C. Stephen Foster,
Richard R. Tamesis
Syphilis is a sexually transmitted, chronic, systemic infection caused by the spirochete Treponema pallidum. Primary infection is followed by an incubation period of ~3 weeks, usually succeeded by the appearance of a primary skin or mucous membrane lesion, the chancre. This lesion, which may appear from 8 days to 6 weeks after infection with T. pallidum, is usually painless and associated with regional lymph node enlargement. The chancre typically heals within a few weeks. The secondary stage of syphilis ensues. Symptoms of this stage (fever, malaise, headache, generalized lymph node enlargement, and rash) generally appear within a few weeks or, at most, a few months after the primary chancre has disappeared. This spirochetemic stage of the disease then subsides, even without antibiotic therapy, and the infection becomes 'latent'. Individuals with historic or serologic evidence of syphilis but with no clinical manifestations by definition have latent syphilis. Secondary syphilitic relapses may develop during this state of latency. Approximately one-third of untreated cases will progress to tertiary syphilis, with syphilitic inflammatory lesions of the heart, aorta, brain, kidney, bone, eye, or skin.
CAUSE
The organism responsible for syphilis, T. pallidum, was discovered by Schaudinn and Hoffman of Hamburg in 1905 in inflammatory lesions from a patient with syphilis. This organism is a thin, spiral-shaped parasite for whom the only known natural host is Homo sapiens. Other mammals can be infected with the organism. The origins are unknown, and several hypotheses exist regarding the development of syphilis in humans. Two main theories, one tracing the development from the tropics and the other tracing the development from native Americans, are most commonly espoused. The first clear descriptions of clinical evidence of syphilis were recorded at the end of the fifteenth century, when a pandemic known as the Great Pox, as distinguished from smallpox, swept over Europe and Asia.[1] Warfare in the fifteenth century, including the seige of Naples by Charles VIII of France, was associated with the spread of what today is known as syphilis among soldiers, prostitutes, and other women who followed the warriors. The disease became known as the French disease among Italians and the Italian disease among the French. It supposedly received its present name from a poem written in 1530 by Fracastoro about an infected shepherd named Sifilis.[2]
EPIDEMIOLOGY
TRANSMISSION
With the notable exception of transplacental transmission from an infected mother to her fetus, the transmission of T. pallidum is almost exclusively sexual. Transmission requires a break in the skin, but T. pallidum can penetrate intact mucous membranes. The primary mode of transmission is through sexual intercourse, but transmission during oral sexual practices may also occur. Transmission after blood transfusions is, in essence, unheard of in civilized societies today because of the screening of blood and blood products for transfusion. The likelihood of transmission of an infectious dose of T. pallidum from an infected to a noninfected individual during sexual intercourse is undoubtably multifactorial. One study based on a placebo-controlled trial of antibiotic efficacy in aborting syphilis in known contacts, however, suggested a 30% incidence of transmission with a single sexual encounter.[3] Few organisms are needed to survive, proliferate, and produce disease. It is estimated that the ID50 inoculum is 57 spirochetes.[4]
INCIDENCE
With the exception of two periods of a rising incidence of syphilis, the incidence of this disease has been steadily decreasing since 1940. Infant deaths resulting from syphilis and new admissions of patients with syphilitic psychoses have fallen 99% since 1940 in the United States, and the total number of cases of late and latent syphilis has fallen 98% since 1943. A decrease of 98% in the number of congenital syphilitic cases has occurred since 1941.[1] An increase in the incidence of syphilis in World War II was noted in all Western countries; this incidence rapidly fell in the 1950s. A smaller rise occurred between 1971 and 1980, which can be accounted for primarily by the increasing incidence of syphilis in the homosexual community. By 1988, there were 40 275 new cases of primary and secondary syphilis reported in the United States. That number had fallen to 16 500 in the 1995 Summary of Notifiable Diseases, and to 7980 in 2004.[4,5] Age-related data show early syphilis to be concentrated in young adults, with many more male than female cases reported.[2] The reported incidence is higher among nonwhites than among whites, higher in urban areas than in rural areas, higher in the southern and southwestern United States, and higher in those states with large urban populations. Grassly and coworkers used time series of annual disease reports for 68 US cities to demonstrate marked 8-11 year cycles in syphilis incidence from the 1980s, which had previously been attributed to changes in sexual behavior.[6] Instead, they showed that the dynamics of syphilis infection can be explained by the 'susceptible-infected-recovered' (SIR) model for microparasitic infections.[7,8] Syphilis stimulates significant but imperfect immunity following recovery from infection. In the SIR model, oscillations in incidence of disease are produced by prolonged immunity following infection combined with a short infection period. Cycles occur because major epidemics exhaust their supply of susceptible individuals. The number of individuals in at-risk groups then gradually increases, eventually providing enough numbers for the next major outbreak.
