Ocular Toxoplasmosis in Human Immunodeficiency Virus-infected Patients Isabelle Cochereau-Massin, M.D., Phuc LeHoang, Ph.D., Marie Lautier-Frau, M.D., Edith Zerdoun, M.D., Lydie Zazoun, M.D., Martin Robinet, M.D., Patricia Marcel, M.D., Brigitte Girard, M.D., Christine Katlama, M.D., Catherine Leport, M.D., Willy Rozenbaum, M.D., Jean Pierre Coulaud, M.D., and Marc Gentilini, M.D.
The files of 45 human immunodeficiency virus-infected patients with ocular toxoplasmosis were reviewed, with a median followup of eight months. The condition was unilateral in 37 of the 45 patients (82%) and was bilateral in eight (18%). Inflammation of the anterior chamber and the vitreous was present in 32 of 53 eyes (60%) and 38 of 53 eyes (72%), respectively. Cytomegalovirus retinitis developed during the follow-up period in nine patients (20%). Cerebral toxoplasmosis was concurrently diagnosed with the ocular toxoplasmosis in 13 patients (29%). The efficacy of the combination of pyrimethamine and sulfadiazine or clindamycin was assessed in 42 patients for the induction therapy and in 38 patients for the maintenance therapy. Induction therapy was always effective within a median period of six weeks. During maintenance treatment, the 24-month relapse rates were 0.20 and 0.18 for the 50-mg/day and 25-mg/day dosage of pyrimethamine, respectively. The overall 12-month survival rate was 0.72. Our results suggested that ocular toxoplasmosis has a better ocular prognosis than cytomegalovirus retinitis, but that it requires appropriate treatment because life-threatening cerebral involvement is often associated.
XOXOPLASMOSIS is an opportunistic ocular in fection in patients infected by the human im munodeficiency virus (HIV). The diagnosis is usually based on clinical criteria and confirmed by therapeutic efficacy. Unlike ocular toxoplasmosis in immunocompetent individuals, the retinal lesions in pa tients with acquired immunodeficiency syn drome (AIDS) are extensive and can cause visual impairment if left untreated.1"1 The infec tion can be generalized, involving the brain, eyes, lungs, heart, digestive tract, lymph nodes, liver, spleen, and bone marrow.6 Cerebral toxo plasmosis is the most common cerebral infec tion in AIDS6 and requires urgent treatment because it can be rapidly fatal. The prevalence of toxoplasmosis varies ac cording to dietary habits and, therefore, from country to country. The prevalence in adults in the United States has been estimated at 15% to 68%,7 compared to 50% to 80% in French adults.8 Experience with ocular toxoplasmosis in HIV-infected patients is limited.1"4'911 We studied the findings in 45 HIV-infected patients with toxoplasmosis, involving a total of 53 eyes.
Subjects and Methods Accepted for publication May 4, 1992. From the Service d'Ophtalmologie, Hôpital PitiéSalpêtrière (Drs. Cochereau-Massin, LeHoang, LautierFrau, Zerdoun, Zazoun, Robinet, Marcel, and Girard); Service des Maladies Infectieuses, Hôpital PitiéSalpêtrière (Dr. Katlama and Gentilini); Services des Maladies Infectieuses, Hôpital Claude Bernard (Drs. Leport and Coulaud); and Service des Maladies In fectieuses, Hôpital Rothschild (Dr. Rozenbaum), Paris, France. Reprint requests to Phuc LeHoang, Ph.D., Service d'Ophtalmologie, Hôpital Pitié-Salpêtrière, 83 Boule vard de l'Hôpital, 75 013, Paris, France.
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The patients in our study were referred to the Ophthalmology Department of the Hôpital Pitié-Salpêtrière between 1983 and 1990. Serologie status for anti-HIV antibodies was determined by means of an enzyme-linked immunosorbent assay (ELISA), and confirmed by Western blot analysis. Acquired immunodefi ciency syndrome was diagnosed according to the Centers for Disease Control criteria.12 Toxoplasmic retinitis was diagnosed on the
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basis of clinical findings. Patient examinations included determination of visual acuity in pa tients who were cooperative, biomicroscopy of the anterior and posterior segments, indirect ophthalmoscopy with fundus drawings, and serial fundus photography and fluorescein angiography if necessary. All the patients were examined by a member of the AIDS team of our department. Cerebral toxoplasmosis was diag nosed on the basis of consistent neurologic findings and computed tomography of the brain. Active toxoplasmic lesions consisted of yel low-white, edematous areas of necrotizing retinitis. The lesions had fluffy borders, few scat tered intraretinal hemorrhages, and occasional vascular sheathing. It was usually accompanied by overlying vitreal inflammation, ranging from mild localized vitreal haze to extensive dense vitreous inflammation reaction. The le sions were homogeneous, without peripheral proliferation or healed center as in cytomegalovirus retinitis. Inactive lesions consisted of atrophie choroid and retina, with epitheli al pigment clumping and occasional vitreal strands. Fluorescein angiography showed early blockage of the lesions, followed by hyperfluorescence that started from the borders and pro gressed toward the center of the lesion. The final lesion on late phases of the angiogram was bigger than the lesion seen on the green-free photograph. The posterior pole was determined as the area defined by and including the vascular arcades, and the periphery was determined as the area outside the vascular arcades. Visual acuity was determined at initial examination and at the last consultation. The involvement of other organs was detected by clinical examina tion, brain computed tomography, and other tests if required (computed tomography, endoscopy, and biopsy). Serologie diagnosis was made using ELISA on serum and aqueous humor samples. The coefficient of Desmonts, 13 calculated using the titers of specific antibodies and total immunoglobulins in serum and aqueous humor, was considered positive when it was greater than 5. All lesions were treated, whether they were sight-threatening. Treatment consisted of the combination of pyrimethamine with either sulfadiazine or clindamycin administered orally. Folinic acid was administered in every case. Like other opportunistic infections in AIDS, toxoplasmosis recurs when therapy is discon tinued 7 · 14 ; treatment therefore consisted of the
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two following phases: an induction regimen to obtain complete healing of the retinochoroidal toxoplasmic lesions, followed by a maintenance regimen. The daily dosages in the induction phase were 50 mg of pyrimethamine, 4 to 6 g of sulfadiazine, and 2.4 g of clindamycin. Mainte nance therapy consisted of 25 or 50 mg of pyrimethamine/day, combined with sulfadia zine or clindamycin given at half dosages, or less, according to the patient's tolerance. Main tenance therapy was continued for as long as possible. Corticosteroids were not used. The cumulative relapse and survival rates were cal culated using the survival method. 15
