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: amoradi1@jhmi.edu
0002-9394/$36.00
http://dx.doi.org/10.1016/j.ajo.2014.10.030

2015 BY

systemic antibiotic treatment. Delay of diagnosis and

chorioretinitis in the macula were associated with visual
loss in these patients. (Am J Ophthalmol 2014;-:
--. 2015 by Elsevier Inc. All rights reserved.)

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.

ELSEVIER INC. ALL

RIGHTS RESERVED.

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

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
1 nuclear sclerosis, 1 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 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

AMERICAN JOURNAL OF OPHTHALMOLOGY

--- 2014

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 16)

HIV Positive
(N 19)

Total
(N 35)

60.4 6 17.4
66
3280

40.2 6 8.2
37
2460

49.4 6 16.5
45
2480

P Valuea

<.01

50% (8)
50% (8)

5.3% (1)
94.7% (18)

25.7% (9)
74.3% (26)

<.01

31.2% (5)
68.8% (11)

47.4% (9)
52.6% (10)

40% (14)
60% (21)

.26

62.5% (10)
6.3% (1)
31.2% (5)
0
0

25% (3/12)
75% (9/12)
0
11.1% (2/18)
50% (9/18)

46.4% (13/28)
35.7% (10/28)
17.9% (5/28)
5.9% (2/34)
25.7% (9)

.27
<.01

25% (4)
50% (8)

36.8% (7)
30.8% (4/13)

31.4% (11)
41.4% (12/29)

.35
.25

7.5 years
1 month55 years

13 month
4 months4 years

4 years
1 month55 years

100% (16)
31.3% (5)
0% (0/5)
62.5% (10)

100% (19)
100% (18/18)
66.7% (8/12)
84.2% (16)

100% (35)
67.6% (23/34)
47.1% (8/17)
74.3% (26)

3 months
2 weeks10 years
31.3% (5)
18.8% (3)

1 month
2 weeks6 months
23% (3/13)
7.7% (1)

2 months
2 weeks10 years
27.6% (8/29)
13.8% (4)

<.01

<.01
.36

.62
.39

CSF cerebrospinal fluid; FTA-Abs fluorescent treponemal antibody absorption; HIV human immunodeficiency virus; IVDU
intravenous drug use; MSM men sex with men; RPR rapid plasma reagin; VDRL Venereal Disease Research Laboratory.
a
P values were calculated using t test, Fisher exact, or 1-sided Fisher exact test.
b
Only 8 patients had confirmed diagnosis of syphilis at presentation.
c
Only tested in 2 patients.

had history of sex with men. Three quarters of the patients

had bilateral disease (74.3%, n 26). FTA-ABS was positive in all of the patients while RPR was only positive in
two thirds of the patients (67.6%, n 23).
The median duration of ocular inflammation at the time
of initial visit to our clinics was 2 months (range 2 weeks to
10 years). Twenty-two eyes had anterior uveitis. The anterior uveitis was isolated in 10 eyes (16.4%), and 12 eyes had
anterior and intermediate uveitis (19.7%). Two eyes had
isolated intermediate uveitis (3.3%), 5 eyes had posterior
uveitis (2 eyes had acute syphilitic posterior placoid
chorioretinitis) (8.2%), 28 eyes (45.9%) had panuveitis,
and 4 eyes had scleritis (6.5%). Presence of 0.5 cells or
VOL. -, NO. -

more in the anterior chamber or vitreous was detected in

45.5% (n 25/48) and 39.1% (n 18/46) of eyes, respectively. A total of 27.3% (n 12/44) of eyes presented with
vitreous haze grade 1 or more.
At the time of presentation, the prevalence of visual
impairment and visual loss was 27.9% (n 17) and 21.3%
(n 13), respectively (Table 2). Two eyes had IOP greater
than 21 mm Hg, and 2 eyes had initial IOP of less than 5 mm
Hg. All but 2 eyes were phakic. Twenty-five of 47 phakic
eyes (53.2%) had cataract at their initial visit. At the initial
visit, cataract was the most common ocular complication
(53.2%, n 25/47), followed by chorioretinitis (35.6%,
n 21). Posterior synechiae was the third most common

