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Ocular Syphilis
Ocular Syphilis RICHARD R. TAMESIS, MD, C. STEPHEN FOSTER, MD, FACS
Abstract: The ability of syphilis to mimic different ocular disorders can lead to
misdiagnosis and delay in appropriate antimicrobial therapy. The authors describe their experience over the past 5 years with the ocular manifestations of syphilis in 25 patients who comprised 2.45% of 1020 new patients. Uveitis was the most common ocular manifestation seen. All patients had positive results from FTA-ASS tests, whereas only 68% had reactive serum VDRLs. Two of five patients tested for human immunodeficiency virus (HIV) antibody were reactive. The authors recommend routine FT A-ASS and VORL screening in patients with uveitis or unexplained ocular inflammation. They also recommend testing for HIV antibody in luetics and aggressive treatment with high-dose aqueous penicillin for syphilis. Ophthalmology 1990; 97:1281-1287
Syphilis is a sexually transmitted disease (STD) caused by the spirochete Treponema pallidum. Although ocular findings have been associated with the secondary stage of the disease where hematogenous dissemination of the spirochete occurs, the presence of ocular involvement is strongly suggestive of involvement of the central nervous system and may be considered to be synonymous with neurosyphilis. Since the late 1970s, the incidence of syphilis has been steadily rising in the United States. By 1988, there were 40,275 new cases of primary and secondary syphilis reported. 1 Syphilis now accounts for approximately 100,000 new STD cases annually. This increase in incidence must be appraised by the fact that the majority of cases seen in private clinics go unreported. 2 One report recently found that 52% of 247 patients from an urban population undergoing oculoplastic ambulatory surgery had reactive FTA-ABS tests. 3 This must be interpreted with caution, however, because the possibility of biological or technical false-positive treponema! tests accounting for the high incidence of FTA-ABS reactivity is not trivial. Although this resurgence in incidence has been attributed to a laxity in morals, it also could be explained by a general lack of
Originally received: September 25, 1989. Revision accepted: May 25, 1990. From the Immunology and Uveitis Service, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston. Presented at the American Academy of Ophthalmology Annual Meeting, New Orleans, OctjNov 1989. Supported by the Susan Morse Hilles Immunology Laboratory Fund. Reprint requests to Richard R. Tamesis, MD, Immunology and Uveitis Service, Massachusetts Eye & Ear Infirmary, Harvard Medical School, 243 Charles St, Boston, MA 02114.
awareness about syphilis among younger medical practitioners.4 Syphilis has long been recognized for its ability to imitate any systemic or ocular inflammatory disease. Although the current incidence of ocular syphilis is not known, Schlaegel and Kao 5 estimated that 1.1% of their uveitis cases from 1970 to 1980 were caused by syphilis. The purpose of this article is to describe the characteristics and occurrences of the different manifestations of syphilitic eye disease and its response to treatment. We also describe four patients who demonstrate the difficulties in correctly identifying syphilis as the cause of their eye disease and two patients with ocular syphilis with concurrent human immunodeficiency virus (HIV) infection.
PATIENTS, MATERIALS, AND METHODS We reviewed the records of 25 patients with ocular syphilis seen in the Immunology and Uveitis Service of the Massachusetts Eye & Ear Infirmary between January 1, 1983, and January 30, 1989. These patients comprised 2.45% of 1020 new patients seen during this period. The diagnosis of ocular syphilis was based on clinical evidence of ocular inflammation not attributable to other causes, such as autoimmune and other infectious diseases, and results of a positive serum FT A-ABS test with or without a history of exposure to syphilis. Serum VORL was obtained in all patients, and ten consented to having a spinal tap performed. The ocular evaluation included best visual acuity, slitlamp biomicroscopy, applanation tonometry, and ophthalmoscopy. Laboratory tests obtained included a complete blood count, sedimentation rate, and urinalysis. The decision to perform further diagnostic studies was based on the clinical presentation of the patient and in1281
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Table 1. Clinical Findings at Presentation Ocular Condition Uveitis Anterior uveitis Intermediate uveitis Posterior uveitis Panuveitis Optic nerve disease Optic neuritis Optic atrophy Scleritis Interstitial keratitis
Male
Female
3 0 2 7
2 1 1 1
1 1 0 2
0 1 1 2
Total(%) 17/25 5/17 1/17 3/17 8/17 3/25 1/25 2/25 1/25 4/25
(68) (29) (6) (18) (47) (12) (4) (8) (4) (16)
Table 2. Serologic and Cerebrospinal Fluid Findings
Serum VORL -positive CSF CSF-VORL-positive Serum-VORL-positive Pleocytosis (>5 cells/ml) Protein (>46 mg/dl) CSF
=
Male (%)
Female (%)
Total (%)
10/15 (67)
7/10(70)
17/25 (68)
3/5 (60) 2/5 (28) 3/5 (38)
1/3 (33) 1/3 (33) 1/3 (33)
4/8 (50) 3/8 (38) 4/8 (50)
cerebrospinal fluid.
eluded x-rays, tests for immune complexes, antinuclear antibody, skin tests, and tests for toxoplasmosis. Treatment with either intramuscular or intravenous penicillin was initiated in consultation with the Infectious Disease Unit of the Massachusetts General Hospital. Records were reviewed and data including demographic information, chief complaints, ocular history and findings, the presence of other ocular and systemic diseases, laboratory findings, and response to treatment were recorded. A patient was designated as having no active disease if results of the ocular examination during the last followup visit showed no signs of inflammation in either eye. Data were tabulated and analyzed using customized database software.