Results Of 1,761 HIV-infected patients examined in the Department of Ophthalmology, 57 (3%) had ocular toxoplasmosis at initial examina tion; the records were available for review in 45 cases. Of these 45 patients, 41 (91%) were men and four (9%) were women, with a mean age of 39 years (range, 24 to 72 years). Thirty-eight (85%) patients were homosexual, five (11%) were intravenous drug abusers, one (2%) had been contaminated by a blood transfusion, and one woman (2%) was the sexual partner of a seropositive man. The median follow-up was eight months (range, one to 40 months). Thirtyfour of the 45 patients (76%) had AIDS. The median time between the diagnosis of AIDS and that of ocular toxoplasmosis was five months (range, zero to 33 months). Ocular toxoplasmosis was the first opportunistic infec tion in the 11 patients without AIDS and pre ceded the serologie diagnosis of HIV infection in five patients. Ocular toxoplasmosis was unilateral in 37 patients (82%) and bilateral in eight patients (18%), for a total of 53 eyes. Vitreitis was present in 38 eyes (72%). In flammation of the anterior segment (character ized by keratic precipitates and anterior flare) was present in 32 eyes (60%). A retinochoroidal scar was present in two eyes (4%) and retinal detachment in one eye (2%). The retinal lesions were unifocal in 44 of the 53 eyes (83%). Eight of the remaining nine eyes had two foci, and one had four, giving a total of 64 toxoplasmic retinal foci. Thirty-three of these 64 lesions (52%) involved the posterior pole and 31 (48%) involved the periphery. The
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areas of necrosis ranged in size, with one third less than or equal to 2 disk diameters, one third more than 5 disk diameters, and the remaining third of intermediate size. The serum antibody titer against Toxoplasma gondii was determined in 26 patients, all of whom had reactive IgG antibodies (range, 1:8 to 1:12,800). Immunoglobulin M antibodies were present in three patients. Desmonts' coef ficient was positive for the aqueous humor of only one of the ten patients tested. The efficacy of induction treatment was as sessed in 42 of the 45 patients (93%). All the retinal lesions healed after a median time inter val of six weeks (range, three to 20 weeks) and the visual acuity improved in most cases (Fig. 1). Initially, 37 patients were treated with pyrimethamine-sulfadiazine, and five were treated with pyrimethamine-clindamycin. Eleven pa tients initially treated with pyrimethamine-sulfadiazine (30%) had to change to pyrimeth amine-clindamycin because of severe side effects. Evaluation of maintenance therapy was pos sible in 38 of the 53 patients (84%). Twenty patients (53%) were treated with pyrimethamine at 25 mg/day and 18 patients (47%) were treated with pyrimethamine at 50 mg/day. Sulfadiazine or clindamycin efficacy could not be accurately evaluated because of the variety of the treatment regimens. The 24-month relapse rate was 0.18 for the 25-mg dosage of pyrimeth amine and 0.20 for the 50-mg dosage (Fig. 2). Most of the relapses developed within six months of the initial diagnosis. Cytomegalovirus retinitis developed in nine patients (20%) during the follow-up period. One patient (2%) had a history of cytomegalo virus retinitis. Ocular toxoplasmosis was diag-
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20/50
20/30
TOXOPLASMOSIS TOXOPLASMOSIS + CMV
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INITIAL VISUAL ACUITY
Fig. 1 (Cochereau-Massin and associates). Initial and final visual acuity in ocular toxoplasmosis. CMV indicates cytomegalovirus retinitis.
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DURATION OF THERAPY (MONTHS)
Fig. 2 (Cochereau-Massin and associates). Relapse rate of ocular toxoplasmosis on maintenance therapy (pyrimethamine, 25 or 50 mg/day).
nosed at the same time as ocular toxoplasmosis in four patients (9%). A cerebral localization of toxoplasmosis was concurrently found in 13 patients (29%). Four patients (9%) h a d a previ ous diagnosis of cerebral toxoplasmosis and four patients (9%) developed a cerebral locali zation later in the course of the disease. The overall 12-month survival rate among the patients with ocular toxoplasmosis was 0.72 (Fig. 3).
Discussion Ocular toxoplasmosis is one of the most com mon infectious causes of retinitis in young immunocompetent subjects. It is characterized by areas of necrotizing retinitis, vitreitis, and inflammation of the anterior segment, which usually resolve spontaneously but often leave pigmented chorioretinal scars. This form of retinitis is attributed to the reactivation of con genital retinal cysts. The initial infection is thought to occur in utero. When a pregnant woman acquires the disease, the risk of vertical transmission is about 40%. 16 The course of ocular toxoplasmosis in immunocompromised hosts is complex, 217,18 depends on the extent of immunosuppression, and can ultimately lead to blindness.1"4·19·20 It can devel op from the reactivation of congenital retinal cysts, newly acquired disease, or from T. gondii newly disseminated to the eye from nonocular disease sites. 9 Impaired cell-mediated immuni ty is an important determinant of reactivation, but other factors probably exist.21 Ocular toxoplasmosis is uncommon com-
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DURATION (MONTHS) Fig. 3 (Cochereau-Massin and associates). Survival rate of patients with ocular toxoplasmosis. pared to cytomegalovirus retinitis (20% of pa tients with AIDS). It can develop in patients with AIDS-related complexes, 1 because it is not a criterion of AIDS. In our experience, it is the second most common retinal infection in AIDS (Cochereau-Massin and associates, unpub lished data, 1990). Our study, although retro spective, provided information on the clinical characteristics, treatment, and prognosis of the disease in AIDS. Ocular toxoplasmosis is the main differential diagnosis in patients with suspected cytomega lovirus retinitis. 11 Clinical features are impor tant for diagnosis. The main difference with cytomegalovirus retinitis is the inflammation of the vitreous and of the aqueous. Vitreitis can range from mild vitreal haze overlying the retinal lesions to extensive dense vitreitis that precludes visualization of the fundus. The reti nal necrotic areas are different from cytomega lovirus lesions, being more fluffy and edematous, generally nonhemorrhagic, and having hazy edges. On angiography, fluorescence starts from the edges of the lesion and progress es to the center. The final area of hyperfluorescence is larger than that of the initial lesion on green-free photographs. In contrast, cytomega lovirus retinitis usually shows hyperfluorescence that starts at the center of the lesion and extends toward the borders. The final hyperfluorescent area of cytomegalovirus retinitis re mains smaller than the lesion observed on green-free photographs. Ocular toxoplasmosis can sometimes manifest as an acute syndrome that resembles retinal necrosis. 2 Most toxoplasmic retinal lesions in AIDS are unifocal and are located in the posterior pole. The areas vary according to the time of diagno
