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Ocular Outcome of Brazilian Patients With Congenital Toxoplasmosis
Abstract
Background:
Retinochoroiditis is the most frequent manifestation of congenital toxoplasmosis. We aimed to describe the ocular outcome and factors that may influence the visual prognosis of these patients.
Methods:
Cohort of patients with confirmed congenital toxoplasmosis seen between 1996 and 2017 in Porto Alegre, southern Brazil.
Results:
Seventy-seven patients were included, of which 65 (85.5%) were identified by routine screening. Median age at the end of the follow-up was 10 years (minimum 2, maximum 25). Retinochoroiditis was present in 55 patients (71.4%). New retinochoroidal lesions developed after the first year of life in 77.8% of the patients who began treatment after the fourth month of life, compared with 35.2% among those treated before 4 months of life (relative risk = 0.45, 95% confidence intervals: 0.27-0.75, P = 0.02) and 33.3% among those treated before 2 months of life (relative risk = 0.42, 95% confidence intervals: 0.25-0.72, P = 0.01). There was a peak incidence of new retinochoroidal lesions between 4 and 5 years and another peak between 9 and 14 years, the latter only among girls. Thirty-four patients with retinochoroiditis were followed up for 10 years or more, and the school performance was appropriate in 28 (82.4%).
Conclusions:
The high incidence of new retinochoroidal lesions during the follow-up period indicates the importance of long-term follow-up of patients with congenital toxoplasmosis. Initiating treatment within the first 4 months of life, especially within the first 2 months, was a protective factor against the later development of retinochoroiditis. Despite the usual favorable prognosis, the high morbidity of congenital toxoplasmosis in Brazil was confirmed.
... The risk for its development later in life has been linked to the initiation and timing of antibiotic treatment after birth. In a South American population, starting antiparasitic therapy as early as possible compared to a delay until the fourth month of life or later has been reported to reduce the risk of ocular lesions within the first 5 years of life from 78% to 33% [1]. While a relatively high incidence of new retinochoroidal lesions during the follow-up period indicates the importance of long-term follow-up for patients with CT in South America, its usefulness in children with asymptomatic infection at birth has been debated in North American and European countries. ...
... Routine diagnostic confirmation in serologically not unequivocally confirmed CT included mouse inoculation, resulting in a delay of up to 4 weeks for the definitive diagnosis and start with therapy [57,58], resulting in a relevant number of late and undiagnosed cases. Earlier diagnosis and fetal treatment have led to better outcomes not only in South American children [1] but also in European children with CT born after 1995, as has been reported [33,59]. In some European countries, treatment is initiated after confirmation of maternal seroconversion during pregnancy, with the objectives of reducing the risk of transmission to the fetus and the severity of the disease after vertical transmission [3]. ...
... Parasite virulence may be a driving force for these extremely poor outcomes [81], but the socioeconomic situation and social and eating behaviour may also contribute to the severity of the disease [65,72,88]. Presumably, a quantification of treatment effects will be easier in severely affected cohorts, and indeed, few recent studies have found support for worse outcomes in insufficiently treated instances of severe fetal toxoplasmosis [1,69,70,89]. ...
Even in the absence of manifestations at birth, children with congenital toxoplasmosis (CT) may develop serious long-term sequelae later in life. This systematic review aims to present the current state of knowledge to base an informed decision on how to optimally manage these pregnancies and children. For this, a systematic literature search was performed on 28th July 2022 in PubMed, CENTRAL, ClinicalTrials.gov, Google Scholar and Scopus to identify all prospective and retrospective studies on congenital toxoplasmosis and its long-term outcomes that were evaluated by the authors. We included 31 research papers from several countries. Virulent parasite strains, low socioeconomic status and any delay of treatment seem to contribute to a worse outcome, whereas an early diagnosis of CT as a consequence of prenatal screening may be beneficial. The rate of ocular lesions in treated children increases over time to 30% in European and over 70% in South American children and can be considerably reduced by early treatment in the first year of life. After treatment, new neurological manifestations are not reported, while ocular recurrences are observed in more than 50% of patients, with a mild to moderate impact on quality of life in European cohorts when compared to a significantly reduced quality of life in the more severely affected South American children. Though CT is rare and less severe in Europe when compared with South America, antenatal screening is the only effective way to diagnose and treat affected individuals at the earliest possible time in order to reduce the burden of disease and achieve satisfying outcomes.
... A recent study from a hospital in Porto Alegre, Brazil reported long-term follow-up of 77 congenitally infected children from a retrospective investigation of patients 1996-2017 (Lago et al., 2021). The children were followed for 2-25 years (Table 2). ...
... Fewer ocular lesions were detected in children who were treated before they were 4 months old (35.2%) vs those treated after they were 12 months old (77.8%), clearly revealing the benefit of early treatment. Two peaks of retinochoroiditis were detected between 4-5 and 9-14 years (Lago et al., 2021). Other lesions in these children were hydrocephalus in 4, microcephalus in 9 and hearing loss in 3 (Lago et al., 2021). ...
... Two peaks of retinochoroiditis were detected between 4-5 and 9-14 years (Lago et al., 2021). Other lesions in these children were hydrocephalus in 4, microcephalus in 9 and hearing loss in 3 (Lago et al., 2021). ...
The morbidity due to congenital toxoplasmosis in humans is very high. Most of these infected children are likely to develop symptoms of clinical toxoplasmosis. Sequelae in fetus resulting from Toxoplasma gondii infections in women who become infected with this parasite during pregnancy can be devastating and enormous efforts are directed in some countries to prevent these consequences. Here, an update on congenital toxoplasmosis in humans, especially the rate of congenital infections in humans worldwide, is provided. Although several countries have surveillance programmes, most information on the rate of congenital transmission is from France and Brazil. Because of compulsory national screening programme in France to detect and treat women with recently acquired T. gondii infection with anti-toxoplasma therapy, the rate of congenital transmission and the severity of disease in children are declining. Infections by this parasite are widely prevalent in Brazil. The severity of clinical toxoplasmosis in Brazilian children is very high and may be associated with the genetic characteristics of T. gondii isolates prevailing in animals and humans in Brazil. Virtually little or no information is available on this topic from China, India and other countries in Asia.
... La frecuencia de TO observada en este estudio es menor a la reportada en un estudio de seguimiento de pacientes con TC en el sur del Brasil, en el que 71,4% de los pacientes presentó retinocoroiditis, en un periodo de seguimiento de 10 años 22 . El tratamiento precoz y el seguimiento a largo plazo de estos pacientes es fundamental, considerando que la reactivación y desarrollo de nuevas lesiones son más frecuentes cuando el tratamiento se inicia después de los cuatro meses de edad 7,22 . ...
... Experiencia Clínica miento 7, 22 . Aunque clínicamente no tenían sintomatología compatible con daño de otros sistemas, en el presente estudio no se incluyeron los resultados del seguimiento y estudios complementarios. ...
Introducción:
La toxoplasmosis ocular (TO) es una retinocoroiditis que evoluciona con varios episodios de inflamación y puede presentarse, tanto en la forma congénita o adquirida de la enfermedad,
Objetivo:
Describir la frecuencia y características clínicas de la TO en lactantes de 0 a 12 meses, hijos de madres con serología positiva para toxoplasmosis en el periodo perinatal.
Metodología:
Estudio descriptivo transversal, ambispectivo. Ingresaron lactantes de 0 a 12 meses de edad, cuyas madres tenían serología positiva para toxoplasmosis en el periodo perinatal, remitidos al servicio de oftalmología pediátrica para evaluación. Se recogieron variables demográficas, serología materna y de los lactantes, y los resultados del examen oftalmológico. Los datos fueron analizados en SPSS-v21.
Resultados:
El 46,4% de 125 lactantes tenían TO, de ellos, 67,2% era de sexo femenino (p = 0,04), la mediana de edad fue de 6 meses, el 41% tenía IgG e IgM positiva. Las lesiones fueron bilaterales en 82,8%, central en 86,2%, e inactivas en 81%. La retinocoroiditis se acompañó de estrabismo en 41%.
Conclusiones:
La frecuencia de TO en esta población de lactantes con toxoplasmosis congénita, fue elevada. Más de 80% de las lesiones oculares eran inactivas, de localización central y compromiso bilateral.
... La frecuencia de TO observada en este estudio es menor a la reportada en un estudio de seguimiento de pacientes con TC en el sur del Brasil, en el que 71,4% de los pacientes presentó retinocoroiditis, en un periodo de seguimiento de 10 años 22 . El tratamiento precoz y el seguimiento a largo plazo de estos pacientes es fundamental, considerando que la reactivación y desarrollo de nuevas lesiones son más frecuentes cuando el tratamiento se inicia después de los cuatro meses de edad 7,22 . ...
... Experiencia Clínica miento 7, 22 . Aunque clínicamente no tenían sintomatología compatible con daño de otros sistemas, en el presente estudio no se incluyeron los resultados del seguimiento y estudios complementarios. ...
Introducción: La toxoplasmosis ocular (TO) es una retinocoroi-ditis que evoluciona con varios episodios de inflamación y puede presentarse, tanto en la forma congénita o adquirida de la enfermedad, Objetivo: Describir la frecuencia y características clínicas de la TO en lactantes de 0 a 12 meses, hijos de madres con serología positiva para toxoplasmosis en el periodo perinatal. Metodología: Estudio descripti-vo transversal, ambispectivo. Ingresaron lactantes de 0 a 12 meses de edad, cuyas madres tenían serología positiva para toxoplasmosis en el periodo perinatal, remitidos al servicio de oftalmología pediátrica para evaluación. Se recogieron variables demográficas, serología materna y de los lactantes, y los resultados del examen oftalmológico. Los datos fueron analizados en SPSS-v21. Resultados: El 46,4% de 125 lactantes tenían TO, de ellos, 67,2% era de sexo femenino (p = 0,04), la mediana de edad fue de 6 meses, el 41% tenía IgG e IgM positiva. Las lesiones fueron bilaterales en 82,8%, central en 86,2%, e inacti-vas en 81%. La retinocoroiditis se acompañó de estrabismo en 41%. Conclusiones: La frecuencia de TO en esta población de lactantes con toxoplasmosis congénita, fue elevada. Más de 80% de las lesiones oculares eran inactivas, de localización central y compromiso bilateral.
... Dois tipos de lesões de retina podem ser observados: retinite aguda -com intensa in amação -e cicatrizes retinianas. O comprometimento macular, frequentemente bilateral, associado a reativações e ao aumento das lesões residuais, pode levar à perda progressiva da visão e evoluir para cegueira (VASCONCELOS-SANTOS et al., 2012;LAGO et al., 2021). ...
