AUTHOR AND EDITOR INFORMATION

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• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Treponema pallidum is the microaerophilic spirochete that causes syphilis, a chronic systemic venereal disease with multiple clinical presentations (ie, the great imitator). Syphilis is characterized by episodes of active disease (primary, secondary, tertiary stages) interrupted by periods of latency. Since the diagnosis frequently is suspected after examination of skin lesions, dermatologists are recognized as experts in the diagnosis and treatment of syphilis. Syphilis is transmitted in 2 ways, either from intimate contact with infectious lesions (most common) or blood transfusions (blood collected during early syphilis), or it is transmitted transplacentally from an infected mother to her fetus.

Pathophysiology

In acquired syphilis, the organism rapidly penetrates intact mucous membranes or microscopic dermal abrasions and, within a few hours, enters the lymphatics and blood to produce systemic infection. The CNS is invaded early in the infection; during the secondary stage, examinations demonstrate that more than 30% of patients have abnormal findings in the cerebrospinal fluid (CSF). During the first 5-10 years after infection, the disease principally involves the meninges and blood vessels, resulting in meningovascular neurosyphilis. Later, the parenchyma of the brain and spinal cord are damaged, resulting in parenchymatous neurosyphilis.

Regardless of the stage of disease and location of lesions, 2 histopathologic hallmarks of syphilis have been noted including obliterative endarteritis and plasma cell–rich mononuclear infiltrates. Endarteritis is caused by the binding of spirochetes to endothelial cells, mediated by host fibronectin molecules bound to the surface of the spirochetes. The resultant endarteritis heals with scar tissue formation.

The mononuclear infiltrates reflect a delayed-type hypersensitivity response to T pallidum, and in certain individuals with tertiary syphilis, this response by sensitized T lymphocytes and macrophages results in gummatous ulcerations and necrosis. Antigens of T pallidum induce host production of treponemal antibodies and nonspecific reagin antibodies. Immunity to syphilis is incomplete. For example, host humoral and cellular immune responses may prevent the formation of a primary lesion (chancre) on subsequent infections with T pallidum, but they are insufficient to clear the organism. This may be because the outer sheath of the spirochete is lacking immunogenic molecules, or it may be because of down-regulation of helper T cells of the TH1 class.

Frequency

United States

The incidence of syphilis had been declining in recent years, with 53,000 reported cases (11,387 primary and secondary cases) in 1996, compared with 113,000 cases (33,962 primary and secondary cases) reported in 1992. However, the number of cases of primary and secondary syphilis increased yearly from 2000-2003. In 2003, 7177 cases were reported to the US Centers for Disease Control and Prevention. Most of this increase has been noted in men, particularly in men who have sex with other men. The overall cases reported in women decreased. More than 80% of cases were reported in the southern United States. Trends for congenital syphilis cases closely parallel those for acquired syphilis cases in women, namely, a decreased incidence over the past decade.

International

Syphilis remains prevalent in many developing countries and in some areas of North America, Asia, and Europe, especially Eastern Europe. In some regions of Siberia, as of 1999, prevalence was 1300 cases per 100,000 population.

Mortality/Morbidity

• Although rarely seen by clinicians since the use of penicillin became widespread in the 1950s, the primary complications of syphilis in adults include neurosyphilis, cardiovascular syphilis, and gumma. Death resulting from syphilis continues to occur. One study found that of 113 recorded deaths resulting from sexually transmitted diseases, 105 were caused by syphilis, with cardiovascular and neurosyphilis accounting for the majority of these deaths.
• These figures have continued to increase since the emergence of the AIDS epidemic, since genital ulcer diseases (including syphilis) are cofactors for the sexual transmission of HIV. Additionally, untreated patients who are HIV seropositive have an increased risk for rapid progression to neurosyphilis and for its complications. In addition, patients with HIV are at greater risk for development or relapse of early symptomatic neurosyphilis for up to 2 years after treatment with intramuscular or intravenous penicillin.
• Congenital syphilis is the most serious outcome of syphilis in women. It has been shown that a higher proportion of infants are affected if the mother has untreated secondary syphilis, compared to untreated early latent syphilis. Since T pallidum does not invade the placental tissue or the fetus until the fifth month of gestation, syphilis causes late abortion, stillbirth, or death soon after delivery in more than 40% of untreated maternal infections. Neonatal mortality usually results from pulmonary hemorrhage, bacterial superinfection, or fulminant hepatitis.

