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Spirochetal Diseases
Key Concepts
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Spirochetal diseases that cause uveitis include a gamut of historical and clinical infections, including syphilis, endemic syphilis, Lyme disease, relapsing fever, and leptospirosis.
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Syphilis remains a common and frequently missed, but treatable, cause of uveitis. Ocular findings can occur in primary, secondary, latent, and tertiary syphilis.
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The Venereal Disease Research Laboratory (VDRL) test can yield false–negative results, especially in the later stages of the disease, and a more sensitive test, such as the fluorescent treponemal antibody absorption (FTA-ABS) test, should be considered when evaluating patients with possible syphilitic uveitis.
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Patients with ocular syphilis should be treated with the recommended regimen for neurosyphilis.
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Lyme disease serology should be ordered in patients with a history or findings consistent with the disease. False-positive results are common when the test is ordered in patients with an extremely low likelihood of Lyme disease.
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Antibiotic regimens for spirochetal disease change frequently. Consulting a physician well versed in treating these diseases is important to ensure the appropriate drug, its dose and route of administration, and length of treatment.
Spirochetal Infections And The Eye
This chapter focuses on uveitis caused by spirochetes. This comprises a variety of infectious diseases with ocular manifestations, including syphilis, bejel, pinta, yaws, Lyme disease, relapsing fever, and leptospirosis. The ocular manifestations of syphilis have been known for well over a century, whereas Lyme disease was first described only in the 1970s. The first section of this chapter is devoted to treponemal infections, of which syphilis is, by far, the most common and important infection to the practicing ophthalmologist. Syphilis remains an important cause of eye disease and blindness in the United States and is diagnosed with increasing frequency in patients with acquired immunodeficiency syndrome (AIDS). Sections on endemic syphilis (bejel) and nonvenereal treponemal infections (yaws and pinta) are also included.
The second part of the chapter contains sections on two infections caused by spirochetes of the genus Borrelia and a section on leptospirosis. Although the cause of syphilis was identified at the beginning of the twentieth century, the causative agent for Lyme disease was not discovered until 1982. Interestingly, Lyme disease and syphilis share many clinical features and should be considered together in the differential diagnosis of infectious diseases with ophthalmic involvement. The chapter also reviews relapsing fever, an additional infection caused by Borrelia that is often misdiagnosed. Leptospirosis is discussed at the end of the chapter and may be an important cause of uveitis of unknown etiology.
Spirochetes
Definition
Spirochetes are a phylum of bacteria characterized by long, helically coiled cells. These bacteria have lengthwise flagella, called axial filaments, which allow the spirochetes to move. There are three groups of spirochetes implicated in human disease: Treponema, which causes syphilis and the nonvenereal treponematoses; Borrelia, which causes relapsing fever and Lyme disease; and Leptospira, which causes leptospirosis.
Venereal Treponemal Diseases
Syphilis
Etiology
Syphilis was originally called the great pox, but it acquired its current name from the title character of a poem written in 1530 by the Veronese physician and poet Girolamo Fracastoro. Syphilis has also been called the great imitator because of the myriad symptoms and signs in its repertoire and its ability to mimic numerous other illnesses. Although clinical descriptions of syphilis date back at least half a millennium, it was not until 1905 that Schaudin and Hoffman isolated the spirochete Treponema pallidum from the skin lesions of patients with syphilis.
After initial infection, there is both a humoral immune response and a cellular immune response. In 1910, Wasserman introduced a complement fixation test to detect nonspecific antibodies that react against cardiolipins, and these antibodies are commonly found in patients with syphilis. The next milestone in the history of syphilis was the use of arsenic derivatives to treat the disease. The coup de grâce in the war against syphilis came in 1943 with the discovery of penicillin, which is the mainstay of therapy even today.