CLINICAL OUTCOMES IN OCULAR SYPHILIS

TABLE 2. Clinical Characteristics of Eyes With Ocular Syphilis at Presentation

HIV Negative
(N 26)

Clinical Characteristics

Visual acuity, % (n)

20/40 or better
<
_20/50 to 20/200
20/200 or worse
IOP, mm Hg
Median
Range
Anatomic location of ocular inflammation, % (n)
Anterior uveitis
Anterior intermediate uveitis
Intermediate uveitis
Posterior uveitis
Panuveitis
Scleritis
Frequency of lens opacities in phakic eyes, % (n)
Nuclear sclerosis
0
1
2
3
4
Cortical change
0
1
2
3
4
Posterior subcapsular cataract
0
0.5
1
2
3
4
Activity of uveitis, % (n)
AC cells (>0.5)
Vitreous cells (>0.5)
_1)
Vitreous haze (>
Cup-to-disc ratio (n 28)
Median
Range

HIV Positive
(N 35)

30.8% (8)
46.2% (12)
23% (6)

65.7% (23)
14.3% (5)
20% (7)

14
328

14
222

3.8% (1)
15.4% (4)
7.7% (2)
3.9% (1)
53.8% (14)
15.4% (4)

Total
(N 61)

50.8% (31)
27.9% (17)
21.3% (13)

P Valuea

.01

14
228
<.01

25.7% (9)
22.9% (8)
0
11.4% (4)
40% (14)
0

16.4% (10)
19.7% (12)
3.3% (2)
8.2% (5)
45.9% (28)
6.5% (4)

32% (8/25)
12% (3/25)
32% (8/25)
0
24% (6/25)

71.4% (15/21)
14.3% (3/21)
14.3% (3/21)
0
0

50% (23/46)
13% (6/46)
23.9% (11/46)
0
13.1% (6/46)

.01

72% (18/25)
4% (1/25)
0
0
24% (6/25)

100% (21/21)
0
0
0
0

84.8% (39/46)
2.2% (1/46)
0
0
13% (6/46)

.01

60% (15/25)
4% (1/25)
8% (2/25)
4% (1/25)
0
24% (6/25)

95.2% (20/21)
4.8% (1/21)
0
0
0
0

76.1% (35/46)
4.3% (2/46)
4.4% (2/46)
2.2% (1/46)
0
13% (6/46)

.01

46.2% (12/26)
44% (11/26)
38.5% (10/26)

59.1% (13/22)
35% (7/20)
11.1% (2/18)

45.5% (25/48)
39.1% (18/46)
27.3% (12/44)

.5
.06
.08

0.25
0.11

0.3
0.10.5

0.275
0.11
Continued on next page

finding in the affected eyes (n 13), followed by optic nerve

involvement (n 8), retinal detachment (n 4), epiretinal
membrane (n 2), cystoid macular edema (CME) (n 2),
posterior vitreous detachment (n 1), intraretinal hemorrhage (n 1), and glaucoma (n 1). No eyes presented
with choroidal neovascularization.
The treatment regimens are summarized in Table 3. Two
patients had been treated previously with intravenous (IV)
penicillin benzathine G, 6 patients with intramuscular
(IM) penicillin benzathine G, and 1 patient with IM peni4

cillin subsequent to IV penicillin. Two patients were

receiving treatment with oral corticosteroids (15-20 mg/
day) at the time of presentation. One patient was being
treated with immunosuppressive drug therapy at presentation (Table 3).

FOLLOW-UP DATA:

Follow-up data were available for 31

patients (54 eyes) with a median of 5 follow-up visits at our
clinics (range: 2-24 visits). Median duration of follow-up
time was 9 months (range: 1 week to 4.4 years).

