1922

CHAPTER 327 SYPHILIS

327
SYPHILIS
EDWARD W. HOOK III

DEFINITION

Syphilis, which is a chronic infectious disease caused by the bacterium Treponema pallidum, is usually acquired by sexual contact with another infected
individual. Syphilis is remarkable among infectious diseases for its large
variety of clinical manifestations. It progresses, if untreated, through primary,
secondary, and tertiary stages. The early stages (i.e., primary and secondary)
are infectious. Spontaneous healing of early lesions occurs, followed by a long
latent period. In about 30% of untreated patients, late disease of the heart,
central nervous system (CNS), or other organs may develop years after the
initial infection. Although the disease is less common now than previously, it
remains a challenge to clinicians because of its protean manifestations, and it
is of interest to biologists because of the prolonged, tenuous balance between
the host and the invading spirochete.

The Pathogen

The causative agent of syphilis, T. pallidum, is closely related to other pathogenic spirochetes (Chapter 328), including those causing yaws (T. pallidum
subspecies pertenue) and pinta (Treponema carateum). T. pallidum is a thin,
helical bacterium approximately 0.15m wide and 6 to 15m long. The
organism has 6 to 14 spirals and is tapered on either end. It is too thin to be
seen by ordinary Gram stain microscopy but can be visualized in wet mounts
by dark-field microscopy or in fixed specimens by silver stain or fluorescent
antibody methods.
Unlike most bacteria, which have protein-rich outer membranes, the
T. pallidum outer membrane appears to be composed of predominantly phospholipids, with few surface-exposed proteins. It has been hypothesized that
because of this structure, syphilis can progress despite the brisk antibody
response to nonsurface-exposed internal antigens, which is the basis for
serologic tests for the diagnosis and management of syphilis. Between the
outer membrane and the peptidoglycan cell wall are six axial fibrils; three are
attached at each end, and they overlap in the center of the organism. They are
structurally and biochemically similar to flagella and are in part responsible
for the organisms motility.
It is possible to culture T. pallidum, but sustained in vitro cultivation is not
yet possible, and yields are very low. Culture is of limited use in research and
of no use in clinical practice. All isolates studied have been susceptible to

CHAPTER 327 SYPHILIS

1923

penicillin and are antigenically similar. The only known natural hosts for
T. pallidum are humans and certain monkeys and higher apes.

EPIDEMIOLOGY

With the exception of congenital syphilis, syphilis is acquired almost exclusively by intimate contact with the infectious lesions of primary or secondary
syphilis (e.g., chancres, mucous patches, condylomata lata). Disease is usually
acquired through sexual intercourse, including anogenital and orogenital
intercourse. Health care workers are sometimes infected during the unsuspecting examination of patients with infectious lesions. Infection by contact
with fomites is extremely uncommon. Before the advent of modern blood
banking techniques, syphilis was occasionally transmitted through the transfusion of blood from persons with T. pallidum bacteremia, and occasional
parenteral transmission still occurs as a result of the sharing of contaminated
needles.
Syphilis is most common in large cities and in young, sexually active individuals. The highest rate is found in men between the age of 20 and 29 years.
In 2008, 69% of the 3141U.S. counties reported no cases of primary or
secondary syphilis, and just 26 locales accounted for about 50% of all reported
infections. The disease is most prevalent in the Southeast.
Syphilis spares no class, race, or group but is more prevalent among
persons living on the margins of society. U.S. syphilis rates are about eightfold greater in African Americans than in non-Hispanic whites (17.3 vs. 2.2
cases per 100,000 people). Increased numbers of different sexual partners
and perhaps the indiscriminate choice of partners increase the risk of acquiring sexually transmitted disease (Chapter 293). Patients with primary and
secondary syphilis name, on average, nearly three different sexual contacts
within the previous 90 days. A traditional cornerstone of syphilis control has
been the epidemiologic investigation and treatment of sexual contacts of
patients with primary or secondary lesions and patients with early latent
disease. As syphilis has become associated with drug use and anonymous sex,
epidemiologic investigations have become less efficacious.
The incidence of syphilis has generally declined worldwide for more than
100 years, with the exception of periods of war or social upheaval. With the
introduction of penicillin, there was a rapid decline in primary and secondary
syphilis, to approximately 4 cases per 100,000 people in 1957. This decline
was followed by reductions in federal expenditures for syphilis control, which
resulted in a resurgence of infectious primary and secondary syphilis in the
United States; peaks of more than 12 cases per 100,000 people were attained
several times from 1965 through the mid-1990s. Because many cases of
syphilis are not reported, the true incidence is much higher.
Over the past 40 years, syphilis epidemics have occurred serially in at least
three U.S. population subgroups. In the 1970s and 1980s, men who had sex
with other men accounted for a disproportionate number of the total cases
of infectious syphilis. Similar trends occurred in other countries. Then, after
a period of decline, U.S. syphilis rates nearly doubled from 1986 to 1990, with
50,578 cases reported in 1990 in an epidemic disproportionately affecting
multiracial heterosexual men and women and occurring contemporaneously
with an epidemic of crack cocaine use. After 1990, syphilis rates again
declined; in 2001, there were 6103 cases of primary and secondary syphilis
reported, one of the lowest numbers since 1959. The epidemic of the late
1980s probably contributed to the spread of human immunodeficiency virus
(HIV) infection (see Syphilis-HIV Interactions) and to dramatic increases in
the rate of congenital syphilis. Since 2000, syphilis rates have begun to
increase in men, especially men infected with HIV, and they have been
increasing since 2005 in women.
Patients with clinically evident late syphilis, particularly those with cardiovascular or gummatous syphilis, are becoming less common, perhaps as a
result of the effectiveness of penicillin therapy for early syphilis. However,
surveys indicate that there are still significant numbers of patients with
untreated neurologic syphilis, especially in older age groups.