... Entre as consequências anatômicas e funcionais decorrentes da toxoplasmose congênita, estão descritas morte fetal, prematuridade, manifestações clínicas e sequelas. As manifestações precoces e as sequelas incluem hepatoesplenomegalia, icterícia, erupção cutânea, pneumonite, lesões de retina, calci cações cerebrais, hidrocefalia, microcefalia, microftalmia, estrabismo, perda visual, convulsões e retardo mental (MITSUKA-BREGANÓ; LOPES-MORI; NAVARRO, 2010;LAGO et al., 2021). ...
Estratégias de vigilância, prevenção e controle dos acidentes ofídicos, escorpiônicos, araneídicos e por lagartas
... Dois tipos de lesões de retina podem ser observados: retinite aguda -com intensa in amação -e cicatrizes retinianas. O comprometimento macular, frequentemente bilateral, associado a reativações e ao aumento das lesões residuais, pode levar à perda progressiva da visão e evoluir para cegueira (VASCONCELOS-SANTOS et al., 2012;LAGO et al., 2021). ...
... Entre as consequências anatômicas e funcionais decorrentes da toxoplasmose congênita, estão descritas morte fetal, prematuridade, manifestações clínicas e sequelas. As manifestações precoces e as sequelas incluem hepatoesplenomegalia, icterícia, erupção cutânea, pneumonite, lesões de retina, calci cações cerebrais, hidrocefalia, microcefalia, microftalmia, estrabismo, perda visual, convulsões e retardo mental (MITSUKA-BREGANÓ; LOPES-MORI; NAVARRO, 2010;LAGO et al., 2021). ...
... Dois tipos de lesões de retina podem ser observados: retinite aguda -com intensa inflamação -e cicatrizes retinianas. O comprometimento macular, frequentemente bilateral, associado a reativações e ao aumento das lesões residuais, pode levar à perda progressiva da visão e evoluir para cegueira(VASCONCELOS-SANTOS et al., 2012;LAGO et al., 2021).A toxoplasmose aguda adquire especial relevância quando acomete a gestante, pela possibilidade da transmissão vertical. As gestantes são, geralmente, assintomáticas. ...
... Entre as consequências anatômicas e funcionais decorrentes da toxoplasmose congênita, estão descritas morte fetal, prematuridade, manifestações clínicas e sequelas. As manifestações precoces e as sequelas incluem hepatoesplenomegalia, icterícia, erupção cutânea, pneumonite, lesões de retina, calcificações cerebrais, hidrocefalia, microcefalia, microftalmia, estrabismo, perda visual, convulsões e retardo mental (MITSUKA-BREGANÓ; LOPES-MORI;NAVARRO, 2010;LAGO et al., 2021).DIAGNÓSTICOO diagnóstico de toxoplasmose pode ser complexo, sendo, em muitos casos, difícil distinguir a infecção aguda da crônica, e deve ser fundamentado na associação entre as manifestações clínicas, os riscos para o adoecimento, a confirmação por meio de estudos sorológicos e, em alguns casos, os exames de imagem e os métodos moleculares. Atualmente, anticorpos contra antígenos de esporozoítas de T. gondii podem ser detectados em soro e em saliva, permitindo verificar se a infecção ocorreu pela ingestão de cistos ou pela ingestão de oocistos do parasito. ...
Guia de Vigilância em Saúde, 5ª ed.: Vigilância da Síndrome Congênita Associada à Infecção pelo Vírus Zika
... Dois tipos de lesões de retina podem ser observados: retinite aguda -com intensa inflamação -e cicatrizes retinianas. O comprometimento macular, frequentemente bilateral, associado a reativações e ao aumento das lesões residuais, pode levar à perda progressiva da visão e evoluir para cegueira(VASCONCELOS-SANTOS et al., 2012;LAGO et al., 2021).A toxoplasmose aguda adquire especial relevância quando acomete a gestante, pela possibilidade da transmissão vertical. As gestantes são, geralmente, assintomáticas. ...
... Entre as consequências anatômicas e funcionais decorrentes da toxoplasmose congênita, estão descritas morte fetal, prematuridade, manifestações clínicas e sequelas. As manifestações precoces e as sequelas incluem hepatoesplenomegalia, icterícia, erupção cutânea, pneumonite, lesões de retina, calcificações cerebrais, hidrocefalia, microcefalia, microftalmia, estrabismo, perda visual, convulsões e retardo mental (MITSUKA-BREGANÓ; LOPES-MORI;NAVARRO, 2010;LAGO et al., 2021).DIAGNÓSTICOO diagnóstico de toxoplasmose pode ser complexo, sendo, em muitos casos, difícil distinguir a infecção aguda da crônica, e deve ser fundamentado na associação entre as manifestações clínicas, os riscos para o adoecimento, a confirmação por meio de estudos sorológicos e, em alguns casos, os exames de imagem e os métodos moleculares. Atualmente, anticorpos contra antígenos de esporozoítas de T. gondii podem ser detectados em soro e em saliva, permitindo verificar se a infecção ocorreu pela ingestão de cistos ou pela ingestão de oocistos do parasito. ...
A filariose linfática, doença parasitaria crônica, e uma das maiores causas mundiais de incapacidades permanentes ou de longo prazo. Acomete, principalmente, os membros inferiores e o trato urogenital, sendo as suas principais apresentações clinicas o linfedema e a hidrocele. É também conhecida como bancroftose, filaríase de Bancrofti, e elefantíase em uma das manifestações crônicas. Causada por vermes nematoides das especies Wuchereria bancrofti, Brugia malayi e Brugia timori. Nas Américas e na África, apenas a espécie W. bancrofti causa a filariose linfatica. Os vermes adultos medem em torno de 4 cm (machos) a até 10 cm (fêmeas) e vivem nos vasos linfáticos dos indivíduos infectados. O único reservatório do parasito e o ser humano que apresenta microfilárias no sangue. Pacientes com formas crônicas avançadas da doença, incluindo elefantíase, raramente apresentam microfilaremia. Desse modo, na maioria das formas crônicas, os indivíduos são amicrofilaremicos, portanto não transmitem o parasito filarial. No Brasil, mosquitos da espécie Culex quinquefasciatus, também conhecidos como pernilongo ou muriçoca, são os responsáveis pela transmissão da W. bancrofti. A transmissão ocorre unicamente pela picada da femea do mosquito vetor com larvas infectantes do parasito. No Brasil, as microfilarias apresentam periodicidade noturna no sangue periférico, com pico de microfilaremia ocorrendo entre 23h e 1h. Durante o dia, as microfilárias localizam-se nos capilares profundos, principalmente nos pulmões e, durante a noite, aparecem no sangue periférico, com maior concentração em torno da meia-noite.
... Dois tipos de lesões de retina podem ser observados: retinite aguda -com intensa inflamação -e cicatrizes retinianas. O comprometimento macular, frequentemente bilateral, associado a reativações e ao aumento das lesões residuais, pode levar à perda progressiva da visão e evoluir para cegueira(VASCONCELOS-SANTOS et al., 2012;LAGO et al., 2021).A toxoplasmose aguda adquire especial relevância quando acomete a gestante, pela possibilidade da transmissão vertical. As gestantes são, geralmente, assintomáticas. ...
... Entre as consequências anatômicas e funcionais decorrentes da toxoplasmose congênita, estão descritas morte fetal, prematuridade, manifestações clínicas e sequelas. As manifestações precoces e as sequelas incluem hepatoesplenomegalia, icterícia, erupção cutânea, pneumonite, lesões de retina, calcificações cerebrais, hidrocefalia, microcefalia, microftalmia, estrabismo, perda visual, convulsões e retardo mental (MITSUKA-BREGANÓ; LOPES-MORI;NAVARRO, 2010;LAGO et al., 2021).DIAGNÓSTICOO diagnóstico de toxoplasmose pode ser complexo, sendo, em muitos casos, difícil distinguir a infecção aguda da crônica, e deve ser fundamentado na associação entre as manifestações clínicas, os riscos para o adoecimento, a confirmação por meio de estudos sorológicos e, em alguns casos, os exames de imagem e os métodos moleculares. Atualmente, anticorpos contra antígenos de esporozoítas de T. gondii podem ser detectados em soro e em saliva, permitindo verificar se a infecção ocorreu pela ingestão de cistos ou pela ingestão de oocistos do parasito. ...
Chapter 8: Chagas Disease - In: Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Articulação Estratégica de Vigilância em Saúde. Guia de Vigilância em Saúde. 5. ed. – Brasília : Ministério da Saúde, 2021. 1.126 p.
... The consequences for the infants that may result in partial or total loss of vision depend on the location where the lesions develop and the extent of the affected tissue [13]. New retinochoroidal lesions developed after the first year of life is common even in patients treated, which indicates the importance of long-term follow-up of patients with CT [14]. ...
... The complex interplay between the host and the T. gondii during congenital and acquired toxoplasmosis may underlie long-term changes in metabolic, epigenetic phenotypic and functional features of the immune response [30,31]. It has been shown that treatment of CT in the first year of life of the infants appears to improve the clinical outcome [14,32]. However, the impact of therapeutic intervention on their immunological profile is poorly addressed. ...
Changes on immune response of children with congenital toxoplasmosis (CT) regarding infection evolution and therapeutic intervention was addressed. Infants with CT presented increased counts of monocytes, CD3-CD16-CD56High, CD3+CD56+ and CD4+ T-cells 1-year after treatment onset (TOXO1-yearAT). Smaller numbers of CD3-CD16-CD56+ and TCRγδ+ T-cells were specifically observed in infants with retinochoroidal lesions (L(+)). When infants were classified based on the baseline status, expansion of CD3-CD16-CD56High and CD4+ T-cells were observed in L(+) who had active, active/cicatricial or cicatricial lesions. Infants who had active or active/cicatricial lesions display augmented numbers of monocytes, CD3-CD16+CD56+, CD3+CD56+, CD8+DR+ and TCRγδ+ T-cells and those with active/cicatricial or cicatricial at baseline displayed increase in CD14+CD64+ monocytes. Moreover, all L(+) had increased IFN-γ+ and IL-10+ CD4+ T-cells, while L(-) had increased ratios of TNF+, IFN-γ+ and IL-4+ NK-cells upon antigen-specific stimulation. Persistent alterations in leukocytes in TOXO1-yearAT suggest long-term sequels in the immune system of infants with CT.
... The rate of development of new lesions in untreated children was reported in 90% of the patients (8,14). In a study conducted in Brazil, 71.4% of the cases had chorioretinitis in early infancy, and the probability of developing new lesions in patients treated in the first two months of life, and the severity of the disease was lower than those treated after 4 months of life (15). ...
Objective:
Congenital toxoplasmosis (CT) can have severe early and late sequelae in children. In this study, we aimed to evaluate the demographic, clinical, treatment characteristics of patients diagnosed with congenital Toxoplasma infection and to highlight the long-term complications of the patients.
Methods:
Patients with CT were included in this study who were followed between 2010 and 2022 in Cukurova University Medical Faculty Hospital. Demographic, clinical and treatment characteristics were searched retrospectively. In the diagnosis of maternal and CT, Toxoplasma IgM, IgG, IgG avidity, T. gondii polymerase chain reaction tests were used along with clinical and symptoms.