OCULAR MANIFESTATIONS
UVEA
Syphilis was believed to be a common cause of iritis before the antibiotic era. In the decade from 1970 to 1980 in a large referral uveitis practice, Schlaegel and Kao estimated that only 1.1% of their uveitis cases were secondary to syphilis.[9] However, they emphasized one of the most important points for ophthalmologists to remember; they did not initially suspect syphilis in most of their 28 patients who were ultimately shown to have this disease, and many of their patients had a nonreactive Venereal Disease Research Laboratory (VDRL) test. The authors emphasized, once again, the 'great imitator' capabilities of syphilis and also stressed the importance of the fluorescent treponemal antibody absorption (FTA-ABS) test in the routine screening of all patients with intraocular inflammation. If this test had not been used in their investigations, three-fourths of their syphilitic iritis cases would have gone undiagnosed. This point is reemphasized as a result of an experience with 25 of 1020 new uveitis referral cases seen between 1 Jan 1983, and 30 Jan 1989.[10] This 2.45% portion of new uveitis referral population had previously undiagnosed syphilis as the cause of their chronic or recurrent intraocular inflammation. More than one-third of these patients had a nonreactive serum VDRL test; all had a positive FTA-ABS test and, on further testing, a positive microhemagglutination assay-T. pallidum (MHA-TP) test. All had total resolution of their uveitis with systemic intravenous penicillin therapy at doses adequate for neurosyphilis.
The iritis of syphilis has no remarkably distinguishing features. Although some authors have stated that ocular manifestations of syphilis are more likely to arise in the secondary stage of acquired syphilis, it is emphasized that in almost every instance in a referral practice, the patients have had latent syphilis with no clinical manifestations prompting a suspicion of this disease. In addition, although the older literature divided syphilitic iritis into three types according to iris features, that in only one of the cases showed an iris pathologic condition that prompted a specific suspicion for syphilis. It is suspected that iritis roseati (with small dilated collections of capillaries in theiris), iritis papulosa (with the iris roseati increasing in size to resemble a papule), and iritis nodosa (with increasing size of iris papulosa forming a yellow-red nodule) may be relatively restricted to cases of syphilitic uveitis that are associated with classic secondary syphilis with extraocular manifestations. Although it is typically thought of syphilis as being a 'granulomatous' disease and, hence, imagine that the iritis of syphilis should be a 'granulomatous' one with mutton-fat keratic precipitates on the corneal endothelium, in fact approximately half of the patients exhibit no keratic precipitates or fine keratic precipitates on the endothelium. One case with iritis nodosa has previously been reported,[10] and the iris lesion in the right eye of this patient, shown in Figure 165.1, is a good example of syphilitic uveitis nodosa.
