Syphilis: Sexually Transmitted Diseases (STD): Merck Manual Professional

Syphilis is caused by the spirochete Treponema pallidum and is characterized by 3 sequential clinical, symptomatic stages separated by periods of asymptomatic latent infection. Common manifestations include genital ulcers, skin lesions, meningitis, aortic disease, and neurologic syndromes. Diagnosis is by serologic tests and adjunctive tests selected based on the disease stage. Penicillin is the drug of choice.

Syphilis is caused by T. pallidum, a spirochete that cannot survive for long outside the human body. T. pallidum enters through the mucous membranes or skin, reaches the regional lymph nodes within hours, and rapidly spreads throughout the body.

Infection is usually transmitted by sexual contact (including genital, orogenital, and anorectal) but may be transmitted nonsexually by skin contact or transplacentally (see Infections in Neonates: Congenital Syphilis). Risk of transmission is about 30% from a single sexual encounter with a person who has primary syphilis, and 60 to 80% from an infected mother to a fetus. Infection does not lead to immunity against reinfection.

Syphilis may manifest at any stage and may affect multiple or single organs, mimicking many other disorders. Syphilis may be accelerated by coexisting HIV infection; in these cases, eye involvement, meningitis, and other neurologic complications are more common and more severe.

Syphilis—Primary (Genital Chancre)

Syphilis—Primary (Anal Chancre)

Syphilis—Primary (Mouth Chancre)

Syphilis—Primary (Digital Chancre)

Primary syphilis: After an incubation period of 3 to 4 wk (range 1 to 13 wk), a primary lesion (chancre) develops at the site of inoculation. The initial red papule quickly forms a chancre, usually a painless ulcer with a firm base; when rubbed, it produces clear fluid containing numerous spirochetes. Nearby lymph nodes may be enlarged, firm, and nontender. Chancres can occur anywhere but are most common on the following:

Secondary syphilis: The spirochete spreads in the bloodstream, producing widespread mucocutaneous lesions, lymph node swelling, and, less commonly, symptoms in other organs. Symptoms typically begin 6 to 12 wk after the chancre appears; about 25% of patients still have a chancre. Fever, loss of appetite, nausea, and fatigue are common. Headache, hearing or balance problems, visual disturbances, and bone pain can also occur.

Over 80% of patients have mucocutaneous lesions; a wide variety of rashes and lesions occur, and any body surface can be affected. Without treatment, lesions may disappear in a few days to weeks, persist for months, or return after healing, but all eventually heal, usually without scarring.

Syphilitic dermatitis is usually symmetric and more marked on the palms and soles. The individual lesions are round, often scale, and may coalesce to produce larger lesions, but they generally do not itch or hurt. After lesions resolve, the affected areas may be lighter or darker than normal. If the scalp is involved, alopecia areata often occurs.

Condyloma lata are hypertrophic, flattened, dull pink or gray papules at mucocutaneous junctions and in moist areas of the skin (eg, in the perianal area, under the breasts); lesions are extremely infectious. Lesions of the mouth, throat, larynx, penis, vulva, or rectum are usually circular, raised, and often gray to white with a red border.

Secondary syphilis can affect any organ. About ½ of patients have lymphadenopathy, usually generalized, with nontender, firm, discrete nodes, and often hepatosplenomegaly. About 10% of patients have lesions of the eyes (uveitis), bones (periostitis), joints, meninges, kidneys (glomerulitis), liver (hepatitis), or spleen. About 10 to 30% of patients have mild meningitis, but < 1% have meningeal symptoms, which can include headache, neck stiffness, cranial nerve lesions, deafness, and eye inflammation (eg, optic neuritis, retinitis).

Syphilis—Secondary (Body)

Syphilis—Secondary (Back)

Syphilis—Secondary (Hands)

Syphilis—Secondary (Soles)

Latent period: Symptoms and signs are absent, but antibodies, detected by serologic tests for syphilis (STS), persist. Because symptoms of primary and secondary syphilis are often minimal or ignored, patients frequently are first diagnosed during the latent stage when routine blood tests for syphilis are done. Syphilis may remain latent permanently, but relapses with contagious skin or mucosal lesions may occur during the early latent period (< 1 yr after infection). Patients are often given antibiotics for other disorders, which may cure latent syphilis and may account for the rarity of late-stage disease in developed countries.