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sis. If untreated, the lesions progressively in vade and destroy the whole retina. If treated, the involvement often remains unilateral. Path ologic studies have shown that the retinal ne crosis is extensive and involves all the layers of the retina, although choroidal inflammation is slight. Trophozoites have been found in the retina and choroid. 9 Serologie tests are not helpful in making the diagnosis. Serum IgG antibodies are usually present at variable levels, attesting to a previ ous primary infection. Some patients have IgM, indicative of a newly acquired infection. The aqueous coefficient is not helpful because it was positive in only 10% of our initial cases. We therefore no longer perform anterior chamber puncture. The poor contribution of serologie studies to the diagnosis could be explained in part by perturbations caused by the severe immunodeficiency in AIDS.22 The isolation of the parasite at the site of infection would thus be helpful. By inoculation to mice, T. gondii has been found in the vitreous of patients with AIDS who have ocular toxoplasmosis, 3 whereas cytologie examination is fruitless. 2 The polymerase chain reaction can be used to detect the T. gondii genome in paraffin-embedded sec tions of retina of immunocompetent patients with ocular toxoplasmosis. 23 This new method is still under evaluation for application to the vitreous and aqueous humor of patients with AIDS. In AIDS, although one third of patients with ocular toxoplasmosis develop cytomegalovirus retinitis, cytomegalovirus retinitis does not ap pear to be more common in patients with ocular toxoplasmosis. Ocular toxoplasmosis is less common than cerebral toxoplasmosis, 24,26 which has been found in up to 40% of autopsy cases.26 This might be related to the smaller mass of neural tissue in the eyes. Cerebral toxoplasmosis was associated with ocular toxoplasmosis in 13 of 65 patients (29%). This association may have been underestimated in our study because brain computed tomography was not systemati cally performed when no neurologic sign was present. Cerebral computed tomography is therefore mandatory when ocular toxoplasmo sis is diagnosed and ophthalmoscopy is manda tory when cerebral toxoplasmosis is diagnosed. Contrary to the situation in healthy individu als, ocular toxoplasmosis in AIDS probably results not only from the reactivation of con genital toxoplasmosis, but also from the dis semination of reactivated nonocular toxo plasmic foci acquired during infancy. 9 This
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hypothesis is supported by the isolation of T. gondii from the blood of patients with AIDS who have cerebral toxoplasmosis 27 and by the lack of preexisting retinochoroidal scars. 12 ' 9 Additionally, the prevalence of toxoplasmic le sions among patients with AIDS is too high to be explained only by reactivation of congenital toxoplasmosis. Ocular toxoplasmosis might also be related to primary infection because IgM was found in three of 26 patients (12%). Treatment is essential to stop the progression of the retinitis and concurrent life-threatening cerebral toxoplasmosis. The presence of ocular lesions is an absolute indication for therapy because they tend to extend to the whole retina. Treatment often provides a retrospective diag nosis because no definitive biologic tests are available. 3 The pyrimethamine-sulfadiazine combination is the usual treatment for toxo plasmosis in immunocompromised patients. 28 It has been active in vitro and in vivo against T. gondii trophozoites. 7 There is no effective thera py against cysts and not all the foci can be eradicated. The drugs act by blocking folate synthesis and, consequently, DNA synthesis by the parasite. The combination also reduces hu man DNA synthesis, inducing bone marrow suppression. Folinic acid is required to prevent this side effect. Zidovudine, an antiretroviral drug widely used in AIDS, is difficult to use concurrently because it enhances bone marrow suppression and may have an antagonistic ac tion on pyrimethamine. 7 At induction dosages, pyrimethamine in combination with sulfadiazine or clindamycin appears to be effective because all the lesions in our patients healed within various therapeutic periods. The pyrimethamine-clindamycin com bination appeared to have similar efficacy in ocular toxoplasmosis, as described for cerebral toxoplasmosis. 7,29 An international, multicenter, double-masked study in which patients are randomly assigned to treatment is still under way in Europe to compare the efficacy of the associations of pyrimethamine-sulfadiazine and pyrimethamine-clindamycin in cerebral toxoplasmosis. On maintenance therapy, the 50-mg dosage of pyrimethamine did not appear to be more effective than the 25-mg dosage. Sulfadiazine induces allergic reactions rang ing from cutaneous rashes to Lyell's syndrome. Other side effects have been described (hepatic cytolysis, nephrotic colitis, and renal insuffi ciency). The side effects of the pyrimethaminesulfadiazine combination led to its discontinua tion in 11 of 37 patients (30%) during the induction course. The main side effect of clin
damycin is pseudomembranous colitis caused by Clostridium perfringens. The recovery of vision after treatment of ocular toxoplasmosis is better than after treat ment of cytomegalovirus retinitis. This is caused by the disappearance of the inflamma tion in the aqueous and vitreous humor, as well as by the healing of retinal lesions. With induc tion dosages, healing is slower in ocular toxo plasmosis (six weeks) than in cytomegalovirus retinitis (two to three weeks). The relapse rate on maintenance therapy is lower for ocular toxoplasmosis than for cytomegalovirus retini tis, in which the median time to disease pro gression has been shown to be 56 days in ganciclovir-treated patients and 59 days in foscarnet-treated patients. 30 This better control of the local infection might be related in part to the lower reactivation of T. gondii when cellular immunosuppression occurs. Additionally, T. gondii remains in cysts that break in case of cellular immunosuppression, although cyto megalovirus remains in the infected cells. Spiramycin and roxithromycin (macrolide antibiotics) are not effective in cerebral toxo plasmosis in AIDS,14 although newer molecules like azithromycin, 31 clarithromycin, and hydroxynaphtoquinone are still being evaluated. We did not use corticosteroid therapy because it further depresses host immune mechanisms; these agents are not absolutely necessary be cause there is little intraretinal inflammation in toxoplasmic lesions in AIDS. 9 Laser photocoag ulation, cryocoagulation, and vitrectomy have not been evaluated. Toxoplasmosis is a common ocular infection in AIDS. It must be distinguished from cyto megalovirus retinitis on the basis of clinical criteria, especially by the aspect of the lesions and the inflammation of the anterior segment and vitreous humor. It seems to have a better ocular prognosis than cytomegalovirus retini tis. However, it requires appropriate treatment by infectious disease specialists to stop the extension of the infection, especially toward life-threatening involvement of the central nervous system.
