clinical manifestations of ocular toxoplasmosis
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1. CliniCal Manifestations of oCular toxoplasMosis in typiCal
forMs
1.1. symptoms and Consequences of loss of Visual function
Visual symptoms and signs linked to toxoplasmosis depend on the localization of lesions.1-7 While verbal children and adults may promptly request an ophthal-mic examination upon the perception of symptoms, the diagnosis of ocular toxoplasmosis may be delayed in preverbal children, and not all older children and adults recognize the symptoms when they are not in the posterior pole or associated with a substantial inflammatory response. Hence, routine follow-up examinations, not prompted solely by reported symptoms or signs for persons with congenital and postnatal ocular toxoplasmosis, are needed to assess lesions. Major visual impairment may be observed
with macular lesion, while peripheral lesions may have no easily detectable effect on vision.2,8-10 Optic neuritis or optic nerve involvement may result in visual field defects or loss of color vision.
In active lesions, vitreous inflammation is usually the first factor leading to symptoms, but a scotoma or diminished visual acuity may also be the first symptom leading to the diagnosis. In inactive lesions, scotomas are directly related to the size and location of retinochoroidal scars. As vitreous opacities may persist after active inflammation of the posterior seg-ment, it may be difficult for patients with poor vision to distinguish floaters linked to persistent vitreous opacities from signs of a recurrent active vitritis. For patients with normal vision, floaters may be easily distinguishable when they are newly occurring.
Use of an Amsler grid daily by those with retinal scars can result in early detection of an active retin-ochoroiditis (Noble et al., unpublished observations, 2010). A vision test can substitute for the Amsler grid
Ocular Immunology & Inflammation, 19(2), 91–102, 2011Copyright © 2011 Informa Healthcare USA, Inc.ISSN: 0927-3948 print/ 1744-5078 onlineDOI: 10.3109/09273948.2011.564068
Received 02 February 2011; revised 08 February 2011; accepted 10 February 2011
Correspondence: Rima McLeod, MD, Professor, The University of Chicago, N310, MC 2114, 5841 S. Maryland, Chicago, IL 60637, USA, E-mail: [email protected]; or Antoine P. Brézin, MD, PhD, Université Paris Descartes, Centre Cochin Ambulatoire d’Ophtalmologie, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France, E-mail: [email protected]
02 February 2011
08 February 2011
10 February 2011
© 2011 Informa Healthcare USA, Inc.
2011
Ocular Immunology & Inflammation
0927-39481744-5078
10.3109/09273948.2011.564068
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Original article
Clinical Manifestations of ocular toxoplasmosisEmmanuelle Delair, MD1, Paul Latkany, MD2, A. Gwendolyn Noble, MD PhD3, Peter
Rabiah, MD4, Rima McLeod, MD5, and Antoine Brézin, MD PhD1
1Université Paris Descartes, Service d’Ophtalmologie, Hôpital Cochin, Paris, France, 2New York Eye and Ear Institute, New York University, New York, New York, USA, 3Northwestern University Children’s Memorial Hospital and the
University of Chicago, Chicago, Illinois, USA, 4Northshore University Health System and the University of Chicago, Chicago, Illinois, USA, and 5The University of Chicago, Chicago, Illinois, USA
abstraCt
Clinical manifestations of ocular toxoplasmosis are reviewed. Findings of congenital and acute acquired ocular toxoplasmosis include retinal scars, white-appearing lesions in the active phase often associated with vitritis. Complications can include fibrous bands, secondary serous or rhegmatogenous retinal detachments, optic neuritis and neuropathy, cataracts, increased intraocular pressure during active infection, and choroidal neo-vascular membranes. Recurrences in untreated congenital toxoplasmosis occur in teenage years. Manifestations at birth are less severe, and recurrences are fewer in those who were treated promptly early in the course of their disease in utero and in the first year of life. Severe retinal involvement is common at diagnosis of symptomatic congenital toxoplasmosis in the United States and Brazil. Acute acquired infections also may be complicated by toxoplasmic retinochoroiditis, with recurrences most common close to the time of acquisition. Suppressive treatment can reduce recurrent disease.
Keywords CNVM, congenital toxoplasmosis, rétinal choriditis, Toxoplasma gondii, uveitis
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in younger children. For lesions outside the central 10 degrees, an Amsler grid may not be as useful in detect-ing new lesions.