AMERICAN JOURNAL OF OPHTHALMOLOGY

--- 2014

TABLE 2. Clinical Characteristics of Eyes With Ocular Syphilis at Presentation (Continued )

Clinical Characteristics

Ocular complications
Cataract
Pseudophakia
Posterior synechiae
Chorioretinitis
Cystoid macular edema
Retinal detachment
Optic nerve involvementb
Ocular HTN (IOP >21 mm Hg)
Hypotony (IOP <5 mm Hg)
Glaucoma
Choroidal neovascularization
Epiretinal membrane

HIV Negative
(N 26)

HIV Positive
(N 35)

Total
(N 61)

69.2% (18/26)
3.8% (1/26)
32% (8/26)
38.5% (10)
7.7% (2/26)
7.7% (2)
3.8% (1)
3.8% (1)
3.8% (1)
4% (1)
0
0

33.3% (7/21)
3% (1/21)
45.5% (5/12)
33.3% (11)
0 (0/21)
6% (2)
21.2% (7)
4.5% (1/22)
4.5% (1/22)
0
0
4.8% (2/21)

53.2% (25/47)
3.6% (2/47)
34.2% (13/38)
35.6% (21)
4.3% (2/47)
6.8% (4)
13.56% (8)
4.2% (2/48)
4.2% (2/48)
1.8% (1)
0
4.4% (2/46)

P Valuea

.02

.06

AC anterior cell; HIV human immunodeficiency virus; HTN hypertension; IOP intraocular pressure.
P values were calculated using Fisher exact or 1-sided Fisher exact test.
b
Includes optic neuritis, optic atrophy, and optic disc swelling.
a

All but 2 patients were treated with systemic antibiotics during follow-up. Twenty-four patients were treated
with IV penicillin only (12-24 million units per day for
10-14 days), 7 patients were treated with IM penicillin
subsequent to IV penicillin therapy, 1 patient was treated
with IM penicillin only, and 1 patient received IV ceftriaxone sodium (2 g/day for 10 days). One of them had been
previously treated for syphilis with IV penicillin, and 1
was not retreated with penicillin therapy owing to
improvement on empiric corticosteroid therapy alone;
thus further treatment with penicillin was deferred. Treatment with oral corticosteroids and immunosuppressive
drugs was part of the treatment regimen in 9 and 4
patients, respectively.
Half of the eyes (n 31, 50.8%) had initial visual acuity
of 20/40 or better. Eighteen eyes (one third of the eyes
with available follow-up data) demonstrated an improvement in visual acuity of at least 2 lines by the time of
last observation. More than half of the eyes had stable visual acuity and 7 eyes (13%) demonstrated a drop in visual
acuity of at least 2 lines during the course of follow-up
(Table 3).

HIV-NEGATIVE VS HIV-POSITIVE PATIENTS:

Nineteen
out of 35 patients were HIV co-infected. Comparing the
HIV-positive with HIV-negative patients revealed that
HIV-positive patients were statistically significantly younger
than those in the HIV-negative group (mean age 40.2 vs
60.4, P < .01). Half of the HIV-negative patients were female and all but 1 of the HIV-positive patients was male
(P < .01). History of smoking, IV drug use, and men with
history of sex with men (MSM) was significantly more prevalent among HIV-positive patients compared with HIV-

VOL. -, NO. -

negative patients. The median time from the initiation of

ocular symptoms to the time patients presented to the uveitis
clinic was 1 month for HIV-negative patients and 3 months
for HIV-positive patients (Table 1).
More than two thirds of eyes of the HIV-positive patients
had initial visual acuity of 20/40 or better (65.76%, n 23)
and less than one third of eyes of HIV-negative patients had
initial visual acuity of 20/40 or better (n 8, P .01).
There was a statistically significant difference in the type
of ocular inflammation among eyes of HIV-positive and
HIV-negative patients (P < .01). Panuveitis was the most
common type of ocular inflammation among our cohort
regardless of the HIV status. Anterior uveitis (isolated or
associated with intermediate uveitis) was observed in about
half of the HIV-positive patients (n 17). However, it
comprised less than 20% of ocular inflammation in
HIV-negative patients (n 4). Comparing the ocular
complications at presentation showed that cataract was
more common in the HIV-negative group (69.2%, n 18
vs 33.3%, n 7, P .02). Optic nerve involvement
(including optic neuritis, optic atrophy, and optic disc
swelling) occurred more frequently in the HIV-positive
patients (n 7 vs n 1, P .06).
Seven out of 19 HIV-positive patients had previously been
treated for syphilis, 4 with IM penicillin only, 2 with IV penicillin only, and 1 with IM penicillin subsequent to IV penicillin. On the other hand, only 2 of the HIV-negative
patients had been previously treated with IM penicillin
only. None of the HIV-positive patients received oral corticosteroids or immunosuppressive drug therapy during the
observed follow-up period. However, 2 HIV-negative patients
had previously been treated with oral corticosteroids and 1 patient had previously been treated with immunosuppressive