RESULTS Twenty-five patients ( 15 men, 10 women) with syphilis affecting the eyes form the basis of this report. The mean age at the time of diagnosis was 47 years for men (range, 30-79 years) and 57 years for women (range, 52-78 years). The mean duration of symptoms before the diagnosis of ocular syphilis was made was 5 years for men (range, 0.0151 years) and 14 years for women (range, 0.12-55 years). Among the men, seven patients had eye symptoms less than 1 year duration, six had symptoms from 1 to 5 years, and two had symptoms for more than 5 years. Among the women, two had symptoms lasting less than 1 year, four had symptoms from 1 to 5 years, and four had symptoms for more than 5 years. One male and one female patient had symptoms for more than 50 years, and both had presented with interstitial keratitis. These differences 1282
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between the sexes were not significant using a 2 X 3 test of independence (G statistic). The mean follow-up evaluation period was 10 months (range, 1-90 months). Most patients (72%) complained of one or more of the following: blurred vision (72% ), ocular pain (32% ), ocular redness (32%), and photophobia (16%). Eleven patients (44%) had ocular involvement in both eyes; 14 (56%) had unilateral involvement. Uveitis was present in 17 patients (68%)-the most common ocular disease seen (Table 1). Less-common inflammatory manifestations were interstitial keratitis in four patients ( 16% ), optic nerve disease (e.g., optic neuritis, optic atrophy) in three (12%), and scleritis in one (4%). When grouped according to the classification system recommended by the International Uveitis Study Group, 6 the uveitis was primarily anterior in five patients (29% ), intermediate in one (6% ), and posterior in three ( 18% ); panuveitis was present in eight patients (47%). Signs of intraocular inflammation involving the posterior segment in the 11 patients with either posterior or panuveitis included diffuse chorioretinitis in 5 (45% ), vitreous cells in 4 (36%), retinal vasculitis in 2 (18%), and papillitis in 1 (9% ). Vitreous membranes with traction retinal detachment developed in two patients. One patient presented with an iris mass that was initially suspected to be malignant. Visual acuities in the involved eye varied considerably at presentation; they were 20/40 or better in 36% of eyes, between 20/50 and 20/100 in 22%, and 20/200 or worse in 42%. Topical steroids and cycloplegics were used acutely. One patient with bilateral panuveitis showed a decrease in the amount of inflammatory cells in his eyes within 6 days of starting intravenous penicillin before he refused to continue with further treatment. The remaining patients had total resolution of active inflammation when seen during the last follow-up visit after completing penicillin treatment. Visual acuity improved by two Snellen lines or better in 22% of affected eyes after penicillin treatment, whereas the remaining eyes had either one Snellen line of improvement or unchanged final vision after treatment. Serum FT A-ABS tests were reactive in all of these patients. Seventeen patients (68%) had reactive serum VDRLs with titers ranging from 1:1 to 1:512 (Table 2). Spinal tap was performed in ten patients, eight of whom were serum VDRL-positive. Four (50%) of these eight patients had reactive VDRLs in their cerebrospinal fluid. One patient had elevated protein levels and three patients had lymphocytic pleocytosis and elevated protein levels. Neither of the two serum VDRL-negative patients who underwent spinal tap had abnormal cerebrospinal fluid levels. No relationship was noted between specific eye findings and the titer of the VDRL in our patients. Hepatitis B surface antigen was detected in the blood of one patient. One of 18 patients who were tested had circulating immune complexes as detected by Raji cell and C1q-binding assays. Two of five patients with severe ocular inflammation, a history of drug abuse, or a history of homosexual activity were seropositive for HIV. Other diagnostic studies in ten patients who were tested for
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toxoplasmosis, tuberculosis, Lyme disease, sarcoidosis, and fungal serologies were unremarkable.
CASE REPORTS Case 1. In December 1986, a 67-year-old man presented with a 2-year history of recurrent blurring of vision and redness in the right eye. The medical history and results of general physical examination were unremarkable. Best-corrected visual acuity was counting fingers at 1 foot in the right eye and 20/40 in the left. Results of slit-lamp examination showed 1+ cells and flare in the right anterior chamber, fine pigmented keratic precipitates, and 3+ cells in the vitreous (Fig 1). Indirect ophthalmoscopy disclosed multifocal areas of intraretinal white infiltrates in the peripheral retina. The left eye was normal. The media haze prevented detailed fluorescein angiographic evaluation of the right eye. The diagnosis of reticulum cell sarcoma with vitreoretinal involvement was considered, and the patient was admitted to the hospital for diagnostic evaluation. Results of the computed tomographic (CT) scan and cerebrospinal fluid examination performed on admission showed no evidence of intracranial lymphoma. A vitreous biopsy done 3 days after admission was initially interpreted as consistent with reticulum cell sarcoma; additional review by two other pathologists resulted in no definitive diagnosis. The VDRL results came back positive at 1: 128 in the serum and 1:512 in the cerebrospinal fluid. The cerebrospinal fluid contained 110 leukocytes ( 100% lymphocytes) and an elevated protein level of 94 mg/dl. The serum FTA-ABS was reactive. Results ofthe HIV antibody test were negative. The patient was treated with 24 MU of intravenous penicillin G daily for 14 days followed by 2.4 MU benzathine penicillin G intramuscularly weekly for 3 weeks. The retinal and intraocular inflammation resolved within 3 weeks, and the visual acuity in the affected eye improved from counting fingers at 1 foot to 20/60. The patient underwent repeat lumbar puncture 9 months later. The cerebrospinal fluid contained four leukocytes, a total protein value of 45 mg/dl, and a reactive VDRL at a titer of 1:4. Case 2. A 29-year-old homosexual man was examined in January 1983 because of photophobia, redness, and blurred vision in the right eye of 1-week duration. Visual acuity was 20/200 in the right eye and 20/20 in the left. Results of slit-lamp examination of the right eye showed 3+ cells and flare in the anterior chamber and vitreous, and posterior iris synechiae. Results of fundus examination disclosed diffuse retinal edema superiorly and temporally with multifocal discrete intraretinal white infiltrates and an intense arterio-obliterative retinal vasculitis (Figs 2,3). The left eye was normal. The diagnosis of acute retinal necrosis was made, and acquired immune deficiency syndrome (AIDS) was suspected. The patient was hospitalized for diagnostic evaluation and therapy, initially with high-dose prednisone. Roentgenograms ofthe chest and paranasal sinuses were normal. T-, B-, and T-cell subsets were within the normal range. The HIV antibody determination was negative. Hepatitis B-surface antigen was detected in the blood, and results of the serum FT AABS test were positive. The VDRL titer was reactive at 1:128 in the serum and 1:2 in the cerebrospinal fluid. The cerebrospinal fluid had three leukocytes with a protein level of 51 mg/dl. The patient was treated with 18 MU of intravenous penicillin G daily for 10 days and 2.4 MU of benzathine penicillin G intramuscularly weekly for 3 weeks. Prednisone was slowly tapered. Retinitis and retinal vasculitis resolved (Fig 4) and the visual acuity improved in the right eye from 20/200 to 20/20 over the ensuing 3 months. After 6 months, the cerebrospinal fluid was normal. Case 3. A 34-year-old, sexually active, bisexual man with a