Natural Course of Untreated Syphilis

The incubation period from the time of exposure to development of the

primary lesion averages approximately 21 days (range, 10 to 90 days). Initially, a painless papule develops at the site of inoculation and soon breaks
down to form a clean-based ulcerthe chancrewith raised, indurated
margins (Fig. 327-1A). The chancre persists for 2 to 6 weeks and then heals
spontaneously. Several weeks later, a secondary stage characterized by lowgrade fever, headache, malaise, generalized lymphadenopathy, and a mucocutaneous rash typically develops. There may be involvement of visceral organs.
The secondary eruption may occur while the primary chancre is still healing

FIGURE327-1. Syphilis lesions. A, Chancre in primary syphilis. B, Palmar lesions of a

coppery color in secondary syphilis. C, Mucous patch in secondary syphilis. D, Condylomata
lata in secondary syphilis (A, C, and D, From Forbes CD, Jackson WF. Color Atlas and Text of
Clinical Medicine, 3rd ed. London: Mosby; 2003; B, From Habif TP, Cambell JI, Quitadamo MJ,
etal. Skin Disease: Diagnosis and Treatment. St. Louis: Mosby; 2001.)

or up to several months after disappearance of the chancre. Secondary lesions

also heal spontaneously within 2 to 6 weeks, and the infection then becomes
latent. In more than 20% of patients with untreated latent syphilis, relapsing
lesions later develop, similar to those of the secondary stage; rarely, the
relapse takes the form of recurrence of the primary chancre. In the era before
antibiotics, late, destructive tertiary lesions involving the eyes, the CNS, the
heart, and other organs, including the skin, eventually developed in about a
third of untreated patients. These lesions may occur a few years to as long as
25 years after infection.
The incidence of late complications of untreated syphilis is currently
unknown, but it seems to be less than that seen previously. Cases of gumma
are now so rare as to be reportable.

PATHOBIOLOGY

T. pallidum may penetrate through normal mucosal membranes and minor

abrasions on epithelial surfaces. The first lesions appear at the site of primary
inoculation. The minimal number of treponemes needed to establish infection is not known but may be as low as one. Multiplication of organisms is
slow, with a division time in rabbits of approximately 33 hours. The slow
growth of treponemes in humans probably accounts in part for the protracted
nature of the illness and for the relatively long incubation period.
Syphilis is a systemic disease from the onset. Treponemes are capable of
specific attachment to host cells, but it is not known whether attachment
results in damage to the host cells. Most treponemes are found in the intercellular spaces, but they are occasionally seen within phagocytic cells. However,
there is no evidence of prolonged intracellular survival of treponemes.
T. pallidum is not known to produce toxins.
The primary pathologic lesion of syphilis is a focal endarteritis with an
increase in adventitial cells, endothelial proliferation, and the presence of an
inflammatory cuff around affected vessels. Lymphocytes, plasma cells, and
monocytes predominate in the inflammatory lesion, and polymorphonuclear
cells are seen in some cases. The vessel lumen is frequently obliterated. With
healing, there is considerable fibrosis. Treponemes may be seen in most early
lesions of syphilis and in some of the late lesions, such as the meningoencephalitis of general paresis.

1924

CHAPTER 327 SYPHILIS

Granulomatous reaction is common in secondary and late syphilis. The

granulomas are histologically nonspecific, and cases of syphilis have been
incorrectly diagnosed as sarcoidosis or other granulomatous diseases. Human
inoculation studies suggest that the pathogenesis of the gumma, which is a
granulomatous lesion, involves hypersensitivity to small numbers of virulent
treponemes introduced into a previously sensitized host.
Intracutaneous inoculation of partially purified antigens of T. pallidum into
patients with syphilis in various stages has shown that delayed cellular hypersensitivity develops only late in secondary syphilis but is uniformly present
in latent syphilis. There may be temporary hyporesponsiveness of lymphocytes to treponemal antigens in patients with primary and secondary syphilis.
It is possible that the waxing and waning of lesions in early syphilis depend
on the balance between the development of effective cellular immunity and
the suppression of thymus-derived lymphocyte function.
The host also responds to infection by producing numerous antibodies; in
some instances, circulating immune complexes may be formed as well. For
example, nephrotic syndrome has occasionally been recognized in secondary
syphilis, and renal biopsy specimens from such patients have shown membranous glomerulonephritis characterized by focal subepithelial basement
membrane deposits containing immunoglobulin G (IgG), C3, and treponemal antibody.

CLINICAL MANIFESTATIONS

Primary Syphilis

The typical lesion of primary syphilis, the chancre, is a painless, clean-based,

indurated ulcer (see Fig. 327-1A). The chancre starts as a papule, but then
superficial erosion results in ulceration. The borders of the ulcer are raised,
firm, and indurated. Occasionally, secondary infections change the appearance and cause a painful lesion. Most chancres are single, but multiple ulcers
are sometimes seen, particularly when skin folds are apposed (i.e., kissing
chancres). An untreated chancre heals in several weeks and leaves a faint scar.
The chancre is usually associated with regional adenopathy, which may be
unilateral or bilateral. The regional nodes are movable, discrete, and rubbery.
If the chancre occurs in the cervix or the rectum, the affected regional iliac
nodes are not palpable.
Chancres can occur at any site of potential inoculation by direct contact,
with most occurring in anogenital locations. Chancres may also be seen in
the pharynx, on the tongue, around the lips, on the fingers, on the nipples,
and in other diverse areas. The morphology depends in part on the area of
the body where they occur and on the hosts immune response. Chancres in
previously infected individuals may be small and remain papular. Chancres
of the finger may appear more erosive and can be quite painful. Chancres of
the anal canal may be missed in men who have sex with men unless a careful
examination is undertaken.

Secondary Syphilis

Between 4 and 8 weeks after the appearance of the primary chancre, signs
and symptoms of secondary syphilis typically develop. Symptoms may
include malaise, fever, headache, sore throat, and other systemic complaints.
Most patients have generalized lymphadenopathy, including involvement of
the epitrochlear nodes. Approximately 30% of patients have evidence of a
healing chancre, although many patients (including a disproportionate
number of women and of men who have sex with men) give no history of a
primary lesion.
At least 80% of patients with secondary syphilis have cutaneous or
mucocutaneous lesions at some point in their illness. The diagnosis is generally first suspected on the basis of the cutaneous eruption. The rash is
often minimally symptomatic, and many patients with late syphilis do not
recall primary or secondary lesions. The rashes are quite varied in appearance but have certain characteristic features. The lesions are usually widespread, are symmetrical in distribution, and are frequently pink, coppery,
or dusky red (particularly the earliest macular lesions). They are generally
nonpruritic, although occasional exceptions have been reported, and they
are rarely vesicular or bullous in adults. They are indurated, except for the
very earliest macular lesions, and frequently have a superficial scale (i.e.,
papulosquamous lesions). The lesions tend to be polymorphic and rounded,
and on healing, they may leave residual pigmentation or depigmentation.
They may be quite faint and difficult to visualize, particularly on darkskinned individuals.
The earliest pink macular lesions are typically seen on the trunk, with
later spread to the rest of the body. The face is often spared, except around
the mouth. Subsequently, a papular rash appears that is usually generalized

