Ocular toxoplasmosis

Ocular Toxoplasmosis Clinical Features and Prognosis of 154 Patients Lotje E. H. Bosch-Driessen, MD, PhD, Tos T. J. M. Berendschot, PhD, Jenny V. Ongkosuwito, MD, PhD, Aniki Rothova, MD, PhD Purpose: To ascertain the clinical features, visual outcome, and recurrence rates of ocular toxoplasmosis (OT) in a large series of patients. To determine the efficacy of various treatment strategies and identify the patients at risk of visual loss. Design: Retrospective noncomparative observational case series. Participants: One hundred fifty-four consecutive patients with active lesions of OT (first attack and/or recurrence) were identified in a cohort of 1300 consecutive patients with uveitis. Mean follow-up was 5.8 years. Intervention: A review of the medical records of 154 patients with active OT. Main Outcome Measures: Patients were subdivided according to clinical and laboratory criteria. Numerous variables were compared per patient and group, including age and gender distribution, onset and course of infection, clinical ocular features, laboratory data, therapeutic strategies and their outcomes, number of recurrences, complications, final visual acuity, and features associated with poor visual outcome. Results: Primary retinal lesions were observed in 28% and a combination of active lesions and old retinochoroidal scars in 72% of the patients at first presentation to the ophthalmologist. Mean age at first presentation with an active OT lesion was 29.5 years. Patients with primary OT were older than those with a combination of active lesions and old scars (P ⬍ 0.001). Serologic characteristics of the acute phase of systemic infection were found in 11% of the patients. Ocular involvement in these patients was associated with advanced age at onset (P ⬍ 0.001) and was characterized by severe intraocular inflammation. Most (82%) of the patients with serologic characteristics of the acute phase of systemic infection had primary lesions (compared with 23% of OT in the chronic phase of systemic infection; P ⬍ 0.001). Extensive retinal lesions were more frequently observed during the acute phase of systemic infection (P ⫽ 0.02) and in patients with primary OT (P ⬍ 0.04). Recurrences, which developed in 79% of all patients followed for more than 5 years, were located predominantly in previously affected eyes (with old scars) in contrast to the sporadic cases of recurrence in the healthy contralateral eye (P ⬍ 0.0001). Standard short-term therapeutic modalities had no effect on visual outcome or future recurrence rates. Legal blindness in one or both eyes was confirmed for 24% of the patients. Blindness of both eyes was more frequent in patients with congenital OT (P ⬍ 0.001). Risk factors for visual loss included congenital infection, OT manifesting during the acute phase of systemic infection, central location and/or extensive retinal lesions, and the administration of corticosteroids without a shield of antiparasitic drugs. Conclusions: Legal blindness in at least one eye developed in 24% of the patients with OT. Recurrences, which developed in 79% of the patients with long-term follow-up, were located predominantly in eyes with toxoplasmic scars. Various short-term therapeutic modalities had no effect on visual outcomes or future recurrence rates, with the exception of a poor visual outcome for patients who received corticosteroids without a shield of antiparasitic drugs. Ophthalmology 2002;109:869 – 878 © 2002 by the American Academy of Ophthalmology. Ocular toxoplasmosis (OT) causes blindness and visual impairment, particularly among the young. Despite years of

Originally received: December 14, 2000. Accepted: August 28, 2001. Manuscript no. 200874. From the Uveitis Center, FC Donders Institute of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands. Supported in part by the Dr. F. P. Fischer Foundation, Utrecht, The Netherlands. Reprint requests to E. H. Bosch-Driessen, MD, FC Donders Institute of Ophthalmology, University Medical Center Utrecht, E.03-136, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. © 2002 by the American Academy of Ophthalmology Published by Elsevier Science Inc.

extensive research, development of novel antitoxoplasmic drugs, and preventive measures directed toward this ubiquitous infection, many basic questions about OT remain unanswered, and curative therapy is not available. Because demographic disease data on OT originate from studies performed in the fifties, up-to-date information on clinical manifestations, course, and prognosis is lacking.1–5 The aim of this study was to describe the clinical manifestations and visual outcome, as well as the efficacy of various treatment strategies, in a large series of patients with OT and, if possible, to identify a profile of patients at risk of visual loss. ISSN 0161-6420/02/$–see front matter PII S0161-6420(02)00990-9

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Ophthalmology Volume 109, Number 5, May 2002 Table 1. Clinical and Laboratory Characteristics of 154 Patients with Ocular Toxoplasmosis at the Time of the First Symptomatic Attack 1. Clinical criteria

Primary OT: no old scars in either eye—37 (24%)

2. Serologic criteria

Acute phase of systemic infection*: 17 (11%)

3. Acquisition of infection

Congenital: 13 (8%)

Recurrent OT: scars in either eye 93 (60%) Chronic phase of systemic infection†: 83 (54%) Postnatal*: 17 (11%)

Undetermined: 24 (16%) Undetermined: 54 (35%) Undetermined: 124 (81%)

*Positive for IgM (10 of 78 performed) and or IgA (9 of 35 performed) against T. gondii. One patient had a fourfold rise in serum IgG against T. gondii. Positive for IgG against T. gondii in serum. In 5 of 83 serum samples IgG ⱖ 1:4096. OT ⫽ ocular toxoplasmosis. †

Patients and Methods We conducted a retrospective analysis of the medical records of 1300 consecutive patients with uveitis, who had consulted our department between 1990 and 1999, to identify patients with the diagnosis of OT (n ⫽ 169, 13%). In this study we included 154 consecutive patients with active lesions of OT (first attack and/or recurrence) and excluded 9 patients with an asymptomatic retinochoroidal scar compatible with the diagnosis of OT, who were not examined during the active stage of the disease. Also excluded were six additional patients, five with retinochoroidal scars compatible with the diagnosis of OT (three with Fuchs’ heterochromic uveitis and two with Coats’ disease) and one patient with presumed congenital toxoplasmosis, microphthalmos, and congenital cataract, in which retinal examination was not possible. Patients with acquired immune deficiency syndrome were not included. Five patients were receiving immunosuppressive medication at the time of first presentation with OT (three posttransplant patients, two with rheumatic disorders). Patients were subdivided according to (1) clinical criteria (primary or recurrent ocular disease; retinal scars already present at first presentation), (2) serologic criteria (acute or chronic phase of

systemic infection), and (3) acquisition of the infection (congenital or postnatally acquired; Table 1). The clinical diagnosis of OT was based on criteria formulated by Holland et al6; in short, the presence of an active creamy-white focal retinal lesion eventually combined with hyperpigmented retinochoroidal scars in either eye. Primary OT was defined as an active creamy-white focal retinal lesion without associated pigmented retinochoroidal scars in either eye.7 Recurrent OT was defined as an active retinochoroidal lesion in the presence of old pigmented retinochoroidal scars in either eye. For the purpose of this study, extensive retinochoroidal lesions were considered to be lesions larger than three optic disc diameters. Central lesions were defined as lesions located within the large vascular arcades. Serologic criteria for the acute phase of systemic infection with Toxoplasma gondii included the presence of IgM and/or IgA antibodies.8 The chronic phase of systemic infection was defined as positive IgG antibodies (any positive titer) without IgM and/or IgA antibodies. Because serum IgG antibodies against T. gondii are present in the greater part of the Dutch population and have no diagnostic value in ocular disease, T. gondii serology was not performed routinely in all cases.9 Nevertheless, for 100 of 154 (65%) patients the serologic data were available. Whenever the Table 2. Characteristics of Patients