Race

In the United States, syphilis is more prevalent among persons of minority race and ethnicity. The reported prevalence of syphilis is somewhat higher among blacks than other ethnic groups. However, this rate has declined significantly in the past few years. From 2000-2003, the primary and secondary syphilis rate declined from 12 cases per 100,000 population to 7.8 cases per 100,000 population in this ethnic group. In 2002, 49.8% of all reported cases were in blacks, compared with 39.2% of cases in 2003.

Sex

The male-to-female ratio has increased over the past 3 years, largely due to the increased rate of disease among men who have sex with other men. In 2003, it was approximately 5:1.

Age

The incidence of syphilis peaks at age 15-34 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

• Primary syphilis occurs within 3 weeks of contact with an infected individual. Patients usually present with a solitary red papule that rapidly forms a painless nonbleeding ulcer or chancre (see Image 1). The chancre usually heals within 4-8 weeks, with or without therapy.
• Secondary syphilis usually presents with a cutaneous eruption within 2-10 weeks after the primary chancre and is most florid 3-4 months after infection. The eruption may be subtle; 25% of patients may be unaware of skin changes.
• • Mild constitutional symptoms of malaise, headache, anorexia, nausea, aching pains in the bones, and fatigue often are present, as well as fever and neck stiffness.
  • A small number of patients develop acute syphilitic meningitis and present with headache, neck stiffness, facial numbness or weakness, and deafness.
• The lesions of benign tertiary syphilis usually develop within 3-10 years of infection. The typical lesion is a gumma, and patient complaints usually are secondary to bone pain, which is described as a deep boring pain characteristically worse at night. Trauma may predispose a specific site to gumma involvement.
• • CNS involvement may occur, with presenting symptoms representative of the area affected, ie, brain involvement (headache, dizziness, mood disturbance, neck stiffness, blurred vision) and spinal cord involvement (bulbar symptoms, weakness and wasting of shoulder girdle and arm muscles, incontinence, impotence).
  • Some patients may present up to 20 years after infection with behavioral changes and other signs of dementia, which is indicative of neurosyphilis.
• A small percentage of infants infected in utero may have a latent form of infection that becomes apparent during childhood and, in some cases, during adult life. The earliest symptom that occurs prior to age 2 years is rhinitis (snuffles), soon followed by cutaneous lesions. After age 2 years, parents may note problems with the child's hearing and language development and with vision. Facial and dental abnormalities may be noted.