References 1. Weiss, A., Margo, C. E., Ledford, D. K., Lockey, R. F., and Brinser, J. H.: Toxoplasmic retinochoroiditis as an initial manifestation of the acquired immune deficiency syndrome. Am. J. Ophthalmol. 101:248, 1986. 2. Parke, D. W., and Font, R. L.: Diffuse toxoplas-
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mie retinochoroiditis in a patient with AIDS. Arch. Ophthalmol. 104:571, 1986. 3. Heinemann, M. H., Gold, J. M. W„ and Maisel, J.: Bilateral toxoplasma retinochoroiditis in a patient with acquired immune deficiency syndrome. Retina 6:224, 1986. 4. Grossniklaus, H. E., Specht, C. S., Allaire, G., and Leavitt, J. A.: Toxoplasma gondii retinochoroiditis and optic neuritis in acquired immune deficiency syndrome. Ophthalmology 97:1342, 1990. 5. Tschirhart, D., and Klatt, E. C : Disseminated toxoplasmosis in the acquired immunodeficiency syndrome. Arch. Pathol. Lab. Med. 112:1237, 1988. 6. Levy, R. M., and Bredesen, D. E.: Central nerv ous system dysfunction in acquired immunodeficien cy syndrome. J. Acquir. Immune Defic. Syndr. 1:41, 1988. 7. Israelski, D. M„ and Remington, J. S.: Toxoplasmic encephalitis in patients with AIDS. Infect. Dis. Clin. North Am. 2:429, 1988. 8. Chakroun, M., Meyohas, M. C , Pelosse, B., Zazoun, L., Vacherot, B., Derouin, F., and Leport, C : Emergence de la toxoplasmose cérébrale au cours du SIDA. Ann. Med. Interne 145:472, 1990. 9. Holland, G. N., Engstrom, R. E., Glasgow, B. J., Berger, B. A., Daniels, S. A., Sidikaro, Y., Harmon, J. A., Fisher, D. H., Boyer, D. S., Rao, N. A., Eagle, R. C , Kreiger, A. E., and Foos, R. Y.: Ocular toxo plasmosis in patients with the acquired immunodefi ciency syndrome. Am. J. Ophthalmol. 106:653, 1988. 10. Friedman, A. H.: The retinal lesions of the acquired immune deficiency syndrome. Trans. Am. Ophthalmol. Soc. 82:447, 1984. 11. Smith, R. E.: Toxoplasmic retinochoroiditis as an emerging problem in AIDS patients. Am. J. Oph thalmol. 106:738, 1988. 12. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immu nodeficiency syndrome. M.M.W.R. 36(suppl. 1):1, 1987. 13. Desmonts, G.: Definitive serological diagnosis of ocular toxoplasmosis. Arch. Ophthalmol. 76:839, 1966. 14. Leport, C , Raffi, F., Matheron, S., Katlama, C , Régnier, B., Saimot, A. G., Marche, C , Vedrenne, C , and Vilde, J. L.: Treatment of central nervous system toxoplasmosis with pyrimethamine-sulfadiazine combination in 35 AIDS-patients. Efficacy of longterm continuous therapy. Am. J. Med. 84:94, 1988. 15. Ederer, F., Axtell, L. M., and Cutler, S. J.: The relative survival rate. A statistical methodology. N.C.I. Monograph 6:101, 1961. 16. Krick, J. A., and Remington, J. S.: Current con cepts in parasitology. Toxoplasmosis in the adult. An overview. N. Engl. J. Med. 298:550, 1978. 17. Hoerni, B., Vallat, M., Durand, M., and Pesme, D.: Ocular toxoplasmosis and Hodgkin's disease. Report of two cases. Arch. Ophthalmol. 96:62, 1978. 18. Pauleikhoff, D., Messmer, E., Beelen, D. W., Foerster, M., and Wessing, A.: Bone-marrow trans plantation and toxoplasmic retinochoroiditis. Graefes Arch. Clin. Exp. Ophthalmol. 225:239,1987.
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19. Nicholson, D. H., and Wolchok, E. B.: Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy. Arch. Ophthalmol. 94:248, 1976. 20. Yeo, J. H., Jakobiec, F. A., Iwamoto, T., Rich ard, G., and Kreissig, I.: Opportunistic toxoplasmic retinochoroiditis following chemotherapy for sys temic lymphoma. A light and electron microscopic study. Ophthalmology 90:885, 1983. 21. Holland, G. N., O'Connor, G. R., Diaz, R. F., Minasi, P., and Wara, W. M.: Ocular toxoplasmosis in immunosuppressed nonhuman primates. Invest. Ophthalmol. Vis. Sci. 29:835, 1988. 22. Wong, B., Gold, J. W. M., and Lange, M.: Cen tral nervous system toxoplasmosis in homosexual men and parenteral drug abusers in New York. High incidence of infection and abnormal antibody re sponses. Clin. Res. 30:698, 1982. 23. Brézin, A. P., Egwuagu, C. E., Burnier, M., Silveira, C , Mahdi, R. M., Gazzinelli, R. T., Beifort, R., and Nussenblatt, R. B.: Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction. Am. J. Ophthalmol. 110:599, 1990. 24. Alonso, R., Heiman-Patterson, T., and Mancall, E. L.: Cerebral toxoplasmosis in acquired im mune deficiency syndrome. Arch. Neurol. 41:321, 1984. 25. Snider, W. D., Simpson, D. M., Nielsen, S., Gold, J. W. M., Metroka, C. E., and Posner, J. B.: Neurological complications of acquired immune defi ciency syndrome. Analysis of 50 patients. Ann. Neurol. 14:403, 1983. 26. Henin, D., Duyckaerts, C , Chaunu, M.-P., Vazeux, R.-M., Brousse, N., Rozenbaum, W., and Hauw, J.-J.: Etude neuropathologique de 31 cas de syndrome d'immunodépression acquise. Rev. Neu rol. (Paris) 143:631, 1987. 27. Tirard, V., Niel, G., Rosenheim, M., Katlama, C , Ciceron, L., Ogunkolade, W., Danis, M., and Gentilini, M.: Diagnosis of toxoplasmosis in patients with AIDS by isolation of parasite from the blood. N. Engl. J. Med. 324:634, 1991. 28. Engstrom, R. E., Holland, G. N., Nussenblatt, R. B., and Jabs, D. A.: Current practices in the man agement of ocular toxoplasmosis. Am. J. Ophthal mol. 111:601, 1991. 29. Leport, C , Bastuji-Garin, S., Perronne, C , Salmon, D., Marche, C , Bricaire, F., and Vilde, J. L.: An open study of the pyrimethamine-clindamycin combination in AIDS patients with brain toxoplas mosis. J. Infect. Dis. 160:557, 1989. 30. Studies of Ocular Complications of AIDS Re search Group, in Collaboration With the AIDS Clini cal Trial Group: Mortality in patients with the ac quired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N. Engl. J. Med. 326:213, 1992. 31. Araujo, F. G., Guptill, D. R., and Remington, J. S.: Azithromycin. A macrolide antibiotic with po tent activity against Toxoplasma gondii. Antimicrob. Agents Chemother. 32:755, 1988.
