Clinical Features and Incidence Rates of Ocular Complications in Patients With Ocular Syphilis AHMADREZA MORADI, SHERVEEN SALEK, EBENEZER DANIEL, SAPNA GANGAPUTRA, TRUCIAN A. OSTHEIMER, BRYN M. BURKHOLDER, THERESA G. LEUNG, NICHOLAS J. BUTLER, JAMES P. DUNN, AND JENNIFER E. THORNE PURPOSE:
To describe the clinical outcomes of ocular
syphilis. DESIGN: Retrospective chart review. METHODS: The charts of patients with
ocular syphilis (regardless of human immunodeficiency virus [HIV] status) seen in a uveitis referral center between 1984 and 2014 were reviewed. RESULTS: The study included 35 patients (61 eyes). Panuveitis was the most common type of ocular inflammation (28 eyes), independent of HIV status. Thirty-three of 35 patients received systemic antibiotics with 24 patients treated with intravenous (IV) penicillin only. When compared to the HIV-positive patients, HIV-negative patients with ocular syphilis were older (P < .001), were more likely to be female (P [ .004), and had poorer visual acuity at presentation (P [ .01). During follow-up, the incidence rates of visual impairment were 0.29 per eyeyear (EY; 95% confidence interval [CI]: 0.06/EY-0.86/ EY) and 0.12/EY (95% CI: 0.01/EY-0.42/EY) among the HIV-negative and the HIV-positive patients, respectively. The incidence of blindness was 0.07/EY (95% CI: 0.009/EY-0.27/EY) and 0.06/EY (95% CI: 0.002/ EY-0.35/EY) among the HIV-negative and the HIVpositive patients, respectively. Longer duration of uveitis prior to diagnosis and chorioretinitis in the macula at presentation were associated with ‡2 Snellen lines of visual loss (P < .01) and visual acuity loss to 20/50 or worse (P [ .03) in HIV-negative patients, respectively. CONCLUSIONS: Syphilis is an uncommon cause of ocular inflammation in both HIV-negative and HIVpositive patients. Visual loss and ocular complications were common among HIV-negative patients even with Accepted for publication Nov 1, 2014. From the Division of Ocular Immunology, Department of Ophthalmology, Johns Hopkins University School of Medicine (A.M., S.S., E.D., S.G., T.A.O., B.M.B., T.G.L., N.J.B., J.P.D., J.E.T.); and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (J.E.T.), Baltimore, Maryland. Dr Dunn is now practicing at the Wills Eye Institute, Philadelphia, Pennsylvania. Dr Ebenezer is now at Scheie Eye Institute and The Center for Preventive Ophthalmology and Biostatistics, Department of Ophthalmology, at the University of Pennsylvania, Philadelphia, Pennsylvania. Dr Gangaputra is now at the Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin. Inquiries to Ahmadreza Moradi, Division of Ocular Immunology, The Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 North Wolfe Street, Woods Building, Room 476, Baltimore, MD 21287; e-mail: [email protected]
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systemic antibiotic treatment. Delay of diagnosis and chorioretinitis in the macula were associated with visual loss in these patients. (Am J Ophthalmol 2015;159: 334–343. Ó 2015 by Elsevier Inc. All rights reserved.)
A
CQUIRED SYPHILIS IS A CHRONIC SEXUALLY TRANS-
mitted disease caused by the spirochete Treponema pallidum. Any portion of the body may be affected, including the eyes.1 Based on the progression of the infection, acquired syphilis is classified into early (primary, secondary, and early latent) syphilis, late syphilis, and neurosyphilis.2,3 Diagnosis of syphilis is based on medical history, clinical findings, and serologic tests.4,5 The eye is a relatively uncommon site of syphilitic infection. However, almost any portion of the eye may be involved in syphilis, and it may mimic different ocular inflammatory disorders.3,6 Therefore, a high index of clinical suspicion is crucial to the accurate clinical diagnosis.2,3,5-8 Syphilis rarely affects the eyes in the primary stage of infection but may affect the eyes in the secondary stage and, more frequently, in late, latent, and tertiary stages.3,6,9,10 Typically the most common ophthalmic finding in ocular syphilis is panuveitis.6,11 However, additional ocular manifestations have been reported, including anterior uveitis, intermediate uveitis, interstitial keratitis, chorioretinitis, retinal vasculitis, retinitis, perineuritis, papillitis, retrobulbar neuritis, optic atrophy, optic nerve gumma, and various stroke syndromes.2,6,10 Even though co-infection with human immunodeficiency virus (HIV) is a common finding in the setting of ocular syphilis, ocular syphilis may occur in immune competent hosts as well.2,6,7 A PubMed online database search using the following terms: (syphilis OR treponema pallidum) AND (eye OR ocular, iridocyclitis, chorioretinitis, uveitis, retinitis, optic neuritis, OR conjunctivitis) revealed a paucity of published studies on the rate of ocular complications and visual outcomes in eyes with syphilitic uveitis, especially in the HIV-negative population. This retrospective study provides the demographics and ophthalmic manifestations of ocular syphilis, incidence rates of ocular complications, and management of both HIV-positive and HIV-negative patients with ocular syphilis seen at a single tertiary care center.
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antibiotics, ophthalmic antibiotic drops, and the use of topical or periocular corticosteroids.