Late or tertiary syphilis: About ¹/₃ of untreated people develop late syphilis, although not until years to decades after the initial infection. Lesions may be clinically classified as benign tertiary syphilis, cardiovascular syphilis, or neurosyphilis.

Benign tertiary gummatous syphilis usually develops within 3 to 10 yr of infection and may involve the skin, bones, and internal organs. Gummas are soft, destructive, inflammatory masses that are typically localized but may diffusely infiltrate an organ or tissue; they grow and heal slowly and leave scars.

Benign tertiary syphilis of bone results in either inflammation or destructive lesions that cause a deep, boring pain, characteristically worse at night.

Cardiovascular syphilis usually manifests 10 to 25 yr after the initial infection as aneurysmal dilation of the ascending aorta, insufficiency of the aortic valve, or narrowing of the coronary arteries. Pulsations of the dilated aorta may cause symptoms by compressing or eroding adjacent structures in the chest. Symptoms include brassy cough, infections, and obstruction of breathing due to pressure on the trachea, hoarseness due to vocal cord paralysis resulting from compression of the left laryngeal nerve, and painful erosion of the sternum and ribs or spine.

Asymptomatic neurosyphilis causes mild meningitis in about 15% of patients originally diagnosed as having latent syphilis, in 25 to 40% of those with secondary syphilis, in 12% of those with cardiovascular syphilis, and in 5% of those with benign tertiary syphilis. Without treatment, it evolves to symptomatic neurosyphilis in 5%. If CSF examination does not detect evidence of meningitis 2 yr after the initial infection, neurosyphilis is unlikely to develop.

Meningovascular neurosyphilis results from inflammation of large- to medium-sized arteries of the brain or spinal cord; symptoms typically occur 5 to 10 yr after infection and range from none to strokes. Initial symptoms may include headache, neck stiffness, dizziness, behavioral abnormalities, poor concentration, memory loss, lassitude, insomnia, and blurred vision. Spinal cord involvement may cause weakness and wasting of shoulder-girdle and arm muscles, slowly progressive leg weakness with urinary or fecal incontinence or both, and, rarely, sudden paralysis of the legs due to thrombosis of spinal arteries.

Parenchymatous neurosyphilis (general paresis, or dementia paralytica) results when chronic meningoencephalitis causes destruction of cortical parenchyma. It usually develops 15 to 20 yr after initial infection and typically does not affect patients before their 40s or 50s. Behavior progressively deteriorates, sometimes mimicking a mental disorder or dementia. Irritability, difficulty concentrating, deterioration of memory, defective judgment, headaches, insomnia, fatigue, and lethargy are common; seizures, aphasia, and transient hemiparesis are possible. Hygiene and grooming deteriorate. Patients may become emotionally unstable and depressed and have delusions of grandeur with lack of insight; wasting may occur. Tremors of the mouth, tongue, outstretched hands, and whole body may occur; other signs include pupillary abnormalities, dysarthria, hyperreflexia, and, in some patients, extensor plantar responses. Handwriting is usually shaky and illegible.

Tabes dorsalis (locomotor ataxia) involves slow, progressive degeneration of the posterior columns and nerve roots. It typically develops 20 to 30 yr after initial infection; mechanism is unknown. Usually, the earliest, most characteristic symptom is an intense, stabbing (lightning) pain in the back and legs that recurs irregularly. Gait ataxia, hyperesthesia, and paresthesia may produce a sensation of walking on foam rubber. Loss of bladder sensation leads to urine retention, incontinence, and recurrent infections. Erectile dysfunction is common.

Most patients with tabes dorsalis are thin and have characteristic sad facies and Argyll Robertson pupils (pupils that accommodate for near vision but do not respond to light). Optic atrophy may occur. Examination of the legs detects hypotonia, hyporeflexia, impaired vibratory and joint position sense, ataxia in the heel-shin test, absence of deep pain sensation, and Romberg's sign. Tabes dorsalis tends to be intractable even with treatment. Visceral crises (episodic pain) are a variant of tabes dorsalis; paroxysms of pain occur in various organs, most commonly in the stomach (causing vomiting) but also in the rectum, bladder, and larynx.

