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Ocular syphilis: case series (20002015) from 2 tertiary care
centres in Montreal, Canada
Julie Vadboncoeur,*Annie-Claude Labbe,
y,z
Claude Fortin,
z,x
Bouchra Serhir,
jj
Yasmine Rabia,*
Kinda Najem,
{
Laurence Jaworski,** Marie-Josee Aubin
{,yy
ABSTRACT RÉSUMÉ
Objective: To describe the demographics, clinical presentation, proportion of co-infection with human immunodeficiency virus (HIV), and
treatment of patients with ocular syphilis seen at the ophthalmology department of 2 tertiary centres in Montreal, Canada.
Design: Retrospective case series.
Participants and Methods: A total of 169 eyes of 115 patients, seen between 2000 and 2015, with a positive syphilis treponemal serol-
ogy and a likely syphilis-related ophthalmologic diagnosis. Subgroup analysis was performed between HIV-infected and HIV-
uninfected patients.
Results: Mean age of onset was 55 years, and 79% were male. Mean presenting logMAR visual acuity was 0.7. HIV status was available
for 66%, of whom 49% were HIV-infected. The anatomical ocular diagnoses included isolated anterior uveitis (18%) and posterior seg-
ment involvement (42%). Both eyes were affected in 47%. Lumbar puncture (LP) was performed in 55%, of whom 22% had a positive
cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test. Antibiotherapy, consisting of intravenous penicillin alone
or in addition to intramuscular benzathine penicillin, was administered in 65 patients (69%). Treatment allowed a visual improvement
of 0.23 logMAR. HIV-infected patients were younger men (p<0.01) and had more abnormal CSF analysis (p= 0.02), but there were
no statistically significant differences in the anatomical location of ocular inflammation or visual function improvement.
Conclusions: Given its varied presentations, syphilis must always be part of the differential diagnosis of intraocular inflammation. HIV
testing and an LP are required in the evaluation of ocular syphilis, which should be treated as neurosyphilis with the appropriate
regimen.
Objectif: Décrire les caractéristiques démographiques, la présentation clinique, la proportion de co-infection avec le virus de l'immuno-
déficience humaine (VIH) et le traitement de la syphilis oculaire au service d'ophtalmologie de 2 centres de soins tertiaires à Montréal,
au Canada.
Nature: Étude rétrospective d'une série de cas.
Participants et méthodes: Un total de 169 yeux de 115 patients examinés entre 2000 et 2015 qui présentaient une syphilis (sérologie
tréponémique positive) et une atteinte ophtalmologique vraisemblablement liée à la syphilis. Une analyse de sous-groupes a été réali-
sée entre les patients porteurs du VIH et les autres.
Résultats: L’âge moyen au début de l'infection était de 55 ans, et 79 % des sujets étaient de sexe masculin. L'acuité visuelle moyenne
lors de l'examen initial se chiffrait à 0,7 logMAR. On connaissait l’état sérologique VIH chez 66 % des sujets (taux d'infection par le
VIH de 49 %). Parmi les diagnostics anatomiques oculaires, citons l'uvéite antérieure isolée (18 %) et l'atteinte du segment postérieur
(42 %). Les deux yeux étaient touchés chez 47 % des sujets. Une ponction lombaire (PL) a été réalisée chez 55 % des sujets, 22 %
desquels ont obtenu un résultat positif lors de l'examen du liquide céphalorachidien (LCR) selon le test du Laboratoire de recherche
sur les maladies vénériennes. Soixante-cinq patients (69 %) ont reçu une antibiothérapie, qui consistait en l'administration intravei-
neuse de pénicilline seule ou en association à la pénicilline benzathine par voie intramusculaire. Le traitement a amélioré l'acuité
visuelle de –0,23 logMAR. Les patients infectés par le VIH étaient plus jeunes (p<0,01) et présentaient plus d'anomalies du LCR
(p= 0,02); cela dit, on ne note aucune différence statistiquement significative quant à la localisation anatomique de l'inflammation ocu-
laire ni à l'amélioration de la fonction visuelle.
Conclusions: Compte tenu des différentes formes que peut prendre la syphilis, cette dernière doit toujours faire partie du diagnostic dif-
férentiel en présence d'une inflammation intraoculaire. Il convient de réaliser un dépistage du VIH et une PL dans l’évaluation de la
syphilis oculaire, laquelle doit être traitée de la même façon qu'une neurosyphilis.
