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Multiple cases of acquired toxoplasmosis retinitis presenting in an outbreak
Multiple Retinitis
Cases of Acquired Toxoplasmosis Presenting in an Outbreak
Andrew J. Burnett, MD,’ Stanley G. Shortt, MD,’ Denise Werker, MD,5 William R. Bowie, MD6
Judith Isaac-Renton,
MD,2,3 Arlene King, MD,4
Objective: The purpose of the study was to examine the variability in presentation and outcome of individuals presenting with acquired toxoplasmosis retinitis in the setting of an outbreak of the disease. Design: The study design was a case series. Participants: Twenty-one eyes of 20 patients with equal gender distribution and a mean age of 54 years followed for 38 to 170 weeks (mean 113.7 weeks) were studied. Intervention: Systemic antimicrobials and corticosteroids when indicated were given. Main Outcome Measures: Visual acuity, media inflammation and clarity, resolution of active retinitis, and appearance of recurrences were observed. Results: Fifteen of 21 lesions were active, and 7 of the total number of lesions fell within the macula-peripapillaty region. Overall, vision improved with treatment except in cases of macular invplvement (3 cases) and persistent vitritis (3 cases). Four recurrences have occurred to date. Conclusions: This is the largest repot-ted outbreak of acquired toxoplasmosis retinitis occurring within a single outbreak. Twenty-one eyes of 20 patients presented with retinal lesions, and on average, those treated for active retinitis had improvement in vision. Ophthalmology 7998; 705:7032- 7037
Toxoplasma go&ii is an ubiquitous, obligate intracellular protozoan and is considered to be the most common cause of infective retinitis in humans.’ Its definitive host is the cat, and intermediate hosts include many animals including humans. Most cases of retinitis have been thought to be congenital in origin with periodic reactivations.“’ Studies in southern Brazil suggest an acquired etiology in most of the affected population of that area.4,s Recently, Montoya and Remington6 suggested that postnatally acquired toxoplasmosis retinochoroiditis in the United States might be more prevalent than realized previously. Several reports of well-documented acquired retinitis exist in the English literature, but these have been isolated cases.7-‘5 To our knowledge, there has been no report of multiple cases of acquired toxoplasmosis retinitis presenting during an epidemic of the infection. Originally Revision
received: accepted:
January 23, 1997. December 5, 1997.
I Section of Ophthalmology, Department of Surgery, Capital Health Region, Victoria, British Columbia, Canada. * Provincial Laboratory, British Columbia Center for Disease Control, Vancouver, British Columbia, Canada. ’ Department ish Columbia,
of Pathology Vancouver,
and Laboratory Medicine, University British Columbia, Canada.
4 Epidemiology Services, British Columbia Vancouver, British Columbia, Canada.
Centre
5 Field Epidemiology Training Program, Laboratory Control, Health Canada, Ottawa, Ontario, Canada. ’ Division of Infectious Diseases, University couver, British Columbia, Canada. Reprint requests Victoria, British
1032
for Disease Centre
of Brmsh
Control,
for Disease
Columbia,
to Andrew J. Burnett, MD, Suite 322, Columbia V8R 6R3, Canada.
of Brit-
Van-
1964 Fort St,
A well-documented outbreak of acquired T. gondii infection occurred in the Greater Victoria area of British Columbia between October 1994 and March 1995, the details of which are described elsewhere.16 During the first 3 months of 1995, seven cases (8 eyes) of acute retinitis with serologic analysis compatible with that of acquired toxoplasmosis were referred to two of the authors (AJB, SGS) by general ophthalmologists and family doctors in the community. Concurrently, the Provincial Laboratory, which performs all serologic analysis for T. gondii in the province, noted a sudden increase in acute toxoplasmosis in Greater Victoria. Positive sera were not only derived from individuals with acute retinitis but from others presenting with lymphadenopathy and constitutional symptoms compatible with the diagnosis. In addition, serologic screening was offered to women in Greater Victoria who were pregnant at any time between October 1994 and the end of April 1995 and yielded 37 cases. In total, 100 patients with acquired and 12 patients with congenital toxoplasmosis were identified. Overwhelming epidemiologic data suggest municipal drinking water as the source of the outbreak. Twenty patients (21 eyes) presented with retinal findings, and examination of 77 of the remaining 80 patients with acquired toxoplasmosis failed to show any evidence of present or past retinitis. The remaining three patients were not examined (two unable to locate, one refused). Six of the 12 patients with congenital toxoplasmosis have retinal scars compatible with the disease, 3 of which are bilateral. We present the 20 cases (21 eyes) of serologically proven acquired toxoplasmosis retinitis presenting in Greater Victoria during the course of 1995.
Burnett et al - Acquired
Methods Cases were studied at the time of initial referral. A case was defined as an individual with serologic findings consistent with acquired toxoplasmosis and evidence of retinal involvement. A full ophthalmic examination, including refraction, tonometry, slit-lamp assessment, and dilated fundus evaluation with indirect ophthalmoscope and contact lens, was performed at initial assessment. Fundus photography and, when appropriate, fluorescein angiography were performed on all patients. Serum for testing was obtained at the time of presentation and at different intervals during follow-up. Details regarding the serologic investigation of cases have been reported previously.‘h Confirmation of immunoglobulin M (IgM) and immunoglobulin G (IgG) (Sabin-Feldman Dye Test) levels was performed in the Toxoplasma Serology Laboratory, Research Institute, Palo Alto Medical Foundation, Palo Alto, California. The differential agglutination test has been described to characterize infections acquired recently or in the past.” The basis of the interpretation of this AC/HS ratio determination relates to the observation that IgM antibodies produced at different stages of infection react differently to epitopes presented by different preparations (methanol-fixed [AC antigen] or formalin-fixed [HS antigen]) of Toxoplasma tachyzoites. This test also was performed in the Toxoplasma Serology Laboratory in Palo Alto. In many cases, follow-up sera were obtained every 3 months. All patients were interviewed in their home or by telephone by the Epidemiology Services of the British Columbia Centre for Disease Control, Vancouver, British Columbia, to identify risk factors for and signs and symptoms of toxoplasmosis. In addition, the general medical history was reviewed with the patient and family doctor, and, where appropriate, further evaluation and investigations were performed.
