++
Typical of syphilis is its clinical progression through several
well-characterized stages, outlined below.
++
Incubation after exposure typically lasts from 1 week to 3 months.
The initial manifestation is the chancre (Figure 19–1),
an indurated, nontender lesion at the site of exposure. Several
lesions may occur at once, but they are more often solitary. Disease
is transmissible through contact with a chancre. In conjunction
with the appearance of the chancre, patients usually develop nonsuppurative,
nontender inguinal lymphadenopathy. Primary lesions can appear at
any site of inoculation, including the perineum, vagina, cervix,
anus, or rectum. Lesions can also appear on the lips or in the oropharynx.
++
++
Without therapy the lesions of primary syphilis typically resolve
over a period of about 3 weeks. By this time spirochetemia, first
to regional lymph nodes and then systemically, has already occurred.
Either coincident with the resolution of the primary lesion or more
commonly several weeks later, the clinical manifestations of secondary
syphilis develop. These have long been considered to be among the
most diverse of all clinicopathologic phenomena. Most often they
present as a diffuse maculopapular rash (Figure 19–2).
Papulosquamous lesions with fine circumferential scaling may involve
the palms and soles (Figure 19–3). Moist heaped-up lesions,
termed condylomata lata, are seen in the intertriginous areas such
as the buttocks and the upper thighs (Figure 19–4). Similar
lesions, termed mucous patches, appear in the nasolabial folds and
in the mouth. The moist lesions characteristic of condylomata lata
and the mucous patch may transmit disease in a particularly efficient
manner. Rashes covered in keratinized epithelium are less likely
to transmit infection.
++
++
++
++
Patchy alopecia, diffuse lymphadenopathy, pharyngitis, or fever
may also be present. Focal involvement of various organ systems,
such as gastritis, uveitis, hepatitis, periostitis, meningitis, and
cerebrovascular accidents, can occur as manifestations of secondary
syphilis. The period of spirochetemia that is linked to the development
of secondary syphilis is the most likely opportunity for transplacental
transmission in the pregnant woman.
++
As in primary syphilis, the clinical manifestations of secondary
stage disease abate with time (ie, weeks) even in the absence of
specific therapy. At this point the disease is considered to have entered
a latent period. Studies have demonstrated that about 25% of
untreated persons with latent syphilis may have recrudescent secondary
symptoms within a 4- to 5-year period after their initial resolution.
The majority of these events occur within 1 year. For the sake of
convention this period within 1 year of exposure is regarded as
the “early latent” period. Beyond this time frame
a period of long-term or “late” latency develops
in which there are no clinical manifestations of infection. For
most of these patients, one of three outcomes can be anticipated:
spontaneous resolution of infection, persistent latent infection
with some level of immunologic control, or development of tertiary
syphilis after a period of years or decades. As many as one third
of untreated patients with latent syphilis may go on to develop
tertiary syphilis. Sexual transmission of syphilis in the latent
stage is not likely.
++
This stage is characterized by an element of end-organ damage. There
are three types of tertiary disease: neurosyphilis, cardiovascular
syphilis, and gummatous (or late benign) syphilis.
++
T pallidum appears to have a particular predilection for the nervous
system. Even in early-stage disease, invasion of the central nervous
system is well documented. Although usually asymptomatic, in some
instances there may be ocular manifestations such as uveitis or
even cerebrovascular accidents. Central nervous system disease that
manifests after long periods of latency is characterized by either
vascular compromise of some portion of the neuroaxis or chronic
debilitating loss of function that correlates with parenchymal destruction.
++
General paresis is characterized by a combination of psychiatric
and neurologic findings. The letters in the word PARESIS correspond
to the prominent findings associated with this aspect of disease:
Personality (emotional lability), Affect (flat), Reflexes (hyperreflexivity),
Eye (Argyll-Robertson pupil), Sensorium (illusions, delusions, hallucinations),
Intellect (memory, judgment impairment), and Speech (slurring).
The classic Argyll-Robertson pupil of late neurosyphilis is characterized
by a pupil that constricts upon accommodation but not to light.
++
Another classic late-stage neurosyphilis syndrome is tabes dorsalis.
As a result of demyelination of the posterior columns of the spinal
cord, patients develop abnormalities in gait, as well as various
sensory abnormalities, including characteristic “lightening” pains,
bladder and bowel dysfunction, and a positive Romberg sign. The
clinical presentation is usually some portion or combination of
these symptoms.
++
A host of inflammatory ocular and otic manifestations is also
attributable to neurosyphilis, as are other cranial nerve abnormalities.