1.2. anterior uveitis
The severity of anterior uveitis can range from a quiet anterior chamber to intense anterior uveitis masking inflammation of the posterior segment and can be either granulomatous or nongranulomatous inflammation. If the diagnosis is delayed, prolonged inflammation of the anterior chamber may lead to irreversible iris synechiae. In a study of 210 patients with active toxoplasmic retin-ochoroiditis, intraocular inflammation was more intense in older patients and increased with the size of areas of retinochoroiditis and in peripheral lesions.11 Secondary ocular hypertension was associated with inflammation of the anterior segment and occurred in 30% of cases. Overall, more intense inflammation may be observed in cases of ocular toxoplasmosis in patients from cer-tain areas of Central and South America. Also, intense anterior inflammation may occur secondary to the retin-ochoroiditis near the ora serrata, which may be missed on initial examination.
1.3. Cataracts
In children with congenital toxoplasmosis, cataracts may occur as a complication of retinochoroiditis and
may follow severe iridocyclitis. In a study of 173 patients, cataracts occurred in 11.6% of these patients (27 eyes of 20 patients).12 The cataracts vary in onset, location, complexity, and progression.12 Cataracts were most commonly found in children with the most severe intraocular disease (e.g., retinal detachment) and no intervention was performed. However, cataracts may cause severe amblyopia in children and may need to be removed surgically. It appears to be prudent to admin-ister antiparasitic medication during surgery to prevent reactivation of chorioretinitis.12
1.4. Vitritis
Inflammation of the vitreous is usually more intense near the active retinochoroiditis. However, there may be no vitritis if the retinal inflammation does not extend to the inner limiting membrane. In cases of intense vitritis, epiretinal membranes may develop and vitreoretinal traction adjacent to the area of retinochoroiditis may occur. The intensity of the vitritis also appears to reflect duration of the process prior to diagnosis and treat-ment, with longer intervals before treatment is initiated associated with more intense inflammatory response. “Headlight in the fog” was a phrase for severe vitritis coined by Richard O’Connor to describe a bright white reflex seen when one shines the light of the indirect opthalmoscope into the back of the eye. Figure 1A is an example of severe vitritis but not as severe as the classic “headlight in the fog” description. This resolved with
A
B
FIGURE 1 (A) Severe vitritis that is less intense than the classic “headlight in fog” appearance (left). Resolving vitritis caused by under-lying active lesion (middle). Resolved healed lesion without vitritis (right). (B) Typical form of ocular toxoplasmosis. Active whitish retinochoroiditis, satellite of a pigmented scar.
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treatment so the underlying active focus then scar are apparent.
1.5. fundus examination
In typical cases active lesions are seen as whitish foci of retinochoroiditis, without well-limited borders, frequently adjacent to a pigmented and/or atrophic scar (Figure 1B). Vasculitis may also be remote from the lesion. When retinal vessels are close to the lesion, signs of vasculitis contiguous to the lesion may be seen (Figure 2). Peri-phlebitis is more frequent than arteritis and retinal hemorrhages can also be seen. In some cases with very intense inflammation, vasculitis may be gen-eralized to retinal areas distant from the primary site of retinochoroiditis.
An active retinochoroidal lesion usually results in an atrophic retinochoroidal scar, which resolves from the
periphery to the center of the lesion, usually leading to pigmentation (Figure 3A, B). The average time for the scarring of an active toxoplasmic area of retinochoroidi-tis often appears to be related to function of the lesion size and resolution often occurs in approximately 3–4 weeks. With prompt diagnosis and treatment, lesions may resolve more rapidly and even heal without creat-ing a scar (Figure 3C left, right).10 Resolution of active toxoplasmic retinochoroiditis in treated newborn infants over the first weeks of life and in children also can occur with rapid initiation of treatment. Figure 3D shows pho-tographs of the retina of a newborn infant with active vitritis (left, labeled “near birth”) with clearing of vitritis and marked but not yet complete resolution of activity of the lesion 3 weeks later (right, labeled “with ongoing treatment”).
1.6 toxoplasma serology
Confirmation of serologic evidence of T.gondii infec-tion is an essential part of establishing the diagnosis of ocular toxoplasmosis. This allows one to suspect the diagnosis in conjunction with the typical appearance of the eye lesions. Presence of T.gondii-specific serum antibody is consistent with and supports the diagnosis of ocular toxoplasmosis but does not prove it; it just establishes that the person has the infection.