Results Twenty-one eyes of 20 patients presented during 1995 with clinical and serologic evidence of acquired T. go&ii retinitis. The epidemiologic study of the outbreak population lists a total of 19 “eye” cases and classifies 1 individual (case 11) as a “node” case in view of his presenting complaint being a mass in the groin.‘” The mean age at the time of presentation was 56 years, with a range of 1.5 to 83 years. The number of males and females was equal. None of the patients were known to have an immunocompromising illness, although case 4 was taking systemic corticosteroids for presumed polymyalgia rheumatica. Follow-up intervals varied depending on the severity of the disease and the response to treatment. Repeat evaluation included full examination of the involved eye and survey of the opposite retina with indirect ophthalmoscope. Mean follow-up was 113.7 weeks, with a range of 38 to 170 weeks. Eight of 20 patients had systemic symptoms and signs consistent with those attributed to acute T. gondii infection. All predatedthe onsetof ophthalmicsymptoms,with a meanof 6 weeksand a range of 2 to 12 weeks.All eight had a loss of energyand a senseof ill health.Sevenof eight patientsreported night sweats,and six of eight patients had fever and chills. Headachewasprominentin sevenof eight patients,andlymphadenopathywasreportedin five of eight. The lymphadenopathy was not necessarilysubstantiatedby a physician. All patients had ophthalmicsymptomsconsistingof floaters, hazy vision,
Toxoplasmosis
Retinitis
or both, with onset0.4 to 26 weeks (mean,8 weeks)before their first visit. Eleven right andten left eyeswere affected. Nineteencases were unilateralwith onebilateral case.Initial visual acuity varied from 20120to hand movements(Table 1). As expected, poorer levels of acuity were seenin patientswith macularlesionsor significantvitritis. Sixteen(76%) of 21 eyeshad anterior chamberreactions,9 of thesehaving granulomatous keratic precipitates.Four of the six eyeswith inactive lesionsdid have someanteriorchamberacti\ ity. Intraocularpressures, measured by applanationtonometry, varied at the time of presentation from 10 to 40 mmHg, with a meanof 21 mmHg. Eyes with keratic precipitateshad a mean of 27 mmHg (range, 16-40 mmHg), and those eyes without keratic precipitateshad 17 mmHg (range,16-40 mmHg).Twenty of the eyeshad a vitreousreactionvarying from cellsabovethe lesionto a generalized vitritis (3 of 21 eyes)with decreasedvision. The location of the lesionswas categorized as described by Holland,lx in which classificationof lesionlocation loosely correlateswith its long-term visual significance.Zone 1 is an area3000pm (2 discdiameters)from the fovea (approximately the areaenclosedby the major temporalvasculararcades)or 1500 pm from the margin of the optic nerve head. Zone 2 extendsanteriorfrom the borderof zone 1to the clinical equator of the eye, identified by the anteriorborder of the ampullaeof the vortex veins. Zone 3 exlendsfrom zone 2 to the ora serrata. Sevenlesionsfell within zone 1, andthe remaininglesionsfell within zone 2, with no lesionsin zone 3 alone. Fifteen active and six inactive lesionswere identified. All patientshad solitary lesions.Lesion activity was defined by appearance.Active lesionswere subdivided accordingto the classificationof FriedmanandKnox.” Largedestructivelesions generallywere raised,creamy yellow patcheswith geographic outline and ill-defined edges.Fourteenof the 15 active lesions fit this description.One lesion (case3) was primarily outer retinal in location at the time of presentationand becamefull thicknesswithin 2 weeks. Inactive lesionshad well-defined edgeswith retinal pigmentjspithelialatrophy and, on occasion, somepigment clumping, minimal overlying vi&is, and no areasfitting the descriptionof an active lesion. Lesion size was measuredin disc areasby clinical observationand, where possible,correlatedwith fundusphotography.Size varied from 1 disc area(DA) in two eyes,2 DA in eight eyes,3 DA in five eyes,and4 DA in six eyes,with a meanlesionsizeof 2.7 DA. No casesof papillitis, neuroretinitis,or retinal vascularocclusionwere seen.Macular edemawaspresentin three zone 1 lesionsthat did not affect the maculadirectly. In the caseof the outer retinal lesion(case3), subretinalfluid extendedunder the fovea. An exudative macularstarwaspresentfor 9 months in a45-year-oldwomanwith 1 DA-sized lesionalongthe inferotemporalarcade(case16) (Figs I, 2). Sabin-FeldmanDye Test resultsvaried from a titer of 1:512 to 1:256,000with a medianof 1:8000.The IgG (ELISA) results were greateror equalto 240 IU in 18 of 20 patientswith 216 IU and 209 IU reportedin the remaining2 patients.The IgM (ELISA) serologicresults were 100% reactive. The fixation indices on the tests varied from 3.4 to greater than 10. The differential agglutinationtest resultswere consistentwith those of infections acquiredrecently in all cases(Table 2). No case of acuteretinitis was seenduring the courseof the outbreak with nonacuteserology. Topical treatmentof iritis wasaccomplishedwith corticosteroids and cycloplegics, and managementof raisedintraocular pressurewas achievedwith topical beta-blockersand,in some cases,with the addition of a systemiccarbonic anhydraseinhibitor. 1033
Ophthalmology Table
Case No.
Age* (yrs)
1 2 3 4a 4b 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20
Sex
30 48 26 79 79 44 83 83 40 77 67 32 49 16 15 ;; 74 56 83 66
M F M F F M M F M F F M M F M F F M M F F
Follow-up (wks)
Eye Involved
R R R R L L L R L R R L R L L R R L L R L
121.3 129.3 47.0 129.7 129.7 133.0 64.711 170.4 135.0 132.6 140.3 105.9 86.1 105.6 158.3 86.7 121.4 38.1 152.4 137.1 79.9
Initial Acuity?
20/30 20/20 20160 lcl/400 201200 20150 2;:o 20150 20170 20130 20120 20/20 20120 20130 5/400 20/400 5/400 20150
Volume 105, Number 6, June 1998 1. Patient
Latest Acuity?
20125 20120 20120 1o/400 20160 20125 20140 NLP 20/20 20150 20/30 2Ol20 20/50 20120 2($40 s/400 20/40 20160 20/200 20140 20120
Clinical
Lesion Zone
Data
Lesion Activity
2 2 2 2
2(1)P 1 1 1 2 2 2 2 2 2 1 1 1 :(I,5 2 2
A A A I A A A A A A I 1 A 1 A 1 A A A A 1
and Outcomes Toxoplasmosis Pathology Affecting Visual OutcomeS
Other Pathology Affecting Visual Outcome
MH cat
wt, phs
wt ERM cat
tm fib fib wt, ret cat
Treatment
T/S + T/S T/S + T/S + T/S + T/S + T/S + S/P + T/S + C+P+M N N T/S + N T/S + N T/S + T/S + T/S + T/S + N
I’ I’ P P P + c P P P
Treatment Duration (wkd
3 3 3 3 3 4 3 4 4 6
P
3
P
4
P P P I’
3 3 4 3
HM = hand movements; NLP = no light perception; A = active retmitis; I = inactive lesion; vlt = vitritis; phs = phthlsls; tm = macular tractlon; fib = macular fibrosis; ret = recurrent lesion in macula; cat = cataract, ERM = epiretinal membrane, MH = macular hole; N = none; T/S = trimethoprim/sulfamethoxazole; P = prednisone; C = clmdamycin; M = minocychne; S/P = sulfadlazme + pyrimethamine (with leucovorin). * Age at time of presentation. t Snellen
acuity measured
in feet.
t Pathology affectmg visual outcome related to toxoplasmosis 5 Initial lesion in zone 2 with recurrence in zone 1.
retinitis.