but is quite marked on the palms and soles (Fig. 327-1B). These rashes
are often associated with a superficial scale and may be hyperpigmented.
When the rash occurs on the face, it may be pustular and resemble acne
vulgaris. Occasionally, the scale may be so great that it resembles psoriasis.
Ulceration may occur and produce lesions resembling ecthyma. In malnourished or debilitated patients, extensive and destructive ulcerative lesions
with a heaped-up crust may occur, the so-called rupial lesions. Lesions
around the hair follicles may result in patchy alopecia of the beard or
scalp.
Ringed or annular lesions may occur, especially around the face, and particularly on dark-skinned individuals. A lesion at the angle of the mouth or
the corner of the nose may have a central linear erosion, the so-called split
papule.
The palate and pharynx may be inflamed. In approximately 30% of secondary syphilis patients, so-called mucous patches (Fig. 327-1C) develop; these
slightly raised, oval areas are covered by a grayish white membrane that, when
raised, reveals a pink base that does not bleed. These lesions may be seen on
the genitalia, in the mouth, or on the tongue; like condylomata lata, they are
highly infectious.
In warm, moist areas such as the perineum, large, pale, flat-topped papules
may coalesce to form condylomata lata (Fig. 327-1D). Papules may also be
seen in the axilla and rarely occur in a generalized form. They are extremely
infectious. These papules are not to be confused with the common venereal
warts (i.e., condylomata acuminata), which are small, often multiple, and
more sharply raised than condylomata lata.
Other manifestations of secondary syphilis include hepatitis, which has
been reported in up to 10% of patients in some series. Jaundice is rare, but
an elevated alkaline phosphatase level is common. Liver biopsy reveals small
areas of focal necrosis and mononuclear infiltrate or periportal vasculitis.
Spirochetes can often be visualized with silver stains. Periostitis with widespread lytic lesions of bone has been reported occasionally; bone scanning
appears to be a sensitive test for early syphilitic osteitis. An immune complex
type of nephropathy with transient nephrotic syndrome has been documented rarely. There may be iritis or an anterior uveitis. Between 10 and 30%
of patients have pleocytosis in cerebrospinal fluid (CSF), but symptomatic
meningitis is seen in less than 1% of patients. Symptomatic gastritis may
occur.

Relapsing Syphilis

After resolution of the primary or secondary skin lesions, 20 to 30% of

patients experience cutaneous recurrences. Recurrent lesions may be fewer
or more firmly indurated than the initial lesions. Like the typical lesions of
primary or secondary syphilis, they are infectious for exposed sexual
partners.

Latent Syphilis

By definition, latent syphilis is the stage at which there are no clinical signs
of syphilis and the CSF is normal. Latency, which begins when the first attack
of secondary syphilis has passed and may last for a lifetime, is usually detected
by reactive serologic tests for syphilis (see Diagnosis). Congenital syphilis
must also be excluded before the diagnosis of latent syphilis can be made.
Patients may or may not have a clinical history of earlier primary or secondary
syphilis.
Latency has been divided into two stages: early and late. Most infectious
relapses occur in the first year, and epidemiologic evidence shows that the
most infectious period is during the first year of infection. Early latency is
therefore defined as the first year after resolution of the primary or secondary
lesions, or as a newly reactive serologic test for syphilis in an otherwise
asymptomatic individual who has had a negative serologic test within the
preceding year. Late latent syphilis is ordinarily not infectious, except for
pregnant women, who can transmit infection to the fetus after many years.
Most cases of latent syphilis are most accurately called latent syphilis of
unknown duration and should be treated in the same manner as late latent
syphilis (see later).

Late Syphilis

Late syphilis (Table 327-1) is usually slowly progressive, although certain

neurologic syndromes may have a sudden onset because of endarteritis
and CNS thrombosis. Late syphilis is not infectious through sexual contact.
Any organ of the body may be involved, but three main types of disease
can be distinguished: late benign (gummatous), cardiovascular, and
neurosyphilis.

CHAPTER 327 SYPHILIS

TABLE 327-1 NEWLY DIAGNOSED TERTIARY SYPHILIS IN 105

PATIENTS IN DENMARK, 1961-1970
TYPE OF TERTIARY SYPHILIS
Neurosyphilis
Asymptomatic
Tabes dorsalis
General paresis
Meningovascular
Optic atrophy
Cardiovascular syphilis
Aortic insufficiency
Aortic aneurysm
Uncomplicated aortitis
Late benign syphilis (gumma)

NO. OBSERVED*
72
45
11
13
1
2
44
16
13
15
4

*Some patients had more than one form of late syphilis.

Autopsy diagnoses only.

Late Benign Syphilis

In the penicillin era, gummas are rare. They typically develop 1 to 10 years
after initial infection and may involve any part of the body. Although gummas
may be destructive, they respond rapidly to treatment and are therefore relatively benign. Histologically, the gumma is a granuloma.
Gummas may be solitary or multiple and most often come to medical
attention as space-occupying lesions. They are usually asymmetrical and are
often grouped. Gummas may start as a superficial nodule or as a deeper lesion
that breaks down to form punched-out ulcers. They are ordinarily indolent,
slowly progressive, and indurated on palpation. There is often central healing,
with an atrophic scar surrounded by hyperpigmented borders. Cutaneous
gummas may resemble other chronic granulomatous ulcerative lesions
caused by tuberculosis, sarcoidosis, leprosy, and other deep fungal infections.
Precise histologic diagnosis may not be possible. However, syphilitic gummas
are the only such lesions to heal dramatically with penicillin therapy.
Gummas may also involve deep visceral organs, particularly the respiratory
tract, gastrointestinal tract, and bones. In addition, they may involve the
larynx or the pulmonary parenchyma. Gummas of the stomach may masquerade as carcinoma of the stomach or lymphoma. Gummas of the liver
were once the most common form of visceral syphilis and often manifested
as hepatosplenomegaly and anemia and occasionally as fever and jaundice.
Skeletal gummas typically produce lesions in the long bones, skull, and clavicle; a characteristic symptom is nocturnal pain. Radiologic abnormalities,
when present, include periostitis and lytic or sclerotic, destructive osteitis.

Cardiovascular Syphilis

The primary cardiovascular complications of syphilis are aortic insufficiency

(Chapter 75) and aortic aneurysm (Chapter 78), usually of the ascending
aorta. Less commonly, other large arteries may be affected, and involvement
of the coronary ostia rarely results in coronary insufficiency. All these complications are caused by obliterative endarteritis of the vasa vasorum, with
resultant damage to the intima and media of the great vessels. This damage
results in dilation of the ascending aorta, but the valve cusps remain normal.
An aneurysm occasionally manifests as a pulsating mass bulging through the
anterior chest wall. Syphilitic aortitis may also involve the descending aorta
proximal to the renal arteries.
Cardiovascular syphilis usually begins within 5 to 10 years of the initial
infection but may not manifest clinically until 20 to 30 years later. Cardiovascular syphilis does not occur after congenital infectiona phenomenon that
remains unexplained.
Asymptomatic aortitis is best diagnosed by visualizing linear calcifications
in the wall of the ascending aorta by radiography. The signs of syphilitic aortic
insufficiency are the same as for aortic insufficiency of other causes. In aortic
insufficiency resulting from dilation of the aortic ring, the decrescendo
murmur is often loudest along the right sternal margin. Syphilitic aneurysms
may be fusiform but are more typically saccular and do not lead to aortic
dissection. Between 10 and 20% of patients with cardiovascular syphilis have
coexistent neurosyphilis.

