The Ocular Manifestations of Syphilis in the Human Immunodeficiency Virus Type 1-infected Host WILLIAM M. McLEISH, MD,t JOSE S. PULIDO, MD, 2 SIMON HOLLAND, MD,t WILLIAM W. CULBERTSON, MD,t KIRK WINWARD, MD 1
Abstract: Nine patients with active ocular or optic nerve involvement by syphilis who also had concurrent human immunodeficiency virus type-1 (HIV-1) infection are described. The ocular manifestations of syphilis led to the discovery of HIV 1 seropositivity in four of nine cases. Fifteen eyes were affected. Ocular man ifestations were: iridocyclitis in three eyes, vitreitis in one eye, retinitis or neu roretinitis in five eyes, papillitis in two eyes, optic perineuritis in two eyes, and retrobulbar optic neuritis in two eyes. Three patients diagnosed with acquired immune deficiency syndrome (AIDS) had the worst initial visual acuities. Six of nine patients had evidence of concomitant central nervous syndrome (CNS) involvement with syphilis. Benzathine penicillin was administered intramuscularly to three patients. All three had relapses. Seven of nine patients treated intra venously with high-dose penicillin had dramatic responses to therapy with im provement in vision and serologies and no evidence of relapse. Regimens accepted for the treatment of neurosyphilis appear to be adequate for the treatment of ocular syphilis in HIV-1-infected patients though further long-term follow-up will be required. Ophthalmology 1990; 97:196-203
Since its description in 1981, the acquired immune de ficiency syndrome (AIDS) produced by the human im munodeficiency virus type-1 (HIV-1) has been associated with multiple opportunistic infections. 1•2 Additional evOriginally received: July 7, 1989. Revision accepted: August 30, 1989. 1
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami. 2 Department of Ophthalmology, University of Iowa College of Medicine, Iowa City. Presented in part at the meeting of the American Uveitis Society, Las Vegas, Nevada, October 1988 and Association for Research in Vision and Ophthalmology, Sarasota, Florida, May 1989. Supported in part by an unrestricted grant from Research to Prevent Blind· ness, Inc, New York. The authors have no proprietary interest in any drug mentioned. Reprint requests to Jose S. Pulido, MD, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, lA 52242.
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idence has accumulated documenting alteration in the natural history of other infectious illnesses including sal monellosis, tuberculosis, and pneumococcal pneumo nia. 3·4 Recent reports have questioned whether concurrent infection with HIV -1 alters the course and effectiveness ofstandard therapy for syphilis as well.s-? Reports ofocu lar syphilis occurring in HIV-1-infected hosts have been few and have suggested a possible alteration in the pattern of ocular involvement but this has been difficult to sub stantiate.5·8-14 We report our recent experience in treating the ocular manifestations of syphilis in a group of HIV !-infected hosts.
PATIENTS AND METHODS Each of the nine patients in this series were examined by at least one of us at either The University of Miami (8 patients) or The University of Iowa (1 patient) between October 1985 and October 1988. All patients had evidence
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of active ocular or optic nerve inflammatory disease. The diagnosis ofsyphilis was established on the basis of positive treponeme-specific serum serologies (FfA-ABS or MHA TP) and the response to antibiotic therapy. Human im munodeficiency virus type-1 exposure was confirmed by the presence of both a positive serum HIV-1 enzyme linked immunosorbent assay (ELISA) and Western blot assay. After December 1987, patients gave informed con sent before HIV -1 testing. Patients with evidence of pos sible concurrent ocular opportunistic infection (i.e., cy tomegalovirus [CMV] retinitis, cryptococcal meningitis with papilledema, and probable toxoplasma retinitis [2 patients] that responded to toxoplasma antibiotic therapy) at the time of their presentation with syphilis were ex cluded from the series. Case 1 in this series has previously been reported. 13 Follow-up was at least 3 months in seven cases (average, 9.4 months; median, 6 months). Cases 3 and 4 did not return for follow-up and attempts at finding these patients were fruitless. One patient (case 8) died 4 months after initial presentation.