11Deceased.
Eleven of the patients treated by the authors (AJB, SGS) began a combination of oral trimethoprim 160 mg and sulfamethoxazole 800 mg (Bactrim DS; Roche, Nutley, NJ) twice daily for 3 to 4 weeks with the addition of prednisone 1 mg/kg per day for 4 days and then tapered off over 3 to 4 weeks. The latter was begun at the same time as the antimicrobial combination with no ill effect observed. No medication-related complications were noted in the group treated by the authors. One patient was treated with the same regimen with the addition of clindamycin and another with the combination drug but no steroid. Other variations included traditional triple therapy of sulfadiazine, pyrimethamine, and prednisone with folinic acid coverage (case 7) and clindamycin with prednisone, the former later changed to minocycline after the appearance of a rash (case 9). The visual outcome is shown in Figures 3 and 4. A trend suggesting improving acuity with time is evident, especially in the group of zone 1 lesions. Lack of improvement was caused by ongoing vitritis with inactive lesions in three patients, necessitating pars plana vitrectomy in two patients (cases 7 and 9), pre-existing macular epiretinal membrane (case 10) and macular hole (case 4a), retinal folds in one macular lesion (case 14), and macular scarring in another (case 15). Case 7 had ongoing vitritis after vitrectomy despite repeat antimicrobial and steroid treatment and has gone on to phthisis. Changes in the size of lesions with treatment were not actively documented. Four recurrences have been reported to date: one adjacent to a perimacular lesion but on the distal side in an 83-year-old man 43 weeks after initial presentation (case 6),
1034
one new lesion in at 26 weeks (case of an 83-year-old lesion in the right weeks (case 15).
the center of the fovea in a 56-year-old man 18), one new lesion in the left posterior pole woman at 13 weeks (case 4), and one new midperiphery of a 75year-old woman at 61
Discussion For the sake of simplicity,
the word
“retinitis”
is used
throughout this article. The authors are well aware of the secondary choroidal inflammatory response in most lesions. This case series is presented to show the variability in presentation as well as some of the unusual, albeit not unique, features seen. The extremely high antibody levels, the preponderance of large lesions, and the older mean age of the patients stand out in this regard. This series also shows the generally satisfactory outcome with relatively simple antimicrobial and steroid treatment. The antibody levels measured in the patients involved in this outbreak are much higher than those usually seen in patients with acute acquired T. go&i infection in Canada and the United States. Sabin-Feldman Dye Test titers in the order of 1:128,000 and 1:256,000 are seldom reported. It is noteworthy that all patients had an acute
Burnett et al * Acquired
Figure
1. Case 16. Fundus photograph
of lesron at the ttme of presentation.
Figure
2. Case 16. Fundus photograph
of lesmn 2 months
htstogram
of visual acmties
Retinitis
after treatment.
Figure 3. Three-dtmenstonal htstogram of wsual acutttes before all mtervals except 12 months, where n = 5. Figure 4. Three-drmenstonal for all mtervals.
Toxoplasmosis
and at dtfferent
Intervals
before and at different
pattern in the AC/HS differential agglutination test, suggesting recently acquired infections. The immunoglobulin E (IgE) ELBA test is the first to show positive titers after the onset of infection, the titers showing a rapid rise and then fall to undetectable levels in a few months. As a consequence, acute acquired infection serology often fails to show this short-lived positive IgE level. In this series, more than half (11 of 20) show positive IgE titers. An explanation for the magnitude of these antibody levels is unclear. A possibility includes an extremely large inoculum or a unique strain of the parasite capable of eliciting an excessive antibody response or both (Dr. JS Remington, personal communication, June 23, 1997). Scrutiny of the lesions shows no significant differences in characteristics from those described in other cases of acquired retinitis, although the prevalence of larger lesions was noticeable. Eleven of the 21 lesions were 3 to 4 DAs in size, with an overall mean of 2.7 DA. Although the lesion sizes are not noted in all cases described in the literature, they tend to be smaller lesions with a 1 to 2
intervals
after the onset of treatment
after the onset of treatment
for zone 1 lessons; n = 6 eyes for
for zone 2 lessons; n = 10 eyes
DA size. Insufficient colmparative data are available to attach significance to this factor. The mean age of 54 years old is higher than expected and significantly higher than the mean age of the noneye cases in the outbreak (27.7 years) (P = 0.000004). Individual cases of acquired toxoplasmosis retinitis reported in the literature have a mean age of 29.4 years (9 patients),7-‘” but the mean age of the 22 patients accumulated by Montoya and Remington6 is 50.2 years, which is more consistent with our experience. Other studies show patients with mixed congenital and acquired retinitis presenting with reactivations or first episodes have mean ages of 25.319 and 28.6 years.’ The reason for the higher mean age in this group is unclear. In the first case-control study performed as part of the investigation of this outbreak, which was comprised of 39 cases, including 14 patients in this series, there were no significant differences on univariate-matched analyses performed in Epi Info ~6.02 (Centers for Disease Control, Atlanta, GA) between patients and their matched control subjects in those per1035
Ophthalmology
Volume 105, Number
6, June 1998
Table 2. Results of Initial SerologicTesting Case NO. 2
6 7 8 9
10 11 12 13 14 15 16 17 18 19 20
Dye Test* 32,000 32,000 128,000 256,000 8000 32,000 8000 2048 4096 2048 512 8000 64,000 16,000 2048 128,000 4096 1024 128,000 8000
1gG ELBA NJ) >240 >240 >240 >240 >240 216 >240 >240 209 ~240 >240 >240 >240 >240 >240 >240 >240 >240 >240 >240
IgM ELBA WI) R(>lO.O) R(>lO.O) R( 10.0) R(9.2) R(>lO.O) R(9.4)
R(14.5) R(3.4) R(8.8) R(6.3) Rt5.6) Ri10.4) R(8.4) R(5.6) R(6.6) R(8.7) R(7 7) R(5.3) R(>lO.O) R(4.4)
IgE ELISA
IgA ELISAt
P P P N
P(14.1) P(5.8) P(5.6) NA P(3.4) NA P(2.2) P(7.9) P(20.0) N(1.4) P(5.1) Pi8.4j P(21.1) P(12.1) N(0.8) NA P(3.2) P(20.8) P(18.5) P(7.2)
N N N
E
AC/f33
PatternS
>1600/>3200 > 1600/3200 >1600/>3200 > 1600/>3200 >1600/1600 800/800 >1600/1600 > 1600;3200 >1600/1600 > 1600/800 > 1600/3200 800/800 800/3200 > 1600/l 600 > 1600/>3200 > 1600/l 600 >1600/>3200 > 1600/l 600 >1600/>3200 >1600/>3200
FI = fixation Index; R = reactive; I’ = positive; N = negatwe; E = equivocal; NA = not avadable. * Sabn-Feldman dye test, reciprocal of titer. t Reciprocal of titer. $ Differential agglutmatlon test (all patterns consistent wth Infection acquired recently).