Syphilis is a sexually transmitted infection caused by Trepo-
nema pallidum ssp. pallidum. Although the penicillin era has
significantly reduced syphilis cases during the 20th century,
an upsurge in cases has been noted since the early 2000s. In
2015, in the province of Quebec, Canada, 737 cases of infec-
tious syphilis were notified to public health authorities, corre-
sponding to a rate of 8.9 per 100,000.
1
The majority of cases
(96%) reported in 2015 were among men. Between 1999
and 2015, rates among men increased by more than 170-
fold, from 0.1 to 17.2 per 100,000.
1
Ocular syphilis is considered to be a form of neurosyphilis.
It presents most frequently in the early infectious stages of
the disease (especially secondary and early latent stages, i.e.,
less than 1 year after being infected). Known as the “great
masquerader,”it can cause a myriad of ocular manifestations,
from AU to retinal vasculitis and optic neuropathy. Although
rare, a worldwide increase in the number of cases of ocular
syphilis is reported in the literature, especially in men having
sex with men (MSM) and in human immunodeficiency virus
(HIV)infected populations.
2
The global increase in ocular
© 2019 Canadian Ophthalmological Society.
Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jcjo.2019.05.009
ISSN 0008-4182
30 CAN J OPHTHALMOL—VOL. 55, NO. 1, FEBRUARY 2020
syphilis cases led us to question whether this rise had been
occurring in the Montreal population over the past 15 years.
In the province of Quebec, ocular syphilis is not a notifiable
disease; hence we have no exact data of its incidence.
The purpose of this study is to describe the demographics,
clinical presentation, proportion of co-infection with HIV,
and treatment of patients with ocular syphilis seen in 2 Mon-
treal tertiary care centres. The secondary purpose of this
study is to compare HIV-infected and HIV-uninfected
patients regarding clinical presentation, cerebrospinal fluid
(CSF) findings, and treatment response as measured by the
mean visual improvement.
TAGGEDH1METHODSTAGGEDEND
Study Population
We conducted a retrospective chart review study of
patients diagnosed with ocular syphilis between January
2000 and December 2015 in the ophthalmology depart-
ments of H^opital Maisonneuve-Rosemont (HMR) and Cen-
tre Hospitalier de l’Universite de Montreal (CHUM). A list
of positive treponemal sera was provided by the provincial
public health laboratory (Laboratoire de sante publique du
Quebec [LSPQ]) and cross-referenced with the list obtained
from laboratory software of HMR and CHUM. All medical
record numbers available on the laboratory list were entered
in the administrative appointment software of both tertiary
care centres, allowing the identification of patients who vis-
ited our 2 ophthalmology departments during the study
period. Only patients with a likely syphilis-related ophthal-
mologic diagnosis and who were evaluated and followed by
the uveitis, cornea, or neuro-ophthalmology services were
included. It is understood that some patients might have
been assessed and treated by an ophthalmologist outside the
University of Montreal tertiary care centres, which could
impact on the frequency of the disease in this study.
The syphilis-related diagnoses were the following: anterior
(AU), intermediate (IU) or posterior uveitis (PU), panuveitis
(PanU), retinal vascular involvement, optic nerve involve-
ment, and interstitial keratitis. Inclusion criteria consisted of
positive treponemal syphilis serology with a syphilis-related
ocular presentation.
Data Collection
Data of patients meeting the inclusion criteria were com-
piled retrospectively from the medical charts and entered
into a database. Data collected included patient demo-
graphics, history of syphilis infection, as well as HIV status.
Ophthalmic findings at presentation included best-corrected
visual acuity (BCVA), intraocular pressure, grade of the
anterior chamber and vitreous inflammation, and slit-lamp
and fundus examination findings. All BCVA data were con-
verted to logMAR equivalents of Snellen acuity for analysis.
BCVA corresponding to counting fingers, hand motion,
and light perception were, respectively, assigned a logMAR
of 1.6, 2, and 2.5. Official ophthalmologic diagnoses were
based on the Standardization of Uveitis Nomenclature
3
guidelines, when applicable. In addition to syphilis serology
results (detailed below), patients underwent standardized
systemic laboratory tests, including complete blood count,
complete metabolic panel, angiotensin converting enzyme,
lysozyme, human leucocyte antigen-B27 for cases of AU,
tuberculin skin test, and chest imaging for sarcoidosis and
tuberculosis. Laboratory data also included, for those who
underwent a lumbar puncture (LP), CSF Venereal Disease
Research Laboratory (VDRL), white blood cells (WBC),
and protein counts in the CSF. Of note, the cut-off used to
define pleocytosis was higher in HIV-infected patients (20
WBC/mL) than in HIV-uninfected patients (5 WBC/
mL).