1.7. fluorescein angiography
Photographs of the fundus are useful to document lesions and to longitudinally assess the evolution of lesion, particularly in cases of recurrences. Fluorescein
FIGURE 2 Scarred and active ocular toxoplasmosis with contigu-ous vasculitis.
FIGURE 3 Follow-up of a toxoplasmic lesion. (A) Active lesion at presentation. (B) Scarred lesion. (C) Active retinal lesion before (left) and completely resolved normal appearing retina within a month of initiating treatment (right). Adapted from McLeod et al.10 with per-mission. (D) Retina photographs for newborn infant with active vitritis (left, labeled “near birth”) with clearing of vitritis and marked but not yet complete resolution of activity of the lesion 3 weeks later (right, labeled “with ongoing treatment”).
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angiography can show signs useful to confirm lesion activity. In some instances small, early active lesions may be difficult to detect at the edge of an older scar, fluores-cein angiography may be useful to confirm the diagno-sis. In typical cases of active disease, a masking lesional effect at the early phase of the angiography is observed, followed by hyperfluorescence progressing from the periphery of the lesion to its center (Figure 4). Vasculitis contiguous to the lesion is seen as hyperfluorescence of the vessel walls, which increases in magnitude in the late phase of the angiography. Scarred quiescent pigmented lesions have a persistent masking effect, often bordered by a hyperfluorescent line. Papillitis is frequently seen as an early staining of the disc, with increasing and lasting
hyperfluorescence. Cystoid macular edema, even distant from the active lesion of retinochoroiditis, can be a com-plication of severe inflammation.
1.8. optical Coherence tomography
Scarred areas of retinochoroiditis are characterized by retinal atrophy at the site of lesions (Figure 5). Optical coherence tomography is also useful to detect retinal edema, to quantify subtle serous retinal detach-ment, which can be triggered by active retinochor-oiditis (Figure 6), or to detect subretinal new vessel formation.
FIGURE 4 Ocular toxoplasmosis with retinal artery occlusion: (A) color fundus photograph, fluorescein angiography; (B) early phase; (C) late phase.
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FIGURE 5 OCT imaging of scarred toxoplasmic lesions and fluorescein angiography. (A) OCT fundus image. (B) Late-phase fluorescein angiography. (C) OCT imaging showing a retinal thinning at the site of the toxoplasmic scar. (D) OCT thickness map showing areas of retinal thinning.
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2. rare, atypiCal, or CoMpliCated forMs of oCular toxoplasMosis
2.1. optic neuropathy
The diagnosis of ocular toxoplasmosis is difficult in the presence of papillitis without other characteristic signs of retinochoroidal inflammation. Whitish inflammatory lesions located on the disc with associated vitritis sug-gest the diagnosis.13 Such lesions located on the disc border are responsible for visual defects occasionally referred to as Jensen scotoma (Figure 7).
2.2. neovascularization
Subretinal neovascularization may be a complication of toxoplasmic retinochoroiditis (Figure 8, top).14,15 In addition to fluorescein angiography, indocyanine green angiography may be useful to visualize the neovascu-lar membrane. In some instances neovascularization may regress once inflammation has resolved. In other instances persistent neovascular membranes histori-cally may require surgical removal but have been more
recently treated by intravitreal anti-VEGF therapy with resolution of the choroidal neovascular membrane (CNVM) and brisk resolution of associated choriore-tinitis (Figure 8, bottom) 16,17
2.3. retinal Vascular occlusions
Vein or retinal vascular occlusions may be a compli-cation of ocular toxoplasmosis (Figure 9). The site of occluded vessels may directly overlie the area of active retinochoroiditis or may be contiguous to the lesion.18–20 Fluorescein angiography is useful to confirm the diag-nosis and to assess the consequences of the retinal vas-cular occlusion.
2.4. epiretinal Membranes
Epiretinal membranes can be a complication of a pro-longed vitritis and are usually attached to or near areas of retinochoroiditis (Figure 10). Secondary tractions may be responsible for retinal tears, vitreo-macular traction with metamorphopsia, and macular edema.
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FIGURE 6 OCT,color fundus photograph and fluorescein angiography imaging of ocular toxoplasmosis with serous detachment of the retina. (A) Color fundus photograph of an active lesion satellite of a toxoplasmic scar. (B) Late phase fluorescein angiography showing a serous detachment of the retina. (C) OCT imaging of serous retinal detachment. (D) OCT thickness mapping showing of the serous retinal detachment.