Neurosyphilis

CNS involvement occurs throughout the natural history of syphilis. Neurosyphilis can be divided into five groups: asymptomatic, syphilitic meningitis,

1925

meningovascular syphilis, tabes dorsalis, and general paresis. Asymptomatic

neurosyphilis can occur at any time, whereas syphilitic meningitis is most
common during the secondary stage of infection. Meningovascular syphilis,
tabes dorsalis, and general paresis are typically manifestations of late syphilis.
The divisions are not absolute, and overlap between syndromes is typical.
Current cases of neurosyphilis are likely to be variants of the classic syndromes, possibly as a result of the use of antimicrobial agents for other
diseases.
Syphilitic Meningitis

Acute to subacute aseptic meningitis can occur at any time after the primary
stage, but it usually occurs within the first year of infection. It frequently
involves the base of the brain and may result in unilateral or bilateral cranial
nerve palsies. Mild aseptic meningitis may be relatively common in patients
with early syphilis, but severe disease occurs in only about 1.5% of untreated
patients. Syphilitic meningitis typically resolves without treatment.
Meningovascular Syphilis

Some patients have sufficient endarteritis and perivascular inflammation to

result in cerebrovascular thrombosis and infarction, generally 5 to 10 years
after the initial infection. Patients frequently have associated aseptic meningitis. Most cerebrovascular accidents are not caused by syphilitic arteritis,
even in patients with a reactive serologic test result for syphilis. However,
syphilis should be considered a potential cause in relatively young patients
with a history of syphilis and without other risk factors for cerebrovascular
accidents.
Tabes Dorsalis

Tabes dorsalis, which appears to be far less common than in the pre-penicillin
era, is a slowly progressive, degenerative disease that involves the posterior
columns and posterior roots of the spinal cord and results in progressive loss
of peripheral reflexes, impairment of vibration and position sense, and progressive ataxia. There may be chronic destructive changes in the large joints
of the affected limbs in far-advanced cases (i.e., Charcots joints). Incontinence of the bladder and impotence are common. Sudden and severely
painful crises of uncertain origin are a characteristic part of the syndrome.
These features typically involve the lower extremities but can occur at any
site. Severe, sharp abdominal pain may lead to exploratory surgery. These
attacks may be triggered by exposure to cold or other stresses or may arise
with no obvious precipitating cause.
Optic atrophy is seen in 20% of cases. In 90% of patients, the pupils are
bilaterally small and fail to constrict further in response to light, but they do
respond normally to accommodation (i.e., Argyll Robertson pupils).
The onset of tabes dorsalis is usually first noticed 20 to 30 years after the
initial infection. Its cause is unclear, and spirochetes cannot be demonstrated
in the posterior column or dorsal root.
General Paresis

This form of neurosyphilis is a chronic meningoencephalitis resulting in the

gradual and progressive loss of cortical function. It typically occurs 10 to 20
years after the initial infection. Pathologically, there is a perivascular and
meningeal chronic inflammatory reaction, with thickening of the meninges,
granular ependymitis, degeneration of the cortical parenchyma, and abundant spirochetes in tissues. In the United States, first admissions to mental
hospitals because of syphilitic psychosis declined from 7694 in 1940 to 154
in 1968, the last year for which definite figures are available.
In its early stages, general paresis results in nonspecific symptoms of early
dementia, such as irritability, fatigability, headaches, forgetfulness, and personality changes. Later, there is impaired memory, defective judgment, lack
of insight, confusion, and often depression or marked elation. Patients may
be delusional, and seizures sometimes occur. There may also be loss of other
cortical functions, including paralysis or aphasia.
Physical signs are primarily those of the altered mental status. Cranial
nerve palsies are uncommon, and optic atrophy is rare. The complete Argyll
Robertson pupil is also uncommon, but irregular or otherwise abnormal
pupils are not infrequent. Peripheral reflexes are often somewhat increased.

Syphilis-HIV Interactions

Syphilis, like other genital ulcer diseases, is associated with a three- to fivefold increased risk for acquisition of HIV infection. Presumably, genital ulcers
act as portals of entry through which HIV may more readily infect exposed
individuals. As a result, HIV serologic testing 3 months after a diagnosis of

1926

CHAPTER 327 SYPHILIS

syphilis is recommended for all patients. Conversely, in individuals with HIV

infection who acquire syphilis, the natural history of the infection may be
modified. HIV-infected syphilis patients are somewhat more likely than nonHIV-infected patients to present initially with secondary syphilis. HIVinfected secondary syphilis patients are also more likely than HIV-negative
secondary syphilis patients to have coexistent chancres, suggesting that the
healing of chancres is delayed or the appearance of secondary manifestations
is accelerated in the presence of HIV coinfection.

Congenital Syphilis

Congenital syphilis results from the transplacental, hematogenous spread of

syphilis from the mother to the fetus. The incidence of congenital syphilis
diagnoses in the United States fell below 1000 per year for the first time in
1975, and fewer than 500 cases occurred each year until 1988, when the
epidemic of syphilis in adults led to parallel increases in congenital infections.
From 1990 through 1993, more than 3000 new cases of congenital syphilis
were reported each year. A Venereal Disease Research Laboratory (VDRL)
test should be performed in all expectant mothers at the beginning of pregnancy and should be repeated near the end of pregnancy in women living in
areas where syphilis is relatively common.
The risk for fetal infection is greatest in the early stages of untreated maternal syphilis and declines slowly thereafter, but the mother can infect her fetus
during at least the first 5 years of her infection. Adequate treatment of the
mother before the 16th week of pregnancy usually prevents clinical illness in
the neonate. Later treatment may not prevent late sequelae of the disease in
the child. Untreated maternal infection may result in stillbirth, neonatal
death, prematurity, or syndromes of early or late congenital syphilis in surviving infants.
Manifestations of early congenital syphilis are often seen in the perinatal
period but may not develop until the infant has been discharged from the
hospital. The disease resembles secondary syphilis in adults, except that the
rash may be vesicular or bullous. The child often has rhinitis, hepatosplenomegaly, hemolytic anemia, jaundice, and pseudoparalysis (i.e., immobility of
one or more extremities) as a result of painful osteochondritis. There may be
thrombocytopenia and leukocytosis. The early stages of congenital syphilis
must be differentiated from congenital rubella, cytomegalovirus infection,
toxoplasmosis, bacterial sepsis, and other diseases.
Late congenital syphilis is defined as congenital syphilis diagnosed more
than 2 years after birth. The disease may remain latent, with no manifestations
of late damage. Cardiovascular alterations have not been observed in patients
with congenital syphilis. Neurologic manifestations are common and may
include eighth cranial nerve deafness and interstitial keratitis. Periostitis may
result in prominent frontal bones of the skull, depression of the bridge of the
nose (saddle nose), poor development of the maxilla, and anterior bowing of
the tibias (saber shins). There may be late-onset arthritis of the knees (Cluttons joints). The permanent dentition may show characteristic abnormalities
known as Hutchinsons teeth; the upper central incisors are widely spaced,
centrally notched, and tapered in the manner of a screwdriver. The molars
may show multiple poorly developed cusps (mulberry molars).