The files of 45 human immunodeficiency virus-infected patients with ocular toxoplasmosis were reviewed, with a median followup of eight months. The condition was unilateral in 37 of the 45 patients (82%) and was bilateral in eight (18%). Inflammation of the anterior chamber and the vitreous was present in 32 of 53 eyes (60%) and 38 of 53 eyes (72%), respectively. Cytomegalovirus retinitis developed during the follow-up period in nine patients (20%). Cerebral toxoplasmosis was concurrently diagnosed with the ocular toxoplasmosis in 13 patients (29%). The efficacy of the combination of pyrimethamine and sulfadiazine or clindamycin was assessed in 42 patients for the induction therapy and in 38 patients for the maintenance therapy. Induction therapy was always effective within a median period of six weeks. During maintenance treatment, the 24-month relapse rates were 0.20 and 0.18 for the 50-mg/day and 25-mg/day dosage of pyrimethamine, respectively. The overall 12-month survival rate was 0.72. Our results suggested that ocular toxoplasmosis has a better ocular prognosis than cytomegalovirus retinitis, but that it requires appropriate treatment because life-threatening cerebral involvement is often associated.
XOXOPLASMOSIS is an opportunistic ocular in fection in patients infected by the human im munodeficiency virus (HIV). The diagnosis is usually based on clinical criteria and confirmed by therapeutic efficacy. Unlike ocular toxoplasmosis in immunocompetent individuals, the retinal lesions in pa tients with acquired immunodeficiency syn drome (AIDS) are extensive and can cause visual impairment if left untreated.1"1 The infec tion can be generalized, involving the brain, eyes, lungs, heart, digestive tract, lymph nodes, liver, spleen, and bone marrow.6 Cerebral toxo plasmosis is the most common cerebral infec tion in AIDS6 and requires urgent treatment because it can be rapidly fatal. The prevalence of toxoplasmosis varies ac cording to dietary habits and, therefore, from country to country. The prevalence in adults in the United States has been estimated at 15% to 68%,7 compared to 50% to 80% in French adults.8 Experience with ocular toxoplasmosis in HIV-infected patients is limited.1"4'911 We studied the findings in 45 HIV-infected patients with toxoplasmosis, involving a total of 53 eyes.
Subjects and Methods Accepted for publication May 4, 1992. From the Service d'Ophtalmologie, Hôpital PitiéSalpêtrière (Drs. Cochereau-Massin, LeHoang, LautierFrau, Zerdoun, Zazoun, Robinet, Marcel, and Girard); Service des Maladies Infectieuses, Hôpital PitiéSalpêtrière (Dr. Katlama and Gentilini); Services des Maladies Infectieuses, Hôpital Claude Bernard (Drs. Leport and Coulaud); and Service des Maladies In fectieuses, Hôpital Rothschild (Dr. Rozenbaum), Paris, France. Reprint requests to Phuc LeHoang, Ph.D., Service d'Ophtalmologie, Hôpital Pitié-Salpêtrière, 83 Boule vard de l'Hôpital, 75 013, Paris, France.
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The patients in our study were referred to the Ophthalmology Department of the Hôpital Pitié-Salpêtrière between 1983 and 1990. Serologie status for anti-HIV antibodies was determined by means of an enzyme-linked immunosorbent assay (ELISA), and confirmed by Western blot analysis. Acquired immunodefi ciency syndrome was diagnosed according to the Centers for Disease Control criteria.12 Toxoplasmic retinitis was diagnosed on the
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basis of clinical findings. Patient examinations included determination of visual acuity in pa tients who were cooperative, biomicroscopy of the anterior and posterior segments, indirect ophthalmoscopy with fundus drawings, and serial fundus photography and fluorescein angiography if necessary. All the patients were examined by a member of the AIDS team of our department. Cerebral toxoplasmosis was diag nosed on the basis of consistent neurologic findings and computed tomography of the brain. Active toxoplasmic lesions consisted of yel low-white, edematous areas of necrotizing retinitis. The lesions had fluffy borders, few scat tered intraretinal hemorrhages, and occasional vascular sheathing. It was usually accompanied by overlying vitreal inflammation, ranging from mild localized vitreal haze to extensive dense vitreous inflammation reaction. The le sions were homogeneous, without peripheral proliferation or healed center as in cytomegalovirus retinitis. Inactive lesions consisted of atrophie choroid and retina, with epitheli al pigment clumping and occasional vitreal strands. Fluorescein angiography showed early blockage of the lesions, followed by hyperfluorescence that started from the borders and pro gressed toward the center of the lesion. The final lesion on late phases of the angiogram was bigger than the lesion seen on the green-free photograph. The posterior pole was determined as the area defined by and including the vascular arcades, and the periphery was determined as the area outside the vascular arcades. Visual acuity was determined at initial examination and at the last consultation. The involvement of other organs was detected by clinical examina tion, brain computed tomography, and other tests if required (computed tomography, endoscopy, and biopsy). Serologie diagnosis was made using ELISA on serum and aqueous humor samples. The coefficient of Desmonts, 13 calculated using the titers of specific antibodies and total immunoglobulins in serum and aqueous humor, was considered positive when it was greater than 5. All lesions were treated, whether they were sight-threatening. Treatment consisted of the combination of pyrimethamine with either sulfadiazine or clindamycin administered orally. Folinic acid was administered in every case. Like other opportunistic infections in AIDS, toxoplasmosis recurs when therapy is discon tinued 7 · 14 ; treatment therefore consisted of the
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two following phases: an induction regimen to obtain complete healing of the retinochoroidal toxoplasmic lesions, followed by a maintenance regimen. The daily dosages in the induction phase were 50 mg of pyrimethamine, 4 to 6 g of sulfadiazine, and 2.4 g of clindamycin. Mainte nance therapy consisted of 25 or 50 mg of pyrimethamine/day, combined with sulfadia zine or clindamycin given at half dosages, or less, according to the patient's tolerance. Main tenance therapy was continued for as long as possible. Corticosteroids were not used. The cumulative relapse and survival rates were cal culated using the survival method. 15