CLINICAL OUTCOMES IN OCULAR SYPHILIS

TABLE 3. Summary of Treatment Regimens and Changes in Visual Acuity of Patients/Eyes With Ocular Syphilis at Presentation and
During the Follow-Up
At Presentation

Treatment, % (n)
IM PCN only
IV PCN only
IV IM PCN
IV CTX
No PCN
Oral corticosteroids
IMT

During the F/U

HIV Negative

HIV Positive

Total

HIV Negative

HIV Positive

Total

(n 16)

(n 19)

(n 35)

(n 16)

(n 19)

(n 35)

12.5% (2)
0
0
0
87.5% (14)
12.5% (2)
6.25% (1)

21.1% (4)
10.5% (2)
5.3% (1)
0
63.2% (12)
0
0

17.1% (6)
5.7% (2)
2.9% (1)
0
74.3% (26)
5.7% (2)
2.9% (1)

6.25% (1)
62.5% (10)
25% (4)
0
6.2% (1)
56.2% (9)
25% (4)

0
73.7% (14)
15.8% (3)
5.3% (1)
5.2% (1)
0
0

2.9% (1)
68.6% (24)
20% (7)
2.9% (1)
5.7% (2)
25.7% (9)
11.4% (4)

At Presentation

Visual acuity, % (n)

20/40 or better
<
_20/50 to 20/200
20/200 or worse
Change in VA by 2 lines, % (n)
Stable
Gain (at least 2 lines gain)
Worse (at least 2 lines drop)

Vision at Last Visit

HIV-Negative Eyes
(n 26)

HIV-Positive Eyes
(n 35)

Total
(n 61)

30.8% (8)
46.2% (12)
23% (6)

65.7% (23)
14.3% (5)
20% (7)

50.8% (31)
27.9% (17)
21.3% (13)

HIV-Negative
Eyes (n 22)

HIV-Positive Eyes
(n 32)

Total
(n 54)

52% (12)
33% (7)
14% (3)

75% (24)
12.5% (4)
12.5% (4)

66.7% (36)
20.3% (11)
13% (7)

50% (11)
36.4% (8)
13.6% (3)

56.2% (18)
31.3% (10)
12.5% (4)

53.7% (29)
33.3% (18)
13% (7)

CTX ceftriaxone sodium; F/U follow-up; HIV human immunodeficiency virus; IM intramuscular; IMT immunomodulatory treatment
(including methotrexate, mycophenolate mofetil, cyclophosphamide, and cyclosporine); IV intravenous; PCN penicillin G benzathine;
VA visual acuity.

drugs. During the follow-up, 9 HIV-negative patients received

oral corticosteroids, and 4 patients received immunomodulatory treatment (including methotrexate, mycophenolate
mofetil, cyclosporine, and cyclophosphamide).

INCIDENCE RATES OF OCULAR COMPLICATIONS AND OF
VISUAL LOSS: Incidence rates for visual loss and structural

ocular complications are summarized in Table 4. In affected

eyes with follow-up, the incidence rate of visual impairment to 20/50 or worse was 0.29/EY (95% CI: 0.06/EY0.86/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 rate of visual loss to 20/200 or worse
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 HIV-positive patients, respectively.
Among the HIV-negative patients, 3 out of 6 eyes with
visual acuity of 20/40 or better at presentation dropped to
the 20/50-20/200 level during the follow-up period. Visual
impairment was permanent in 1 eye and reversible in the
other 2 eyes. In these 2 eyes, visual acuity returned to 20/
40 and 20/30 over the follow-up period of 3 and 9 months,
_2 Snellen lines visual loss,
respectively. In the 3 eyes with >
the mean duration of uveitis at presentation, prior to diagnosis of syphilis, was 12 months. This was higher than the
mean duration of uveitis prior to diagnosis among eyes with
visual acuity that was stable or improved (3 months, P
6

