Objective To describe the clinical course and prognosis of ocular syphilis in patients infected with HIV-1 in the antiretroviral therapy (ART) era.
Methods We conducted a single-centre retrospective chart review of ocular syphilis in patients infected with HIV-1 diagnosed between August 1997 and July 2015. The prognosis of best-corrected visual acuity (BCVA) was analysed.
Results The study subjects were 30 eyes of 20 men who had sex with men (MSM) (median age, 41). Loss of vision and posterior uveitis were the most common ocular clinical features (43%) and location of inflammation at presentation (50%), respectively. The median baseline BCVA was 0.4 (IQR 0.2–1.2), including three eyes with hand motion. BCVA≤0.4 at diagnosis was significantly associated with posterior uveitis or panuveitis (p=0.044). Seventy-five per cent were treated with intravenous benzylpenicillin and 53% were diagnosed with neurosyphilis. After treatment (median follow-up: 21 months), BCVA improved in 89% of the eyes, including all eyes with hand motion, to a median BCVA of 1.2 (IQR 0.8–1.2). Kaplan–Meier analysis showed that >28 days of ocular symptoms before diagnosis was the only factor associated with poor prognosis of BCVA. Three patients (15%) developed recurrence after treatment.
Conclusions The prognosis of BCVA in HIV-infected patients with ocular syphilis in the ART era was favourable after proper treatment. Having >28 days of ocular symptoms before diagnosis was associated with poor prognosis. Changes in visual acuity in HIV-infected MSM should prompt an immediate assessment for ocular syphilis as delays in diagnosis and therapy can lead to irreversible visual loss.
- PROGNOSTIC INDICATORS
- ANTIRETROVIRAL THERAPY
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Syphilis is a chronic sexually transmitted infection caused by Treponema pallidum and there has been resurgence in reported syphilis cases in recent years among men who have sex with men (MSM), particularly among those with HIV-1 infection in resource-rich settings.1 ,2 The incidence of cytomegalovirus retinitis has decreased after the introduction of antiretroviral therapy (ART).3 In contrast, cases of ocular syphilis are still being diagnosed and reported in the literature, and it is uncertain how the introduction of ART has impacted the incidence of ocular syphilis.4 Especially in the USA, the reported cases of ocular syphilis are increasing,5 and the clinical advisory on ocular syphilis was recently released from Centers for Disease Control and Prevention.6 The eye is a relatively uncommon site of syphilitic infection, but any eye structure can be involved and, if untreated, it can result in significant visual impairment. In addition, there is no typical clinical presentation or findings.7 Therefore, the diagnosis should be suspected in any patient infected with HIV-1 who presents with ocular symptoms.
To date, there are only few case series on ocular syphilis in patients infected with HIV-1, and the majority of these reports included small sample size and patients diagnosed before and after the introduction of ART.8 Furthermore, there is only little information on the prognosis of visual acuity in ocular syphilis,7 and such findings varied mainly due to the small sample size and differences in study designs.4 ,7 In the present study, we used the best-corrected visual acuity (BCVA), the best distance vision with eyeglasses or contact lenses to describe visual acuity. The BCVA score of 1.0, 0.4 and 0.1 corresponds to 20/20, 20/50 and 20/200 visions, respectively. Normal vision is generally considered to be the BCVA score of 1.0 and visual impairment is usually defined as decrease in BCVA to ≤0.4.8 ,9
The aim of the present study was to describe the clinical presentation and clinical course of ocular syphilis, with a special focus on prognosis of visual acuity in patients infected with HIV-1 in the ART era.