Acquisition of Infection Congenital Ocular Toxoplasmosis N (%) Total (N ⫽ 154) Acquisition of infection Congenital OT (n ⫽ 13) Postnatally acquired OT (n ⫽ 17) Undetermined (n ⫽ 124) Serologic criteria Acute phase (n ⫽ 17)† Chronic phase (n ⫽ 83) Undetermined (n ⫽ 54) Clinical criteria Primary OT (n ⫽ 37) Recurrent OT (n ⫽ 93) Undetermined (n ⫽ 24)

Postnatally Acquired Ocular Toxoplasmosis

Serologic Criteria

Undetermined

Acute Phase†

Chronic Phase

N (%)

N (%)

N (%)

N (%)

N (%)

13 (8)

17 (11)

124 (81)

17 (11)

83 (54)

54 (35)

13 (100) 0 (0)

0 (0) 17 (100)

0 (0) 0 (0)

17 (100)

0 (0) 0 (0)

0 (0) 0 (0)

0 (0)

0 (0)

124 (100)

0 (0)

83 (67)

41 (33)

0 (0) 13 (24)

17 (100) 0 (0) 0 (0)

0 (0) 83 (100) 41 (76)

17 (100) 0 (0) 0 (0)

0 (0) 83 (100) 0 (0)

0 (0) 0 (0) 54 (100)

0 (0) 11 (12) 2 (8)

14 (38) 2 (2) 1 (4)

23 (62) 80 (86) 21 (9)

14 (38) 2 (2) 1 (4)

20 (54) 55 (59) 8 (33)

3 (8) 36 (39) 15 (63)

‡

‡

*In all patients with congenital OT, old scars were already present at first presentation with OT. IgM n ⫽ 10 (of 78 performed), IgA n ⫽ 9 (of 35 performed), a fourfold rise in serum IgG titer n ⫽ 1. The exact serologic data from the perinatal period are unknown (with the exception of one case with IgG titer above 1:16000. OT ⫽ ocular toxoplasmosis.

† ‡

870

Undetermined

Bosch-Driessen et al 䡠 Ocular Toxoplasmosis

Figure 2. Number of patients as a function of age at presentation with ocular toxoplasmosis. Figure 1. Cumulative percentage of patients as a function of age at first presentation with ocular toxoplasmosis (n ⫽ 154).

diagnosis of OT was uncertain and/or detailed retinal evaluation was not possible because of vitreous opacities, confirmation of the diagnosis of OT was achieved by analysis of intraocular fluids (n ⫽ 63, intraocular antibody production and polymerase chain reaction).10 –13 This retrospective study included 13 patients with congenital OT. For all 13 patients, diagnosis of OT was based on the presence of quiescent retinal toxoplasmic scars before the age of 2 years; none of these patients had active ocular disease or were being treated at the time of diagnosis. The exact serologic data from the perinatal period could not, however, be traced (with the exception of one case with IgG titers exceeding 1:16000). In our study, however, the inclusion criterion was an active attack of OT. Therefore, all patients with congenital OT (and quiescent retinal scars from an early age) included in this study were not enrolled

during the perinatal period but later in their life when they consulted our department with active disease. Legal blindness was defined as the best-corrected visual acuity of the affected eye equal to or less than 20/200.14 –16 Visual outcome is given by the final optimal visual acuity (not the worst visual acuity at any visit). We compared numerous variables per patient and various groups of patients, including gender and age distribution, clinical features, laboratory data, onset and course of infection, number of recurrences, therapeutic strategies and their outcomes, complications, and final visual acuity, as well as possible risk factors for visual loss. Differences in proportions among groups were compared by means of the chi-square test and Fisher’s exact test. For comparison of the means of groups the Student’s t test and the Mann– Whitney U test were used. P values ⬍ 0.05 were considered statistically significant.

with Ocular Toxoplasmosis Clinical Criteria Primary Ocular Toxoplasmosis N (%)

Recurrent Ocular Toxoplasmosis

Undetermined

Mean Age at First Symptomatic Attack

Unilateral Involvement

Bilateral Involvement

N (%)

N (%)

Years (range)

N (%)

N (%)

37 (24)

93 (60)

24 (16)

29.5 (5–89)

104 (68)

50 (32)

0 (0) 14 (82)

11 (85) 2 (12)

2 (15) 1 (6)

17.4 (5–33) 50.6 (12–76)

2 (15) 15 (88)

11 (85) 2 (12)

23 (19)

80 (64)

21 (17)

29.6 (7–89)

87 (70)

37 (30)

14 (82) 20 (24) 3 (5)

2 (12) 55 (66) 36 (67)

1 (6) 8 (10) 15 (28)

50.6 (12–76) 29.9 (8–89) 22.6 (5–44)

15 (88) 57 (68) 32 (59)

2 (12) 26 (31) 22 (41)

37 (100) 0 (0) 0 (0)

0 (0) 93 (100) 0 (0)

0 (0) 0 (0) 24 (100)

41.9 (8–89) 26.2 (6–63) 22.8 (5–58)

35 (95) 49 (53) 20 (83)

2 (5) 44 (47) 4 (17)

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Ophthalmology Volume 109, Number 5, May 2002