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3-week history of redness and photophobia in the right eye was evaluated in May 1983. He had a history of gonorrhea and syphilis in the 1970s and was treated twice with intramuscular benzathine penicillin G (2.4 MU) in 1977. Records showed that his initial VDRL titer of 1:32 had decreased to I: I by 1979. Results of physical examination showed nodular, erythematous skin lesions on the patient's head, back, legs, and soles (Fig 5), and condylomata lata on his penis. Best visual acuity was 20/25 in the right eye and 20/20 in the left. Results of slit-lamp examination of the right eye showed 2+ flare and cells in the anterior chamber, mutton fat keratic precipitates, and a 3-mm iris mass temporally. The anterior segment of the left eye was normal. Indirect ophthalmoscopy disclosed areas of chorioretinal atrophy in the periphery of both eyes. Ultrasonography showed that the mass in the iris extended to probable ciliary involvement. Chest x-ray was normal, and results of skin tests for PPD, mumps, and Candida were negative. A biopsy of the skin lesions showed perivascular and periappendageal lymphohistiocytic and plasmacytic inflammatory infiltrates. Although these histopathologic findings were suggestive of syphilis, this was not immediately recognized by the dermatopathologist in this case. The serum was negative for antibody to HIV. Results of the FTA-ABS test were positive, and the serum VDRL was positive at a titer of 1: 512. Re-examination of the skin biopsy with silver stains showed spirochetes (Fig 6). The cerebrospinal fluid showed a nonreactive VDRL, two leukocytes, and protein level of 42 mg/dl. The patient was treated with 12 MU of intravenous penicillin G daily for I 0 days and 2.4 MU of benzathine penicillin G IM weekly for 3 weeks. Over the next 4 weeks, the visual acuity of the right eye improved to 20/20, and the iris mass disappeared. The patient has not returned since then for further follow-up examinations. Case 4. A 63-year-old woman was seen in May 1983 with a !-year history of chronic scleritis in the right eye, unresponsive to prednisone and azathioprine therapy. Her visual acuity was 20/25 in the right eye and 20/20 in the left. Anterior scleral thinning with overlying episcleral inflammation was noted circumferentially at the right limbus. Results of biomicroscopic examination showed 1+ flare and cells in the right anterior chamber and in the anterior vitreous. Rheumatoid factor, antinuclear antibody, and results of angiotensin-converting enzyme tests were unremarkable. Scleral biopsy showed subacute inflammation. No dark field examination was performed on the specimen. Prednisone was tapered and oxyphenbutazone (200 mg daily) was begun. The inflammation slowly resolved. The patient returned in July 1985 with nodular scleritis in the left eye. This new episode prompted repeat laboratory studies, including tests for syphilis. The patient was treated with topical prednisolone acetate 1% four times daily, scopolamine 0.25% twice daily, and oxyphenbutazone 100 mg orally twice daily. Clq and Raji cell tests for circulating immune complexes were positive at 19% and 268 11g AHG Eqjml, respectively. Results of the serum FTA-ABS were positive, and results ofthe serum VDRL test were reactive at I :2. The patient was advised to undergo treatment. She, however, did not return until 7 months later when she again presented with active nodular scleritis in the left eye. The patient was hospitalized and treated with intravenous penicillin (24 MU every day for 10 days) followed by weekly intramuscular injections of 2.4 MU of benzathine penicillin for three doses. She refused spinal tap. The scleritis resolved within 2 weeks after the first penicillin dose. The topical steroid drops were tapered and discontinued over 8 weeks. Results of the follow-up VDRL test were negative. The patient has had no recurrences of her scleritis I year after penicillin treatment. Case 5. A 35-year-old man presented in December 1988 with a 2-month history of progressively decreasing vision in both eyes. He had a history of intravenous cocaine abuse and an extended
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Fig 1. Top left, retroillumination photograph of the right eye of case I shows clumps of cells present in the vitreous. Fig 2. Top right, right ocular fundus of case 2 shows retinal vasculitis and retinal edema along the superior temporal arcade. Fig 3. Second row left, fluorescein angiogram of case 2 shows leakage of dye from the superior temporal vessels and some staining coming from the RPE. Fig 4. Second row right, right ocular fundus of case 2, 3 months after treatment with intravenous penicillin, shows RPE atrophic changes over the area of previous inflammation. Fig 5. Third row left, erythematous, nodular skin lesions on the leg of case 3. Fig 6. Third row right, light micrograph of skin biopsy of case 3 shows a spirochete within the epidermis (Warthin-Starry; original magnification, X25). Fig 7. Bottom, right ocular fundus photograph of case 5 shows areas of white infiltrates and extensive retinal hemorrhages in the temporal periphery of the retina producing a picture similar to that seen in acute retinal necrosis.
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relationship with a prostitute. Results of physical examination disclosed a moderately cachectic male with a maculopapular rash on his soles and palms. Visual acuity was 20/70 in the right eye and light perception in the left eye. Both eyes had 2 + aqueous flare and cells with mutton fat keratic precipitates; the vitreous contained 2+ cells in the right eye and 4+ cells in the left. Indirect ophthalmoscopy disclosed an area of serous retinal detachment with multifocal areas of white infiltrates located in the temporal periphery of the right fundus (Fig 7). The left fundus could not be visualized. Serologic studies disclosed a positive serum VDRL at a titer of 1:512, a reactive FTA-ABS, and a strongly positive test for HIV antibody. The patient refused spinal tap. Chest xray and CT scan of the head were normal. Serologies and cultures for toxoplasmosis, Lyme disease, fungal infections, tuberculosis, and cytomegalovirus were negative. Intravenous penicillin G (24 MU) was administered daily. A mild Jarisch-Herxheimer reaction developed after the first dose of intravenous penicillin. The vision improved to hand motions in the left eye over the next 4 days, and there was a marked decrease in the inflammation in both eyes. On the sixth day of intravenous penicillin therapy, the patient refused further medication and left the hospital against medical advice. Case 6. A 30-year-old man was evaluated in January 1989 for a 2-week history of a red, painful right eye and blurry vision. Visual acuity was 20/70 in the right eye and 20/30 in the left eye. Results of slit-lamp examination of the right eye showed mutton fat keratic precipitates and 3+ flare and cells in the anterior chamber and vitreous. Results of fundus examination of the right eye disclosed arteriolar sheathing with inflammatory exudates and multiple areas of chorioretinal infiltrates in the inferotemporal periphery of the fundus. Serologic studies disclosed antibody to HIV and a reactive FT A-ABS test. Results ofthe serum, aqueous, and cerebrospinal fluid VDRL tests were nonreactive. The cerebrospinal fluid had two leukocytes and a protein level of 36 mg/dl. Serologies and cultures for toxoplasmosis, cytomegalovirus, fungi, tuberculosis, and Lyme disease were negative. The patient was treated with 24 MU of intravenous penicillin daily for 10 days and 2.4 MU of benzathine penicillin G weekly for three doses. The visual acuity of the right eye improved to 20/25, and the uveitis had completely resolved within 1 month. The patient has not returned since then for a repeat spinal tap.
DISCUSSION Syphilis was considered to be one of the most common causes of intraocular inflammation before 1925. The advent of antibiotic therapy led to a marked change in the epidemiology of syphilis; by 1955, it was believed that syphilis had been eradicated. 7 This disease has been inexorably increasing, however, over the past two decades. Iritis, chorioretinitis, interstitial keratitis, retinal vasculitis, papillitis, and optic atrophy are well-known ocular manifestations of syphilis. 5·8- 17 Iris papules, 18 neuroretinitis, 19·20 episcleritis, and scleritis21 also have been described previously and were present in our series of 25 patients. Other manifestations that have been reported by others include cystoid macular edema, 22 optic perineuritis,23·24 and exudative retinal detachment. 25 The absence of pathognomonic signs and the notorious ability of syphilis to mimic any ocular and systemic inflammatory disease can often lead to misdiagnosis and delay in appropriate therapy as illustrated in cases 1 to 4.