METHODS STUDY POPULATION:
A retrospective chart review was performed on all patients with ocular syphilis (International Classification of Disease [ICD] codes 090-099) who presented to the Division of Ocular Immunology at the Wilmer Eye Institute of The Johns Hopkins Hospital between 1984 and July 1, 2014. The diagnosis of ocular syphilis was made by a uveitis specialist based on clinical history, ophthalmic findings, imaging, and positive serologic testing. To confirm the diagnosis and exclude other causes of uveitis, all patients had a laboratory examination and imaging studies, which included a chest x-ray, rapid plasma regain (RPR) test, fluorescent treponemal antibody absorption test (FTA-ABS) or microagglutination assay for Treponema pallidum (MHA-TP), lumbar puncture for cerebrospinal fluid (CSF) analysis for venereal disease research laboratory (VDRL), and Lyme antibody test. Additional diagnostic testing, including serologies for toxoplasmosis and viral causes when clinically suspected and polymerase chain reaction (PCR) of anterior chamber or vitreous samples, was performed as clinically indicated. The preservation of data confidentiality was addressed properly during this study, since it was conducted with the approval of The Johns Hopkins University School of Medicine Institutional Review Board (IRB) and in accordance with the principles of the Declaration of Helsinki. Data collection was compliant with the Health Insurance Portability and Accountability Act (HIPAA).
DATA COLLECTION:
Data of all patients evaluated and treated for ocular syphilis, dating to the establishment of the service in 1984, were collected retrospectively from clinical charts and entered into a database for subsequent statistical analysis. These charts use flow sheets that require the treating ophthalmologist to enter specific clinical information on each patient at each visit, as well as clinic notes.12 Other data collected by chart review included demographic features (including age, sex, race, ethnicity, tobacco use, men who have history of sex with men, and intravenous drug use); past medical history (such as diabetes and hypertension); past history of syphilis infection and the duration of infection; and past history of ocular syphilis and the duration of ocular inflammation at presentation. Ophthalmic findings at every visit included visual acuity, intraocular pressure, slit-lamp examination findings, the grade of inflammation in the anterior chamber and in the vitreous, and fundus examination and findings. SUN (standardization of uveitis nomenclature) guidelines were used to classify the ocular inflammation.13 Data on ocular surgeries and procedures were obtained. Syphilis-associated serologic test results (FTA-ABS or MHA-TP 6 RPR 6 CSF VDRL) were documented. Treatment data collected included the route and dose of systemic
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MAIN OUTCOME MEASURES:
Main outcome measures were incidence of visual acuity loss and ocular complications. Visual impairment (defined as decrease in bestcorrected visual acuity to 20/50 or worse) and blindness (defined as decrease to 20/200 or worse) were the 2 main functional visual outcomes in this study. Change in visual acuity was designated based on the gain or loss of 1 or 2 Snellen lines and categorized into groups of stable vision, visual gain, or visual worsening. The incidence rates of structural ocular complications were assessed based on the presence of findings on dilated ophthalmic examination and confirmed by appropriate imaging modalities if clinically indicated. Ocular hypertension was defined as an intraocular pressure (IOP) of greater than 21 mm Hg in an eye _22 mm Hg. The develwith no documented history of IOP > opment of new-onset cataract was defined as the presence of 1þ nuclear sclerosis, 1þ cortical change, or trace posterior subcapsular change seen on clinical examination in an eye in which no cataract had been reported on prior visits.
STATISTICAL ANALYSIS:
The statistical analyses were performed using Stata statistical software (version 10.0, 2007; Stata Corp, College Station, Texas, USA). Demographics and clinical characteristics at presentation were tabulated for study patients and the affected eyes in Tables 1 and 2, respectively. Numerical and categorical variables were compared among HIV-negative and HIVpositive patients/eyes and P values were calculated using t test and x2 (Fisher exact test), respectively. All P values were nominal. Incidence rates for ocular complications were calculated as the number of events divided by the sum of the eye-years (EY) of the at-risk eyes. Poisson 95% confidence intervals (CI) were calculated for the estimated incidence rate of ocular complications during the follow-up period. Regression analyses on possible confounding factors were not performed owing to the small sample size.
RESULTS CLINICAL CHARACTERISTICS OF THE ENTIRE COHORT AT PRESENTATION: Thirty-five patients (61 eyes) met
study criteria and were included in the study (Table 1). These 35 patients comprised 2.25% of 2707 new patients with active ocular inflammation seen during the study period and tested for syphilis. The median age at presentation was 45 years (range 24-80 years). Nine patients were female (25.7%). African-Americans comprised 60% of patients (n ¼ 21); the remainder were white. Smoking data were available for 28 patients and of these, 15 (54%) were current or former smokers. Two of our patients reported a history of intravenous drug use and 9 of the men
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TABLE 1. Demographic and Clinical Characteristics of Patients With Ocular Syphilis at Presentation
