test (VDRL).

Overall, 49 patients (78%) had a documented eye examination consistent with ocular syphilis. Uveitis (anterior uveitis, posterior uveitis, or panuveitis) was the most common diagnosis documented in the eye examination. Fifteen patients received a severe eye diagnosis; 1 patient was diagnosed with retinitis and retinal detachment.

A total of 35 (56%) patients were HIV infected; 11 of whom (31%) were diagnosed with HIV at the same time as ocular syphilis. Similar proportions of HIV-infected and HIVuninfected ocular syphilis patients had a severe eye diagnosis, CSF analysis performed, or positive CSF VDRL. However, a larger proportion of HIV-infected patients with a CD4 count <350 cells/μL reported only ocular symptoms of syphilis (55.6%), compared with HIV-infected patients with a CD4 count ≥350 cells/μL (10%).

In this in-depth analysis of ocular syphilis, we found an increase in ocular syphilis cases in North Carolina from 2014 to 2015, in the setting of increased awareness of ocular manifestations of syphilis. Ocular syphilis was diagnosed in all stages of syphilis and in both HIV-infected and HIV-uninfected patients. Although a subset of patients experienced severe symptoms, including vision loss, most patients recovered visual function following treatment.

The epidemiology of ocular syphilis in North Carolina is similar to that reported in previous investigations. The predominance of ocular syphilis in men, particularly men aged >40 years, is consistent with what has been reported recently in the United States [14], and elsewhere [6, 7]. The high proportion of cases in men and MSM is also consistent with the epidemiology of syphilis in the United States [1]. However, studies from the United Kingdom [6] and the Netherlands [7] found a lower proportion of ocular syphilis patients known to be HIV infected (31.7% and 35.9%, respectively) than our investigation.

The extent to which HIV infection influences the development or severity of ocular symptoms in ocular syphilis is unclear. This investigation found a higher prevalence of ocular syphilis among HIV-infected syphilis cases, compared to syphilis cases without HIV. However, in this investigation and another US-based investigation, only half of patients diagnosed with ocular syphilis were HIV infected [14]. In previous studies of ocular syphilis, HIV-infected patients were more likely to be diagnosed with posterior uveitis [4, 19], and have findings in follow-up suggesting possible treatment failure [20, 21]. More recent studies, however, have not found a relationship between HIV status and anatomical location of uveitis, CSF abnormalities, bilateral eye disease, presenting or final visual acuity, or reactive CSF VDRL [6, 7, 14]. While the presence of HIV infection alone might not determine ocular involvement, the degree of immunosuppression from HIV could modify ocular symptoms. CDC's 8-jurisdiction evaluation found that patients with a CD4 count <500 cells/μL were more likely to have a reactive CSF VDRL and bilateral ocular disease [14]. Although not statistically significant, this investigation found that, among HIV-infected ocular syphilis patients, those with a low CD4 count were more likely to present without other more common syphilis symptoms, compared to patients with a higher CD4 count.

Treatment of ocular syphilis is important for visual function improvement. In a report from the preantibiotic era, 9%–12% of patients with syphilitic iritis developed blindness [22]. In a retrospective review, worse posttreatment visual acuity was noted with a treatment delay of >12 weeks after symptom onset, while improved posttreatment visual acuity was observed in those treated with IV antibiotics [7]. A recent report of 6 cases described 2 patients with blindness after delayed treatment for ocular syphilis [5]. In our investigation, lack of other syphilis manifestations was associated with delayed treatment. In addition, patients who were assessed by an eye doctor had almost a week's delay in initiation of treatment. While we did not find this to be associated with vision loss or residual visual defects, other studies have found clinical implications associated with treatment delays [5, 7]. Provider education, especially for eye doctors who might not be accustomed to screening for syphilis, could potentially shorten delays in treatment.

We were unable to assess differences in outcome after treatment between patients who received IV penicillin and those who received IM penicillin only, because of small numbers and substantial differences between these populations; none of the patients who received only IM penicillin had a severe eye diagnosis or presented with vision loss.

Most patients reported health insurance at the time of diagnosis. Lack of health insurance coverage was associated with residual visual deficits. Although no difference was found in time to care or treatment by insurance status, it is possible that differences in healthcare access could have impacted outcomes. Furthermore, lack of health insurance could have resulted in a subset of persons with ocular syphilis remaining undiagnosed, and therefore not identified by our investigation.

This investigation had several limitations. First, awareness of ocular syphilis in North Carolina increased over the course of our investigation; DIS were encouraged to ask about ocular symptoms and utilize the “eye/conjunctiva” checkbox in 2015, potentially leading to an increase in case ascertainment in 2015, compared to 2014. If ocular symptoms were not uniformly elicited and recorded during routine syphilis investigations, our numbers could be an underestimate of the true ocular syphilis burden. This could also have led to misclassification of true ocular cases as nonocular syphilis cases, potentially biasing results of our comparisons. Additionally, patients presenting to a clinician with ocular symptoms who never received a syphilis diagnosis are missing from our analysis. With respect to patient interviews, follow-up time varied by patient and could have impacted symptom recall. Additionally, eyesight in follow-up interviews was based on self-reported visual function, not standardized examinations. Finally, we did not interview syphilis patients without ocular manifestations, limiting our ability to compare some characteristics (eg, healthcare access).

The increase in reports of ocular syphilis, in North Carolina and across the United States, may be due to increased recognition of ocular manifestations in the setting of increased syphilis cases, or a true increase in the proportion of syphilis cases with ocular disease. We could not assess trends over time, because systematically collected information on suspected ocular syphilis is not available before 2014 in North Carolina. Preliminary reports from North Carolina in 2016 show a stable or slight increase in the proportion of syphilis patients with ocular manifestations (data not shown). While this was one of the largest ocular syphilis investigations published to date, further investigation is needed to better understand the increase in reports of ocular syphilis, and to identify potential risk factors influencing development of ocular disease.

The number of ocular syphilis cases increased in North Carolina during 2014–2015, in the context of an increase in all syphilis diagnoses. Ocular manifestations of syphilis can have substantial impact on visual function, even causing vision loss. Patients with syphilis should be asked about symptoms of syphilis complications, including vision or neurologic changes. All patients diagnosed with syphilis who have ocular manifestations should immediately be treated for neurosyphilis with IV penicillin and referred for ophthalmologic examination. In addition, patients with inflammatory eye disease without a known cause should have an evaluation of syphilis, regardless of risk factors. Prompt identification of ocular syphilis, urgent ophthalmologic evaluation, and appropriate treatment are critical for management of ocular syphilis.