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One patient (case 1) presented with a chronic vitreitis of 2 years' duration, and reticulum cell sarcoma was the suspected diagnosis. This patient might have undergone radiation treatment had it not been for the debate over the vitreous biopsy results and the subsequent discovery of positive serologies for syphilis. In two other patients (cases 2 and 5 ), the ocular findings appeared to be that of an acute retinal necrosis of unknown etiology. An iris or ciliary body tumor was considered in case 3 before the positive syphilis serologic results and previous records of treatment for syphilis were obtained. This was believed to represent a case of reinfection rather than a failure of previous treatment. The cause for the scleritis in case 4 was not recognized for more than 3 years. Involvement of the other eye prompted repeat laboratory studies, including serologic tests for syphilis, which then identified the patient as having active syphilis. Several patients had been previously treated by other practitioners for more than 1 year before they were seen by our service and diagnosed to have syphilis. This lag in making the proper diagnosis again demonstrates the need to be aware of syphilis as a possibility in a patient with ocular inflammation. More than one third of our patients had a nonreactive serum VDRL; this finding confirms the experience of others. 5·8·26 In patients with late syphilis, the serum VDRL is approximately 70% sensitive, and the FT A-ABS test is 98% sensitive. 5·7·8·26 ·27 This emphasizes the great importance of the FTA-ABS test. To obtain only a serum VDRL test without a serum FTA-ABS test will allow one to miss 30 to 40% of cases of late syphilis. Indeed, the FT A-ABS proved to be important in one patient (case 6) who had positive FT A-ABS and HIV antibody results but nonreactive VDRL tests and whose uveitis subsequently resolved with penicillin treatment. The VDRL titer reflects the systemic activity of the disease; its value lies in monitoring the response to treatment. A persistent fall in VDRL titers after treatment provides essential evidence of an adequate response to therapy. Our philosophy in the diagnostic pursuit of an etiology for ocular inflammation is parsimonious in general. We select diagnostic studies based almost exclusively on leads from a careful review of systems and from the physical findings. The reason for advocating routine FT A-ABS testing should be obvious from this report. There is evidence that the MHA-TP test is more specific than the FT A-ABS test in sick persons 27 and may be useful in confirming a positive FTA-ABS result as it comes into greater use. Penicillin G has remained the drug of choice for all stages of syphilis since its introduction 40 years ago. Other antibiotics that are effective in syphilis therapy include erythromycin, the tetracyclines, and possibly the thirdgeneration cephalosporins. However, the optimal dose and duration of therapy have not been established for any stage of the disease and multiple regimens for therapy currently exist. Numerous reports of treatment failures3·28-31 and data showing that benzathine penicillin does not reach treponemicidal levels within the cerebrospinal 1285
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fluid 32- 35 have raised concerns that the current recommendations of the Centers for Disease Control, Atlanta, 36 may be inadequate, particularly in syphilis complicated by AIDS. 37- 39 We report two cases of concurrent ocular syphilis and HIV infection, one of whom had negative serum and cerebrospinal fluid VORL titers. To date, there have been 14 previous case reports ofHIV-positive young adult patients with concurrent ocular syphilis in the literature. 37 •38•40- 48 In these reports, severe uveitis developed in nine patients, two had necrotizing retinitis, and the other three presented with optic neuritis or retrobulbar neuritis. 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. 37 In view of these reports, we believe, therefore, that all patients with ocular syphilis should now be evaluated for HIV and vice versa. We currently admit all patients with ocular syphilis to the hospital and recommend examination of the cerebrospinal fluid for cells, protein, and serologic values. Because of previous reports of therapeutic failures using intramuscular benzathine penicillin and experimental data suggesting that complete spirochetal sterilization may be impossible unless high dosages and prolonged periods of treatment are used, 34 we treat them with the neurosyphilis regimen of 12 to 24 MU of aqueous crystalline penicillin G intravenously daily for at least 10 days, followed by 2.4 MU benzathine penicillin G intramuscularly weekly for 3 weeks. 8 •38 Although some authors have recommended the use of doxycycline, 39 tetracycline, or erythromycin in the treatment of penicillin-allergic luetics, there is minimal experience using these drugs, and properly controlled studies have not been performed. We prefer instead to have patients proven to be penicillin allergic undergo penicillin desensitization before treating with penicillin. Many patients who give a history of penicillin allergy prove negative when skin-tested for immediate hypersensitivity to penicillin and could be given aqueous crystalline penicillin G under close supervision in the hospital. Close follow-up in collaboration with an infectious disease specialist and repeat serum and cerebrospinal fluid VORL titers to monitor the adequacy of treatment remain essential in these patients.
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7.
8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
29.
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36. Center for Disease Control. Syphilis-CDC recommended treatment schedules, 1976. MMWR 1976; 25:101-7. 37. Johns DR, Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N Engl J Med 1987; 316:1569-72. 38. Berry CD, Hooton TM, Collier AC, Lukehart SA. Neurologic relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection. N Engl J Med 1987; 316:1587-9. 39. Tramont EC. Syphilis in the AIDS era. N Engl J Med 1987; 316: 1600-1. 40. Richards BW, Hessburg TJ, Nussbaum JN. Recurrent syphilitic uveitis [Letter). N Engl J Med 1989; 320:62. 41. Levy JH, Liss RA, Maguire AM. Neurosyphilis and ocular syphilis in patients with concurrent human immunodeficiency virus infection. Retina 1989; 9:175-80. 42. Zaidman GW. Neurosyphilis and retrobulbar neuritis in a patient with AIDS. Ann Ophthalmol 1986; 18:260-1.
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43. Carter JB, Hamill RJ, Matoba AY. Bilateral syphilitic optic neuritis in a patient with a positive test for HIV. Arch Ophthalmol 1987; 105: 1485-6. 44. Kleiner RC, Najarian L, Levenson J, Kaplan HJ. AIDS complicated by syphilis can mimick uveitis and Crohn's disease [Letter]. Arch Ophthalmol1987; 105:1486-7. 45. Zambrano W, Perez GM, Smith JL. Acute syphilitic blindness in AIDS. J Clin Neuro Ophthalmol1987; 7:1-5. 46. Stoumbos VD, Klein ML. Syphilitic retinitis in a patient with acquired immunodeficiency syndrome-related complex [Letter). Am J Ophthalrnol1987; 103:103-4. 47. Radolf JD, Kaplan RP. Unusual manifestations of secondary syphilis and abnormal humoral immune response to Treponema pallidum antigens in a homosexual man with asymptomatic human immunodeficiency virus infection. JAm Acad Dermatol1988; 18:423-8. 48. Passe MS, Rosenbaum JT. Ocular syphilis in patients with human immunodeficiency virus infection. Am J Ophthalmol1988; 106:1-6.