Results:
Eighteen children (two twins) with CT and their mothers (n=16) were included in the study. Median age was 1 month. Ten (55.5%) of the children were male. CT diagnosis was made during pregnancy in 7 mothers (resulting in 8 babies) and postnatally in 9 mothers (resulting in 10 babies). The mothers of 5 (31.1%) babies with CT received spiramycin treatment during pregnancy. Three (60%) of 5 pregnant women who received spiramycin were diagnosed in the first trimester, 4 (80%) of the babies did not have any sequale and only 1 (20%) had microphthalmia. Ocular involvement was the most common presentation of the disease occured in 10 patients (55.5%), hydrocephalus and intracranial calcification developed in five patients (27.7%). Hearing loss developed in 2 (11.1%) patients. During the follow-up period, seizures developed in 3 patients (16.6%), microcephaly in 2 patients (11.1%), and neurodevolopmental retardation in 7 patients (38.8%), two of the patients had severe mental retardation. One (5.5%) patient with hydrocephalus died at 36 months of age due to complications after ventriculoperitoneal shunt application.
Conclusion:
In our study, we observed severe sequelae in vision, hearing, and neurodevelopmental aspects in children diagnosed with CT at birth and during follow-ups. Early diagnosis and treatment of infants, along with the detection of Toxoplasma infection during pregnancy, are essential in preventing severe sequelae that may arise due to CT.
... In the present study, the immunochromatography test (rapid test) was used as a diagnostic tool for the investigation of antibodies produced in response to T. gondii antigen [16]. While, enzyme linked immunosorbent assay test (ELISA) was used as a conformational idiagnostic tool because it has high specificity and sensitivity to detect antibodies against T. gondii [17][18][19]. In the present investigation, there was significant difference in the diagnosis of ocular toxoplasmosis by using ELISA and immunochromatography (rapid) methods and this finding was fit with the finding of Hassaneina et al. (2018) [16]. ...
Toxoplasma gondii is an intracellular protozoan parasite that causes ocular toxoplasmosis with most complications such as developing eye lesions and impaired vision. During the period from October 2021 to April 2022, a total of 174 blood samples were taken from ocular infected patients whom visited Shahid Dr. Aso Hospital in Sulaimani City, Iraq. These samples were tested serologically for detection of anti-Toxoplasma gondii antibodies (IgG and IgM) with both imunochromatograhpy (rapid test) and ELISA. The serological test demonstrated that 63 IgG (36.2%) and 4 IgM (2.2%) were positive by rapid test imunochromatograhpy. While, 80 IgG (45.9%) and 2 IgM (1.1%) were positive by ELISA. Most of the infections (58.75%) were between 50-69 years old. All patients (80) were examined for intraocular toxoplasmosis lesion, only 10 patients (12.5%) including 2 males (2.5%) and 8 females (10%) had ocular toxoplasmosis lesions. Most of the lesions were scars (old type) while, in some patients they were active lesions. The types of lesions, numbers per each eye, lesion diameter and comparison with the IgG and IgM titers were demonstrated.
BACKGROUND
Congenital toxoplasmosis (CT) can be accompanied by serious organ manifestations, particularly retinochoroiditis, and may occur throughout life. We aimed to monitor long-term ocular prognosis in a large French cohort of patients with CT and its changes over time in the context of mandatory prenatal screening (since 1992) and incidence decrease since 2008.
METHODS
Patients with CT diagnosed between 1987 and 2021 were prospectively included and followed for up to 35 years. The effect of the period of conception on the risk of first retinochoroiditis has been tested using a flexible extension of the Cox model. Incidence rates of retinochoroiditis were estimated.
RESULTS
A total of 646 infected live born children were followed for a median of 12 years (range, 0.5–35); 187 patients (29%) had at least 1 ocular lesion (first at a median age of 5 years; range, 0–26 years) with peaks at 7 and 12 years. Early maternal infection and the presence of nonocular signs at birth were associated with a higher risk of retinochoroiditis, whereas delayed diagnosis of CT (after birth versus before or at birth) was associated with a lower risk (13% decrease for each additional month after birth; P = .01). A period effect for the risk of developing retinochoroiditis in patients born after 2008 was not detected.
CONCLUSIONS
Despite prenatal screening and prolonged perinatal treatment, retinochoroiditis is not a rare event in French patients with CT and can occur well into adulthood, with peak incidences at 7 and 12 years of age. It rarely causes severe damage but warrants regular follow-up into adulthood.
Introduction and purpose Toxoplasmosis, a prevalent parasitic infection caused by Toxoplasma gondii, impacts approximately one-third of the global population. Among congenital infections, Congenital Toxoplasmosis (CT) ranks second only to CMV infection in neonates. The severity of fetal and neonatal clinical manifestations depends on factors such as gestational age during infection, parasite load, infectious strain virulence, and maternal immune status. The organogenesis stage in the second trimester is identified as the critical period (10th-24th gestational weeks). Fetal CT may present with ultrasound-detected abnormalities, including intracranial calcifications, microcephaly, hydrocephalus, ascites, hepatosplenomegaly or severe intrauterine growth restriction. Even in the absence of symptoms at birth, CT can lead to long-term consequences such as hydrocephalus, seizures, and cognitive, auditory, and visual impairments. The aim of this study is to present a clinical case of a patient with CT infection complicated by treatment-resistant hydrocephalus and neurological symptoms, including muscle tone disturbances and seizures. Conclusion The significance of screening tests cannot be overstated, as early intervention is crucial to prevent enduring complications. Routine counseling for pregnant women is imperative to raise awareness about Toxoplasma gondii infection, empowering them to adopt necessary preventive measures. Additionally, further research is warranted to assess the efficacy of diverse treatment protocols, the risk of adverse effects, and the effectiveness of emerging therapeutic agents.
Purpose: To describe the most important cause of infectious posterior uveitis in pediatric patients.
Methods: Review of the literatura.
Results: The most important causes of infectious uveitis in pediatric patients are: cat-scratch disease, toxocariasis, tuberculosis, viral diseases and toxoplasmosis. Ocular manifestations include retinitis, neuroretinitis, choroidal granulomas, peripheral granulomas and posterior pole granulomas.
Conclusion: Infectious posterior uveitis is a challenging subject and should be considered in the differential diagnosis of any posterior uveitis in children. Infectious uveitis must be excluded before initiating immunosuppressive therapy.
Background: Ocular toxoplasmosis (OT) is caused by the parasite Toxoplasma gondii. OT is the leading cause of posterior uveitis globally; it is a recurrent disease that may result in visual impairment and blindness. This systematic review and meta-analysis aim to summarize and evaluate the risk factors for recurrences, visual impairment, and blindness described in the literature worldwide.
Methods and findings: We performed a systematic literature search in PubMed, Embase, VHL, Cochrane Library, Scopus, and DANS EASY Archive. All studies reporting patients with clinically and serologically confirmed OT presenting any clinical or paraclinical factor influencing recurrences, visual impairment, and blindness were included. Studies presenting secondary data, case reports, and case series were excluded. An initial selection was made by title and abstract, and then the studies were reviewed by full text where the eligible studies were selected. Then, the risk of bias was assessed through validated tools. Data were extracted using a validated extraction format. Qualitative synthesis and quantitative analysis were done. This study was registered on PROSPERO (CRD42022327836).
Results: Seventy two studies met the inclusion criteria. Fifty-three were summarized in the qualitative synthesis in three sections: clinical and environmental factors, parasite and host factors, and treatment-related factors. Of the 72 articles, 39 were included in the meta-analysis, of which 14 were conducted in South America, 13 in Europe, four in Asia, three multinational, two in North America and Central America, respectively, and only one in Africa. A total of 4,200 patients with OT were analyzed, mean age ranged from 7.3 to 65.1 year of age, with similar distribution by sex. The frequency of recurrences in patients with OT was 49% (95% CI 40%–58%), being more frequent in the South American population tan in Europeans. Additionally, visual impairment was presented in 35% (95% CI 25%–48%) and blindness in
20% (95% CI 13%–30%) of eyes, with a similar predominance in South Americans than in Europeans. On the other hand, having lesions near the macula or adjacent to the optic nerve had an OR of 4.83 (95% CI; 2.72–8.59) for blindness, similar to having more than one recurrence that had an OR of 3.18 (95% CI; 1.59–6.38). Finally, the prophylactic therapy with Trimethoprim/Sulfamethoxazole versus the placebo showed a protective factor of 83% during the first year and 87% in the second year after treatment.
Conclusion: Our Systematic Review showed that clinical factors such as being older
than 40 years, patients with de novo OT lesions or with less than one year after the first episode, macular area involvement, lesions greater than 1 disc diameter, congenital toxoplasmosis, and bilateral compromise had more risk of recurrences. Also, environmental and parasite factors such as precipitations, geographical region where the infection is acquired, and more virulent strains confer greater risk of recurrences. Therefore, patients with the above mentioned clinical, environmental, and parasite factors could benefit from using prophylactic therapy.
This literature review aims to give an overview of the current knowledge concerning how a toxoplasmosis infection affects the mother and her fetus. A thorough search of PubMed and a complimentary search of Google Scholar databases were used to identify relevant studies for this review. Although a Toxoplasma gondii infection is preventable, this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil. Maternal-to-fetal transmission of this infection can result in devastating ophthalmic and neurological consequences for the fetus. Although a toxoplasmosis infection can result in long-term effects on the fetus, chronic disease is also associated with mental illness in mothers. Effective treatment can reduce the risk of congenital toxoplasmosis and the long-term consequences of infection in the fetus. Without appropriate screening and education programs, this infection will remain largely undiagnosed.
Purpose of Review
Review building of programs to eliminate Toxoplasma infections.
Recent Findings
Morbidity and mortality from toxoplasmosis led to programs in USA, Panama, and Colombia to facilitate understanding, treatment, prevention, and regional resources, incorporating student work.
Summary
Studies foundational for building recent, regional approaches/programs are reviewed. Introduction provides an overview/review of programs in Panamá, the United States, and other countries. High prevalence/risk of exposure led to laws mandating testing in gestation, reporting, and development of broad-based teaching materials about Toxoplasma. These were tested for efficacy as learning tools for high-school students, pregnant women, medical students, physicians, scientists, public health officials and general public. Digitized, free, smart phone application effectively taught pregnant women about toxoplasmosis prevention. Perinatal infection care programs, identifying true regional risk factors, and point-of-care gestational screening facilitate prevention and care. When implemented fully across all demographics, such programs present opportunities to save lives, sight, and cognition with considerable spillover benefits for individuals and societies.
Purpose of Review
Review international efforts to build a global public health initiative focused on toxoplasmosis with spillover benefits to save lives, sight, cognition and motor function benefiting maternal and child health.
Recent Findings
Multiple countries’ efforts to eliminate toxoplasmosis demonstrate progress and context for this review and new work.
