Chapter 50 Syphilis ROBERT S. WEINBERG Table Of Contents |
HISTORY PATHOGENESIS INCIDENCE OCULAR SYPHILIS SYPHILITIC UVEITIS LABORATORY TESTS TREATMENT SUMMARY AND RECOMMENDATIONS REFERENCES |
Despite a decline in the incidence of syphilis in the United States during the 1990s, the increased incidence in the United States during the 1980s is being mirrored now in other parts of the world. It is likely that more and more physicians will be treating patients with the disease. The ophthalmologist may be the first physician to examine a patient with syphilis, and the increased number of patients with systemic syphilis means a greater likelihood of seeing patients with ocular syphilis. Familiarity with the disease, the laboratory tests available for diagnosis, and effective therapeutic regimens used to treat syphilis are important in managing a curable form of uveitis. |
HISTORY |
The earliest epidemic of syphilis was described in the late 1400s and early 1500s.1 Syphilis may have been introduced into western Europe in 1493 after Columbus's initial voyage to the Western Hemisphere.2 Syphilitic involvement of the nervous system was first described in the 1800s.3 In 1903, syphilis was first transmitted to experimental animals, and in 1905 Schaudinn and Hoffman discovered Treponema pallidum to be the causative agent.4 The Wassermann blood test for syphilis was developed in 1907.4 In 1918 Igesheimer wrote a book on syphilis that covered syphilitic ocular disease.5 In 1943 the introduction of penicillin revolutionized the treatment of the disease.3 Antibiotics were found in the 1950s to treat syphilis in penicillin-allergic patients.3 In the 1980s there was an increase in the incidence of syphilis associated with the increased incidence of intravenous drug abuse and AIDS.6 Although in the 1990s the incidence of new cases of syphilis in the United States declined, syphilis still remains a significant health problem, not only in the United States, but in many developing countries and in Eastern Europe.7,8 |
PATHOGENESIS |
Syphilis is an infectious disease caused by the spiral motile flagellated
bacteria T. pallidum. The organism is a fastidious, microaerophilic obligate parasite of humans
and has not been cultured in vitro.9 However, the genome sequence of T. pallidum is available and may provide information about virulence.9 Inoculation occurs through the epithelium and is followed by a generalized transient infection (spirochetemia). A primary chancre develops at the inoculation site, generally genital or oral, and regional lymphadenopathy follows. In the secondary stage of syphilis, there is hematogenous spread to local foci in the skin and mucous membranes. During the tertiary stage of syphilis, there is diffuse low-grade inflammation with degeneration and necrosis in the cardiovascular and central nervous systems. Ocular involvement is present in congenital syphilis and may occur in primary, secondary, or tertiary syphilis. In latent syphilis, patients are seroreactive but have no other disease activity. |
INCIDENCE |
The incidence of syphilis in the United States, measured by the number of cases reported to the Centers for Disease Control (CDC), began to decline during the 1990s.10 Elsewhere in the world, reporting mechanisms are less well established, but the incidence of syphilis still appears to be increasing.11,12 With an increased rate of primary and secondary syphilis, there is an increased likelihood of congenital syphilis. Because syphilitic genital ulceration may increase the transmission of the AIDS virus, there is an increased risk of AIDS associated with an increase in the incidence of syphilis.13 |
OCULAR SYPHILIS | ||||||||||||||||
Ocular involvement may occur at any stage of syphilis. In congenital syphilis, acute
iridocyclitis may be present from birth to age 6 months. Chorioretinitis
with the “salt and pepper” fundus, foci of
old choroiditis, areas of retinal pigment epithelial hypertrophy, and
atrophy may occur at any time after 6 months. Vitritis may be present. Interstitial
keratitis may be present at birth but is more commonly
a late manifestation, occurring bilaterally and between ages 5 and 20.14 In acquired syphilis, chancre of the conjunctiva or lids may be seen in the primary stage. In secondary syphilis, nonspecific conjunctivitis, scleroconjunctivitis, and syphilides (painless white nodules on the conjunctiva) have all been described.5 Iris roseola, early diffuse hyperemia of the iris vasculature, and late localized iris inflammation have been reported.15 Iritis and iridocyclitis are common. Syphilitic uveitis in tertiary syphilis may occur up to 20 years after the primary infection. Any part of the eye can be affected by syphilis (Table 1).