Physical

• Primary syphilis
• • The primary lesion (chancre) occurs on the penis or scrotum of 70% of men with syphilis and on the vulva, cervix, or perineum of more than 50% of women with syphilis.
  • The primary lesion usually is a single ulcerated lesion with a surrounding red areola. The edge and base of the ulcer have a cartilaginous (buttonlike) consistency on palpation.
  • The lesion is highly infectious; when abraded, it exudes a clear serum containing numerous T pallidum organisms.
  • Extragenital chancres occur most commonly above the neck, typically affecting the lips or oral cavity.
  • The regional lymph nodes usually enlarge painlessly and are firm, discrete, and nontender.
• Secondary syphilis
• • The protean manifestations of the secondary stage usually include localized or diffuse symmetric mucocutaneous lesions and generalized nontender lymphadenopathy (see Media Files 3-4).
  • The healing primary chancre may remain present in 15-25% of patients.
• • Initial lesions are bilaterally symmetric, pale red to pink (in light-skinned persons) or pigmented (in dark-skinned persons), discrete, round macules that measure 5-10 mm in diameter and are distributed on the trunk and proximal extremities.
  • After several days or weeks, red papular lesions 3-10 mm in diameter appear. These lesions often become necrotic and are distributed widely with frequent involvement of the palms and soles.
  • Tiny papular follicular syphilids involving hair follicles may result in patchy alopecia. In addition to the classic moth-eaten alopecia, a diffuse alopecia also has been reported.
  • In 10% of patients, highly infectious papules develop at the mucocutaneous junctions and, in moist intertriginous skin, become hypertrophic and dull pink or gray (condyloma lata; see Media File 2).
  • From 10-15% of patients with secondary syphilis develop superficial mucosal erosions on the palate, pharynx, larynx, glans penis, vulva, or in the anal canal and rectum. These mucous patches are circular silver-gray erosions with a red areola.
  • Ocular abnormalities, such as iritis, are a rare clinical finding, although anterior uveitis has been reported in 5-10% of patients with secondary syphilis.
  • Less common findings include periostitis, arthralgias, meningitis, nephritis, hepatitis, and ulcerative colitis.
• Tertiary syphilis
• • Gummas may be identified on the skin, in the mouth, and in the upper respiratory tract. They appear most commonly on the leg just below the knee.
  • Gummas may be multiple or diffuse but usually are solitary lesions that range from less than 1 cm to several centimeters in diameter.
  • Cutaneous gummas are indurated, nodular, papulosquamous or ulcerative lesions that form characteristic circles or arcs with peripheral hyperpigmentation.
• • The most common clinical finding on cardiovascular examination is a diastolic murmur with a tambour quality, secondary to aortic dilation with valvular insufficiency.
  • Symptomatic neurosyphilis produces various clinical syndromes that develop in approximately 5% of patients with syphilis who remain untreated. The most common presentation of meningovascular syphilis (diffuse inflammation of the pia and arachnoid along with widespread arterial involvement) is an indolent stroke syndrome involving the middle cerebral artery.
  • Cranial nerve palsies and pupillary abnormalities occur with basilar meningitis.
  • Argyll Robertson pupil, which occurs almost exclusively in neurosyphilis, is a small irregular pupil that reacts normally to accommodation but not to light.
  • Tabes dorsalis presents with signs of demyelination of the posterior columns, dorsal roots, and dorsal root ganglia (eg, ataxic wide-based gait and foot slap, areflexia and loss of position, deep pain and temperature sensations). Deep ulcers of the feet can result from loss of pain sensation.
  • Rare findings include iritis, with possible adhesion of the iris to the anterior lens, producing a fixed pupil (not to be confused with Argyll Robertson pupil).
• Congenital syphilis: The manifestations of untreated congenital syphilis can be divided into those that are expressed prior to age 2 years (early) or after age 2 years (late).
• • Early manifestations
  • • Early signs and symptoms include development of a diffuse rash, characterized by extensive sloughing of the epithelium, particularly on the palms, soles, and skin around the mouth and anus.
    • A compilation of early clinical presentations of congenital syphilis in 9 studies involving a total of 212 infants included abnormal bone radiographs (61%), hepatomegaly (51%), splenomegaly (49%), petechiae (41%), other skin rashes (35%), anemia (34%), lymphadenopathy (32%), jaundice (30%), pseudoparalysis (28%), and snuffles (23%).
    • A classic mucocutaneous sign is depressed linear scars radiating from the orifice of the mouth and termed rhagades (Parrot lines).
  • Late manifestations
  • • Late signs and symptoms are rare and, if encountered, usually involve complications including interstitial keratitis, cranial nerve VIII deafness, corneal opacities, and/or recurrent arthropathy.
    • The clinical manifestations of untreated congenital neurosyphilis present in 25% of patients older than age 6 years and correspond to those of adult neurosyphilis.
    • Gummatous periostitis occurs in patients aged 5-20 years and tends to cause destructive lesions of the palate and nasal septum (saddle nose).
    • Dental abnormalities may be evident, such as centrally notched and widely spaced, peg-shaped, upper central incisors (Hutchinson teeth) and sixth-year molars with multiple poorly developed cusps (mulberry molars).
    • Peculiar bone findings include frontal bossing of Parrot and Higoumenakia sign, which is unilateral irregular enlargement of the sternoclavicular portion of the clavicle secondary to periostitis.