Epidemiology
In the late 1980s, there was a substantial increase in the rates of primary and secondary syphilis and an increased incidence of congenital syphilis, especially in the inner cities. In 1986, only 57 cases of congenital syphilis were reported in New York City, but in 1989, more than 1000 cases were documented. With focused efforts to reduce syphilis in the United States, in 2000, the rate of primary and secondary syphilis was 2.1 cases per 100,000 population, the lowest since reporting began in 1941. From 2001 to 2004, the rate increased to 2.7 cases per 100,000 population. Approximately 84% of cases occurred in men. The incidence of primary and secondary syphilis also varied by race/ethnicity. The incidence of primary and secondary syphilis in 2004 was 9 per 100,000 among black, 1.6 among white, 3.2 among Hispanic, 1.2 among Asian/Pacific Islander, and 3.2 among American Indian/Alaska Native populations. Since reaching a low in 2000, the number of cases of syphilis in the United States has continued to increase, predominantly in men ( Fig. 11.1 ). With an estimated 11 million new cases annually, syphilis remains a common infection globally, especially in resource-limited countries, where it is the second leading cause of stillbirths. Syphilis is also a problem in patients coinfected by human immunodeficiency virus (HIV). These patients may not mount a serologic response to the treponemal infection and thus elude diagnosis. In addition, standard therapy may be insufficient to eradicate the infection in these immunocompromised patients. ,
Although syphilis is a nationally notifiable disease in the United States, ocular manifestations are not reportable to the Centers for Disease Control and Prevention (CDC). After clusters of ocular syphilis were reported in early 2015, the CDC reviewed syphilis surveillance and case investigation data from 2014, 2015, or both to ascertain syphilis cases with ocular manifestations. A total of 388 suspected ocular syphilis cases were identified, 157 in 2014 and 231 in 2015. Overall the number of syphilis cases with ocular manifestations was 0.53% in 2014 and 0.65% in 2015, ranging from 0.17% to 3.9%, depending on the reporting region. Greater than 90% of the patients were men and one-half of the patients were HIV positive.
Clinical course
T. pallidum is a spirochete that is approximately 0.01 to 0.02 μm wide and 5 to 20 μm long. Although it cannot survive long outside of the body, it can be cultured and remains viable for several days. Syphilis is transmitted almost exclusively via sexual contact, including sexual intercourse, orogenital or anorectal contact, and occasionally kissing. The disease is most infectious in patients with untreated primary syphilis or secondary syphilis with skin lesions. Disease can also be transmitted by patients with early latent syphilis, especially if they have mucocutaneous involvement; however, disease in patients with late latent syphilis or tertiary syphilis is not infectious. Congenital syphilis occurs with transplacental spread of the spirochete. Interestingly, infection with syphilis does not confer lasting immunity, especially if treatment is received early in the course of the disease.
T. pallidum can penetrate intact mucous membranes or abraded skin. The period of incubation varies from 10 to 90 days but averages 3 weeks. Before primary skin lesions appear, the spirochete spreads via the lymphatics to the bloodstream and then disseminates from there.
As with many of the spirochetal diseases, the clinical course of syphilis is divided into stages: primary, secondary, and tertiary syphilis ( Box 11.1 ).
BOX 11.1
Syphilis: Key Features
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Caused by the spirochete Treponema pallidum
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Transmitted almost exclusively via sexual contact
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Congenital syphilis occurs with transplacental spread of the spirochete
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Disease is divided into stages: primary, secondary, latent, and tertiary
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Tertiary syphilis is subdivided into three subgroups: benign tertiary syphilis, cardiovascular syphilis, and neurosyphilis
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If untreated, syphilis will disseminate
Clinical manifestations
Primary syphilis
The chancre is the predominant lesion of primary syphilis. It appears about 4 weeks after infection and heals in about 1 to 2 months in untreated individuals. The lesion typically begins as a single erythematous papule at the inoculation site and later erodes to form a painless ulcer. Multiple chancres can occur, especially in patients coinfected with HIV. Serous fluid from these lesions teems with spirochetes. Lesions occur on the penis, anus, and rectum in men and on the cervix, vulva, and perineum in women. Small lesions may also occur on the lips, tongue, buccal mucosa, and skin, and chancres of the eyelids and conjunctiva have also been described.
