Congenital syphilis.  Congenital syphilis results from the

Table 10-1  Ocular manifestations of syphilis

PRIMARY SYPHILIS

Chancres of the eyelid and conjunctiva

SECONDARY SYPHILIS

Blepharitis

Madarosis

Conjunctivitis

Dacryocystitis

Dacryoadenitis

Keratitis

Iris nodules

Iridocyclitis

Episcleritis

Scleritis

Chorioretinitis

Vitritis

Neuroretinitis

Disc edema

Exudative retinal detachment

Perivasculitis

TERTIARY SYPHILIS

Gummas of the eyelids

Unilateral interstitial keratitis

Punctate stromal keratitis

Bilateral periostitis of the orbital bone

Episcleritis

Scleritis

Anterior and posterior uveitis

Chorioretinitis

Vasculitis

Venous and arterial occlusive disease

Exudative retinal detachment

Macular edema

Neuroretinitis

Vitritis

Pseudoretinitis pigmentosa

Chorioretinal neovascular membrane

Lens dislocation

Argyll Robertson pupil

Oculomotor palsies

CONGENITAL SYPHILIS

Bilateral interstitial keratitis

Pigmentary retinitis

Glaucoma

Keratouveitis

Figure 10-1.  Iris nodule caused by syphilis. (From Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. N Engl J Med 1984; 310: 972–81.)

Spirochetes

neuroretinitis may occur and is often localized to the peripapillary area.19 This is followed by a pigmentary retino­ pathy similar in appearance to retinitis pigmentosa. Disc edema (Fig. 10-3), exudative retinal detachment, and perivasculitis are less common findings.20–22

The gummas of tertiary syphilis can involve the eyelids, and if extensive can cause destructive ulceration, but gummatous dacryoadenitis and infiltration of the lacrimal sac have only rarely been reported. Conjunctival vascular changes occur, but gummas of the conjunctiva almost never occur. As seen in secondary syphilis, syphilitic blepharitis with madarosis is common. A diffuse bilateral periostitis is the most common orbital finding of tertiary syphilis. Uniocular interstitial keratitis is the most common corneal finding in tertiary syphilis, but punctate stromal keratitis can occur with iritis. Episcleritis and scleritis occur, but discrete gummas of the sclera are rare. Uveitis is a common finding in late tertiary syphilis. Halperin and colleagues23 stated that the main posterior segment complications of acquired syphilis include chorioretinitis, vasculitis, venous and arterial occlusive disease, retinal detachment with choroidal effusion, macular edema, neuroretinitis, optic neuritis, vitritis (Fig. 10-2A), and pseudoretinitis pigmentosa (Fig. 10-2B). Choroidal neovascular membranes and subretinal fibrosis (Fig. 10-4) can also occur. A posterior placoid chorioretinitis has been described in late latent syphilis.23a Vitreous opacities are common, and lens dislocation has been reported in many patients.

The most typical manifestation of congenital syphilis is bilateral interstitial keratitis, which appears later in life. A pigmentary retinitis and glaucoma can also occur as a result of congenital syphilitic keratouveitis.

The Argyll Robertson pupil and disc edema are most commonly seen in meningovascular syphilis, along with oculomotor palsies and other pupillary abnormalities. Later in the course of meningovascular syphilis, optic atrophy occurs. A complete Argyll Robertson pupil is rare in cases of general paresis, but, as with optic atrophy, is more common in cases of tabes dorsalis.

Diagnosis

The diagnosis of syphilis is based on the clinical history, physical examination, and laboratory tests. Although darkfield examination or immunofluorescent staining of mucocutaneous lesions can lead to the prompt diagnosis of primary, secondary, and early congenital syphilis, most physicians order serologic tests to make or confirm a diagnosis. There are both nontreponemal and treponemal tests. Confusion often arises in determining whether a VDRL test should be ordered rather than an FTA-ABS test, and in the interpretation of the results. In this section the various diagnostic tests for syphilis are explained, and a strategy for ordering tests is outlined (Box 10-2).

Darkfield microscopy can be used to identify spirochetes present in tissue fluids. T. pallidum is difficult to distinguish from other spirochetes, and so darkfield examination requires expertise. In clinical practice, greater reliance is placed on the serologic test for syphilis.

The two most commonly used screening tests for syphilis are the VDRL test and the rapid plasma reagin (RPR) test. Both of these are nontreponemal reaginic tests. Infection with T. pallidum stimulates nonspecific antibodies against

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Figure 10-3.  A, Patient with acquired syphilis who presented with papillitis and retinitis. B, The findings resolved following treatment with intravenous antibiotics. (Courtesy Phuc Le Hoang, MD.)

Box 10-2  Diagnosis of syphilis – key points

•Diagnosis is based on clinical history, physical examination, and laboratory tests

•There are both nontreponemal and treponemal tests for syphilis

•Nontreponemal tests are often used to screen for syphilis.   The two most common screening tests are the Venereal Disease Research Laboratory (VDRL) test and the rapid plasma reagin (RPR) test

•Treponemal tests are more sensitive in diagnosing patients with latent or late syphilis and more specific than the VDRL. The most commonly used treponemal test is the fluorescent treponemal antibody absorption (FTA-ABS) test

Figure 10-4.  Extensive subretinal fibrosis caused by ocular syphilis. (Courtesy Rubens Belfort Jr, MD.)

cardiolipin. The VDRL test quantitates these antibodies by use of slide flocculation. The VDRL test is well standardized, and the result is reported as reactive, weakly reactive, borderline, or nonreactive. The rapid plasma reagin test is a similar assay for detecting anticardiolipin antibody.