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FIGURE 165.1 Iris nodule, syphilitic uveitis. Note the true mass in the substance of the iris periphery at the 8-9 o'clock position. |
Inflammatory cells may accumulate in the vitreous body to varying degrees (including nearly to the point of vitreal opacification) in syphilitic panuveitis or posterior uveitis. It may be difficult to evaluate the choroid and retina in such instances, but if and when the retina can be seen, sectors or foci of active choroiditis will usually be found. Placoid chorioretinitis may occur in immunocompetent[11,12] or in human immunodeficiency virus (HIV)-infected individuals.[13] The outer retina, retinal pigment epithelium, and choroid are affected, and the lesions tend to present in the posterior pole. Vitreal cells are typical, and a serous detachment secondary to an outpouring of serum and inflammatory cells may produce the unusual appearance of a macular or retinal 'pseudohypopyon'.[12] A diffuse retinitis or neuroretinitis without choroiditis can also occur, as can papillitis. Disk edema in a patient with periphlebitis and cells in the vitreous,[14] central retinal vein occlusion with disk edema,[15] or even simple disk edema (caused by a gumma of the optic nerve)[16] should probably be sufficient reason for considering the possibility of syphilis and requesting an FTA-ABS test. Indeed, a healthy dictum for all ophthalmologists to follow would be that any patient with iritis and papillitis should be considered to have syphilis unless proved otherwise. An example of sectoral neuroretinitis secondary to undiagnosed syphilis is shown in Figure 165.2, and an example of undiagnosed syphilitic multifocal chorioretinitis is shown in Figure 165.3. Figure 165.4 depicts syphilitic uveitis and associated papillitis.
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FIGURE 165.2 Sector retinitis, syphilitic uveitis, retinal vasculitis, and retinitis. Note the sector of the retina, beginning at the disk and extending superiorly, with infiltrate retinitis and associated retinal vasculitis. |
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FIGURE 165.3 Syphilitic multifocal choroiditis. Multifocal chorioretinal lesions, now healed, with scarring in a patient with previous active syphilis with multifocal choroiditis. |
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FIGURE 165.4 Syphilitic uveitis with papillitis. Note the swelling of the optic nerve and the hazy view of the nerve secondary to the associated inflammatory cells in the vitreous anterior to the disc. |
NEUROOPHTHALMIC MANIFESTATIONS
In addition to the possibility of papillitis previously described, optic neuritis,[17-19] optic perineuritis,[20,21] and papilledema[22] have been described as ocular manifestations in patients with ocular syphilis. Zambrano and associates reported the occurrence of bilateral syphilitic optic neuritis in a bisexual man with AIDS; this patient's visual acuity deteriorated over a period of ~12 h from 20/20 bilaterally to total bilateral blindness.[23] Toshniwal reported optic perineuritis, characterized by swollen optic discs without raised intracranial pressure and visual dysfunction, in a patient with secondary syphilis and a complaint of recurrent headache.[21]
CORNEA AND SCLERA
Syphilis can cause corneal inflammation, and unlike the multifaceted uveitis presentations possible with syphilis, syphilitic keratitis is typically an interstitial keratitis (i.e., a nonulcerative and nonsuppurative inflammation of the corneal stroma). Untreated, this stromal keratitis is frequently accompanied by stromal neovascularization. A variety of agents may causeinterstitial keratitis (Table 165.1), but syphilis may be the second most common cause after herpes simplex virus.[24] Approximately 10% of cases of interstitial keratitis secondary to syphilis are associated with acquired syphilis; 90% are seen with congenital syphilis. Syphilitic interstitial keratitis may be diffuse and generalized, or it may be localized. When localized, the area affected is commonly a sector of cornea (Fig. 165.5). The keratitis may be subtle, and in the photophobic patient with minimal circumlimbal injection, patience and practice are required to discover the subtle, diffuse patina of tiny, tan inflammatory cells in the affected area of the corneal stroma. As the inflammatory process increases, the density of the inflammatory cell population rises, and the 'infiltrate' is easier to see, as is the associated corneal edema. An associated iritis with or without keratic precipitates may develop, and peripheral corneal neovascularization may ensue. Untreated, the keratitis may progress to involve the entire cornea, with progressive neovascularization of the stroma, enormous photophobia, and discomfort and decreased visual acuity for the patient. The inflammatory process may slowly regress over the ensuing 2 years, leaving a scarred cornea with emptied or 'ghost' stromal vessels (Fig. 165.6). One or both eyes may be affected. In congenital syphilitic keratitis, both eyes are affected, either simultaneously or sequentially, in more than 75% of patients.[18]
TABLE 165.1 -- Causes of Interstitial Keratitis
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Bacterial |
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Syphilis |
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Leprosy |
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Tuberculosis |
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Chlamydia |
