Ocular syphilis

SURVEY OF OPHTHALMOLOGY

VOLUME 37 - NUMBER 3. NOVEMBER-DECEMBER

1992

REVIEWS IN MEDICINE NEIL M. BRESSLER AND SUSAN B. BRESSLER, EDITORS

Ocular Syphilis CURTIS E. MARGO, M.D.,‘12AND LATIF M. HAMED, M.D. ’

Departments of ‘Ophthalmology and 2Pathology, University of Florida College of Medicine, Gainesville, Florida.

Abstract. There has been a steady increase in the number of cases of syphilis in the United

States since the middle 198Os, with a dramatic rise in incidence among heterosexual men and women and of congenital syphilis. There also have been changes in geographic distribution of cases and an association with cocaine use. The ophthalmologic manifestations of syphilis are broad. There is anecdotal evidence that the natural history of syphilitic infection is altered by coinfection with human immunodeficiency virus. The potential of coinfection with HIV makes the clinical evaluation, treatment, and assessment of therapeutic outcome of syphilitic infection more confounding and controversial. This article provides a review of the changing demographics and ophthalmic manifestations of syphilis, the current status of laboratory testing techniques, and management of ocular syphilis. (SUIT Ophthalmol 3’7:203-220, 1992)

Key words.

syphilis

??

immunodeficiency AIDS venereal disease ??

??

Human infection with Treponemu pallidum causes syphilis, a complex systemic illness, the natural history of which has been arbitrarily subdivided into three stages.‘66 This slender, tightly coiled bacterium is too small to be visualized by light microscopy, and is difficult to cultivate in vitro. Because pathogenic spirochetes cannot be routinely isolated and identified in the laboratory, the diagnosis of syphilis is usually based on a history of exposure, clinical findings, and the results of serologic tests. Identification of characteristic spirochetes with darkfield microscopy establishes the diagnosis in patients with active mucocutaneous lesions. Syphilis is primarily a sexually transmitted disease, but it can be spread by transfusion of fresh blood, or by accidental contact with an infected lesion. The helical bacteria, 5-15 microns in

approaches to various types

ocular syphilis

??

neurosyphilis

??

length and less than 0.18 microns in width, is small enough to pass through the placenta. Perhaps no other infectious disease has had such a profound influence on the course of civilization.32~126~‘74 Even after the etiology and modes of transmission were known, public health measures generally were ineffective in slowing the spread of syphilis. The protean manifestations of syphilis, its ability to mimic other diseases, and the social stigma associated with infection contributed to this failure. Not until the widespread availability of penicillin after World War II was there any appreciable and consistent decline in the rate of infection.77 It is possible that as the incidence of syphilis declined, physicians became less familiar with its broad clinical spectrum, and the chances of delayed and erroneous diagnoses increased.‘6~‘7~37 203

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Despite the success of antibiotic treatment over the past four decades, there has been a resurgence in primary and secondary syphilis over the last six or seven years, due in part to the socioeconomic factors that promote high-risk sexual behavior and cocaine use.‘34,135 This article will examine the epidemiology of the new syphilis epidemic. The ophthalmologic manifestations of syphilis, the current status of laboratory testing, and recommendations for treatment and control will be reviewed.

I. Bacteriology T. pallidurn belongs to the same family (Spirochaetaceae) as Borrelia and hptospira. The nonvenereal treponematoses caused by subspecies T. p. pertenue (yaws), T. p. caruteu (pinta), and T. p. indistinendemicum (bejel) are morphologically guishable from T. pallidurn and display only subtle immunologic differences.4 DNA hybridization studies have confirmed the close relationship between the pathogenic treponemes.44 The clinical distinction between these diseases is based on epidemiologic factors and clinical findings. T. pallidurn does not grow on routine culture media, but can remain motile in specially enriched media for up to a week.*’ Virulent organisms can be maintained in rabbits for long periods.” The recent ability to clone the entire T. pallidurn (Nicols strain) genome should help overcome many of the problems associated with in vitro cultivation.“’ The amorphous external layer of the bacterium contains periplasmic flagella located near the end of each organism.‘” A surface-associated hyaluronidase enzyme has been identified which may play a role in dissemination from the site of primary innoculation.45 Although long considered an obligate anaerobe, T. pallidurn has been shown to take up oxygen and degrade glucose aerobically.5 Virulent strains demonstrate optimal metabolic activity when oxygen concentration is between 10 and 20%.5

II. Immunology Immunity to infection occurs, but does not confer absolute protection.‘* In general, the longer the infection remains untreated, the greater the chances of acquiring protective immunity after treatment. Humoral antibodies are only partially protective. Cell-mediated immunity has a complex role in the pathogenesis of syphilis. It imparts some resistance to infection in experimental animals, but also may be a key factor in the development of late complications in

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humans.54 The waxing and waning course of syphilis has been difficult to correlate with specific features of the host immune response. According to epidemiologic studies, about a third of all susceptible persons exposed to T. PalZidiumwill develop syphilis.’ I7 This contrasts with the results of one experimental study in which all human volunteers without serologic evidence of prior infection became infected when challenged with an innoculum.‘* Normal human serum has some antitreponemecidal activity in vitro.67 Patients with congenital syphilis can become reinfected when exposed to T. pallidurn during adulthood.46,48 The humoral and cellular responses which begin during the primary stage of syphilis do not prevent the early hematogenous dissemination of treponemes or the development of the secondary stage. The organism has a phospholipidrich outer coat with a paucity of surface antigens, although as many as 14 T. pallidurn-specific antigens can be identified using the Western blot technique.‘j5 An antibody response to several outer membrane proteins of T. pallidurn is found in the serum of patients with primary syphilis. Different antibodies appear as the infection progresses,64 but their role in host defense and their relationship to the antibodies involved in standard serologic tests are not completely understood. T, pallidurn immobilization antibody, for example, both immobilizes and inactivates T. palhum in vitro, but does not confer protective immunity clinically. Both reagin and treponemal antibodies are primarily IgG immunoglobulins. IgM and IgA immunoglobulins also are present with appreciable concentrations of IgM found in untreated patients.3*‘z3 The number of organisms reaches a maximum during the secondary stage of the disease, but with time diminishes even without treatment. Eventually, the host response in most immune competent patients successfully suppresses the infection and results in a state of clinical latency. Cell-mediated and humoral immunity are probably involved in this process, but their precise roles are poorly understood. The cell-mediated immune response to the Nichols strain of T. pallidum as measured by a lymphocyte transformation test has varied, depending on the population being studied.53,54

III. Clinical Stages A. GENERAL

CLASSIFICATION

The natural history of untreated syphilis has been documented in two large studies during the

205 invasion During Early Dissemination I

Acute Syphilitic

I

Early Asymptomatic Neurosyphilis

Meningovascular

Late Asymptomatic

Tabes Dorsalis

General Paresis

-

-4

Spontaneous Resolution

Fig. 1. Diagram showing the conceptual relationship between neurosyphilis and the clinical manifestations of early and late infection. (Reprinted from Tramont EC’@ with permission of the author and Churchill Livingstone Publ.)

