Are You Confident of the Diagnosis?

What you should be alert for in the history

Syphilis is still a relatively common disease. It should be suspected in anyone with a genital ulcer. It should be considered in anyone who is sexually active with nearly any kind of rash. (The exception is vesicular lesions which are exceptionally rare in syphilis). Syphilis is often called ’the great imitator’ because of so many signs and symptoms that are indistinguishable from many other diseases.)

Characteristic findings on physical examination

Primary syphilis

Primary syphilis is characterized by a cutaneous ulcer at the site of inoculation of the spirochetes, most commonly in the genital area and occurs 10 to 90 days (average 3 weeks) after exposure. Initially, a papule is seen, which subsequently ulcerates in the center, becoming the classic chancre (Figure 1).

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Figure 1.

A classic syphilitic chancre

A chancre is usually around 1cm in diameter, firm, painless, round/oval, with raised borders, and sometimes covered with yellowish necrotic slough. Usually it is single, but multiple chancres are not uncommon. The chancre is often accompanied by inguinal lymphadenopathy which may be painful.

Variations on the classic presentation of chancres are common with pain being seen or deeper ulcers on occasion. The chancre of primary syphilis may have a hemorrhagic necrotic base. This type of chancre is called ’Hunterian chancre’. Hunterian chancres can be seen in up to half of cases.

Kissing ulcers are sometimes found in areas where two surfaces are directly in contact with each other – such as the vulva. Although chancres occur most commonly on the genitals, they may be seen on any part of the body where inoculation occurs.

Secondary syphilis

Secondary syphilis usually appears 3 weeks to 6 months (average 6 weeks) after appearance of a chancre and usually recedes in 2 to 12 weeks. It is in secondary syphilis where the diversity of skin lesions along with the varied signs and symptoms often cause syphilis to be confused with many other diseases.

All the skin lesions in secondary syphilis are infectious as they harbor bacteria. The skin lesions of secondary syphilis often are the first observed clinical manifestation of syphilis in those practicing receptive vaginal or anal intercourse, since primary lesions may occur in the anus or vagina and may not be recognized by the patient.

In secondary syphilis, the patient develops oval, pink, non-scaly macules or patches on the trunk. These lesions are called ’roseola syphilitica’. Sometimes, macular eruptions evolve and become papulopustular. They are copper colored. They can be intensely itchy. The patient may also develop scaly, copper colored plaques on the palms and soles (Figure 2).

Figure 2.

Secondary syphilis

Secondary syphilis skin lesions may also be papular. Papule color varies from reddish-brown in new lesions to brown in the older lesions. Early papules tend to be shiny, but gradually they become covered with a thin layer of scale (papulosquamous syphilides). A thin, white scaling ring on the surface of the lesion, known as Biette’s collarette, is a helpful diagnostic sign, although it is not pathognomonic.

When the lesions are pruritic and when hyperkeratosis is pronounced, the eruption may resemble psoriasis. The occasional presence of the Koebner phenomenon further contributes to this confusion.

Other skin manisfestations of secondary syphilis include:

–Condyloma lata: characterized by wart like, painless, moist papules most commonly seen in the genital area. It is present in one third of the patients with secondary syphilis. They contain high numbers of spirochetes and are considered highly infectious (Figure 3).

–Alopecia syphilitica: a non-inflammatory and non-cicatricial hair loss that can present in diffuse pattern, moth eaten pattern or a combination of both.

–Mucous patches are present in up to 30% of cases. They involve oral cavity, pharynx, larynx and genital areas.

Figure 3.

Condyloma lata

Expected results of diagnostic studies

Dark-field microscopy

Dark-field microscopy is the most specific technique for diagnosing syphilis when active chancre or condyloma latum is present. However, its accuracy is limited by the experience of the operator performing the test, the number of large treponemes in the lesion, and the presence of non-pathologic treponemes in oral and genital lesions.

In the preparation for dark-field microscopy, the lesion is cleansed and abraded gently with a gauze pad. Once a serous exudate appears, it is collected on a glass slide and examined under a microscope equipped with a dark-field condenser. Treponema pallidum is identified by its characteristic corkscrew appearance. Given the inherent difficulties of dark-field microscopy, negative examinations on three different days are necessary before a lesion may be considered negative for T. pallidum.