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Lyme agent |
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Protozoal |
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Acanthamoeba |
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Malaria |
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Trypanosomiasis |
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Leishmaniasis |
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Other |
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Cogan's syndrome |
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Sarcoidosis |
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Lymphoma |
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Viral |
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Herpes simplex |
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Herpes zoster |
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Epstein-Barr virus |
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Rubella |
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Rubeola |
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Vaccinia |
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Variola |
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Mumps |
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Helminthic |
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Cysticercosis |
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Onchocerciasis |
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FIGURE 165.5 Sector interstitial keratitis and luetic, old, inactive sector interstitial keratitis with stromal scarring in the inferonasal quadrant in a patient with previously treated syphilis. |
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FIGURE 165.6 Luetic sector interstitial keratitis with ghost vessels in the deep corneal stroma (extremely difficult to capture on film and reproduce). |
Syphilitic scleritis may be nodular or diffuse. We have never seen a case of necrotizing scleritis secondary to syphilis. Syphilitic scleritis has no distinguishing features and, hence, is diagnosed only because the ophthalmologist has cleverly included, as routine, an FTA-ABS test as part of the diagnostic survey in all patients with scleritis, interstitial keratitis, or uveitis.
DIAGNOSIS
Syphilis may be definitively diagnosed by direct or indirect techniques. Direct techniques include the darkfield examination, in which exudate from a suspected syphilitic lesion is examined by microscopy with a darkfield technique. The corkscrew-shaped T. pallidum motile organisms are seen directly. Fluorescein-labeled anti-T. pallidum antibodies may be used in an immunofluorescence analysis of exudate or material taken from a suspected syphilitic lesion. The antibody will stick to syphilitic organisms in the exudate or specimen and will be seen by the characteristic apple-green fluorescence when the specimen is examined under the fluorescence microscope. Detection of spirochetes in tissue specimens can be accomplished through special staining techniques, including the Warthin-Starry method. The spirochetes are seen directly in the tissue specimens as shown in Figure 165.7.
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FIGURE 165.7 Spirochetes (arrow) in the cornea, as demonstrated by silver stain, after penetrating keratoplasty in a patient with secondary syphilis and active interstitial keratitis. |
Indirect techniques depend on serologic studies, including Treponema-specific and nontreponemal tests. These nontreponemal tests detect antibodies directed against lipoidal antigens. The primary nontreponemal test used in the United States is the VDRL. This test is typically positive in patients with active syphilis and negative in patients with successfully treated syphilis. In patients with latent syphilis, however, the serum VDRL test is only ~70% sensitive. As discussed before, 35% of Schlaegel and Kao's cases of ocular syphilis would have been misdiagnosed if the authors had relied solely on the VDRL as the diagnostic test for syphilis.[8] More than a third of the patients have nonreactive serum VDRL tests.[9] These findings dramatically emphasize the importance of never relying on the VDRL as the sole screening test for the possibility of ocular syphilis. The standard treponemal tests for syphilis in the United States are the FTA-ABS and the MHA-TP. The FTA-ABS test is 98% sensitive, even in latent syphilis. This test will remain positive for life, regardless of whether the patient has been treated. The VDRL titer, in contrast, reflects the systemic activity of the disease, and hence, its major value, in ouropinion, lies in monitoring the response to treatment. A persistent fall in VDRL titers after treatment provides essential evidence of an adequate response to therapy. Polymerase chain reaction (PCR) testing for T. pallidum DNA is the most sensitive and specific test, but it is currently not economically feasible for routine analyses.[25]
EVALUATION FOR ASYMPTOMATIC NEUROSYPHILIS
Patients with positive serologic tests for syphilis should have their cerebrospinal fluid (CSF) examined for VDRL titers, total protein, and cell counts including a differential count. Without a positive CSF VDRL test, an elevated white blood cell count with a predominance of lymphocytes in the CSF or an elevated total protein level is indicative of neurologic involvement, and the patient should be treated accordingly as for neurosyphilis.