CASE REPORTS Case 4. A 39-year-old black man presented in October 1987 with a !-week history of pain in his left eye. The patient has a history of intravenous drug abuse dating back to 1973. A serum VDRL and FfA-ABS drawn in 1977 were nonreactive. In 1981, the patient was admitted for gastrointestinal bleeding, diffuse adenopathy, and a maculopapular rash on the soles and palms. Serum VDRL was positive at I :32 and the FfA-ABS was 4+ positive. Secondary syphilis with gastrointestinal involvement was diagnosed and the patient was treated with benzathine pen icillin (2.4 MU, intramuscularly [IM]). The patient's condition gradually improved and he was discharged 4 weeks after ad mission. The patient admitted to continued drug abuse and ex posure to prostitutes since 1981. He denied any constitutional symptoms. Results of physical examination showed a visual acuity of20/ 30 in the right eye and 20/100 in the left. The pupils were ir regular in shape and poorly reactive to light. Ocular motility and intraocular pressures (lOPs) were normal. Results of slit lamp examination demonstrated 2+ cell and flare with granu lomatous keratic precipitates and extensive posterior synechiae in both eyes. Results of fundus examination in both eyes were unremarkable. Serologic testing showed a serum VDRL of I: 256, FTA-ABS 4+ positive, and a positive HIV-1 ELISA and Western blot assay. The patient subsequently received benzathine penicillin (4.8 MU, IM) over the course of2 weeks. The patient improved and had 20/20 visual acuity in both eyes with quiet anterior segments on follow-up examination 3 weeks later. In December 1987, tinnitus and a persistent frontal headache developed which became unresponsive to analgesics. Results of a lumbar puncture showed 10 leukocytes/cumm ( 100% mono nuclear), protein of 84 mg/dl, and a positive cerebrospinal fluid (CSF)-VDRL. There were no focal findings on neurologic ex amination. The patient was admitted and received penicillin (120 MU, intravenously [IV]) over a 10-day period. During that time, the patient noted complete relief of symptoms. He was discharged, subsequently failed to return, and is lost to fol low-up.
Case 5. A 34-year-old black, homosexual man presented in November 1987 with a 3-month complaint of irritation and blurred vision in the left eye. He had been treated for syphilis 3 years earlier with IM penicillin after a penile chancre developed. Apparently, the lesion cleared with no further symptoms and he reported limited sexual contact since that time. Several weeks before presentation, the patient was found to have a positive HIV-1 ELISA and Western blot assay. Results of physical examination showed a visual acuity of20/ 20 in the right eye and 20/60 in the left. The pupils reacted briskly without an afferent pupillary defect. Ocular motility and lOPs were normal. Results of slit-lamp examination were re markable for fine keratic precipitates and I+ cell and flare in the left eye. Results of funduscopic examination showed 3+ vitreous cell and a hyperemic optic disc in the left eye. The right eye was normal. Serum FfA-ABS and MHA-TP were positive (serum rapid plasma reagin [RPR] was lost). The patient received benzathine penicillin (2.4 MU, IM) and was started on topical corticosteroids and cycloplegics. One week later, the patient noted dramatic symptomatic relief, and his visual acuity improved to 20/15 in the right eye and 20/30 in the left. The patient was then seen in follow-up 4 months after his initial presentation. At that time, his visual acuity was 20/20 in both eyes. Results of his ocular examination were remarkable only for residual vitreous debris in the left eye. The serum RPR titer was I :8. When seen again at 6 months posttreatment, the patient's titer had risen to I :64. Results of his ocular examination were completely normal and he denied any constitutional symptoms or complaints. His sexual partner had received an tibiotic therapy after discovery of the patient's illness and the patient denied any other sexual contacts. Benzathine penicillin (2.4 MU, IM) was again administered. The patient was lost to follow-up for a period of 5 months. In September 1988, results of his ocular examination were again normal. His serum RPR titer had further risen to 1:128. He again denied any new sexual contacts. The patient refused hospitalization for high-dose IV penicillin therapy because he feared possible disclosure of his HIV -I status and subsequent loss of his insurance coverage. The patient was treated with a 14-day course of oral doxycycline (200 mg daily) without com plication. When seen in follow-up I month later, results of his ocular examination were unremarkable. There had been a four fold reduction in his serum RPR titer to 1:32. When last seen 6 months after therapy, the patient's serum RPR titer remained at I :32. He currently remains symptomless. Case 8. A 46-year-old white, bisexual man was seen in June 1988 complaining of floaters and decreased vision in the right eye for 2.5 weeks. The patient explicitly denied knowledge of previous exposure to syphilis. He denied any constitutional symptoms. His past medical history was unremarkable. Results of his physical examination showed a visual acuity of 20/80 in the right eye and 20/20 in the left. There was a I+ afferent pupillary defect in the right eye as well as a temporal depression on confrontational visual field testing. Ocular motility and lOPs were normal. Results of slit-lamp examination showed trace cell and flare in the right eye. Results of funduscopic ex amination showed 2+ vitreous cell and a large area of necrotizing retinitis with a surrounding serous retinal detachment which extended nasally from the optic disc in the right eye (Fig I). The left fundus only had mild optic disc hyperemia. The initial clinical impression was toxoplasmic retinitis and the patient was begun on minocycline (200 mg daily) pending further laboratory evaluation. Serologic tests subsequently showed a negative serum RPR, positive FfA-ABS, and negative toxoplasma IgM and IgG titers. The serum HIV-1 ELISA was
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Fig 1. Top, montage of the right eye of case 8 which demonstrates the large nasal wedge-shaped area of syphilitic neuroretinitis. Cotton-wool spots also are noted in the macula. Fig 2. Center le.fi, typical maculo papular rash on the soles of the feet ofcase 6 who had secondary syphilis. Center right, pretreatment fundus photograph of case 6 which shows a wedge-shaped area of retinitis. Fig 3. Bottom, disc photograph of case 2 which demonstrates the disc swelling in syphilitic optic perineuritis.