Other lesions: Syphilitic ocular and otic manifestations can occur at any stage of the disease. Ocular syndromes can affect virtually any part of the eye; they include interstitial keratitis, uveitis (anterior, intermediate, and posterior), chorioretinitis, retinitis, retinal vasculitis, and cranial nerve and optic neuropathies. Otosyphilis may affect the cochlea (causing hearing loss and tinnitus) or vestibular system (causing vertigo and nystagmus).

Trophic lesions, secondary to hypoesthesia of the skin or periarticular tissues, may develop in the later stages. Trophic ulcers may develop on the soles of the feet and penetrate as deeply as the underlying bone. Neurogenic arthropathy (Charcot's joints) a painless joint degeneration with bony swelling and abnormal range of movement is a classic manifestation of neuropathy (see Joint Disorders: Neurogenic Arthropathy).

Syphilis should be suspected in patients with typical mucocutaneous lesions or unexplained neurologic disorders, particularly in areas where the infection is prevalent. In such areas, it should also be considered in patients with a broad range of unexplained findings. Because clinical manifestations are so diverse and advanced stages are now relatively rare in most developed countries, syphilis may escape recognition. Patients with HIV and syphilis may have atypical or accelerated disease.

Diagnostic test selection depends on which stage of syphilis is suspected. Cases must be reported to public health agencies.

Diagnostic tests for syphilis: Tests include serologic tests for syphilis (STS), which consist of screening (reaginic) and confirmatory (treponemal) tests, and darkfield microscopy. T. pallidum cannot be grown in vitro. Reaginic tests use lipid antigens (cardiolipin from bovine hearts) to detect reagin (human antibodies that bind to lipids). The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are sensitive, simple, and inexpensive reaginic tests that are used for screening but are not specific for syphilis. Results may be presented qualitatively (eg, reactive, weakly reactive, borderline, or nonreactive) and quantitatively as titers (eg, positive at 1:16 dilution).

Many disorders other than treponemal infections (eg, SLE, antiphospholipid antibody syndromes) can produce a positive (biologically false-positive) reagin test result. CSF reaginic tests are reasonably sensitive for early disease but less so for late neurosyphilis. CSF reagin tests can be used to diagnose neurosyphilis or to monitor response to treatment by measuring antibody titers.

Treponemal tests detect antitreponemal antibodies qualitatively and are very specific for syphilis. They include the following:

If they do not confirm treponemal infection after a positive reaginic test, the reaginic result is biologically false-positive. Treponemal tests of CSF are controversial, but some authorities believe the FTA-ABS test is sensitive.

Neither reaginic nor treponemal tests become positive until 3 to 6 wk after the initial infection. Thus, a negative result is common in early primary syphilis and does not exclude syphilis until after 6 wk. Reaginic titers decline after effective treatment, becoming negative by 1 yr in primary and by 2 yr in secondary syphilis. Treponemal tests usually remain positive for many decades, despite effective treatment.

Darkfield microscopy directs light obliquely through a slide of exudate from a chancre or lymph node aspirate to directly visualize spirochetes. Although the skills and equipment required are not usually available, darkfield microscopy is the most sensitive and specific test for early primary syphilis. The spirochetes appear against a dark background as bright, motile, narrow coils that are about 0.25 μm wide and 5 to 20 μm long. They must be distinguished morphologically from nonpathogenic spirochetes, which may be part of the normal flora, especially of the mouth.

Primary syphilis: Primary syphilis is usually suspected based on relatively painless genital (but occasionally extragenital) ulcers. Syphilitic ulcers should be differentiated from other sexually transmitted genital lesions (see Table 1: Sexually Transmitted Diseases (STD): Differentiating Common Sexually Transmitted Genital Lesions

). Co-infections with 2 ulcer-causing pathogens (eg, herpes simplex virus plus T. pallidum) are not rare.