preantibiotic era, and analyzed thoroughly in several subsequent papers.24S’33*‘47Both original studies had shown that the disease has a complex and variable course. Progression to late syphilis is unpredictable, but a definite increase in mortality does occur. There is no racial difference in syphilis-associated death, but blacks tend to develop cardiovascular complications more often than whites, while whites are more prone to neurologic complications.24~133 Briefly, syphilis has been divided into three stages which overlap chronologically.‘47*155~166 The primary stage is characterized by an ulcerative lesion referred to as a chancre, occurring at the site where T. pallidurn penetrates the skin or mucous membrane. The organism enters the lymphatics and blood stream and disseminates shortly after contact. Primary dissemination is rarely associated with systemic symptoms. The median incubation period from the time of contact to ulceration is three weeks (range three days to three months). Primary lesions heal spontaneously in two to eight weeks. The secondary stage refers to the period of time when the systemic treponemal load is greatest (usually 2-12 weeks after contact). The secondary stage may be manifest by fever, malaise, lymphadenopathy, and mucocutaneous lesions. Clinically apparent secondary syphilis occurs in 60-90% of patients. “A primary chancre may still be present in as many as a third of patients with

secondary syphilis.“’ Evidence of central nervous system infection can be demonstrated in nearly a fourth of patients with early syphilis who have no neurologic findings using the rabbit infectivity test. g6The term “early” syphilis includes primary, secondary, and early latent stages, usually less than two years’ duration.“*‘s4 The secondary stage of syphilis subsides in weeks to months, but can recur, usually within one year and rarely after four. The tertiary stage refers to the various late sequalae of infection. Most late complications involve the vasovasorum of the aorta or the central nervous system. Focal inflammatory lesions (gummas) can affect any organ. Approximately a third of untreated patients go on to tertiary syphilis, with less than 10% developing clinical neurosyphilis.24 A “quarternary” stage of syphilis was used in the older literature, but was abandoned because there was no general agreement on its defmition.i5s The term was revived recently by Morgello and Laufer114 to describe a necrotizing encephalitic form of meningovascular syphilis occurring in patients with HIV infection. The term serves to distinguish this aggressive form of infection from tabes dorsalis and general paresis of tertiary syphilis. B. NEUROSYPHILIS The central

nervous

system can be involved

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in all stages of syphilis (Fig. 1).g6*110~11z~‘51~‘61~166 gression of the disease, reduces parenchymal Symptomatic neurosyphilis can take one of sevinflammation and edema, but does not usually eral forms: the early forms consist of acute menreverse major structural deficits. ingitis and cerebrovascular neurosyphilis, and Hooshmand74 reported a series of 24 1 patients with neurosyphilis (with positive PTA-ABS tests the late forms consist of general paresis and tabes dorsalis.15’ The clinical classification of neuroof serum and CSF), many of whom had previoussyphilis, however, is imperfect due to the multily undescribed forms of progressive neurologic tude of vascular and parenchymous sequelae disease. These so-called atypical manifestations that occur at various stages of the disease. Neuroof neurosyphilis indicate that the signs of neurologic symptoms associated with positive CSF syphilis are mostly nonspecific and overlap with findings (positive serology, increased protein, signs of other neurologic conditions. It is possiand leukocytosis) at any stage of the disease is ble that inadequate antibiotic treatment may indicative of neurosyphilis.“jl The clinical signifihave a role in causing these atypical neurological cance of so-called “asymptomatic neurosyphilis” manifestations.75 is not fully understood. Does true neurosyphilis C. CONGENITAL SYPHILIS exist in patients who are asymptomatic, but have abnormal CSF findings? Isolation of virulent treThe clinical manifestations of congenital ponemes from the CSF in nearly a fourth of pasyphilis occur at various times throughout life.47 tients with early syphilis and no neurological abTwo years of age has been selected as an arbinormalities indicates that bacterial invasion of trary division between early and late onset congenital syphilis.36 It is important to emphasize the CNS is probably more common than generally thought. g6The subsequent course of patients the alarming increase in congenital syphilis notwith early, silent CNS infection who receive inaded over the last 10 years. Recently, the number of equate treatment for neurosyphilis is unknown. cases of congenital syphilis reported to the CDC Since the introduction of antibiotics, the frehas been the highest in nearly 30 years.1g,21 The quency of general paresis and tabes dorsalis have reasons for this increase are complex, but failure decreased considerably. ” In contrast, there has to detect and prevent this new epidemic may be been an increase in the incidence of ocular syphidue to social factors related to unemployment, lis and early meningovascular syphilis.151 The drug use, and prostitution, as well as the diagreason for this shift in clinical manifestations is nostic limitations of serologic tests.35,54 unclear. The CDC recommends that all states perform Patients with syphilitic meningitis may present serologic screens on expectant mothers at the with headache, nausea, stiff neck, confusion, and beginning of prenatal care and at the beginning cranial nerve palsies. Syphilitic meningitis occurs of the third trimester. 23Women who live in areas within months to years of primary infection and with a high incidence of syphilis should also be may coincide with the skin rash of secondary tested prior to delivery. 23,40*61 This strategy, howsyphilis. ‘,“J’* The most commonly affected craever, will fail to detect primary syphilis during nial nerves are II, VII, and VIII.1o7 The CSF the incubation period before seroconversiones5s141 findings are consistent with an aseptic meningiSince fetal infection can still occur durtis. Neurologic signs and symptoms generally ing the period of seronegativity, the diagnostic resolve over weeks to months even without treatyield can be increased by performing a thorough ment. Cranial nerve deficits, however, may perprenatal examination looking for clinical signs of sist. infection. Any suspicious mucocutaneous lesion Syphilitic cerebrovascular disease is an impormust be studied by darkfield microscopy. Antant diagnostic consideration in young patients other potential cause for serologic-false negative with strokes. Late cerebrovascular syphilis usualtests in expectant mothers is the prozone phely develops 5-10 years after the primary infecnomenon due to excess reagin antibody.141 The tion, and often presents suddenly with signs and prozone reaction can be corrected by repeat testsymptoms of vascular insufficiency. A similar ing with diluted serum. Because infants do not presentation can be seen in early syphilis when always have signs or symptoms that suggest conthe host is immunocompromised.@ Syphilitic genital syphilis, a serologic test should be stroke syndromes are largely irreversible. The performed on all infants who have aseptic mendiagnosis of syphilitic cerebrovascular disease reingitis, enlarged liver, or hematologic abnorlies heavily on positive serologic studies from semalities. rum and CSF. Antibiotic treatment limits proThe dramatic increase in incidence of congeni-

TABLE

TABLE

1

Ocular and Facial Manifestations of Congenital Syphilis OCULAR Cornea1 opacities Sequelae of uveitis Cataract Glaucoma Pigmentary retinopathy Optic atrophy FACIAL Cranial nerve palsies/deafness Supraorbital thickening Saddlenose deformity Short maxilla

Arched palate Prominent mandible Frontal bossing Malformed teeth Perioral fissures (rhagades)

tal syphilis will certainly affect ophthalmology, because the ocular complications are a prominent feature of the disease (Table 1). Congenital syphilis can be difficult to diagnose when it presents with ocular symptoms because many ophthalmologists have become unfamiliar with the disease in the antibiotic era.