It is more than reasonable to consider syphilis in the differential diagnosis
of nearly any psychiatric or neurologic presentation. Neurosyphilis
is discussed in more detail in Chapter 20.
+++
Cardiovascular Syphilis
++
Unlike neurosyphilis, and probably as a result of the widespread
use of systemic antibiotics with activity against T pallidum for
different clinical conditions, cardiovascular syphilis is not as
common today as it once was. T pallidum damages the muscular intima
of the aorta and with time the resultant weakening leads to the
development of an aortic aneurysm, usually of the ascending arch.
Dissection, however, is uncommon. Dilation resulting from syphilitic
aortitis in turn leads to aortic regurgitation. Involvement of the
coronary ostia may compromise myocardial blood flow.
+++
Gummatous (or Late Benign) Syphilis
++
Gummatous disease is also extremely uncommon and is characterized
by indolent destructive lesions of skin, soft tissue, and bony structures.
Significant scarring may result in disfigurement. Visceral organs
and the central nervous system may also be involved. Gummas may
vary widely in size from small defects to large tumor-like masses.
Interestingly, treponemes cannot routinely be found in tissue specimens
from these lesions. The process is suspected to be largely immune mediated.
++
Under ordinary circumstances T pallidum cannot be cultivated
in agar-based medium. Beyond clinical suspicion, diagnosis is made
or confirmed through the use of darkfield microscopy, two-stage
serologic tests, nucleic acid amplification tests (NAATs), direct
antigen tests, or special tissue stains. The first two tests are
the most commonly available. Clinicians should inform patients that
reactive laboratory tests for syphilis are reportable to public
health authorities.
++
T pallidum is too slender to be adequately observed by ordinary
light microscopy and fails to take up usual stains. Instead it can
be observed using darkfield techniques, which require a microscope equipped
with a special condenser that angles light to allow only those rays
reflected by the object of interest to enter the objective. The
organism appears white against an otherwise black background, hence
the term darkfield. Under such observation, the treponeme can be
visualized as a corkscrew-shaped organism rotating along its long
axis.
++
Darkfield microscopy is only useful when examining the moist
lesions of primary syphilis or condylomata lata. For darkfield specimen
collection, lesions must first be cleaned with saline-soaked gauze.
Serous exudate is then pressed against a glass slide, which must
be immediately examined before the specimen desiccates. Darkfield
examination may also be used for aspirates from involved lymph nodes.
The yield from resolving lesions is low.
++
Traditionally, a diagnosis of syphilis of any stage should be confirmed
through the use of two-stage serologic tests.
++
Initial testing is performed with a nontreponemal serologic test.
These tests use a laboratory-prepared lecithin-cholesterol antigen
to detect treponemal-directed antibody in the target serum specimen.
The sensitivity of these tests (which include rapid plasma reagin [RPR],
Venereal Disease Research Laboratory [VDRL], and
toluidine red unheated serum test [TRUST]), is
very good. Specificity is slightly less reliable. A variety of factors
can produce false-positive reactions, including older age, autoimmune
disease, intravenous drug use, and recent vaccination.
++
Nontreponemal tests can be performed both quantitatively and
qualitatively. Repeated tests on serially diluted specimens allow
for a determination of the strength of the reaction, which roughly correlate
with the extent of infection. Conversely, treatment success can
be measured by demonstration of declining nontreponemal test titers
over time. Because up to 20% of nontreponemal tests may
be nonreactive in primary syphilis, if that is a concern either
repeat testing 1 week later or testing with a treponemal specific
test is indicated.
+++
Treponemal-Specific Tests
++
To rule out false-positive tests, when used for diagnosis, reactive
nontreponemal serologic tests must be confirmed. This is done using
treponemal-specific tests, which include the fluorescent treponemal
antibody absorbed (FTA-ABS), T pallidum particle agglutination (TP-PA),
and T pallidum hemagglutination assay (TPHA). The antigens for these
tests vary, but all have in common the use of true treponemal antigen
as a key reagent. The microhemagglutination–T pallidum (MHA-TP)
test is no longer commercially available in the United States.
++
Treponemal tests tend to be labor intensive and expensive when
compared with the nontreponemal tests. They are usually interpreted
qualitatively and may remain reactive for the remainder of the life
of the individual irrespective of the success of therapy. They are
considered both sensitive and specific. The treponemal-specific
tests may become reactive before the nontreponemal tests in the
earliest stages of primary infection. That observation leads some
experts to recommend the use of treponemal specific tests in the
evaluation of a patient with suspected primary syphilis. Commonly,
if the nontreponemal serologic test is nonreactive, the testing
algorithm ceases.