Characteristics
Demographics Age, y Mean Median Range Sex, % (n) Female Male Race, % (n) White African-American Smoker, % (n) Never Current Former IVDU, % (n) MSM, % (n) Clinical characteristics Past history of syphilis infection Documented diagnosis of syphilis at presentation Duration of syphilis (y)b Median Range Diagnostic methods Positive FTA-Abs test, % (n) Positive RPR test, % (n) CSF VDRLc Bilateral involvement, % (n) Uveitis duration prior to presentation Median Range Hypertension, % (n) Diabetes mellitus, % (n)
HIV Negative (N ¼ 16)
HIV Positive (N ¼ 19)
Total (N ¼ 35)
60.4 6 17.4 66 32–80
40.2 6 8.2 37 24–60
49.4 6 16.5 45 24–80
P Valuea
_Two Snellen lines improvement in VA
Tamesis et al 19906
Puech et al 201018
Hughes et al 201026
Eandi et al 201225
Yap et al 201419
Li et al 201118
Shalaby et al 199711
Tucker et al 201116
Tran et al 200521,a
25 1020
8 300
13 NR
16d NR
12 NR
13 NR
16 NRc
39 2706
17 2000
100% 62.5% (5) 52 6 11.8
92.3% (12) 46.2% (6) 41.7
87.5% (14) 56.3% (9) 40 (28–57)
91.7% (11) 25% (3) 49.5 (24–84)
60% (15) 40% (2/5)b 51 M: 5 (0.01–51) y F: 14 (0.12–55) y 10 (1–90) NR
3 d–1 y
NR
24 6 7.8 75% (6)
NR 53.8% (7)
29% (5) 0 6% (1) 18% (3) 47% (8) 4% (1) 0 16% (4) 12% (3)
0 0 0 37.5% (3) 25% (2) 0 12.5% (1) 0 25% (2)
0 0 0 0 54% (7) 0 0 0 0
36% 22% 42%
37.5% (3) 0 62.5% (5)
69.2% 19.2% 11.6%
NR NR NR NR 22%
100% (8) 0 0 NR NR
100% (13) 0 0 NR NR
14.2 (4–30) d 2.9 (0.5–8) 46.7% (7)
NR 14.5 (1–73) 50% (6)
NR
53.8% (21) NR 42.7
100% (12) 70.6%
NR
14 (2–21) d
NR 30.7% (4)
3 0
NR NR
7.25 (0.5–34) 33% (4)
38.5% (5) 0 0 23% (3) 30.1% (4) 0 0 0 38.5% (5)
31% (4) 23% (3) 0 0 38% (5) 0 0 0 8% (1)
33.3% (13) 0 2.6% (1) 10.3% (4) 53.8% (21) 0 0 0 0
8.3% (1) 0 0 91.7% (11)
73% (19) 7.7% (2) 19.3% (5)
NR NR NR
35% (7) 30% (6) 35% (7)
83.4% (20) 8.3% (2) 8.3% (2) 75% (12/16 eyes) NR
NR NR NR NR NR
61.1% (11) 27.8% (5) 0 NR 93.7% (15)
33.3% (6) 0 5.6% (1) 27.8% (5) 33.3% (6) 0 0 0 11.1% (2)
59.4% 15.6% 25%
38.8% (7) 50% (9) 11.1% (2)
27.3% 18.2% 54.5%
77.8% (14) 16.7% (3) 5.6% (1) NR NR
90% 10% 0 NR NR
96% (24) 4% (1) 0 NR NR
92.3% (12) 100% 37 NR
12% (3) 0 0 100% (16) 0 0 8% (2) 0 0
HIV ¼ human immunodeficiency virus; N/R ¼ result not reported; VA ¼ visual acuity. This study only described the demographics and clinical characteristics of the 12 HIV-positive patients. b HIV was tested only in 5 patients. c In this study, only HIV infected patients were evaluated and HIV-positive patients with ocular syphilis were included. d Only acute syphilitic posterior placoid chorioretinitis cases. a
100% 100% 38 (23–55)
0 0 0 25% (5)
341
of ocular syphilis.16,17,19 Half of the HIV-negative patients in our study were male and none of them gave a history of sex with men. On the other hand, all but 1 HIV-positive patients were male and 50% of them gave a history of sex with men, which is in accordance with the known risk factor for syphilis in general and ocular syphilis.11,16,18,20,21 Syphilis can involve almost any portion of the eye. Panuveitis comprised the most common type of ocular inflammation in our study (45.9%), which is higher than published reports in HIV-positive patients with ocular syphilis (20%).16 In contrast, optic nerve involvement has been reported in 20%-38% of HIV-positive patients with ocular syphilis but was a very rare finding in our HIV-negative patients.16,18 Finally, 4 eyes (16%) of HIVnegative patients in our study had scleritis, which is an uncommon finding in other reports, as the majority of reports on ocular syphilis focus primarily on intraocular inflammation.11,17-19 Syphilis infection comprised approximately 0.4% of patients with scleritis in our clinical practice.22 Amaratunge and associates reviewed 143 original descriptions of patients with syphilitic uveitis in 41 different papers between 1984 and June 2008. Their findings revealed that isolated anterior uveitis was primarily reported in HIV-positive patients; and only 1 HIVnegative patient had isolated anterior uveitis in the literature.23 Our findings support their results. Hence, presence of anterior uveitis secondary to syphilis should raise the suspicion of HIV infection. Although the median duration of uveitis prior to presentation was 2 months, the range of durations was quite broad (2 weeks to 10 years). The median duration of uveitis prior to presentation was 1 month among HIV-positive patients and 3 months among HIV-negative patients, respectively. Those with longer duration of uveitis appeared to have experienced a greater delay in diagnosis and in institution of treatment for syphilis. This delay may explain the amount of structural ocular complications observed in our HIV-negative series, which was comparable to other studies,5,8,16,21 as well as the poor visual outcome in some of our cases. Indeed, there was a statistically significant delay in diagnosis among HIV-negative eyes that experienced 2 or more lines of visual acuity loss (P ¼ .01). New-onset ocular hypertension during the follow-up period (incidence rate of 0.19/EY) was one of the most common ocular complications during the follow-up among HIV-negative patients. This finding was in support of the previous published studies about the association of ocular syphilis and increase in IOP.24 More than two thirds of the HIV-negative eyes and half of HIV-positive eyes presented to our clinic with visual impairment or blindness, mainly owing to chorioretinitis with macular involvement or structural ocular complications involving the posterior pole. This finding of poor visual acuity at presentation was comparable to other published studies.6,11,17,19
342