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Abstract: The ability of syphilis to mimic different ocular disorders can lead to
misdiagnosis and delay in appropriate antimicrobial therapy. The authors describe their experience over the past 5 years with the ocular manifestations of syphilis in 25 patients who comprised 2.45% of 1020 new patients. Uveitis was the most common ocular manifestation seen. All patients had positive results from FTA-ASS tests, whereas only 68% had reactive serum VDRLs. Two of five patients tested for human immunodeficiency virus (HIV) antibody were reactive. The authors recommend routine FT A-ASS and VORL screening in patients with uveitis or unexplained ocular inflammation. They also recommend testing for HIV antibody in luetics and aggressive treatment with high-dose aqueous penicillin for syphilis. Ophthalmology 1990; 97:1281-1287
Syphilis is a sexually transmitted disease (STD) caused by the spirochete Treponema pallidum. Although ocular findings have been associated with the secondary stage of the disease where hematogenous dissemination of the spirochete occurs, the presence of ocular involvement is strongly suggestive of involvement of the central nervous system and may be considered to be synonymous with neurosyphilis. Since the late 1970s, the incidence of syphilis has been steadily rising in the United States. By 1988, there were 40,275 new cases of primary and secondary syphilis reported. 1 Syphilis now accounts for approximately 100,000 new STD cases annually. This increase in incidence must be appraised by the fact that the majority of cases seen in private clinics go unreported. 2 One report recently found that 52% of 247 patients from an urban population undergoing oculoplastic ambulatory surgery had reactive FTA-ABS tests. 3 This must be interpreted with caution, however, because the possibility of biological or technical false-positive treponema! tests accounting for the high incidence of FTA-ABS reactivity is not trivial. Although this resurgence in incidence has been attributed to a laxity in morals, it also could be explained by a general lack of
Originally received: September 25, 1989. Revision accepted: May 25, 1990. From the Immunology and Uveitis Service, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston. Presented at the American Academy of Ophthalmology Annual Meeting, New Orleans, OctjNov 1989. Supported by the Susan Morse Hilles Immunology Laboratory Fund. Reprint requests to Richard R. Tamesis, MD, Immunology and Uveitis Service, Massachusetts Eye & Ear Infirmary, Harvard Medical School, 243 Charles St, Boston, MA 02114.
awareness about syphilis among younger medical practitioners.4 Syphilis has long been recognized for its ability to imitate any systemic or ocular inflammatory disease. Although the current incidence of ocular syphilis is not known, Schlaegel and Kao 5 estimated that 1.1% of their uveitis cases from 1970 to 1980 were caused by syphilis. The purpose of this article is to describe the characteristics and occurrences of the different manifestations of syphilitic eye disease and its response to treatment. We also describe four patients who demonstrate the difficulties in correctly identifying syphilis as the cause of their eye disease and two patients with ocular syphilis with concurrent human immunodeficiency virus (HIV) infection.
PATIENTS, MATERIALS, AND METHODS We reviewed the records of 25 patients with ocular syphilis seen in the Immunology and Uveitis Service of the Massachusetts Eye & Ear Infirmary between January 1, 1983, and January 30, 1989. These patients comprised 2.45% of 1020 new patients seen during this period. The diagnosis of ocular syphilis was based on clinical evidence of ocular inflammation not attributable to other causes, such as autoimmune and other infectious diseases, and results of a positive serum FT A-ABS test with or without a history of exposure to syphilis. Serum VORL was obtained in all patients, and ten consented to having a spinal tap performed. The ocular evaluation included best visual acuity, slitlamp biomicroscopy, applanation tonometry, and ophthalmoscopy. Laboratory tests obtained included a complete blood count, sedimentation rate, and urinalysis. The decision to perform further diagnostic studies was based on the clinical presentation of the patient and in1281
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Table 1. Clinical Findings at Presentation Ocular Condition Uveitis Anterior uveitis Intermediate uveitis Posterior uveitis Panuveitis Optic nerve disease Optic neuritis Optic atrophy Scleritis Interstitial keratitis
Male
Female
3 0 2 7
2 1 1 1
1 1 0 2
0 1 1 2
Total(%) 17/25 5/17 1/17 3/17 8/17 3/25 1/25 2/25 1/25 4/25
(68) (29) (6) (18) (47) (12) (4) (8) (4) (16)
Table 2. Serologic and Cerebrospinal Fluid Findings
Serum VORL -positive CSF CSF-VORL-positive Serum-VORL-positive Pleocytosis (>5 cells/ml) Protein (>46 mg/dl) CSF
=
Male (%)
Female (%)
Total (%)
10/15 (67)
7/10(70)
17/25 (68)
3/5 (60) 2/5 (28) 3/5 (38)
1/3 (33) 1/3 (33) 1/3 (33)
4/8 (50) 3/8 (38) 4/8 (50)
cerebrospinal fluid.
eluded x-rays, tests for immune complexes, antinuclear antibody, skin tests, and tests for toxoplasmosis. Treatment with either intramuscular or intravenous penicillin was initiated in consultation with the Infectious Disease Unit of the Massachusetts General Hospital. Records were reviewed and data including demographic information, chief complaints, ocular history and findings, the presence of other ocular and systemic diseases, laboratory findings, and response to treatment were recorded. A patient was designated as having no active disease if results of the ocular examination during the last followup visit showed no signs of inflammation in either eye. Data were tabulated and analyzed using customized database software.