.01). Eyes with active chorioretinitis had higher rates of visual impairment when compared to eyes without chorioretinitis (1.26/EY vs 0.12/EY, P .03). However, rates of
blindness were not significantly different. Use of immunosuppressive drug therapy occurred in a minority of patients
(n 4). Eyes of patients receiving immunosuppressive drug
therapy had lower rates of blindness when compared to eyes
of patients not receiving immunosuppression. However,
the rates of visual impairment were similar between the 2
groups.
Six eyes developed new-onset ocular hypertension during the follow-up period with an incidence rate of 0.20/EY
(95% CI: 0.07/EY-0.43/EY). Six eyes developed epiretinal
membrane (incidence rate 0.21/EY; 95% CI: 0.07/
EY-0.45/EY). Three eyes developed new-onset CME
(incidence rate 0.11/EY; 95% CI: 0.02/EY-0.31/EY).
One eye developed chorioretinitis (incidence rate
0.04/EY; 95% CI: 0.001/EY-0.24/EY). One eye developed
ocular hypertension (incidence rate 0.03/EY; 95% CI:
0.0007/EY-0.16/EY). No eyes developed new cataract,
posterior synechiae, retinal detachment, optic neuropathy, choroidal neovascularization, or hypotony during
the follow-up course. Based on the available data, no additional structural ocular complications were observed
among HIV-positive patients treated with penicillin in
this cohort during follow-up.

AMERICAN JOURNAL OF OPHTHALMOLOGY

--- 2014

TABLE 4. Incidence Rate of Ocular Complications in Eyes With Ocular Syphilis During the Follow-up Period
HIV-Negative Eyes

Ocular Complications

_20/50 to
Visual impairment (VA drop to <
20/200)
Legal blindness (VA drop to 20/200 or
worse)
Ocular HTN (IOP >21 mm Hg)
Hypotony (IOP <5 mm Hg)
CNV
CME development
Optic nerve involvement
Retinal detachment
Chorioretinitis
ERM
Glaucoma
Posterior synechiae
Cataract

Number
at Risk

HIV-Positive Eyes
Number at
Risk

Number
of Events

Incidence
Ratea

0.060.86

21

0.12

0.010.42

0.07

0.0090.27

26

0.06

0.0020.35

0.19
0
0
0.11
0
0
0.04
0.2
0.03
0
0

0.070.42
N/A
N/A
0.020.31
N/A
N/A
0.0010.24
0.070.45
0.00070.16
N/A
N/A

21
21
32
21
25
30
21
19
31
7
14

0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0

Number
of Events

Incidence
Ratea

0.29

17

21
21
22
20
21
20
13
22
21
16
6

6
0
0
3
0
0
1
6
1
0
0

Poisson Exact
CI 95%

Poisson Exact
CI 95%

N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A

CI confidence interval; CME cystoid macular edema; CNV choroidal neovascularization; ERM epiretinal membrane; HIV human
immunodeficiency virus; HTN hypertension; IOP intraocular pressure; N/A not applicable; VA visual acuity.
a
Per eye-year.

DISCUSSION
SYPHILIS IS AN UNCOMMON INFECTIOUS DISEASE IN THE

United States. However, there appears to be a recent

reemergence of syphilis in the United States.14 There has
been a sharp and significant increase in the incidence of
primary and secondary syphilis infection each year from
2001 through 2009.14 The Baltimore-Towson metropolitan statistical area had the fifth-highest rate of reported
cases of primary and secondary syphilis in 2012 (11.2 rate
per 100 000 population, 307 reported cases) compared
with other metropolitan areas in the United States. Moreover, syphilis is frequently found in association with HIV
infection, and Baltimore has the third-highest rate of
HIV co-infection in MSM who present with primary or secondary syphilis to the Sexually Transmitted Disease (STD)
Surveillance Network clinics in the United States.14 The
high rate of co-infection is attributable to similar risk factors for contracting the 2 diseases.6,15,16 Although ocular
syphilis is uncommon and typically presents in the latelatent and tertiary phases of the infection, lack of treatment
of primary or secondary syphilis could result in high prevalence rates of late-latent and tertiary syphilis and therefore
increased number of cases of ocular syphilis. Furthermore,
syphilitic eye disease may occur in immune competent individuals and outcomes in these patients have been less
commonly reported. Since delay in diagnosis of ocular
syphilis could result in poorer clinical outcomes, it is important to consider ocular syphilis in the differential diagnosis
of ocular inflammation.
VOL. -, NO. -