sonal habits or lifestyles that were explored as potential risk factors for acquiring toxoplasmosis (unpublished data, 1995). The question of age-related predisposition has been entertained. The interface between host factors, such as age, and parasite factors, such as pathogenicity, is not understood. Whether the specific outbreak-causing strain of Toxoplasma predisposesto ocular trophism is not known. Whether the organism involved was more virulent, and therefore more invasive or more destructive, is speculative. Additionally, the parasite inoculum might have been a contributing factor, either because of the inoculum size or becausethe infective form was oocysts rather than tissue cysts. The size of the inoculum is unknown and cannot be determined. Oocysts are, however, known to be highly infective.2”‘2’ Based on the positive experience of Rothova et a12* and Opremcak et al” and considering the cost, toxicity, and uncertain availability of traditional triple therapy, we elected to treat patients with the trimethoprim-sulfamethoxazole combination and prednisone. The question of a reduction in lesion size with treatment was not formally addressedand so cannot be compared with the results of Rothova et a1,22showing a reduction of lesion size with triple therapy compared with our regimen. The incidence of acquired toxoplasmosis retinitis as a presenting sign in this outbreak cannot be calculated without knowing the total number of infected individuals. The epidemiologic studies associated with this outbreak showed a rate of infection of 0.9% in the 3812 screened pregnant women and 2.4% in potential control subjects screened for 1 of the case-control studies. Considering the population of Greater Victoria in 1994 was estimated
1036
at 321,585, an estimated 2894 to 7718 individuals were infected.16 Therefore, in this outbreak, between 0.26% and 0.69% of those presumed to be infected presented with retinitis. No data are available to ascertain the number of eye casesnot captured in this study. Although it is probable that the more severe casescame to our attention, we have no data to addressthis possibility. This is the largest reported seriesof acquired toxoplasmosis retinitis related to a single outbreak. Lesions were consistent with acute toxoplasmosis retinitis, and serologic testing confirmed the acute acquired nature of the infection. Responseto treatment generally was favorable, although the potentially destructive nature of the disease in the eye was well shown.
References Tabbara KF. Ocular toxoplasmosis. 14:349-51.
Int Ophthalmol
1990;
PerkinsES. Ocular toxoplasmosis.Br J Ophthalmol 1973; 57:1-17. NussenblattRB, Belfort R Jr. Ocular toxoplasmosis:anold diseaserevisited.JAMA 1994;271:304-7. GlasnerPD, Silveira C, Kruszon-Moran D, et al. An unusually high prevalence of ocular toxoplasmosis in Southern Brazil. Am J Ophthalmol 1992;114:136-44. 5. Silveira C, Belfort R, Bumier M, et al. Acquired toxoplasmic infection as a cause of toxoplasmic retinochoroiditis
in families.Am J Ophthalmol1988;106:362-4. 6. Montoya JG, RemingtonJS. Toxoplasmicchorioretinitisin
Burnett
7. 8. 9. 10. 11. 12. 13. 14. 1.5.
et al * Acquired
the setting of acute acquired toxoplasmosis. Clin Infect Dis 1996:23:277-82. Kayhoe DE, Jacobs L, Beye HK, et al. Acquired toxoplasmosis. N Engl J Med 1957;257:1247-54. Neumann CG, Hilton C, Barreda A. Acquired toxoplasmosis in a child. Am J Dis Child 1960; 100: 14 l-4. Saari M, Vuorre I, Neiminen H, et al. Acquired toxoplasmic chorioretinitis. Arch Ophthalmol 1976;94: 1485-8. Michelson JB, Shields JA, McDonald PR, et al. Retinitis secondary to acquired toxoplasmosis with isolation of the parasite. Am J Ophthalmol 1978; 86:548-52. Masur H, Jones TC, Lempert JA, et al. Outbreak of toxoplasmosis in a family and documentation of acquired retinochoroiditis. Am J Med 1978;64:396-402. Gump DW, Holden RA. Acquired chorioretinitis due to toxoplasmosis. Ann Intern Med 1979;90:58-60. Akstein RB, Wilson LA, Teutsch SM. Acquired toxoplasmosis. Ophthalmology 1982;89: 1299-302. Hausmann N, Richard G. Acquired ocular toxoplasmosis. Ophthalmology 1991;98:1647-51. Opremcak EM, Scales DK, Sharpe MR. Trimethoprim-Sulfamethoxazole therapy for ocular toxoplasmosis. Ophthalmology 1992;99:920-5.
Toxoplasmosis
Retinitis
16. Bowie WR, King AS, Werker DH, et al. Outbreak of toxoplasmosis associated wi1.h municipal drinking water. Lancet 1997;350:173-7. 17. Dannemann BR, Vaughan WC, Thulliez P, et al. Differential agglutination test for diagnosis of recently acquired infection with Toxoplasma go&ii. J Clin Microbial 1990;28: 1928-33. 18. Holland GN, Buhles WC, Mastre B, et al. A controlled retrospective study of g.lncyclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. Arch Ophthalmol 1989; 107: 1759-66. 19. Friedmann CT, Knox DL. Variations in recurrent active toxoplasmic retinochoroiditis. Arch Ophthalmol 1969; 8 I:48 I -93. 20. Miller NL, Frenkel JK, Dubey JP. Oral infections with Toxoplasma cysts and oocysts in felines, other mammals, and in birds. J Parasitol 1972;58:928-37. 21. Dubey JP, Lunney JK, Shen SK, et al. Infectivity of low numbers of Toxoplasmic gonclii oocysts to pigs. J Parasitol 1996;82:438-43. 22. Rothova A, Meenken C, Buitenhuis HJ, et al. Therapy for ocular toxoplasmosis, Am J Ophthalmol 1993; 115:5 1723.