DIAGNOSIS

Dark-Field Examination

The most definitive means of syphilis diagnosis is finding spirochetes of

typical morphology and motility in lesions of early acquired or congenital
syphilis. Dark-field examination is often positive in cases of primary syphilis
and in patients with the moist mucosal lesions of secondary and congenital
syphilis. The result may occasionally be positive for aspirates of lymph nodes
in secondary syphilis. False-negative results may occur in primary syphilis
because of the application of soaps, antiseptics, or other compounds toxic to
T. pallidum to the lesions. A single negative result is therefore insufficient to
exclude syphilis. For high-risk individuals (e.g., drug users, homosexually
active men), it is appropriate to treat presumptively based on suspicious
lesions after performing serologic tests. Confusion may also arise because of
the presence of spirochetes that are morphologically indistinguishable from
T. pallidum organisms in the mouth, particularly around the gingival margins.
Living T. pallidum organisms demonstrate gradual motion to and fro, rotational movement around the long axis, and rather sudden 90-degree flexing
near the center of the organism. Because most physicians do not have the
proper equipment and are not familiar with dark-field microscopy techniques, public health authorities can be called for assistance. T. pallidum may
also be demonstrated in biopsy or pathologic specimens by fluorescent antibody stains or by silver stains.

TABLE 327-2 SEROLOGIC TESTS FOR SYPHILIS

TYPE

USE

NONTREPONEMAL (ANTICARDIOLIPIN) ANTIBODIES

VDRL (slide flocculation)
RPR (circle card) (agglutination)

Screening, quantitation of response to

treatment
Screening, quantitation of response to
treatment

SPECIFIC TREPONEMAL ANTIBODIES

FTA-ABS (immunofluorescence with
absorbed serum)
TP-PA (microhemagglutination)
EIA

Confirmatory, diagnostic; not for routine

screening
Similar to FTA-ABS but can be
quantified and automated
Confirmatory and increasingly used for
screening; automated

EIA = enzyme immunoassay; FTA-ABS = fluorescent treponemal antibody absorption test; RPR =
rapid plasma regain test; TP-PA = Treponema pallidumparticle agglutination; VDRL = Venereal
Disease Research Laboratory.

TABLE 327-3 FREQUENCY OF POSITIVE SEROLOGIC TESTS

IN UNTREATED SYPHILIS
STAGE
Primary

VDRL (%)
70

FTA-ABS (%)
85

TP-PA (%)
50-60

Secondary

99

100

100

Latent or late

70

98

98

FTA-ABS = fluorescent treponemal antibody absorption test; TP-PA = Treponema pallidumparticle

agglutination; VDRL = Venereal Disease Research Laboratory.

Serologic Tests
Two basic types of serologic tests (Table 327-2) are widely used to diagnose
infection with T. pallidum: (1) nontreponemal tests that detect antibodies
reactive with diphosphatidylglycerol (cardiolipin), which is a normal component of many tissues, and (2) tests that detect antibodies to specific treponemal antigens.

Nontreponemal Tests

The standard tests to detect anticardiolipin antibody are the VDRL and rapid
plasma reagin (RPR) tests, which are slide flocculation tests. The VDRL and
RPR are readily quantified, so they are the tests of choice for monitoring
patients responses to treatment. The relative proportion of patients with a
false-positive VDRL result depends on the prevalence of syphilis in the community; the lower the prevalence of syphilis, the higher the proportion of
reactive VDRL test results from nonsyphilitic causes.
The VDRL test begins to turn positive less than 1 week after onset of the
chancre; thus, a nonreactive VDRL test does not exclude primary syphilis,
particularly if the lesion is less than 1 week old. The VDRL test result is positive in 99% of patients with secondary syphilis (Table 327-3). Patients with
advanced HIV infection may have negative test results, and some patients
have such high titers of antibody that they are in antibody excess; dilution of
their serum paradoxically results in conversion of a negative test result to a
positive one, the so-called prozone reaction. VDRL reactivity tends to diminish in later stages of syphilis, and only about 70% of patients with cardiovascular or neurosyphilis have positive VDRL test results.
The quantitative titer of the VDRL or RPR test is somewhat useful in diagnosis and is quite useful for monitoring the therapeutic response. The titer is
reported as the highest dilution that gives a positive response. Most patients
with secondary syphilis have titers of at least 1:16. Most patients with falsepositive VDRL test results have titers of less than 1:8. No single titer is
diagnostic by itself. Significant rises (four-fold or greater) in paired sera,
however, strongly indicate acute syphilis.

Treponemal Tests

Several types of treponemal tests are widely used. Agglutination of particles

to which T. pallidum antigens have been fixed is the basis of the T. pallidum
particle agglutination (TP-PA) test. More recently, treponemal enzyme

CHAPTER 327 SYPHILIS

immunoassays (EIAs) have become available from several manufacturers and

have gained favor because of their low cost and ease of use.
The treponemal tests are best used to confirm that persons with reactive
nontreponemal tests have antibodies to T. pallidum. Results of treponemal
tests are not reliably quantified. They are sensitive and have a high degree
of specificity, in that only approximately 1% of normal individuals have reactive treponemal tests. They are reactive in 85% of patients with primary
syphilis, 99% with secondary syphilis, and at least 95% with late syphilis.
They may therefore be the only test with a positive result in patients with
cardiovascular or neurologic syphilis. For patients with late syphilis, treponemal tests often remain reactive for life, despite adequate therapy. The fluorescent treponemal antibody absorption (FTA-ABS) test is reported in terms
of relative brilliance of fluorescence, from borderline to 4 plus, and most
laboratories report only tests with 2 plus or greater reactivity as positive. For
patients lacking historical or clinical evidence of syphilis but with a reactive
FTA-ABS test result, the test should be repeated. Use of another treponemal
test, such as the TP-PA test, may be helpful in problem cases. The TP-PA
test is slightly less sensitive than the VDRL or FTA-ABS test in primary
syphilis. Its sensitivity and specificity are otherwise nearly identical to those
of the FTA-ABS test.
EIAs for the detection of antitreponemal antibodies use cloned T. pallidum
antigens generated from bacterial expression systems. EIA serologic tests
permit the screening of large numbers of sera and have performance characteristics (sensitivity, specificity, predictive values) similar to those of other
treponemal tests. Persons with syphilis diagnosed by treponemal antigen
EIAs should be tested with quantitative nontreponemal tests such as the
VDRL or RPR for confirmation and to permit the use of these tests to evaluate the subsequent response to therapy.