Results General Characteristics In total, 82 females and 72 males were included in this study. Mean follow-up was 5.8 years (median, 3 years; range, 6 months–35 years). Mean age at first presentation to the ophthalmologist with an active OT lesion was 29.5 years (median, 26 years; range, 5– 89 years; Table 2). Subclinical (quiet) retinochoroidal scars in addition to active lesions were observed in 93 of 130 patients (72%) at the time of first presentation with active OT. These old scars were located in the eye with the active lesion (n ⫽ 56), in both eyes (n ⫽ 33), and in the contralateral eyes (n ⫽ 4). No previous scars (primary OT) were observed in 37 of 130 (28%) patients. The presence of old scars at the moment of first presentation was unknown in 24 cases. Because of the presence of old scars at first presentation, the exact time of onset of ocular disease could not be determined reliably for all patients. However, in 75% (113 of 150) of the patients, OT became manifest before the age of 35 years (in 60% between 15 and 35 years; Fig 1). At the end of follow-up, bilateral disease was present in 50 (32%) patients, resulting in 204 affected eyes and 104 healthy contralateral eyes. Patients with primary OT were older than those who were first seen with a combination of active lesions and old scars (recurrent OT, mean age, 41.9 years; median, 38 years compared with 26.2 years; median, 25 years; P ⬍ 0.001, Table 2.). Seasonal variation in the occurrence of first attacks, recurrences, primary OT, or onset of the acute phase of the systemic infection was not found. Congenital toxoplasmosis was documented in 13 of 154 (8%) and a postnatal infection in 17 of 154 (11%) patients. The exact moment of the infection with T. gondii remained undetermined for most patients (n ⫽ 124, 81%, Table1). Bilateral ocular involvement was more common in congenital OT than in the other groups of patients (11 of 13, 85% vs. 39 of 141, 28%, P ⬍ 0.001, Table 2). Serologic characteristics of the acute phase of systemic infection were present in 17 of 100 (17%) patients. Serologic characteristics of the chronic phase of systemic infection were present in 83 of 100 (83%) patients; for 54 patients serologic examinations were not available; Table 1). Serum IgG levels greater than 1:4096 were found for 16 patients, in 11 of 16 (69%) cases during the acute phase of systemic infection (in addition to IgM and/or IgA). Of the remaining five patients with IgG levels greater than 1:4096 (but without associated IgM and/or IgA), four had primary OT, and one already had recurrent ocular disease. Two peaks in presenting age were noted (Fig 2.). Active OT that became manifest during the chronic phase of systemic infection developed mainly between 15 and 35 years (mean, 29.9 years; range, 12–76 years), whereas active OT during the acute stage of systemic infection presented between 50 and 70 years (only four patients were younger than 40 years; mean, 50.6 years; range, 8 – 89 years). Of the 17 patients with serologic characteristics of the acute phase of systemic infection, 14 (82%) had primary OT (compared with 20 of 86 patients with serologic characteristics of the chronic phase of systemic infection, P ⬍ 0.001).

Characteristics of Retinal Lesions Locations of retinal lesions are summarized in Table 3. Central lesions developed in 108 of 204 (53%) affected eyes. Peripheral retinal lesions (outside the large vascular arcades) were present in 81 of 204 (40%) eyes (Table 3). Macular lesions were more common in the eyes of patients with a congenital infection (11 of 24 [46%] eyes vs. 29 of 180 [16%] eyes; P ⬍ 0.001), whereas peripheral lesions were more common among patients with postnatally acquired toxoplasmosis (10 of 19

872

[53%] eyes vs. 3 of 24 [13%] eyes, P ⫽ 0.006). Retinal lesions adjacent to the optic nerve, which became manifest in 23 of 109 (21%) patients during the chronic phase of systemic infection, were absent in patients with OT during the acute phase (0 of 19, 0%; P ⫽ 0.03). Extensive retinal lesions were observed more often during the acute phase of systemic infection (5 of 17 [29%] vs. 13 of 137 [9%] in the chronic phase; P ⫽ 0.02) and in patients with primary OT (8 of 37 [22%] vs. 10 of 117 [9%] with recurrent OT; P ⫽ 0.04). Of the patients with extensive primary lesions, four were initially diagnosed as having acute retinal necrosis (all had laboratory characteristics of the acute phase of systemic infection). During follow-up, extensive retinal lesions developed in 11 additional patients. Associated clinical characteristics during attacks of OT are given in Table 4. Intraocular inflammation was more severe in patients with postnatally acquired and/or primary OT (Table 4).

Treatment Treatment of the first attack of OT was identified in 125 patients (antiparasitic drugs for 12, combination of antiparasitic drugs with corticosteroids for 49, corticosteroids alone for 27, and no treatment for 37 patients, Table 5). To be included in the antiparasitic treatment groups, the drugs had to be administered for at least 4 weeks. Extensive retinal lesions developed more frequently among patients who received corticosteroids without antiparasitic medication or were receiving immunosuppressive therapy at the time of their first OT attack (10 of 27 [37%] vs. 19 of 98 [19%]; P ⫽ 0.05). Legal blindness of eyes with centrally located lesions (n ⫽ 69) was more common among patients who received corticosteroids without antiparasitic medications compared with those treated with antiparasitic drugs with or without the addition of corticosteroids (8 of 19 [42%] vs. 5 of 50 [10%]; P ⫽ 0.003). No further differences were observed between the treated and untreated patients (or within the different groups of treated patients, specifically no difference was found when patients treated with pyrimethamine and clindamycin regimens were compared) in the visual outcome, the number of future recurrences, or the interval between the initially treated attack and the onset of recurrent disease. Multiple active lesions, which occurred simultaneously during the same attack, were noted in 14 patients. Six of these patients (43%) had previously received corticosteroids without a shield of antiparasitic drugs (6 of 27 [22%] vs. 8 of 98 [82%]; P ⬍ 0.05).

Recurrences Recurrent OT developed in 92 of 154 (60%) patients, including 15 of 37 (41%) patients who were initially seen with primary OT (Table 6). The percentage of patients with recurrences increased with follow-up time. When old asymptomatic scars were considered to represent primary lesions of OT, the total number of patients with recurrent OT became 132 of 154 (86%). Recurrent OT became manifest in 84 of 172 (49%) eyes already affected with OT and in 3 of 107 (3%) initially healthy eyes (P ⬍ 0.0001). Mean interval between recurrences was 3 years (range, 2 months–25 years; median, 2 years). Of all patients for whom the interval between the first attack and the first recurrence was known (n ⫽ 82), 44 (54%) developed a recurrence within 2 years of the onset of the initial symptomatic retinal lesion. Recurrent OT after the age of 45 years occurred in 19 patients, 10 (53%) of whom developed their first manifestation of OT after the age of 45. No associations heralding the onset of recurrences were recognized. No differences in recurrence rates were observed between treated and untreated patients or among the different therapeutic modalities, between congenital and postnatal OT, and primary and recurrent OT (Table 6). Furthermore, the recurrence rate was not associated with the