Nontreponemal tests

Syphilitic infection leads to the production of non-specific antibodies that react to cardiolipin. This reaction is the basis of traditional nontreponemal tests such as VDRL and RPR. False positive tests are common and occur in pregnancy, malignancy, acute viral infection, several chronic infections such as HIV and TB, and various autoimmune diseases.

These tests may show a ’prozone phenomenon’ in which large amount of antibodies block the antibody-antigen reaction, causing a false-negative test result in undiluted test samples. It is specifically observed in secondary syphilis, when antibody titers are too high.

Nontreponemal tests are widely used for screening. However, their usefulness is limited by decreased sensitivity in early primary syphilis and during late syphilis, when up to one-third of patients may be nonreactive. After adequate treatment of syphilis, nontreponemal tests eventually become nonreactive. Titers are not interchangeable between different test types, so the same tests should be used for follow up evaluations.

Treponemal specific tests

These tests detect antibodies to antigenic components of T. pallidum. These tests are usually used to confirm the diagnosis of syphilis in patients with a reactive nontreponemal test. They are also used in patients with clinical evidence of syphilis who have negative nontreponemal test.

Treponemal-specific tests include the Enzyme Immunoassay (EIA) for anti-treponemal IgG, the T. pallidum hemagglutination (TPHA) test, the microhemagglutination test with T. pallidum antigen, the fluorescent treponemal antibody-absorption test (FTA-abs), and the enzyme-linked immunosorbent assay.

Treponemal tests have sensitivities and specificities equal to or higher than those for nontreponemal tests. In addition, false-positive results can occur, especially when the FTA-abs test is used in patients with SLE and Lyme disease. Unlike nontreponemal tests, which show a decline in titers or become nonreactive with effective treatment, treponemal –specific tests usually remain reactive for life; therefore, these tests are not useful for assessing treatment efficacy.

Diagnosis confirmation

The differential diagnosis of secondary syphilis is vast, as it can mimic any exanthematous maculopapular eruption. The most common differential diagnoses include: pityriasis rosea, drug or viral eruption, psoriasis, condyloma acuminata and lichen planus. The one morphology that is rare in syphilis is vesicular. Only very rarely will syphilis present as vesicular lesions (known as great pox) – most commomly seen in this era with HIV coinfection.

Tertiary syphilis

Cutaneous manifestations may develop any time after the secondary stage lesions resolve, with ’precocious’ lesions noted within the first 2 years and the late syphilides between 2 and 30 years. Tertiary skin lesions of skin can be divided into three types: granulomatous nodules, psoriasiform granulomatous plaques, and gummas.

Nodular and noduloulcerative syphilis

The lesions begin as superficial, firm, pink/purple papules or nodules in a grouped configuration that rapidly extend peripherally in an irregular manner. Over time, central healing and advancing borders produce plaques with annular, arciform, serpiginous configurations that may reach over 30cm. As the nodules grow, the skin appears red and eventually breaks down, resulting in ulcerations with raised borders and slightly purulent, crusted surfaces.

Even if untreated, the lesions heal over the years, leaving non-contractile, atrophic scars with increased or decreased pigmentation.

Psoriasiform/squamous syphilis

These lesions are the same but have scaling over the surface with a reddish hue. The Auspitz sign is negative. There is little ulceration or scarring.


Gummas are painless pink to dusky red granulomatous nodules of various sizes that are more common on the scalp, forehead, buttocks, and presternal, supraclavicular, or pretibial areas. The infiltration starts in the subcutaneous tissue and subsequently involves the dermis, the epidermis and the underlying tissues.

Gummas have a characteristic tendency to necrose, which begins in the middle of lesions where the tissue turns into a slimy and stringy mass; this has given rise to the name ’gumma’. Ulceration may occur and is typically cylindrical, punched out, and covered with an adherent yellowish-white slough. Large gummas may have several skin perforations and undergo necrotic changes that cause destruction of the intervening bridges of skin.

Benign tertiary syphilis of mucous membrane

The most commonly involved mucous membranes are those of the palate and of the nose. Ulcers in these areas may cause destruction of the bony and cartilaginous structures (saddle nose) or perforations that sometimes persist despite treatment. Gummas, nodules, and diffuse inflammation, with ulcers covered by a gray slough may appear in the tonsils, pharynx and tongue.