1037
Cases of Acquired Toxoplasmosis Presenting in an Outbreak
Andrew J. Burnett, MD,’ Stanley G. Shortt, MD,’ Denise Werker, MD,5 William R. Bowie, MD6
Judith Isaac-Renton,
MD,2,3 Arlene King, MD,4
Objective: The purpose of the study was to examine the variability in presentation and outcome of individuals presenting with acquired toxoplasmosis retinitis in the setting of an outbreak of the disease. Design: The study design was a case series. Participants: Twenty-one eyes of 20 patients with equal gender distribution and a mean age of 54 years followed for 38 to 170 weeks (mean 113.7 weeks) were studied. Intervention: Systemic antimicrobials and corticosteroids when indicated were given. Main Outcome Measures: Visual acuity, media inflammation and clarity, resolution of active retinitis, and appearance of recurrences were observed. Results: Fifteen of 21 lesions were active, and 7 of the total number of lesions fell within the macula-peripapillaty region. Overall, vision improved with treatment except in cases of macular invplvement (3 cases) and persistent vitritis (3 cases). Four recurrences have occurred to date. Conclusions: This is the largest repot-ted outbreak of acquired toxoplasmosis retinitis occurring within a single outbreak. Twenty-one eyes of 20 patients presented with retinal lesions, and on average, those treated for active retinitis had improvement in vision. Ophthalmology 7998; 705:7032- 7037
Toxoplasma go&ii is an ubiquitous, obligate intracellular protozoan and is considered to be the most common cause of infective retinitis in humans.’ Its definitive host is the cat, and intermediate hosts include many animals including humans. Most cases of retinitis have been thought to be congenital in origin with periodic reactivations.“’ Studies in southern Brazil suggest an acquired etiology in most of the affected population of that area.4,s Recently, Montoya and Remington6 suggested that postnatally acquired toxoplasmosis retinochoroiditis in the United States might be more prevalent than realized previously. Several reports of well-documented acquired retinitis exist in the English literature, but these have been isolated cases.7-‘5 To our knowledge, there has been no report of multiple cases of acquired toxoplasmosis retinitis presenting during an epidemic of the infection. Originally Revision
received: accepted:
January 23, 1997. December 5, 1997.
I Section of Ophthalmology, Department of Surgery, Capital Health Region, Victoria, British Columbia, Canada. * Provincial Laboratory, British Columbia Center for Disease Control, Vancouver, British Columbia, Canada. ’ Department ish Columbia,
of Pathology Vancouver,
and Laboratory Medicine, University British Columbia, Canada.
4 Epidemiology Services, British Columbia Vancouver, British Columbia, Canada.
Centre
5 Field Epidemiology Training Program, Laboratory Control, Health Canada, Ottawa, Ontario, Canada. ’ Division of Infectious Diseases, University couver, British Columbia, Canada. Reprint requests Victoria, British
1032
for Disease Centre
of Brmsh
Control,
for Disease
Columbia,
to Andrew J. Burnett, MD, Suite 322, Columbia V8R 6R3, Canada.
of Brit-
Van-
1964 Fort St,
A well-documented outbreak of acquired T. gondii infection occurred in the Greater Victoria area of British Columbia between October 1994 and March 1995, the details of which are described elsewhere.16 During the first 3 months of 1995, seven cases (8 eyes) of acute retinitis with serologic analysis compatible with that of acquired toxoplasmosis were referred to two of the authors (AJB, SGS) by general ophthalmologists and family doctors in the community. Concurrently, the Provincial Laboratory, which performs all serologic analysis for T. gondii in the province, noted a sudden increase in acute toxoplasmosis in Greater Victoria. Positive sera were not only derived from individuals with acute retinitis but from others presenting with lymphadenopathy and constitutional symptoms compatible with the diagnosis. In addition, serologic screening was offered to women in Greater Victoria who were pregnant at any time between October 1994 and the end of April 1995 and yielded 37 cases. In total, 100 patients with acquired and 12 patients with congenital toxoplasmosis were identified. Overwhelming epidemiologic data suggest municipal drinking water as the source of the outbreak. Twenty patients (21 eyes) presented with retinal findings, and examination of 77 of the remaining 80 patients with acquired toxoplasmosis failed to show any evidence of present or past retinitis. The remaining three patients were not examined (two unable to locate, one refused). Six of the 12 patients with congenital toxoplasmosis have retinal scars compatible with the disease, 3 of which are bilateral. We present the 20 cases (21 eyes) of serologically proven acquired toxoplasmosis retinitis presenting in Greater Victoria during the course of 1995.
Burnett et al - Acquired
Methods Cases were studied at the time of initial referral. A case was defined as an individual with serologic findings consistent with acquired toxoplasmosis and evidence of retinal involvement. A full ophthalmic examination, including refraction, tonometry, slit-lamp assessment, and dilated fundus evaluation with indirect ophthalmoscope and contact lens, was performed at initial assessment. Fundus photography and, when appropriate, fluorescein angiography were performed on all patients. Serum for testing was obtained at the time of presentation and at different intervals during follow-up. Details regarding the serologic investigation of cases have been reported previously.‘h Confirmation of immunoglobulin M (IgM) and immunoglobulin G (IgG) (Sabin-Feldman Dye Test) levels was performed in the Toxoplasma Serology Laboratory, Research Institute, Palo Alto Medical Foundation, Palo Alto, California. The differential agglutination test has been described to characterize infections acquired recently or in the past.” The basis of the interpretation of this AC/HS ratio determination relates to the observation that IgM antibodies produced at different stages of infection react differently to epitopes presented by different preparations (methanol-fixed [AC antigen] or formalin-fixed [HS antigen]) of Toxoplasma tachyzoites. This test also was performed in the Toxoplasma Serology Laboratory in Palo Alto. In many cases, follow-up sera were obtained every 3 months. All patients were interviewed in their home or by telephone by the Epidemiology Services of the British Columbia Centre for Disease Control, Vancouver, British Columbia, to identify risk factors for and signs and symptoms of toxoplasmosis. In addition, the general medical history was reviewed with the patient and family doctor, and, where appropriate, further evaluation and investigations were performed.