Bosch-Driessen et al 䡠 Ocular Toxoplasmosis Table 3. Characteristics of Retinal Lesions in Ocular Toxoplasmosis (Affected Eyes) Location of Retinal Lesions (N ⴝ 204 eyes) Within Vascular Arcades (central) Macular Total (N ⫽ 204 affected eyes) Acquisition of infection Congenital OT (n ⫽ 24) Postnatally acquired OT (n ⫽ 19) Undetermined (n ⫽ 161) Serologic criteria Acute phase (n ⫽ 19) Chronic phase (n ⫽ 109) Undetermined (n ⫽ 76) Clinical criteria Primary OT (n ⫽ 39) Recurrent OT (n ⫽ 136) Undetermined (n ⫽ 29)

Adjacent to optic nerve

Other central location

Peripheral

Both Central and Peripheral

Extensive Retinal Lesions (⬎ 3 Optic Disc Diameters) at Presentation

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

40 (20)

35 (17)

33 (16)

81 (40)

15 (7)

18 (12)

11 (46) 4 (21) 25 (16)

1 (4) 0 (0) 34 (21)*

4 (17) 2 (10) 27 (17)

3 (13) 10 (53) 68 (42)

5 (20) 3 (16) 7 (4)

1 (8) 5 (29) 12 (10)

4 (21) 18 (17) 18 (24)

0 (0) 23 (21)* 12 (16)

2 (10) 16 (15) 15 (20)

10 (53) 47 (43) 24 (32)

3 (16) 5 (5) 7 (9)

5 (29) 11 (10) 2 (3)

6 (15) 28 (21) 6 (21)

9 (23)† 18 (13)‡ 8 (28)

3 (8) 27 (20) 3 (10)

18 (46) 53 (39) 10 (34)

3 (8) 10 (7) 2 (7)

8 (21) 10 (11) 0 (0)

*In four patients combined with other lesions; central (n ⫽ 2) or peripheral (n ⫽ 2). †

In one patient combined with other central lesions. In three patients combined with other lesions; central (n ⫽ 1) or peripheral (n ⫽ 1). OT ⫽ ocular toxoplasmosis.

‡

size of the retinal lesions, the presence of IgM and/or IgA, or the levels of serum IgG antibodies. Seven of the 82 (9%) female patients with OT developed recurrences of the ocular disease during pregnancy, 4 of them during every subsequent pregnancy. The total number of female OT patients with pregnancies was not known. Five of all 154 OT patients (3%) reported recurrences after blunt ocular trauma (n ⫽ 2) or after removal of a corneal foreign body (n ⫽ 3). Satellite lesions had developed in 105 of 132 (80%) patients with recurrent disease (including those with old subclinical scars). Isolated lesions, not adjacent to old scars, developed in 27 of 132 (20%) patients with recurrent disease. Isolated recurrent lesions were not associated with the age at onset of OT, presentation during the acute or chronic stage of systemic infection, or specific treatment regimens. Seventy-six OT patients were followed for at least 5 years (mean follow-up of 60 patients with recurrences was 14 years, for 16 patients without recurrences 13 years, difference not significant). Mean recurrence rate was 2.8 (range, 0 –10 recurrences per person). When patients with a single attack were excluded, the recurrence rate (for those with recurrent disease) was 3.5. When subclinical scars were considered as the first attack of OT and were added to the number of recurrences followed clinically, the mean recurrence rate per person increased to 3.8 (range, 0 –11 recurrences per person) and 4.6 for those with recurrent disease. Within the first 5 years of follow-up, recurrences developed in 33 of 60 (55%) patients; 22 (37%) patients developed recurrences after an interval of more than 5 years (range, 6 –17 years); for 5 patients (8%) the interval between the first attack and first recurrence was unknown. Of 76 OT patients who were followed for more than 5 years, 60 (79%) developed one or more recurrences resulting in a total number of 274 active OT attacks (first attacks and recurrences). Of these, 215 of 274 (78%) took place between the ages of 15 and 45 years (Fig 3). Recurrent disease in both eyes developed in 11 of 76 (14%) patients, 9 (82%) of whom had retinal scars in both eyes at the time of first presentation. Recurrences occurred in 10 of

25 (40%) contralateral eyes with subclinical retinal scars compared with only 2 of 51 (4%) unaffected contralateral eyes (P ⬍ 0.001).

Complications Complications developed in 67 of 154 (44%) patients, whereby 27 of 154 (18%) required at least one (intra)ocular surgical procedure. Cataracts developed in 20 of 154 (13%) patients, 14 of whom underwent a cataract extraction. Retinal detachment occurred in nine (6%) patients. Surgical removal of subretinal neovascularization was performed in one case and enucleation because of a painful atrophic eye in another. Complications were more frequent among patients presenting with active OT during the acute phase of systemic infection (12 of 17 [71%] vs. 38 of 83 [46%] for patients who were initially seen during the chronic phase; P ⫽ 0.05). Cataracts, ischemic retinal areas, and phthisis developed more frequently in patients with postnatally acquired and/or primary OT compared with the other groups of patients (Table 7). Anterior uveitis without any detectable retinal inflammation (n ⫽ 7) and retinal detachment (n ⫽ 9) occurred more often in patients who were seen during the acute phase of systemic infection than in those who were seen during the chronic phase of systemic infection (P ⫽ 0.03 and P ⫽ 0.007, respectively, Table 7). Of the 19 patients with cystoid macular edema during active attacks, only 2 patients developed persistent cystoid macular edema.

Visual Outcome Blindness in one eye developed in 37 of 154 (24%) patients (39 of 204 affected eyes, 19%). In 2 of 154 (1%) patients, both eyes became legally blind (both patients had congenital OT; 2 of 13 [15%] vs. 0 of 141 [0%]; P ⬍ 0.001). Legal blindness was caused predominantly by the macular location of the retinal lesion (29 of 37 [78%] patients; 31 of 39 [80%] eyes), followed by retinal detachment (5 of 37 [14%] patients; 5 of 39 [13%] eyes), and optic

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Ophthalmology Volume 109, Number 5, May 2002 Table 4. Clinical Characteristics of Patients with Ocular Toxoplasmosis Total

Mutton fat keratic precipitates Iridic granulomas Heterochromia Segmental atrophy of iris High intraocular pressure Scleritis Papillitis CME Vasculitis

Acquisition of Infection

N ⫽ 154 N (%)

Congenital Ocular Toxoplasmosis N ⫽ 13 N (%)

Postnatally Acquired Ocular Toxoplasmosis N ⫽ 17 N (%)

17 (11)

0 (0)

6 (4) 4 (3) 1 (0.6) 21 (14) 1 (0.6) 20 (13) 20 (13) 25 (16)