TABLE 1. Ocular Involvement in Syphilis
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SYPHILITIC UVEITIS |
Syphilitic uveitis is a curable form of uveitis, albeit one that can lead
to permanent and profound loss of vision if not diagnosed and treated
promptly. Reports of the incidence of syphilitic uveitis in patients
with syphilis vary, and there are no recent studies. The relative incidence
of syphilitic uveitis compared with all uveitis cases reported
ranges from 0.8% to 4.3%.16,17 Syphilis is an increasing cause of new uveitis in the elderly.18 There are no pathognomonic features of syphilitic uveitis. Iridocyclitis in early disease may be unilateral and severe. In late tertiary syphilis, iridocyclitis may also be unilateral and appear 4 to 6 months after inadequate treatment of tertiary syphilis. Syphilitic chorioretinitis also has no pathognomonic features. There may be multifocal chorioretinal infiltrates, overlying vitritis, and papillitis.19 Early findings include vitritis (Fig. 1), multifocal chorioretinitis (Fig. 2), optic neuritis, retinal vasculitis, retinal hemorrhages, and retinal edema. Pigment proliferation is present late in the course of the disease (Fig. 3). Presenting complaints in patients with acute syphilitic uveitis include blurred vision, pain, redness, photophobia, and floating spots. Ocular involvement may be unilateral or bilateral, and acute or chronic. Syphilitic uveitis may be described as a panuveitis, but frequently the anatomic terms iritis, iridocyclitis, vitritis, chorioretinitis, and retinal vasculitis are appropriate, depending on which part of the eye appears to be involved primarily. The differential diagnosis of syphilitic uveitis when iritis is the primary presentation includes the HLA-B27 positive syndromes. When more posterior involvement is present, with vitreous cells and active retinitis, several entities must be considered (Table 2). History and laboratory studies are helpful in the differentiation. Cytomegalovirus infection may coexist with syphilitic infection in the patient with AIDS and must be considered as a cause of inflammation in any patient immunosuppressed for whatever reason. Syphilis is more rapidly progressive in HIV-infected patients.20 In these patients, dense vitritis may be the presenting ocular abnormality.21 Toxoplasmosis can be differentiated by the presence of a compatible lesion and a positive Toxoplasma titer. Candida endophthalmitis may coexist with syphilis in an intravenous drug abuser. Behçet's disease may be difficult to rule out clinically, especially when there is oral or genital ulceration, but HLA typing may be helpful. Sarcoidosis must be considered in any differential diagnosis of posterior uveitis, but it is less likely if levels of angiotensin converting enzyme and serum lysozyme and the chest radiograph are normal. Intraocular lym phoma (reticulum cell sarcoma) should be considered in the elderly patient with vitreous cell. Intraocular lymphoma may be diagnosed by cytologic examination of the vitreous. The problem is that syphilis may be present even when there are other causes of uveitis. If tests for syphilis are positive, the patient should be treated for syphilis, even when the patient has other likely sources of inflammation.
TABLE 2 Differential Diagnosis of Posterior Syphilitic Uveitis Cytomegalovirus retinitis
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LABORATORY TESTS |
Ophthalmologists, who may be the first physicians to see a patient with
syphilis, should be familiar with the various tests available to confirm
a diagnosis of syphilis. There are three types of tests for syphilis: direct
identification of treponemes, nontreponemal serologic tests, and
treponemal serologic tests. Direct identification of treponemes
is possible in primary syphilis by examining exudate from a primary lesion
or chancre with a compound microscope with a dark-field condenser (dark-field
examination). Also available is the direct fluorescent antibody T. pallidum test, which entails fluorescein-labeled anti-T. pallidum globulin incubation and fluorescence microscopy. The disadvantage of this
test is that incubation requires a delay of 24 to 48 hours; the dark-field
examination can be done immediately. The nontreponemal tests
for syphilis detect antibodies against lipoidal antigen. The Venereal
Disease Research Laboratory (VDRL) test uses cardiolipin-lecithin-cholesterol
antigen mixed with heated serum on a glass slide. Flocculation
is read microscopically and reported as reactive, nonreactive, or weakly
reactive. The reactivity can be quantitated by serial dilution of
serum, and cerebrospinal fluid (CSF) can be tested. The rapid plasma reagent (RPR) test
is similar but does not require the use of heated serum.22 These tests become reactive during primary syphilis. The titer rises initially
and then decreases with time (even in untreated cases), and it