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FIGURE 7 Peripapillary scarred retinochoroiditis. 7A: Fundus photograph. 7B: Goldmann perimetry showing a Jensen’s scotoma.
FIGURE 8 (Top) Ocular toxoplasmosis with submacular neovascular membrane: (A).fundus photograph; (B) indocyanin green angiog-raphy. (Bottom) Choroidal neovascular membrane with hemorrhage presenting with acute loss of vision, which resolved with treatment with pyrimethamine, sulfadiazine, and intraocular injection of lucentis. Adapted from Benevento et al.16 with permission.
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These cases have sometimes been treated with surgi-cal removal of epiretinal membranes after the active phase of retinochoroiditis with a favorable visual outcome.21
2.5. serous retinal detachments
Serous retinal detachments are a complication of retin-ochoroiditis. Vitritis is usually moderate in these cases. Serous detachments may extend distally from the area of retinochoroiditis and be responsible for decreased visual acuity when they reach the macula. Fluorescein angiography and optical coherence tomography (OCT) may be useful to confirm the diagnosis. Angiograms show an early fluorescence masking and a late-phase staining. OCT is particularly useful to monitor reattach-ment of subtle serous exudation.
2.6. retinal detachments
Retinal tears may be located near active or scarred foci of retinochoroiditis. In other instances, including after intense and prolonged vitritis, vitreoretinal trac-tion strands or tractional retinal detachments may be observed (Figure 11).22,23
3. the speCial probleM of Congenital oCular toxoplasMosis
in the united states and brazil When there is no prenatal
diagnosis and early treatMent as Contrasted With oCular
Manifestations in franCe Where there is prenatal diagnosis and early treatMent of the fetus by
treatMent of the Mother
Time of detection, treatment, and parasite and host genetics modify initial presentations. In the United States, congenital toxoplasmosis is most often diagnosed by detection of severe signs and symptoms in the new-born infant in the absence of any systematic prenatal diagnosis and treatment.2-6,9,24–26 Only Massachusetts and New Hampshire have a postnatal screening program.27 In a cohort study of children diagnosed at birth, severe involvement was common at routine ophthalmologic examinations. Findings are summarized in Table 1.2 Macular lesions were predominant. Although not widely appreciated by ophthalmoligists, visual acu-ity may be remarkably good with macular scars.2,9
FIGURE 11 Secondary tractional retinal detachment with a large area of toxoplasmic retinochoroiditis.
FIGURE 9 Ocular toxoplasmosis with retinal vessel occlusion: (A) arterial occlusion; (B) vein occlusion.
FIGURE 10 Ocular toxoplasmosis with secondary epiretinal membrane.
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This likely reflects the depth of lesions and degree of involvement of the fovea, as shown by a study of some of these patients with OCT9 and in a larger unpub-lished experience (Latkany, Noble, Rabiah, McLeod et al, manuscript in preparation, 2011). Occlusion treat-ment for amblyopia may markedly improve visual acuity with substantial macular scars (Noble, Menon, Rabiah, McLeod, et al., manuscript in preparation). In the Massachusetts screening program, 19% of the infants detected had retinal disease.27 Examinations were at different sites and by different examiners and not documented with photographs. In Belo Horizointe, Brazil in a widespread newborn screening program, 50% of the ~200 children had ocular lesions during a 7-month period, reflecting the endemic high incidence
of congenital toxoplasmosis; 50% of the infants had active retinochoroiditis at birth.28
In contrast to this, in France with systematic prena-tal treatment, and perhaps also reflecting differences in parasite and human genetics of those infected or other influences on well-being during gestation, active disease and central locations of lesions are rare,29–38 as are other signs of active disease. This was not always the case in France. Reviewing the earlier literature, Couvreur and Desmonts noted 76% of the infants born had retinal disease before prenatal diagnosis and treatment were introduced in France.39–45 In a newborn screening program in Denmark, a similar proportion infants had retinal disease at birth. A brief period of treatment (3 months, doses of medicines not specified)
TABLE 1 Ophthalmologic manifestations of congenital toxoplasmosis.