0 (0) 0 (0) 0 (0) 1 (8) 0 (0) 1 (8) 0 (0) 2 (15)

Serologic Criteria

P Value

Acute Phase N ⫽ 17 N (%)

Chronic Phase N ⫽ 83 N (%)

6 (35)

0.020

6 (35)

7 (8)

0.004

4 (24) 0 (0) 1 (6) 6 (35) 0 (0) 1 (6) 6 (35) 5 (29)

0.060 — 0.570 0.080 — 0.820 0.020 0.330

4 (24) 0 (0) 1 (5) 6 (35) 0 (0) 1 (6) 6 (35) 5 (29)

2 (2) 3 (4) 0 (0) 10 (12) 1 (1) 11 (13) 12 (14) 15 (18)

0.001 0.430 0.200 0.020 0.830 0.350 0.040 0.290

Clinical Criteria Recurrent Ocular Toxoplasmosis N ⫽ 93 N (%)

P Value

10 (27)

4 (4)

0.000

5 (14) 0 (0) 1 (3) 12 (32) 1 (3) 5 (14) 8 (22) 13 (35)

1 (1) 4 (4) 0 (0) 7 (8) 0 (0) 11 (12) 12 (13) 10 (11)

0.002 0.20 0.11 0.000 0.11 0.79 0.38 0.001

Primary Ocular Toxoplasmosis P N ⫽ 37 Value N (%)

CME ⫽ cystoid macular edema.

nerve atrophy (3 of 37 [8%] patients; 3 of 39 [7%] eyes). Legal blindness was more common among patients who had ever been treated with corticosteroids (oral and/or periocular administration) without antiparasitic drugs (compared with patients who received other or no treatments: 15 of 39 [38%] vs. 9 of 85 [11%]; P ⫽ 0.0004) and among patients with a central location of the chorioretinal lesions (29 of 88 [33%] eyes with central lesions vs. 6 of 81 [7%] eyes with peripheral lesions; P ⬍ 0.0001) and/or eyes with extensive retinal lesions (16 of 34 [47%] vs. 23 of 170 [14%]; P ⬍ 0.0001). Visual outcome was also poor for those with congenital toxoplasmosis and those who were seen during the acute phase of systemic infection (compared with patients for whom the moment of acquisition of the infection was unknown: legal blindness was found in 9 of 13 [69%] vs. 22 of 124 [18%]; P ⬍ 0.001 and 6 of 17 [35%] vs. 22 of 124 [18%]; P ⫽ 0.03, respectively). In patients with congenital OT, legal blindness was caused mainly by the macular location of scars (10 of 11, 91% eyes), whereas in patients with the onset of OT occurring during the acute phase of systemic infection, it was due mainly to the complications of intraocular inflammation (P ⫽ 0.03). The mean number of recurrences in legally blind and not legally blind eyes did not differ significantly (2.6 and 2.7, respectively). No additional risk factors for visual loss were identified; specifically, no difference in visual outcome was observed between treated and untreated patients.

Discussion This study describes the clinical features and visual outcome of OT in a large series of patients with OT. Legal blindness in at least one eye was found in 24% of all OT patients. The recurrence rate was 79% in patients with a follow-up of more than 5 years, and this was not influenced by the antiparasitic treatments used. Furthermore, in this study a higher risk of the development of recurrences was found for eyes with toxoplasmic scars (compared with eyes without detectable retinal scars; 49% vs. 3%; P ⬍ 0.0001). Visual prognosis was not affected by the use of multiple antiparasitic medications. Despite administration of the currently recommended treatment regimens, visual prognosis

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of OT has not improved over the last 50 years.17–22 The only effect of medications that we could identify was the poor visual outcome for those receiving corticosteroids without antiparasitic drugs. Mean age at first presentation with symptomatic OT in our study was 29.5 years, 60% of the cases became manifest between 15 and 35 years, which is similar to the mean age of first attacks reported previously.5,23 The exact age at onset of OT, however, remains unknown for most OT patients, because at the time of the first clinical presentation with active OT, quiescent subclinical retinochoroidal scars were already present in most patients (93 of 130; 72%). The presence of inactive retinal scars at the time of first presentation with active lesions has already been noticed.5,18,24 The presence of old scars (together with the absence of Table 5. Treatment Regimens of First Attacks of Ocular Toxoplasmosis* (n ⫽ 125) Treatment

Number of Patients

Pyrimethamine, sulfadiazine Pyrimethamine, sulfadiazine, prednisone Pyrimethamine, azithromycin Pyrimethamine, azithromycin, prednisone Clindamycin Clindamycin, prednisone Clindamycin, sulfadiazine, prednisone Corticosteroids None Miscellaneous†

7 23 2 10 2 12 1 27 37 4

*Treatment was given for at least 4 weeks, and dosages included pyrimethamine: first day 100 mg followed by 50 mg daily; sulfadiazine 4 ⫻ 1 g daily; azithromycin 500 mg every other day; clindamycin 4 ⫻ 300 mg daily; prednisone in combination with antiparasitic drugs: starting dose 60 mg with gradual taper off; prednisone solely: various dosages. Included erythromycin (n ⫽ 1), erythromycin with prednisone (n ⫽ 1), cotrimoxazole with prednisone (n ⫽ 2).

†

Bosch-Driessen et al 䡠 Ocular Toxoplasmosis Table 6. Recurrences in Ocular Toxoplasmosis

Total (n ⫽ 154) Acquisition of infection Congenital OT (n ⫽ 13) Postnatally acquired OT (n ⫽ 17) Undetermined (n ⫽ 124) Serologic criteria Acute phase (n ⫽ 17) Chronic phase (n ⫽ 83) Undetermined (n ⫽ 54) Clinical criteria Primary OT (n ⫽ 37) Recurrent OT (n ⫽ 93) Undetermined (n ⫽ 24)

Recurrences N (%)

Recurrences in Both Eyes N (%)

Mean Recurrence Rate

Mean Follow-up (in Years)

92 (60)

16 (10)

1.6

5.8

8 (62) 8 (47) 76 (61)

2 (15) 2 (12) 12 (10)

1.2 1 1.8

6.9 4.6 7.3

8 (47) 54 (65) 30 (56)

2 (12) 10 (12) 4 (7)

1 2 1.3

4.6 7.1 7.3

15 (41) 59 (63) 18 (75)

2 (5) 12 (13) 2 (8)

0.9 1.8 2.0

3.3 7.8 8.9

*Without subclinical scars. OT ⫽ ocular toxoplasmosis.