Secondary syphilis
If left untreated, disease in patients with primary syphilis will progress to secondary syphilis 4 to 10 weeks after the initial manifestations of the disease. One of the unique characteristics of syphilis is that it always disseminates. The skin is involved in about 90% of patients with secondary syphilis. A healing chancre may be present in patients with secondary syphilis, especially in persons with concurrent HIV infection. A generalized rash is characteristic of secondary syphilis and may be maculopapular or pustular. The rash commonly occurs on the flexor and volar surfaces of the body, typically the palms and the soles. The rash usually resolves without scarring, but some patients are left with areas of hyper- or hypopigmentation. Mucous membranes become eroded, forming erythematous patches. Condylomata lata is another characteristic dermatologic manifestation of secondary syphilis. The papules develop at the mucocutaneous junctions and in moist areas of the skin and appear as dull pink or gray hypertrophic lesions. Systemic symptoms of secondary syphilis include fever, malaise, headache, nausea, anorexia, and joint pain. Generalized lymphadenopathy is found in both primary and secondary syphilis. Syphilitic infiltration of the kidneys, liver, and gastrointestinal tract also occurs in secondary syphilis, and about 10% of patients have ocular involvement. Anterior uveitis is the predominant eye finding in early secondary syphilis and may be the most common ocular lesion in syphilis. Some patients may demonstrate cerebrospinal fluid (CSF) pleocytosis, and a few of these patients experience acute syphilitic meningitis with headache, neck stiffness, cranial nerve palsies, and disk edema. Similar to the clinical course of primary syphilis, the signs and symptoms of secondary disease often resolve spontaneously within 1 to 6 months.
Latent syphilis
In untreated persons, a diagnosis of latent syphilis is made with positive serologic tests for the disease in the absence of CSF abnormalities or clinical manifestations. Early latent syphilis is defined as encompassing latent syphilis during the first year after initial infection. Some of these patients may have recurrences of infectious mucocutaneous lesions. The late latent phase of syphilis occurs after 1 year of infection, and during this stage of the disease, infectious relapses are rare. Most patients who have not been treated remain in this late latent phase of the disease; however, about 30% go on to experience tertiary syphilis.
Tertiary syphilis
Tertiary syphilis is also called late syphilis and is often subdivided into three groups: benign tertiary syphilis, cardiovascular syphilis, and neurosyphilis, although it is important to note that syphilis can involve the central nervous system (CNS) at all stages of the disease.
Benign tertiary syphilis
Also known as late benign syphilis, the gumma is the typical lesion of benign tertiary syphilis and is a chronic granulomatous lesion that heals with scarring and fibrosis. It is a rare finding in the penicillin era and responds rapidly to treatment. Gummas tend to develop in the skin, mucous membranes, and skeletal system but can occur in almost any tissue and have even been found in the brain and in the choroid of the eye.
Cardiovascular syphilis
The lesions of cardiovascular syphilis include aortitis and aortic aneurysms, aortic valvular insufficiency, and narrowing of the coronary ostia. The disease starts about 5 to 10 years after infection, but symptoms of cardiovascular syphilis may not be clinically evident for more than 20 years.
Neurosyphilis
This condition is said to occur in 5% to 10% of untreated patients with syphilis. Asymptomatic neurosyphilis is found in some patients who have a positive CSF–Venereal Disease Research Laboratory (VDRL) test result but no symptoms of CNS disease. In addition, invasion of the CNS by T. pallidum may be more common in early syphilis than once thought. Lukehart et al. isolated T. pallidum from CSF in 12 (30%) of 40 patients with untreated primary and secondary syphilis, and an additional four patients, who did not have T. pallidum in the isolates but had reactive CSF on the VDRL test. Neurosyphilis can occur at any time in the course of the disease. Uveitis and hearing loss are more common in the earlier stages.