No. of treated patients with
finding (%) (NO. = 76)No. of historical patients with
finding (%) (NO.= 18)Total no. of patients with
finding (%) (NO. = 94)Strabismus 26 (34) 5 (28) 31 (33)Nystagmus 20 (26) 5(28) 25 (27)Microphthalmia 10(13) 2(11) 12(13)Phthisis 4(5) 0(0) 4(4)Microcornea 15 (20) 3(17) 18(19)Cataract 7 (9) 2(11) 9(10)Vitritis (active) 3 (4)* 2(11) 5(5)Retinitis (active) 6(8) 4 (22) 10(11)Chorioretinal scars 56 (74) 18(100) 74 (79)Macular 39/72 (54)’ 13/17(76) 52/89 (58)Juxtapapillary 37/72 (51) 9/17(53) 46/89 (52)Peripheral 43/72 (58) 14/17(82) 57/89 (64)Retinal detachment 7(9) 2(11) 9(10)Optic atrophy 14(18) 5 (28) 19(20)*Two additional patients, not included in this table, were receiving treatment and retinochoroiditis had resolved, but vitreous cells and veils persisted at time of examination.‘Numerator represents number of patients with finding; denominator is the total number, unless otherwise specified. Number in parentheses is percentage. Patients with bilateral retinal detachment in whom the location of scars was not possible were excluded from the denominator. Adapted with permission from Mets et al2.
0 12 18 246age in months
0 12 18 246age in months
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0,85
0,90
0,95
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0,90
0,95
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ions
FIGURE 12 New eye lesions in children who had <8 or ≥8 weeks delay from diagnosis in utero to treatment. (A) Kaplan-Meier plots show-ing the age at diagnosis of a first retinochoroiditis according to the delay between maternal infection and first treatment: <4 weeks (solid line), 4–8 weeks (dashed line), and >8 weeks (dotted line). (B) Kaplan-Meier estimate of the age at diagnosis of a first retino-choroiditis during the first 2 years of life among 300 infants. Adapted from Kieffer et al.10 with permission.
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was not sufficient to prevent later disease.46 In the study in Paris, in the time before initiating treatment of the fetus, treating the mother significantly modified the rate of subsequent recurrences in the infants and children up to the age of 2 years (Figure 12).
4. CliniCal CharaCteristiCs of aCquired oCular toxoplasMosis
In three large series of ocular toxoplasmosis of acute acquired origin, the age of patients ranged from 12 to 83 years, with a mean of 56.3 years.47–49 The lack of pig-mented scar tissue, near or distant to the site of active retinochoroiditis, is typically associated with postnatally acquired active toxoplasmic retinochoroiditis. Serologic testing can confirm the acute acquired infection.
In postnatally acquired toxoplasmosis, as in congeni-tal toxoplasmic retinochoroiditis, recurrent lesions also can be located remote from scarred lesions, although new lesions are often located as satellites of pigmented congenital toxoplasmic scars. The average lesion size may be larger, greater than 3–4 disc diameters, in acquired infections. Retinochoroidal lesions are more frequently bilateral in congenital infections.50 Cases of intermediate uveitis have been reported in rela-tion with activity of acquired toxoplasmosis. In these cases, lesions located near the ora serrata can be dif-ficult to detect and may be missed on initial fundus examinations.51
In the United States in mothers of congenitally infected children, 7.7% had retinal lesions consistent with toxoplasmic retinal scars, although none threat-ened vision. In this series of 130 mothers of 173 chil-dren, 7.7% of mothers had retinal lesions consistent with toxoplasmosis.52
5. Course of oCular toxoplasMosis
The natural course of ocular toxoplasmosis as well as its visual prognosis depends on the frequency for recur-rences and rapidity with which active disease is treated so destruction of the retina is minimized.2,9,25,26,38,53,54 In a study with a 5-year follow-up after an active toxoplas-mic retinochoroiditis, a recurrence was observed in 79% of patients.55 The mean time between two recurrences was 3 years (range 2 months to 25 years). Among 274 active episodes of ocular toxoplasmosis, 78% occurred in patients aged 15–45 years, with a peak frequency around the age of 25 years. Recurrences sometimes occurred in the contralateral eye, e.g., in 15% of cases. When recurrences occurred in the same eye the active lesion was usually located near a scarred lesion. In the U.S. cohorts, peaks of incidence occurred at about 6–7 years and in adolescence (~10–15 years), which was similar to those in the cohort described by Binquet et al.38
In the prospective study of children in the United States with congenital toxoplasmosis treated in infancy, the frequency of new retinochoroiditis lesions was 31% over a 25-year follow-up. In children with moderate or severe involvement at birth treated dur-ing their first year of life it was 34%.25 The incidence was 10% for those with no evidence of disease at birth. It was 14% for those with mild involvement at birth.26 Lesions were central in 14% of children and peripheral in 25% of cases. New lesions were more frequently observed from 5 to 7 years and in teenag-ers (between 15 and 20 years). In untreated patients, the frequency of new lesions was 72%, with central lesions in 52% of cases and peripheral lesions in 45% of cases26 (Figure 13).