Results Of 1,761 HIV-infected patients examined in the Department of Ophthalmology, 57 (3%) had ocular toxoplasmosis at initial examina tion; the records were available for review in 45 cases. Of these 45 patients, 41 (91%) were men and four (9%) were women, with a mean age of 39 years (range, 24 to 72 years). Thirty-eight (85%) patients were homosexual, five (11%) were intravenous drug abusers, one (2%) had been contaminated by a blood transfusion, and one woman (2%) was the sexual partner of a seropositive man. The median follow-up was eight months (range, one to 40 months). Thirtyfour of the 45 patients (76%) had AIDS. The median time between the diagnosis of AIDS and that of ocular toxoplasmosis was five months (range, zero to 33 months). Ocular toxoplasmosis was the first opportunistic infec tion in the 11 patients without AIDS and pre ceded the serologie diagnosis of HIV infection in five patients. Ocular toxoplasmosis was unilateral in 37 patients (82%) and bilateral in eight patients (18%), for a total of 53 eyes. Vitreitis was present in 38 eyes (72%). In flammation of the anterior segment (character ized by keratic precipitates and anterior flare) was present in 32 eyes (60%). A retinochoroidal scar was present in two eyes (4%) and retinal detachment in one eye (2%). The retinal lesions were unifocal in 44 of the 53 eyes (83%). Eight of the remaining nine eyes had two foci, and one had four, giving a total of 64 toxoplasmic retinal foci. Thirty-three of these 64 lesions (52%) involved the posterior pole and 31 (48%) involved the periphery. The
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areas of necrosis ranged in size, with one third less than or equal to 2 disk diameters, one third more than 5 disk diameters, and the remaining third of intermediate size. The serum antibody titer against Toxoplasma gondii was determined in 26 patients, all of whom had reactive IgG antibodies (range, 1:8 to 1:12,800). Immunoglobulin M antibodies were present in three patients. Desmonts' coef ficient was positive for the aqueous humor of only one of the ten patients tested. The efficacy of induction treatment was as sessed in 42 of the 45 patients (93%). All the retinal lesions healed after a median time inter val of six weeks (range, three to 20 weeks) and the visual acuity improved in most cases (Fig. 1). Initially, 37 patients were treated with pyrimethamine-sulfadiazine, and five were treated with pyrimethamine-clindamycin. Eleven pa tients initially treated with pyrimethamine-sulfadiazine (30%) had to change to pyrimeth amine-clindamycin because of severe side effects. Evaluation of maintenance therapy was pos sible in 38 of the 53 patients (84%). Twenty patients (53%) were treated with pyrimethamine at 25 mg/day and 18 patients (47%) were treated with pyrimethamine at 50 mg/day. Sulfadiazine or clindamycin efficacy could not be accurately evaluated because of the variety of the treatment regimens. The 24-month relapse rate was 0.18 for the 25-mg dosage of pyrimeth amine and 0.20 for the 50-mg dosage (Fig. 2). Most of the relapses developed within six months of the initial diagnosis. Cytomegalovirus retinitis developed in nine patients (20%) during the follow-up period. One patient (2%) had a history of cytomegalo virus retinitis. Ocular toxoplasmosis was diag-
+ •
20/100
20/50
20/30
TOXOPLASMOSIS TOXOPLASMOSIS + CMV
20/25
20/20
INITIAL VISUAL ACUITY
Fig. 1 (Cochereau-Massin and associates). Initial and final visual acuity in ocular toxoplasmosis. CMV indicates cytomegalovirus retinitis.
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.Q. PYRIMETHAMINE 25
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12
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60
DURATION OF THERAPY (MONTHS)
Fig. 2 (Cochereau-Massin and associates). Relapse rate of ocular toxoplasmosis on maintenance therapy (pyrimethamine, 25 or 50 mg/day).
nosed at the same time as ocular toxoplasmosis in four patients (9%). A cerebral localization of toxoplasmosis was concurrently found in 13 patients (29%). Four patients (9%) h a d a previ ous diagnosis of cerebral toxoplasmosis and four patients (9%) developed a cerebral locali zation later in the course of the disease. The overall 12-month survival rate among the patients with ocular toxoplasmosis was 0.72 (Fig. 3).
Discussion Ocular toxoplasmosis is one of the most com mon infectious causes of retinitis in young immunocompetent subjects. It is characterized by areas of necrotizing retinitis, vitreitis, and inflammation of the anterior segment, which usually resolve spontaneously but often leave pigmented chorioretinal scars. This form of retinitis is attributed to the reactivation of con genital retinal cysts. The initial infection is thought to occur in utero. When a pregnant woman acquires the disease, the risk of vertical transmission is about 40%. 16 The course of ocular toxoplasmosis in immunocompromised hosts is complex, 217,18 depends on the extent of immunosuppression, and can ultimately lead to blindness.1"4·19·20 It can devel op from the reactivation of congenital retinal cysts, newly acquired disease, or from T. gondii newly disseminated to the eye from nonocular disease sites. 9 Impaired cell-mediated immuni ty is an important determinant of reactivation, but other factors probably exist.21 Ocular toxoplasmosis is uncommon com-
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1.0 -
0.8 W 1< 0.6 -
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DURATION (MONTHS) Fig. 3 (Cochereau-Massin and associates). Survival rate of patients with ocular toxoplasmosis. pared to cytomegalovirus retinitis (20% of pa tients with AIDS). It can develop in patients with AIDS-related complexes, 1 because it is not a criterion of AIDS. In our experience, it is the second most common retinal infection in AIDS (Cochereau-Massin and associates, unpub lished data, 1990). Our study, although retro spective, provided information on the clinical characteristics, treatment, and prognosis of the disease in AIDS. Ocular toxoplasmosis is the main differential diagnosis in patients with suspected cytomega lovirus retinitis. 11 Clinical features are impor tant for diagnosis. The main difference with cytomegalovirus retinitis is the inflammation of the vitreous and of the aqueous. Vitreitis can range from mild vitreal haze overlying the retinal lesions to extensive dense vitreitis that precludes visualization of the fundus. The reti nal necrotic areas are different from cytomega lovirus lesions, being more fluffy and edematous, generally nonhemorrhagic, and having hazy edges. On angiography, fluorescence starts from the edges of the lesion and progress es to the center. The final area of hyperfluorescence is larger than that of the initial lesion on green-free photographs. In contrast, cytomega lovirus retinitis usually shows hyperfluorescence that starts at the center of the lesion and extends toward the borders. The final hyperfluorescent area of cytomegalovirus retinitis re mains smaller than the lesion observed on green-free photographs. Ocular toxoplasmosis can sometimes manifest as an acute syndrome that resembles retinal necrosis. 2 Most toxoplasmic retinal lesions in AIDS are unifocal and are located in the posterior pole. The areas vary according to the time of diagno