++
Laboratories, particularly those processing large numbers of
specimens, recently have been turning to enzyme-linked immunoassay
technologies that make use of the treponemal-specific test as a
screening test. Reactive tests by this method may be confirmed and
quantitated by a traditional nontreponemal-specific test. Discordant
tests may be further examined using a traditional treponemal test.
The significance of an isolated reactive treponemal-specific test
is unclear. It may reflect a false-positive test or a previously
treated (knowingly or unknowingly) case of syphilis.
+++
Nucleic Acid Amplification Tests
++
The advantages of tests that rely on nucleic acid amplification
techniques to diagnose infectious diseases are obvious. They are
exquisitely sensitive as well as very specific. They do not rely
on viable organisms yet directly assay those organisms. These techniques
are available primarily as a research tool; however, in certain
public health facilities or clinics connected to academic research centers,
T pallidum nucleic acid amplification tests such as polymerase chain
reaction are available to clinicians to help with syphilis diagnosis.
+++
Biopsy and Special Stains
++
Treponemes can on rare occasions be visualized in tissue
using special stains, including silver stain.
+++
Determination of Syphilis Stage
++
The staging of syphilis is an important aspect of the clinical
diagnosis. Identification of the disease stage determines the treatment,
further management, and partner notification practices.
++
Between the period of exposure until just before development of
signs, serologic tests are not reactive. Diagnosis is purely presumptive
and is based on a history of sexual exposure to someone with syphilis.
Treatment at this stage will prevent seroconversion and development
of clinical disease.
++
The chancre of primary syphilis is similar to yet unlike the ulcers
of the other common causes of genital ulcer disease. Clinicians
are highly likely to misdiagnose a genital ulcer purely on clinical grounds.
Therefore, diagnostic tests for other etiologic agents of genital
ulcer disease should be performed in addition to those performed
for syphilis (eg, herpes simplex virus culture or PCR).
++
If darkfield microscopy is available, exudate from the lesion
may be examined for spirochetes. The sensitivity of darkfield microscopy
is somewhat operator dependent as well as dependent on the quality
of the specimen. If characteristic corkscrew-shaped organisms are
observed in a specimen from a patient who is likely to have syphilis,
then the diagnosis is almost certain. Care must be taken, however,
because nonpathogenic spirochetes are sometimes observed in the
oral or rectal secretions of persons without syphilis. If a darkfield
microscope is unavailable, then direct fluorescent antibody testing
of the specimen may be appropriate.
++
Serologic testing supports the suspicion of syphilis. In the
earliest phases of primary syphilis, the nontreponemal serologic
test may be nonreactive while the treponemal-specific test is almost always
reactive. However, within a short time (eg, days) both tests should
be reactive.
++
A rash of any type in a sexually active individual should be considered
as potential syphilis until proven otherwise. The appearance of
syphilis-associated rashes is so varied that reliance on some “characteristic” quality
would be a mistake. Ordinarily, rashes of secondary syphilis do
not present as ulcerative lesions and therefore do not yield moist
surfaces for proper darkfield examination. The only exceptions are
the perineal lesions of condylomata lata and mucous patches of the
oropharyngeal area.
++
Reflecting the systemic nature of this stage of infection, nontreponemal
test titers are high. Although truly nonreactive (or low-titer)
nontreponemal test results in secondary syphilis have been reported,
they are very uncommon. One situation that calls for caution in
interpreting serologic tests is the so-called prozone phenomenon,
which occurs when the concentration of antitreponemal antibodies
is so high that the characteristic flocculation reaction that produces
a reactive specimen cannot occur. This phenomenon is overcome by
diluting the specimen and rerunning the test.
++
By definition latent syphilis is clinically inapparent. The only
evidence of infection is a reactive serologic test. The nontreponemal
serologic test titer is usually fairly low (ie, ≤1:8).
++
Diagnostic criteria for neurosyphilis are discussed in detail in
Chapter 20. Reactive serologic tests in the setting of an aortic
aneurysm may be construed as evidence of cardiovascular syphilis.
A definitive diagnosis requires a pathologic specimen (ie, tissue
biopsy). The range of tissues involved and the varying extent of
inflammation that may be manifest in syphilitic gummas mean that
almost any chronic destructive lesions of the body may be caused
by syphilis. Serologic tests are usually reactive. Titers may range
from reactive at only low dilution to reactive at very high dilutions.
The prozone phenomenon was described earlier. Rare treponemes may
be visualized on pathologic specimens.