Differential Diagnosis

The differential diagnosis of a genital ulcer (Chapter 293) includes genital

herpes (Chapter 382), chancroid (Chapter 309), lymphogranuloma venereum (Chapter 326), and a number of other ulcerative processes. Classically,
herpetic ulcers are multiple, painful, superficial, and, if seen early, vesicular.
However, atypical manifestations may be indistinguishable from a syphilitic
chancre. Genital herpes is much more common than syphilis and is now the
most common cause of a typical chancre in North America. Syphilitic
chancres may also be coinfected with herpes simplex virus in about 15% of
cases. The ulcers of chancroid are usually painful, often multiple, and frequently exudative and nonindurated. Lymphogranuloma venereum may
produce a small, papular lesion associated with regional adenopathy. Other
conditions that must be distinguished include granuloma inguinale (Chapter
324), drug eruptions, carcinoma, superficial fungal infections (Chapter 446),
traumatic lesions, and lichen planus (Chapter 446). In most cases, the final
distinction is based on dark-field examination, which is positive only in syphilis, and on serologic test results.
The differential diagnosis of the skin lesions of secondary syphilis includes
pityriasis rosea (Chapter 446), which can be differentiated by the occurrence
of lesions along lines of skin cleavage and frequently by the presence of a
herald patch. Drug eruptions, acute febrile exanthems, psoriasis, lichen
planus, scabies, and other diseases must also be considered in some cases. A
mucous patch may superficially resemble oral candidiasis (i.e., thrush). Infectious mononucleosis (Chapter 385) may appear very similar to secondary
syphilis, with sore throat, generalized adenopathy, hepatitis, and a generalized
rash. Hepatitis (Chapter 150) may also cause confusion.

False-Positive Serologic Test Results for Syphilis

The VDRL or RPR test is reactive in patients with other treponemal diseases
such as pinta, yaws, and endemic syphilis (Chapter 328). These tests may also
be falsely reactive in persons who do not have treponemal infections based
on a negative clinical history or negative results of serum treponemal tests.
Acute (<6 months) false-positive VDRL test results occur with low frequency in patients with atypical pneumonia, malaria, and other bacterial or
viral infections, and they may occur after smallpox or other vaccinations as
well. Chronic false-positive VDRL test results (persisting >6 months) are
relatively common in patients with autoimmune disorders such as systemic
lupus erythematosus (SLE; Chapter 274), parenteral drug users, HIVinfected patients, patients with leprosy, and the aged. Between 8 and 20% of
patients with SLE have false-positive VDRL test results. Chronic false-positive VDRL test results in female patients 20 years or younger indicate a significant risk for the future development of SLE, thyroiditis, or other
autoimmune disorders. As many as a third of parenteral drug users have

1927

false-positive VDRL test results. More than 1% of persons 70 years old and
10% of those older than 80 also have low-titer, false-positive VDRL test
results. In most cases of false-positive VDRL tests, the titer is less than 1:8,
although a few patients with lymphoma and other diseases have very hightiter, false-positive results.
There is also an increased incidence of false-positive treponemal test
results in other chronic inflammatory diseases associated with hyperglobulinemia, including rheumatoid arthritis and biliary cirrhosis. Occasionally,
reproducible positive FTA-ABS results are obtained in patients with no clinical or historical evidence of syphilis and no evidence of diseases typically
associated with false-positive FTA-ABS results. If the diagnosis is in doubt
and if the patient is not allergic to penicillin, it is often prudent to treat for
possible syphilis.

Neurosyphilis

Asymptomatic neurosyphilis is diagnosed when there are CSF abnormalities,

such as lymphocytic pleocytosis, protein elevation, or a reactive VDRL test
result, in a syphilis patient in the absence of signs and symptoms of neurologic disease. Although numerous other processes can cause CSF pleocytosis or protein elevations, false-positive CSF VDRL test results are rare
in the absence of a traumatic tap. If the CSF is normal 2 years or longer
after the initial infection, a positive CSF finding is not likely to develop
later. Routine lumbar punctures to examine CSF are not indicated in early
syphilis unless the patient is known to have HIV infection. Lumbar puncture
in HIV-infected persons with early syphilis is the subject of controversy.
Although a nonreactive CSF FTA-ABS result may be useful to rule out the
diagnosis, no diagnosis of neurosyphilis should be based solely on the CSF
FTA-ABS test.
In syphilitic meningitis, the CSF shows a lymphocytic pleocytosis, with
increased protein and usually normal glucose concentrations. The CSF
VDRL test is nearly always reactive. Rarely, the CSF glucose concentration is
decreased. Without treatment, syphilitic meningitis generally resolves,
similar to the course of other manifestations of early syphilis. This syndrome
can mimic tuberculous or fungal meningitis or nonpurulent meningitis of
various causes.
In tabes dorsalis, the VDRL test for serum is nonreactive in as many as 30
to 40% of patients, and 10 to 20% of patients (even before the advent of
penicillin) have normal CSF VDRL results. The FTA-ABS test for serum is
nearly always reactive.
In general paresis, the CSF is nearly always abnormal, with lymphocytic
pleocytosis and an increased total protein concentration. The VDRL test is
usually reactive for CSF and serum.

Congenital Syphilis

Because many infants with congenital syphilis may be clinically normal at

birth but develop serious, symptomatic disease some weeks later, it is important to determine whether a newborn with a reactive VDRL or FTA-ABS test
result has passively transferred maternal antibody or is actively infected. If the
mother has been adequately treated for syphilis during pregnancy and the
infant is clinically normal at birth, one option is to monitor the infant carefully by serial examinations and VDRL titers. If the reactive VDRL result for
the infant is caused by passively transferred maternal antibody, the titer will
fall markedly in the first 2 months of life; a rising titer indicates active disease
and the need for treatment. However, the risk of improper follow-up of
VDRL-positive but clinically normal neonates makes the immediate empirical administration of effective therapy an attractive alternative.