RESULTS Twenty-five patients ( 15 men, 10 women) with syphilis affecting the eyes form the basis of this report. The mean age at the time of diagnosis was 47 years for men (range, 30-79 years) and 57 years for women (range, 52-78 years). The mean duration of symptoms before the diagnosis of ocular syphilis was made was 5 years for men (range, 0.0151 years) and 14 years for women (range, 0.12-55 years). Among the men, seven patients had eye symptoms less than 1 year duration, six had symptoms from 1 to 5 years, and two had symptoms for more than 5 years. Among the women, two had symptoms lasting less than 1 year, four had symptoms from 1 to 5 years, and four had symptoms for more than 5 years. One male and one female patient had symptoms for more than 50 years, and both had presented with interstitial keratitis. These differences 1282
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between the sexes were not significant using a 2 X 3 test of independence (G statistic). The mean follow-up evaluation period was 10 months (range, 1-90 months). Most patients (72%) complained of one or more of the following: blurred vision (72% ), ocular pain (32% ), ocular redness (32%), and photophobia (16%). Eleven patients (44%) had ocular involvement in both eyes; 14 (56%) had unilateral involvement. Uveitis was present in 17 patients (68%)-the most common ocular disease seen (Table 1). Less-common inflammatory manifestations were interstitial keratitis in four patients ( 16% ), optic nerve disease (e.g., optic neuritis, optic atrophy) in three (12%), and scleritis in one (4%). When grouped according to the classification system recommended by the International Uveitis Study Group, 6 the uveitis was primarily anterior in five patients (29% ), intermediate in one (6% ), and posterior in three ( 18% ); panuveitis was present in eight patients (47%). Signs of intraocular inflammation involving the posterior segment in the 11 patients with either posterior or panuveitis included diffuse chorioretinitis in 5 (45% ), vitreous cells in 4 (36%), retinal vasculitis in 2 (18%), and papillitis in 1 (9% ). Vitreous membranes with traction retinal detachment developed in two patients. One patient presented with an iris mass that was initially suspected to be malignant. Visual acuities in the involved eye varied considerably at presentation; they were 20/40 or better in 36% of eyes, between 20/50 and 20/100 in 22%, and 20/200 or worse in 42%. Topical steroids and cycloplegics were used acutely. One patient with bilateral panuveitis showed a decrease in the amount of inflammatory cells in his eyes within 6 days of starting intravenous penicillin before he refused to continue with further treatment. The remaining patients had total resolution of active inflammation when seen during the last follow-up visit after completing penicillin treatment. Visual acuity improved by two Snellen lines or better in 22% of affected eyes after penicillin treatment, whereas the remaining eyes had either one Snellen line of improvement or unchanged final vision after treatment. Serum FT A-ABS tests were reactive in all of these patients. Seventeen patients (68%) had reactive serum VDRLs with titers ranging from 1:1 to 1:512 (Table 2). Spinal tap was performed in ten patients, eight of whom were serum VDRL-positive. Four (50%) of these eight patients had reactive VDRLs in their cerebrospinal fluid. One patient had elevated protein levels and three patients had lymphocytic pleocytosis and elevated protein levels. Neither of the two serum VDRL-negative patients who underwent spinal tap had abnormal cerebrospinal fluid levels. No relationship was noted between specific eye findings and the titer of the VDRL in our patients. Hepatitis B surface antigen was detected in the blood of one patient. One of 18 patients who were tested had circulating immune complexes as detected by Raji cell and C1q-binding assays. Two of five patients with severe ocular inflammation, a history of drug abuse, or a history of homosexual activity were seropositive for HIV. Other diagnostic studies in ten patients who were tested for
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toxoplasmosis, tuberculosis, Lyme disease, sarcoidosis, and fungal serologies were unremarkable.
CASE REPORTS Case 1. In December 1986, a 67-year-old man presented with a 2-year history of recurrent blurring of vision and redness in the right eye. The medical history and results of general physical examination were unremarkable. Best-corrected visual acuity was counting fingers at 1 foot in the right eye and 20/40 in the left. Results of slit-lamp examination showed 1+ cells and flare in the right anterior chamber, fine pigmented keratic precipitates, and 3+ cells in the vitreous (Fig 1). Indirect ophthalmoscopy disclosed multifocal areas of intraretinal white infiltrates in the peripheral retina. The left eye was normal. The media haze prevented detailed fluorescein angiographic evaluation of the right eye. The diagnosis of reticulum cell sarcoma with vitreoretinal involvement was considered, and the patient was admitted to the hospital for diagnostic evaluation. Results of the computed tomographic (CT) scan and cerebrospinal fluid examination performed on admission showed no evidence of intracranial lymphoma. A vitreous biopsy done 3 days after admission was initially interpreted as consistent with reticulum cell sarcoma; additional review by two other pathologists resulted in no definitive diagnosis. The VDRL results came back positive at 1: 128 in the serum and 1:512 in the cerebrospinal fluid. The cerebrospinal fluid contained 110 leukocytes ( 100% lymphocytes) and an elevated protein level of 94 mg/dl. The serum FTA-ABS was reactive. Results ofthe HIV antibody test were negative. The patient was treated with 24 MU of intravenous penicillin G daily for 14 days followed by 2.4 MU benzathine penicillin G intramuscularly weekly for 3 weeks. The retinal and intraocular inflammation resolved within 3 weeks, and the visual acuity in the affected eye improved from counting fingers at 1 foot to 20/60. The patient underwent repeat lumbar puncture 9 months later. The cerebrospinal fluid contained four leukocytes, a total protein value of 45 mg/dl, and a reactive VDRL at a titer of 1:4. Case 2. A 29-year-old homosexual man was examined in January 1983 because of photophobia, redness, and blurred vision in the right eye of 1-week duration. Visual acuity was 20/200 in the right eye and 20/20 in the left. Results of slit-lamp examination of the right eye showed 3+ cells and flare in the anterior chamber and vitreous, and posterior iris synechiae. Results of fundus examination disclosed diffuse retinal edema superiorly and temporally with multifocal discrete intraretinal white infiltrates and an intense arterio-obliterative retinal vasculitis (Figs 2,3). The left eye was normal. The diagnosis of acute retinal necrosis was made, and acquired immune deficiency syndrome (AIDS) was suspected. The patient was hospitalized for diagnostic evaluation and therapy, initially with high-dose prednisone. Roentgenograms ofthe chest and paranasal sinuses were normal. T-, B-, and T-cell subsets were within the normal range. The HIV antibody determination was negative. Hepatitis B-surface antigen was detected in the blood, and results of the serum FT AABS test were positive. The VDRL titer was reactive at 1:128 in the serum and 1:2 in the cerebrospinal fluid. The cerebrospinal fluid had three leukocytes with a protein level of 51 mg/dl. The patient was treated with 18 MU of intravenous penicillin G daily for 10 days and 2.4 MU of benzathine penicillin G intramuscularly weekly for 3 weeks. Prednisone was slowly tapered. Retinitis and retinal vasculitis resolved (Fig 4) and the visual acuity improved in the right eye from 20/200 to 20/20 over the ensuing 3 months. After 6 months, the cerebrospinal fluid was normal. Case 3. A 34-year-old, sexually active, bisexual man with a