Congenital Syphilis

T. pallidum can be transmitted from mother to fetus at any stage of pregnancy. Untreated maternal infection may cause fetal loss, prematurity, neonatal death or nonfatal congenital syphilis.

Early congenital syphilis

This commonly manifests within 3 months of birth. Skin lesions include characteristic vesiculobullous eruptions (syphilitic pemphigus) or a copper colored rash on the palms and soles and papular lesions around nose and mouth (Figure 4).

Figure 4.

Early congenital syphilis (syphilitic pemphigus)

Late congenital syphilis

This typically manifests 2 years after birth. The most important signs include frontal and parietal bossing (bony prominences of forehead), saber shins (sharp anterior bowing of tibia), saddle nose, Hutchison’s incisors (small, notched, peg-shaped upper incisors), mulberry molars (multiple rounded rudimentary cusps on permanent first molars), rhagades (linear scars at the angle of mouth, nose and anus), Hutchinson’s triad (composed of Hutchinson’s teeth, interstitial keratitis and sensorineural deafness), Clutton’s joints (synovitis and joint effusion), short maxillae and a high arched palate.

Who is at Risk for Developing this Disease?

Syphilis is a predominantly sexually transmitted infectious disease caused by the spirochete T. pallidum. Other modes of transmission are transplacental from mother to unborn child, accidental inoculation, and through blood transfusions.

In the United States, health officials reported over 36,000 cases of syphilis in 2006, including 9,756 cases of primary and secondary (P&S) syphilis. In 2006, half of all P&S syphilis cases were reported from 20 counties and 2 cities; and most P&S syphilis cases occurred in persons 20 to 39 years of age. The incidence of P&S syphilis was highest in women 20 to 24 years of age and in men 35 to 39 years of age.

Reported cases of congenital syphilis in newborns increased from 2005 to 2006, with 339 new cases reported in 2005 compared to 349 cases in 2006. In 2006, 64% of the reported P&S syphilis cases were among men who have sex with men (MSM).

What is the Cause of the Disease?

T. pallidum is a motile, corkscrew-shaped spirochete. Spirochetes are gram negative and have a flagellar bundle running through their periplasmic space causing the cells to move in a corkscrew fashion. Its size varies from 6 to 20um. T. pallidum carries a relatively small genome, and it uses host biosynthesis to fulfill some of its metabolic needs. T. pallidum cannot be cultured in the laboratory and therefore cannot be investigated using conventional lab techniques.

Systemic Implications and Complications

In secondary syphilis, the majority of patients present with skin lesions (more than 80% of the cases), which are usually preceded by a ’flu like syndrome’. Hepatosplenomegaly can be often found. Diversity of skin lesions with a combination of signs and symptoms are often confused with many other diseases. All the skin lesions in secondary syphilis are infectious as they harbor bacteria. Rare manifestations include hepatitis, kidney disease, arthritis, periostitis, optic neuritis, interstitial keratitis and uveitis.

Skeletal tertiary syphilis is classified as gummatous osteitis, periostitis and sclerosing osteitis. The most common manifestations are tenderness, swelling and nocturnal pain. Most commonly involved bones are the tibia, skull and clavicle.

Cardiovascular syphilis clinically presents as ascending aortic aneurysm, aortic insufficiency and coronary osteal stenosis.

Early forms of neurosyphilis usually occur within a few months or years after infection, and are characterized by meningovascular involvement. Clinical manifestations include acute syphilitic meningitis, basilar meningitis that typically involves cranial nerves III, VI, VII and VIII, and an endarteritis that presents as a stroke-like syndrome with seizures.

Late forms of neurosyphilis usually occur decades after infection. Clinical manifestations include general paresis (secondary to widespread CNS parenchymal damage) and tabes dorsalis (secondary to involvement of posterior column tract and dorsal root ganglia).