One type of neurosyphilis, meningovascular syphilis, presents as aseptic meningitis, which can occur any time after primary syphilis. Unilateral or bilateral cranial nerve palsies are common, and headache, neck stiffness, dizziness, lassitude, and blurred vision occur. The classic neuro-ophthalmic finding of neurosyphilis is the Argyll Robertson (AR) pupil. This is a small, irregular pupil that is unreactive to light but normally reactive to accommodation; it is commonly seen in cases of meningovascular syphilis, in which the base of the brain is involved. If the spinal cord is involved, patients may experience bulbar symptoms, muscle weakness and wasting, and slowly progressive spastic paraplegia with bladder incontinence.
T. pallidum may also invade the substance of the brain. Parenchymatous neurosyphilis is a meningoencephalitis, with progressive loss of cortical function. Patients can experience altered mental status and even syphilitic psychosis, with irritability, reduced memory, poor judgment, confusion, and delusions. Seizures may occur. On neurologic examination, patients demonstrate tremors of the mouth and tongue, hyperreflexia, and, in some cases, extensor plantar responses. Pathologically, the brain parenchyma is infiltrated with spirochetes, and the meninges are inflamed and thickened. CSF is hypercellular, and the VDRL test result is positive. Cranial nerve palsies, however, are uncommon, and optic atrophy is rare. Although pupillary abnormalities may be seen, a complete AR pupil is not characteristic. Neurosyphilis should still be considered in the differential diagnosis of advanced neurologic disease with generalized paresis, although this finding is rare in the United States.
Tabes dorsalis is a form of neurosyphilis, with involvement of the posterior columns and the posterior roots of the spinal cord, resulting in pain, ataxia, sensory changes, reduced tendon reflexes, and ocular findings. Severe stabbing pain in the lower extremities heralds this form of neurosyphilis. Unsteadiness and a wide-based gait develop later, followed by hyperesthesia and paresthesia. Incontinence and impotence are other common sequelae. Charcot arthropathy occurs in the large joints that are devoid of sensation and are prone to destructive changes. AR pupils are frequent in this form of neurosyphilis, and optic atrophy is commonly found.
Congenital syphilis
Congenital syphilis results from the transplacental transmission of T. pallidum from the mother to the fetus. Untreated primary or secondary syphilis is almost invariably transmitted to the fetus, whereas transmission in later stages of the disease occurs less frequently. Transmission to the fetus can occur at any time during the pregnancy, but fetal damage tends to occur after the fourth month when fetal immunologic competence starts. Congenital syphilis is preventable with proper treatment of the mother; therefore all expectant mothers should have a VDRL test at the beginning and near the end of pregnancy. In fact, serologic screening of women at the time pregnancy is first diagnosed and screening of all infants at the time of delivery is now mandatory in New York State.
Signs and symptoms of early congenital syphilis may not appear until several days after birth, and Dorfman and Glaser stated that the diagnosis of congenital syphilis may be missed if serologic tests are not performed for both the mother and her infant at the time of delivery. A generalized rash develops and resembles the rash of secondary syphilis, except that in the infant, the rash may be vesicular or bullous. Rhinitis (also called snuffles ), jaundice, hepatosplenomegaly, anorexia, and pseudoparalysis may also be found. Osteochondritis and pathologic fractures are common, and radiographic changes on bone films are present in greater than 90% of patients. Chorioretinitis is often evident in the first few months of life.
Congenital syphilis may mimic other congenital infections, such as rubella, cytomegalovirus infection, and toxoplasmosis. A positive serologic test result for syphilis may be caused by passive transfer of antibody from the mother; therefore diagnosis of congenital syphilis is based on a positive FTA-ABS test result and a rising VDRL titer. Results of serologic tests performed in infants and their mothers may be negative at the time of delivery if syphilis is acquired toward the end of the pregnancy.
After 2 years, the child is described as having late congenital syphilis. Like syphilis in adults, late congenital syphilis may remain latent with few sequelae, although cardiovascular involvement does occur; and meningovascular syphilis with neurologic manifestations, including eighth cranial nerve deafness, is common. Acute syphilitic meningitis, generalized paresis, and tabes dorsalis are less common. Interstitial keratitis is the classic ophthalmic sign of congenital syphilis, occurring in 10% of patients.