EVALUATION FOR HIV
There are reports in the literature of HIV-positive young adult patients with concurrent ocular syphilis.[26] This is not surprising given the similar mode of transmission in both disease entities. There is evidence that syphilis may pursue a more aggressive course in patients who are concurrently infected with HIV, rendering standard therapy for primary and secondary syphilis inadequate.[27] In view of these reports, we believe that all patients with ocular syphilis should now be evaluated for HIV and vice versa. The Centers for Disease Control recommends that an asymptomatic patient with a positive treponemal confirmatory test and whose VDRL titer exceeds 1:32 or alternatively whose CD4 Th count is below 350 should be evaluated for neurosyphilis.[28] HIV-infected patients and those patients with ocular, tertiary and neurosyphilis should have a reassessment of the CSF by VDRL every 3 months. A source of substantial concern arises with reports of proven[29] or suspected syphilis[30] in seronegative HIV-infected individuals. Clinical suspicion and penicillin therapeutic trials have been enlightening in these instances. Emergence of molecular diagnostic techniques (e.g., polymerase chain reaction technology) makes it possible now to more definitively establish evidence of microbial causes of uveitis,[31] and we believe increasing use of this technology on aqueous and vitreous specimens will clarify the cause as microbial in many instances of unusual or atypical ocular inflammation.
TREATMENT
PATIENTS WITHOUT PENICILLIN ALLERGY
Patients with ocular syphilis should be treated in the same way that patients with tertiary syphilis are treated. This philosophy has been adopted for two reasons: (1) the blood-ocular barrier is as much a hindrance to adequate spirocheticidal doses of penicillin as is the blood-brain barrier and (2) some evidence exists suggesting that patients with syphilitic ocular inflammation may have central nervous system syphilis without VDRL-positive CSF. We therefore recommend that the assistance of an infectious disease expert be obtained and that all patients with ocular syphilis should be hospitalized and treated using 18-24 million units per day of intravenous aqueous crystalline penicillin G (3-4 million units every 4 h or continuous infusion) for 10-14 days. An alternative regimen consisting of 10-14 days of procaine penicillin 2.4 million units IM once daily with plus probenecid 500 mg orally four times a day can be used if compliance with therapy can be ensured. Some infectious disease specialists also administer benzathine penicillin 2.4 million units IM once a week up to 3 weeks after completion of these neurosyphilis treatment regimens. The Jarisch-Herxheimer reaction, which is due to lysis of spirochetes and release of endotoxin-like antigens triggering an autoimmune crisis, can develop in HIV-positive and secondary stage patients. Patients should be informed about this possible adverse reaction. An acute febrile reaction frequently accompanied by headache, myalgia and other flu-like symptoms occurs within the first 24 h after any therapy for syphilis and may induce early labor or cause fetal distress in pregnant women. This concern should not, however, prevent or delay therapy. The use of aspirin or steroids may prevent this.[32] Patients can become re-infected. For this reason, all sexual partners must be screened and treated. HIV testing and sexually transmitted disease counseling should also be offered.
PATIENTS WITH PENICILLIN ALLERGY
Some authors have recommended doxycycline,[33] tetracycline, or erythromycin in the treatment of penicillin-allergic patients with syphilis. It is as yet unclear whether this therapeutic approach is sufficient therapy in most patients with neurosyphilis, and little to no experience exists with these treatment regimens in patients with ocular syphilis. Some investigators believe that 'penicillin-allergic' patients should be carefully evaluated and possibly desensitized and then treated with penicillin. Many patients with penicillin 'allergy' in fact do not have a true allergy at all. Careful allergy testing is advocated in patients with syphilis who claim to have a penicillin allergy. Such patients who have negative skin test results can safely undergo the aforementioned penicillin treatment program with close in-hospital monitoring. In addition, although penicillin allergy desensitization can be lengthy, costly, and complex, this alternative for treating the individual with ocular syphilis or neurosyphilis who has been proved to be allergic to penicillin is not without merit.
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