Darkfield microscopy of exudate from a chancre or lymph node aspirate may be diagnostic. If results are negative or the test is unavailable, a reaginic STS is done. If results are negative or the test cannot be done immediately but a skin lesion has been present for < 3 wk (before STS becomes positive) and an alternate diagnosis seems unlikely, treatment may be instituted, and the STS repeated in 2 to 4 wk. Patients with syphilis should be tested for other sexually transmitted diseases (STDs), including HIV, at diagnosis and 6 mo later.

Secondary syphilis: Because syphilis can mimic many diseases, it should be considered when any cutaneous eruption or mucosal lesion is undiagnosed, particularly if patients have any of the following:

Clinically, secondary syphilis may be mistaken for a drug eruption, rubella, infectious mononucleosis, erythema multiforme, pityriasis rubra pilaris, fungal infection, or, particularly, pityriasis rosea. Condyloma lata may be mistaken for warts, hemorrhoids, or pemphigus vegetans; scalp lesions may be mistaken for ringworm or idiopathic alopecia areata.

Secondary syphilis is excluded by a negative reaginic STS, which is virtually always reactive during this stage, often with a high titer. A compatible syndrome with a positive STS (reaginic or treponemal) warrants treatment. Uncommonly, this combination represents latent syphilis coexisting with another skin disease. Patients with secondary syphilis should be tested for other STDs and for asymptomatic neurosyphilis.

Latent syphilis: Asymptomatic, latent syphilis is diagnosed when reaginic and treponemal STSs are positive in the absence of symptoms or signs of active syphilis. Such patients should have a thorough examination, particularly genital, skin, neurologic, and cardiovascular examinations, to exclude secondary and tertiary syphilis. Treatment and serologic follow-up for up to several years may be needed to ensure the success of therapy because reaginic STS titers decrease slowly.

Late or tertiary syphilis: Patients with symptoms or signs of tertiary syphilis (particularly unexplained neurologic abnormalities) require STS. If the test is reactive, the following should be done:

At this stage of syphilis, a reaginic STS is nearly always positive, except in a few cases of tabes dorsalis.

In benign tertiary syphilis, differentiation from other inflammatory mass lesions or ulcers may be difficult without biopsy.

Cardiovascular syphilis is suggested by symptoms and signs of aneurysmal compression of adjacent structures, particularly stridor or hoarseness.

Syphilitic aortic aneurysm is suggested by aortic insufficiency without aortic stenosis and, on chest x-ray, widening of the aortic root and linear calcification on the walls of the ascending aorta. Diagnosis of aneurysm is confirmed with aortic imaging (transesophageal echocardiography, CT, or MRI).

In neurosyphilis, most symptoms and signs, except for Argyll Robertson pupil, are nonspecific, so that diagnosis relies heavily on a high index of clinical suspicion. Asymptomatic neurosyphilis is diagnosed based on abnormal CSF (typically, lymphocytic pleocytosis and elevated protein) and a reactive CSF reaginic test. In parenchymatous neurosyphilis, the CSF reaginic and serum treponemal tests are reactive and CSF typically has lymphocytic pleocytosis and elevated protein. If present, HIV may confound the diagnosis because it causes mild pleocytosis and various other neurologic symptoms.

In tabes dorsalis, serum reaginic tests may be negative if patients have been previously treated, but serum treponemal tests are usually positive. CSF usually has lymphocytic pleocytosis and elevated protein, and sometimes reaginic or treponemal test results are positive; however, in many treated patients, CSF is normal.

The treatment of choice in all stages of syphilis and during pregnancy is sustained-release penicillin (ie, benzathine penicillin). All sex partners within the past 3 mo (if primary syphilis is diagnosed) and within 1 yr (if secondary syphilis is diagnosed) should be evaluated and, if infected, treated.

Primary, secondary, and latent syphilis: Benzathine penicillin G Some Trade Names
BICILLIN
WYCILLIN
Click for Drug Monograph
2.4 million units IM once produces blood levels that are sufficiently high for 2 wk to cure primary, secondary, and early (< 1 yr) latent syphilis. Doses of 1.2 million units are usually given in each buttock to reduce local reactions. Additional injections of 2.4 million units should be given 7 and 14 days later for late (> 1 yr) latent syphilis or latent syphilis of unknown duration because treponemes occasionally persist in the CSF after single-dose regimens.