During the follow-up period, rates of visual impairment for HIV-negative and HIV-positive patients were 0.29/EY and 0.12/EY, respectively. Rates of legal blindness for HIV-negative and HIV-positive patients were 0.07/EY and 0.06/EY, respectively. Although 87% of eyes observed in this study either maintained or improved in visual acuity, the outcome of vision loss was substantial. Other studies that included HIV-negative patients with ocular syphilis also reported high frequencies of visual loss.25 These data, however, were not rates but frequencies observed over variable follow-up periods, which makes comparison with our series difficult.13 Syphilis was diagnosed in 8 HIV-negative patients (50%) and 13 HIV-positive patients as a result of evaluation of the ocular inflammation by a uveitis specialist. While approximately two thirds of our patients (68%) had a positive RPR test, all of the patients had positive FTA-ABS test result. This finding emphasizes the importance of a high index of clinical suspicion of ocular syphilis in view of unexplained ocular inflammation even with a negative RPR test result. Treatment with penicillin was refused in 1 HIV-negative patient. Initially the patient’s uveitis responded to topical corticosteroid therapy and was followed by an outside ophthalmologist. However, the patient was referred back to our clinic with persistent inflammation, CME, and visual loss to 20/400 in the right eye and 20/100 in the left eye with 16 months follow-up after the initial presentation. Whether institution of penicillin therapy would have improved clinical outcomes is unknown. One HIVpositive patient who had been previously treated for syphilis with IV penicillin was not treated systemically. Four out of 16 HIV-negative patients were treated with immunosuppressive drug therapy during the observation period. Lower rates of CME and blindness were observed in these eyes. However, the development of other ocular complications and visual impairment were similar among eyes not receiving immunosuppressive drug therapy. The role of immunosuppressive drug therapy in these cases requires further study. The main limitations of this study include its retrospective design and relatively small sample size, which limits our ability to control for confounding variables and to perform multiple statistical analyses. Referral bias may also be present, as all patients were seen at a tertiary care medical center. The numbers of ocular complications were low, making the point estimations of individual complication rates less stable and the confidence intervals quite broad. Despite these limitations, we present the incidence rates and 95% confidence intervals of ocular complications to provide a better estimation about the outcomes of ocular syphilis. We hope that this will allow for combining small studies over time to establish more precise rates of complications attributable to ocular syphilis.
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In conclusion, syphilis is an uncommon cause of ocular inflammation. Visual loss, ocular hypertension, epiretinal membrane, and cystoid macular edema were common even with treatment with intravenous penicillin among
the HIV-negative subgroup. Delay in the diagnosis owing to lack of clinical suspicion in patients without high-risk sexual behavior and presence of chorioretinitis in the posterior pole appeared to be associated with poorer visual outcomes.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and the following were reported. Jennifer E. Thorne serves a consultant for Abbvie (North Chicago, Illinois), Gilead (Foster City, California), Navigant (Chicago, Illinois), and XOMA (Berkeley, California). Jennifer E. Thorne has grant funding from the National Eye Institute (Bethesda, Maryland), and Allergan (Irvine, California). None of the sponsors had any role in the design and conduct of the report; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, and approval of this manuscript. The authors indicate no funding support. Contributions of authors: design and conduct of study (A.R.M., S.S.S., E.D., S.G., J.P.D., J.E.T.); collection, management, analysis, and interpretation of data (all authors); preparation of manuscript (A.R.M., S.S.S., J.P.D., J.E.T.); and review and approval of manuscript (all authors).
REFERENCES 1. Lukehart SA. Syphilis. In: Kasper DL, Fauci AS, eds. Harrison’s Infectious Diseases. 2nd ed. USA: Mc Graw Hill; 2010. 2. Margo CE, Hamed LM. Ocular syphilis. Surv Ophthalmol 1992;37(3):203–220. 3. Whitcup SM. Spirochetal diseases. In: Nussenblatt RB, Whitcup SM, eds. Uveitis: Fundamentals and Clinical Practice. 4th ed. China: Mosby Elsevier Inc; 2010:142–160. 4. Maves RC, Cachay ER, Young MA, Fierer J. Secondary syphilis with ocular manifestations in older adults. Clin Infect Dis 2008;46(12):e142–e145. 5. Gass JD, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology 1990; 97(10):1288–1297. 6. Tamesis RR, Foster CS. Ocular syphilis. Ophthalmology 1990; 97(10):1281–1287. 7. Passo MS, Rosenbaum JT. Ocular syphilis in patients with human immunodeficiency virus infection. Am J Ophthalmol 1988;106(1):1–6. 8. Cunningham ET Jr, Eandi CM, Pichi F. Syphilitic uveitis. Ocul Immunol Inflamm 2014;22(1):2–3. 9. Baglivo E, Kapetanios A, Safran AB. Fluorescein and indocyanine green angiographic features in acute syphilitic macular placoid chorioretinitis. Can J Ophthalmol 2003;38(5):401–405. 10. de Souza EC, Jalkh AE, Trempe CL, Cunha S, Schepens CL. Unusual central chorioretinitis as the first manifestation of early secondary syphilis. Am J Ophthalmol 1988;105(3):271–276. 11. Shalaby IA, Dunn JP, Semba RD, Jabs DA. Syphilitic uveitis in human immunodeficiency virus-infected patients. Arch Ophthalmol 1997;115(4):469–473. 12. Thorne JE, Jabs DA, Peters GB, Hair D, Dunn JP, Kempen JH. Birdshot retinochoroidopathy: Ocular complications and visual impairment. Am J Ophthalmol 2005;140(1): 45–51. 13. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol 2005;140(3):509–516. 14. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2012. Atlanta: U.S. Department