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sis. If untreated, the lesions progressively in vade and destroy the whole retina. If treated, the involvement often remains unilateral. Path ologic studies have shown that the retinal ne crosis is extensive and involves all the layers of the retina, although choroidal inflammation is slight. Trophozoites have been found in the retina and choroid. 9 Serologie tests are not helpful in making the diagnosis. Serum IgG antibodies are usually present at variable levels, attesting to a previ ous primary infection. Some patients have IgM, indicative of a newly acquired infection. The aqueous coefficient is not helpful because it was positive in only 10% of our initial cases. We therefore no longer perform anterior chamber puncture. The poor contribution of serologie studies to the diagnosis could be explained in part by perturbations caused by the severe immunodeficiency in AIDS.22 The isolation of the parasite at the site of infection would thus be helpful. By inoculation to mice, T. gondii has been found in the vitreous of patients with AIDS who have ocular toxoplasmosis, 3 whereas cytologie examination is fruitless. 2 The polymerase chain reaction can be used to detect the T. gondii genome in paraffin-embedded sec tions of retina of immunocompetent patients with ocular toxoplasmosis. 23 This new method is still under evaluation for application to the vitreous and aqueous humor of patients with AIDS. In AIDS, although one third of patients with ocular toxoplasmosis develop cytomegalovirus retinitis, cytomegalovirus retinitis does not ap pear to be more common in patients with ocular toxoplasmosis. Ocular toxoplasmosis is less common than cerebral toxoplasmosis, 24,26 which has been found in up to 40% of autopsy cases.26 This might be related to the smaller mass of neural tissue in the eyes. Cerebral toxoplasmosis was associated with ocular toxoplasmosis in 13 of 65 patients (29%). This association may have been underestimated in our study because brain computed tomography was not systemati cally performed when no neurologic sign was present. Cerebral computed tomography is therefore mandatory when ocular toxoplasmo sis is diagnosed and ophthalmoscopy is manda tory when cerebral toxoplasmosis is diagnosed. Contrary to the situation in healthy individu als, ocular toxoplasmosis in AIDS probably results not only from the reactivation of con genital toxoplasmosis, but also from the dis semination of reactivated nonocular toxo plasmic foci acquired during infancy. 9 This
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hypothesis is supported by the isolation of T. gondii from the blood of patients with AIDS who have cerebral toxoplasmosis 27 and by the lack of preexisting retinochoroidal scars. 12 ' 9 Additionally, the prevalence of toxoplasmic le sions among patients with AIDS is too high to be explained only by reactivation of congenital toxoplasmosis. Ocular toxoplasmosis might also be related to primary infection because IgM was found in three of 26 patients (12%). Treatment is essential to stop the progression of the retinitis and concurrent life-threatening cerebral toxoplasmosis. The presence of ocular lesions is an absolute indication for therapy because they tend to extend to the whole retina. Treatment often provides a retrospective diag nosis because no definitive biologic tests are available. 3 The pyrimethamine-sulfadiazine combination is the usual treatment for toxo plasmosis in immunocompromised patients. 28 It has been active in vitro and in vivo against T. gondii trophozoites. 7 There is no effective thera py against cysts and not all the foci can be eradicated. The drugs act by blocking folate synthesis and, consequently, DNA synthesis by the parasite. The combination also reduces hu man DNA synthesis, inducing bone marrow suppression. Folinic acid is required to prevent this side effect. Zidovudine, an antiretroviral drug widely used in AIDS, is difficult to use concurrently because it enhances bone marrow suppression and may have an antagonistic ac tion on pyrimethamine. 7 At induction dosages, pyrimethamine in combination with sulfadiazine or clindamycin appears to be effective because all the lesions in our patients healed within various therapeutic periods. The pyrimethamine-clindamycin com bination appeared to have similar efficacy in ocular toxoplasmosis, as described for cerebral toxoplasmosis. 7,29 An international, multicenter, double-masked study in which patients are randomly assigned to treatment is still under way in Europe to compare the efficacy of the associations of pyrimethamine-sulfadiazine and pyrimethamine-clindamycin in cerebral toxoplasmosis. On maintenance therapy, the 50-mg dosage of pyrimethamine did not appear to be more effective than the 25-mg dosage. Sulfadiazine induces allergic reactions rang ing from cutaneous rashes to Lyell's syndrome. Other side effects have been described (hepatic cytolysis, nephrotic colitis, and renal insuffi ciency). The side effects of the pyrimethaminesulfadiazine combination led to its discontinua tion in 11 of 37 patients (30%) during the induction course. The main side effect of clin
damycin is pseudomembranous colitis caused by Clostridium perfringens. The recovery of vision after treatment of ocular toxoplasmosis is better than after treat ment of cytomegalovirus retinitis. This is caused by the disappearance of the inflamma tion in the aqueous and vitreous humor, as well as by the healing of retinal lesions. With induc tion dosages, healing is slower in ocular toxo plasmosis (six weeks) than in cytomegalovirus retinitis (two to three weeks). The relapse rate on maintenance therapy is lower for ocular toxoplasmosis than for cytomegalovirus retini tis, in which the median time to disease pro gression has been shown to be 56 days in ganciclovir-treated patients and 59 days in foscarnet-treated patients. 30 This better control of the local infection might be related in part to the lower reactivation of T. gondii when cellular immunosuppression occurs. Additionally, T. gondii remains in cysts that break in case of cellular immunosuppression, although cyto megalovirus remains in the infected cells. Spiramycin and roxithromycin (macrolide antibiotics) are not effective in cerebral toxo plasmosis in AIDS,14 although newer molecules like azithromycin, 31 clarithromycin, and hydroxynaphtoquinone are still being evaluated. We did not use corticosteroid therapy because it further depresses host immune mechanisms; these agents are not absolutely necessary be cause there is little intraretinal inflammation in toxoplasmic lesions in AIDS. 9 Laser photocoag ulation, cryocoagulation, and vitrectomy have not been evaluated. Toxoplasmosis is a common ocular infection in AIDS. It must be distinguished from cyto megalovirus retinitis on the basis of clinical criteria, especially by the aspect of the lesions and the inflammation of the anterior segment and vitreous humor. It seems to have a better ocular prognosis than cytomegalovirus retini tis. However, it requires appropriate treatment by infectious disease specialists to stop the extension of the infection, especially toward life-threatening involvement of the central nervous system.