Study design and patients
We conducted a retrospective chart review of patients infected with HIV-1 who presented with ocular syphilis to outline the clinical presentation, clinical features and prognosis of ocular syphilis, with a special focus on visual acuity, at the AIDS Clinical Center, National Center for Global Health and Medicine (NCGM), Tokyo, Japan. We selected all patients who were diagnosed with syphilis or whose rapid plasma reagin (RPR) titres were ≥8 from the electronic database during the study period, and all medical records of such patients were reviewed. The study patients fulfilled all of the following inclusion criteria: (1) diagnosis of ocular syphilis established by an experienced ophthalmologist at our clinic based on findings compatible with ocular syphilis, such as uveitis or scleritis,8 between August 1997 and July 2015; (2) positive T. pallidum hemagglutination test (TPHA) and (3) patients infected with HIV based on positive HIV-1 western blot assay or HIV-1 RNA PCR. When ruling out other ocular diseases was difficult, the response to syphilis treatment was also taken into account for the diagnosis of ocular syphilis. At our hospital, patients with HIV infection undergo routine ophthalmologic examination by an ophthalmologist that includes dilated retinal examination using indirect ophthalmoscopy, during the first visit to the clinic.10 If the diagnosis of ocular diseases cannot be confirmed, ophthalmological examination is repeated within 1–4 weeks.11 The exclusion criteria applied in the present study were (1) patients who were diagnosed with ocular syphilis at a different clinic before their visit to our clinic and (2) patients aged <20 years.
The first author (MT) selected the medical records of all candidate patients for ocular syphilis during the study period. Then an experienced ophthalmologist (SY) reviewed the set of medical records of each case to determine whether the cases fit into the predefined criteria for the study patients.
Data on the following parameters were collected from the medical chart: age, sex, race, sexual orientation, ophthalmologic complaints, laterality, type and anatomic location of ocular lesions, duration of ocular symptoms before diagnosis, CD4 cell count, HIV-1 RNA load, ART use, TPHA and RPR titre, the stage of syphilis (primary, secondary and tertiary12 ,13), results of cerebrospinal fluid (CSF) examination, type and duration of antibiotic therapy, BCVA at diagnosis and at follow-up visits, recurrence of ocular syphilis and serological response to syphilis treatment. Anatomic location of uveitis was classified according to the Standardisation of Uveitis Nomenclature working group criteria.9
The criteria used for the diagnosis of neurosyphilis included positive serology and one or more abnormalities on CSF examination (white blood cells >10/μL; protein >50 mg/dL, without an alternative diagnosis and/or reactive CSF-RPR).14 ,15 Serological success of syphilis treatment was defined as at least fourfold decrement in RPR titre within 24 months after initiation of treatment.16 Follow-up serum RPR titre was examined at the discretion of the attending physician. At our clinic, written informed consent is obtained from each patient to store serum samples at the first and subsequent visits. Based on this, the RPR data from the stored samples were also used to supplement the RPR data from daily clinical practice in order to determine the response to treatment.16 Recurrence of ocular syphilis was defined as repeated episodes of ophthalmologic findings separated by periods of inactivity without treatment for at least 3 months.9
The study was approved by the Human Research Ethics Committee of NCGM (NCGM-G-001623-02) and conducted according to the principles expressed in the Declaration of Helsinki. Informed consent was waived because this study only used data gained from clinical practice.
Analyses were performed and results were presented both at the subject level and at the eye level. Basic characteristics, including baseline BCVA, were presented by descriptive statistics. Variables associated with visual impairment at baseline and recurrence were investigated by the Mann–Whitney' U test and Fisher's exact test (χ2 test) for continuous and categorical variables, respectively. The Wilcoxon signed rank test was used for comparison of BCVA at diagnosis and end of follow-up. The Kaplan–Meier method was used to describe improvement in BCVA above 0.4 and 1.0, for patients with baseline BCVA of 0.4 or less and 1.0 or less, respectively. Statistical significance was defined as two-sided p<0.05. All statistical analyses were performed with The Statistical Package for Social Sciences V.21.0 (SPSS, Chicago, Illinois, USA).
