Learning Objectives:
·
To review the epidemiology and risk factors for syphilis
·
To review the pathogenesis and systemic
manifestations of syphilis
·
To review the various ocular manifestations and
treatment for syphilis
Time Credit:
2 hours
Case
A 45 year old male presents to the eye doctor with symptoms
of decreased vision and floaters in his left eye. He says that the symptoms have been gradually worsening for
the last several weeks, and has never had such symptoms before. There are no symptoms of flashes or
visual field loss, and he has no complaints with the right eye.
The patient reports being otherwise healthy and is on no
medications. However, he does tell
you he had a painless ulcer on the shaft of his penis about 2 months ago which
lasted for several weeks before resolving. His sexual history is significant for multiple male
partners. He has never been
screened for sexually transmitted infections.
On exam, visual acuity is 6/7.5 and 6/15 in the right and
left eyes, respectively. Anterior
segment exam is normal in both eyes.
In the left eye, multiple yellow-gray inflammatory lesions are seen on
the posterior pole and are associated with mild vitritis.
What bacteria, shown in the electron microscope
picture above, is a likely culprit for this patient’s presentation?
• HIV
INCORRECT - Human immunodeficiency virus (HIV) is the virus responsible for AIDS. HIV has many complications in the posterior segment including AIDS retinopathy and opportunistic infections (e.g. CMV retinitis, toxoplasmic retinochoroiditis). However HIV is not a bacteria and does not resemble the graphic from the electronic microscope.
• Syphilis
CORRECT
• Toxoplasmosis
INCORRECT - Toxoplasmosis may cause an infectious retinochoroiditis, especially in immunocompromised individuals. However, the appearance on electronic microscopy is one of a spirochete bacteria.
• Chlamydia trachomatis
INCORRECT - Chlamydia is a sexually transmitted infection caused by the obligate intracellular pathogen Chlamydia trachomatis. The patient’s presentation is not typical of Chlamydia.
Introduction
Syphilis is a sexually-transmitted infection (STI) caused by
the spirochete bacterium Treponema
pallidum. Although
significantly less common than before the era of antibiotics, it has been
increasing in incidence over the last decade or so. It most commonly affects homosexual males but can affect
males and females of all age groups.1 It may also be transmitted to the fetus
during pregnancy or delivery, causing congenital syphilis. It is often termed the “great mimicker”
for its ability to manifest in a variety of ways, especially in the eyes.
Although this module is intended for the eye care
professional, the non-ocular manifestations of syphilis will be thoroughly
discussed as knowledge of non-ocular manifestations is critical for diagnosing
the condition in patients presenting with ocular complaints.
Microbiology
Syphilis is caused by the bacteria Treponema pallidum (T
Pallidum), a small, highly motile, spiral gram-negative bacterium.2 Its small size makes it difficult to
see on ordinary microscopy.2 Its structure consists of a cytoplasmic
membrane enclosed by an outer membrane, with a thin layer of peptidoglycan in
between.2 Endoflagella present in the periplasmic
space account for the bacteria’s motility.3 Compared to other bacteria, T pallidum
divides very slowly, with a doubling time of 33 hours in vivo.4 Humans are the only known reservoir for
the bacteria.
Transmission
Syphilis is most often acquired through sexual
transmission. The bacteria may be
spread by direct contact with infectious primary or secondary lesions (see
below for description of systemic disease), entering the body through tiny
breaks in the skin or intact mucous membranes.2 Studies suggest the risk of acquiring
the disease through sexual contact with an infected partner in the previous 30
days is 16-30%.5, 6
Treponema pallidum is an extremely virulent organism. The number of organisms to cause
disease in 50% of individuals is estimated at a mere 57.7 Following inoculation, the bacteria
reproduces locally as well as in draining lymph nodes. Early infection is characterized by
accumulation of polymorphonuclear leukocytes in lymph nodes, and later T
lymphocytes and B-cells. With the
bacteria’s high virulence it spreads quickly into both the bloodstream as well
as cerebrospinal fluid (CSF).8 The average incubation period is 2 to 4
weeks, but may be as long as 3 months in some individuals.2
Risk factors
Risk factors for syphilis include:
· High-risk sexual activities: anal
intercourse is a major risk factor for syphilis, with homosexuals and bisexuals
being at the highest risk (in medicine it is common to refer to a male having
intercourse with another male as “MSM”).10, 11 Other high risk sexual activities
include multiple heterosexual partners and unprotected intercourse with
prostitutes.10
· Coexisting HIV infection: coinfection
of syphilis and HIV (human immunosufficiency virus, the cause of AIDS) is
common- some studies have found upwards of 40% of individuals with syphilis as
having coexisting HIV infection, even in developed countries.12 HIV and syphilis share many similar
risk factors, and it is possible syphilis facilitates the transmission of HIV.13 Generally, ocular and neurologic
disease associated with syphilis is more common and more severe in patients
with HIV infection.14 Patients with coexisting HIV
infection also have an increased risk of asymptomatic neurosyphilis (i.e.