4,5
Treatment data included type, dose, route of admin-
istration of systemic antibiotics, and post-treatment BCVA.
During the timespan of the study, different serodiagnosis
algorithms were used. From 2000 to 2009, a traditional serology
algorithm starting with a nontreponemal test, the rapid plasma
reagin test (RPR), was used. From 2010 to 2015, a reverse
sequence serology algorithm, starting with a treponemal test, an
enzyme immunoassay (EIA), was used.
In the traditional algorithm (Fig. 1a), a positive RPR was fol-
lowed by at least one confirmatory treponemal test (performed
at the LSPQ). Clinicians using the traditional algorithm could
also order a treponemal test, even when the RPR was negative,
if their clinical suspicion of ocular syphilis was high (special
request). In the reverse sequence algorithm (Fig. 1b), a positive
EIA was followed by an RPR. Positive qualitative RPR sera
were tested by quantitative RPR. From 2010 to 2014, only
EIA-positive and RPR-negative sera were sent to LSPQ for con-
firmation. The algorithm changed again in 2015, where sera
with positive EIA and positive RPR with low titres (1:1 to 1:4)
were also sent to LSPQ for confirmation.
The list obtained from the LSPQ database captured all
patients with a positive syphilis serology until 2010. To cap-
ture all cases from 2010 onward, the list of positive syphilis
sera from both laboratories (HMR and CHUM) was
extracted from the respective laboratory software and cross-
referenced with the list obtained from the LSPQ. Duplicates
were then deleted.
RPR carbon antigen test (at HMR: Pulse ScientificInc.,
Burlington, Ont.; at the CHUM: Wampole Impact from
Alere (Abbott), Mississauga, Ont) and syphilis treponemal
EIA (at HMR: Trep-Sure Syphilis Total Antibody EIA from
Trinity Biotech, Burlington, Ont; at the CHUM: Captia
Syphilis Total Antibody from Trinity Biotech and BioPlex
2200 Syphilis IgG from Bio-Rad Laboratories, Mississauga,
Ont) assays were performed in the tertiary care centre laborato-
ries according to the manufacturer’s recommendations.
Confirmatory treponemal tests were performed at the LSPQ
using an algorithm combining one or more treponemal confir-
matory assays (Fig. 1): T. pallidum particle agglutination assay
(TPPA; Fujirebio Diagnostics, Inc, Seguin, TX), fluorescent
treponemal antibody absorption (FTA-ABS; ZEUS Scientific,
Branchburg, NJ), and/or line immunoassay (INNO-LIA;
Fujirebio Europe, N.V., Gent, Belgium). All assays were
conducted according to the manufacturer’s recommendations.
Ocular syphilis: case series (20002015)—Vadboncoeur et al.
CAN J OPHTHALMOL—VOL. 55, NO. 1, FEBRUARY 2020 31
When using the traditional algorithm, a serology profile
was defined as positive for syphilis in the presence of at least
one positive confirmatory treponemal test (TPPA, FTA-ABS,
INNO-LIA) and either a positive or negative nontreponemal
test (RPR). When the reverse sequence algorithm was used, a
serology profile was defined as positive for syphilis in the
presence of a positive treponemal test (EIA) and either a posi-
tive nontreponemal test (RPR) with a titer of 1:8 or more, or
a second positive confirmatory treponemal test (TPPA, FTA-
ABS, or INNO-LIA).
Ethics Statement
All work was conducted following the Declaration of Hel-
sinki. The ethics approval was obtained by HMR and
CHUM ethics research committees.
Statistical Analysis
Statistical analysis was performed using Stata statistical
software 2017 (version 14, Stata Corp, College Station, TX).