Deformities of the permanent teeth occur after early syphilitic infection. The characteristic Hutchinson teeth are notched, thin, upper incisors with abnormal spacing. The term Hutchinson triad refers to the occurrence of Hutchinson teeth, interstitial keratitis, and deafness, but the occurrence of all three in the same patient is unusual. The bone lesions of early congenital syphilis tend to progress in late congenital syphilis, with the development of syphilitic arthritis. Finally, gummas may develop in the subcutaneous tissue and produce ulcerative skin lesions.
Ocular manifestations
Table 11.1 lists some of the more common eye manifestations of the different stages of syphilis. Ophthalmic manifestations of primary syphilis are limited to chancres of the eyelid and the conjunctiva. A primary syphilitic lesion in the lacrimal gland is extremely rare but has been reported.
TABLE 11.1
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 Disk 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 |
The eyelids are commonly involved in the rash of secondary syphilis, and blepharitis and loss of lashes and eyebrows are common. Conjunctivitis mimicking trachoma has also been seen in secondary syphilis, but dacryocystitis and dacryoadenitis are rare. Keratitis, iris nodules ( Fig. 11.2 ), iridocyclitis, episcleritis, and scleritis have all been reported in secondary syphilis. Late in the secondary stage, vitritis and chorioretinitis may develop ( Fig. 11.3A ). Diffuse neuroretinitis may occur and is often localized to the peripapillary area. This is followed by a pigmentary retinopathy similar in appearance to retinitis pigmentosa (see Fig. 11.3B ). Disk edema, exudative retinal detachment, perivasculitis, and subretinal fibrosis can also occur ( Figs. 11.4 and 11.5 ).
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. 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 et al. 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 (see Fig. 11.3A ), and pseudoretinitis pigmentosa (see Fig. 11.3B ). Choroidal neovascular membranes and subretinal fibrosis ( Fig. 11.6 ) can also occur. Posterior placoid chorioretinitis has been described in late latent syphilis. 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. Pigmentary retinitis and glaucoma can also occur as a result of congenital syphilitic keratouveitis.
The AR pupil and disk 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 AR 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 test findings. Algorithms for testing patients suspected of having syphilis change frequently, so consultation with an infectious disease specialist can be useful in determining which tests to order, depending on the individual patient and the presumed stage of the disease. Although darkfield microscopy or immunofluorescent staining of mucocutaneous lesions can aid in the prompt diagnosis of primary, secondary, and early congenital syphilis, most physicians order serologic tests to make or confirm a diagnosis. Darkfield microscopy can be used to identify spirochetes present in tissue fluids. T. pallidum is difficult to distinguish from other spirochetes, so darkfield examination requires expertise. Sensitive and specific polymerase chain reaction (PCR) tests for T. pallidum have been developed but are not commercially available. Serologic tests include both nontreponemal and treponemal tests. Both tests are reactive in persons with any treponemal infection, including syphilis, endemic syphilis, yaws, and pinta. Confusion often arises in determining whether a rapid plasma reagin (RPR) test or 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 11.2 ).
BOX 11.2
Diagnosis of Syphilis: Key Points
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Diagnosis is based on clinical history, physical examination, and laboratory tests.
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There are both nontreponemal and treponemal tests for syphilis.
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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.
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Treponemal tests are more sensitive in diagnosing patients with latent or late syphilis and more specific than the VDRL test. The most commonly used treponemal test is the fluorescent treponemal antibody absorption (FTA-ABS) test.
The two most commonly used screening tests for syphilis are the VDRL test and the RPR test. Both are nontreponemal reaginic tests. Infection with T. pallidum stimulates nonspecific antibodies against cardiolipin. The VDRL test quantitates these antibodies with the 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 RPR test is easier to perform than the VDRL test and is often used as a quick screening test; however, the VDRL test is more accurate for examining CSF.