systemic symptoms and lack of serologic evidence of acute toxoplasmic infection) in most patients with OT might explain why this disease was previously attributed only to congenital infection.5,25–27 The more advanced age of patients with the onset of OT during the acute phase of systemic infection has already been reported and was attributed to the possible decline of cell-mediated immunity in the elderly.28,29 It is possible that there is a specific group of older patients at risk of developing OT in the wake of postnatally acquired infection. With the exception of immunosuppression in acquired immune deficiency syndrome or during the use of immunosuppressive therapy, the possible risk factors for the development of ocular involvement in the wake of postnatally acquired infections have not yet been identified. The frequency of ocular involvement in postnatally acquired toxoplasmosis is not known. Research into this aspect is difficult, because ocular involvement might become manifest after a long disease-free interval, at a time when the systemic disease has already entered its chronic phase.30 –33 So far, differentiation between a previous congenital and a previous postnatal infection by clinical or laboratory means is not possible. Therefore, the exact moment of acquisition of the infection is known only for patients with ocular involvement during the acute phase of infection (which is either congenitally or postnatally acquired). However, OT which becomes manifest in the wake of the chronic phase of the disease is far more common (83% compared with 11% in this series). Therefore, the ratio of congenital versus a postnatal origin of OT is still unknown. In The Netherlands, the annual infection risk of postnatal toxoplasmosis has been reported to be highest between the ages of 15 and 29 years.7 Patients of this age are not usually initially seen with OT and the serologic characteristics of the acute phase of systemic infection. Ocular symptoms even in this young group of patients might therefore represent a late complication of previously acquired postnatal disease and not a late manifestation of congenital infection, as previously presumed.30,32,33,34

We found a rate of 28% for primary ocular lesions in OT. Fourteen of these 37 (38%) patients with primary OT had the serologic characteristics of the acute phase of systemic disease. The remaining 23 patients with primary OT had the serologic characteristics of the chronic phase of infection. In the past, these patients would have been considered to have the ocular manifestations of congenital infection. Although intervals of more than 10 years between the initial moment of infection and onset of OT have been described for congenital disease and cannot be ruled out in all of these cases, it is not very likely that patients with primary OT that becomes manifest after the age of 40 years have congenital disease.35 Bilateral involvement in OT was previously reported to vary between 22% and 40%, which is consistent with the 32% found in this series.4,5,24,27,36,37 Bilateral involvement was observed in most patients with congenital toxoplasmosis (65%–97%), for our patients this percentage was 85%.18,38 – 40 The exact location of the lesions in OT was not reported in most of the previous studies.5,23,41 In our series, macular lesions were found in 58% of the patients with congenital toxoplasmosis, which is in agreement with ear-

Figure 3. Total number of attacks ( n ⫽ 274) of ocular toxoplasmosis according to age for 60 patients followed for at least 5 years.

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Ophthalmology Volume 109, Number 5, May 2002 Table 7. Complications of Ocular Toxoplasmosis Acquisition of Infection

Anterior uveitis without retinal involvement Posterior synechiae Cataract Vitreous hemorrhage Persistent vitreous activity/opacities Preretinal membranes Retinal vascular occlusion Ischemic retinal areas Subretinal neovascularization Retinal breaks Retinal detachment Optic nerve atrophy Phthiysis

Total N ⫽ 154 N (%)

Congenital Infection N ⫽ 13 N (%)

Postnatally Acquired Infection N ⫽ 17 N (%)

7 (5)

0 (0)

6 (4) 20 (13) 3 (2) 32 (21)

Clinical Criteria

P Value

Primary Ocular Toxoplasmosis N ⫽ 37 N (%)

Recurrent Ocular Toxoplasmosis N ⫽ 93 N (%)

P Value

2 (2)

0.030

7 (19)

12 (13)

0.380

1 (6) 7 (41) 1 (6) 6 (35)

4 (5) 7 (8) 0 (0) 15 (18)

0.850 0.000 0.170 0.110

2 (5) 8 (22) 1 (3) 9 (24)

3 (3) 7 (8) 2 (2) 17 (18)

0.560 0.020 0.850 0.440

0.600 0.170 0.080

2 (12) 3 (18) 4 (24) 0 (0)

7 (8) 4 (5) 3 (4) 1 (1)

0.660 0.060 0.020 0.830

3 (8) 6 (16) 5 (14) 0 (0)

8 (9) 1 (1) 3 (3) 1 (1)

0.930 0.001 0.030 0.530

0.430 0.260 0.570 0.310

0 (0) 4 (24) 1 (6) 2 (12)

6 (7) 2 (2) 3 (4) 0 (0)

0.310 0.007 0.860 0.030

1 (3) 4 (11) 2 (5) 2 (5)

7 (8) 4 (4) 4 (4) 0 (0)

0.300 0.160 0.790 0.030

P Value

Acute Phase N ⫽ 17 N (%)

Chronic Phase N ⫽ 83 N (%)

3 (18)

0.160

3 (18)

0 (0) 2 (15) 0 (0) 0 (0)

1 (6) 7 (41) 1 (6) 6 (35)

0.570 0.130 0.570 0.020

11 (7) 7 (4.5) 8 (5) 1 (4)

1 (8) 0 (0) 0 (0) 0 (0)

2 (12) 3 (18) 4 (24) 0 (0)

9 (6) 9 (6) 6 (4) 2 (1)

1 (8) 1 (8) 0 (0) 0 (0)

0 (0) 4 (24) 1 (6) 2 (12)

lier studies.18,42 However, a prospective study by Mets et al40 reports peripheral lesions in 64% of the patients with congenital toxoplasmosis. This difference might be explained by the asymptomatic nature of peripheral lesions that could lead to underestimation of their frequency in retrospective series, such as ours. Legal blindness in at least one eye developed in nearly one quarter of our patients. Main causes of legal blindness were macular location of the retinal lesions and retinal detachment, findings that are consistent with the literature.12,43 Ocular involvement during the acute phase of postnatal toxoplasmosis occurs predominantly in elderly patients.28,44 Large ocular lesions with severe vitritis, as well as granulomatous anterior segment inflammation frequently associated with elevated intraocular pressure, were also noted more frequently in this group of patients (Tables 3, 5, and 6).45,46 The poor outcome for these patients was previously (as mentioned earlier) attributed to a decrease in cell-mediated immunity at advanced age.29 It might be that, in addition to advanced age, the (probably underestimated) anterior segment features in postnatal OT, combined with poor visibility of the retina, also contributed to the (initial) incorrect diagnosis.29 The subsequent use of corticosteroids without the addition of antiparasitic drugs during the early phase of systemic toxoplasmosis may have contributed to the development of large lesions and the poor ocular outcome for these patients. However, the more severe inflammation might also be related to other, as yet unknown, parasiterelated or host-related factors. The poor prognosis for patients (wrongly) treated with corticosteroids without a shield of antiparasitic drugs was evident in this study and is consistent with previous findings.47,48 Seven patients had anterior uveitis without associated active retinal lesions; all already had old retinal scars. Severe anterior uveitis in OT has recently also been described