Continuous variables were compared using the ttest, and cat-
egorical variables were compared using the Fisher’s exact test
Fig. 1—Syphilis serology algorithms used throughout the study period. (A) Traditional algorithm starting with a nontreponemal test
(RPR), 2000–2009. (B) Reverse sequence algorithm starting with a treponemal test (EIA), 2010–2015. CHUM, Centre hospitalier de
l’Université de Montréal; EIA, enzyme immunoassay; FTA-abs, fluorescent treponemal antibody absorption; HMR, H^
opital Mai-
sonneuve-Rosemont; LSPQ, Laboratoire de santé publique du Québec; RPR, rapid plasma reagin; TPPA, Treponema pallidum
particle agglutination assay. Special request: Clinicians could order a treponemal test even when the RPR was negative, if the
clinical suspicion of ocular syphilis was high. Notes: From 2010 to 2014, only EIA-positive/RPR-negative sera were sent to LSPQ
for confirmation. The algorithm changed in 2015, where sera with positive EIA and positive RPR with low titres (1:1 to 1:4) were
also sent to the LSPQ (grey box). Adapted from Institut national de santé publique du Québec (INSPQ) with permission
38,39
Ocular syphilis: case series (20002015)—Vadboncoeur et al.
32 CAN J OPHTHALMOL—VOL. 55, NO. 1, FEBRUARY 2020
or x
2
test to calculate pvalues. All pvalues were nominal and
statistical significance was set at p<0.05. We elected not to
adjust the pvalues with the Bonferroni correction because of
the descriptive nature of our study as well as the limited num-
ber of comparisons with small sample size.
TAGGEDH1RESULTSTAGGEDEND
Clinical Characteristics of the Entire Cohort
From a list of 10,821 positive sera from the 2 tertiary care
centres of the study, 4680 patients were identified of whom
588 had visited one of the ophthalmology departments, and
115 met the inclusion criteria (Table 1). These 115 patients
represented 2.5% of all patients with a positive syphilis serum
during the study period. Ninety-one patients (79%) were
male. The mean age at presentation was 55 years. Gender of
sexual partners was known only in 60 patients (52%), all
male; 32/60 men had a history of sex with men (MSM). A
co-infection with HIV was identified in 37 patients (32%)
(mean CD4 = 358.29 §195.04), 39 patients (34%) had a
negative HIV test, and HIV status was unknown in 39
(34%). In our case series, the most common stage recorded
at presentation was secondary syphilis, accounting for 30%
of cases, followed by tertiary (26%) and late latent (26%)
syphilis. The infectious stages of syphilis represented one-
third of cases.
Fig. 1 Continued.
Ocular syphilis: case series (20002015)—Vadboncoeur et al.
CAN J OPHTHALMOL—VOL. 55, NO. 1, FEBRUARY 2020 33
Clinical Presentation and Work-Up
Of the 115 patients (total of 169 eyes), 54 (47%) had
bilateral disease. Mean presenting logMAR BCVA was 0.70
(Snellen equivalent of 20/100). Uveitis or cornea specialists,
depending on the affected anatomical location, evaluated all
patients, and a neuro-ophthalmologist additionally evaluated
some patients. Twenty-four eyes (14%) were diagnosed with
interstitial keratitis. Uveitis was diagnosed in 110 eyes (65%
of our cases): isolated AU (31 eyes; 28%), AU and IU
(8 eyes; 7%), isolated IU (12 eyes; 11%), PU (32 eyes;
29%), and PanU (27 eyes; 25%). Overall, 22 patients (19%
of our cases) had neuro-ophthalmologic involvement: optic
neuropathy in 19 patients (26 eyes) and oculomotor involve-
ment in 3 patients (3 eyes). Nine eyes (5%) were diagnosed
with other conditions related to syphilis, including episcleritis
and scleritis. Macular edema was an accompanying complica-
tion in 10 patients (9%), noted in 12 eyes (7%).
An LP was performed in 63 patients (55%). In 45 (71%)
of these, CSF analysis revealed at least one abnormal value
(CSF VDRL, elevated WBC count, or protein concentra-
tion). CSF VDRL was positive in 14 patients (22%). A high
WBC count was noted in 28 patients (44%) and an increased
protein concentration in 38 (60%). The ophthalmologic
diagnoses of the 63 patients who had an LP and of the 75
patients who did not have an LP are shown in Table 2. There
was no statistically significant difference in the anatomical
location of intraocular inflammation between the groups
(p= 0.08).
Treatment
Ninety-four patients (82%) were treated with antibiotics. Of
these, 65 patients (69%) received intravenous penicillin alone or
in combination with intramuscular (IM) benzathine penicillin.
IM benzathine penicillin alone was used in 25 patients (27%).
Four patients (4%) were treated with other antibiotics (doxycy-
cline, azithromycin, or ceftriaxone) due to a history of penicillin
allergy. Twenty-one patients (18% of cases) were not treated.