positive for antibody to p24 antigen, whereas the Western blot was reported as negative. The patient was lost to follow-up for 7 weeks at which time he returned complaining of worsening vision in the right eye. He had taken the minocycline only intermittently. Visual acuity in the right eye was now 20/300 and results of funduscopic ex amination showed dense vitreous cellularity which obscured vi sualization of the disc and fundus. Visual acuity in the left eye was 20/20 and results of fundus examination were remarkable for two cotton-wool spots. Results of repeat laboratory studies showed a nonreactive serum RPR, 3+ positive FFA-ABS, un diluted toxoplasmosis titer of 0, negative Lyme IgM, and IgG titers. Serum HIV-1 ELISA was repeatedly reactive and the
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Western blot assay was now positive. The absolute T4 cell count was 158/cumm with a T4/T8 ratio of 0.37. Lumbar puncture demonstrated 10 leukocytes/cumm (90% mononuclear), protein of 44 mg/dl, and a negative CSF VDRL and cryptococcal antigen assay. Cerebrospinal fluid cultures for bacteria and fungi were negative. Cerebrospinal fluid cytology demonstrated only mature lymphocytes. Additional serum and CSF specimens were sent to the Alfred Fournier Institute in Paris for further analysis. Results from the Fournier Institute showed a 2+ positive serum TPI, positive FTA-ABS and MHA-TP, negative FT A-ABS IgM, and VDRL. With the exception of a positive HIV -1 p24 anti body, results of all other CSF studies were negative. The patient was begun on an empiric course of high-dose
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penicillin for suspected syphilitic retinitis. After receiving 144 MU IV over a 10-day period, the patient's visual acuity in the right eye had improved to 20/100 with remarkable clearing of the retinitis ultimately leaving retinal pigment epithelial mottling and atrophy nasal to the disc. There was, as well, a significant diminution of the vitritis. By 21 days after treatment, his visual acuity was 20/25 and stayed at that level until he died 3 months later. Repeat serum RPR testing was negative at 3 and 12 days after penicillin therapy. Twelve days after treatment, the patient was seen by the neu rology service for complaints of left-sided 'weakness. Magnetic resonance imaging demonstrated a large infiltrating mass lesion in the right basal ganglia. Repeat lumbar puncture showed 8 leukocytes/cumm ( 100% mononuclear), protein of 31 mg/dl, and negative CSF VDRL and cytology. One month after his penicillin treatment, the patient was begun on high-dose oral dexameth asone and later underwent a brain biopsy which confirmed the presence of a CNS lymphoma. His visual acuity continued to be 20/25 with clear media. Despite cranial irradiation, the patient died of lymphoma-related complications 2 months after diag nosis. Permission for autopsy was denied.
RESULTS We report on nine patients with a positive HIV serology by ELISA and Western Blot, a positive FTA-ABS or MHA-TP, and ocular involvement by syphilis who re sponded to syphilitic antibiotic therapy. All were men between 23 and 62 years of age. Three met the criteria for AIDS. The risk factors for HIV exposure as well as syphilis exposure were homosexuality /bisexuality and IV drug abuse. Ocular symptoms Jed to the discovery of HIV seropositivity in almost 50% of the cases. The clinical findings and results of treatment are sum marized in Table 1. Cases 4 and 5 in the case reports illustrate patients who were IM benzathine penicillin treatment failures who responded to regimens accepted for neurosyphilis. Case 8 illustrates the problem of fol lowing RPR titers in patients with low T4 levels. Absolute T4 cell counts were done in eight patients; four had counts greater than 200/cumm, and four had less than 200/cumm, with three of these patients having AIDS. There did not appear to be a relation between the degree of T 4 cell depression and the severity of ocular disease with the possible exception of an increased fre quency ofparenchymous optic nerve involvement in those patients with T4 cell counts less than 200/cumm (75 ver sus 25%). Two patients had secondary syphilis at the time of pre sentation, one patient had early latent syphilis, and six patients' syphilis staging could not be defined. Three of these six had been treated for syphilis 3, 6, and 20 years earlier. All patients had a positive serum FTA-ABS. Seven of eight patients had positive serum reagin titers initially ranging from 1:8 to 1:2048. Case 8 had a negative VORL but had a dramatic treatment response to IV penicillin as well as a low T4 count. In general, there was no apparent relation between the severity of the disease and the initial serum reagin.