A total of 23 patients infected with HIV with probable ocular syphilis were selected during the study period. After careful reviewing by the ophthalmologist, three patients were excluded (see online supplementary figure S1), and data of the remaining 30 eyes of 20 patients were analysed. All study patients were Japanese MSM with a median age of 41 years (IQR 32.5–46.5) (table 1). The median CD4 counts and HIV-1 load were 394/μL (IQR 157–652) and 8700 copies/mL, respectively. ART had been started in seven (35%) patients at diagnosis of ocular syphilis. Ten patients had bilateral ocular involvement. All study patients had visual symptoms at presentation and the median duration of ocular symptoms before diagnosis was 60 days (IQR 28–210). Clinical signs and symptoms compatible with primary, secondary or tertiary syphilis were identified in 0 (0%), 4 (20%) and 1 (5%) patients, respectively. Serum RPR titres in 19 out of 20 patients were ≥1:32.
Lumbar puncture for the examination of CSF was performed before treatment in 17 patients and 9 (53%) patients were diagnosed with neurosyphilis. The median CSF leucocyte count and protein levels were 9/μL (IQR 3–26) and 42 mg/dL (IQR 29.5–60.5), respectively. RPR and TPHA in CSF were positive in 8 (47%) and 14 (82%) patients, respectively. Fluorescent treponemal antibody-absorption in CSF was analysed only in six patients and all were positive.
The clinical ophthalmologic manifestations are presented in tables 2 and 3. The most common ocular symptoms at presentation were loss of vision (n=13, 43%), followed by myodesopsia and blurred vision (n=8, 27%), ocular hyperaemia (n=6, 20%), defect of visual fields and photophobia (n=3, 10%) and ocular pain and foreign body sensation (n=2, 6.7%). Posterior uveitis was the most common location of ocular inflammation (n=15, 50%). Scleritis and optic neuritis were observed in 6 eyes (20%) and 16 eyes (53%), respectively. Acute syphilitic posterior placoid chorioretinitis, which was characterised by the presence of one or more placoid, yellowish outer retinal lesions, typically in the macula, were observed in two eyes with BCVA of 0.4 and 0.6, both of which subsequently improved to BCVA of 1.2 after treatment.
The treatment regimen for syphilis and prognosis are summarised in online supplementary table S1. Fifteen patients (75%) were treated with intravenous benzylpenicillin (24 MU per day) with or without other medications, such as oral amoxicillin plus probenecid before or after intravenous benzylpenicillin.16 Five patients (25%) did not receive intravenous benzylpenicillin. The median duration of antibiotic treatment was 21 days (IQR 14–28). Two (10%) patients used concurrent systemic corticosteroids based on the recommendation of the ophthalmologist. Successful treatment of syphilis was confirmed serologically in 17 out of 19 patients (89%); the data for 1 patient was missing because the follow-up period was <24 months.
The BCVA was recorded in 29 eyes at diagnosis and in 25 eyes at follow-up. The BCVA at diagnosis was 1.2 in 7 eyes and ≤1.0 in the other 18 eyes, including 3 eyes with hand motion. Improvement of BCVA was observed in 16 eyes (89%) at the end of the follow-up. The median BCVA values at diagnosis and the end of follow-up were 0.4 (IQR 0.2–1.2) and 1.2 (0.8–1.2) (p=0.001), respectively. The prognosis of the three eyes with hand motion was also favourable; with BCVA at the end of follow-up of 0.6, 0.9 and 1.2. The Kaplan–Meier curves (figure 1) show the time for BCVA to exceed 0.4 or 1.0 after treatment.17
Table 3 lists the factors associated with BCVA of ≤0.4 at diagnosis. Loss of vision (p=0.003) and posterior uveitis or panuveitis (p=0.044) were significantly associated with BCVA of ≤0.4 at diagnosis. On the other hand, BCVA of three patients with scleritis or hyperaemia were maintained as 1.0, 1.2 and 1.2.