compatible CSF), especially with an RPR >1:16 or CDF count <350.9 There is no correlation between ocular
findings and stage of HIV infection (i.e. CD4 count).15 Syphilis is the most common bacterial
eye infection in HIV-positive patients.16
· Intravenous drug use: as with other
infectious agents such as HIV and hepatitis viruses, syphilis may be spread
through intravenous drug use.10
Epidemiology
Prior to the introduction of penicillin in the late 1940s,
syphilis was a common worldwide infection associated with significant morbidity
and mortality. Rates of syphilis
dramatically decreased following the widespread production of penicillin at
this time. In the 1960s and 1970s,
a resurgence of the disease occurred, particularly in MSMs, as attitudes
towards homosexuality lilberalized.2 In the 1980s, coinciding with safer
sexual practices in the face of the HIV epidemic, another fall in the incidence
of syphilis occurred.2
Since the late 1990s, syphilis has once again been on the rise. Developed countries such as Scotland,17 France,18 England,19 and the United States20 have all reported
increasing incidences. In France, the
incidence increased 6-fold between 1998 and 2001.18 In the United States, rates have
continued to increase since the 1990s- approximately 7000 cases were diagnosed
in 2002, 8000 cases in 2004 and nearly 10000 in 2006.21, 22
Various theories exist for the latest epidemic/pandemic of
syphilis including the increasing homosexual male population and the (false)
widespread belief that HIV/AIDS is merely a chronic diseases with the use of
highly-active antiretroviral therapy.23 Worldwide, there are approximately 12
million new cases of syphilis each year, with 90% occurring in developing
countries.24
Systemic Disease
We will first consider the systemic manifestations of
syphilis. The disease is most
commonly divided into primary, secondary, latent, and tertiary syphilis. We will discuss each:
Primary Syphilis
Primary syphilis occurs as a result of direct contact of
skin or mucous membranes with an infected person, occurring 3-30 days after
exposure.13 It is most commonly characterized by a
painless chancre that presents as a
single, painless ulcer in the genital area. The lesion actually starts as a macule, progressing to a
papule and later to an erosion when the covering epithelium is lost. The erosion progresses to ulceration as
more tissue is lost. The centre of
the chancre is usually clean with a serous exudate. The border of the lesion is well-demarcated.
In women, chancres are typically found on the cervix, labia
majora, labia minora, fourchette, or urethra.25 In heterosexual men they are usually
confined to the penus, however extra-genital chancres are present in
approximately 1/3 of cases of primary syphilis in MSM.26 A relatively common location in homosexual
males is the anus/rectum, perhaps explaining the increased rates of
transmission in homosexual males as individuals may not be aware of
asymptomatic lesions in an area not readily visible. It should be noted that chancres can be present in many forms
and can affect almost any area of the human body.2
Chancres are commonly multiple and can occasionally be
painful, especially if present on the fingers, tongue, or anus.2, 27 Some series have reported multiple
chancres to be present in 40-50% of cases.27, 28 It is likely that HIV co-infection
increases the risk of having multiple chancres.
Lymph node enlargement (lymphadenopathy) is another key feature
of primary syphilis, with involvement usually in regional nodes around the
chancre. Lymphadenopathy usually
becomes apparent about a week after chancre formation.
Untreated, primary chancres may persist for weeks,
especially in HIV+ individuals. It
is not uncommon for them to persist until the secondary stage of syphilis.
Secondary
Syphilis
Secondary syphilis result from systemic spread of treponemes,
and occurs in virtually all patients with untreated primary syphilis.13 It most commonly occurs 4-10 weeks
following chancre appearance and signifies hematogenous dissemination of the
bacteria.29 It classically affects the skin, mucous
membranes, and lymph glands, although it may also lead to neurologic,
ophthalmologic, gastrointestinal, and hepatic disease.29 A diffuse maculopapular rash is the presenting complaint in
approximately 70% of patients with secondary syphilis and most commonly affects
the palms and soles.29 Other symptoms/signs may include a
pustular rash, condyloma lata, fever, generalized lymphadenopathy, headache,
malaise, anorexia, nausea, joint pain, mouth ulceration, and hair loss.23, 30
Similar to the primary stage, many of the manifestations of
secondary syphilis will eventually resolve without treatment.29
Latent Syphilis
The latent stage of syphilis follows resolution of
symptoms/signs in the secondary stage and is characterized by a relative
absence of manifestations. It is
often divided into early latent and late latent. In early latent syphilis, there are no clinical signs of
infection but treponemal serology is reactive (patients can still have
recurrent oral and cutaneous lesions).23 The late latent stage is defined as
beginning two years after initial infection, or one year in the United States.31 In the late latent stage relapses may
occur rarely.23
Tertiary Syphilis
Tertiary syphilis affects 15-40% of untreated patients and
may occur decades after initial infection.32 Tertiary syphilis may be divided into
three different forms: neurosyphilis, cardiovascular syphilis, and gummatous
syphilis.