The reasons for lack of treatment were prior syphilitic treatment
with IM benzathine penicillin (n = 7), refusal (n = 4), and loss
to follow-up (n = 10). Post-treatment monitoring of the serum
nontreponemal test was available in only 44 patients (38%) and
29 patients (25%) at, respectively, 6 and 12 months. The final
logMAR BCVA was 0.5 (Snellen equivalent of 20/60).
HIV-Infected Versus HIV-Uninfected Patients
Of the 76 patients for whom the HIV status was known,
37 patients (49%) were co-infected with HIV (Table 3).
Men accounted for all HIV-infected patients. HIV-infected
patients were younger than HIV-uninfected patients (mean
age 43 vs 53 years; p<0.01). Nearly two-thirds of HIV-
infected patients were MSM in comparison with 7 (18%) in
the HIV-uninfected group (p<0.01). There was no statisti-
cally significant difference between groups concerning BCVA
at presentation and laterality. The difference between the
groups in the anatomical diagnoses was not statistically signif-
icant. An LP was performed in 31 (84%) HIV-infected
patients in comparison with 22 (56%) HIV-uninfected (p
0.01). Overall, HIV-infected patients had a higher rate of
abnormal CSF analysis results (p= 0.02). Abnormally ele-
vated WBC was more frequent in HIV-infected patients,
even considering the different WBC cut-offs (22 HIV-
infected patients with >20 WBC/mL vs 5 HIV-uninfected
patients with >5 WBC/mL; p<0.01). Elevated protein
Table 1—Baseline characteristics of patients with ocular syphilis
Characteristics Total (n = 115)
Age, years 55.11 §15.75
Sex, n (%)
Male 91 (79)
Female 24 (21)
HIV status, n (%)
Known positive HIV 29 (25)
Newly diagnosed HIV 8 (7)
Negative HIV 39 (34)
Unknown 39 (34)
Laterality, n (%)
Unilateral 61 (53)
Bilateral 54 (47)
Stages of syphilis, n (%)
Congenital 3 (3)
Primary 1 (1)
Secondary 35 (30)
Early latent 0 (0)
Late latent 30 (26)
Tertiary 30 (26)
Undetermined 16 (14)
Lumbar puncture, n (%)
Performed 63 (55)
Not performed 52 (45)
Abnormal lumbar puncture, n (%)
At least 1 abnormal value 45 (71)
Positive VDRL 14 (22)
Elevated white blood cells*28 (44)
Elevated proteins
y
38 (60)
Antibiotics, n (%)
Penicillin (IV, or IV & IM) 65 (57)
Penicillin (IM only) 25 (22)
Others
z
4 (3)
No treatment 21 (18)
logMAR BCVA (Snellen equivalent)
Presenting 0.7 (20/100)
Final 0.5 (20/60)
x
BCVA, best-corrected visual acuity; CSF, cerebrospinal fluid; HIV, human immunodeficiency
virus; IM, intramuscular; IV, intravenous; VDRL, Venereal Disease Research Laboratory; WBC,
white blood cell.
*Considered positive if >5 for HIV-negative patient, >20 WBC/mL for HIV-positive patient.
y
Considered positive if >0.40 g/L.
z
Others include doxycycline, azithromycin, and ceftriaxone.
x
p<0.01 (calculated using the ttest).
Table 2—Classification of ophthalmic diagnosis according to the
lumbar puncture status
Anatomical Location
of Ocular Inflammation,
n (%)*
LP Performed
(n = 94)
LP Not Performed
(n = 75)
Total
(n = 169)
Interstitial keratitis 7 (8) 17 (23) 24 (14)
Anterior uveitis 18 (19) 13 (17) 31 (18)
Anterior + intermediate uveitis 4 (4) 4 (5) 8 (5)
Intermediate uveitis 5 (5) 7 (9) 12 (7)
Posterior uveitis 15 (16) 17 (23) 32 (19)
Panuveitis 20 (21) 7 (9) 27 (16)
Optic nerve involvement 18 (19) 8 (11) 26 (16)
Others
y
7 (8) 2 (3) 9 (5)
LP, lumbar puncture.
*n refers to number of eyes.
y
Others include VI nerve palsy, scleritis, episcleritis, and retinal detachment.
Ocular syphilis: case series (20002015)—Vadboncoeur et al.
34 CAN J OPHTHALMOL—VOL. 55, NO. 1, FEBRUARY 2020
concentration was also more frequent in HIV-infected
patients (23 vs 10 patients; p= 0.02). No statistical differen-
ces were found between HIV-infected and HIV-uninfected
populations regarding CSF VDRL positivity, antibiotherapy
regimen, and mean visual improvement.