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of Health and Human Services, CDC; 2014. Available at: http://www.cdc.gov/std/stats12/default.htm. Accessed September 21, 2014. Barile GR, Flynn TE. Syphilis exposure in patients with uveitis. Ophthalmology 1997;104(10):1605–1609. Tucker JD, Li JZ, Robbins GK, et al. Ocular syphilis among HIV-infected patients: A systematic analysis of the literature. Sex Transm Infect 2011;87(1):4–8. 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. Li JZ, Tucker JD, Lobo AM, et al. Ocular syphilis among HIVinfected individuals. Clin Infect Dis 2010;51(4):468–471. Yap SC, Tan YL, Chio MT, Teoh SC. Syphilitic uveitis in a Singaporean population. Ocul Immunol Inflamm 2014;22(1): 9–14. Yang P, Zhang N, Li F, Chen Y, Kijlstra A. Ocular manifestations of syphilitic uveitis in chinese patients. Retina 2012; 32(9):1906–1914. Tran TH, Cassoux N, Bodaghi B, Fardeau C, Caumes E, Lehoang P. Syphilitic uveitis in patients infected with human immunodeficiency virus. Graefes Arch Clin Exp Ophthalmol 2005;243(9):863–869. Akpek EK, Thorne JE, Qazi FA, Do DV, Jabs DA. Evaluation of patients with scleritis for systemic disease. Ophthalmology 2004;111(3):501–506. Amaratunge BC, Camuglia JE, Hall AJ. Syphilitic uveitis: a review of clinical manifestations and treatment outcomes of syphilitic uveitis in human immunodeficiency virus-positive and negative patients. Clin Experiment Ophthalmol 2010; 38(1):68–74. Reddy S, Cubillan LD, Hovakimyan A, Cunningham ET Jr. Inflammatory ocular hypertension syndrome (IOHS) in patients with syphilitic uveitis. Br J Ophthalmol 2007;91(12): 1610–1612. Eandi CM, Neri P, Adelman RA, Yannuzzi LA, Cunningham ET Jr, International Syphilis Study Group. Acute syphilitic posterior placoid chorioretinitis: report of a case series and comprehensive review of the literature. Retina 2012;32(9):1915–1941. Hughes EH, Guzowski M, Simunovic MP, Hunyor AP, McCluskey P. Syphilitic retinitis and uveitis in HIV-positive adults. Clin Experiment Ophthalmol 2010;38(9):851–856.
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Biosketch Dr Ahmadreza (Reza) Moradi is a Postdoctoral Research Fellow at Johns Hopkins University, School of Medicine. He holds Doctor of Medicine degree from Shahid Beheshti University of Medical Sciences (2009). To become a clinician-scientist practicing in academic ophthalmology and teaching, he has performed clinical research at the Wilmer Eye Institute since 2012. Moradi’s interests and current research projects focus on ocular immunology and diseases of the retina.
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To describe the clinical outcomes of ocular
syphilis. DESIGN: Retrospective chart review. METHODS: The charts of patients with
ocular syphilis (regardless of human immunodeficiency virus [HIV] status) seen in a uveitis referral center between 1984 and 2014 were reviewed. RESULTS: The study included 35 patients (61 eyes). Panuveitis was the most common type of ocular inflammation (28 eyes), independent of HIV status. Thirty-three of 35 patients received systemic antibiotics with 24 patients treated with intravenous (IV) penicillin only. When compared to the HIV-positive patients, HIV-negative patients with ocular syphilis were older (P < .001), were more likely to be female (P [ .004), and had poorer visual acuity at presentation (P [ .01). During follow-up, the incidence rates of visual impairment were 0.29 per eyeyear (EY; 95% confidence interval [CI]: 0.06/EY-0.86/ EY) and 0.12/EY (95% CI: 0.01/EY-0.42/EY) among the HIV-negative and the HIV-positive patients, respectively. The incidence of blindness was 0.07/EY (95% CI: 0.009/EY-0.27/EY) and 0.06/EY (95% CI: 0.002/ EY-0.35/EY) among the HIV-negative and the HIVpositive patients, respectively. Longer duration of uveitis prior to diagnosis and chorioretinitis in the macula at presentation were associated with ‡2 Snellen lines of visual loss (P < .01) and visual acuity loss to 20/50 or worse (P [ .03) in HIV-negative patients, respectively. CONCLUSIONS: Syphilis is an uncommon cause of ocular inflammation in both HIV-negative and HIVpositive patients. Visual loss and ocular complications were common among HIV-negative patients even with Accepted for publication Nov 1, 2014. From the Division of Ocular Immunology, Department of Ophthalmology, Johns Hopkins University School of Medicine (A.M., S.S., E.D., S.G., T.A.O., B.M.B., T.G.L., N.J.B., J.P.D., J.E.T.); and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (J.E.T.), Baltimore, Maryland. Dr Dunn is now practicing at the Wills Eye Institute, Philadelphia, Pennsylvania. Dr Ebenezer is now at Scheie Eye Institute and The Center for Preventive Ophthalmology and Biostatistics, Department of Ophthalmology, at the University of Pennsylvania, Philadelphia, Pennsylvania. Dr Gangaputra is now at the Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin. Inquiries to Ahmadreza Moradi, Division of Ocular Immunology, The Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 North Wolfe Street, Woods Building, Room 476, Baltimore, MD 21287; e-mail: [email protected]
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systemic antibiotic treatment. Delay of diagnosis and chorioretinitis in the macula were associated with visual loss in these patients. (Am J Ophthalmol 2015;159: 334–343. Ó 2015 by Elsevier Inc. All rights reserved.)