IV. Laboratory Testing Demonstration of live treponemes by darkfield microscopy is a means of confirming the diagnosis of syphilis before seroconversion occurs lo-20 days after contact.‘54 Although direct microscopy is considered a highly specific test for syphilis, its true sensitivity has been difficult to evaluate.” Direct fluorescent antibody microscopy (DFA-TP) is another technique of examining potentially infected lesions directly and can be performed on fixed slides.73 The test requires less technical experience to interpret than darkfield microscopy. Although the technique was introduced several decades ago, the test is not widely available. 18’ The serologic tests for syphilis are the mainstay of diagnosis when there are no lesions to examine by direct microscopy. Serologic tests for syphilis are divided into two groups: those that detect antibody to cardiolipin-lecithin-cholester01 antigen (nontreponemal tests) and those that detect antibody against treponemal antigens.4’ The two most commonly used nontreponemal tests are the Veneral Disease Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR). The treponemal tests include the fluorescent tre-

2

Causes of Biological False-positive Serologic Tests* INFECTIOUS CAUSES Bacterial endocarditis Infectious mononucleosis Leprosy Leptospirosis Lyme disease Lymphogranuloma venereum Malaria Measles Mycoplasma pneumonia Psittacosis Scarlet fever Tuberculosis Viral hepatitis NON-INFECTIOUS CAUSES Advanced age Chronic liver disease Connective tissue disease Intravenous drug abuse Lupus erythematosus Multiple blood transfusions Pregnancy Systemic malignancy *Nontreponemal

and treponemal

tests

ponemal antibody absorption test (FTA-ABS), hemagglutination treponemal test for syphilis (HATE), Treponemulpallidum hemagglutination assay (TPHA-TP) and the microhemagglutination (MHA) test. False positive tests occur with both nontreponemal and treponemal tests (Table 2). There is no ideal test. 125The selection and interpretation of a specific test must take into account its diagnostic sensitivity and specificity at each stage of syphilis (Table 3), as well as the context in which it is being used. Is the test being performed as a screen or to confirm a suspected clinical diagnosis (i.e., rule in a diagnosis)? In general, the diagnostic sensitivity of a laboratory test decreases with decreasing prevalence of disease, whereas diagnostic specificity increases with decreasing prevelance. The optimal utilization of serologic tests to detect syphilis in the general population (i.e., use as a low prevalence screening test) favors the ruling out, but not the ruling in of disease. According to decision analysis theory, nontreponemal tests are best suited for general screening (i.e., low prevalence of disease) with any positive result confirmed with a treponemal test.5gas’6a When the likelihood of syphilis is high (e.g., clinical suspicious uveitis), a treponemal test should be ordered. A positive

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MARGO, HAMED

TABLE 3 Reactivity of Nontreponemul and Treponemal Testsfor Syphilis* Stage of

Syphilis

Primary Secondary Latent Late Congenital

Percent Reactive (Number Tested) VDRL+

RPR+

70.5 (542)

80.6 (238)

100 (182) 90.4 (521) 68.2 (44) 87.5 (7)

100 (74) 89.7 (195) 75.0 (12) 100 (10)

TPI +

MHA+

FIA-ABS +

57.3 (119) 99.4 (156) 96.7 (60) 91.7 (12)

77.3 (485) 100 (166) 97.5 (836) 94.7 (75) 100 (17)

91.5 (695) 100 (309) 97.1 (681) 100 (56) 100 (25)

*From Huber TW: Syphilis serology. Clin Microbial Newsletter 6:48, 1984. Copyright by Elsevier Science Publishing Co., Inc. Reprinted by permission of the publisher. Test+ VDRL: Veneral Disease Research Laboratory RPR: rapid plasma reagin TPI: Treponemu pallidurn immobilization

MHA: Microhemagglutination FTA-ABS: fluorescent treponemal antibody absorption

result would have a higher predictive value in this situation, because treponemal tests are at least as sensitive and more specific than nontreIt has been argued ponemal tests. 8,47,59a,65a,76a,77,154 that syphilis screening should be discontinued in populations where the prevalence of syphilis is very low (e.g., premarital screening), because the number of false positive tests may approach or exceed the number of true positives.40” Nontreponemal tests also are used to monitor treatment because their titers decrease following effective therapy (see Section IX). Numerous studies have shown that both nontreponemal and treponemal tests have decreased specificity in persons who are ill due to various causes.65a The potential unreliability of serologic tests for syphilis in patients with concurrent HIV infection suggests that when serologic tests are negative but syphilis is clinically suspected, other test methods should be used. These include dark-field microscopsy and DFATP applied to lesion exudate, or direct examination of tissue (usually skin biopsy) with DFA-TP or with silver stains.‘j8,‘@ A. CEREBROSPINAL NEUROSYPHILIS

FLUID TESTS

FOR

Of particular importance in the diagnosis of neurosyphilis is the interpretation of the results of CSF serology. The CDC recommends the use of the CSF-VDRL test to establish the diagnosis of neurosyphilis when serologic tests are positive.78 The RPR is less desirable than the VDRL for use on CSF specimens because of its high rate of false-positive results. ” The role of the CSF-

FTA-ABS in diagnosing neurosyphilis is controversial.28 Claims that the test may be too sensitive and may overdiagnose the disease have been difficult to verify. 2g,78 Other investigators have found the CSF-FTA-ABS both insensitive and nonspecific compared to the rabbit infectivity testg6 Davis and Schmitt *’ believe that the CSFFTA-ABS test is more sensitive for neurosyphilis screening, but less specific than the CSF-VDRL for distinguishing active from past syphilis. Most authorities agree that a nonreactive serum FTA-ABS excludes the diagnosis of neurosyphilis.15’ Biologic false-negative tests are rare, except possibly in persons with HIV infection. While some studies have shown a nonreactive CSF-FTA-ABS rules out neurosyphilis in patients with positive serum FTA-ABS,2g~78~‘02this has not been confirmed by others.“j It is highly unusual to have a positive CSF-VDRL and negative CSF-FTA-ABS.3g~41 Although a large number of diseases can cause a false-positive serum VDRL, these diseases rarely cause false positive results in the CSF.g1,g7 There is no “gold standard” test for the diagnosis of neurosyphilis. 96 A CSF leukocytosis and elevated CSF protein concentration in a person with neurologic symptoms at any stage of syphilis greater than one year’s duration is consistent with the diagnosis of neurosyphilis.77’16’ In this clinical setting, most experts would treat accordingly, even if the CSF-VDRL were not reactive.77 The CSF-VDRL and RPR are relatively insensitive for the diagnosis of neurosyphilis with false-negative rates ranging from 19-50%.2.13,7’, lo7,15iThus, a negative nontreponemal test on the

OCULAR SYPHILIS CSF does not preclude the diagnosis of neurosyphilis. When the CSF-VDRL is positive, it is usually of low titer (i.e., 1: 4 or less).” One advantage of the CSF-VDRL in evaluating patients with suspected neurosyphilis is when the possibility of previously treated disease cannot be excluded. In this situation, the CSF-VDRL may be superior to the FTA-ABS in distinguishing currently active neurosyphilis from past syphilis (see Section IX).2s

V. Epidemiology Following the widespread availability of penicillin after World War II, there was a dramatic decrease in deaths attributed to syphilis and in the number of persons institutionalized with neurosyphilis.” For reasons that are not entirely clear, the annual reported incidence of syphilis reached a nadir in the mid- 1950s and slowly rose until the mid-1980s. Public health reports, however, are subject to certain inherent biases. Nearly half of all new cases of syphilis occurring in the United States may go unreported.5’ Nevertheless, during the 1970s and 198Os, syphilis was more common among men, with the male to female ratio peaking at 3.5 to 1. This gender disparity began to emerge before the AIDS pandemic, and has been attributed to increased transmission of syphilis in homosexual men. Perhaps because of the growing practice of “safe sex” among homosexual men, the rate of syphilis in this high-risk group has been recently declining. The incidence of syphilis is highest in large metropolitan areas, where the age-adjusted syphilis ratios for minorities are the greatest.” Since 1985, there has been an alarming increase in the incidence of syphilis among heterosexual men and women, and in congenital syphilis.‘8~‘g~ *‘s** The epidemic has been centered in major urban areas on the east and west coasts and on the gulf coast. In some cities the rates of primary and secondary syphilis have begun to slowly decline.” The increase in cases involving black heterosexual men is particularly high, perhaps because many belong to medically hard-to-reach groups. I8 The current syphilis epidemic appears linked to unemployment, illicit drug use, prostitution, and family disruption.‘8,35,‘“4