876

Serologic Criteria

in six immunocompetent patients with evidence of a recently acquired systemic toxoplasmosis infection.49 Anterior uveitis could be caused by the parasite itself, but it is also possible that small chorioretinal lesions were not detected at ophthalmoscopy.50,51 The development of recurrent disease in our study increased with follow-up time, being 79% for those followed for at least 5 years; most attacks occurred between the ages of 15 and 45 years. In the literature, recurrence rates of 40% to 78% were reported, but all of these studies had shorter follow-up periods.5,21,27,52 A decrease in recurrence rate to 7% to 14% after short-term (usually 6 –12 weeks) treatment with antiparasitic drugs has been found in occasional studies.17,20,22,53,54 However, the follow-up time in these studies was highly variable, sometimes less than 2 years, which might explain the discrepancies with our data. Furthermore, the presence of different T. gondii strains associated with differences in pathogenicity and sensitivity to therapies cannot be ruled out. A decrease in recurrence rate was reported after long-term (1 year) treatment of congenital toxoplasmosis with antiparasitic drugs, but again the follow-up time was limited.55 Because no data are available on the efficacy of long-term treatment of OT in immunocompetent adults, the question of whether the recurrence rate is really independent of treatment cannot be answered definitively. It has always been assumed that the risk of recurrence is low beyond the age of 45.56 Our study confirms this hypothesis, because the recurrence rate for this age group was low (5% to 12%). However, only occasional patients were followed beyond the age of 45, with the result that the determination of the exact recurrence rate for older patients is at present not feasible. However, the chance of recurrence at an advanced age is greater for patients who develop their first attack of OT after the age of 45. Recurrences occurred mainly in eyes with old subclinical scars (49%) in contrast to the “de novo” occurrence of OT

Bosch-Driessen et al 䡠 Ocular Toxoplasmosis in the previously nonaffected eye, which was seldom encountered (3%; P ⬍ 0.0001). This phenomenon, which was also noted for presumed ocular histoplasmosis syndrome, might be very valuable when counseling the individual patient.57 To summarize, nearly one quarter of our patients with OT developed legal blindness in at least one eye, and 79% of the patients on long-term follow-up developed recurrences, which occurred predominantly in eyes with old scars. So far, the various short-term therapeutic modalities used for OT have had no effect on visual outcome or future recurrence rates, with the exception of corticosteroid monotherapy that was associated with a poor visual outcome. Despite the limitations of the retrospective nature of this study, we have provided an up-to-date description of the clinical manifestations, course, and prognosis of OT. These data might be of value when advising and treating patients with this ocular infection and are crucial for future prospective studies.

References 1. Sabin AB, Eichenwald H, Feldman HA, Jacobs L. Present status of clinical manifestations of toxoplasmosis in man. JAMA 1952;150:1063–9. 2. Campbell Wilder H. Toxoplasma chorioretinitis in adults. Arch Ophthalmol 1952;48:127–36. 3. Remington JS, Jacobs L, Kaufman HE. Toxoplasmosis in the adult. N Engl J Med 1960;262:180 – 6. 4. Hogan MJ. Ocular toxoplasmosis in adult patients. Surv Ophthalmol 1961;6:935–51. 5. Friedmann CT, Knox DL. Variations in recurrent active toxoplasmic retinochoroiditis. Arch Ophthalmol 1969;81:481– 93. 6. Holland GN, O’Connor GR, Belfort R Jr, Remington JS. Toxoplasmosis. In: Pepose JS, Holland GN, Wilhelmus KR, eds. Ocular Infection and Immunity. St. Louis, MO: Mosby, 1996;1183–223. 7. Bosch-Driessen EH, Rothova A. Recurrent ocular disease in postnatally acquired toxoplasmosis. Am J Ophthalmol 1999; 128:421–5. 8. Ongkosuwito JV, Bosch-Driessen EH, Kijlstra A, Rothova A. Serologic evaluation of patients with primary and recurrent ocular toxoplasmosis for evidence of recent infection. Am J Ophthalmol 1999;128:407–12. 9. van der Veen J, Polak MF. Prevalence of toxoplasma antibodies according to age with comments on the risk of prenatal infection. J Hyg (Lond) 1980;85:165–74. 10. Kijlstra A, Luyendijk L, Baarsma GS, et al. Aqueous humor analysis as a diagnostic tool in toxoplasma uveitis. Int Ophthalmol 1989;13:383– 6. 11. de Boer JH, Verhagen C, Bruinenberg M, et al. Serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am J Ophthalmol 1996;121: 650 – 8. 12. Montoya JG, Parmley S, Liesenfeld O, et al. Use of the polymerase chain reaction for diagnosis of ocular toxoplasmosis. Ophthalmology 1999;106:1554 – 63. 13. Jones CD, Okhravi N, Adamson P, et al. Comparison of PCR detection methods for B1, P30, and 18S rDNA genes of T. gondii in aqueous humor. Invest Ophthalmol Vis Sci 2000; 41:634 – 44.