A
CQUIRED SYPHILIS IS A CHRONIC SEXUALLY TRANS-
mitted disease caused by the spirochete Treponema pallidum. Any portion of the body may be affected, including the eyes.1 Based on the progression of the infection, acquired syphilis is classified into early (primary, secondary, and early latent) syphilis, late syphilis, and neurosyphilis.2,3 Diagnosis of syphilis is based on medical history, clinical findings, and serologic tests.4,5 The eye is a relatively uncommon site of syphilitic infection. However, almost any portion of the eye may be involved in syphilis, and it may mimic different ocular inflammatory disorders.3,6 Therefore, a high index of clinical suspicion is crucial to the accurate clinical diagnosis.2,3,5-8 Syphilis rarely affects the eyes in the primary stage of infection but may affect the eyes in the secondary stage and, more frequently, in late, latent, and tertiary stages.3,6,9,10 Typically the most common ophthalmic finding in ocular syphilis is panuveitis.6,11 However, additional ocular manifestations have been reported, including anterior uveitis, intermediate uveitis, interstitial keratitis, chorioretinitis, retinal vasculitis, retinitis, perineuritis, papillitis, retrobulbar neuritis, optic atrophy, optic nerve gumma, and various stroke syndromes.2,6,10 Even though co-infection with human immunodeficiency virus (HIV) is a common finding in the setting of ocular syphilis, ocular syphilis may occur in immune competent hosts as well.2,6,7 A PubMed online database search using the following terms: (syphilis OR treponema pallidum) AND (eye OR ocular, iridocyclitis, chorioretinitis, uveitis, retinitis, optic neuritis, OR conjunctivitis) revealed a paucity of published studies on the rate of ocular complications and visual outcomes in eyes with syphilitic uveitis, especially in the HIV-negative population. This retrospective study provides the demographics and ophthalmic manifestations of ocular syphilis, incidence rates of ocular complications, and management of both HIV-positive and HIV-negative patients with ocular syphilis seen at a single tertiary care center.
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antibiotics, ophthalmic antibiotic drops, and the use of topical or periocular corticosteroids.
METHODS STUDY POPULATION:
A retrospective chart review was performed on all patients with ocular syphilis (International Classification of Disease [ICD] codes 090-099) who presented to the Division of Ocular Immunology at the Wilmer Eye Institute of The Johns Hopkins Hospital between 1984 and July 1, 2014. The diagnosis of ocular syphilis was made by a uveitis specialist based on clinical history, ophthalmic findings, imaging, and positive serologic testing. To confirm the diagnosis and exclude other causes of uveitis, all patients had a laboratory examination and imaging studies, which included a chest x-ray, rapid plasma regain (RPR) test, fluorescent treponemal antibody absorption test (FTA-ABS) or microagglutination assay for Treponema pallidum (MHA-TP), lumbar puncture for cerebrospinal fluid (CSF) analysis for venereal disease research laboratory (VDRL), and Lyme antibody test. Additional diagnostic testing, including serologies for toxoplasmosis and viral causes when clinically suspected and polymerase chain reaction (PCR) of anterior chamber or vitreous samples, was performed as clinically indicated. The preservation of data confidentiality was addressed properly during this study, since it was conducted with the approval of The Johns Hopkins University School of Medicine Institutional Review Board (IRB) and in accordance with the principles of the Declaration of Helsinki. Data collection was compliant with the Health Insurance Portability and Accountability Act (HIPAA).
DATA COLLECTION:
Data of all patients evaluated and treated for ocular syphilis, dating to the establishment of the service in 1984, were collected retrospectively from clinical charts and entered into a database for subsequent statistical analysis. These charts use flow sheets that require the treating ophthalmologist to enter specific clinical information on each patient at each visit, as well as clinic notes.12 Other data collected by chart review included demographic features (including age, sex, race, ethnicity, tobacco use, men who have history of sex with men, and intravenous drug use); past medical history (such as diabetes and hypertension); past history of syphilis infection and the duration of infection; and past history of ocular syphilis and the duration of ocular inflammation at presentation. Ophthalmic findings at every visit included visual acuity, intraocular pressure, slit-lamp examination findings, the grade of inflammation in the anterior chamber and in the vitreous, and fundus examination and findings. SUN (standardization of uveitis nomenclature) guidelines were used to classify the ocular inflammation.13 Data on ocular surgeries and procedures were obtained. Syphilis-associated serologic test results (FTA-ABS or MHA-TP 6 RPR 6 CSF VDRL) were documented. Treatment data collected included the route and dose of systemic
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MAIN OUTCOME MEASURES:
Main outcome measures were incidence of visual acuity loss and ocular complications. Visual impairment (defined as decrease in bestcorrected visual acuity to 20/50 or worse) and blindness (defined as decrease to 20/200 or worse) were the 2 main functional visual outcomes in this study. Change in visual acuity was designated based on the gain or loss of 1 or 2 Snellen lines and categorized into groups of stable vision, visual gain, or visual worsening. The incidence rates of structural ocular complications were assessed based on the presence of findings on dilated ophthalmic examination and confirmed by appropriate imaging modalities if clinically indicated. Ocular hypertension was defined as an intraocular pressure (IOP) of greater than 21 mm Hg in an eye _22 mm Hg. The develwith no documented history of IOP > opment of new-onset cataract was defined as the presence of 1þ nuclear sclerosis, 1þ cortical change, or trace posterior subcapsular change seen on clinical examination in an eye in which no cataract had been reported on prior visits.
STATISTICAL ANALYSIS:
The statistical analyses were performed using Stata statistical software (version 10.0, 2007; Stata Corp, College Station, Texas, USA). Demographics and clinical characteristics at presentation were tabulated for study patients and the affected eyes in Tables 1 and 2, respectively. Numerical and categorical variables were compared among HIV-negative and HIVpositive patients/eyes and P values were calculated using t test and x2 (Fisher exact test), respectively. All P values were nominal. Incidence rates for ocular complications were calculated as the number of events divided by the sum of the eye-years (EY) of the at-risk eyes. Poisson 95% confidence intervals (CI) were calculated for the estimated incidence rate of ocular complications during the follow-up period. Regression analyses on possible confounding factors were not performed owing to the small sample size.