VI. Syphilis and the AIDS Pandemic The recent rise in the number of new cases of syphilis coincides temporally with the AIDS pandemic.‘35 Historical and serological evidence of previous infection with Treponema pallidurn show

209 a strong association with an increased risk of HIV infection.58f’46,‘57 The disruption of the mucosal epithelial barrier in syphilitic ulcers, along with the presence of mononuclear cells in these ulcers which are targeted by the HIV virus, may explain this increased risk. It is therefore recommended that testing for both syphilis and HIV be administered to patients who test positive for either condition.‘3g Some authors have suggested primary HIV infection may produce skin and genital ulcers mimicking syphilis infection.14 Conversely, some case reports suggest that the clinical spectrum of syphilis and the rapidity of its progression may be modified by concurrent HIV infection.@.” Theoretically, this is not surprising since a competent immune response is necessary to control the manifestations of syphilis following the initial spirochetemia. However, this topic has not yet been addressed prospectively to provide an assessment of the frequency of these atypical features. The concept that a cure for syphilis is dependent upon the interaction between the host’s immunologic status and the effect of administered antibiotics was advanced as early as 1970.“’ The AIDS era has provided an unfortunate experiment of nature to test this concept. Both syphilis and AIDS are protean diseases, each having a variable course and broad range of manifestations making assessment of reports addressing atypical features of syphilis in coinfected patients difficult.‘4T5g Nevertheless, the majority of patients with dual infection show the typical clinical features of syphilis. Numerous anecdotal reports have stressed, however, the predisposition of patients with HIV infection for developing virulent, accelerated, or atypical syphilitic disease.30~sg~‘30, 150~‘68 For instance, HIV-infected people may be at a higher risk for developing neurosyphilis, even after penicillin therapy for the initial disease.g*“~25~86~g6*“5~“8~“g This recrudescence is rarely observed in immunocompetent patients, who manage after standard penicillin therapy to contain the infection throughout life. However, exceptions to this exist, and HIV-negative patients have developed neurosyphilis during standard therapy for secondary syphilis.34 The anecdotal nature of the reports describing a modified clinical profile of syphilis in HIV-infected persons does not allow definitive conclusions, despite some theoretical support.s5 The normal host response to infection with Treponema pallidurn utilizes the humoral and cellmediated systems, both of which have been doc-

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umented to be abnormal with HIV infection. Most HIV-infected patients show a normal serologic response to syphilis infection.g0 Some patients with HIV infection may show false-negaIn addition to the tive tests for syphilis. 68,84~103~164 prozone phenomenon, this has been documented to be due either to insufficient antibody response or to decreased or lost immunoreactivity. Both of these possibilities reflect inadequate Bcell response to newly encountered antigens.@s6’ In the majority of cases, however, nontreponema1 tests are positive, often at higher titers than in non-HIV-infected patients, due to the polyclonal B-cell activation that occurs with HIV infection. This polyclonal activation also may account for false-positive syphilis testing. In addition, the nontreponemal test titers may fail to decline after adequate therapy because of the polyclonal B-cell stimulation; thus, a valuable method to monitor response to therapy is lost. Treponemal tests, like the FTA-ABS and the MHA-TP, thought to remain reactive for life even after adequate therapy, may also be falsely negative. 66*84The sensitivity of treponemal tests to detect previous syphilitic episodes is estimated to be 93% in asymptomatic, HIV-positive persons, but drops to 62% in symptomatic patients.‘j6 This sensitivity drop is most likely due to progressive immune dysfunction.

VII. Ophthalmologic Manifestations of Syphilis The ophthalmologic manifestations of syphilis are numerous, and have been comprehensively reviewed by several authors.38~12’~‘62~1’5~i’ The 6 literature is replete with anecdotal case reports describing ophthalmic manifestations of syphilis in HIV-infected patients. g2The clinical findings include uveitis, retinitis, perineuritis, papillitis, retrobulbar neuritis, optic atrophy, optic nerve gumma and various stroke syndromes.7~15~87~8s~ 10*,127,132,153,159,178,182,183 The authors

often point

out

that various unusual features of their cases may have resulted from a presumed synergism thought to exist in dual infection with HIV. Without prospective studies, however, it is difficult to determine if these clinical variations are still part of the broad spectrum of manifestations of ocular syphilis described in the early ophthalmic literature. A concise anatomic-based survey of the ophthalmologic findings in syphilis with emphasis on recently described conditions is presented.

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MARGO, HAMED

A. CONJUNCTIVA Both chancres of the conjunctiva (primary syphilis) and gummatous involvement (late syphilis) have been described in the preantibiotic era. 38 Conjunctivitis is probably a relatively common finding in secondary syphilis, but because symptoms are usually mild, it may be overlooked when more ominous systemic or ocular findings are present. Occasionally, however, luetic conjunctivitis causes intense chemosis and vascular injection and may be accompanied by scleritis. The inflammatory infiltrate in syphilitic conjunctivitis is similar to that in the skin during secondary syphilis, which consists predominantly of lymphocytes and plasma cells. Granulomatous conjunctivitis histologically identical to sarcoidosis also can occur.‘56 In such situations, the demonstration of spirochetes with silver stains will establish the diagnosis. B. SCLERA Watson and Hayreh’72 reported that scleroconjunctivitis is a common finding in secondary syphilis. Isolated episcleritis or scleritis, however, is distinctly uncommon during any stage of the disease, but, when present, is usually a feature of secondary or late syphilis.173 When scleritis is the sole manifestation of latent disease, the diagnosis of syphilis can be easily overlooked.“’ In at least one anecdotal report, syphilitic scleritis in an immune-competent patient progressed after treatment with benzathine penicillin, but did respond to a ten-day regimen of intravenous penicillin G.“’ Because the patient had no signs of neurosyphilis and normal CSF studies, the role of CSF examination in patients with leutic scleritis is unresolved.

c.

CORNEA

The cornea1 manifestations of congenital and acquired syphilis have been thoroughly described by several authors.1223176 Syphilitic interstitial keratitis (IK) is usually due to congenital infection, but may occasionally be acquired. Because of the delay in clinical manifestations of congenital infection, the etiology of IK may not always be apparent. It is unclear if the cornea1 inflammation is due to direct infection or to a hypersensitivity reaction. The inflammatory reaction of acquired IK may simulate that of staphylococcal marginal keratitis.“’ IK is usually associated with uveitis initially, but as the uveal inflammation subsides, cornea1 scarring develops (Fig. 2). Stromal vascularization is a consis-

Fig. 2. Late onset interstitial keratitis due to congenital syphilis showing dense macular haze centrally. The cornea1 changes developed bilaterally when the patient was in his early teens.

tent feature of IK, but may be difficult to visualize within a stromal scar (i.e., ghost vessels). A variety of secondary degenerative changes can occur in longstanding cases. 6g Alterations in Descemet’s membrane with the development of ridges, webs, or thick scrolls which may festoon the anterior chamber are highly characteristic of congenital syphilitic IK.‘439170 The treatment of syphilitic IK with penicillin appears to have little effect on its clinical course once keratitis has developed to the stage of vascularization.122~176 D. CRYSTALLINE

LENS

Congenital and acquired cataracts in patients with syphilis are most likely due to uveal inflammation. The causal association of syphilis with dislocation of the crystalline lens remains unproven, although anecdotal reports continue to appear in the literature.13’ E. GLAUCOMA Secondary glaucoma in syphilis is caused by several distinct mechanisms. Presumed syphilitic subluxation or complete dislocation of the lens can result in mechanical closure of the angle. More often, however, uveitic glaucoma occurs in the setting of either congenital or acquired syphilitic iridocyclitis.148 Inflammatory pseudotumor of the iris has also been associated with elevated intraocular pressure. l6 Both open- and closed-angle forms of glaucoma have been described with syphilitic IK.56,160,165

Fig. 3. Patient with bilateral uveitis and positive serum VDRL (titer > 1: 5 12) and FfA-ABS tests. There are extensive posterior synechiae and inflammatory nodules (presumed granulomas) of the iris. Anterior segment inflammation including iris nodules resolved when treated with intravenous penicillin.