Results Twenty-one eyes of 20 patients presented during 1995 with clinical and serologic evidence of acquired T. go&ii retinitis. The epidemiologic study of the outbreak population lists a total of 19 “eye” cases and classifies 1 individual (case 11) as a “node” case in view of his presenting complaint being a mass in the groin.‘” The mean age at the time of presentation was 56 years, with a range of 1.5 to 83 years. The number of males and females was equal. None of the patients were known to have an immunocompromising illness, although case 4 was taking systemic corticosteroids for presumed polymyalgia rheumatica. Follow-up intervals varied depending on the severity of the disease and the response to treatment. Repeat evaluation included full examination of the involved eye and survey of the opposite retina with indirect ophthalmoscope. Mean follow-up was 113.7 weeks, with a range of 38 to 170 weeks. Eight of 20 patients had systemic symptoms and signs consistent with those attributed to acute T. gondii infection. All predatedthe onsetof ophthalmicsymptoms,with a meanof 6 weeksand a range of 2 to 12 weeks.All eight had a loss of energyand a senseof ill health.Sevenof eight patientsreported night sweats,and six of eight patients had fever and chills. Headachewasprominentin sevenof eight patients,andlymphadenopathywasreportedin five of eight. The lymphadenopathy was not necessarilysubstantiatedby a physician. All patients had ophthalmicsymptomsconsistingof floaters, hazy vision,
Toxoplasmosis
Retinitis
or both, with onset0.4 to 26 weeks (mean,8 weeks)before their first visit. Eleven right andten left eyeswere affected. Nineteencases were unilateralwith onebilateral case.Initial visual acuity varied from 20120to hand movements(Table 1). As expected, poorer levels of acuity were seenin patientswith macularlesionsor significantvitritis. Sixteen(76%) of 21 eyeshad anterior chamberreactions,9 of thesehaving granulomatous keratic precipitates.Four of the six eyeswith inactive lesionsdid have someanteriorchamberacti\ ity. Intraocularpressures, measured by applanationtonometry, varied at the time of presentation from 10 to 40 mmHg, with a meanof 21 mmHg. Eyes with keratic precipitateshad a mean of 27 mmHg (range, 16-40 mmHg), and those eyes without keratic precipitateshad 17 mmHg (range,16-40 mmHg).Twenty of the eyeshad a vitreousreactionvarying from cellsabovethe lesionto a generalized vitritis (3 of 21 eyes)with decreasedvision. The location of the lesionswas categorized as described by Holland,lx in which classificationof lesionlocation loosely correlateswith its long-term visual significance.Zone 1 is an area3000pm (2 discdiameters)from the fovea (approximately the areaenclosedby the major temporalvasculararcades)or 1500 pm from the margin of the optic nerve head. Zone 2 extendsanteriorfrom the borderof zone 1to the clinical equator of the eye, identified by the anteriorborder of the ampullaeof the vortex veins. Zone 3 exlendsfrom zone 2 to the ora serrata. Sevenlesionsfell within zone 1, andthe remaininglesionsfell within zone 2, with no lesionsin zone 3 alone. Fifteen active and six inactive lesionswere identified. All patientshad solitary lesions.Lesion activity was defined by appearance.Active lesionswere subdivided accordingto the classificationof FriedmanandKnox.” Largedestructivelesions generallywere raised,creamy yellow patcheswith geographic outline and ill-defined edges.Fourteenof the 15 active lesions fit this description.One lesion (case3) was primarily outer retinal in location at the time of presentationand becamefull thicknesswithin 2 weeks. Inactive lesionshad well-defined edgeswith retinal pigmentjspithelialatrophy and, on occasion, somepigment clumping, minimal overlying vi&is, and no areasfitting the descriptionof an active lesion. Lesion size was measuredin disc areasby clinical observationand, where possible,correlatedwith fundusphotography.Size varied from 1 disc area(DA) in two eyes,2 DA in eight eyes,3 DA in five eyes,and4 DA in six eyes,with a meanlesionsizeof 2.7 DA. No casesof papillitis, neuroretinitis,or retinal vascularocclusionwere seen.Macular edemawaspresentin three zone 1 lesionsthat did not affect the maculadirectly. In the caseof the outer retinal lesion(case3), subretinalfluid extendedunder the fovea. An exudative macularstarwaspresentfor 9 months in a45-year-oldwomanwith 1 DA-sized lesionalongthe inferotemporalarcade(case16) (Figs I, 2). Sabin-FeldmanDye Test resultsvaried from a titer of 1:512 to 1:256,000with a medianof 1:8000.The IgG (ELISA) results were greateror equalto 240 IU in 18 of 20 patientswith 216 IU and 209 IU reportedin the remaining2 patients.The IgM (ELISA) serologicresults were 100% reactive. The fixation indices on the tests varied from 3.4 to greater than 10. The differential agglutinationtest resultswere consistentwith those of infections acquiredrecently in all cases(Table 2). No case of acuteretinitis was seenduring the courseof the outbreak with nonacuteserology. Topical treatmentof iritis wasaccomplishedwith corticosteroids and cycloplegics, and managementof raisedintraocular pressurewas achievedwith topical beta-blockersand,in some cases,with the addition of a systemiccarbonic anhydraseinhibitor. 1033
Ophthalmology Table
Case No.
Age* (yrs)
1 2 3 4a 4b 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20
Sex
30 48 26 79 79 44 83 83 40 77 67 32 49 16 15 ;; 74 56 83 66
M F M F F M M F M F F M M F M F F M M F F
Follow-up (wks)
Eye Involved
R R R R L L L R L R R L R L L R R L L R L
121.3 129.3 47.0 129.7 129.7 133.0 64.711 170.4 135.0 132.6 140.3 105.9 86.1 105.6 158.3 86.7 121.4 38.1 152.4 137.1 79.9
Initial Acuity?
20/30 20/20 20160 lcl/400 201200 20150 2;:o 20150 20170 20130 20120 20/20 20120 20130 5/400 20/400 5/400 20150
Volume 105, Number 6, June 1998 1. Patient
Latest Acuity?
20125 20120 20120 1o/400 20160 20125 20140 NLP 20/20 20150 20/30 2Ol20 20/50 20120 2($40 s/400 20/40 20160 20/200 20140 20120
Clinical
Lesion Zone
Data
Lesion Activity
2 2 2 2
2(1)P 1 1 1 2 2 2 2 2 2 1 1 1 :(I,5 2 2
A A A I A A A A A A I 1 A 1 A 1 A A A A 1
and Outcomes Toxoplasmosis Pathology Affecting Visual OutcomeS
Other Pathology Affecting Visual Outcome
MH cat
wt, phs
wt ERM cat
tm fib fib wt, ret cat
Treatment
T/S + T/S T/S + T/S + T/S + T/S + T/S + S/P + T/S + C+P+M N N T/S + N T/S + N T/S + T/S + T/S + T/S + N
I’ I’ P P P + c P P P
Treatment Duration (wkd
3 3 3 3 3 4 3 4 4 6
P
3
P
4
P P P I’
3 3 4 3
HM = hand movements; NLP = no light perception; A = active retmitis; I = inactive lesion; vlt = vitritis; phs = phthlsls; tm = macular tractlon; fib = macular fibrosis; ret = recurrent lesion in macula; cat = cataract, ERM = epiretinal membrane, MH = macular hole; N = none; T/S = trimethoprim/sulfamethoxazole; P = prednisone; C = clmdamycin; M = minocychne; S/P = sulfadlazme + pyrimethamine (with leucovorin). * Age at time of presentation. t Snellen
acuity measured
in feet.
t Pathology affectmg visual outcome related to toxoplasmosis 5 Initial lesion in zone 2 with recurrence in zone 1.
retinitis.
