Reexamining Syphilis: An Update on Epidemiology, Clinical Manifestations, and Management

Molly E Kent, PharmD; Frank Romanelli, PharmD MPH BCPS


The Annals of Pharmacotherapy. 2008;42(2):226-236. 

In This Article

Clinical Manifestations

Once acquired, syphilis passes through a series of 4 overlapping stages commonly referred to as primary syphilis, secondary syphilis, latent syphilis, and tertiary syphilis. These stages are characterized by unique symptoms, clinical manifestations, and levels of infectivity (Figure 1).[2,13,22,23,24,25,26,27,28,29,30,31,32,33]

Figure 1.

Stages and clinical manifestations of syphilis. CSF = cerebrospinal fluid; VDRL = Venereal Disease Research Laboratory.

Primary Syphilis

A syphilis chancre usually develops at the site of treponeme inoculum.[2] The characteristic syphilis chancre starts as a papule that eventually forms a painless, indurated, nonpurulent ulcer with a clean base and a sharply marginated border that ranges in size from 0.3 to 3 cm.[34,35] There is usually a single chancre present, but multiple lesions have been reported.[34] Diagnosis based purely on the presence of a chancre is problematic, as atypical lesions may appear in up to 60% of cases.[22,23] Additionally, lesions located in areas such as the pharynx, cervix, urethra, and rectum frequently escape detection. If the site of treponeme inoculum is not in the genital area, an extragenital chancre develops and may have an atypical presentation, with pain as a predominant symptom.[36] The majority of extragenital chancres occur in the mouth (40-70%) but have been reported on multiple body parts, including the hands of healthcare workers. The varied presentation of the syphilis chancre can be explained by differences in the inoculum of treponeme, the immune status of the patient, the site, and concomitant antibiotics at the time of infection.

Regional lymphadenopathy occurs in up to 80% of cases approximately 7-10 days after the chancre appears and is more often associated with genital lesions.[34,35,36] Without treatment, the chancre heals in approximately 3-6 weeks and a delayed-type hypersensitivity response, not the humoral immune system, is the predominant mechanism for clearing the initial localized infection.[23,37,38] Lymphadenopathy usually persists after the initial chancre has healed and both the primary chancre (30%) and lymphadenopathy may overlap into the secondary syphilis stage, particularly in patients infected with HIV.[36,39]

Secondary Syphilis

A rash of varying severity is the most common initial presenting symptom.[13] This rash often appears on the palms, soles, flanks, and arms and can range from macular to follicular and occasionally to pustular.[1,13] The rash is typically nonpruritic and initially presents as symmetrical 3-10 mm pink or red macules, which can progress to a macular papular or pustular rash.[1,40,41] If untreated, the rash resolves over several weeks, usually without scarring.[39] Additionally, up to 7% of patients may experience alopecia characterized by patchy hair loss of the scalp, beard, and lateral eyebrows, which is referred to as a "moth-eaten appearance."[36,39]

Patients may also experience sore throats due to inflammatory involvement of the pharynx or the tonsils.[39] Condylomata lata (white gray mucous lesions, ranging in size from 5 to 10 mm) are found in 5-22% of patients.[36,39] Genital lesions ranging from macules to condylomata lata may also occur.[1] Although the incidence of these effects is rare, syphilis can cause renal, ophthalmologic, hepatic, bone, and/or joint disease.[2]

Early Neurosyphilis. In untreated or undertreated patients whose cerebral spinal fluid (CSF) is invaded by T. pallidum, 4 possible events may occur: spontaneous resolution, asymptomatic neurosyphilis, syphilitic meningitis, or progression to late neurosyphilis.[2] Syphilitic meningitis usually occurs within the first 6 months of infection or at the time of the secondary rash.[27,42,43] Cranial nerve involvement may lead to sensorineural deafness in up to 20% of patients and ocular abnormalities such as optic neuritis.[43]

Latent Syphilis

Latent syphilis is a stage in which patients are seroreactive but asymptomatic.[24] It occurs between the disappearance of secondary syphilis symptoms and the appearance of tertiary syphilis manifestations or therapeutic cure.

Tertiary Syphilis

Tertiary syphilis is characterized by long-term complications of the disease.[22] The 3 main forms of tertiary syphilis are late benign, cardiovascular, and neurosyphilis. During this stage, syphilis is not transmittable. Late benign syphilis has also been called gummatous syphilis after its primary lesion, the gumma.[1] The gumma is a granulomatous-like lesion that is indolent and can range in size from minuscule deposits to large masses. The lesions can cause serious complications depending on their size and location via local destruction of tissues.[1,13] The most common sites of involvement are the skin, bone, and liver, but the gumma lesions can affect any organ.[26] Cutaneous manifestations may range from superficial nodules to granulomatous masses, which may break down to form ulcers.[1] Despite the high rates of cardiovascular syphilis in studies of the natural history of syphilis, tertiary syphilis is now rare due to antibiotic treatment.[1,25] The most common manifestation is aortitis, usually involving the ascending aorta.[26]

Neurosyphilis. Meningovascular syphilis is caused by focal syphilitic endarteritis in the blood vessels of the brain, meninges, and spinal cord leading to infarcts and transitory or permanent ischemic incidents.[1] Meningitis may overlap with meningovascular syphilis; therefore, many patients may have concomitant headache or nausea.[42] The severity of symptoms depends on the number of infarcts and sites involved.[1,13]

Classic late parenchymal neurosyphilis, presenting as general paresis or tabes dorsalis, is due to extensive damage of the parenchyma in cortical regions of the brain or the spinal cord, respectively.[1] Both forms of parenchmyal neurosyphilis have become rare in the antibiotic era.[13] Early symptoms of paresis mimic other forms of dementia and include impairment of memory function, irritability, changes in physical appearance, speech impairments, and psychotic symptoms.[1,27] Over time, the disease will advance and progressive dementia may develop.[13]

Demyelinization of the posterior column, dorsal roots, and dorsal root ganglia in the spinal cord is the primary pathological process in tabes dorsalis leading to symptoms.[1] "Lightning pains," which most commonly affect the lower extremities, are the characteristic symptoms of tabes dorsalis and can occur in 75-90% of patients.[13,27] Damage to the posterior column impairs position and vibration sense, leading to a positive Romberg sign and wide-based gait.[1] The hips, knees, and ankles can develop a trophic degenerative joint disease known as Charcot's joints. Approximately 10-15% of patients will experience a visceral crisis consisting of sudden onset epigastric pain, vomiting, and/or acute urinary retention.[13] Optical abnormalities are common, with 50% of patients developing Argyll Robertson pupils (small, irregular pupils that accommodate but do not react to light) and 20% of patients developing optic atrophy.[13,27]


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