Summary
Problems with potential solutions proposed include accessibility of accurate, inexpensive diagnostic testing, pre-natal screening and facilitating tools, missed and delayed neonatal diagnosis, restricted access, high costs, delays in obtaining medicines emergently, delayed insurance pre-approvals and high medicare copays taking considerable physician time and effort, harmful shortcuts being taken in methods to prepare medicines in settings where access is restricted, reluctance to perform ventriculoperitoneal shunts promptly when needed without recognition of potential benefit, access to resources for care, especially for marginalized populations, and limited use of recent advances in management of neurologic and retinal disease which can lead to good outcomes.
Toxoplasma gondii est un parasite intra-cellulaire infectant près d’un tiers de la population mondiale. Généralement asymptomatique, la toxoplasmose est associée à une symptomatologie grave chez les patients immunodéprimés et dans le cas d’infection congénitale. Négligée par les pouvoirs publics, la phase chronique de l’infection a longtemps été sous-estimée. Cette méconnaissance entraîne donc des questions telles que quel est le meilleur protocole thérapeutique ? quelle est la meilleure stratégie diagnostique ? Récemment une stratégie de dissémination très avancée a été suspectée, sur la base de la théorie de la manipulation comportementale de l’hôte. Chez l’Homme, une telle manipulation peut avoir des effets majeurs cérébraux, neurologiques ou psychologiques. Quoi qu’il en soit, son impact sur le sommeil, qui constitue un index particulièrement sensible des fonctions cérébrales, est pour le moment inconnu. C’est pourquoi nous avons établi un modèle murin expérimental afin d’étudier les effets de Toxoplasma gondii sur le cycle éveil-sommeil. Nous avons montré que l’infection chronique par T. gondii était associée de manière persistante avec une augmentation de l’éveil et une diminution du sommeil, ce qui cadre avec la stratégie du parasite pour faciliter sa dissémination grâce à la prédation de son hôte. Nos résultats montrent pour la première fois les conséquences directes de l’infection toxoplasmique sur le comportement, pouvant avoir un impact majeur sur l’apparition de pathologies neuropsychiatriques et neurodégénératives.
This is the only book to cover toxoplasmosis of animals and humans thoroughly in one single source. Found worldwide from Alaska to Australasia, Toxoplasma gondii is the cause of one of the most common parasitic infections in humans, livestock, companion animals, and wildlife, and is included on the list of potential bioterrorism microbes. Furthermore, T. gondii has been and continues to be used extensively as a model for the cell biology of apicomplexan parasites. In the decade since the second edition of this book was published, there has been an explosion of knowledge concerning the parasite Toxoplasma gondii and toxoplasmosis. This update provides unique information on all known host types for this parasite, with an additional chapter on history, substantial updates throughout, and a detailed focus on the biology of the parasite in Chapter 2. The third edition is compiled by author JP Dubey, an authority on T. gondii who has worked with virtually all hosts of the protozoan during the last 55 years, including humans, all livestock species, wildlife, and zoo animals. The book distills the voluminous and potentially confusing scientific literature, that has grown geometrically in the 30+ years since the publication of the first edition, into a comprehensive resource for all professionals, graduate students and researchers working in this field.
Women infected with toxoplasmosis during pregnancy do not present symptoms in most cases, but the consequences of the congenital infection may be severe for the unborn child. Fetal damage can range from asymptomatic to severe neurological alterations to retinal lesions prone to potential flare up and relapses lifelong. Despite the possible severity of outcome, congenital toxoplasmosis (CT) is a neglected disease. There is no consensus regarding screening during pregnancy, prenatal/postnatal treatment or short or medium term follow-up. Since 1992, France has offered systematic serological testing to non-immune pregnant women, monthly until delivery. Any maternal infection is thus detected; moreover, diagnosis of congenital infection can be made at birth and follow-up can be provided. “Guidelines” drawn up by a multidisciplinary group are presented here, concerning treatment, before and after birth. The recommendations are based on the regular analysis of the literature and the results of the working group. The evaluation of the recommendations takes into account the robustness of the recommendation and the quality of the evidence.
Purpose:
To study visual acuity, refractive errors, eccentric fixation, and reading performance in patients with toxoplasmic macular retinochoroiditis.
Methods:
Twenty-three participants with bilateral toxoplasmic macular retinochoroiditis and 4 with toxoplasmic macular retinocho-roiditis in their unique eye were evaluated. Participants reported their eye dominance, confirmed by the Portus and Miles test. Best corrected visual acuity, spherical equivalent refraction, magnification need, and reading speed were measured. Microperimetry (MAIA, Centervue - Padova, Italy) recorded the preferred retinal locus and fixation stability by means of the bivariate contour ellipse area. Fourteen eyes from 14 normally sighted subjects served as controls.
Results:
Mean ± SD best corrected visual acuity was better in the dominant eye than in the nondominant eye: 0.9 ± 0.2 (logMAR 0.5 to 1.4) vs. 1.2 ± 0.3 (logMAR 0.6 to 1.7) (p<0.0001, paired t-test). Spherical equivalent myopia of -4.00 or higher was present in 42% of the eyes. Microperimetry was performed in 42 eyes. Eccentric fixation was observed in all examined eyes. In 14 eyes (33%), the preferred retinal locus was placed (in the retina) superior temporal to the macular lesion, in 10 (24%) superior nasal, in 6 (14%) inferior temporal, and in 12 (28%) inferior nasal. There was no significant difference in the distribution of the preferred retinal locus position between dominant and nondominant eyes (p=0.85, Pearson test). There was no correlation between reading speed and the distance between the preferred retinal locus and the estimated original foveal position (r=-0.09; p=0.73), the bivariate contour ellipse area (r=-0.19; p=0.44), or best corrected visual acuity (r=0.024; p=0.92).
Conclusions:
Myopia is more prevalent in patients with toxoplasmic macular retinochoroiditis. Reading speed is not dependent on preferred retinal locus position, stability, or visual acuity. Nevertheless, documentation of fixation provides new data on the impact of visual impairment in these patients and may be useful for rehabilitation efforts.
Significance
A majority of emerging infectious diseases in humans are transmitted from animals. It is generally agreed that our behavior can influence our exposure to such pathogens, but little is known regarding our role in shaping evolution in such pathogens. Such understanding would aid in their control, to the benefit of public health. Our results indicate that expansion of agriculture influenced not only the biogeography but also the virulence of Toxoplasma gondii . By linking landscape ecology to parasite virulence, our framework contributes a fundamentally unique perspective on the ecology and evolution of infectious disease.
Prompt diagnosis and rapid initiation of medical treatment are critical for the best outcomes in infants with congenital toxoplasmosis. This is important for pregnant women, fetuses, and infants, including those with active retinitis and choroidal neovascular membranes. For hydrocephalus, prompt placement of a ventriculoperitoneal shunt is key for improved outcomes. Pyrimethamine and Sulfadiazine with Leucovorin are first-line medicines. For later recurrences of active retinitis, Azithromycin or Clindamycin are sometimes substituted for Sulfadiazine as second-line treatments, given with Pyramethamine. Following resolution of active retinitis, these medicines may be useful without Pyrimethamine for suppression and avoid the risk of hypersensitivity from Trimethoprim/Sulfamethoxazole. Antibody to VEGF, in conjunction with antimicrobial therapy, results in resolution of choroidal neovascular membranes. Serologic screening of seronegative pregnant women to detect primary infection during gestation, and facilitating medicine administration and thereby preventing or treating fetal infection, is an optimal, apparently cost-effective, means to reduce disease. Definitively curative medicines currently being developed likely will improve future management and outcomes of this disease.
This paper summarizes prevalence of Toxoplasma gondii in humans and animals and associated correlates of infection, clinical spectrum of disease in humans, and genetic diversity of T. gondii isolates from Colombia. Recent studies, especially in the states of Antioquia, Quindio and Cundinamarca, indicate that toxoplasmosis is a major public health problem. Approximately half of the women of child bearing age have T. gondii antibodies, and the clinical disease in congenitally infected children is more severe than in Europe. Limited studies indicate that the strains of T. gondii from Colombia are genetically and phenotypically different than in Europe and North America. However, epidemiological factors, such as the involvement of domestic and/or wild animals in transmission, the distribution of strain diversity by natural geographic regions, and the variation in risk factors between regions that are associated with human infection in Colombia, remain unknown. Areas of research for the future are outlined. This review should be of interest to biologists, veterinarians, physicians, and parasitologists.
Congenital toxoplasmosis (CT) can elicit severe damage to several organs, especially the eye, and may be manifested at birth or later. We assessed the long-term ocular prognosis in a cohort of congenitally infected children treated according to a standardized protocol and monitored for up to 22 years.
This prospective study included confirmed cases of CT, which were identified by obligatory antenatal screening at the Lyon (France) reference center between 1987 and 2008. Data obtained through ocular examinations were recorded on a standardized form and confirmed by an independent external committee. Risk factors for retinochoroiditis were identified by using a multivariable Cox model and a flexible model that accounted for changes in the factor effects during follow-up.
A total of 477 of 485 infected live-born children were followed for a median of 10.5 years (75th percentile: 15.0 years). During the follow-up, 142 patients (29.8%) manifested at least 1 ocular lesion. Lesions were unilateral in 98 individuals (69.0%) and caused no vision loss in 80.6%. Lesions were first manifested at a median age of 3.1 (0.0-20.7) years. In 48 (33.8%) of the children, recurrences or new ocular lesions occurred up to 12 years after the appearance of the first lesion. Early maternal infection and confirmation of CT in children, prematurity, and nonocular CT lesions at baseline were associated with a higher risk of retinochoroiditis.
Although the consequences of CT are rarely severe in treated children, regular postnatal monitoring is nevertheless justified because of the lifelong persisting risk of new ocular manifestations.
Between December 1981 and May 1991, 44 infants and children with congenital toxoplasmosis were referred to our study group.
A uniform approach to evaluation and therapy was developed and is described herein along with the clinical characteristics
of these infants and children. In addition, case histories that illustrate especially important clinical features or previously
undescribed findings are presented. Factors that contributed to the more severe disabilities included delayed diagnosis and
initiation of therapy; prolonged, concomitant neonatal hypoxia and hypoglycemia; profound visual impairment; and prolonged,
uncorrected increased intracranial pressure with hydrocephalus and compression of the brain. Years after therapy was discontinued,
three children developed new retinal lesions (without loss of visual acuity when therapy for Toxoplasma gondii was initiated promptly), and three children experienced a new onset of afebrile seizures. Most remarkable were the normal
developmental, neurological, and ophthalmologic findings at the early follow-up evaluations of many—but not all—of the treated
children despite severe manifestations, such as substantial systemic disease, hydrocephalus, microcephalus, multiple intracranial
calcifications, and extensive macular destruction detected at birth. These favorable outcomes contrast markedly with outcomes
reported previously for children with congenital toxoplasmosis who were untreated or treated for only 1 month.