Secondary endothelialization of the angle (actually pseudoangle) has been reported in one histologic study.5” Patients who develop IK early in infancy may be prone to small anterior segments with narrow angles. This anatomic configuration will predispose the patient to angle-closure in later life.56,16o F. UYEAL TRACT AND RETINA Iritis and iridocyclitis are commonly associated with other more prominent manifestations of ocular syphilis, although they can be the predominant findings in secondary syphilis (Fig. Anterior segment inflammation is 3). 38,143a*161a nonspecific and may be granulomatous or nonDilated iris capillaries granulomatous. 38,gg,‘oo~145 (roseola) during the secondary stage are reportedly due to treponemal emboli.38 Various patterns of postinflammatory iris atrophy can occur. The clinical manifestations of syphilitic chorioretinitis are broad and include vasculitis with and without arterial occlusion,26*1139142macular edema 10,g3stellate maculopathy,43 disciform maculai detachment,33~63~140pseudoretinitis pigmentosa (Fig. 4), retinal detachment, uveal effusion31 central retinal vein occlusion,” subretinal neovascular membrane formation,‘j2 retinal necrobig blind spot syndrome,“‘” and neurosis, ‘OWN’ retinitis.1’52 Gass et a155recently described six patients with evidence of secondary syphilis who showed one or more large macular or juxtapapillary placoid lesions at the level of the RPE (Figs. 5 and 6). The

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Fig. 4. Old chorioretinal scar with intraretinal pigment migration following treatment of syphilitic chorioretinitis. The patient presented several years earlier with secondary syphilis and active bilateral vitritis with multifocal chorioretinitis.

lesions were yellowish or grey with faded centers, associated with vitritis. On fluorescein angiography, they revealed early hypofluorescence and late staining. Early focal “leopard-spot” hypofluorescence and retinal perivenous staining are additional angiographic findings (Fig. 7). Three of four patients tested by Gass et a155 showed positive HIV titers. The fundus findings were so characteristic as to be thought nearly pathognomanic. The condition has been termed acute “syphilitic posteriors placoid chorioretinitis.“55 The differential diagnosis includes acute posterior multifocal placoid pigment epitheliopathy and atypical serpiginous choroidopathy. G. PUPILLOMOTOR

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Fig. 5. Pale yellow posterior placoid lesion (arrows) in a 4%year-old man with syphilis and negative HIV test. (Reprinted from Gass JDM et a155 with permission of the authors and Ophthalmology).

like pupil has been described in patients with multiple sclerosis, diabetes mellitus, alcoholism, and encephalitis.% A key differential feature in these cases is pupil size, which when small is characteristic of neurosyphilis. Dilated pupils that are fixed to both light and near stimuli also has been reported in advanced neurosyphilis with external ophthalmoplegia.‘52

PATHWAYS

The classic pupillary finding in syphilitic disease, the Argyll Robertson pupil, may be seen in early neurosyphilis, but is more common in the late disease.% The pupils are unequal, irregular, and profoundly miotic, with a light-near dissociation. More commonly, light-near dissociation occurs with normal pupillary size. Light-near dissociation most likely occurs secondary to interruption of internuncial neurons connecting the Edinger-Westphall nuclei with the pretectal nuclei.g4,10gThe miosis of Argyll Robertson pupil should not be confused with that of Horner’s syndrome, which may accompany neurosyphilis, and at times present with a clinical picture of Raeder’s syndrome.“’ Although most often associated with neurosyphilis, an Argyll Robertson-

Fig. 6. Posterior placoid lesions (black arrows) consisting in part of a crescent-shaped area of pale yellow (white arrows). Visual acuity was 20/30. The VDRL was positive 1: 64; and HIV test was not done. (Reprinted from Gass JDM et a155with permission of the authors and Ophthalmology.)

213

OCULAR SYPHILIS H. RETROCHIASMAL VISUAL PATHWAY AND DISTURBANCES IN OCULAR MOTILITY The clinical manifestations of early neuro syphilis result from involvement of blood vessels and meninges, while in late syphilis parenchymal involvement predominates. Any region of the brain can be affected, accounting for the enormity of neuroophthalmologic manifestations. Early neurosyphilis may affect the cranial nerves, including the optic nerve and the ocular motor nerves. Isolated, as well as complicated, palsies of the third, fourth, and sixth cranial nerves most often accompany syphilitic basilar meningitis. Focal gummas along the nerves, superior orbital fissure syndrome,“’ brainstem infarction, or syphilitic aneurysmal compression or hemorrhage tend to be late manifestions. Supranuclear gaze palsies may also occur.“* More subtle eye movement abnormalities, such as alternations in the smooth pursuit and saccadic systems, can be detected when looked for.‘s’ The associated arteritis may lead to a variety of stroke-like syndromes. Middle or posterior cerebral artery infarction may result in a homonymous hemianopia. Syphilitic basilar meningitis or gummas may cause a chiasmal syndrome with bitemporal hemianopia. Bilateral involvement has been reported to lead to cortical blindness. Lateral medullary plate syndrome, including ipsilateral Horner’s syndrome and vestibular nystagmus, may result from infarction of the posterior inferior cerebellar artery. Brainstem structures can be involved at any level, giving rise to internuclear ophthalmoplegia, gaze paresis syndromes, and pupillary abnormalities. Late neurosyphilitic disease includes general paresis and tabes dorsalis. Pupillary abnormalities and ocular motor palsies may occur in either condition, but are more common in tabes.

7. Top: A 50-year-old woman with secondary syphilis and bilateral posterior placoid chorioretinitis. The outer retina and retinal pigment epithelium of the left eye reveals a subtle greyish thickening (within arrows), best appreciated with binocular contact lens examination. There is mild vitritis. A circular light reflex is noted around the macula. Corrected visual acuity is 20/200. Bottom: Late phase of the fluorescein angiogram shows “leopard spot” pattern of hypo- and hyperfluorescence corresponding to the area of outer retinal-RPE thickening. The disc leaks fluorescein. Clinical findings resolved and visual acuity improved to 20/40 following intravenous penicillin therapy. (Courtesy of Scott Pauter, MD)

Fig.

I. EYELIDS AND ORBIT Cutaneous involvement of the eyelids with syphilis is rare, other than the generalized skin rash seen with secondary syphilis. The eyelid chancre of primary syphilis is diagnosed by scraping exudate from the ulcer bed.” Primary syphilitic ulcers of the eyelid have the same clinical features as genital lesions, and respond to treatment with benzathine penicillin.” Condylomata lata are found in secondary syphilis, usually in warm, moist areas such as the groin or axilla. When seen on the eyelid skin they are usually associated with widespread involvement of the face.‘*’ The lesion of condylomata

latum begins as a papule, but will become flattened and macerated if located on an opposed skin surface. Lesions teem with spirochetes and are highly infectious. Temporary loss of the brows and lashes also can be seen in secondary syphilis.