DIFFERENTIALS

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Other Problems to be Considered

Erosive balanitis
Traumatic superinfected lesions

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• In suspected acquired syphilis, perform nontreponemal serology screening using Venereal Disease Research Laboratory (VDRL), rapid plasma reagin (RPR), or the recently developed ICE Syphilis recombinant antigen test. Then, test sera yielding a positive or equivocal reaction by the fluorescent treponemal antibody-absorption (FTA-ABS), quantitative VDRL/RPR, and microhemagglutination assay Treponema pallidum (MHA-TP) tests.
• Dark-field microscopy is essential in evaluating moist cutaneous lesions, such as the chancre of primary syphilis or the condyloma lata of secondary syphilis. When dark-field microscopy is not available, direct immunofluorescence staining of fixed smears (direct fluorescent antibody Treponema pallidum [DFA-TP]) is an option. Both procedures detect the causative organism at a rate of approximately 85-92%.
• For evaluation of infants with suspected congenital syphilis, the 19S immunoglobulin M FTA-ABS serology test or the Captia Syphilis-M test currently is recommended. Every pregnant woman should undergo a nontreponemal test at her first prenatal visit, and women at high risk of exposure should have a repeat test in the third trimester and again at delivery.

Imaging Studies

• Radiologic abnormal findings commonly seen with advanced gummas of bone include periostitis, destructive osteitis, or sclerosing osteitis.
• For cardiovascular complications of tertiary syphilis, linear calcification of the ascending aorta on chest films suggests asymptomatic syphilitic aortitis.
• Angiography may be useful to distinguish between abdominal aneurysms of syphilitic versus arteriosclerotic origin since 10% of syphilitic aneurysms occur superior to the renal arteries, while arteriosclerotic abdominal aneurysms usually are found inferior to the renal arteries.

Other Tests

• Echocardiogram and ECG may help confirm cardiovascular syphilis.

Procedures

• Biopsy may be necessary to differentiate gummas from coincidental granulomatous conditions.
• Lumbar puncture for CSF examination is indicated in the following situations: neurologic signs or symptoms, treatment failure or plans to administer treatment other than penicillin, a serum reagin titer of greater than or equal to 1:32, seropositive HIV, and other changes indicative of active syphilis (eg, gumma, aortitis). Additionally, the only means by which the occurrence of asymptomatic neurosyphilis in latent syphilis can be excluded is via CSF examination.

Histologic Findings

Primary syphilis: Skin lesions reveal perivascular infiltration, chiefly by lymphocytes, plasma cells, and macrophages, with capillary endothelial proliferation and subsequent obliteration of small blood vessels.

Secondary syphilis: Skin lesions reveal hyperkeratosis of the epidermis, capillary proliferation with endothelial swelling in the superficial corium, and transmigration of polymorphonuclear neutrophils. In the deeper dermis, perivascular infiltration by monocytes, plasma cells, and lymphocytes occurs.

Tertiary lesions: Gummas consist of granulomatous inflammation with a center of coagulated necrotic material and margins composed of plump or palisaded macrophages and fibroblasts surrounded by large numbers of mononuclear leukocytes, chiefly plasma cells. Treponemes are scant in these gummas and are difficult to demonstrate. Aortitis reveals inflammatory scarring of the tunica media, secondary to obliterative endarteritis of the vasa vasorum. A patchy uneven loss of the medial elastic fibers and muscle cells is evident.