In a longitudinal study, the rate of recurrences has been shown to decrease with time after an episode of active ocular toxoplasmosis.56 The relative risk for a recurrence decreased by 72% each decade after an active toxoplasmic retinochoroiditis. The recurrence risk was lesser if the first attack occurred later in life, with a 15% decrease by decade of age at the time of the first episode. In a study in Brazil, recurrences were most frequent closer to the time of initial acqui-sition.56 Recurrences were effectively suppressed with trimethoprim–sulfamethoxazole (TMP-SMX), but this treatment had a relatively high rate of hypersensitivity associated with the SMX.57
7. susCeptibility genes for oCular toxoplasMosis
Certain genes—e.g., a gene that transports retinylidene ethanolamine outside rod cells, which is associated with susceptibility to macular degeneration, and a collagen gene that is associated with Stickler disease—also have susceptibility alleles for retinochoroiditis in those with congenital toxoplasmosis.58 This observation has not yet been used to predict susceptibility to ocular toxo-plasmosis but it is possible that it may be useful in this manner in the future.
8. ConClusions
Typical and atypical findings of congenital and acute acquired ocular toxoplasmosis include retinal scars, white-appearing lesions in the active phase often associated with vitritis when active. Complications can include fibrous bands, secondary serous or rhegmatogenous retinal detachments, optic neuri-tis and neuropathy, cataracts, increased intraocular pressure during active infection, and choroidal neo-vascular membranes. Recurrences appear to be the rule in untreated congenital toxoplasmosis25,26,52–54 and these often occur in the teenage years.25,26,38 Manifestations at birth appear to be much less
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severe, and recurrences less frequent in those who were treated promptly early in the course of their disease in utero and in the first year of life.2,25,26,29,30,35,38 Severe retinal involvement is the rule at diagnosis of symptomatic congenital toxoplasmosis in the United States; and in Fiocruz, Brazil, active disease is pres-ent in 50% of newborn infants detected in a newborn screening program. Recurrences for children not treated in the first year of life appear to be common in teenage years. Acute acquired infections also may be complicated by toxoplasmic retinochoroiditis with recurrences most common close to the time of acqui-sition. Suppressive treatment can reduce recurrent disease. Incidence and manifestations of this disease vary geographically. For example, in certain areas of Brazil, 20% of persons have ocular toxoplasmosis, and 50% of those are over the age of 50 years. When scars are present at diagnosis and there are no other manifestations of congenital infection, and serologic tests reflect a remote rather than an active, recently acquired infection, the anatomy of the retinal disease and the signs and symptoms cannot be distinguished between congenital versus postnatal acquisition of the infection.
Toxoplasmic retinochoroidal disease is a significant cause of loss of vision and affects subsequent quality of life. The natural history of the signs and symptoms of this infection as described herein are modified by treat-ment of the parasite when it is actively destroying the retina, but medicines to eliminate the latent stage, which is the source of recurrences, are not available at present. Suppressive treatment with TMP-SMX has been shown to reduce the incidence of recurrences of infection for persons in Sao Paulo, Brazil.57
aCknoWledgMent
This work was supported by NIH NIAID R01 27530 and gifts from the Taub, Engel, Mann, and Cornwell families(RM). We thank Daniel Lee and Jane Babiarz for their assistance with preparation of this manuscript.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
referenCes
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FIGURE 13 Recurrent retinal disease and new lesions in children who are historical patients who missed being treated in the first year (left) and those who were treated in the first year with pyrimethamine and sulfadiazine (right). Both left and right, incidence rate: number of patients with new lesions per person-year. Blue shaded area in left and right is confidence interval. Adapted from McLeod et al.10 and Phan et al.,25, 26 with permission.
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Clinical manifestations of ocular toxoplasmosis 101
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