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3-week history of redness and photophobia in the right eye was evaluated in May 1983. He had a history of gonorrhea and syphilis in the 1970s and was treated twice with intramuscular benzathine penicillin G (2.4 MU) in 1977. Records showed that his initial VDRL titer of 1:32 had decreased to I: I by 1979. Results of physical examination showed nodular, erythematous skin lesions on the patient's head, back, legs, and soles (Fig 5), and condylomata lata on his penis. Best visual acuity was 20/25 in the right eye and 20/20 in the left. Results of slit-lamp examination of the right eye showed 2+ flare and cells in the anterior chamber, mutton fat keratic precipitates, and a 3-mm iris mass temporally. The anterior segment of the left eye was normal. Indirect ophthalmoscopy disclosed areas of chorioretinal atrophy in the periphery of both eyes. Ultrasonography showed that the mass in the iris extended to probable ciliary involvement. Chest x-ray was normal, and results of skin tests for PPD, mumps, and Candida were negative. A biopsy of the skin lesions showed perivascular and periappendageal lymphohistiocytic and plasmacytic inflammatory infiltrates. Although these histopathologic findings were suggestive of syphilis, this was not immediately recognized by the dermatopathologist in this case. The serum was negative for antibody to HIV. Results of the FTA-ABS test were positive, and the serum VDRL was positive at a titer of 1: 512. Re-examination of the skin biopsy with silver stains showed spirochetes (Fig 6). The cerebrospinal fluid showed a nonreactive VDRL, two leukocytes, and protein level of 42 mg/dl. The patient was treated with 12 MU of intravenous penicillin G daily for I 0 days and 2.4 MU of benzathine penicillin G IM weekly for 3 weeks. Over the next 4 weeks, the visual acuity of the right eye improved to 20/20, and the iris mass disappeared. The patient has not returned since then for further follow-up examinations. Case 4. A 63-year-old woman was seen in May 1983 with a !-year history of chronic scleritis in the right eye, unresponsive to prednisone and azathioprine therapy. Her visual acuity was 20/25 in the right eye and 20/20 in the left. Anterior scleral thinning with overlying episcleral inflammation was noted circumferentially at the right limbus. Results of biomicroscopic examination showed 1+ flare and cells in the right anterior chamber and in the anterior vitreous. Rheumatoid factor, antinuclear antibody, and results of angiotensin-converting enzyme tests were unremarkable. Scleral biopsy showed subacute inflammation. No dark field examination was performed on the specimen. Prednisone was tapered and oxyphenbutazone (200 mg daily) was begun. The inflammation slowly resolved. The patient returned in July 1985 with nodular scleritis in the left eye. This new episode prompted repeat laboratory studies, including tests for syphilis. The patient was treated with topical prednisolone acetate 1% four times daily, scopolamine 0.25% twice daily, and oxyphenbutazone 100 mg orally twice daily. Clq and Raji cell tests for circulating immune complexes were positive at 19% and 268 11g AHG Eqjml, respectively. Results of the serum FTA-ABS were positive, and results ofthe serum VDRL test were reactive at I :2. The patient was advised to undergo treatment. She, however, did not return until 7 months later when she again presented with active nodular scleritis in the left eye. The patient was hospitalized and treated with intravenous penicillin (24 MU every day for 10 days) followed by weekly intramuscular injections of 2.4 MU of benzathine penicillin for three doses. She refused spinal tap. The scleritis resolved within 2 weeks after the first penicillin dose. The topical steroid drops were tapered and discontinued over 8 weeks. Results of the follow-up VDRL test were negative. The patient has had no recurrences of her scleritis I year after penicillin treatment. Case 5. A 35-year-old man presented in December 1988 with a 2-month history of progressively decreasing vision in both eyes. He had a history of intravenous cocaine abuse and an extended
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Fig 1. Top left, retroillumination photograph of the right eye of case I shows clumps of cells present in the vitreous. Fig 2. Top right, right ocular fundus of case 2 shows retinal vasculitis and retinal edema along the superior temporal arcade. Fig 3. Second row left, fluorescein angiogram of case 2 shows leakage of dye from the superior temporal vessels and some staining coming from the RPE. Fig 4. Second row right, right ocular fundus of case 2, 3 months after treatment with intravenous penicillin, shows RPE atrophic changes over the area of previous inflammation. Fig 5. Third row left, erythematous, nodular skin lesions on the leg of case 3. Fig 6. Third row right, light micrograph of skin biopsy of case 3 shows a spirochete within the epidermis (Warthin-Starry; original magnification, X25). Fig 7. Bottom, right ocular fundus photograph of case 5 shows areas of white infiltrates and extensive retinal hemorrhages in the temporal periphery of the retina producing a picture similar to that seen in acute retinal necrosis.
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relationship with a prostitute. Results of physical examination disclosed a moderately cachectic male with a maculopapular rash on his soles and palms. Visual acuity was 20/70 in the right eye and light perception in the left eye. Both eyes had 2 + aqueous flare and cells with mutton fat keratic precipitates; the vitreous contained 2+ cells in the right eye and 4+ cells in the left. Indirect ophthalmoscopy disclosed an area of serous retinal detachment with multifocal areas of white infiltrates located in the temporal periphery of the right fundus (Fig 7). The left fundus could not be visualized. Serologic studies disclosed a positive serum VDRL at a titer of 1:512, a reactive FTA-ABS, and a strongly positive test for HIV antibody. The patient refused spinal tap. Chest xray and CT scan of the head were normal. Serologies and cultures for toxoplasmosis, Lyme disease, fungal infections, tuberculosis, and cytomegalovirus were negative. Intravenous penicillin G (24 MU) was administered daily. A mild Jarisch-Herxheimer reaction developed after the first dose of intravenous penicillin. The vision improved to hand motions in the left eye over the next 4 days, and there was a marked decrease in the inflammation in both eyes. On the sixth day of intravenous penicillin therapy, the patient refused further medication and left the hospital against medical advice. Case 6. A 30-year-old man was evaluated in January 1989 for a 2-week history of a red, painful right eye and blurry vision. Visual acuity was 20/70 in the right eye and 20/30 in the left eye. Results of slit-lamp examination of the right eye showed mutton fat keratic precipitates and 3+ flare and cells in the anterior chamber and vitreous. Results of fundus examination of the right eye disclosed arteriolar sheathing with inflammatory exudates and multiple areas of chorioretinal infiltrates in the inferotemporal periphery of the fundus. Serologic studies disclosed antibody to HIV and a reactive FT A-ABS test. Results ofthe serum, aqueous, and cerebrospinal fluid VDRL tests were nonreactive. The cerebrospinal fluid had two leukocytes and a protein level of 36 mg/dl. Serologies and cultures for toxoplasmosis, cytomegalovirus, fungi, tuberculosis, and Lyme disease were negative. The patient was treated with 24 MU of intravenous penicillin daily for 10 days and 2.4 MU of benzathine penicillin G weekly for three doses. The visual acuity of the right eye improved to 20/25, and the uveitis had completely resolved within 1 month. The patient has not returned since then for a repeat spinal tap.
DISCUSSION Syphilis was considered to be one of the most common causes of intraocular inflammation before 1925. The advent of antibiotic therapy led to a marked change in the epidemiology of syphilis; by 1955, it was believed that syphilis had been eradicated. 7 This disease has been inexorably increasing, however, over the past two decades. Iritis, chorioretinitis, interstitial keratitis, retinal vasculitis, papillitis, and optic atrophy are well-known ocular manifestations of syphilis. 5·8- 17 Iris papules, 18 neuroretinitis, 19·20 episcleritis, and scleritis21 also have been described previously and were present in our series of 25 patients. Other manifestations that have been reported by others include cystoid macular edema, 22 optic perineuritis,23·24 and exudative retinal detachment. 25 The absence of pathognomonic signs and the notorious ability of syphilis to mimic any ocular and systemic inflammatory disease can often lead to misdiagnosis and delay in appropriate therapy as illustrated in cases 1 to 4.