Fifteen eyes in these nine patients had evidence of ocu lar syphilis. Presenting visual acuity was 20/30 or better in 33% of the involved eyes, 20/40 to 20/100 in 20%, and 20/200 or Jess in 47%. All patients with optic nerve in volvement had 20/200 or less. All patients who had AIDS presented with a visual acuity of 20/200 or less. Iridocy clitis as the only ocular sign was seen in three eyes, vitritis in one eye, retinitis or neuroretinitis in five eyes (Fig 2), papillitis in two eyes, optic perineuritis in two eyes (Fig 3), 15 •16 and retrobulbar optic neuritis in two eyes. Six patients had evidence of neurosyphilis (66%). Three had clinical evidence of acute syphilitic meningitis in cluding one patient (case 7) who refused lumbar puncture. The three other patients had asymptomatic neurosyphilis. Seven of the nine patients consented to lumbar puncture. Of these patients, five had laboratory evidence of neuro syphilis. All five patients had pleocytosis ranging from 10 to 32 mononuclear cells/cumru. Cerebrospinal fluid pro tein was elevated in all five patients. A positive CSF VORL occurred in four of these cases. A sixth patient (case 8) had pleocytosis, but a normal CSF protein level, and neg ative CSF VORL. Because a CNS lymphoma was sub sequently diagnosed in this patient, he is not included in our statistics regarding neurosyphilis. Three patients were treated with at least 2.4 MU ofiM benzathine penicillin, the previously recommended dos age for secondary syphilis. 17 All three failed therapy. Ret initis occurred in case 3, 12 months after IM treatment. Acute syphilitic meningitis occurred in case 4 3 weeks after IM treatment and serologic relapse occurred in case 5 3 months after initial treatment with 2.4 MU IM and again after 5 months following retreatment with a second dose of 2.4 MU IM. Seven of the nine patients, including two who were benzathine penicillin failures, received penicillin G ( 104 240 MU, IV) over 10 to 14 days. All noted a dramatic improvement in their clinical condition. Three of the seven patients were available for follow-up at 6 months or more posttreatment, and they continue to have no ev idence of clinical or serologic relapse. Two patients were lost to follow-up before 3 months (cases 3, 4), another died at 4 months (case 8), and CMV retinitis developed in one patient (case 1) shortly after completion of treat ment for syphilis. Two individuals were treated with a regimen of high dose oral antibiotic which has previously been demon strated to be effective in treating neurosyphilis. 18- 20 Both patients had dramatic clinical response. Their serum re agin titers were reduced fourfold by 2 months after ther apy, and no relapse has occurred with a follow-up of 6 months. Case 9 was treated with amoxicillin (6 g orally daily) and probenecid (2 g orally daily) for a total of 18 days. Case 5 was treated with doxycycline (200 mg orally daily) for 14 days after he refused IV penicillin therapy. Final visual acuities after treatment were excellent with only 2 ( 13%) of 15 eyes not achieving a visual acuity of 20/30 or better within 2 months. The degree of T4 cell count depression did not appear to have an effect on final visual outcome. 199
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Table 1. Clinical Findings and Results of Treatment
Age Case No. (yrs)/Sex
Previous Syphilis Exposure
Clinical Stage of Current Infection
Primary Ocular Manifestations of Current Infection
Neurologic Manifestations of Current Infection
Presenting Serum Titers
Follow-up Serum Titers (reagin)
23/ M
Denied
Undefined
Retrobulbar optic neuritis, OU
Asymptomatic neurosyphilis; CSF VORL(-), pleocytosis(+)*; elevated protein(+)
RPR 1:512 FTA-ABS 4+
RPR 1:8@ 3 mos 1:16 @ 7 mos 1:8@ 17 mos 1:4@ 34 mos
2
26/ M
Denied
Undefined
Optic perineuritis,
Acute syphilitic meningitis; elevated protein(+), CSF VORL 1:2, pleocytosis(+)
RPR 1:64 FTA-ABS 4+
RPR 1:32@ 1 mo 1:8@ 6 mos
3
23/M
Secondary, 1986
Early latent or relapse
Neuroretinitis, OD; anterior uveitis, OU
Asymptomatic neurosyphilis, elevated proteins(±), CSF VORL 1:4, pleocytosis(+)
RPR 1:512 FTA-ABS 4+
Lost to follow-up
4
39/ M
Anterior uveitis, Secondary, Relapse or ou reinfection 1981
Acute syphilitic meningitis; elevated protein(+); CSF VORL(+), pleocytosis(+)
VORL 1:256
Lost to follow-up
Asymptomatic; refused LP
RPR-Iost FTA-ABS(+)
RPR 1:8@ 3 mos 1:64 @ 5 mos 1:128@ 10 most 1:32@ 1 most 1:32 @ 6 mos§
ou
FTA-ABS 4+
5
34/M
Primary, 1984
Vitreitis, OS Relapse or reinfection
6
30/M
Denied
Secondary
Retinitis, OU
Asymptomatic; negative LP
VORL 1:128 FTA-ABS(+ )
VORL 1:16@ 5 mos 1:2@8mos
7
34/M
Denied
Secondary
Papillitis, OU
Acute syphilitic refused LP
VORL 1:32 FTA-ABS 4+
VORL 1:32 @ 1 mos 1:4@ 3 mos
8
46/M
Denied
Undefined
Neuroretinitis, OD
Elevated protein(-); CSF VORL(-) , pleocytosis(+); CNS lymphoma
RPR Nonreactive VORL nonreactive @ 3 mos FTA-ABS 4+ RPR nonreactive @ 3 mos
9
62/ M
Undefined
Abstract: Nine patients with active ocular or optic nerve involvement by syphilis who also had concurrent human immunodeficiency virus type-1 (HIV-1) infection are described. The ocular manifestations of syphilis led to the discovery of HIV 1 seropositivity in four of nine cases. Fifteen eyes were affected. Ocular man ifestations were: iridocyclitis in three eyes, vitreitis in one eye, retinitis or neu roretinitis in five eyes, papillitis in two eyes, optic perineuritis in two eyes, and retrobulbar optic neuritis in two eyes. Three patients diagnosed with acquired immune deficiency syndrome (AIDS) had the worst initial visual acuities. Six of nine patients had evidence of concomitant central nervous syndrome (CNS) involvement with syphilis. Benzathine penicillin was administered intramuscularly to three patients. All three had relapses. Seven of nine patients treated intra venously with high-dose penicillin had dramatic responses to therapy with im provement in vision and serologies and no evidence of relapse. Regimens accepted for the treatment of neurosyphilis appear to be adequate for the treatment of ocular syphilis in HIV-1-infected patients though further long-term follow-up will be required. Ophthalmology 1990; 97:196-203
