Figure 163.1 Secondary syphilis. Papulosquamous lesions on soles. (Courtesy of David Schlossberg, MD.)
The diagnosis of primary or secondary syphilis is based on the characteristic chancres or mucocutaneous lesions, along with demonstration of T. pallidum by direct detection methods. Like the chancre, these manifestations of secondary syphilis resolve spontaneously with or without therapy. However, a small proportion of patients develop complications, such as hepatitis, syphilitic glomerulonephritis with nephrotic syndrome, anterior uveitis, choroiditis, arthritis, bursitis, or osteitis.
T. pallidum can invade the central nervous system during any stage of syphilis. Asymptomatic neurosyphilis can occur with laboratory abnormalities in the cerebrospinal fluid (CSF) during primary or secondary syphilis. These abnormalities may resolve spontaneously or with treatment, or result in early symptomatic neurosyphilis in 5% of patients.
Syphilitic meningitis most commonly occurs during the first year of infection. Patients may present with headache, fever, stiff neck, and photophobia. Cerebral involvement may result in seizures or hemiplegia. Cranial nerve palsies are especially common. Characteristic CSF findings include a lymphocytic pleocytosis, increased protein, and hypoglycorrhachia in slightly less than half of cases. The diagnosis is confirmed by a reactive serum non-treponemal antibody test and the Venereal Disease Research Laboratory (VDRL) test in CSF. Other manifestations of early neurosyphilis may include cranial neuritis or ocular involvement.
Meningovascular syphilis usually occurs about 5 to 12 years after infection in patients between the ages of 30 and 50 years and may involve the cerebrum, brainstem, or spinal cord. The pathophysiology involves chronic meningitis and infarction due to syphilitic endarteritis. In cerebrovascular syphilis, the middle cerebral artery is most commonly involved, and hemiparesis, aphasia, and seizures commonly occur. CSF usually reveals a lymphocytic pleocytosis with increased protein and a positive CSF VDRL. Spinal syphilis, a relatively uncommon entity, may present as meningomyelitis or transverse myelitis.
The major parenchymatous forms of neurosyphilis are general paresis and tabes dorsalis, which tend to occur between 2 and 30 years and 3 and 50 years, respectively, after initial infection. Both are now uncommon diseases.
General paresis is a chronic meningoencephalitis that results from direct invasion of the brain by T. pallidum and combines both psychiatric and neurologic manifestations. Early symptoms, such as irritability, memory loss, headache, and personality changes, may evolve into emotional lability, paranoia, and confusion. Pupillary abnormalities occur in more than half of patients with general paresis. Abnormal reflexes, slurred speech, and tremors are also common. In untreated patients, the interval between onset of symptoms and death can range from a few months to about 5 years.
Serum non-treponemal serologic tests are reactive in 95% to 100% of patients with generalized paresis. CSF VDRL is usually positive, but a negative result alone does not exclude the diagnosis. Differential diagnosis includes Alzheimer’s disease, chronic alcoholism, and multiple sclerosis.
Tabes dorsalis is characterized by lightning pains and various combinations of other neurologic signs and symptoms, such as ataxia; bladder disturbances; pupillary abnormalities; absent ankle or knee reflexes; Romberg’s sign; impaired vibratory and position sense; and development of extremely large, unstable, painless joints known as Charcot’s joints. Lightning pains are paroxysms of severe stabbing pains, which usually occur in the legs. Although most patients have positive serum non-treponemal tests, 10% of patients with tabes will have nonreactive non-treponemal titers but positive treponemal tests. CSF may be normal or may reveal lymphocytic pleocytosis and elevated protein.
Nonneurologic manifestations of tertiary syphilis
Syphilitic heart disease, now an uncommon cause of cardiovascular disease, occurs 15 to 30 years after initial infection. During the early phases of infection, T. pallidum can disseminate to the heart and lodge in the aortic wall, where they may cause endarteritis of the vasa vasorum of the aorta with resultant scarring and destruction of the vessel’s wall. Major cardiac manifestations include thoracic aneurysm, aortic regurgitation (without associated aortic stenosis), and coronary ostial stenosis.
Late benign syphilis is another now uncommon form of tertiary syphilis. It results from the chronic inflammatory response to T. pallidum and the formation of a granulomatous type of lesion called a gumma. Gummas may be ulcerative, nodular, or noduloulcerative and most commonly occur in the skin and bones but may also invade the viscera, muscles, and other structures.
Syphilis in persons with HIV infection
Because syphilis and human immunodeficiency virus (HIV) infection share means of transmission and other risk factors, both infections often coexist. Moreover, syphilis, like other genital ulcer diseases, facilitates HIV transmission. Clinical observation and case reports suggest that HIV-infected patients may experience a more aggressive course of syphilis, with more frequent occurrence of neurosyphilis especially in the early stages of infection. Occasional unusual serologic reactions can occur in HIV-infected patients including very high or fluctuating non-treponemal antibody titers; false-positive non-treponemal tests and false-negative treponemal tests have also been documented. Nevertheless, available data suggest that HIV infection does not significantly change the presentation, clinical course, or response to treatment of syphilis.
Syphilis in pregnancy
The clinical manifestations of syphilis are not altered in pregnancy; however, syphilis has widespread complications for both the infected mother and the fetus. Adverse pregnancy outcomes include early fetal loss, preterm delivery, low birth weight, and congenital syphilis in the neonate.
Direct microscopic examination can provide immediate diagnosis of primary and secondary syphilis. Dark-field microscopy must be used because T. pallidum’s narrow width (0.15 μm) renders the organism below the level of resolution of light microscopy. Wet preparations can be made from the skin or mucous membrane lesions of primary or secondary syphilis. Examination reveals tightly coiled organisms 6 to 14 μm long and 0.25 to 0.30 μm wide, with corkscrew motility. When examination of specimens must be delayed or oral lesions evaluated, direct fluorescent antibody testing can be useful. This test specifically detects T. pallidum and eliminates confusion with oral treponemal saprophytes whose morphology is similar to that of T. pallidum. Polymerase chain reaction (PCR) assays for diagnosis of syphilitic lesions have been developed and used in research studies; however, none are yet commercially available.
Serologic tests for syphilis measure either nonspecific non-treponemal antibody or specific treponemal antibody. Non-treponemal antibody tests measure immunoglobulin G (IgG) and immunoglobulin M (IgM) to lipoidal material released from damaged host cells as well as to lipoprotein-like material and cardiolipin released by the treponemes. Non-treponemal antibody titers generally correlate with disease activity; titers fall progressively over time and are expected to decrease 4-fold in response to therapy. The following non-treponemal tests are commonly used: VDRL test, rapid plasma reagin (RPR), the toluidine red unheated serum test (TRUST), and the unheated serum reagin test (USR). Biologic false-positive non-treponemal test results occur in 1% to 2% of the general population, and are associated with several conditions including viral infections, pregnancy, malignancy, autoimmune diseases, and advanced age. False-negative results can occur from the prozone phenomenon in which patients with high non-treponemal titers can have weak or negative results at low dilutions due to excess antibody, although this is rare.
Specific treponemal antibody tests are needed to confirm a current or past diagnosis of syphilis. These tests detect antibodies formed in response to treponemal antigens. Treponemal tests usually remain reactive after treatment, but a small proportion of infected persons can become seronegative. Commonly used treponemal tests include the fluorescent antibody absorption (FTA-ABS), microhemagglutination assay for T. pallidum (MHA-TP), and the T. pallidum particle agglutination (TP-PA) test for syphilis.
Several new automated treponemal enzyme immunoassays (EIAs), chemiluminescence immunoassays, and immunoblots for T. pallidum