RESULTS CLINICAL CHARACTERISTICS OF THE ENTIRE COHORT AT PRESENTATION: Thirty-five patients (61 eyes) met
study criteria and were included in the study (Table 1). These 35 patients comprised 2.25% of 2707 new patients with active ocular inflammation seen during the study period and tested for syphilis. The median age at presentation was 45 years (range 24-80 years). Nine patients were female (25.7%). African-Americans comprised 60% of patients (n ¼ 21); the remainder were white. Smoking data were available for 28 patients and of these, 15 (54%) were current or former smokers. Two of our patients reported a history of intravenous drug use and 9 of the men
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TABLE 1. Demographic and Clinical Characteristics of Patients With Ocular Syphilis at Presentation
Characteristics
Demographics Age, y Mean Median Range Sex, % (n) Female Male Race, % (n) White African-American Smoker, % (n) Never Current Former IVDU, % (n) MSM, % (n) Clinical characteristics Past history of syphilis infection Documented diagnosis of syphilis at presentation Duration of syphilis (y)b Median Range Diagnostic methods Positive FTA-Abs test, % (n) Positive RPR test, % (n) CSF VDRLc Bilateral involvement, % (n) Uveitis duration prior to presentation Median Range Hypertension, % (n) Diabetes mellitus, % (n)
HIV Negative (N ¼ 16)
HIV Positive (N ¼ 19)
Total (N ¼ 35)
60.4 6 17.4 66 32–80
40.2 6 8.2 37 24–60
49.4 6 16.5 45 24–80
P Valuea
_Two Snellen lines improvement in VA
Tamesis et al 19906
Puech et al 201018
Hughes et al 201026
Eandi et al 201225
Yap et al 201419
Li et al 201118
Shalaby et al 199711
Tucker et al 201116
Tran et al 200521,a
25 1020
8 300
13 NR
16d NR
12 NR
13 NR
16 NRc
39 2706
17 2000
100% 62.5% (5) 52 6 11.8
92.3% (12) 46.2% (6) 41.7
87.5% (14) 56.3% (9) 40 (28–57)
91.7% (11) 25% (3) 49.5 (24–84)
60% (15) 40% (2/5)b 51 M: 5 (0.01–51) y F: 14 (0.12–55) y 10 (1–90) NR
3 d–1 y
NR
24 6 7.8 75% (6)
NR 53.8% (7)
29% (5) 0 6% (1) 18% (3) 47% (8) 4% (1) 0 16% (4) 12% (3)
0 0 0 37.5% (3) 25% (2) 0 12.5% (1) 0 25% (2)
0 0 0 0 54% (7) 0 0 0 0
36% 22% 42%
37.5% (3) 0 62.5% (5)
69.2% 19.2% 11.6%
NR NR NR NR 22%
100% (8) 0 0 NR NR
100% (13) 0 0 NR NR
14.2 (4–30) d 2.9 (0.5–8) 46.7% (7)
NR 14.5 (1–73) 50% (6)
NR
53.8% (21) NR 42.7
100% (12) 70.6%
NR
14 (2–21) d
NR 30.7% (4)
3 0
NR NR
7.25 (0.5–34) 33% (4)
38.5% (5) 0 0 23% (3) 30.1% (4) 0 0 0 38.5% (5)
31% (4) 23% (3) 0 0 38% (5) 0 0 0 8% (1)
33.3% (13) 0 2.6% (1) 10.3% (4) 53.8% (21) 0 0 0 0
8.3% (1) 0 0 91.7% (11)
73% (19) 7.7% (2) 19.3% (5)
NR NR NR
35% (7) 30% (6) 35% (7)
83.4% (20) 8.3% (2) 8.3% (2) 75% (12/16 eyes) NR
NR NR NR NR NR
61.1% (11) 27.8% (5) 0 NR 93.7% (15)
33.3% (6) 0 5.6% (1) 27.8% (5) 33.3% (6) 0 0 0 11.1% (2)
59.4% 15.6% 25%
38.8% (7) 50% (9) 11.1% (2)
27.3% 18.2% 54.5%
77.8% (14) 16.7% (3) 5.6% (1) NR NR
90% 10% 0 NR NR
96% (24) 4% (1) 0 NR NR
92.3% (12) 100% 37 NR
12% (3) 0 0 100% (16) 0 0 8% (2) 0 0
HIV ¼ human immunodeficiency virus; N/R ¼ result not reported; VA ¼ visual acuity. This study only described the demographics and clinical characteristics of the 12 HIV-positive patients. b HIV was tested only in 5 patients. c In this study, only HIV infected patients were evaluated and HIV-positive patients with ocular syphilis were included. d Only acute syphilitic posterior placoid chorioretinitis cases. a
100% 100% 38 (23–55)
0 0 0 25% (5)
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of ocular syphilis.16,17,19 Half of the HIV-negative patients in our study were male and none of them gave a history of sex with men. On the other hand, all but 1 HIV-positive patients were male and 50% of them gave a history of sex with men, which is in accordance with the known risk factor for syphilis in general and ocular syphilis.11,16,18,20,21 Syphilis can involve almost any portion of the eye. Panuveitis comprised the most common type of ocular inflammation in our study (45.9%), which is higher than published reports in HIV-positive patients with ocular syphilis (20%).16 In contrast, optic nerve involvement has been reported in 20%-38% of HIV-positive patients with ocular syphilis but was a very rare finding in our HIV-negative patients.16,18 Finally, 4 eyes (16%) of HIVnegative patients in our study had scleritis, which is an uncommon finding in other reports, as the majority of reports on ocular syphilis focus primarily on intraocular inflammation.11,17-19 Syphilis infection comprised approximately 0.4% of patients with scleritis in our clinical practice.22 Amaratunge and associates reviewed 143 original descriptions of patients with syphilitic uveitis in 41 different papers between 1984 and June 2008. Their findings revealed that isolated anterior uveitis was primarily reported in HIV-positive patients; and only 1 HIVnegative patient had isolated anterior uveitis in the literature.23 Our findings support their results. Hence, presence of anterior uveitis secondary to syphilis should raise the suspicion of HIV infection. Although the median duration of uveitis prior to presentation was 2 months, the range of durations was quite broad (2 weeks to 10 years). The median duration of uveitis prior to presentation was 1 month among HIV-positive patients and 3 months among HIV-negative patients, respectively. Those with longer duration of uveitis appeared to have experienced a greater delay in diagnosis and in institution of treatment for syphilis. This delay may explain the amount of structural ocular complications observed in our HIV-negative series, which was comparable to other studies,5,8,16,21 as well as the poor visual outcome in some of our cases. Indeed, there was a statistically significant delay in diagnosis among HIV-negative eyes that experienced 2 or more lines of visual acuity loss (P ¼ .01). New-onset ocular hypertension during the follow-up period (incidence rate of 0.19/EY) was one of the most common ocular complications during the follow-up among HIV-negative patients. This finding was in support of the previous published studies about the association of ocular syphilis and increase in IOP.24 More than two thirds of the HIV-negative eyes and half of HIV-positive eyes presented to our clinic with visual impairment or blindness, mainly owing to chorioretinitis with macular involvement or structural ocular complications involving the posterior pole. This finding of poor visual acuity at presentation was comparable to other published studies.6,11,17,19