Since its description in 1981, the acquired immune de ficiency syndrome (AIDS) produced by the human im munodeficiency virus type-1 (HIV-1) has been associated with multiple opportunistic infections. 1•2 Additional evOriginally received: July 7, 1989. Revision accepted: August 30, 1989. 1
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami. 2 Department of Ophthalmology, University of Iowa College of Medicine, Iowa City. Presented in part at the meeting of the American Uveitis Society, Las Vegas, Nevada, October 1988 and Association for Research in Vision and Ophthalmology, Sarasota, Florida, May 1989. Supported in part by an unrestricted grant from Research to Prevent Blind· ness, Inc, New York. The authors have no proprietary interest in any drug mentioned. Reprint requests to Jose S. Pulido, MD, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, lA 52242.
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idence has accumulated documenting alteration in the natural history of other infectious illnesses including sal monellosis, tuberculosis, and pneumococcal pneumo nia. 3·4 Recent reports have questioned whether concurrent infection with HIV -1 alters the course and effectiveness ofstandard therapy for syphilis as well.s-? Reports ofocu lar syphilis occurring in HIV-1-infected hosts have been few and have suggested a possible alteration in the pattern of ocular involvement but this has been difficult to sub stantiate.5·8-14 We report our recent experience in treating the ocular manifestations of syphilis in a group of HIV !-infected hosts.
PATIENTS AND METHODS Each of the nine patients in this series were examined by at least one of us at either The University of Miami (8 patients) or The University of Iowa (1 patient) between October 1985 and October 1988. All patients had evidence
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of active ocular or optic nerve inflammatory disease. The diagnosis ofsyphilis was established on the basis of positive treponeme-specific serum serologies (FfA-ABS or MHA TP) and the response to antibiotic therapy. Human im munodeficiency virus type-1 exposure was confirmed by the presence of both a positive serum HIV-1 enzyme linked immunosorbent assay (ELISA) and Western blot assay. After December 1987, patients gave informed con sent before HIV -1 testing. Patients with evidence of pos sible concurrent ocular opportunistic infection (i.e., cy tomegalovirus [CMV] retinitis, cryptococcal meningitis with papilledema, and probable toxoplasma retinitis [2 patients] that responded to toxoplasma antibiotic therapy) at the time of their presentation with syphilis were ex cluded from the series. Case 1 in this series has previously been reported. 13 Follow-up was at least 3 months in seven cases (average, 9.4 months; median, 6 months). Cases 3 and 4 did not return for follow-up and attempts at finding these patients were fruitless. One patient (case 8) died 4 months after initial presentation.
CASE REPORTS Case 4. A 39-year-old black man presented in October 1987 with a !-week history of pain in his left eye. The patient has a history of intravenous drug abuse dating back to 1973. A serum VDRL and FfA-ABS drawn in 1977 were nonreactive. In 1981, the patient was admitted for gastrointestinal bleeding, diffuse adenopathy, and a maculopapular rash on the soles and palms. Serum VDRL was positive at I :32 and the FfA-ABS was 4+ positive. Secondary syphilis with gastrointestinal involvement was diagnosed and the patient was treated with benzathine pen icillin (2.4 MU, intramuscularly [IM]). The patient's condition gradually improved and he was discharged 4 weeks after ad mission. The patient admitted to continued drug abuse and ex posure to prostitutes since 1981. He denied any constitutional symptoms. Results of physical examination showed a visual acuity of20/ 30 in the right eye and 20/100 in the left. The pupils were ir regular in shape and poorly reactive to light. Ocular motility and intraocular pressures (lOPs) were normal. Results of slit lamp examination demonstrated 2+ cell and flare with granu lomatous keratic precipitates and extensive posterior synechiae in both eyes. Results of fundus examination in both eyes were unremarkable. Serologic testing showed a serum VDRL of I: 256, FTA-ABS 4+ positive, and a positive HIV-1 ELISA and Western blot assay. The patient subsequently received benzathine penicillin (4.8 MU, IM) over the course of2 weeks. The patient improved and had 20/20 visual acuity in both eyes with quiet anterior segments on follow-up examination 3 weeks later. In December 1987, tinnitus and a persistent frontal headache developed which became unresponsive to analgesics. Results of a lumbar puncture showed 10 leukocytes/cumm ( 100% mono nuclear), protein of 84 mg/dl, and a positive cerebrospinal fluid (CSF)-VDRL. There were no focal findings on neurologic ex amination. The patient was admitted and received penicillin (120 MU, intravenously [IV]) over a 10-day period. During that time, the patient noted complete relief of symptoms. He was discharged, subsequently failed to return, and is lost to fol low-up.