Recent studies of Toxoplasma gondii isolates from animals in Brazil have revealed high genetic diversity. Many of these isolates are virulent to mice. It is
speculated that these isolates may also be virulent to humans. However, there is very limited data regarding T. gondii strains from human infection. Therefore, it is not clear whether there is any association between parasite genotypes and
disease phenotypes. In this study, a total of 27 T. gondii strains were isolated from humans with congenital toxoplasmosis in Minas Gerais state, Brazil. The genetic variability was
assessed by restricted fragment length polymorphism in 11 loci (SAG1, 5′ plus 3′ SAG2, alternative [alt.] SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico). Genetic analysis of 24 strains revealed 14 different genotypes, including 7 previously identified from animals and 7 new
types. The widespread genotype BrII accounted for 29% (7/24) of the isolates and was the dominant genotype involved in this
study. This is the first report of genotyping of T. gondii isolates obtained from blood samples from newborns with congenital toxoplasmosis. Genotypic characterization of these isolates
suggests high genetic diversity of T. gondii in this human population in Brazil. Future studies are needed to determine the source of contamination of this human population.
Toxoplasma gondii is an unicellular coccidian parasite with worldwide distribution. It is estimated that more than a third of the world's population has been infected with the parasite, but seroprevalence is unevenly distributed across countries and different socioeconomic strata. The majority of newborns with congenital toxoplasmosis do not have any clinical signs of the disease at birth; however, 30-70% of those with clinical abnormalities were not detected initially, and are found to have new retinal lesions consistent with toxoplasmicchorioretinitis later in life. Congenital toxoplasmosis can also cause fetal death, stillbirths or long-term disabling sequelae, particularly among untreated infants. The disease appears to be more frequent and severe at certain latitudes. Congenital toxoplasmosis can be prevented and treated during gestation. Less severe disease is commonly reported in countries where prenatal screening and treatment have been systematically implemented. By contrast, severe disease appears to be observed primarily in infants born to untreated mothers. For definition purposes, it is best to use the term toxoplasma or Toxoplasma gondii infection when referring to asymptomatic patients with primary or chronic infection, and toxoplasmosis when referring to patients with symptoms or signs.
SUMMARY Infections by the protozoan parasite Toxoplasma gondii are widely prevalent in humans and animals in Brazil. The burden of clinical toxoplasmosis in humans is considered to be very high. The high prevalence and encouragement of the Brazilian Government provides a unique opportunity for international groups to study the epidemiology and control of toxoplasmosis in Brazil. Many early papers on toxoplasmosis in Brazil were published in Portuguese and often not available to scientists in English-speaking countries. In the present paper we review prevalence, clinical spectrum, molecular epidemiology, and control of T. gondii in humans and animals in Brazil. This knowledge should be useful to biologists, public health workers, veterinarians, and physicians. Brazil has a very high rate of T. gondii infection in humans. Up to 50% of elementary school children and 50-80% of women of child-bearing age have antibodies to T. gondii. The risks for uninfected women to acquire toxoplasmosis during pregnancy and fetal transmission are high because the environment is highly contaminated with oocysts. The burden of toxoplasmosis in congenitally infected children is also very high. From limited data on screening of infants for T. gondii IgM at birth, 5-23 children are born infected per 10 000 live births in Brazil. Based on an estimate of 1 infected child per 1000 births, 2649 children with congenital toxoplasmosis are likely to be born annually in Brazil. Most of these infected children are likely to develop symptoms or signs of clinical toxoplasmosis. Among the congenitally infected children whose clinical data are described in this review, several died soon after birth, 35% had neurological disease including hydrocephalus, microcephaly and mental retardation, 80% had ocular lesions, and in one report 40% of children had hearing loss. The severity of clinical toxoplasmosis in Brazilian children may be associated with the genetic characteristics of T. gondii isolates prevailing in animals and humans in Brazil.
Congenital toxoplasmosis remains a public health problem throughout the world. Long-term longitudinal studies are still needed to argument controversial screening and treatment strategies and to enable to accurately counsel parents.
We conducted a prospective cohort study over 16 years in Marseilles, France. Seronegative pregnant women underwent monthly serological testing. Children were treated antenatally with rovamycine as soon as maternal infection was detected and with pyrimethamine and sulfadoxine in case of positive Toxoplasma PCR on amniotic fluid. Postnatal treatment with pyrimethamine and sulfadoxine was systematically prescribed for one year and possibly continued at the physician discretion.
127 children were included. 24 children (18.9%) presented ocular lesions causing visual impairment in eight cases. Eleven children (8.7%) presented with ocular lesions at birth, mostly macular. Sixteen children (12.6%) developed ocular lesions during follow-up, mostly peripheral. The first ocular lesion could occur as late as 12 years after birth. No significant risk factor of chorioretinitis was identified including gestational age at infection, type of antenatal treatment and shorter postnatal treatment.
These results confirm the overall good prognosis of congenital toxoplasmosis in Europe but highlight though a low risk of late ocular manifestation. Chorioretinitis affected 18.9% of children suffering from congenital toxoplasmosis despite antenatal and neonatal screening associated with early treatment. Long-standing follow-up is needed because first lesion can occur as late as 12 years after birth. Late lesions were less often macular but nevertheless caused sometimes visual impairment.
To review current evidence for the treatment of ocular toxoplasmosis (OT).
Narrative review and expert recommendations.
Meta-analysis and selected original articles from the medical literature were reviewed critically. Expert recommendations were analyzed.
Numerous observational studies suggest a benefit of short-term antimicrobial therapy for toxoplasmic retinochoroiditis in immunocompetent patients, although its efficacy has not been proven in randomized clinical trials. A randomized clinical trial revealed that intermittent trimethoprim/sulfamethoxazole treatment could decrease the rate of recurrence in high-risk patients. Intravitreal injection of clindamycin and dexamethasone was an acceptable alternative to the classic treatment for OT in a randomized clinical trial.
Opinions about therapy differ and controversy remains about its type, efficacy, and length. Intravitreal therapy may be promising for OT. A recent description of the presence of parasitemia in patients with active and inactive ocular toxoplasmosis raises new questions that need to be explored.
The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known.
Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07-0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2-15) after maternal seroconversion at 10 weeks, and 18 (9-75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21-2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%-38.1%).
The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors' Summary.
Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients.
Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA.
The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis.
The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.
Summary:
Background: Despite three decades of prenatal screening for congenital toxoplasmosis in some European countries, uncertainty remains about the effectiveness of prenatal treatment.
Methods: We did a systematic review of cohort studies based on universal screening for congenital toxoplasmosis. We did a meta-analysis using individual patients' data to assess the effect of timing and type of prenatal treatment on mother-to-child transmission of infection and clinical manifestations before age 1 year. Analyses were adjusted for gestational age at maternal seroconversion and other covariates.
Findings: We included 26 cohorts in the review. In 1438 treated mothers identified by prenatal screening, we found weak evidence that treatment started within 3 weeks of seroconversion reduced mother-to-child transmission compared with treatment started after 8 or more weeks (adjusted odds ratio [OR] 0·48, 95% CI 0·28–0·80; p=0·05). In 550 infected liveborn infants identified by prenatal or neonatal screening, we found no evidence that prenatal treatment significantly reduced the risk of clinical manifestations (adjusted OR for treated vs not treated 1·11, 95% CI 0·61–2·02). Increasing gestational age at seroconversion was strongly associated with increased risk of mother-to-child transmission (OR 1·15, 95% CI 1·12–1·17) and decreased risk of intracranial lesions (0·91, 0·87–0·95), but not with eye lesions (0·97, 0·93–1·00).
Interpretation: We found weak evidence for an association between early treatment and reduced risk of congenital toxoplasmosis. Further evidence from observational studies is unlikely to change these results and would not distinguish whether the association is due to treatment or to biases caused by confounding. Only a large randomised controlled clinical trial would provide clinicians and patients with valid evidence of the potential benefit of prenatal treatment.
To evaluate the ocular manifestations of congenital toxoplasmosis at the first ophthalmological examination of children up to the age of 12 months.
Cross-sectional study of 44 children with a confirmed diagnosis of congenital toxoplasmosis. In all patients, complete ophthalmological examinations were performed under sedation. The patients underwent biomicroscopy of the anterior segment, skiascopy under cyclopegia, and indirect binocular ophthalmoscopy with maximum mydriasis.
The mean age of patients was 4.2 months. Of the 44 children evaluated, 31 (70.4%) presented ocular involvement and 29 (65.9%) of them had retinochoroiditis lesions. The retinochoroiditis lesions were bilateral in 22 (75.8%) patients and unilateral in 7 (24.2%). The retinochoroiditis lesions were active in 8 (15.7%) eyes and had healed in 43 (84.3%). Most of the lesions were concentrated in the papillomacular area (76.3%). Other associated ocular alterations were present in 22 children, the most prevalent being cataract, microphthalmia, and strabismus.
Ocular involvement in congenital toxoplasmosis might be much more frequent and occurs earlier than previously described.
The influence of patient age on various features of ocular toxoplasmosis has been a subject of study for many years. The age at which Toxoplasma gondii infection occurs in different populations is related to socioeconomic factors and studies suggest that ocular toxoplasmosis is a more severe disease at the extremes of age. The prevalence of ocular involvement is markedly different between individuals with congenital and those with post-natally acquired infections. Even among those with post-natally acquired infections, age influences the risk and timing of ocular involvement. The severity of toxoplasmic retinochoroiditis (in terms of lesion size, location and associated inflammation) is also affected by patient age at the time of initial infection or recurrence. The risk of recurrent toxoplasmic retinochoroiditis is influenced by age at the time of initial infection and age at most recent episode of active disease. Understanding of relationships between ocular toxoplasmosis and patient age is incomplete; evidence has often been indirect and in some cases conflicting. The influence of patient age on ocular toxoplasmosis should be studied in a systematic manner to provide a better understanding of disease mechanisms and to provide clinical information that can used to establish better strategies for disease treatment and prevention.
Toxoplasmic retinochoroiditis appears to be more severe in Brazil, where it is a leading cause of blindness, than in Europe, but direct comparisons are lacking. Evidence is accumulating that more virulent genotypes of Toxoplasma gondii predominate in South America.
We compared prospective cohorts of children with congenital toxoplasmosis identified by universal neonatal screening in Brazil and neonatal or prenatal screening in Europe between 1992 and 2003, using the same protocol in both continents.
Three hundred and eleven (311) children had congenital toxoplasmosis: 30 in Brazil and 281 in Europe, where 71 were identified by neonatal screening. Median follow up was 4.1 years in Europe and 3.7 years in Brazil. Relatively more children had retinochoroiditis during the first year in Brazil than in Europe (15/30; 50% versus 29/281; 10%) and the risk of lesions by 4 years of age was much higher: the hazard ratio for Brazil versus Europe was 5.36 (95%CI: 3.17, 9.08). Children in Brazil had larger lesions, which were more likely to be multiple and to affect the posterior pole (p<0.0001). In Brazil, visual impairment (<6/12 Snellen) was predicted for most affected eyes (87%, 27/31), but not in Europe (29%; 20/69, p<0.0001). The size of newly detected lesions decreased with age (p = 0.0007).