Patients with >28 days of ocular symptoms before diagnosis were significantly less likely to achieve BCVA of >0.4 or >1.0 compared with those without such symptoms (log-rank test, p=0.09 and p=0.003, respectively); 8 out of 11 eyes (73%) with >28 days of ocular symptoms did not achieve BCVA of >1.0, while 5 out of 5 eyes (100%) with ≤28 days of ocular symptoms showed such achievement (Fisher's exact test, p=0.013). Furthermore, serologically confirmed successful syphilis treatment was significantly associated with time to exceed BCVA of 0.4 for eyes with baseline BCVA of ≤0.4 (log-rank test, p=0.016), although no such association with time to exceed BCVA of 1.0 was noted for eyes with baseline BCVA of ≤1.0 (p=0.209).
Three (15%) patients presented with recurrence of ocular manifestations 3, 6 and 10 months, respectively, after initial favourable response to treatment (intravenous benzylpenicillin or ampicillin/sulbactam). ART had been already initiated and serum RPR did not increase to fourfold in two out of three patients. CSF examination was not performed at the time of recurrence for all three patients. Two out of the three patients with recurrence did not have any ocular symptoms. The ocular findings in each patient were retinal vasculitis, chorioretinitis, and loss of vision and decline in critical flicker frequency, respectively. The ocular findings and BCVA in patients (no. 2 and 16 in table 2) without ocular symptoms improved after additional treatment: for patient no. 2, 21-day doxycyclin (DOXY) followed by 16-day intravenous benzylpenicillin, vitreous surgery and 13-month DOXY and for patient no. 16, 28-day amoxicillin plus probenecid. The other patient (no. 7 in table 2) was lost to follow-up after additional treatment with 28-day amoxicillin plus probenecid, and further examination could not be performed. Recurrence of ocular syphilis was significantly associated with younger age (median 31.0 (IQR 31.0–32.0) vs 41.0 (36.0–46.5), p=0.032) and lower BCVA at diagnosis (median 0.2 (IQR 0.1–0.2) vs 0.9 (IQR 0.325–1.2), p=0.037).
Neurosyphilis, high RPR titre at baseline or low CD4 count were not significantly associated with recurrence of ocular syphilis.
Variables related to HIV infection, such as CD4 count, HIV-1 load and ART use at diagnosis were not associated with baseline BCVA, prognosis or recurrence of ocular syphilis.
To our knowledge, this is the largest case series of ocular syphilis in patients infected with HIV in the ART era. The results showed favourable prognosis of ocular syphilis; BCVA improved after treatment (at the end of follow-up) in 89% of the eyes. Even the BCVA of the three eyes with hand motion improved to 0.6, 0.9 and 1.2 after treatment. Furthermore, improvement of BCVA was fast; most eyes with baseline BCVA of ≤0.4 improved to >0.4 within 2 months after treatment, and those with baseline BCVA of ≤1.0 improved to >1.0 within 3 months after treatment (figure 1). These encouraging results are consistent with previous studies,18 ,19 which showed significant improvement of BCVA in most patients with ocular syphilis within 3 months of treatment.
The study also showed two other important findings. First, the presence of ocular symptoms for >28 days before diagnosis was significantly associated with poor prognosis of BCVA. This finding highlights the need for considering ocular syphilis in the differential diagnosis of uveitis, as well as the importance of early diagnosis and early treatment. Second, two out of three patients who developed recurrence of ocular syphilis did not have any ocular symptoms at recurrence. This warrants regular ophthalmological follow-up after treatment for ocular syphilis, since retreatment can improve BCVA, as shown in this study. It is also noteworthy that achievement of serologically confirmed successful syphilis treatment was associated with good prognosis of BCVA, highlighting the importance of regular serological follow-up, in addition to ophthalmological follow-up, to confirm treatment success even after proper treatment.
With regard to the factors associated with baseline visual acuity, our study identified posterior lesions of uveitis, including posterior or pan-uveitis, as significant factors associated with lower baseline BCVA (p=0.044). This finding could be related to the fact that posterior uveitis can impair the retina, choroid and optic nerve, and ultimately lead to deterioration of visual acuity. Seventy per cent of the eyes in the present study presented with posterior or pan-uveitis, suggesting that posterior lesion is common among patients infected with HIV-1.4
Although evidence is scarce, optic neuritis might be more common in patients infected with HIV-1 than those without infection, since optic neuritis was reported in 20%–78% of HIV-infected patients with ocular syphilis,4 ,20 but only 3.8%–29% of patients without HIV infection.8 ,21 In the present study, optic neuritis was observed in 53% of the patients, supporting the findings of the above studies. On the other hand, our results showed that none of the parameters of HIV infection, such as CD4 cell count, HIV-1 load and ART use, was associated with BCVA at diagnosis, prognosis or recurrence of ocular syphilis.