Case 5. A 34-year-old black, homosexual man presented in November 1987 with a 3-month complaint of irritation and blurred vision in the left eye. He had been treated for syphilis 3 years earlier with IM penicillin after a penile chancre developed. Apparently, the lesion cleared with no further symptoms and he reported limited sexual contact since that time. Several weeks before presentation, the patient was found to have a positive HIV-1 ELISA and Western blot assay. Results of physical examination showed a visual acuity of20/ 20 in the right eye and 20/60 in the left. The pupils reacted briskly without an afferent pupillary defect. Ocular motility and lOPs were normal. Results of slit-lamp examination were re markable for fine keratic precipitates and I+ cell and flare in the left eye. Results of funduscopic examination showed 3+ vitreous cell and a hyperemic optic disc in the left eye. The right eye was normal. Serum FfA-ABS and MHA-TP were positive (serum rapid plasma reagin [RPR] was lost). The patient received benzathine penicillin (2.4 MU, IM) and was started on topical corticosteroids and cycloplegics. One week later, the patient noted dramatic symptomatic relief, and his visual acuity improved to 20/15 in the right eye and 20/30 in the left. The patient was then seen in follow-up 4 months after his initial presentation. At that time, his visual acuity was 20/20 in both eyes. Results of his ocular examination were remarkable only for residual vitreous debris in the left eye. The serum RPR titer was I :8. When seen again at 6 months posttreatment, the patient's titer had risen to I :64. Results of his ocular examination were completely normal and he denied any constitutional symptoms or complaints. His sexual partner had received an tibiotic therapy after discovery of the patient's illness and the patient denied any other sexual contacts. Benzathine penicillin (2.4 MU, IM) was again administered. The patient was lost to follow-up for a period of 5 months. In September 1988, results of his ocular examination were again normal. His serum RPR titer had further risen to 1:128. He again denied any new sexual contacts. The patient refused hospitalization for high-dose IV penicillin therapy because he feared possible disclosure of his HIV -I status and subsequent loss of his insurance coverage. The patient was treated with a 14-day course of oral doxycycline (200 mg daily) without com plication. When seen in follow-up I month later, results of his ocular examination were unremarkable. There had been a four fold reduction in his serum RPR titer to 1:32. When last seen 6 months after therapy, the patient's serum RPR titer remained at I :32. He currently remains symptomless. Case 8. A 46-year-old white, bisexual man was seen in June 1988 complaining of floaters and decreased vision in the right eye for 2.5 weeks. The patient explicitly denied knowledge of previous exposure to syphilis. He denied any constitutional symptoms. His past medical history was unremarkable. Results of his physical examination showed a visual acuity of 20/80 in the right eye and 20/20 in the left. There was a I+ afferent pupillary defect in the right eye as well as a temporal depression on confrontational visual field testing. Ocular motility and lOPs were normal. Results of slit-lamp examination showed trace cell and flare in the right eye. Results of funduscopic ex amination showed 2+ vitreous cell and a large area of necrotizing retinitis with a surrounding serous retinal detachment which extended nasally from the optic disc in the right eye (Fig I). The left fundus only had mild optic disc hyperemia. The initial clinical impression was toxoplasmic retinitis and the patient was begun on minocycline (200 mg daily) pending further laboratory evaluation. Serologic tests subsequently showed a negative serum RPR, positive FfA-ABS, and negative toxoplasma IgM and IgG titers. The serum HIV-1 ELISA was
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Fig 1. Top, montage of the right eye of case 8 which demonstrates the large nasal wedge-shaped area of syphilitic neuroretinitis. Cotton-wool spots also are noted in the macula. Fig 2. Center le.fi, typical maculo papular rash on the soles of the feet ofcase 6 who had secondary syphilis. Center right, pretreatment fundus photograph of case 6 which shows a wedge-shaped area of retinitis. Fig 3. Bottom, disc photograph of case 2 which demonstrates the disc swelling in syphilitic optic perineuritis.