is estimated that 25% of untreated patients become nonreactive after 5 years.22 The titer of the VDRL or RPR falls after treatment, and the rate of fall
appears dependent on the duration of infection before treatment. Biologic
false-positive reactions are uncommon but may occur during pregnancy, mononucleosis, leprosy, with aging, or in systemic lupus erythematosus. Lyme
disease, caused by Borrelia burdorferi, can cause a positive VDRL or RPR result. Treponemal tests detect antibodies against T. pallidum. The fluorescent treponemal antibody absorption (FTA-ABS) test uses heated test serum mixed with sorbent to remove nonspecific antibody, incubation of slides containing T. pallidum antigen, and fluorescein-labeled antihuman globulin applied to the slides. Examination is by fluorescence microscopy, and the test is reported as either reactive or nonreactive. The microhemagglutination (MHA-TP) test for T. pallidum uses sensitized sheep erythrocytes coated with lysed T. pallidum. Agglutination occurs when antitreponemal antibody is present in serum. Again, the result is reported as reactive or nonreactive. These tests have a lower incidence of false positivity (rarely being positive in connective tissue diseases) and are more specific and sensitive than the nontreponemal tests.22 Reactive treponemal tests tend to remain reactive regardless of treatment or disease activity. However, approximately 20% of patients treated during the primary stage have negative treponemal tests after several years.23 The FTA-ABS appears to be more sensitive than the MHA-TP for identifying primary syphilis.24 Additional diagnostic tests using polymerase chain reaction techniques or enzyme immunoassay, either with pooled recombinant T. pallidum antigens or T. pallidum whole antigen, appear to be both sensitive and specific but are not as commonly used as the FTA-ABS and MHA-TP.22,25,26 Examination of CSF is helpful both diagnostically and therapeutically in patients with syphilitic uveitis. CSF examination is recommended in any patient with ophthalmic involvement, because central nervous system disease may occur during any stage of syphilis.23 Inflammation in the central nervous system is manifest by CSF protein elevation and pleocytosis, and both abnormalities tend to revert to normal with treatment. However, there are no uniformly accepted criteria for the diagnosis of asymptomatic neurosyphilis. The CSF VDRL test is helpful if positive, but the test is only 27% sensitive for diagnosing neurosyphilis. CSF MHA-TP or CSF FTA-ABS may help to diagnose neurosyphilis in patients with a negative CSF VDRL but minimal CSF pleocytosis or protein elevation.27 |
TREATMENT |
Multiple treatment regimens are available for treating syphilis, and there
are no controlled studies demonstrating that one regimen is significantly
better than another. However, the CDC has released guidelines
for the therapy of syphilis, and these are generally accepted as being
correct and appropriate for treatment of the disease. At present, there
are no specific CDC guidelines for the treatment of syphilitic uveitis. Because
uveitis can occur at any stage of the disease, and because
ocular disease implies neurologic involvement and is often associated
with neurosyphilis, treatment of syphilitic uveitis with a neurosyphilis
regimen is advised. Effectiveness of therapy in patients with CSF
pleocytosis can be monitored by semiannual CSF cell counts until the
cell count returns to normal.23 CDC guidelines for the treatment of syphilis are shown in Table 3. Penicillin remains the drug of choice for treatment of syphilitic uveitis.23 Oral azithromycin may be an alternative choice in patients allergic to penicillin, but its efficacy in neurosyphilis has not been determined.28 Desensitization to penicillin may be necessary in penicillin-allergic patients.23
TABLE 3 Treatment of Neurosyphilis and Syphilitic Uveitis Aqueous crystalline penicillin G 18–24 million units a day, administered as 3–4 million units IV q4h for 10–14 days (may be followed by benzathine penicillin 2.4 million units IM) or Procaine penicillin 2,4 million units IM daily, plus probenecid 500 mg PO QID, both for 10–14 days (may be followed by benzathine penicillin 2.4 million units IM)
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SUMMARY AND RECOMMENDATIONS |
Syphilis must be considered as a cause of ocular inflammation in any adult, especially one with multiple sexual partners. Ocular inflammation caused by syphilis may occur as anterior, posterior, or diffuse uveitis. Ocular inflammation caused by syphilis may be unilateral or bilateral. Laboratory examination should include both nontreponemal and treponemal tests. The workup of syphilitic uveitis should include CSF examination. Therapy of syphilitic uveitis should be a neurosyphilis regimen. Syphilis is a treatable cause of uveitis in patients with AIDS and is a curable form of uveitis. |