14. Kupfer C, Underwood B, Gillen T. Leading causes of visual impairment worldwide. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology: Clinical Practice. Philadelphia: Saunders, 1994;1249 –55. 15. McGavin DDM. The World Health Organization categories of visual impairment. Community Eye Health 1993;6:2. 16. Thylefors B, Negrel AD, Pararajasegaram R, Dadzie KY. Global data on blindness. Bull World Health Organ 1995;73: 115–21. 17. Fajardo RV, Furgiuele FP, Leopold IH. Treatment of toxoplasmosis uveitis. Arch Ophthalmol 1962;67:712–20. 18. O’Connor GR, Manifestations and management of ocular toxoplasmosis. Bull NY Acad Med 1974;50:192–210. 19. Tate GW Jr, Martin RG. Clindamycin in the treatment of human ocular toxoplasmosis. Can J Ophthalmol 1977;12: 188 –95. 20. Lakhanpal V, Schocket SS, Nirankari VS. Clindamycin in the treatment of toxoplasmic retinochoroiditis. Am J Ophthalmol 1983;95:605–13. 21. Rothova A, Buitenhuis HJ, Meenken C, et al. Therapy of ocular toxoplasmosis. Int Ophthalmol 1989;13:415–9. 22. Lam S, Tessler HH. Quadruple therapy for ocular toxoplasmosis. Can J Ophthalmol 1993;28:58 – 61. 23. Gilbert RE, Dunn DT, Lightman S, et al. Incidence of symptomatic toxoplasma eye disease: aetiology and public health implications. Epidemiol Infect 1999;123:283–9. 24. Rothova A. Ocular involvement in toxoplasmosis [published erratum appears in Br J Ophthalmol 1993;77:683] [review]. Br J Ophthalmol 1993;77:371–7. 25. Perkins ES. Ocular toxoplasmosis [review]. Br J Ophthalmol 1973;57:1–17. 26. Duke-Elder S, ed. System of Ophthalmology, vol. 15. Summary of Systemic Ophthalmology. St. Louis: Mosby, 1976; 158. 27. Saari M. Toxoplasmic chorioretinitis affecting the macula. Acta Ophthalmol (Copenh) 1977;55:539 – 47. 28. Montoya JG, Remington JS. Toxoplasmic chorioretinitis in the setting of acute acquired toxoplasmosis. Clin Infect Dis 1996;23:277– 82. 29. Johnson MW, Greven CM, Jaffe GJ, et al. Atypical, severe toxoplasmic retinochoroiditis in elderly patients. Ophthalmology 1997;104:48 –57. 30. Masur H, Jones TC, Lempert JA, Cherubini TD. Outbreak of toxoplasmosis in a family and documentation of acquired retinochoroiditis. Am J Med 1978;64:396 – 402. 31. Akstein RB, Wilson LA, Teutsch SM. Acquired toxoplasmosis. Ophthalmology 1982;89:1299 –302. 32. Melamed J. Acquired ocular toxoplasmosis-late onset. In: Nussenblatt RB, Whitcup SM, Caspi RR, Gery I, eds. Advances in Ocular Immunology. New York: Elsevier Science, 1994;449 –52. 33. Couvreur J, Thulliez P. Toxoplasmose acquise a`localisation oculaire ou neurologique. 49 cas. Presse Me´ d 1996;25:438 – 42. 34. Leblanc A, Bamberger J, Guillien F, et al. Choriore´ tinite toxoplasmique acquise a` re´ ve´ lation tardive. Arch Fr Pediatr 1985;42:37–9. 35. Peyron F, Wallon M, Bernardoux C. Long-term follow-up of patients with congenital ocular toxoplasmosis [letter]. N Engl J Med 1996;334:993– 4. 36. Melamed J. Clinical appearance of toxoplasmic retinochoroiditis. In: Dernouchamps JP, Verougstraete C, Caspers-Velu L, Tassignon MJ, eds. Recent Advances in Uveitis: Proceedings of the Third International Symposium on Uveitis. New York: Kugler Publications, 1993;283– 88. 37. Gilbert RE, Stanford MR, Jackson H, et al. Incidence of acute

877

Ophthalmology Volume 109, Number 5, May 2002

38. 39. 40. 41. 42. 43. 44. 45.

46. 47. 48.

symptomatic toxoplasma retinochoroiditis in south London according to country of birth. BMJ 1995;310:1037– 40. Feldman HA, Miller LT Congenital human toxoplasmosis. Ann NY Acad Sci 1956;64:180 – 4. Meenken C, Assies J, van Nieuwenhuizen O. Long term ocular and neurological involvement in severe congenital toxoplasmosis. Br J Ophthalmol 1995;79:581– 4. Mets MB, Holfels E, Boyer KM, et al. Eye manifestations of congenital toxoplasmosis. Am J Ophthalmol 1997;123:1–15. Koppe JG, Loewer-Sieger DH, De Roever-Bonnet H. Results of 20-year follow-up of congenital toxoplasmosis. Lancet 1986;1:254 – 6. Roizen N, Swisher CN, Stein MA, et al. Neurologic and developmental outcome in treated congenital toxoplasmosis. Pediatrics 1995;95:11–20. Bosch-Driessen EH, Karimi S, Stilma JS, Rothova A. Retinal detachment in ocular toxoplasmosis. Ophthalmology 2000; 107:36 – 40. Ronday MJH, Luyendijk L, Baarsma GS, et al. Presumed acquired ocular toxoplasmosis. Arch Ophthalmol 1995;113: 1524 –9. Pillat A, Thalhammar O. Herdfo¨ rmige iridocyclitis als (einzige) manifestation einer erworbenen toxoplasmose, a¨ tiologisch gesichert durch titerkurve und tierversuch. Graefes Arch Clin Exp Ophthalmol 1957;158:403–15. Spaulding AG, Font RL. Acquired toxoplasmic chorioretinitis. Surv Ophthalmol 1967;12:16 –23. Bosch-Driessen EH, Rothova A. Sense and nonsense of corticosteroid administration in the treatment of ocular toxoplasmosis [review]. Br J Ophthalmol 1998;82:858 – 60. Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: Funda-

878

49.

50. 51. 52.

53. 54. 55.

56. 57.

mentals and Clinical Practice, 2nd ed. St. Louis: Mosby, 1996;211–28. Holland GN, Muccioli C, Silveira C, et al. Intraocular inflammatory reactions without focal necrotizing retinochoroiditis, in patients with acquired systemic toxoplasmosis. Am J Ophthalmol 1999;128:413–20. Rehder JR, Burnier MB Jr, Pavesio CE, et al. Acute unilateral toxoplasmic iridocyclitis in an AIDS patient. Am J Ophthalmol 1988;106:740 –1. Auer C, Bernasconi O, Herbort CP. Indocyanine green angiography features in toxoplasmic retinochoroiditis. Retina 1999;19:22–9. Timsit JC Bloch-Michel E. [Efficacy of specific chemotherapy in the prevention of recurrences of toxoplasmic chorioretinitis during the 4 years following treatment]. J Fr Ophtalmol 1987; 10:15–23. Canamucio CJ, Hallett JW, Leopold IH. Recurrence of treated toxoplasmic uveitis. Am J Ophthalmol 1963;55:1035–9. Guldsten H. Clindamycin and sulphonamides in the treatment of ocular toxoplasmosis. Acta Ophthalmol (Copenh) 1983;61: 51–7. Mc Auley J, Boyer KM, Patel D. Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial [published erratum appears in Clin Infect Dis 1994;19:820]. Clin Infect Dis 1994;18:38 –72. Desmonts G. Definitive serological diagnosis of ocular toxoplasmosis. Arch Ophthalmol 1966;76:839 –51. Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: Fundamentals and Clinical Practice, 2nd ed. St. Louis: Mosby, 1996;229 –37.