11Deceased.
Eleven of the patients treated by the authors (AJB, SGS) began a combination of oral trimethoprim 160 mg and sulfamethoxazole 800 mg (Bactrim DS; Roche, Nutley, NJ) twice daily for 3 to 4 weeks with the addition of prednisone 1 mg/kg per day for 4 days and then tapered off over 3 to 4 weeks. The latter was begun at the same time as the antimicrobial combination with no ill effect observed. No medication-related complications were noted in the group treated by the authors. One patient was treated with the same regimen with the addition of clindamycin and another with the combination drug but no steroid. Other variations included traditional triple therapy of sulfadiazine, pyrimethamine, and prednisone with folinic acid coverage (case 7) and clindamycin with prednisone, the former later changed to minocycline after the appearance of a rash (case 9). The visual outcome is shown in Figures 3 and 4. A trend suggesting improving acuity with time is evident, especially in the group of zone 1 lesions. Lack of improvement was caused by ongoing vitritis with inactive lesions in three patients, necessitating pars plana vitrectomy in two patients (cases 7 and 9), pre-existing macular epiretinal membrane (case 10) and macular hole (case 4a), retinal folds in one macular lesion (case 14), and macular scarring in another (case 15). Case 7 had ongoing vitritis after vitrectomy despite repeat antimicrobial and steroid treatment and has gone on to phthisis. Changes in the size of lesions with treatment were not actively documented. Four recurrences have been reported to date: one adjacent to a perimacular lesion but on the distal side in an 83-year-old man 43 weeks after initial presentation (case 6),
1034
one new lesion in at 26 weeks (case of an 83-year-old lesion in the right weeks (case 15).
the center of the fovea in a 56-year-old man 18), one new lesion in the left posterior pole woman at 13 weeks (case 4), and one new midperiphery of a 75year-old woman at 61
Discussion For the sake of simplicity,
the word
“retinitis”
is used
throughout this article. The authors are well aware of the secondary choroidal inflammatory response in most lesions. This case series is presented to show the variability in presentation as well as some of the unusual, albeit not unique, features seen. The extremely high antibody levels, the preponderance of large lesions, and the older mean age of the patients stand out in this regard. This series also shows the generally satisfactory outcome with relatively simple antimicrobial and steroid treatment. The antibody levels measured in the patients involved in this outbreak are much higher than those usually seen in patients with acute acquired T. go&i infection in Canada and the United States. Sabin-Feldman Dye Test titers in the order of 1:128,000 and 1:256,000 are seldom reported. It is noteworthy that all patients had an acute
Burnett et al * Acquired
Figure
1. Case 16. Fundus photograph
of lesron at the ttme of presentation.
Figure
2. Case 16. Fundus photograph
of lesmn 2 months
htstogram
of visual acmties
Retinitis
after treatment.
Figure 3. Three-dtmenstonal htstogram of wsual acutttes before all mtervals except 12 months, where n = 5. Figure 4. Three-drmenstonal for all mtervals.
Toxoplasmosis
and at dtfferent
Intervals
before and at different
pattern in the AC/HS differential agglutination test, suggesting recently acquired infections. The immunoglobulin E (IgE) ELBA test is the first to show positive titers after the onset of infection, the titers showing a rapid rise and then fall to undetectable levels in a few months. As a consequence, acute acquired infection serology often fails to show this short-lived positive IgE level. In this series, more than half (11 of 20) show positive IgE titers. An explanation for the magnitude of these antibody levels is unclear. A possibility includes an extremely large inoculum or a unique strain of the parasite capable of eliciting an excessive antibody response or both (Dr. JS Remington, personal communication, June 23, 1997). Scrutiny of the lesions shows no significant differences in characteristics from those described in other cases of acquired retinitis, although the prevalence of larger lesions was noticeable. Eleven of the 21 lesions were 3 to 4 DAs in size, with an overall mean of 2.7 DA. Although the lesion sizes are not noted in all cases described in the literature, they tend to be smaller lesions with a 1 to 2
intervals
after the onset of treatment
after the onset of treatment
for zone 1 lessons; n = 6 eyes for
for zone 2 lessons; n = 10 eyes
DA size. Insufficient colmparative data are available to attach significance to this factor. The mean age of 54 years old is higher than expected and significantly higher than the mean age of the noneye cases in the outbreak (27.7 years) (P = 0.000004). Individual cases of acquired toxoplasmosis retinitis reported in the literature have a mean age of 29.4 years (9 patients),7-‘” but the mean age of the 22 patients accumulated by Montoya and Remington6 is 50.2 years, which is more consistent with our experience. Other studies show patients with mixed congenital and acquired retinitis presenting with reactivations or first episodes have mean ages of 25.319 and 28.6 years.’ The reason for the higher mean age in this group is unclear. In the first case-control study performed as part of the investigation of this outbreak, which was comprised of 39 cases, including 14 patients in this series, there were no significant differences on univariate-matched analyses performed in Epi Info ~6.02 (Centers for Disease Control, Atlanta, GA) between patients and their matched control subjects in those per1035
Ophthalmology
Volume 105, Number
6, June 1998
Table 2. Results of Initial SerologicTesting Case NO. 2
6 7 8 9
10 11 12 13 14 15 16 17 18 19 20
Dye Test* 32,000 32,000 128,000 256,000 8000 32,000 8000 2048 4096 2048 512 8000 64,000 16,000 2048 128,000 4096 1024 128,000 8000
1gG ELBA NJ) >240 >240 >240 >240 >240 216 >240 >240 209 ~240 >240 >240 >240 >240 >240 >240 >240 >240 >240 >240
IgM ELBA WI) R(>lO.O) R(>lO.O) R( 10.0) R(9.2) R(>lO.O) R(9.4)
R(14.5) R(3.4) R(8.8) R(6.3) Rt5.6) Ri10.4) R(8.4) R(5.6) R(6.6) R(8.7) R(7 7) R(5.3) R(>lO.O) R(4.4)
IgE ELISA
IgA ELISAt
P P P N
P(14.1) P(5.8) P(5.6) NA P(3.4) NA P(2.2) P(7.9) P(20.0) N(1.4) P(5.1) Pi8.4j P(21.1) P(12.1) N(0.8) NA P(3.2) P(20.8) P(18.5) P(7.2)
N N N
E
AC/f33
PatternS
>1600/>3200 > 1600/3200 >1600/>3200 > 1600/>3200 >1600/1600 800/800 >1600/1600 > 1600;3200 >1600/1600 > 1600/800 > 1600/3200 800/800 800/3200 > 1600/l 600 > 1600/>3200 > 1600/l 600 >1600/>3200 > 1600/l 600 >1600/>3200 >1600/>3200
FI = fixation Index; R = reactive; I’ = positive; N = negatwe; E = equivocal; NA = not avadable. * Sabn-Feldman dye test, reciprocal of titer. t Reciprocal of titer. $ Differential agglutmatlon test (all patterns consistent wth Infection acquired recently).