OCULAR SYPHILIS
One patient (case 1) presented with a chronic vitreitis of 2 years' duration, and reticulum cell sarcoma was the suspected diagnosis. This patient might have undergone radiation treatment had it not been for the debate over the vitreous biopsy results and the subsequent discovery of positive serologies for syphilis. In two other patients (cases 2 and 5 ), the ocular findings appeared to be that of an acute retinal necrosis of unknown etiology. An iris or ciliary body tumor was considered in case 3 before the positive syphilis serologic results and previous records of treatment for syphilis were obtained. This was believed to represent a case of reinfection rather than a failure of previous treatment. The cause for the scleritis in case 4 was not recognized for more than 3 years. Involvement of the other eye prompted repeat laboratory studies, including serologic tests for syphilis, which then identified the patient as having active syphilis. Several patients had been previously treated by other practitioners for more than 1 year before they were seen by our service and diagnosed to have syphilis. This lag in making the proper diagnosis again demonstrates the need to be aware of syphilis as a possibility in a patient with ocular inflammation. More than one third of our patients had a nonreactive serum VDRL; this finding confirms the experience of others. 5·8·26 In patients with late syphilis, the serum VDRL is approximately 70% sensitive, and the FT A-ABS test is 98% sensitive. 5·7·8·26 ·27 This emphasizes the great importance of the FTA-ABS test. To obtain only a serum VDRL test without a serum FTA-ABS test will allow one to miss 30 to 40% of cases of late syphilis. Indeed, the FT A-ABS proved to be important in one patient (case 6) who had positive FT A-ABS and HIV antibody results but nonreactive VDRL tests and whose uveitis subsequently resolved with penicillin treatment. The VDRL titer reflects the systemic activity of the disease; its value lies in monitoring the response to treatment. A persistent fall in VDRL titers after treatment provides essential evidence of an adequate response to therapy. Our philosophy in the diagnostic pursuit of an etiology for ocular inflammation is parsimonious in general. We select diagnostic studies based almost exclusively on leads from a careful review of systems and from the physical findings. The reason for advocating routine FT A-ABS testing should be obvious from this report. There is evidence that the MHA-TP test is more specific than the FT A-ABS test in sick persons 27 and may be useful in confirming a positive FTA-ABS result as it comes into greater use. Penicillin G has remained the drug of choice for all stages of syphilis since its introduction 40 years ago. Other antibiotics that are effective in syphilis therapy include erythromycin, the tetracyclines, and possibly the thirdgeneration cephalosporins. However, the optimal dose and duration of therapy have not been established for any stage of the disease and multiple regimens for therapy currently exist. Numerous reports of treatment failures3·28-31 and data showing that benzathine penicillin does not reach treponemicidal levels within the cerebrospinal 1285
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fluid 32- 35 have raised concerns that the current recommendations of the Centers for Disease Control, Atlanta, 36 may be inadequate, particularly in syphilis complicated by AIDS. 37- 39 We report two cases of concurrent ocular syphilis and HIV infection, one of whom had negative serum and cerebrospinal fluid VORL titers. To date, there have been 14 previous case reports ofHIV-positive young adult patients with concurrent ocular syphilis in the literature. 37 •38•40- 48 In these reports, severe uveitis developed in nine patients, two had necrotizing retinitis, and the other three presented with optic neuritis or retrobulbar neuritis. 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. 37 In view of these reports, we believe, therefore, that all patients with ocular syphilis should now be evaluated for HIV and vice versa. We currently admit all patients with ocular syphilis to the hospital and recommend examination of the cerebrospinal fluid for cells, protein, and serologic values. Because of previous reports of therapeutic failures using intramuscular benzathine penicillin and experimental data suggesting that complete spirochetal sterilization may be impossible unless high dosages and prolonged periods of treatment are used, 34 we treat them with the neurosyphilis regimen of 12 to 24 MU of aqueous crystalline penicillin G intravenously daily for at least 10 days, followed by 2.4 MU benzathine penicillin G intramuscularly weekly for 3 weeks. 8 •38 Although some authors have recommended the use of doxycycline, 39 tetracycline, or erythromycin in the treatment of penicillin-allergic luetics, there is minimal experience using these drugs, and properly controlled studies have not been performed. We prefer instead to have patients proven to be penicillin allergic undergo penicillin desensitization before treating with penicillin. Many patients who give a history of penicillin allergy prove negative when skin-tested for immediate hypersensitivity to penicillin and could be given aqueous crystalline penicillin G under close supervision in the hospital. Close follow-up in collaboration with an infectious disease specialist and repeat serum and cerebrospinal fluid VORL titers to monitor the adequacy of treatment remain essential in these patients.
•
7.
8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
29.
REFERENCES 30. 1. Centers for Disease Control. Summary-cases of specified notifiable diseases United States. MMWR 1989; 37:802. 2. Goldsmith MF. 'Silent epidemic' of 'social disease· makes STD experts raise their voices. JAMA 1989; 261 :3509-10. 3. Spoor TC, Ramocki JM, Nesi FA, Sorscher M. Ocular syphilis 1986. Prevalence of FTA-ABS reactivity and cerebrospinal fluid findings. J Clin Neuro Ophthalmol1986; 7:191-5. 4. Poitevin M, Collar! P, Bolger! M. Syphilis in 1986. J Clin Neuro Ophthalmol1987; 7:11-9. 5. Schlaegel TF Jr, Kao SF. A review (1970-1980) of 28 presumptive cases of syphilitic uveitis. Am J Ophthalmol1982; 93:412-4. 6. Bloch-Michel E, Nussenblatt RB. International uveitis study group rec-
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43. Carter JB, Hamill RJ, Matoba AY. Bilateral syphilitic optic neuritis in a patient with a positive test for HIV. Arch Ophthalmol 1987; 105: 1485-6. 44. Kleiner RC, Najarian L, Levenson J, Kaplan HJ. AIDS complicated by syphilis can mimick uveitis and Crohn's disease [Letter]. Arch Ophthalmol1987; 105:1486-7. 45. Zambrano W, Perez GM, Smith JL. Acute syphilitic blindness in AIDS. J Clin Neuro Ophthalmol1987; 7:1-5. 46. Stoumbos VD, Klein ML. Syphilitic retinitis in a patient with acquired immunodeficiency syndrome-related complex [Letter). Am J Ophthalrnol1987; 103:103-4. 47. Radolf JD, Kaplan RP. Unusual manifestations of secondary syphilis and abnormal humoral immune response to Treponema pallidum antigens in a homosexual man with asymptomatic human immunodeficiency virus infection. JAm Acad Dermatol1988; 18:423-8. 48. Passe MS, Rosenbaum JT. Ocular syphilis in patients with human immunodeficiency virus infection. Am J Ophthalmol1988; 106:1-6.
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