positive for antibody to p24 antigen, whereas the Western blot was reported as negative. The patient was lost to follow-up for 7 weeks at which time he returned complaining of worsening vision in the right eye. He had taken the minocycline only intermittently. Visual acuity in the right eye was now 20/300 and results of funduscopic ex amination showed dense vitreous cellularity which obscured vi sualization of the disc and fundus. Visual acuity in the left eye was 20/20 and results of fundus examination were remarkable for two cotton-wool spots. Results of repeat laboratory studies showed a nonreactive serum RPR, 3+ positive FFA-ABS, un diluted toxoplasmosis titer of 0, negative Lyme IgM, and IgG titers. Serum HIV-1 ELISA was repeatedly reactive and the
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Western blot assay was now positive. The absolute T4 cell count was 158/cumm with a T4/T8 ratio of 0.37. Lumbar puncture demonstrated 10 leukocytes/cumm (90% mononuclear), protein of 44 mg/dl, and a negative CSF VDRL and cryptococcal antigen assay. Cerebrospinal fluid cultures for bacteria and fungi were negative. Cerebrospinal fluid cytology demonstrated only mature lymphocytes. Additional serum and CSF specimens were sent to the Alfred Fournier Institute in Paris for further analysis. Results from the Fournier Institute showed a 2+ positive serum TPI, positive FTA-ABS and MHA-TP, negative FT A-ABS IgM, and VDRL. With the exception of a positive HIV -1 p24 anti body, results of all other CSF studies were negative. The patient was begun on an empiric course of high-dose
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OCULAR SYPHILIS IN HIV-1 PATIENTS
penicillin for suspected syphilitic retinitis. After receiving 144 MU IV over a 10-day period, the patient's visual acuity in the right eye had improved to 20/100 with remarkable clearing of the retinitis ultimately leaving retinal pigment epithelial mottling and atrophy nasal to the disc. There was, as well, a significant diminution of the vitritis. By 21 days after treatment, his visual acuity was 20/25 and stayed at that level until he died 3 months later. Repeat serum RPR testing was negative at 3 and 12 days after penicillin therapy. Twelve days after treatment, the patient was seen by the neu rology service for complaints of left-sided 'weakness. Magnetic resonance imaging demonstrated a large infiltrating mass lesion in the right basal ganglia. Repeat lumbar puncture showed 8 leukocytes/cumm ( 100% mononuclear), protein of 31 mg/dl, and negative CSF VDRL and cytology. One month after his penicillin treatment, the patient was begun on high-dose oral dexameth asone and later underwent a brain biopsy which confirmed the presence of a CNS lymphoma. His visual acuity continued to be 20/25 with clear media. Despite cranial irradiation, the patient died of lymphoma-related complications 2 months after diag nosis. Permission for autopsy was denied.
RESULTS We report on nine patients with a positive HIV serology by ELISA and Western Blot, a positive FTA-ABS or MHA-TP, and ocular involvement by syphilis who re sponded to syphilitic antibiotic therapy. All were men between 23 and 62 years of age. Three met the criteria for AIDS. The risk factors for HIV exposure as well as syphilis exposure were homosexuality /bisexuality and IV drug abuse. Ocular symptoms Jed to the discovery of HIV seropositivity in almost 50% of the cases. The clinical findings and results of treatment are sum marized in Table 1. Cases 4 and 5 in the case reports illustrate patients who were IM benzathine penicillin treatment failures who responded to regimens accepted for neurosyphilis. Case 8 illustrates the problem of fol lowing RPR titers in patients with low T4 levels. Absolute T4 cell counts were done in eight patients; four had counts greater than 200/cumm, and four had less than 200/cumm, with three of these patients having AIDS. There did not appear to be a relation between the degree of T 4 cell depression and the severity of ocular disease with the possible exception of an increased fre quency ofparenchymous optic nerve involvement in those patients with T4 cell counts less than 200/cumm (75 ver sus 25%). Two patients had secondary syphilis at the time of pre sentation, one patient had early latent syphilis, and six patients' syphilis staging could not be defined. Three of these six had been treated for syphilis 3, 6, and 20 years earlier. All patients had a positive serum FTA-ABS. Seven of eight patients had positive serum reagin titers initially ranging from 1:8 to 1:2048. Case 8 had a negative VORL but had a dramatic treatment response to IV penicillin as well as a low T4 count. In general, there was no apparent relation between the severity of the disease and the initial serum reagin.