Neurosyphilis is caused by infection of the central nervous
system (CNS). In reality, CNS
involvement occurs early (i.e. in primary and secondary syphilis) but is
usually assymptomatic.30 Rarely, this “early neurosyphilis” may
cause meningitis. In neurosyphilis
associated with tertiary syphilis (“late neurosyphilis”), many possible
manifestations may occur including syphilitic meningitis, meningovascular
syphilis (apathy and seizures), general paresis (dementia), or tabes
dorsalis. The latter is caused by
the bacteria affecting the posterior columns and roots of the spinal cord,
causing poor balance and lower extremity pain.33 Late neurosyphilis is occasionally
asymptomatic.
Manifestations of cardiovascular syphilis may include
syphilitic aortitis, resultant aneurysm formation, and valvular
insufficiencies.
Gummatous syphilis is characterized by the formation of
gummas, which appear as soft tumor-like balls of inflammation affecting the
skin, bone, liver, or elsewhere.
They are granulomatous in nature.
Individuals with tertiary syphilis are not infectious.
Congenital Syphilis
Transmission of syphilis from mother to fetus during
pregnancy or delivery may cause congenital syphilis. Transplacental transmission usually occurs after 10 weeks of
gestation and is more frequent with primary or secondary syphilis.34 The greatest risk of transmission
occurs during the early stage of infection- in general the greater the interval
between the original infection and pregnancy the less the transmission and
better the outcome. The risk of
transmission is as high as 80% in the first four years following untreated
primary syphilis.34 Transmission at birth may occur by
direct contact with infections lesions.34
Clues to diagnosis in utero include thickened placental
villi (microscopically villi are hypercellular with acute and chronic
inflammation and proliferative fetal vascular changes) and spirochetes in
umbilical vessel walls.34
At birth, 2/3 of live infants with congenital syphilis are
asymptomatic. Fatality is rare
with appropriate treatment during pregnancy.34 The manifestations are often divided
into early signs (present in the first 2 years of life) and late signs (arising
during the first 2 decades of life).
The most common early signs of congenital syphilis are
hepatomegaly, rash (bullous skin disease known as pemphigus syphiliticus),
fever, neurosyphilis, pneumonitis, rhinitis, generalized lymphadenopathy, and ascites.35 Common laboratory abnormalities include
leukocytosis, Coombs-negative haemolytic anemia, thrombocytopenia, proteinuria,
hematuria, periostitis, and osteochondritis.35 Early ocular manifestations may include
chorioretinitis, glaucoma, uveitis, and cranial nerve palsies.35
Late manifestations occur in 40% of untreated
survivors. Characteristic signs
include a saddle-nose deformity from collapse of the bony part of the nose,
frontal bossing (prominence of the brow ridge), clavicular thickening, saber
shins (anterior bowing of the mid-tibia), Hutchinson teeth (blunted upper
incisors), deafness, and palate defects.
Ocular manifestations of late congenital syphilis may include
interstitial keratitis, corneal scarring, and glaucoma.34
Current recommendations on screening for syphilis in
pregnancy differ by country but most women are screened early in pregnancy, as well
as later if they are at high risk.
All pregnant women with serologic evidence of infection should be promptly
treated with IM penicillin (see below).
The treatment of the newborn depends on several factors and should be
managed by a paediatrician or infectious disease specialist. With appropriate treatment the risk of
developing congenital syphilis is reduced.
Ocular Manifestations
Ocular syphilis is relatively rare, although paralleling the
epidemiology of syphilis its incidence is also increasing in the developed
world.23 Unlike other ocular infections, there
are no pathognomonic signs of ocular syphilis- its manifestations are
considered “protean”.23
Ocular involvement in acquired syphilis usually occurs in
the secondary or tertiary stages of disease, although it may occur at any stage.15 Syphilis may involve any structure of
the eye. Ocular disease is most
commonly bilateral, 67-89% by some series.36-38 Case reports in the literature have
described cases whereby ocular syphilis was brought to attention by acute and
severe ocular disease in patients treated with intravitreal triamcinolone.39
Although ocular syphilis can take on almost any form, we
will briefly discuss some of the more common manifestations:
Lids/lashes
· Chancres: chancres may occur on
the eyelid and conjunctiva during primary syphilis.