VIII. Treatment A. EARLY SYPHILIS Penicillin G is the drug of choice for treating all stages of syphilis,‘05 although the amount needed

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MARGO, I-IAMED

1992

TABLE

4

Recommended Treatment Regimens* Primary

Alternative

Early syphilis (Primary, secondary, or latent less than one year)

Penicillin G benzathine

2.4 million U IM once

Late syphilis (more than one year’s duration, cardiovascular, gumma, latelatent) Neurosyphilis

Penicillin G benzathine

2.4 million U IM weekly

OR

x

Penicillin G Pennicillin G procaine plus probenecid Penicillin G

Congenital syphilis OR

Pennicillin G procaine

4).

Skin testing for penicillin allergy is recommended for persons who have a history of such allergy.‘s4 When penicillin cannot be used, alternative antibiotics are available, but none yields as low a failure rate as penicillin and all require multiple doses.lE4 B. LATE SYPHILIS

Recommended treatment of syphilis of more than one year’s duration without evidence of CNS involvement consists of three doses of benzathine penicillin G at weekly intervalslo The need for CSF examination in patients with latent syphilis and a normal neurologic examination is unclear.ls4 A small but unknown proportion of patients have asymptomatic neurosyphilis and may require more vigorous treatment. The following findings have been considered risk factors for asymptomatic neurosyphilis and justify examination of the CSF: evidence of aortitis, visceral gummas, ocular inflammation, and serum nontreponemal titers > 1: 32.1s4 Lumbar punc-

Doxycycline’ 100 mg oral bid x 4 weeks

3 weeks

2 to 5 million U IV q4h x lo-14 days 2.4 million U IM daily 500 mg qid orally both

No proven effective alternative; allergic patients should be desensitized x

lo-14 days 50,000 U/kg IM or IV q812h for lo-14 days 50,000 U/kg IM daily for lo-14 days

1. OR tetracycline 500 mg oral qid. 2. Limited experience; use only if compliance and follow-up are assured. *From Medical Letter: Treatment of Sexually Transmitted Diseases. 33: 119-124, sion of Medical Letter, Inc.

to achieve cure remains a topic of debate. ‘I6 Early syphilis (primary, secondary, or latent of less than one year’s duration) in immunocompetent persons can be treated effectively with benzathine penicillin G. The repository formulation is given once as an intramuscular injection (Table

Doxycycline’ 100 mg oral bid x 2 weeks Ceftriaxone 250 mg IM once daily x 10 days’

1991. Published with permis-

ture also is warranted when planning therapy with a drug other than penicillin, or in patients with HIV coinfection. C. NEUROSYPHILIS There is no consensus on the optimal therapy for neurosyphilis. ‘38~184Most authorities recommend intravenous aqueous penicillin G, 2-4 million units every four hours for lo-14 days.105*‘5’ An alternate regimen consists of intramuscular procaine penicillin G plus oral probenecid for 10-14 days.lo5 There is no proven effective alternative drug to penicillin for the treatment of neurosyphilis. D. SYPHILIS

IN PREGNANCY

Penicillin in doses appropriate for the stage of the disease is the treatment of choice for syphilis diagnosed during pregnancy. Since there are no good alternative antibiotics to use during pregnancy, women who are allergic to penicillin must consider desensitization.ro5 E. CONGENITAL

SYPHILIS

Optimal therapy for congenital syphilis is not known. la4Ten to 14 day reg imens of either intravenous aqueous penicillin G or procaine penicillin G are recommended.ro5 Ceftriaxone and ampicillin seem to be reasonable alternative drugs,

215 but their efficacy in this clinical setting has not been thoroughly tested.184 F. OCULAR SYPHILIS The treatment of ocular syphilis is controversial. There have been no systematic studies to discern the frequency of neurosyphilis, asymptomatic or otherwise, in patients with ocular disease. However, some evidence suggests a high prevalence of concomitant neurosyphilis in patients with ocular involvement.‘~52~‘21~156a*‘56b The problem of determining optimal treatment for ocular syphilis is compounded by the fact that no uniform agreement exists on the clinical significance of ocular involvement. If one adheres to the concept that the eye is an embryological derivation of the brain and is therefore part of it, then involvement of the optic nerve (i.e., syphilitic papillitis or optic neuritis), retina, or other ocular neuroepithelial structures would, strictly speaking, constitute neurosyphilis. The clinical significance of uveitis, the most common form of ocular involvment, is less apparent. Many authorities consider uveitis a risk factor for neurosyphilis, while others imply by their treatment regimens that it is neurosyphilis. We usually examine the CSF in all patients with uveitis, retinitis, or optic neuritis, and administer treatment sufficiently vigorous for neurosyphilis irrespective of the CSF findings.162 It can be argued that CSF examination is unnecessary if all patients with ocular syphilis receive the same neurosyphilis regimen. The reason CSF studies are obtained is to roughly quantitate the activity of CNS disease, when present, and to establish the status of CSF serologic tests for future reference. CSF concentrations of penicillin following treatment with benzathine penicillin are unmeasurable due to poor CNS penetration of the Although no studies have been drug. 57~12g~16g done to measure ocular levels, one expects these to be similarly low. While the treponemicidal levels of penicillin are not known, such low concentrations may be well below what is required, especially in immunocompromised individuals. G. SYPHILIS AND CONCURRENT INFECTION

HIV

Based upon case reports describing relapse following conventional therapy or a synergistic interaction between the two infections, some clinicians have advocated that the treatment of syphilis in all coinfected patients be aggressive, generally consisting of a course sufficient to cure

neurosyphilis irrespective of whether CNS involvement is suspected or not.42 This approach has several disadvantages, since it overtreats some patients and is inconvenient to others.” Longterm maintenance therapy, according to some authors, may be justified in some patients.s2,167 The CSF formula is generally abnormal, but nonspecific, both in patients with single infection with HIV or Treponema pallidurn.” Therefore, unless CSF nontreponemal antibody is present, it is difficult to diagnose neurosyphilis in an HIV-infected person on the basis of CSF findings alone. Many patients with CNS early syphilis have negative CSF-VDRL tests and show only abnormal CSF cell counts and protein levels. Similar nonspecific CSF abnormalities are present in 40-60% of HIV-infected patients without syphilis. ‘O Therefore, the diagnostic benefit of CSF studies in HIV-infected patients suspected to harbor neurosyphilis is uncertain. Given the poor CNS penetration of benzathine penicillin, it is to be avoided in coinfected patients.