TREATMENT

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Medical Care

Penicillin remains the mainstay of treatment and the standard by which other modes of therapy are judged.

• Penicillin use is the only therapy used widely for neurosyphilis, congenital syphilis, or syphilis during pregnancy. Rarely, T pallidum has been found to persist following adequate penicillin therapy; however, there is no indication that the organism has acquired resistance to penicillin.
• In patients with allergy to penicillin, skin testing and desensitization are recommended. Make every effort to document penicillin allergy before choosing an alternative treatment because the efficacy of alternative regimens is questionable in all stages of syphilis. Many treatment failures have been reported.
• Tetracycline, erythromycin, and ceftriaxone have shown antitreponemal activity in clinical trials; however, they currently are recommended only as alternative treatment regimens in patients allergic to penicillin.

Consultations

Consultations are necessary depending on the specific complications and organ systems affected.

MEDICATION

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Penicillin is the mainstay of treatment, the standard by which other modes of therapy are judged, and the only therapy that has been used widely for neurosyphilis, congenital syphilis, or syphilis during pregnancy. On rare occasions, T pallidum has been found to persist after adequate penicillin therapy; however, no indication exists that T pallidum has acquired resistance to the drug.

Tetracycline, erythromycin, and ceftriaxone have shown antitreponemal activity in clinical trials but currently are recommended only as alternative treatment regimens in patients allergic to penicillin.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Tetracycline (Sumycin)
Description	Alternative agent for penicillin-allergic patients. Treats gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).
Adult Dose	Primary, secondary, and early latent disease: 500 mg PO qid for 14 d Late latent syphilis with normal CSF, cardiovascular syphilis, and late benign (gumma) disease: 500 mg PO qid for 28 d
Pediatric Dose	<8 years: Not recommended >8 years: 25-50 mg/kg/d (10-20 mg/lb) PO qid
Contraindications	Documented hypersensitivity; severe hepatic dysfunction; pregnancy (hepatotoxicity to mother, transplacental to fetus); breastfeeding
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Erythromycin (EES, E-Mycin, Eryc)
Description	Alternative agent for penicillin-allergic patients. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes causing RNA-dependent protein synthesis to arrest. For treatment of staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half-total daily dose may be taken q12h. For more severe infections, double the dose.
Adult Dose	250 mg stearate/base (or 400 mg ethylsuccinate) PO q6h or 500 mg q12h
Pediatric Dose	Not recommended 30-50 mg/kg/d PO in divided doses; consider double dosing for neurologic involvement
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI side effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name	Ceftriaxone (Rocephin)
Description	Alternative agent for penicillin-allergic patients. Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin binding proteins.
Adult Dose	2 gm qd IM/IV for 10-14 d
Pediatric Dose	Not recommended 75-100 mg/kg IV/IM qd for 10-14 d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections, and promotion of non-susceptible organisms may occur with prolonged use or repeated therapy; caution in breastfeeding

FOLLOW-UP

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Further Outpatient Care

• Patients with treated primary or secondary syphilis
• • Perform quantitative VDRL testing at 1, 3, 6, and 12 months following treatment.
  • If the VDRL titer of 1:8 or more fails to fall at least 4 fold within 12 months or if the titer starts to rise, consider more intensive retreatment, and examine the CSF.
  • If all clinical and serologic examinations remain satisfactory for 2 years following treatment, the patient can be reassured that cure is complete, and no further follow-up care is needed.
• Patients with latent syphilis
• • Perform quantitative reagin testing for up to 2 years.
  • Schedule annual follow-up visits for an indefinite period of time for patients with persistently positive serologic tests.
• Patients with benign tertiary or cardiovascular syphilis: Patients should be observed by the physician for the rest of their lives to monitor for complications.
• Patients with neurosyphilis (both symptomatic and asymptomatic): Examine the CSF (cell count, protein, reagin titer) every 3-6 months for 3 years or until CSF findings return to normal.