T. gondii causes more severe ocular disease in congenitally infected children in Brazil compared with Europe. The marked differences in the frequency, size and multiplicity of retinochoroidal lesions may be due to infection with more virulent genotypes of the parasite that predominate in Brazil but are rarely found in Europe.
This study was set up to determine the long term ocular and systemic sequelae in patients with severe congenital toxoplasmosis.
Cross sectional and retrospective study of 17 patients with severe congenital toxoplasmosis.
In addition to chorioretinitis (100%), the most common abnormal ocular features were optic nerve atrophy (83%), visual acuity of less than 0.1 (85%), strabismus, and microphthalmos. In 50% of cases we observed iridic abnormalities and about 40% developed a cataract. Overt endocrinological disease, diagnosed in five of 15 patients, included panhypopituitarism (n = 2), gonadal failure with dwarfism (n = 1), precocious puberty with dwarfism and thyroid deficiency (n = 1), and diabetes mellitus and thyroid deficiency (n = 1). The observed endocrinological involvement was associated in all cases with obstructive hydrocephalus with a dilated third ventricle and optic nerve atrophy.
The recognition of long term ocular, neurological, and endocrinological sequelae of congenital toxoplasmosis is important for medical management of these severely handicapped patients.
We evaluated the clinical presentation and determined the ocular and neurologic sequelae in children with congenital toxoplasmosis in Brazil, taking into consideration the shortage of national publications on this disease. Follow-up evaluations were made of 43 children with congenital toxoplasmosis referred to Santa Casa de São Paulo, during a period of at least five years. Selection of the cases was based in clinical and laboratory criteria. A clear predominance of children with subclinical presentation of the disease at birth (88%) was found. Of the 43 children, 22 (51%) developed neurological manifestations. Using skull radiography, we detected neuroradiologic alterations in seven children (16%) and with tomography in 33 children (77%). Neurological sequelae were identified in 15 children (54%) in the group with cerebral calcifications and in 7 (47%) in the group without cerebral calcifications. We observed chorioretinitis in 95% of the cases. Reactivation of cicatricial lesions and the emergence of new ocular lesions were observed in five cases. The most frequent neurological manifestation was a delay in neuropsychomotor development. Most remarkable was the finding that cerebral calcifications were not associated with a higher incidence of neurological sequelae among the children. Chorioretinitis was the main ocular sequel of the infection, found in nearly all children; it can manifest years from birth, even in children submitted to specific therapy druing the first year of life, highlighting the importance of a follow-up of these children.
The aim of this study was to identify the high-risk factors associated with the development of ocular lesions in a large cohort of children with congenital toxoplasmosis (CT), irrespective of their gestational age at the time of maternal infection. Children were managed according to a standardized protocol and monitored for up to 14 years at the Croix-Rousse Hospital, Lyon, France. Cox model and a flexible regression, spline-based method were used for the analysis. During a median follow-up time of 6 years, 79 of the 327 children (24%) had at least one retinochoroidal lesion. No bilateral impairment of visual acuity was observed. The risk of a child developing ocular disease was higher not only when mothers were infected early during pregnancy, which was expected, but also when CT was diagnosed prior to or at the time of birth, when non-ocular manifestations were present at baseline and when birth was premature.
Retinochoroiditis is the most frequent consequence of congenital toxoplasmosis. Early diagnosis and treatment are believed to reduce the risk of visual impairment. We report on the clinical evolution of ocular lesions and final visual function in a prospective cohort of congenitally infected children who were identified during monthly maternal prenatal screening.
The study included 327 congenitally infected children who were monitored for up to 14 years at the Croix Rousse Hospital in Lyon, France. Data on date of maternal infection; time and type of therapy; antenatal, neonatal, and postnatal work-ups; and ocular status were analyzed.
All mothers but 52 had been treated. Pyrimethamine and sulfadiazine was given in utero to 38% of children and after birth to 72% of newborns. Fansidar was given for an average duration of 337 days in all but 2 children. After a median follow-up of 6 years, 79 (24%) children had at least 1 retinochoroidal lesion. In 23 (29%) of them, at least 1 new event had been diagnosed up to 10 years after detection of the first lesions: reactivation of an existing lesion (1 case), new lesion in a previously healthy location (19 cases), or both (3 cases). Fifty-five children had lesions in 1 eye; of the 45 children for whom final visual acuity data were available, 31 (69%) had normal vision. Twenty-four children had lesions in both eyes; of the 21 for whom final visual acuity data were available, 11 had normal vision in both eyes. None had bilateral visual impairment.
Clinicians, parents, and elder children with congenital infection should be informed that late-onset retinal lesions and relapse can occur many years after birth but that the overall ocular prognosis of congenital toxoplasmosis is satisfactory when infection is identified early and treated accordingly.
Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. The aim of this study was to determine the nature of the latter in treated cases of the disease and to assess their impact on visual function.
Four hundred and thirty consecutive children with serologically confirmed congenital toxoplasmosis were included in this study. Data were prospectively collected using standardized ophthalmological assessment forms. The presence of retinochoroiditis and of associated pathologies was ascertained, and their impact on visual function was assessed.
After a median follow-up of 12 years [range 0.6-26 years], 130 children manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth and 264 additional ones during the follow-up period. Of these, 48 (17%) were active when first diagnosed. Twenty-five of the 130 children (19%) had other associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral microphthalmia, and 4 (3%) with cataracts. Most of these events were detected after the onset of retinochoroiditis. None of the children presented with ocular involvement in the absence of chorioretinal lesions. Macular lesions occurred more frequently in children with associated pathologies (p<0.0001), and associated pathologies were likewise more common in individuals with macular lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3 of these eyes it was due not to an associated pathology but to macular retinochoroiditis.
At the end of the follow-up period, ocular involvement existed in 30% of the treated children with congenital toxoplasmosis. Associated eye pathologies were manifested less frequently than anticipated. They may occur later in life and are an indirect marker of the severity of congenital toxoplasmosis, but they do not have a direct impact on visual acuity. The overall functional prognosis of congenital toxoplasmosis is better than would be expected on the basis of literature findings, with only 2 of the 130 children suffering bilateral visual impairment.
To document loss of central field in patients with scars from toxoplasmic retinochoroiditis close to the disc after resolution of disease.
Patients with a clinical diagnosis of toxoplasmic retinochoroiditis were enrolled from four centres. Automated central visual field testing was performed when their disease had settled and retinal photographs of the lesions were taken. The type of central field defect (whether absolute or relative) and whether it broke out to the periphery were correlated with the size of the retinochoroidal scar and its proximity to the optic nerve head.
69 eyes were enrolled; 16 (26%) were discarded because of poor field performance. Of the 53 remaining eyes, 31 showed absolute defects and 20 relative defects. Scars within one disc diameter of the disc were more likely to be associated with absolute defects breaking out to the periphery.
The scarring induced by toxoplasmic retinochoroiditis is associated with considerable field loss when it occurs close to the optic nerve head. Current treatment is unlikely to ameliorate this situation. The degree of visual field loss should be an outcome measure for future trials of the efficacy of treatment trials for the disease.
Without treatment, congenital toxoplasmosis has recurrent, recrudescent, adverse outcomes. Long-term follow-up of infants with congenital toxoplasmosis treated throughout their first year of life with pyrimethamine and sulfadiazine has not been reported.
Between 1981 and 2004, one hundred twenty infants (current mean age +/- standard deviation, 10.5 +/- 4.8 years) with congenital toxoplasmosis were treated with 1 of 2 doses of pyrimethamine plus sulfadiazine; therapy was initiated shortly after birth and continued for 12 months. Children who received treatment were evaluated at birth and at predetermined intervals; the focus of the evaluations was on prespecified end points: motor abnormalities, cognitive outcome, vision impairment, formation of new eye lesions, and hearing loss.
Treatment of infants without substantial neurologic disease at birth with pyrimethamine and sulfadiazine for 1 year resulted in normal cognitive, neurologic, and auditory outcomes for all patients. Treatment of infants who had moderate or severe neurologic disease (as defined in this article in the Treatments subsection of Methods) at birth resulted in normal neurologic and/or cognitive outcomes for >72% of the patients, and none had sensorineural hearing loss. Ninety-one percent of children without substantial neurologic disease and 64% of those with moderate or severe neurologic disease at birth did not develop new eye lesions. Almost all of these outcomes are markedly better than outcomes reported for children who were untreated or treated for 1 month in earlier decades (P<.01 to P<.001). Sex and severity of disease were comparable in our 2 treatment groups, and no significant differences in efficacy or toxicity were noted between the 2 treatment groups (P > .05).
Although not all children did well with treatment, the favorable outcomes we noted indicate the importance of diagnosis and treatment of infants with congenital toxoplasmosis.
The purpose of this work was to determine whether visual impairment caused by toxoplasmic chorioretinitis is associated with impaired performance of specific tasks on standardized tests of cognitive function. If so, then we worked to determine whether there are patterns in these difficulties that provide a logical basis for development of measures of cognitive function independent of visual impairment and compensatory intervention strategies to facilitate learning for such children.
Sixty-four children with congenital toxoplasmosis with intelligence quotient scores > or = 50 and visual acuity sufficient to cooperate with all of the intelligence quotient subscales had assessments of their vision, appearance of their retinas, and cognitive testing performed between 3.5 and 5 years of age. These evaluations took place between 1981 and 1998 as part of a longitudinal study to determine outcome of congenital toxoplasmosis. Children were evaluated at 3.5 or 5 (37 children) or both 3.5 and 5 (27 children) years of age. Cognitive function was measured using the Wechsler Preschool and Primary Scale of Intelligence-Revised. Wechsler Preschool and Primary Scale of Intelligence-Revised scale scores were compared for children grouped as those children who had normal visual acuity in their best eye (group 1), and those who had impaired vision in their best eye (acuity < 20/40) because of macular disease (group 2). Demographic characteristics were compared for children in the 2 groups. Test scores were compared between groups using all of the 3.5-year-old visits, all of the 5-year-old visits, and using each child's "last" visit (ie, using the 5-year-old test results when a child was tested at both 3.5 and 5 years of age or only at 5 years, otherwise using the 3.5-year-old test results). The results were similar and, therefore, only the results from the last analysis are reported here.