IX. Determining the Adequacy of Treatment Traditionally, the adequacy of treatment (i.e., cure) has been presumptive based on the resolution of clinical findings and the demonstration of a declining serologic titer (usually nontreponema1 tests) after therapy. The rate of decline in serologic titers depends on several variables, particularly the stage of infection, the absolute titer prior to treatment, and the number of previous treponemal infections. Persons who have been infected for a long time prior to treatment, persons with high pretreatment titers, and persons with a history of multiple exposures have a slower rate of declining titer after treatment, and are less likely to become seronegative.g5*‘36 Fiumara4’p5’ reported the rate of nontreponema1 test seroconversion for primary and secondary syphilis to be 100% at 12 and 24 months, but treatment consisted of twice the dose of benzathine penicillin normally recommended by the Center for Disease Control. Schroeter et a1’44 reported 97% of patients with primary syphilis and 77% of patients with secondary syphilis to seroconvert after two years. Similar results have been reported by others.‘28 In a historical cohort study of 1090 patients with early syphilis treated with a standard regimen of penicillin, nontrepomenal titers (RPR) declined 2- and S-tube dilutions by 6 and 12 months in primary and secondary syphilis.136

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Ninety-five percent of patients with primary and secondary syphilis seroconverted by 36 months. Approximately a quarter of patients had a nonreactive FTA-ABS test, and 13% had a non-reactive MHA-TP test. Although rates of decline of nontreponemal titers were slow, most patients with early syphilis did seroconvert or achieve stable low titers. Of note in this study, however, is the relatively high rate of seroconversion with treponemal tests. This fact becomes important when treponemal tests are used for epidemiologic studies, because they will underestimate the number of patients with previous syphilis. In summary, immunocompetent patients with early syphilis should be followed clinically and serologically for resolution of clinical disease and for seroconversion, or stable low titers of nontreponemal tests. g5 The criterion proposed by Guinan” that a fourfold and eightfold decrease of nontreponemal titer should occur by three and six months, respectively, in early syphilis may be too stringent.g5 A. SYPHILIS

WITH HIV COINFECTION

Management of patients with concurrent HIV infection is problematic. While closer follow-up is prudent, the role of repeat examination of the CSF is unclear, unless it is to be examined for virulent treponemes by darkfield microscopy or by a rabbit innoculation test. Two reports describe appropriate reduction in serologic titers in patients with syphilis and concurrent HIV infection, but with persistent organisms in the CSF.“,g6 This observation questions the reliability of serum titers in determining the adequacy of treatment in immunocompromised persons. In a serological case-control study, it was shown that HIV-positive patients with primary syphilis versus HIV-negative controls were less likely to have a fourfold or greater RPR decrease or to seroconvert within six months of treatment.16’ In HIV-infected patients, the associated immunological dysfunction itself may cause nontreponema1 titers to remain elevated or to fall, rendering the criteria less reliable. Given the possibility of a more aggressive syphilitic infection, and the unreliability of a criterion to ascertain a cure after therapy, some authorities have advocated that all coinfected patients be treated with a regimen adequate enough to cure neurosyphilis.

X. Summary The resurgence of syphilis over the last decade and its association with AIDS has changed the way that physicians evaluate and manage pa-

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MARGO, HAMED

tients with both diseases. Certain socioeconomic factors have contributed to the spread of these infections because they promote high-risk sexual behavior. The possibility of coinfection must be considered in any person infected with either T. p&urn or HIV. The serologic tests for syphilis, both treponemal and nontreponemal, are probably less reliable when coinfection with HIV exists. Because the natural history of syphilis and its response to therapy may differ from that anticipated in patients with dual infection, more vigorous antibiotic treatment and clinical follow-up have been proposed. Many physicians have become unfamiliar with the broad clinical spectrum of syphilis in the antibiotic era, and recent anecdotal case reports reaffirm the potential of syphilis to confound diagnosticians. The increased incidence of congenital syphilis with its propensity for ocular complications is certain to impact ophthalmology. As the AIDS pandemic enters its second decade, the importance of collaborative interactions among physicians and scientists who deal with infectious diseases will heighten.

References 1. Arruga J, Valentines J, Mauri F, et al: Neuroretinitis in acquired syphilis. Ophthalmology92~262-270, 1985 2. Aupy M, Benetier MP, Laporte A, et al: Neurosyphilitic arteritis. Clinical, paraclinical and therapeutic data: A review of six cases. Sem Hasp 58: 1101-l 106, 1982 3. Baker-Zander SA, Hook EW III, Bonin P, et al: Antigen of Treponemal pallidurn recognized by IgG and IgM antibodies during syphilis in humans. J Infect Dis I51:264 272, 1985 4. Baker-Zander SA, Lukehart SA: Molecular basis of immunologic cross reactivity between Trepomena pal&m and Trepomena pertenue. Infect Immunol 42:634638, 1983 5. Baseman JB, Nichols JC, Hayes NS: Virulent Treponemu pallidum: Aerobe or anaerobe? Infect Immun 13:704 ill, 1976 6. Bayne LL, Schmidley JW, Goodin DS: Acute syphilitic meningitis. Arch Neural 43:137-138, 1986 7. Becerra LI, Ksiazek SM, Savino PJ, et al: Syphilitic uveitis in human immunodeficiency virus-infected and noninfected patients. Ophthalmology 96:1727-1730, 1989 8. Beck JR: Likelihood ratios. Another enhancement of sensitivity and specificity. Arch Path01 L.ab Med 110: 685-686, 1986 9. Beck-Sague CM, Alexander ER, Jaffe HW: Neurosyphilis and HIV infection [letter]. N Engl J Med 317:1473, 1987 10. Belin MW, Baltch AL, Hay PB: Secondary syphilitic uveitis. Am J Ophthulmol 92:2 10-214, 1981 11. Berry CD, Hooton TM, Collier AC, Lukehart SA: Neurologic relapse following benzathine penicillin therapy for secondary syphilis. N Engl J Med 316:1587-1589, 1987 12. Blout JH, Holmes KK: Epidemiology of syphilis and the non-venereal treponematoses, in Johnson RC (ed): The Biology of Parasitic Spirochetes. New York, Academic Press, 1976, pp 157-176 13. Burke JM, Schaberg DR: Neurosyphilis in the antibiotic era. Neurology 35:1368-1371, 1985

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OCULAR SYPHILJS 14. Calza A-M, Kinloch S, Mainetti C, et al: Primary human immunodeficiency virus infection mimicking syphilis.] Infect LX.s164.615-616, 1991 15. Carter JB, Hamil RJ, Matoba AY: Bilateral syphilitic optic neuritis in a patient with a positive test for HIV. Arch Ophth&wl105:1485-1486, 1987 16. Case Records of the Massachusetts General Hospital. N Engl J Med 310:973-981, 1984 17. Case Records of the Massachusetts General Hospital. N Engl J Med 325:4lU22, 1991 18. CDC: Primary and secondary syphilis - United States, 1981-1990. n;rMWR 40.3141323, 1991 19. CDC: Congenital syphilis - New York City, 19861988. MMWR 38:825-829, 1989 20. CDC: Centers for Disease Control. Recommendations for diagnosing and treating syphilis in HIV-infected 1988 patients. MMWR 37:600-608, 21. CDC: Syphilis and congenital syphilis - United States 19851988. MMWR 37:486--189, 1988 22. CDC: Continuing increase in infectious syphilis United States. MMWR 37:35-38, 1988 23. CDC: Guidelines for the prevention and control of congenital syphilis. MMWR 37 (suppl #I):l-13, 1988 24 Clark EG, Danbolt N: The Oslo study of the natural course of untreated syphilis. An epidemiologic investiuation based on a re-study of the Boeck-Bruusgaard _ material. Med Clin N Am 4&:613-623, 1964 25. Clark R. Carlisle IT: Neurosvnhilis and HIV infection. West Med J 81:12%4-1205, lg88 26. Crouch ER, Goldberg MF: Retinal periarteritis secondary to syphilis. Arch Ophthulmol 93:384-387, 1975 27. Currie JN, Coppeto JR, Lessell S: Chronic syphilitic meningitis resulting in a superior orbital fissure syndrome and posterior fossa gumma. A report of two cases followed for 20 years. 1 Clin Neuro-ophthulmol 8: 145-159, 1988 ’ ” 28. Davis LE. Schmitt IW: Clinical sipnilicance of cerebrospinal fluid tests f& neurosyphilys. Ann Neural 25:5055, 1989 29. Davis LE, Sperry S: The CSF-FfA test and the significance of blood contamination. Ann Neural 6:68-69, 1979 30. Dawson S, Evans BA, Lawrence AG: Benign tertiary syphilis and HIV infection. AIDS 2:315-316, 1988 31. DeLuise VP. Clark SW III. Smith I, Collart P: Syphilitic retinal detachment and uveal e&ion. Am J Ophkalmol 94~757-761, 1982 32. Denhie CC: A History of.Syphilis. Springfield, Charles C Thomas, 1962 33. De Souza EC, Jalkh AE, Trempe CL, et al: Unusual central chorioretinitis as the first manifestation of early 1988 secondary syphilis. Am J Ophthalmol105:271-276, 34. DiNubile MJ, Copare FJ, Gekowski KM: Neurosyphilis develoninz during treatment of secondary syphilis with benzathinz penicclin in a patient withoutserologic evidence of human immunodeficiency virus infection. Am 1990 J Med 88:45-48, 35. Dorfman DH, Glaser JH: Congenital syphilis presenting in infants after the newborn period. N Engl J Med 323:1299-1302, 1990 36. Drigre KB, White GL, Cremer SA, Massanari RM: Lateonset congenital syphilis. A retrospective look at University of Iowa Hospital admissions. 1 Clin Neuro-Ophthulmdl ll:l-6, 199i 37. Drusin LM. Toof-Olstein B. Levv-Zombeck E: Epidemiology of infe&ous syphilis at a tertiary hospital:Arch Intern Med 135:901-909, 1979 38. Duke-Elder S: System of Ophthalmology. Vol IX: Diseases of the Uveal Tract. St Louis, CV Mosby, 1966, pp 292-321 39. Escobar MR, Dalton HP, Allison MJ: Fluorescent antibody tests for syphilis using cerebrospinal fluid: Clinical correlation in 150 cases. Am J Clin Path01 53:886-890, 1970