TAGGEDH1DISCUSSIONTAGGEDEND
Despite its increasing incidence, syphilis itself remains a
relatively uncommon presentation of ocular inflammation,
responsible for less than 2% of all uveitis cases in the United
States.
68
The greater Montreal region consistently has the
highest incidence of infectious syphilis in the province of
Quebec.
1
The increase in infectious syphilis has led to the
rise of ocular syphilis cases reported over the past 15 years.
9
In our 2 tertiary care centres, 115 patients were diagnosed
with ocular syphilis out of a total of 10,821 positive sera, rep-
resenting a prevalence of 2.5%. Some cases of ocular syphilis
might not have been included either because the treating
physicians did not detect them (no ophthalmology consulta-
tion was ordered) or because they were managed by ophthal-
mologists outside our centres. These 2 possibilities would
have the effect of underestimating the actual rate of ocular
syphilis. While ocular syphilis has been described at all stages
of the disease, intraocular inflammation is usually associated
with secondary syphilis.
6,10,11
This is in accordance with our
findings, with 30% of cases classified at the secondary stage.
Ocular syphilis is frequently associated with HIV co-infection
(varying from 20% to 70% in published reports).
12
Horberg
showed that HIV-infected patients were 86 times more likely to
have syphilis than HIV-uninfected patients.
13
Despite the
apparent association between the 2 infections, it is worrisome to
notice that over one-third of our patients did not have HIV test-
ing. Of those tested, 32% were HIV co-infected. A positive
syphilis test should prompt the clinicians to perform HIV
screening, as recommended by the authors of the prospective
British Ocular Syphilis Study (BOSS), where 30% of the
patients were HIV-infected.
2
Population-based ocular syphilis studies show a mean age at
presentation between 41 and 61 years.
7,8,1426
With a mean
age of 55 years at presentation, our group is similar to the popu-
lations mentioned above. A review of the published ocular syph-
ilis literature shows that HIV-infected patients are significantly
younger
6,13,27
; our results are in line with this finding (43 years
[HIV-infected] vs 53 years [HIV-uninfected]). The majority of
our population were men (79%); this is in keeping with the
reports in the literature.
28
The male predominance remains
when analyzing HIV-infected (100%) and HIV-uninfected
(85%) patients. A Swiss prospective cohort study in an HIV-
infected population indicated that more than 70% of patients
with positive treponemal serology were MSM
29
;wefoundthat
63% of our HIV-positive subpopulation with ocular syphilis
was MSM. Although there was a very slight predominance of
unilateral presentation in our population (53%), similar to the
Singaporean, Australian, and Korean populations,
13,21,22
the
usual presentation is bilateral ocular disease.
7,13,15,17,19,20,25
Numerous studies in the literature have shown a preponderance
for bilateral involvement in HIV-infected patients; however, in
keeping with the BOSS study, HIV status had no influence on
laterality in our case series.
2
Ocular syphilis can affect all structures of the eye. In our
research, posterior segment involvement (IU, PU, PanU) was
the most common clinical manifestation followed by isolated
AU. PU and PanU are the most commonly reported presen-
tation of syphilitic uveitis.
7,13,23,28
Contrary to previously
published case series where patients with isolated AU were
14.5 times more likely to be HIV-infected, 11 of our HIV-
negative patients (19%) presented with isolated AU versus 9
(17%) of our HIV-infected patients.
30
Given the idiopathic
nature of many cases of uveitis, it can be difficult to distin-
guish whether some of the cases are genuinely due to syphilis
or due to another unidentified cause in a patient with inci-
dental positive syphilis test results. This uncertainty might
lead to an over-representation of AU in our study.