There were 48 children with normal visual acuity in their best eye (group 1) and 16 children with impaired vision because of macular involvement in their best eye (group 2). Ethnicity and socioeconomic scores were similar. There was a significantly greater proportion of males in group 2 compared with group 1 (81% vs 46%). There was no significant diminution in Wechsler Preschool and Primary Scale of Intelligence-Revised test scores between 3.5 and 5 years of age for the 27 children tested at both of these ages. Verbal intelligence quotient, performance intelligence quotient, full-scale intelligence quotient scores, and all of the scaled scores except arithmetic and block design were significantly lower for children in group 2 compared with group 1. The majority of the differences remained statistically significant or borderline significant after adjusting for gender. However, the difference in overall verbal scores does not remain statistically significant. Mean +/- SD verbal (98 +/- 20) and performance (95 +/- 17) intelligence quotients were not significantly different for children in group 1. However, verbal (88 +/- 13) and performance intelligence quotients (78 +/- 17) were significantly different for children in group 2. For children in group 2, their lowest scale scores were in object assembly, geometric design, mazes, and picture completion, all timed tests that involved visual discrimination of linear forms with small intersecting lines. In the 2 scales scored that did not differ between groups 1 and 2, arithmetic and block design, timing and vision but not linear forms were components of the tasks. Children with monocular and binocular normal visual acuity did not differ in verbal, performance, or full-scale intelligence quotients or any of the subscale tests. Difficulty with sight or concomitant neurologic involvement also seemed to impact the ability to acquire information, comprehension skills, and vocabulary and performance in similarities testing. After controlling for gender, however, these differences were diminished, and there were no longer differences in overall verbal scores. As noted above, results were generally similar when all of the tests for 3.5-year-olds or 5-year-olds were analyzed separately. At the 3.5-year visit there were fewer significant differences between the 2 groups for the verbal components than at the 5-year visit.
In children with congenital toxoplasmosis and bilateral macular disease (group 2) because of toxoplasmic chorioretinitis, scaled scores were lowest on timed tests that require discrimination of fine intersecting lines. Although the severity of ocular and neurologic involvement is often congruent in children with congenital toxoplasmosis, ophthalmologic involvement seems to account for certain specific limitations on tests of cognitive function. Children with such visual impairment compensate with higher verbal skills, but their verbal scores are still less than those of children with normal vision, and in some cases significantly so, indicating that vision impairment might affect other aspects of cognitive testing. Patterns of difficulties noted in the subscales indicate that certain compensatory intervention strategies to facilitate learning and performance may be particularly helpful for children with these impairments. These patterns also provide a basis for the development of measures of cognitive function independent of visual impairment.
To assess functional impairment in terms of visual acuity reduction and visual field defects in inactive ocular toxoplasmosis.
61 patients with known ocular toxoplasmosis in a quiescent state were included in this prospective, cross-sectional study. A complete ophthalmic examination, retinal photodocumentation and standard automated perimetry (Octopus perimeter, program G2) were performed. Visual acuity was classified on the basis of the World Health Organization definition of visual impairment and blindness: normal (> or =20/25), mild (20/25 to 20/60), moderate (20/60 to 20/400) and severe (<20/400). Visual field damage was correspondingly graded as mild (mean defect <4 dB), moderate (mean defect 4-12 dB) or severe (mean defect >12 dB).
8 (13%) patients presented with bilateral ocular toxoplasmosis. Thus, a total of 69 eyes was evaluated. Visual field damage was encountered in 65 (94%) eyes, whereas only 28 (41%) eyes had reduced visual acuity, showing perimetric findings to be more sensitive in detecting chorioretinal damage (p<0.001). Correlation with the clinical localisation of chorioretinal scars was better for visual field (in 70% of the instances) than for visual acuity (33%). Moderate to severe functional impairment was registered in 65.2% for visual field, and in 27.5% for visual acuity.
In its quiescent stage, ocular toxoplasmosis was associated with permanent visual field defects in >94% of the eyes studied. Hence, standard automated perimetry may better reflect the functional damage encountered by ocular toxoplasmosis than visual acuity.
Most infants born with congenital Toxoplasma infection are asymptomatic in the newborn period, and therefore their infection is not recognized. We performed follow-up evaluations on 24 such children. The mean age of these children at last examination was 8.5 years. In group I (13 children), the diagnosis was made prospectively. In group II (11 children), no symptoms or signs were noted in the newborn period and the diagnosis was made only after the first sign developed. Eighty-five percent of the children in group I and all of the children in group II have developed chorioretinitis. In group I, three children (23%) have unilateral blindness; in group II, three children (27%) and five children (45%) have unilateral and bilateral blindness, respectively. One child (8%) in group I and two children (18%) in group II developed severe, permanent neurologic sequelae after they initially presented with eye disease. Two of the children in each group are now retarded (IQ score range, 36 to 62). Six of the children in group I who were tested sequentially have had lower IQ scores (mean change from 97 to 74) on repeat tests performed an average of 5.5 years later. Less severe neurologic, intellectual, and audiologic deficits were observed in other children in each group. Treatment of some children may have had a beneficial effect on their outcome.
Background:
There are few studies reporting frequency and control of adverse events associated with congenital toxoplasmosis treatment. The objective of this study is to describe treatment adherence and adverse hematologic events in a cohort of children identified with congenital toxoplasmosis in Minas Gerais, Brazil.
Methods:
Children were treated with sulfadiazine, pyrimethamine and folinic acid and were evaluated clinically and by laboratory tests at regular intervals.
Results:
Of 146,307 live newborns who participated in the Neonatal Screening Program in Minas Gerais in 2006-2007, 190 had congenital toxoplasmosis. Among the 171 children whose treatment data were available, 73.1% completely adhered to antiparasitic therapy. Hematologic adverse events (macrocytic anemia and/or neutropenia and/or thrombocytopenia) were diagnosed in 44% of them. The most common adverse event was neutropenia (31%). In most cases, it was not severe and reversed following increase in folinic acid dosage (25.7%) or temporary treatment suspension (1.8%). No infections were observed in association with neutropenic events. Significant associations were detected between macrocytic anemia and lower weight z-score at first medical appointment (p = 0.03), and between severe neutropenia (<500/mm) and lower weight z-score towards the end of treatment (p = 0.04).
Conclusions:
The high frequency of hematologic adverse events found, especially in malnourished children, highlight the importance of careful monitoring of these children throughout treatment, as well as considering nutritional aspects and the need for higher doses of folinic acid. With adequate monitoring, antiparasitic treatment was feasible and relatively safe in the setting of this large screening program for congenital toxoplasmosis.
Congenital toxoplasmosis (CT) is a parasitic disease that can cause significant fetal and neonatal harm. Coordinated efforts by pregnant women, researchers, physicians, and health policy makers regarding potential primary and secondary preventive measures for CT and their implementation may lead to a lower incidence of CT as well as lower morbidity and mortality rates associated with CT. In the United States, the age-adjusted seroprevalence of Toxoplasma gondii among women of childbearing age (15-44 years) has declined over time (15%, 11%, and 9% in 1988-1994, 1999-2004, and 2009-2010, respectively; among US-born women only, the seroprevalence rates during these time periods were 13%, 8%, and 6%, respectively). Thus, approximately 91% of women of childbearing age in the United States are susceptible to Toxoplasma infection. Should these women become infected during pregnancy and remain undiagnosed and untreated, they could deliver an infant with CT. However, the incidence of acute primary infection is likely very low in the current era and is probably much lower than the 1.1 in 1000 pregnant women originally reported in 1960s.
Background:
Population seroprevalence and rates of mother-to-child transmission are important in determining the incidence of congenital toxoplasmosis. (CT) Mother-to-child transmission depends on the timing of acute maternal infection and treatment during pregnancy. The incidence of CT varies widely across geographic regions, ranging from 1 to 10 cases per 10,000 live births. The incidence of symptomatic disease varies from 0.15 to 0.34 cases per 10,000.
Methods:
This is a review of patients treated at a pediatric CT clinic at a university hospital in the south of Brazil, from 2004 to 2014.
Results:
The annual incidence of CT varied from 0 to 14 cases per 10,000 live births, with a mean incidence of 6 cases per 10,000 during the 10 years studied (CI 95%: 3.02-8.91). The incidence of symptomatic CT varied from 0 to 9 cases per 10,000 live births, with a mean incidence of 5 per 10,000 (CI 95%: 2.44-6.94). There were 5 (14.3%) asymptomatic cases. The main findings were retinochoroiditis (54%), intracranial calcifications (37.5%) and altered cerebrospinal fluid (37.5%).
Conclusions:
The incidence of CT and the rate of symptomatic cases were in accordance with the previous data from other studies in Brazil, being significantly higher than in previous North American and European studies.
Every 3 years, the International Congress on Congenital Toxoplasmosis meeting gathers experts with different backgrounds who are involved in congenital toxoplasmosis: gynecologists, pediatricians, ophthalmologists, microbiologists, epidemiologists and research scientists. Most attendees come from the Americas and Europe, where substantial work has been performed to better understand this disease. Two presentations that stressed major current issues in the field of toxoplasmosis are summarized here.
Congenital toxoplasmosis can cause significant neurologic manifestations and other untoward sequelae.
The Palo Alto Medical Foundation Toxoplasma Serology Laboratory database was searched for data on infants 0 to 180 days old, in whom congenital toxoplasmosis had been confirmed and who had been tested for Toxoplasma gondii-specific immunoglobulin G (IgG), IgM, and IgA antibodies, between 1991 and 2005. Their clinical findings were confirmed at the National Collaborative Chicago-based Congenital Toxoplasmosis Study center. We reviewed available clinical data and laboratory profiles of 164 infants with congenital toxoplasmosis whose mothers had not been treated for the parasite during gestation.
One or more severe clinical manifestations of congenital toxoplasmosis were reported in 84% of the infants and included eye disease (92.2%), brain calcifications (79.6%), and hydrocephalus (67.7%). In 61.6% of the infants, eye disease, brain calcifications, and hydrocephalus were present concurrently. T. gondii-specific IgM, IgA, and IgE antibodies were demonstrable in 86.6%, 77.4%, and 40.2% of the infants, respectively. Testing for IgM and IgA antibodies increased the sensitivity of making the diagnosis of congenital toxoplasmosis to 93% compared with testing for IgM or IgA individually. IgM and IgA antibodies were still present in 43.9% of infants diagnosed between 1 and 6 months of life.
Our study reveals that severe clinical signs of congenital toxoplasmosis including hydrocephalus, eye disease, or intracranial calcifications occurred in 85% infants whose sera were referred to our reference Toxoplasma Serology Laboratory during a period of 15 years. Laboratory tests, including serologic and polymerase chain reaction tests, were critical for diagnosis in the infants. Our results contrast remarkably with those of European investigators who rarely observe severe clinical signs in infants with congenital toxoplasmosis.
Long-term evolution of congenital toxoplasmosis is not documented. We assessed the outcome of treated congenital toxoplasmosis in a cohort of adult individuals who had undergone ante- and postnatal treatment to provide information for pediatricians and parents on the evolution of the disease.