Patients with a history of IgE (anaphylactic or urticarial) allergic reactions to penicillin should not be treated with a cephalosporin because they may have an allergic reaction. Azithromycin Some Trade Names
ZITHROMAX
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2 g po in a single dose or doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
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100 mg po bid for 14 days may be used, but efficacy of these drugs is not well-defined, particularly for late latent syphilis, and the 14-day regimen requires good adherence. If adherence to the 14-day regimen cannot be ensured, the risk of using a cephalosporin may be justifiable. Ceftriaxone Some Trade Names
ROCEPHIN
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125 mg IM or IV once/day for 10 days has been effective in a limited number of patients.

Late or tertiary syphilis: Benign or cardiovascular tertiary syphilis can be treated in the same way as late latent syphilis.

For ocular syphilis or neurosyphilis, aqueous penicillin 3 to 4 million units IV q 4 h for 10 days (best penetrates the CNS but may be impractical) or procaine penicillin G Some Trade Names
BICILLIN
WYCILLIN
Click for Drug Monograph
2.4 million units IM once/day plus 500 mg probenecid Some Trade Names
No US trade name
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po qid is recommended; both drugs are given for 10 to 14 days, followed by benzathine penicillin 2.4 million units once/wk for 3 wk. For patients who have penicillin allergies, azithromycin Some Trade Names
ZITHROMAX
Click for Drug Monograph
and doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph
are effective, so penicillin desensitization is usually not indicated. Ceftriaxone Some Trade Names
ROCEPHIN
Click for Drug Monograph
2 g IM or IV once/day for 14 days can also be effective, but cross-sensitivity with cephalosporins is a concern so it is usually avoided.

Treatment of asymptomatic neurosyphilis appears to prevent the development of new neurologic deficits. Patients with neurosyphilis may be given oral or IM antipsychotics to help control paresis. Patients with tabes dorsalis and lightning pains should be given analgesics as needed; carbamazepine Some Trade Names
TEGRETOL
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200 mg po tid or qid sometimes helps.

Jarisch-Herxheimer reaction (JHR): Most patients with primary or secondary syphilis, especially those with secondary syphilis, have a JHR within 6 to 12 h of initial treatment. It typically manifests as malaise, fever, headache, sweating, rigors, anxiety, or a temporary exacerbation of the syphilitic lesions. The mechanism is not understood, and JHR may be misdiagnosed as an allergic reaction. JHR usually subsides within 24 h and poses no danger. However, patients with general paresis or a high CSF cell count may have a more serious reaction, including seizures or strokes, and should be warned and observed accordingly. Unanticipated JHR may occur if patients with undiagnosed syphilis are given antitreponemal antibiotics for other infections.

The importance of repeated tests to confirm cure should be explained to patients before treatment. Examinations and reaginic tests should be done at 3, 6, and 12 mo after treatment and annually thereafter until the test is nonreactive. Failure of titers to decline by 4-fold at 6 mo suggests treatment failure and indicates the need for retreatment. After successful treatment, primary lesions heal rapidly, and plasma reaginic titers fall and usually become qualitatively negative within 9 to 12 mo. In about 15% of patients with primary or secondary syphilis treated as recommended, the reaginic titer does not decrease by 4-fold—the criterion used to define response at 1 yr after treatment. Treponemal tests may remain positive for decades or permanently and should not be measured to monitor progress. Serologic or clinical relapse, usually affecting the nervous system, may occur after 6 to 9 mo, but the cause may be reinfection rather than relapse.

Patients with neurosyphilis require CSF testing at 6-mo intervals until the CSF cell count is normal. In HIV-infected patients, persisting CSF pleocytosis may represent effects of HIV rather than persisting neurosyphilis. Normal CSF, serologic test, and examination results for 2 yr indicates probable cure. If the CSF WBC count remains abnormal 2 yr after maximal treatment, it is unclear whether treatment should be continued. Indications for retreatment with a more intensive regimen of antibiotics include a reaginic test that remains reactive for > 2 yr, an increasing titer, and clinical relapse.