Syphilis has been reported to account for 1%-5% of the

ocular inflammation cases in tertiary referral centers in the
United States.6,11,15 The 35 cases presenting to our tertiary
center with ocular syphilis over 3 decades confirms the
rarity of ocular syphilis even in an area with a high
incidence of syphilis infection in the United States.
However, it also highlights the importance of raising
clinical suspicion of syphilis in view of unexplained
decreased vision in patients with ocular inflammation
and ordering the appropriate laboratory tests (eg, FTAABS) in those settings. In our center, ocular syphilis
accounted for 2.25% of the 2707 new patients presenting
with ocular inflammation, which is comparable to the previous studies (Table 5).6,11,17
The median age of patients with ocular syphilis differed
according to HIV status, with HIV-negative patients being
statistically significantly older than the HIV-positive patients (median age 66 years vs 37 years old, respectively).
The median age of the HIV-positive patients in our study
is comparable with other published cases in the literature.16,18 It is possible that the HIV-negative patients
with ocular syphilis may have been asymptomatic at the
time of their original exposure to syphilis or they may
considered themselves to be at low risk of acquiring syphilis. In addition, clinicians may be less likely to consider a
diagnosis of syphilis in this age group, especially in the
absence of obvious risk factors, leading to prolonged
chronic infection and an increased risk for ocular involvement later in life.4 The frequency of bilateral disease in our
study (74.3%) was higher than previously published reports

CLINICAL OUTCOMES IN OCULAR SYPHILIS

8
TABLE 5. Summary of Ocular Complications and Visual Outcomes of Patients With Ocular Syphilis During Follow-up in Some of the Noted Studies

AMERICAN JOURNAL OF OPHTHALMOLOGY

Number of patients
Total number of uveitis cases during the
study period
Male sex, % (n)
Co-infection with HIV, % (n)
Mean/median (range) age at the time of
diagnosis of ocular inflammation, y
Mean/median duration of symptoms before
diagnosis
Mean follow-up evaluation, mo
Unilateral involvement
Type of ocular inflammation, % (n)
Anterior uveitis
Anterior/intermediate uveitis
Intermediate uveitis
Posterior uveitis
Panuveitis
Scleritis
Episcleritis
Interstitial keratitis
Optic nerve involvement
Visual acuity at presentation, % (n)
20/40 or better
Between 20/50 and 20/200
20/200 or worse
Final visual acuity, % (n)
20/40 or better
Between 20/50 and 20/200
20/200 or worse
>
_One Snellen line improvement in VA
>
_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 (2857)

91.7% (11)
25% (3)
49.5 (2484)

60% (15)
40% (2/5)b
51
M: 5 (0.0151) y
F: 14 (0.1255) y
10 (190)
NR

3 d1 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 (430) d
2.9 (0.58)
46.7% (7)

NR
14.5 (173)
50% (6)

NR

53.8% (21)
NR
42.7

100% (12)
70.6%

NR

14 (221) d

NR
30.7% (4)

3
0

NR
NR

7.25 (0.534)
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 human immunodeficiency virus; N/R result not reported; VA 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 (2355)

0
0
0
25% (5)

--- 2014

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 .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

VOL. -, NO. -

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 patients 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.

CLINICAL OUTCOMES IN OCULAR SYPHILIS

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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AMERICAN JOURNAL OF OPHTHALMOLOGY

--- 2014

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. Moradis interests and current research projects focus on ocular immunology and diseases of the retina.

VOL. -, NO. -

CLINICAL OUTCOMES IN OCULAR SYPHILIS

10.e1