TREATMENT
T. pallidum is inhibited by less than 0.01g/mL of penicillin G. Because
treponemes divide slowly and penicillin acts only on dividing cells, it is necessary to maintain serum levels of penicillin for many days (Table 327-4).

Early Infectious Syphilis

Early syphilis (<1 year) can be treated with a single injection of 2.4 million
U of benzathine penicillin G, which provides low but effective serum levels for
more than 2 weeks and cures approximately 95% of patients. It is not necessary to examine CSF at this stage because penicillin prevents the later development of neurosyphilis.
Individuals with other sexually transmitted diseases may have been exposed
to syphilis at the time they became infected. Treatment with a single dose of
-lactam antibiotics (penicillins, cephalosporins), which provide relatively high

1928

CHAPTER 327 SYPHILIS

TABLE 327-4 PENICILLIN TREATMENT FOR SYPHILIS AS RECOMMENDED BY THE U.S. PUBLIC HEALTH SERVICE
Dosage and Administration
BENZATHINE PENICILLIN G
Total of 2.4 million U; single IM dose of two
injections of 1.2 million U in one session

AQUEOUS BENZYLPENICILLIN G OR PROCAINE

PENICILLIN G
Total of 4.8 million U IM in doses of 600,000U/day for 8
consecutive days

Late latent (>1yr) or when CSF was not examined

in latency; cardiovascular syphilis, late benign
(cutaneous, osseous, visceral gumma)

Total of 7.2 million U IM in doses of 2.4 million

U at 7-day intervals over a 21-day period

Total of 9 million U IM in doses of 600,000U/day over a

15-day period

Symptomatic or asymptomatic neurosyphilis

2-4 million U aqueous (crystalline) penicillin G

IV q4h for at least 10 days

2-4 million U procaine penicillin IM daily and probenecid

500mg orally four times daily, for 10-14 days

CSF normal: Total of 50,000U/kg IM in a

single or divided dose at one session
CSF normal: Same as for early congenital
syphilis, up to 2.4 million U

CSF abnormal: Total of 50,000U/kg/day IM for 10

consecutive days
CSF abnormal: 200,000-300,000U/kg/day aqueous
crystalline penicillin IV for 10-14 days

INDICATIONS FOR SYPHILIS THERAPY*

Primary, secondary, and early latent syphilis (<1yr);
epidemiologic treatment

Congenital
Infants
Older children

*In pregnancy, treatment depends on the stage of syphilis.

Individual doses can be divided for injection in each buttock to minimize discomfort.

For aqueous penicillin, give in two divided intravenous doses per day; for procaine penicillin, give as one daily dose intramuscularly.
CSF = cerebrospinal fluid.

serum levels for a brief period, is ineffective in established early syphilis but is
curative if the disease is still in the incubating stage. The ceftriaxone regimen
used for gonorrhea (Chapter 307) is probably curative for incubating syphilis,
but careful follow-up is indicated if there is reason to suspect exposure to
syphilis in a patient treated for gonorrhea with ceftriaxone. Single-dose
therapy with 2.0g of azithromycin administered orally was as effective as
benzathine penicillin therapy in several studies of early syphilis, but treatment
failures have been reported in persons with coexistent HIV infection.1 Currently, azithromycin should not be used for the treatment of early syphilis
unless close follow-up can be ensured.
For patients allergic to penicillin, 100mg of doxycycline orally twice daily
for 14 days is recommended. Particularly careful follow-up is necessary for
patients treated with drugs other than penicillin because they may not be fully
compliant with these prolonged courses of oral therapy and these regimens
have been less fully evaluated clinically. Ceftriaxone, given in doses of 500mg
to 1.0g intramuscularly daily for 10 days, may be effective but has been
studied only in small numbers of patients with syphilis. Quinolone antibiotics
have essentially no effect on syphilis.

Syphilis in Pregnancy

Syphilis of More than 1 Years Duration

Proper treatment of the mother usually prevents active congenital syphilis

in the neonate. However, infected infants may be clinically normal at birth,
and the infant may be seronegative if the mothers infection was acquired
late in pregnancy. The infant should be treated at birth if the mother has
received no treatment or inadequate treatment or has been treated with
drugs other than penicillin, if the mother has not yet responded to possibly
effective therapy, or if the infant cannot be carefully monitored for several
months after birth. The infants CSF should be examined before treatment.
If the CSF is normal, the child can be treated with a single intramuscular
injection of 50,000 U/kg (up to 2.4 million U) of benzathine penicillin G. If
the CSF is abnormal, the infant should be treated with 50,000 U/kg of
aqueous penicillin G given intramuscularly or intravenously twice daily for
a minimum of 10 days. Alternatively, a single daily intramuscular injection
of 50,000 U/kg of procaine penicillin may be given for 10 days. Antimicrobial
agents other than penicillin are not recommended for treating congenital
syphilis.

Prolonged therapy with intramuscular injections of 2.4 million U of benzathine penicillin G weekly for 3 weeks is recommended for the treatment
of late latent syphilis and latent syphilis of unknown duration. Limited evidence suggests that treating latent syphilis with a total dose of 7.2 million
U of benzathine penicillin over a 3-week period is curative, even if the patient
has asymptomatic neurosyphilis. However, because of the possible lack of
efficacy of benzathine penicillin G in some patients with CNS syphilis, CSF
examination should be considered in those with latent syphilis to exclude
asymptomatic neurosyphilis, particularly HIV-positive patients, in whom the
prevalence of asymptomatic neurosyphilis is higher. Alternatively, a lumbar
puncture can be performed at the conclusion of the follow-up period
(2 years); if the CSF is normal, the patient can be reassured that neurosyphilis
will not develop.
Larger doses of penicillin are recommended for persons with proven neurosyphilis (see Table 327-4). General paresis responds well to penicillin therapy
if administered early, although progressive neurologic decline may develop
later in as many as a third of treated patients. Carbamazepine in doses of 400
to 800mg/day reportedly treats the lightning pains of tabes dorsalis effectively. Published studies show that a total of 6.0 to 9.0 million U of penicillin G
results in a satisfactory clinical response in approximately 90% of patients with
neurosyphilis who do not have HIV infection. There are anecdotal reports of
increased treatment failures in patients with concomitant HIV infection, and
there is considerable rationale to treat these patients with intravenous penicillin G (20 million U/day for at least 10 days). Therapy for neurosyphilis can result
in increased CSF pleocytosis for 7 to 10 days after starting treatment and may
transiently convert a normal CSF to abnormal.
Although there is no evidence that therapy with antimicrobial drugs is clinically beneficial in patients with cardiovascular syphilis, treatment is recommended to prevent further progression of disease and because approximately
15% of patients with cardiovascular syphilis have associated neurosyphilis. If
patients are allergic to penicillin, it is mandatory that the CSF be examined
before therapy is undertaken; if the CSF is abnormal, desensitization to penicillin is generally recommended. With a normal CSF, tetracycline (500mg orally
four times a day) or doxycycline (100mg orally two times a day) taken for 4
weeks is probably effective.