· Others: blepharitis and
madarosis may be associated with syphilis infection
Conjunctiva/cornea/sclera
· Conjunctivitis: in secondary syphilis
a mild papillary conjunctivitis may occur.29 Less commonly, a granulomatous
conjunctivitis similar to that with sarcoidosis can occur.40
· Keratitis: keratitis with
syphilis is typically immune-mediated, nonulcerative, and nonsuppurative
inflammation of the corneal stroma.30 This interstitial keratitis may be
localized or diffuse, and unilateral or bilateral. It may be associated with iritis and occasionally keratic
precipitates. Untreated keratitis may
lead to corneal neovascularization and scarring. Prior to antibiotics, syphilis was the most common cause of
interstitial keratitis.41 Today it is the most common cause after
herpes.42
· Episcleritis/scleritis: episcleritis
and scleritis are rare in isolation but can be associated with syphilis,
especially in the secondary stage for episcleritis and tertiary stage for
scleritis.43 Syphilitic scleritis may be nodular or
diffuse.43
Uveitis
Uveitis is the most common ocular finding in syphilis. It can occur at any stage of disease,
with syphilis accounting for about 1-5% of all cases of uveitis in the
developed world.10, 36, 41 2-5% of patients with secondary
syphilis have uveitis- this increases to 9% in patients with HIV infection
receiving HAART.44 Uveitis is commonly associated with
central nervous system involvement (asymptomatic or symptomatic). Different patterns of uveitis may
occur:
· Anterior uveitis: anterior uveitis may
be granulomatous (more common) or nongranulomatous. Typical symptoms include pain, redness, and photophobia. Findings may include iris nodules, keratic
precipitates, dilated iris vessels (iris roseolae), iris atrophy, posterior
synechiae, and lens dislocation.33 Anterior uveitis may occur in isolation
or be associated with vitritis.
· Posterior uveitis: posterior uveitis is the
most common variant of uveitis in syphilis.43 It is most often painless but may cause
severe vision loss. Of patients
with syphilis and posterior uveitis, approximately 75% have chorioretinitis,
15% panuveitis, and 10% retinal vasculitis.45
o
Chorioretinitis: two types
of chorioretinitis may occur with syphilis- more common is the disseminated
type which presents as usually bilateral, yellow-grey inflammatory lesions
associated with vitritis.46 The lesions have a preference for the
posterior pole and mid-periphery, and are initially small but can coalesce to
become large confluent lesions.29 Less commonly is a variant called
posterior placoid chorioretinitis that can affect the optic disc or macular
region and is limited to the retinal pigment epithelium (RPE).46 It is often seen as macular
or juxtapapillary placoid yellowish or grey lesions with faded centres, at the
level of the RPE, accompanied by vitritis.29 It is likely due to deposition of
soluble immune complexes at the RPE-choriocapillaris and possibly retinal
vessels.46
o
Retinitis: Retinitis
may also occur without choroidal involvement, commonly affecting the posterior
pole and characterized by focal areas of retinal edema, vasculitis, papillitis,
and vitritis with minimal if any anterior segment inflammation.29 Occasionally syphilis may present as
necrotizing retinitis in the midperiphery and peripheral retina.47 Patches of retinitis may become
confluent and be associated with vasculitis and vascular occlusion.29 It may resemble acute retinitis or
progressive outer retinal necrosis but is slowly progressive and shows good
response to intravenous penicillin.
o
Retinal
vasculitis:
occasionally syphilis can manifest as isolated retinal vasculitis, affecting
any retinal vessel.48 Vasculitis may range from mild disease
only evident on fluorescein angiography to obliteration of vessels from
occlusive vasculitis, even masquerading as branch retinal vein occlusion.49
· Intermediate: syphilis may present as
vitritis only, especially in HIV-positive individuals.43
· Keratouveitis: uveitis and corneal
involvement together may be seen.
· Uveitic complications: uveitic
complications such as exudative/serous retinal detachment and glaucoma may
occur.29
Optic nerve involvement
Syphilis may cause papillitis, neuroretinitis, or
retrobulbar optic neuritis.
Syphilitic optic neuropathy is typically seen only in late disease and
may cause vision loss.43
Neuro-ophthalmic
manifestations
· Argyll Robertson pupil: the Argyll
Robertson pupil is specific to syphilis and characterized by light-near
dissociation, i.e. pupils that constrict with accommodation but not to
light. They are usually unequal,
irregular, and bilaterally small.
It may occur early but is more common late in the disease process. The pathophysiology is thought to be
related to an interruption in neuronal connections between the
Edinger-Westphall and pretectal nuclei.50
· Cranial nerve palsies: the ocular
motor nerves and optic nerve may be involved during early neurosyphilis, with
possible manifestations including third, fourth, and sixth nerve palsies as
well as supranuclear gaze palsies.
Pupillary abnormalities and ocular motor palsies can also be seen with
late neurosyphilis.29