The Centers for Disease Control and Prevention (CDC)
guidelines, the Canadian Guidelines on Sexually Transmitted
Infections, and the 2014 European Guidelines instruct physi-
cians to order an LP for analysis of CSF in all patients
Table 3—Subgroup analysis of characteristics between HIV posi-
tive and HIV negative
Characteristics HIV Positive
(n = 37)
HIV Negative
(n = 39)
p*
Age, years 43.22 §11.75 53.35 §11.64 <0.01
Gender, n (%) 0.03
Male 37 (100) 33 (85)
Female 0 (0) 6 (15)
Sexual orientation,
n (%)
<0.01
MSM 24 (65) 7 (18)
Heterosexual 2 (5) 15 (38.5)
Bisexual 1 (3) 2 (5)
Unknown 10 (27) 15 (38.5)
Anatomical location
of ocular
inflammation, n (%)
y
0.31
Interstitial keratitis 0 (0) 2 (4)
Isolated anterior uveitis 9 (17) 11 (19)
Anterior + intermediate uveitis 2 (4) 4 (7)
Intermediate uveitis 4 (7) 6 (11)
Posterior uveitis 8 (15) 10 (18)
Panuveitis 12 (23) 15 (27)
Optic nerve involvement 12 (23) 7 (12)
Others
z
6 (11) 1 (2)
Lumbar puncture, n (%) <0.01
Performed 31 (84) 22 (56)
Not performed 6 (16) 17 (44)
Antibiotics, n (%) 0.41
Penicillin (IV, or IV & IM) 29 (78) 28 (72)
Penicillin (IM only) 3 (8) 8 (21)
Others
x
1 (3) 1 (2)
No treatment 4 (11) 2 (5)
logMAR BCVA (Snellen
equivalent)
Presenting 0.4 (20/50) 0.8 (20/120)
Final 0.2 (20/30) 0.5 (20/60)
Mean visual
improvement
0.24 0.28 0.20
BCVA, best-corrected visual acuity; CSF, cerebrospinal fluid; HIV, human immunodeficiency
virus; IM, intramuscular; IV, intravenous; MSM, men who have sex with men; VDRL, Venereal
Disease Research Laboratory; WBC, white blood cell.
*pvalues were calculated using the ttest, Fisher’s exact test, or x
2
test of significance.
y
n refers to number of eyes.
z
Others include VI nerve palsy, scleritis, episcleritis, and retinal detachment.
x
Others include doxycycline, azithromycin, and ceftriaxone.
Ocular syphilis: case series (20002015)—Vadboncoeur et al.
CAN J OPHTHALMOL—VOL. 55, NO. 1, FEBRUARY 2020 35
presenting with neurologic clinical manifestations, including
cranial nerve dysfunction, meningitis, stroke, acute altered
mental status, and auditory or ophthalmic abnormalities.
Consequently, all patients with ocular syphilis regardless of
their symptoms and findings should undergo an LP, irrespec-
tive of the site of inflammation.
3133
According to the CDC guidelines, patients have confirmed
neurosyphilis if they have a positive CSF VDRL; patients have
probable neurosyphilis if they have a negative CSF VDRL but
both neurological manifestations consistent with neurosyphilis
and an abnormal CSF WBC count (>5WBC/mL) or protein
concentration (0.5 g/L).
31
Known to be highly specific, the CSF
VDRL has, however, a poor sensitivity, ranging from 30% to
70%.
34
Therefore, a negative test cannot rule out neurosyphilis.
The diagnosis of probable neurosyphilis can be confounded in
cases with HIV co-infection, where abnormal CSF WBC count
or protein concentration may be due solely to HIV. As shown by
Appleman et al
35
and García et al,
36
HIV infection was responsi-
ble for abnormalities of CSF in 38% to 69% of cases. A meta-
analysis in HIV-infected patients with ocular syphilis showed that
57% had positive CSF VDRL, 74% had elevated CSF WBC
count, and 75% had raised CSF protein concentration.
24
In our
analysis, 71% of patients, all stages combined, had CSF abnor-
malities, whether a positive CSF VDRL, elevation of WBC, or
abnormal protein concentration. This proportion is in line with
the literature showing that LP reveals CSF abnormalities in up to
70% of patients with early stage syphilis.
37
Furthermore, although
there was no difference for CSF VDRL results between our HIV-
infected and HIV-uninfected groups, abnormal elevation of
WBC and protein was statistically significantly more frequent in
HIV-infected patients. This may be explained by the fact that
HIV infection itself can be responsible for some of the CSF
abnormalities. We took measures to minimize this effect by opt-
ing for a stricter definition of pleocytosis on CSF analysis in HIV-
infected patients (WBC >20 WBC/mL). We must also keep in
mind the fact that 84% of HIV-infected patients versus 56% of
HIV-uninfected patients hadanLP,andthismightinfluence the
difference seen between the 2 subgroups. It is difficult to say with
certainty whether HIV-infected patients with abnormal CSF
meet the definition of probable neurosyphilis or not. The inci-
dence of neurosyphilis might be overestimated due to anomalies
attributable to the HIV infection itself.
For all stages of syphilis, penicillin is the treatment of choice.