Because of the risk to the fetus, evaluation and treatment of a pregnant

VDRL-positive patient must be rapid, particularly those first seen in the later
stages of pregnancy. If a confirmatory FTA-ABS test is positive and the patient
has not been treated, penicillin should be administered in doses appropriate
for early or late syphilis, as outlined earlier. For penicillin-allergic patients,
penicillin desensitization is preferred; patients should not be treated with
tetracycline or erythromycin because of toxicity (tetracycline) or lack of efficacy (erythromycin). For patients who are VDRL positive but FTA-ABS negative
and have no clinical signs of syphilis, treatment may be withheld; a quantitative VDRL test and another FTA-ABS test should be repeated in 4 weeks. If
the VDRL titer has risen four-fold or more, or if clinical signs of syphilis have
developed, the patient should be treated. If, after repeat examination, the
diagnosis remains equivocal, the patient should be treated to prevent possible disease in the neonate. After treatment, a quantitative VDRL titer should
be monitored monthly; if it rises four-fold, the patient should be treated a
second time.

Congenital Syphilis

Jarisch-Herxheimer Reactions

Up to 60% of patients with early syphilis and a significant proportion of

patients with later stages of syphilis experience a transient febrile reaction
after therapy for syphilis. The pathogenesis is unclear, but it may be caused by
the liberation of antigens from spirochetes.
This reaction usually occurs in the first few hours after therapy, peaks at 6
to 8 hours, and disappears within 12 to 24 hours of therapy. Occasionally,
Jarisch-Herxheimer reactions are mistaken for allergic reactions to syphilis
therapy. Temperature elevation is usually low grade, and there is often associated myalgia, headache, and malaise. The skin lesions of secondary syphilis are
frequently exacerbated during the Jarisch-Herxheimer reaction, and cutaneous lesions that were not visible may become visible. The reaction is generally
of no clinical significance and in most cases can be treated with salicylates.
Corticosteroids have been used to prevent adverse effects of the Jarisch-Herxheimer reaction, but there is no evidence that they are clinically beneficial
(other than reducing fever) or necessary. Institution of treatment with small
doses of penicillin does not prevent the reaction.

PREVENTION

All patients with syphilis should be reported to public health authorities. In

the absence of an effective vaccine, control of syphilis depends on finding and
treating persons with infectious lesions of primary and secondary syphilis
before they can transmit the disease, as well as finding and treating individuals with incubating syphilis before infectious lesions develop. All patients
with early syphilis (primary, secondary, or early latent) should be carefully
interviewed by qualified persons to determine the nature of their recent
sexual contacts. Approximately 16% of the named recent contacts of patients
with early syphilis are found to have active, untreated syphilis on examination, and a similar proportion of individuals named as suspects or associates
also have active syphilis.
Treatment of the sexual contacts of patients with early syphilis with 2.4
million U of benzathine penicillin G intramuscularly is recommended even
if the contacts are clinically and serologically normal on examination. This is
because syphilis eventually develops in 30% of clinically normal contacts who
are untreated. In general, preventive treatment is given to all sexual contacts
in the past 90 days, although nearly all cases of syphilis in contacts develop
within 60 days of exposure.

PROGNOSIS

Follow-up Examinations

All HIV-seronegative patients with early or congenital syphilis should return

for quantitative VDRL titers and clinical examination 6 and 12 months after
treatment. For HIV-positive patients, serologic tests should be repeated at 1,
2, 3, 6, 9, and 12 months. Patients with late latent syphilis should also be
examined 24 months after therapy.
In about 85% of patients with early (i.e., primary, secondary, or early latent)
syphilis, quantitative VDRL titers decline two or more dilutions (four-fold)
by 6 and 12 months after therapy. Prolonged reactive VDRL test results are
associated with higher initial VDRL titers, prolonged infection, more
advanced stage (primary < secondary < early latent), or repeated infection.
Chronic, low-titer VDRL reactivity after therapy is much more common in
cases of late syphilis and should not be viewed with alarm. Treponemal tests
may remain positive for years despite adequate therapy. A four-fold or greater
rise in VDRL titer after therapy is sufficient evidence for repeat treatment.
Patients with treated early syphilis are susceptible to reinfection, and many
clinical and serologic relapses after therapy are probably reinfections. As such,
they represent failures of proper epidemiologic case finding and preventive
therapy for the patients sexual contacts.
Patients with neurosyphilis should be monitored with serologic tests for
at least 3 years and with repeat CSF examinations at 6-month intervals. CSF
pleocytosis is the first abnormality to disappear, but cell counts may not be
normal for 1 to 2 years. Elevated CSF protein levels fall even more slowly,
followed by a change in the positive CSF VDRL test, which may take years
to become negative. It is not known whether high-dose intravenous penicillin
therapy accelerates the return of CSF to normal. Rising CSF cell counts,
protein, and VDRL titer obtained at follow-up are an indication for repeat
treatment.
Antibiotic therapy should ultimately cure essentially all patients with early
or secondary syphilis, although treatment failures may occur in patients with
concomitant HIV infection. In tabes dorsalis, penicillin usually arrests progression but does not reverse the symptoms. Meningovascular syphilis generally responds well, except for residual damage resulting from ischemic infarcts.
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1. Hook EW, Behets F, Van Damme K, et al. A phase III equivalence trial of azithromycin versus benzathine penicillin G for treatment of early syphilis. J Infect Dis. 2010;201:1729-1735.

SUGGESTED READINGS
French P, Gomberg M, Janier M, et al. IUSTI: 2008 European guidelines on the management of syphilis.
Int J STD AIDS. 2009;20:300-309. Consensus guidelines.
Tucker JD, Bu J, Brown LB, et al. Accelerating worldwide syphilis screening through rapid testing: a
systematic review. Lancet Infect Dis. 2010;10:381-386. Review of several available rapid tests, with a
focus on the best evaluated immunochromatographic strip test to detect Treponema antibody.
Wolff T, Shelton E, Sessions C, et al. Screening for syphilis infection in pregnant women: evidence for
the U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med.
2009; 150:710-716. New evidence to support universal screening of pregnant women for syphilis.
Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted
diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59:1-110. National recommendations.