References 1. Weiss, A., Margo, C. E., Ledford, D. K., Lockey, R. F., and Brinser, J. H.: Toxoplasmic retinochoroiditis as an initial manifestation of the acquired immune deficiency syndrome. Am. J. Ophthalmol. 101:248, 1986. 2. Parke, D. W., and Font, R. L.: Diffuse toxoplas-
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mie retinochoroiditis in a patient with AIDS. Arch. Ophthalmol. 104:571, 1986. 3. Heinemann, M. H., Gold, J. M. W„ and Maisel, J.: Bilateral toxoplasma retinochoroiditis in a patient with acquired immune deficiency syndrome. Retina 6:224, 1986. 4. Grossniklaus, H. E., Specht, C. S., Allaire, G., and Leavitt, J. A.: Toxoplasma gondii retinochoroiditis and optic neuritis in acquired immune deficiency syndrome. Ophthalmology 97:1342, 1990. 5. Tschirhart, D., and Klatt, E. C : Disseminated toxoplasmosis in the acquired immunodeficiency syndrome. Arch. Pathol. Lab. Med. 112:1237, 1988. 6. Levy, R. M., and Bredesen, D. E.: Central nerv ous system dysfunction in acquired immunodeficien cy syndrome. J. Acquir. Immune Defic. Syndr. 1:41, 1988. 7. Israelski, D. M„ and Remington, J. S.: Toxoplasmic encephalitis in patients with AIDS. Infect. Dis. Clin. North Am. 2:429, 1988. 8. Chakroun, M., Meyohas, M. C , Pelosse, B., Zazoun, L., Vacherot, B., Derouin, F., and Leport, C : Emergence de la toxoplasmose cérébrale au cours du SIDA. Ann. Med. Interne 145:472, 1990. 9. Holland, G. N., Engstrom, R. E., Glasgow, B. J., Berger, B. A., Daniels, S. A., Sidikaro, Y., Harmon, J. A., Fisher, D. H., Boyer, D. S., Rao, N. A., Eagle, R. C , Kreiger, A. E., and Foos, R. Y.: Ocular toxo plasmosis in patients with the acquired immunodefi ciency syndrome. Am. J. Ophthalmol. 106:653, 1988. 10. Friedman, A. H.: The retinal lesions of the acquired immune deficiency syndrome. Trans. Am. Ophthalmol. Soc. 82:447, 1984. 11. Smith, R. E.: Toxoplasmic retinochoroiditis as an emerging problem in AIDS patients. Am. J. Oph thalmol. 106:738, 1988. 12. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immu nodeficiency syndrome. M.M.W.R. 36(suppl. 1):1, 1987. 13. Desmonts, G.: Definitive serological diagnosis of ocular toxoplasmosis. Arch. Ophthalmol. 76:839, 1966. 14. Leport, C , Raffi, F., Matheron, S., Katlama, C , Régnier, B., Saimot, A. G., Marche, C , Vedrenne, C , and Vilde, J. L.: Treatment of central nervous system toxoplasmosis with pyrimethamine-sulfadiazine combination in 35 AIDS-patients. Efficacy of longterm continuous therapy. Am. J. Med. 84:94, 1988. 15. Ederer, F., Axtell, L. M., and Cutler, S. J.: The relative survival rate. A statistical methodology. N.C.I. Monograph 6:101, 1961. 16. Krick, J. A., and Remington, J. S.: Current con cepts in parasitology. Toxoplasmosis in the adult. An overview. N. Engl. J. Med. 298:550, 1978. 17. Hoerni, B., Vallat, M., Durand, M., and Pesme, D.: Ocular toxoplasmosis and Hodgkin's disease. Report of two cases. Arch. Ophthalmol. 96:62, 1978. 18. Pauleikhoff, D., Messmer, E., Beelen, D. W., Foerster, M., and Wessing, A.: Bone-marrow trans plantation and toxoplasmic retinochoroiditis. Graefes Arch. Clin. Exp. Ophthalmol. 225:239,1987.
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19. Nicholson, D. H., and Wolchok, E. B.: Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy. Arch. Ophthalmol. 94:248, 1976. 20. Yeo, J. H., Jakobiec, F. A., Iwamoto, T., Rich ard, G., and Kreissig, I.: Opportunistic toxoplasmic retinochoroiditis following chemotherapy for sys temic lymphoma. A light and electron microscopic study. Ophthalmology 90:885, 1983. 21. Holland, G. N., O'Connor, G. R., Diaz, R. F., Minasi, P., and Wara, W. M.: Ocular toxoplasmosis in immunosuppressed nonhuman primates. Invest. Ophthalmol. Vis. Sci. 29:835, 1988. 22. Wong, B., Gold, J. W. M., and Lange, M.: Cen tral nervous system toxoplasmosis in homosexual men and parenteral drug abusers in New York. High incidence of infection and abnormal antibody re sponses. Clin. Res. 30:698, 1982. 23. Brézin, A. P., Egwuagu, C. E., Burnier, M., Silveira, C , Mahdi, R. M., Gazzinelli, R. T., Beifort, R., and Nussenblatt, R. B.: Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction. Am. J. Ophthalmol. 110:599, 1990. 24. Alonso, R., Heiman-Patterson, T., and Mancall, E. L.: Cerebral toxoplasmosis in acquired im mune deficiency syndrome. Arch. Neurol. 41:321, 1984. 25. Snider, W. D., Simpson, D. M., Nielsen, S., Gold, J. W. M., Metroka, C. E., and Posner, J. B.: Neurological complications of acquired immune defi ciency syndrome. Analysis of 50 patients. Ann. Neurol. 14:403, 1983. 26. Henin, D., Duyckaerts, C , Chaunu, M.-P., Vazeux, R.-M., Brousse, N., Rozenbaum, W., and Hauw, J.-J.: Etude neuropathologique de 31 cas de syndrome d'immunodépression acquise. Rev. Neu rol. (Paris) 143:631, 1987. 27. Tirard, V., Niel, G., Rosenheim, M., Katlama, C , Ciceron, L., Ogunkolade, W., Danis, M., and Gentilini, M.: Diagnosis of toxoplasmosis in patients with AIDS by isolation of parasite from the blood. N. Engl. J. Med. 324:634, 1991. 28. Engstrom, R. E., Holland, G. N., Nussenblatt, R. B., and Jabs, D. A.: Current practices in the man agement of ocular toxoplasmosis. Am. J. Ophthal mol. 111:601, 1991. 29. Leport, C , Bastuji-Garin, S., Perronne, C , Salmon, D., Marche, C , Bricaire, F., and Vilde, J. L.: An open study of the pyrimethamine-clindamycin combination in AIDS patients with brain toxoplas mosis. J. Infect. Dis. 160:557, 1989. 30. Studies of Ocular Complications of AIDS Re search Group, in Collaboration With the AIDS Clini cal Trial Group: Mortality in patients with the ac quired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N. Engl. J. Med. 326:213, 1992. 31. Araujo, F. G., Guptill, D. R., and Remington, J. S.: Azithromycin. A macrolide antibiotic with po tent activity against Toxoplasma gondii. Antimicrob. Agents Chemother. 32:755, 1988.