The sensitivity and the specificity of the VDRL test vary, depending on the stage of disease (Table 10-2). The VDRL test starts to become positive about 1–2 weeks after the appearance of the primary chancre and is positive in 99% of patients with secondary syphilis.24 In later stages of the disease, however, the VDRL test reactivity decreases, and only about 70% of patients with cardiovascular syphilis or neurosyphilis have a positive VDRL test result. In addition, the VDRL test often becomes nonreactive after treatment for syphilis.

The serologic tests for syphilis are not 100% specific, and false-positive results can occur, especially in patients with other spirochetal diseases and connective tissue diseases (Table 10-3). Any weakly reactive or reactive VDRL test needs to be confirmed with a more specific test. The tests used for this purpose are the treponemal tests for syphilis, such as the T. pallidum agglutination tests (TPHA and MHA-TP) or the more commonly used FTA-ABS test. The T. pallidum immobilization test is almost completely specific for syphilis, but is expensive and difficult to perform and therefore rarely used. The microhemagglutination–T. pallidum (MHA-TP) assay for antibodies to T. pallidum is another specific test for syphilis but is also used less frequently than the FTA-ABS test. In the FTA-ABS test, the patient’s serum is absorbed with extracts of nonpathogenic treponemes to remove possible

Table 10-2  Patients with positive results to VDRL and FTA-ABS tests Percentage of patients with positive results

Late or latent syphilis

Test

VDRL, Venereal Disease Research Laboratory; FTA-ABS, fluorescent treponemal antibody absorption.

Table 10-3  Causes of false-positive serologic test results for syphilis

SPIROCHETAL INFECTIONS

Endemic syphilis (bejel)

Yaws and pinta

Leptospirosis

Lyme disease

Relapsing fever

OTHER INFECTIONS

Chancroid

Chickenpox

Hepatitis

HIV infection

Infectious mononucleosis

Leprosy

Lymphogranuloma venereum

Malaria

Measles

Mycoplasma pneumonia

Pneumococcal pneumonia

Rickettsial disease

Scarlet fever

Subacute bacterial endocarditis

Tuberculosis

Trypanosomiasis

NONINFECTIOUS CAUSES

Blood transfusions

Chronic liver disease

Connective tissue disease

Narcotic addiction

Pregnancy

Vaccination

cross-reacting antitreponemal antibody that is not specific for T. pallidum. The absorbed serum is then made to react against T. pallidum, and specific antibodies are detected by the addition of fluorescein-labeled antihuman γ-globulin. Results are reported as nonreactive or as 1+ to 4+ positive, based on the intensity of the fluorescence.

A weakly reactive FTA-ABS test may not be reproducible. The FTA-ABS test is more sensitive than the VDRL test at all stages of syphilis, but it is more expensive and difficult to perform. The FTA-ABS test is also not entirely specific for syphilis, because false-positive results are seen in patients with systemic lupus erythematosus, biliary cirrhosis, and some connective tissue diseases, such as rheumatoid arthritis (see Table 10-3).

Because serologic tests for syphilis may take several weeks to become reactive, immediate diagnosis requires

Spirochetes

demonstration of treponemes in tissue fluid by darkfield microscopy. The VDRL test is an excellent screening test for patients with later primary syphilis and secondary syphilis. The sensitivity of the VDRL test is 99% for patients with secondary syphilis; however, all positive results should be confirmed with an FTA-ABS test.

Because the sensitivity of the VDRL test may be only 70% in patients with latent or late syphilis, both VDRL and FTA-ABS tests should be ordered if a later stage of disease is suspected. From the ophthalmic standpoint, many patients with uveitis or disc edema are suspected of having late syphilis, and many uveitis specialists and neuro-ophthalmologists routinely order both VDRL and FTA-ABS tests in the evaluation of these patients. As stated above, in the United States, testing for syphilis has consisted of initial screening with an inexpensive nontreponemal test, with subsequent testing of reactive specimens with a treponemal test. Some clinical laboratories have started using automated treponemal tests and then retest reactive results with a nontreponemal test.24a It is not clear what the recommendations are for patients who test positive with the treponemal test and then negative for the nontreponemal test. If not previously treated, these patients should probably be treated for late latent syphilis.

In addition, all patients who may have had syphilis for more than a year should have a lumbar puncture for CSF examination. A cell count, differential count, protein determination, and VDRL test should be performed on the CSF to look for evidence of neurosyphilis. As stated previously, CNS invasion by T. pallidum may be common in early syphilis.15 The finding of CNS involvement is important because the recommended therapy is different from that for patients without CNS involvement. Serologic tests for neurosyphilis can also be confusing. The CSF-VDRL is insensitive but highly specific. A CSF serologic diagnosis is usually based on production of local antitreponemal antibodies, and an intrathecal T. pallidum antibody index can be calculated.

Infants born with congenital syphilis have positive VDRL and FTA-ABS test results from the passive transfer of immunoglobulin (Ig) G antibodies across the placenta; therefore, an IgM FTA-ABS test is used to diagnose congenital syphilis because IgM antibodies do not cross the placenta, and a positive test result would indicate actual infection in the infant.25

Patients with undiagnosed interstitial keratitis should be suspected of having late congenital syphilis. A thorough history of previous therapy should be elicited, and patients should then undergo VDRL and FTA-ABS tests and a CSF examination. If the CSF VDRL test result is positive, some experts recommend that the patient be treated as for latent syphilis (Table 10-4). Patients with a positive serum VDRL or FTA-ABS result but negative CSF findings are treated as for primary or secondary syphilis.

Finally, newer diagnostic techniques may be helpful in diagnosing syphilis in patients with ocular manifestations of syphilis. The polymerase chain reaction (PCR) may be used to detect T. pallidum in ocular specimens such as aqueous humor.

Prognosis

Most patients recover without long-term sequelae if syphilis is recognized and treated early. If untreated, about 25% of

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