Complications

• For a discussion of the complications of syphilis, see Mortality/Morbidity.

Prognosis

• For patients diagnosed with either primary or secondary syphilis (without auditory/neurologic/ocular involvement), the prognosis is good following appropriate treatment.
• For patients diagnosed with tertiary syphilis, overall prognosis depends on the duration and extent of disease activity, along with prior attempts to treat the disease. For example, prognosis for advanced symptomatic disease in cardiovascular syphilis is poor, unless it is treated with high doses of intravenous penicillin. In contrast, in patients with neurosyphilis complicated by optic atrophy and blindness, the ability to regain vision remains poor despite attempts with high-dose penicillin.
• For patients who are pregnant and have early syphilis, it is likely that the mother will deliver a child not infected by syphilis (assuming the mother was treated appropriately).

Patient Education

• For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center. Also, see eMedicine's patient education article Syphilis.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to diagnose syphilis correctly can have potentially serious legal ramifications. This is particularly true in pregnant women. If syphilis is in the differential diagnosis, serologic testing is indicated, even if the likelihood is small.

Special Concerns

• Encourage all patients with syphilis to undergo HIV testing. Those with HIV seropositivity should undergo CSF examination.

MULTIMEDIA

Section 10 of 11  

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• Multimedia
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Media file 1:  Syphilitic chancre.
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Media file 2:  Condylomata lata.
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Media file 3:  Secondary syphilis - Exanthem.
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Media file 4:  Secondary syphilis - Exanthem.
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REFERENCES

Section 11 of 11

• Authors and Editors
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• References

• Akovbian VA, Gomberg MA, Prokhorenkov VI. Syphilitic vignettes from Russia. Dermatol Clin. Oct 1998;16(4):687-90, x. [Medline].
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• Corbie-Smith G. The continuing legacy of the Tuskegee Syphilis Study: considerations for clinical investigation. Am J Med Sci. Jan 1999;317(1):5-8. [Medline].
• Cox DL, Chang P, McDowall AW, Radolf JD. The outer membrane, not a coat of host proteins, limits antigenicity of virulent Treponema pallidum. Infect Immun. Mar 1992;60(3):1076-83. [Medline].
• Dismukes WE, Delgado DG, Mallernee SV, Myers TC. Destructive bone disease in early syphilis. JAMA. Dec 6 1976;236(23):2646-8. [Medline].
• Fitzgerald TJ. The Th1/Th2-like switch in syphilitic infection: is it detrimental?. Infect Immun. Sep 1992;60(9):3475-9. [Medline].
• Fiumara NJ. Treatment of primary and secondary syphilis. Serological response. JAMA. Jun 27 1980;243(24):2500-2. [Medline].
• Garnett GP, Aral SO, Hoyle DV, et al. The natural history of syphilis. Implications for the transmission dynamics and control of infection. Sex Transm Dis. Apr 1997;24(4):185-200. [Medline].
• Lukehart SA, Holmes KK. Syphilis. In: Fauci AS, ed. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill;1998:1023-33.
• Nakashima AK, Rolfs RT, Flock ML, et al. Epidemiology of syphilis in the United States, 1941--1993. Sex Transm Dis. Jan-Feb 1996;23(1):16-23. [Medline].
• Rosen T, Brown TJ. Genital ulcers. Evaluation and treatment. Dermatol Clin. Oct 1998;16(4):673-85, x. [Medline].
• Schmid GP. Serologic screening for syphilis. Rationale, cost, and realpolitik. Sex Transm Dis. Jan-Feb 1996;23(1):45-50. [Medline].
• Sule RR, Deshpande SG, Dharmadhikari NJ, Joshi VR. Late cutaneous syphilis. Cutis. Mar 1997;59(3):135-7. [Medline].
• Young H. Syphilis. Serology. Dermatol Clin. Oct 1998;16(4):691-8. [Medline].

Article Last Updated: Aug 10, 2005