sonal habits or lifestyles that were explored as potential risk factors for acquiring toxoplasmosis (unpublished data, 1995). The question of age-related predisposition has been entertained. The interface between host factors, such as age, and parasite factors, such as pathogenicity, is not understood. Whether the specific outbreak-causing strain of Toxoplasma predisposesto ocular trophism is not known. Whether the organism involved was more virulent, and therefore more invasive or more destructive, is speculative. Additionally, the parasite inoculum might have been a contributing factor, either because of the inoculum size or becausethe infective form was oocysts rather than tissue cysts. The size of the inoculum is unknown and cannot be determined. Oocysts are, however, known to be highly infective.2”‘2’ Based on the positive experience of Rothova et a12* and Opremcak et al” and considering the cost, toxicity, and uncertain availability of traditional triple therapy, we elected to treat patients with the trimethoprim-sulfamethoxazole combination and prednisone. The question of a reduction in lesion size with treatment was not formally addressedand so cannot be compared with the results of Rothova et a1,22showing a reduction of lesion size with triple therapy compared with our regimen. The incidence of acquired toxoplasmosis retinitis as a presenting sign in this outbreak cannot be calculated without knowing the total number of infected individuals. The epidemiologic studies associated with this outbreak showed a rate of infection of 0.9% in the 3812 screened pregnant women and 2.4% in potential control subjects screened for 1 of the case-control studies. Considering the population of Greater Victoria in 1994 was estimated
1036
at 321,585, an estimated 2894 to 7718 individuals were infected.16 Therefore, in this outbreak, between 0.26% and 0.69% of those presumed to be infected presented with retinitis. No data are available to ascertain the number of eye casesnot captured in this study. Although it is probable that the more severe casescame to our attention, we have no data to addressthis possibility. This is the largest reported seriesof acquired toxoplasmosis retinitis related to a single outbreak. Lesions were consistent with acute toxoplasmosis retinitis, and serologic testing confirmed the acute acquired nature of the infection. Responseto treatment generally was favorable, although the potentially destructive nature of the disease in the eye was well shown.
References Tabbara KF. Ocular toxoplasmosis. 14:349-51.
Int Ophthalmol
1990;
PerkinsES. Ocular toxoplasmosis.Br J Ophthalmol 1973; 57:1-17. NussenblattRB, Belfort R Jr. Ocular toxoplasmosis:anold diseaserevisited.JAMA 1994;271:304-7. GlasnerPD, Silveira C, Kruszon-Moran D, et al. An unusually high prevalence of ocular toxoplasmosis in Southern Brazil. Am J Ophthalmol 1992;114:136-44. 5. Silveira C, Belfort R, Bumier M, et al. Acquired toxoplasmic infection as a cause of toxoplasmic retinochoroiditis
in families.Am J Ophthalmol1988;106:362-4. 6. Montoya JG, RemingtonJS. Toxoplasmicchorioretinitisin
Burnett
7. 8. 9. 10. 11. 12. 13. 14. 1.5.
et al * Acquired
the setting of acute acquired toxoplasmosis. Clin Infect Dis 1996:23:277-82. Kayhoe DE, Jacobs L, Beye HK, et al. Acquired toxoplasmosis. N Engl J Med 1957;257:1247-54. Neumann CG, Hilton C, Barreda A. Acquired toxoplasmosis in a child. Am J Dis Child 1960; 100: 14 l-4. Saari M, Vuorre I, Neiminen H, et al. Acquired toxoplasmic chorioretinitis. Arch Ophthalmol 1976;94: 1485-8. Michelson JB, Shields JA, McDonald PR, et al. Retinitis secondary to acquired toxoplasmosis with isolation of the parasite. Am J Ophthalmol 1978; 86:548-52. Masur H, Jones TC, Lempert JA, et al. Outbreak of toxoplasmosis in a family and documentation of acquired retinochoroiditis. Am J Med 1978;64:396-402. Gump DW, Holden RA. Acquired chorioretinitis due to toxoplasmosis. Ann Intern Med 1979;90:58-60. Akstein RB, Wilson LA, Teutsch SM. Acquired toxoplasmosis. Ophthalmology 1982;89: 1299-302. Hausmann N, Richard G. Acquired ocular toxoplasmosis. Ophthalmology 1991;98:1647-51. Opremcak EM, Scales DK, Sharpe MR. Trimethoprim-Sulfamethoxazole therapy for ocular toxoplasmosis. Ophthalmology 1992;99:920-5.
Toxoplasmosis
Retinitis
16. Bowie WR, King AS, Werker DH, et al. Outbreak of toxoplasmosis associated wi1.h municipal drinking water. Lancet 1997;350:173-7. 17. Dannemann BR, Vaughan WC, Thulliez P, et al. Differential agglutination test for diagnosis of recently acquired infection with Toxoplasma go&ii. J Clin Microbial 1990;28: 1928-33. 18. Holland GN, Buhles WC, Mastre B, et al. A controlled retrospective study of g.lncyclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. Arch Ophthalmol 1989; 107: 1759-66. 19. Friedmann CT, Knox DL. Variations in recurrent active toxoplasmic retinochoroiditis. Arch Ophthalmol 1969; 8 I:48 I -93. 20. Miller NL, Frenkel JK, Dubey JP. Oral infections with Toxoplasma cysts and oocysts in felines, other mammals, and in birds. J Parasitol 1972;58:928-37. 21. Dubey JP, Lunney JK, Shen SK, et al. Infectivity of low numbers of Toxoplasmic gonclii oocysts to pigs. J Parasitol 1996;82:438-43. 22. Rothova A, Meenken C, Buitenhuis HJ, et al. Therapy for ocular toxoplasmosis, Am J Ophthalmol 1993; 115:5 1723.
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