The sensitivity and the specificity of the VDRL test vary, depending on the stage of disease ( Table 11.2 ). , The VDRL test result becomes positive about 1 to 2 weeks after the appearance of the primary chancre and is positive in 99% of patients with secondary syphilis. In the 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.
Table 11.2
Sensitivity and Specificity of the VDRL and FTA-ABS tests
| Test | Sensitivity by Stage of Syphilis, % (range) | Specificity of Test, % (range) | |||
|---|---|---|---|---|---|
| Primary | Secondary | Latent | Tertiary | ||
| VDRL | 78 (74-87) | 100 | 96 (88-100) | 71 (37-94) | 98 (96-99) |
| FTA-ABS | 84 (70-100) | 100 | 100 | 96 | 97 (84-100) |
VDRL, Venereal Disease Research Laboratory; FTA-ABS, fluorescent treponemal antibody absorption.
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 11.3 ). Any VDRL test result that is given as “weakly reactive”” or “reactive” 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 ( Treponema pallidum hemagglutination assay [TPHA] and microhemagglutination assay with Treponema pallidum antigen [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 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 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 gammaglobulin. Results are reported as “nonreactive” or as “1+ to 4+ positive,” based on the intensity of the fluorescence.
Table 11.3
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 Human immunodeficiency virus (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 |
An FTA-ABS test result reported as weakly reactive 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 11.3 ).
Because serologic tests for syphilis may take several weeks to see a reactive result, immediate diagnosis requires 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 approximately 100% for patients with secondary syphilis. Because the sensitivity of the VDRL test may be only 70% in patients with tertiary syphilis, an FTA-ABS test should be ordered if a later stage of disease is suspected. From the ophthalmic standpoint, many patients with uveitis or disk 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 earlier, 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. 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. Because the price of the FTA-ABS test has decreased and the speed of testing has improved, the FTA-ABS is being used as the initial screening test for syphilis, especially where there is a strong suspicion for the disease.
In addition, all patients who may have had syphilis for more than a year should undergo lumbar puncture for CSF examination. Cell count, differential count, protein determination, and the VDRL test should be performed on CSF samples to look for evidence of neurosyphilis. As stated previously, CNS invasion by T. pallidum may be common in early syphilis. 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 test is insensitive but highly specific. CSF serologic diagnosis is usually based on the 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 G (IgG) antibodies across the placenta; therefore an immunoglobulin M (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.
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 CSF examination. If the CSF-VDRL test result is positive, some experts recommend that the patient be treated as for latent syphilis ( Table 11.4 ). Patients with a positive serum VDRL or FTA-ABS result but negative CSF findings are treated as for primary or secondary syphilis.
Table 11.4
Treatment of Syphilis
| Primary, Secondary, and Early Latent Syphilis in Adults |
| Benzathine penicillin G, 2.4 million units intramuscularly (IM) in a single dose. If penicillin allergies exist, treat with doxycycline, 100 mg orally (PO) two times daily × 2 weeks or tetracycline 500 mg PO four times daily for 2 weeks. |
| Latent and Tertiary Syphilis or Syphilis of Unknown Duration |
| Benzathine penicillin G, 7.2 million units total, administered as three doses of 2.4 million units IM each at 1-week intervals. |
| Neurosyphilis and Ocular Syphilis in Adults |
| Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units intravenously (IV) every 4 hours or continuous infusion for 10–14 days. |
| Congenital Syphilis in Infants and Children |
| Early Latent Syphilis |
| Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose. |
| Late Latent Syphilis |
| Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as three doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units). |
Although not commercially available, newer diagnostic techniques have been used to diagnose syphilis in patients with ocular manifestations of syphilis. PCR analysis may be used to detect T. pallidum in ocular specimens, such as aqueous humor, when available in the research setting. Finally, because individuals at the highest risk for syphilis are also at risk for HIV infection, tests for both infections should be ordered. Serologic testing after treatment is important for every patient with syphilis to ensure adequate treatment of the disease.
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