Fifteen eyes in these nine patients had evidence of ocu lar syphilis. Presenting visual acuity was 20/30 or better in 33% of the involved eyes, 20/40 to 20/100 in 20%, and 20/200 or Jess in 47%. All patients with optic nerve in volvement had 20/200 or less. All patients who had AIDS presented with a visual acuity of 20/200 or less. Iridocy clitis as the only ocular sign was seen in three eyes, vitritis in one eye, retinitis or neuroretinitis in five eyes (Fig 2), papillitis in two eyes, optic perineuritis in two eyes (Fig 3), 15 •16 and retrobulbar optic neuritis in two eyes. Six patients had evidence of neurosyphilis (66%). Three had clinical evidence of acute syphilitic meningitis in cluding one patient (case 7) who refused lumbar puncture. The three other patients had asymptomatic neurosyphilis. Seven of the nine patients consented to lumbar puncture. Of these patients, five had laboratory evidence of neuro syphilis. All five patients had pleocytosis ranging from 10 to 32 mononuclear cells/cumru. Cerebrospinal fluid pro tein was elevated in all five patients. A positive CSF VORL occurred in four of these cases. A sixth patient (case 8) had pleocytosis, but a normal CSF protein level, and neg ative CSF VORL. Because a CNS lymphoma was sub sequently diagnosed in this patient, he is not included in our statistics regarding neurosyphilis. Three patients were treated with at least 2.4 MU ofiM benzathine penicillin, the previously recommended dos age for secondary syphilis. 17 All three failed therapy. Ret initis occurred in case 3, 12 months after IM treatment. Acute syphilitic meningitis occurred in case 4 3 weeks after IM treatment and serologic relapse occurred in case 5 3 months after initial treatment with 2.4 MU IM and again after 5 months following retreatment with a second dose of 2.4 MU IM. Seven of the nine patients, including two who were benzathine penicillin failures, received penicillin G ( 104 240 MU, IV) over 10 to 14 days. All noted a dramatic improvement in their clinical condition. Three of the seven patients were available for follow-up at 6 months or more posttreatment, and they continue to have no ev idence of clinical or serologic relapse. Two patients were lost to follow-up before 3 months (cases 3, 4), another died at 4 months (case 8), and CMV retinitis developed in one patient (case 1) shortly after completion of treat ment for syphilis. Two individuals were treated with a regimen of high dose oral antibiotic which has previously been demon strated to be effective in treating neurosyphilis. 18- 20 Both patients had dramatic clinical response. Their serum re agin titers were reduced fourfold by 2 months after ther apy, and no relapse has occurred with a follow-up of 6 months. Case 9 was treated with amoxicillin (6 g orally daily) and probenecid (2 g orally daily) for a total of 18 days. Case 5 was treated with doxycycline (200 mg orally daily) for 14 days after he refused IV penicillin therapy. Final visual acuities after treatment were excellent with only 2 ( 13%) of 15 eyes not achieving a visual acuity of 20/30 or better within 2 months. The degree of T4 cell count depression did not appear to have an effect on final visual outcome. 199
OPHTHALMOLOGY
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FEBRUARY 1990
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VOLUME 97
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NUMBER 2
Table 1. Clinical Findings and Results of Treatment
Age Case No. (yrs)/Sex
Previous Syphilis Exposure
Clinical Stage of Current Infection
Primary Ocular Manifestations of Current Infection
Neurologic Manifestations of Current Infection
Presenting Serum Titers
Follow-up Serum Titers (reagin)
23/ M
Denied
Undefined
Retrobulbar optic neuritis, OU
Asymptomatic neurosyphilis; CSF VORL(-), pleocytosis(+)*; elevated protein(+)
RPR 1:512 FTA-ABS 4+
RPR 1:8@ 3 mos 1:16 @ 7 mos 1:8@ 17 mos 1:4@ 34 mos
2
26/ M
Denied
Undefined
Optic perineuritis,
Acute syphilitic meningitis; elevated protein(+), CSF VORL 1:2, pleocytosis(+)
RPR 1:64 FTA-ABS 4+
RPR 1:32@ 1 mo 1:8@ 6 mos
3
23/M
Secondary, 1986
Early latent or relapse
Neuroretinitis, OD; anterior uveitis, OU
Asymptomatic neurosyphilis, elevated proteins(±), CSF VORL 1:4, pleocytosis(+)
RPR 1:512 FTA-ABS 4+
Lost to follow-up
4
39/ M
Anterior uveitis, Secondary, Relapse or ou reinfection 1981
Acute syphilitic meningitis; elevated protein(+); CSF VORL(+), pleocytosis(+)
VORL 1:256
Lost to follow-up
Asymptomatic; refused LP
RPR-Iost FTA-ABS(+)
RPR 1:8@ 3 mos 1:64 @ 5 mos 1:128@ 10 most 1:32@ 1 most 1:32 @ 6 mos§
ou
FTA-ABS 4+
5
34/M
Primary, 1984
Vitreitis, OS Relapse or reinfection
6
30/M
Denied
Secondary
Retinitis, OU
Asymptomatic; negative LP
VORL 1:128 FTA-ABS(+ )
VORL 1:16@ 5 mos 1:2@8mos
7
34/M
Denied
Secondary
Papillitis, OU
Acute syphilitic refused LP
VORL 1:32 FTA-ABS 4+
VORL 1:32 @ 1 mos 1:4@ 3 mos
8
46/M
Denied
Undefined
Neuroretinitis, OD
Elevated protein(-); CSF VORL(-) , pleocytosis(+); CNS lymphoma
RPR Nonreactive VORL nonreactive @ 3 mos FTA-ABS 4+ RPR nonreactive @ 3 mos
9
62/ M
Undefined