Ocular syphilis being considered synonymous to neurosyphilis,
patients should be treated with intravenous penicillin G.
31
From this definition, only 57% of the patients in our whole
cohort were treated according to the guidelines. One would
think that the HIV-infected patients would have been
treated with respect to the neurosyphilis protocol given their
added immunocompromised state; however, there was no differ-
ence in the route of administration between HIV-infected and
uninfected patients. As mentioned previously, there was no sig-
nificant differences in the presenting or final BCVA as well as
the mean visual improvement between HIV-infected and unin-
fected patients; this is in keeping with other reports in the litera-
ture leading us to believe that co-infection with HIV is not
necessarily synonymous with worse visual prognosis.
2,8
Per
CDC guidelines, treatment response should be monitored with
clinical, serological, and CSF evaluation minimally 6 and 12
months after the completion of antibiotherapy.
31
Disturbingly,
only 37% of patients had a 6-month post-treatment serology,
and a mere 24% had a 12-month control.
This study has limitations. The retrospective design of the
study makes it sometimes difficult to analyze the data consid-
ering the evolution of guidelines, investigations, and treat-
ments over the past 15 years. Incomplete medical records
also limit the validity of our findings. Univariate analyses
were performed due to the relatively small sample size, nota-
bly when comparing HIV-infected and uninfected patients,
possibly inducing confounding factors, as they were not con-
trolled through multivariable analysis.
Ocular syphilis was present in 2.5% of all reported syphilis
cases in 2 tertiary care centres in Montreal, Canada. This report is
the most extensive case series of ocular syphilis in Canada. This
retrospective study on a large group of patients with ocular syphi-
lis allowed us to address the situation in this era of resurgence of a
once considered rare condition and to better characterize the criti-
cal association with HIV infection. Given the myriad of clinical
presentations, testing for syphilis should be part of the investiga-
tive work-up of any ocular inflammation. Due to the high likeli-
hood of concomitant HIV infection in ocular syphilis, HIV
testing should be done in all patients presenting with suspected or
diagnosed syphilis and vice versa. LP remains an essential diagnos-
tic tool in ocular syphilis and allows monitoring of response to
treatment; in accordance with the Canadian guidelines on sexu-
ally transmitted disease, it must be integrated into the routine
evaluation and follow-up of patients with ocular syphilis. More-
over, regular follow-up appointments and behavioural counseling
should be done with all patients. The critical importance of part-
ner treatment should not be overlooked and should be instituted
promptly. Because syphilis is a systemic communicable disease, a
multidisciplinary approach, including ophthalmology, infectious
disease, and neurology experts, must be put forward to ensure
optimal patient management.
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Footnotes and Disclosure:
The authors have no proprietary or commercial interest in any mate-
rials discussed in this article.
This work was supported by a research grant from the Fonds de
Recherche en Ophtalmologie de l’Universite de Montreal (FROUM).
From the *Ophthalmology Resident, Universite de Montreal, Mon-
treal, Que.;
y
Division of Infectious Diseases and Medical Microbiol-
ogy, H^opital Maisonneuve-Rosemont (HMR), CIUSSS de l’Est-de-
l’
^
Ile-de-Montreal, Montreal, Que.;
z
Department of Microbiology,
Infectious Diseases and Immunology, Faculty of Medicine, Mon-
treal, Que.;
x
Department of Medical Microbiology and Infectious
Diseases, Centre Hospitalier de l’Universite de Montreal (CHUM),
Montreal, Que.;
jj
Laboratoire de sante publique du Quebec, Institut
national de sante publique du Quebec, Ste-Anne-de-Bellevue, Que.;
{
Department of Ophthalmology, CUO-HMR, CIUSSS de l’Est-
de-l’
^
Ile-de-Montreal, Montreal, Que.; **Department of Ophthal-
mology, CHUM, Montreal, Que.;
yy
Department of Social and Pre-
ventive Medicine, School of Public Health, Universite de Montreal,
Montreal, Que.
Originally received Sep. 20, 2018. Final revision Apr. 15, 2019.
Accepted May. 27, 2019.
Correspondence to Julie Vadboncoeur, Department of Ophthalmol-
ogy, CUO-HMR, 5415, boulevard de l’Assomption, Montreal,
Que. H1T 2M4. julie.vadboncoeur@umontreal.ca
Ocular syphilis: case series (20002015)—Vadboncoeur et al.
CAN J OPHTHALMOL—VOL. 55, NO. 1, FEBRUARY 2020 37