40. Ewing Cl, Roberts C, Davidson DC, Arya OP: Early congenital syphilis still occurs. Arch Di.s Child 60: 11281133, 1985 40a.Felman YM: Reneal of mandated nremarital tests for syphilis: a survey of state health dfficers. Am J Public Health 71:155-159, 1981 41. Felman YM, Nikitas JA: Syphilis serology today. Arch Denatol I J6:85-89, 1980 42. Fernandez-Guerrero ML, Miranda C, Cenjor C, Sanabria F: The treatment of neurosyphilis in patients with HIV infection. JAMA 259:1495-1496, 1988 43. Fewell AG: Unilateral neuroretinitis of syphilitic origin with a striate figure at the macula. Arch Ophthulmol 8:615, 1932 44. Fieldsteel AH, Miao RH: Genetics of treponema, in Schell RF, Mushes DM (eds): Puthogenesis and Immunology of Treponenuzl Infection. New York, Marcel Dekker, 1983 45. Fitzgerald TJ, Repesh LA: The hyaluronidase associated with Treponzma pallidurn facilitates treponemal dissemination. Infect Immun 55:1023-1028, 1987 46. Fiumara NJ: Acquired syphilis in a patient with congenital syphilis. JAMA 193:70-7 1, 1965 47. Fiumara NJ, Lessell S: Manifestations of late congenital syphilis: an analysis of 271 patients. Arch Dermutol IO2:78-83, 1970 48. Fiumara NJ: Acquired syphilis in three patients with coneenital svnhilis. N Enel I Med 290:1119-l 120, 1974 primary syphi49. Fi&ara NJ: ‘Treatment:
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plications of acquired syphilis. Am J Ophthalmol 108: 554-562, 1989 63. Hamed LM: Unusual central chorioretinitis as the first manifestation of early secondary syphilis [letter]. Am J Ophthalmol ZO6:110, 1988 64. Hanff PA, Fehniger TE, Miller TN, Lovett MA: Humoral immune resp&se to polypeptides of Treponema pallidum. I lmmunol129:1287-1291. 1982 65. Han& PA, Miller JN, Lovett MA: Molecular characterization of common treponemal antigens. Infect lmmun 40:825-829, 1983 65a.Hart G: Svnhihs test in diagnostic and theraneutic decision making. Ann Intern Ged 104:368-376: 1986 66. Hass JS, Bolan G, Larsen SA, et al: Sensitivity of treponemal tests for detecting prior treated syphilis during human immunodeficiency virus infection. J Znfect Dis 162:862-866, 1990 67. Hederstedt B: Studies on the Trepanemupallidum immobilization activity in normal human serum; 2. Serum factors participating in the normal serum immobilization reaction. Acta Path01 Microbial Scan 84:135-141. 1976 68. Hicks CB, Benson PM, Lupton GP, et al: Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi’s sarcoma. Ann Intern Med 107:492-495, 1987 69. Hill IC. Maske R. Bowen RM: Secondarv localized amvloid&is of the cornea associated with tertiary syphilis. Cornea 9:98-101, 1990 70. Hollander H: Cerebrospinal fluid normalities and abnormalities in individuals infected with human immunodeficiency virus. J Infect Dis 158:855-858, 1988 71. Holmes MD. Brant-Zawadski MM. Simon RP: Clinical manifestation of meningovascular syphilis. Neurology 1984 34:553-556, 72. Hook EW III: AIDS commentary. Syphilis and HIV infection. J Infect Dk Z60:530-534, 1989 73. Hook EW III, Roddy RE, Lukehart SA, et al: Detection of Trepomena pallidurn in lesion exudates with a pathogen-specific monoclonal antibody. J Clin Microbial 22: 241-244, 1985 74. Hooshmand H, Escobar MR, Kopl SW: Neurosyphilis. 1972 A study of 241 patients. JAMA 219:72&729, 75. Hotson JR Modern neurosyphilis: A partially treated chronic meningitis. West J Med 135:191-200, 1981 76. Hovind Hougen K: Morphology, in Schell RF, Musher DM (eds): Pathogenesis and Immunology of Treponemul lnfection. New York, Marcel Dekker, 1983, pp 3-28 76a.Huber TW: Syphilis serology. -. Clin Micro Newsletter 6:47-50, 1984 77. Hutchinson CM, Hook EW III: Syphilis in adults. Med Clin N Am 74(6):1389-1416, 199d78. laffe HW. Kabins SA: Examination ofcerebrosninal fluid in patients with syphilis. Rev Infect Dis ‘4(suppl): 842-847, 1982 79. Jaffe HW, Larsen SA, Peters M, et al: Test for treptomenal antibody in CSF. Arch Intern Med 138:252-255, 1978 80. Jenkins HW, Sandok PL: In vitro cultivation of Treponemu #all&m, in Schell RF, Muscher DM (eds): Pathogenesis and Immunology of Treponemul Infection. New York, Marcel Dekker, 1983, Ch. 5, nn 71-98 81. Jeyakumar W, Chithra A, Shanmugasundararaj A: Primary syphilis of the eyelid: case report. Genitourin Med 65:192-193, 1989 82. Johns DR, Tierney M, Felsenstein D: Alteration in the natural history of neurosyphihs by concurrent infection with human immunod&ciency ‘virus. N Engl J Med 316:1569-1572, 1987 83. Johns DR, Tierney M, Parker SW: Pure motor hemiplegia due to meningovascular neurosyphilis. Arch Neural 44:1062-1065, 1987 84. Johnson PDR, Graves SR, Stewart L, et al: Specific

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Author address: Curtis E. Margo, M.D., Department of Ophthalmology, Unversity of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC Box 21, Tampa, FL 3361211799. Reprints are not available.