Lumbar puncture and CSF examination should be performed in all patients with ocular syphilis, due to the high incidence of neurosyphilis,12 and follow-up CSF examination is recommended for the assessment of treatment response.12 ,22 It was reported previously that serum RPR titre of ≥1:32 increases the odds of neurosyphilis 5.98-fold in patients infected with HIV.23 In this study, serum RPR titre was ≥1:32 in 95% of the patients, compatible with previous studies,4 ,12 ,19 ,24–26 and 53% of those who underwent CSF examination were diagnosed with neurosyphilis based on CSF findings. The high prevalence of neurosyphilis among patients with ocular syphilis supports the above-mentioned recommendations by the guidelines.9
This study has several limitations. First, the number of study patients was small due to the low incidence of ocular syphilis,8 and thus some of the results, such as factors associated with recurrence, need to be interpreted with caution. However, it is noteworthy that the present study is the largest of HIV-infected ocular syphilis cases in the ART era. Second, again due to the low incidence of ocular syphilis, this study was retrospective in design, with some missing data and variable follow-up period of ophthalmological examination. To overcome this limitation, the medical charts of candidate patients were reviewed first by an infectious disease specialist (MT) and then by an experienced ophthalmologist (SY) to determine eligibility for inclusion in the study, and prognosis of BCVA was analysed with the Kaplan–Meier curve (figure 1).17 Since ocular syphilis is a rare disease, it is difficult to conduct prospective studies and it is important to accumulate the data from case series such as this study. Third, we identified three patients with recurrence of ocular syphilis after treatment. Although it is difficult to completely negate the possibility of reinfection of syphilis, these cases were considered as recurrence, because reinfection of syphilis and progression to ocular syphilis within such a short time period is extremely rare. Furthermore, in two out of three patients, serum RPR titre did not increase to fourfold, which is the diagnostic requirement for reinfection with syphilis.27
We conclude that the prognosis of BCVA in HIV-infected patients with ocular syphilis was favourable after treatment based on its improvement in 89% of the eyes. However, having >28 days of ocular symptoms before diagnosis was associated with poor prognosis, and recurrence could occur without any ocular symptom. We should consider ocular syphilis in the differential diagnosis of uveitis in order to diagnose and treat it early, and also should consider following up ocular findings regularly after treatment. Accumulation of more data is necessary for better understanding of ocular syphilis in patients infected with HIV.
Prognosis of visual acuity in HIV-positive patients with ocular syphilis in the antiretroviral therapy era was generally favourable.
Having more than 28 days of ocular symptoms before diagnosis was associated with poor prognosis.
Impaired visual acuity in HIV-positives should prompt an immediate assessment for ocular syphilis as delays in diagnosis and therapy can lead to irreversible visual loss.
The authors thank all other clinical staff at the AIDS Clinical Center and Department of Ophthalmology for their help in completion of this study.
Handling editor Jackie A Cassell
Contributors MT, TN and SY did the study design and conception. MT, TN, SY, KT, YK, NK, SO and HG collected the data. MT and TN did the data management and the statistical analyses. All authors participated in revising it critically for important intellectual content, and approved the final version for publication.
Funding This work was supported by Grant-in Aids for AIDS research from the Japanese Ministry of Health, Labour, and Welfare (H23-AIDS-001 and H24-AIDS-003).
Competing interests None declared.
Ethics approval The Human Research Ethics Committee of National Center for Global Health and Medicine (NCGM-G-001623-02).
Provenance and peer review Not commissioned; externally peer reviewed.
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