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During the follow-up period, rates of visual impairment for HIV-negative and HIV-positive patients were 0.29/EY and 0.12/EY, respectively. Rates of legal blindness for HIV-negative and HIV-positive patients were 0.07/EY and 0.06/EY, respectively. Although 87% of eyes observed in this study either maintained or improved in visual acuity, the outcome of vision loss was substantial. Other studies that included HIV-negative patients with ocular syphilis also reported high frequencies of visual loss.25 These data, however, were not rates but frequencies observed over variable follow-up periods, which makes comparison with our series difficult.13 Syphilis was diagnosed in 8 HIV-negative patients (50%) and 13 HIV-positive patients as a result of evaluation of the ocular inflammation by a uveitis specialist. While approximately two thirds of our patients (68%) had a positive RPR test, all of the patients had positive FTA-ABS test result. This finding emphasizes the importance of a high index of clinical suspicion of ocular syphilis in view of unexplained ocular inflammation even with a negative RPR test result. Treatment with penicillin was refused in 1 HIV-negative patient. Initially the patient’s uveitis responded to topical corticosteroid therapy and was followed by an outside ophthalmologist. However, the patient was referred back to our clinic with persistent inflammation, CME, and visual loss to 20/400 in the right eye and 20/100 in the left eye with 16 months follow-up after the initial presentation. Whether institution of penicillin therapy would have improved clinical outcomes is unknown. One HIVpositive patient who had been previously treated for syphilis with IV penicillin was not treated systemically. Four out of 16 HIV-negative patients were treated with immunosuppressive drug therapy during the observation period. Lower rates of CME and blindness were observed in these eyes. However, the development of other ocular complications and visual impairment were similar among eyes not receiving immunosuppressive drug therapy. The role of immunosuppressive drug therapy in these cases requires further study. The main limitations of this study include its retrospective design and relatively small sample size, which limits our ability to control for confounding variables and to perform multiple statistical analyses. Referral bias may also be present, as all patients were seen at a tertiary care medical center. The numbers of ocular complications were low, making the point estimations of individual complication rates less stable and the confidence intervals quite broad. Despite these limitations, we present the incidence rates and 95% confidence intervals of ocular complications to provide a better estimation about the outcomes of ocular syphilis. We hope that this will allow for combining small studies over time to establish more precise rates of complications attributable to ocular syphilis.
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In conclusion, syphilis is an uncommon cause of ocular inflammation. Visual loss, ocular hypertension, epiretinal membrane, and cystoid macular edema were common even with treatment with intravenous penicillin among
the HIV-negative subgroup. Delay in the diagnosis owing to lack of clinical suspicion in patients without high-risk sexual behavior and presence of chorioretinitis in the posterior pole appeared to be associated with poorer visual outcomes.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and the following were reported. Jennifer E. Thorne serves a consultant for Abbvie (North Chicago, Illinois), Gilead (Foster City, California), Navigant (Chicago, Illinois), and XOMA (Berkeley, California). Jennifer E. Thorne has grant funding from the National Eye Institute (Bethesda, Maryland), and Allergan (Irvine, California). None of the sponsors had any role in the design and conduct of the report; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, and approval of this manuscript. The authors indicate no funding support. Contributions of authors: design and conduct of study (A.R.M., S.S.S., E.D., S.G., J.P.D., J.E.T.); collection, management, analysis, and interpretation of data (all authors); preparation of manuscript (A.R.M., S.S.S., J.P.D., J.E.T.); and review and approval of manuscript (all authors).
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Biosketch Dr Ahmadreza (Reza) Moradi is a Postdoctoral Research Fellow at Johns Hopkins University, School of Medicine. He holds Doctor of Medicine degree from Shahid Beheshti University of Medical Sciences (2009). To become a clinician-scientist practicing in academic ophthalmology and teaching, he has performed clinical research at the Wilmer Eye Institute since 2012. Moradi’s interests and current research projects focus on ocular immunology and diseases of the retina.
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