Treatment Options

Primary, secondary or early latent (less than 1 years duration), cardiovascular or benign tertiary

–Benzathine enicillin 2.4 million units IM single dose

–Penicillin allergic – doxycycline 100mg orally twice a day for 2 weeks or Ceftriaxone 1gm intramuscularly/intravenously daily for 10 days

–Azithromycin 2 gms orally – one dose: note treatment failures have been recorded, not advised for HIV positive patients

Late latent (greater than 1 yrs duration or unknown duration)

–Benzathine penicillin 2.4 million units intramuscularly weekly x 3 doses

–Penicillin allergic – doxycycline100mg orally twice a day for 4 weeks

All patients with secondary syphilis coinfected with HIV should have a lumbar puncture and if positive treated for neurosyphilis.

Lumbar puncture should be considered in all patients with late latent secondary syphilis.


–Aqueous penicillin G 3-4 million units every 4 hours for 10-14 days, or

–Aqueous procaine penicillin G 2.4 million units daily intramuscularly plus probenecid 500mg 4 times a day – both for 10-14 days

–Penicillin allergic – desensitization and treatment with penicillin

–Doxycycline 200mg orally twice daily for a month (scant evidence)

Optimal Therapeutic Approach for this Disease

Use of penicillins in the various stages of syphilis has been supported by clinical efficacy for more than 50 years. Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis such as doxycycline, tetracycline or Azithromycin.

No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in HIV-infected patients.

Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. There is some data that doxycycline 200mg orally twice a day for one month can be used in neurosyphilis.

Patient Management

Response to treatment should be monitored with nontreponemal tests (such as RPR, VDRL titers) at 6 and 12 months in early syphilis and at 6, 12 and 24 months for late latent syphilis. If the titer rises by 4-fold or fails to fall by 4-fold in primary and secondary syphilis, the patient should be re-treated and should be evaluated for HIV.

In treated neurosyphilis, CSF cell counts should be monitored every 6 months for 2 years or until normal, and quantitative RPR or VDRL should be monitored every 6 months for 2 years. In HIV infected individuals, it should be monitored more closely at 3, 6, 9, 12 and 24 months.

Practitioners are often faced with the issue of what to do with asymptomatic patients who have been treated for syphilis in the past (greater than 1 year) who continue to have low level RPR titres (serofast). The following is advised based on clinical experience:

–Titres greater than 1:16 should be retreated as late latent syphilis

–Patients with continued high risk sexual behaviors should be retreated regardless of titres

–A two or more increase in titres should prompt retreatment

–If titres are low (1:16 or less) the results should be discussed with the patient – retreat if the patient so desires

–If HIV positive – retreatment is suggested

–Consider neurosyphilis in all serofast patients

Unusual Clinical Scenarios to Consider in Patient Management

HIV and syphilis

Although the treatment of all stages of syphilis is unaltered in the HIV-infected patient, HIV-infected persons should be evaluated clinically and serologically more closely for treatment failure.

The Jarish- Herxheimer reaction

When spirochetes are first treated and killed they may release antigens that cause an immunologic reaction that presents with a serum-sickness-like reaction. It is manifested by high-grade fever, myalgia, chills, headache and rarely vascular collapse. Sometimes, this reaction can induce labor or cause fetal distress in pregnant women (this should not prevent or delay therapy).

Some experts recommend that patients with high RPR titres take aspirin with the treatment. All patients should be told of the possibility of the reaction when first treated and advised to have aspirin nearby if needed.

What is the Evidence?

Fiallo, P, Bastos, R. (A detailed description of the clinical manifestations of various stages of syphilis with references.)

Lautenschlager, S, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, BA, Paller, AS. Fitzpatrick’s Dermatology in General Medicine. (Describes various dermatological manifestations of primary, secondary, tertiary and congenital syphilis in depth.)

Larsen, SA, Steiner, BM, Rudolph, AH. “Laboratory diagnosis and interpretation of tests for syphilis”. Clin Microbiol Rev. vol. 8. 1995. pp. 1-21. (Describes treponemal and nontreponemal tests in depth with references.)

Sanchez, M, Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Syphilis”. Treatment Of Skin Diseases. 2010. pp. 730-733. (An excellent brief review of treatment of syphilis with annotated references and review of controversies in treatment.)

“Sexually transmitted diseases guidelines 2010”. MMWR. vol. 59. 2010. pp. 1-106. (Updated CDC syphillis treatment guidelines.)