We conducted a questionnaire study on 126 adults with congenital toxoplasmosis (mean age: 22.2 years; age range: 18-31 years) monitored regularly until the time of inclusion. The main outcome measures were quality of life (Psychological General Well-Being Index) and visual function (VF14 questionnaire), and the outcomes were correlated with disease-specific factors.
Of the 102 patients (80.9%) who were finally included in the study, 12 (11.8%) presented neurologic effects and 60 (58.8%) manifested ocular lesions; in the latter category, 13 individuals (12.7%) had reduced visual function. The overall global quality-of-life score (74.7 ± 14.2) was close to the expected normal range for the general population (73.7 ± 15.3). Overall, visual function was only slightly impaired (M = 97.3; 95% confidence interval, 95.8-98.8). Although disease-independent critical life circumstances were associated with a reduced Psychological General Well-Being Index, this index was not influenced by any of the clinical characteristics of congenital toxoplasmosis. Neurologic pathologies, reduced visual acuity, foveal location of the retinal lesion, and squinting contributed to decreased visual function at follow-up.
Our data reveal that treated congenital toxoplasmosis has little effect on the quality of life and visual function of the affected individuals. These encouraging findings may help to alleviate the anxiety of affected individuals and their parents.
Maternal toxoplasmosis infection acquired during pregnancy carries significant risk of fetal damage. We aimed to assess the long-term outcome of children and young adults with congenital toxoplasmosis diagnosed and treated in utero.
This was a 20 year prospective study (1985-2005). All mothers received spiramycin, alone or associated with pyrimethamine-sulfadoxine, and underwent amniocentesis and monthly ultrasound screening. Infected children were followed every 3-6 months.
Of 666 liveborn children (676 mothers), 112 (17%) had congenital toxoplasmosis. Among these, 107 were followed up for 12-250 months: 79 were asymptomatic (74%) and 28 had chorioretinitis (26%). Only 1 child had a serious neurological involvement.
The percentage of chorioretinitis in treated children depends on length of follow-up, but this complication occurs mainly before the age of 5 years and almost always before the age of 10 years. Visual impairment was infrequently severe, and outcome appears consistently good. Long-term follow-up is recommended to monitor ocular and neurological prognosis, whatever the practical difficulties.
To report results of early ophthalmologic examinations in a large cohort of newborns with congenital toxoplasmosis (CT) after neonatal screening.
Cross-sectional analysis of a cohort.
A total of 178 newborns with confirmed CT from 146,307 screened babies (95% of live births) from Minas Gerais state, southeastern Brazil.
From November 2006 to May 2007, newborns underwent neonatal screening by immunoglobulin (Ig)M capture of dried blood samples. On all positive or suspected cases, confirmative serology was performed on babies and their mothers. Congenital toxoplasmosis was confirmed in newborns who had IgM and/or IgA and IgG, or IgG associated with suggestive ocular lesions (with IgM and IgG in the mother). Ophthalmologic evaluation consisted of indirect ophthalmoscopy with a lid speculum. Pediatric examination and radiologic studies of the central nervous system were also performed. In selected cases, biomicroscopy of the anterior segment, fundus photographs, or ultrasonography (B-scan) was performed.
Prevalence of retinochoroidal lesions, either cicatricial or active, and their location and associated findings, such as vascular sheathing, hemorrhage, vitreous opacities, and retinal detachment, were evaluated. The occurrence of cataract, microphthalmia, microcephaly, intracranial calcification, and hydrocephalus was also recorded.
Of 146,307 neonates screened, 190 had CT, yielding a prevalence of 1 in 770 live births, of whom 178 (93.7%) underwent standardized ophthalmologic examination at an average age of 55.6+/-16.6 days. Of these 178 infants, 142 (79.8%) had retinochoroidal lesions consistent with CT in at least 1 eye. Bilateral involvement was noted in 113 patients (63.5%). Macular involvement was seen in 165 eyes (46.3%) of 111 patients (62.4%). Active lesions were observed in 142 eyes (39.9%) of 85 patients (47.8%). These lesions were located in the macula of 75 eyes (21.1%) and were associated with retinal vascular sheathing in 44 eyes (12.4%).
A high prevalence of CT was encountered (1/770) with high rates of early retinochoroidal involvement ( approximately 80%) and many active lesions (in approximately 50%), indicating a possibly more severe ocular involvement by CT in Brazil than in other parts of the world. The hypotheses of higher parasite virulence and increased individual susceptibility are being currently investigated.
In patients with congenital toxoplasmosis new lesions continue to appear well after the age of 5 years, and the impairments can be severe. Screening of women for toxoplasmosis before pregnancy thus seems advisable.
Most infants born with congenital Toxoplasma infection are asymptomatic in the newborn period, and therefore their infection is not recognized. We performed follow-up evaluations on 24 such children. The mean age of these children at least examination was 8.5 years. In group I (13 children), the diagnosis was made prospectively. In group II (11 children), no symptoms or signs were noted in the newborn period and the diagnosis was made only after the first sign developed. Eighty-five percent of the children in group I and all of the children in group II have developed chorioretinitis. In group I, three children (23%) have unilateral blindness; in group II, three children (27%) and five children (45%) have unilateral and bilateral blindness, respectively. One child (8%) in group I and two children (18%) in group II developed severe, permanent neurologic sequelae after they initially presented with eye disease. Two of the children in each group are now retarded (IQ score range, 36 to 62). Six of the children in group I who were tested sequentially have had lower IQ scores (mean change from 97 to 74) on repeat tests performed an average of 5.5 years later. Less severe neurologic, intellectual, and audiologic deficits were observed in other children in each group. Treatment of some children may have had a beneficial effect on their outcome.
The T1 (interferon-gamma, interleukin-12, interleukin-2) and T2 (interleukin-4, interleukin-10, interleukin-6) cytokine groups constitute two polar responses of the immune system. The T1 group is a predominantly cellular response, while the T2 group response is mainly humoral. The hypothesis forwarded here links these subgroups of induced cytokines to the various clinical forms of human toxoplasmosis. Ocular toxoplasmosis in immunocompetent patients could be attributed to a T1 hyper-response, whereas congenital toxoplasmosis, toxoplasmic encephalitis (in immunodeficient patients) and active chronic toxoplasmosis (with persistent lymphadenophathy) would be characterized by a predominantly T2 response. Confirmation that this kind of immunological imbalance effectively underlies the various clinical forms of toxoplasmosis would open the way for a new range of treatments based on immunomodulation.
To determine the natural history of treated and untreated congenital toxoplasmosis and impact of this infection on vision.
In this prospective, longitudinal study, 76 newborns were treated with pyrimethamine and sulfadiazine for approximately one year, and 18 individuals not treated during their first year of life entered the study after age 1 year (historical patients).
Chorioretinal scars were the most common eye finding in all patients and were most common in the periphery (58% of treated and 82% of historical patients). Macular scars were present in 54% of the treated patients; 41% were bilateral. Macular scars were present in 76% of the historical patients; 23% were bilateral. Visual acuity in the presence of macular lesions ranged from 20/20 to 20/400. Of the patients followed up from the newborn period and treated, 29% had bilateral visual impairment, with visual acuity for the best eye of less than 20/40. Causes for this visual impairment in eyes with quiescent lesions included macular scars, dragging of the macula secondary to a peripheral lesion, retinal detachment, optic atrophy, cataract, amblyopia, and phthisis. There were recurrences in both treated (13%, 7/54) and previously untreated historical patients (44%, 8/18). The total, median, and range of years of follow-up during which recurrences were observed were, for treated patients, 189 years (total), five years (median) and three to ten years (range) and, for historical, untreated patients, 160 years (total), 11 years (median), and three to 24 years (range). New lesions occurred in previously normal retinas and also contiguous to older scars. Active lesions appeared to become quiescent within ten to 14 days after beginning pyrimethamine and sulfadiazine therapy.
Many children with congenital toxoplasmosis have substantial retinal damage at birth and consequent loss of vision. Nonetheless, vision may be remarkably good in the presence of large macular scars. Active lesions become quiescent with treatment.
The relationship between ocular toxoplasmosis and levels of toxoplasma specific antibodies was examined in 195 patients. Using clinical information collected by questionnaires, patients were divided into: 97 with ocular toxoplasmosis (group 1) and 98 with ocular lesions not due to toxoplasma (group 2). The geometric mean of dye test titres (+/-S.D. natural log titre) in group 1 was 53.2 (+/-0.95) compared with 24.6 (+/-1.11) in group 2 (P < 0.001). Young females tended to have more active lesions compared with young males (P < 0.05). There was an age-dependent difference in dye test titres between the groups (P < 0.001). Group 1 showed a decline in titre with age compared with an increase in group 2. Ocular toxoplasmosis was diagnosed most frequently among 21-30 year olds. More group 1 patients had dye test titres > or = 65 iu/ml than group 2 (P < 0.05). Dye test titres > or = 65 iu/ml support a diagnosis of ocular toxoplasmosis whereas lower titres suggest other causes for eye lesions.
To describe the ophthalmologic outcomes of cases of congenital toxoplasmosis treated prenatally and postnatally.
Observational case series.
Follow-up ophthalmologic examinations of 18 children born to mothers who were infected before 25 weeks gestation were performed concurrently by two ophthalmologists. The infection in these children was first suspected when their mothers seroconverted during gestation. Toxoplasmic infection of the fetus was diagnosed by fetal blood or amniotic fluid analysis. Mothers were treated by a regimen of alternating pyrimethamine-sulfonamides and spiramycin during gestation. Pyrimethamine-sulfonamides treatment was continued from birth to 1 year of age.
The median age of the children was 4.5 years (range 1-11), when the follow-up ophthalmologic examinations were performed. Visual acuity was decreased in only one child, who had extensive bilateral macular and peripheral lesions. A posterior pole scar was noted in four eyes (four children) for whom visual acuity remained normal. Peripheral lesions were observed in nine eyes (five children). Both eyes were normal in 11 of 18 (61%) of the children.
In these children at a high risk for congenital toxoplasmic retinochoroiditis, a favorable visual outcome was observed in all but one case.
Isolates of Toxoplasma gondii, which is responsible for a wide range of clinical manifestations are grouped into three clonal lineages of different virulence in mice. However, it is not clear whether this genotypic pattern is associated with the clinical profile of the disease in humans nor is the geographical distribution of the genotypes known. This is mainly due to difficulties in obtaining parasitic DNA from patients. The available data are therefore limited and originate from acute or congenital infections or from animals. A non-invasive assay is needed to address issues of strain type, geographical distribution and severity of clinical toxoplasmosis. To serotype T. gondii strains, we have developed an enzyme-linked immunosorbent assay (ELISA) that uses polymorphic polypeptides specific to the three clonal lineages and derived from two dense granule antigens, GRA5 and GRA6. Two hundred and fifty-two sera from chronically infected pregnant women from three different European countries and Colombia were investigated. The analysis of genotype-specific antibody response showed a homogeneous type II distribution in the European samples compared with types I and III but no type II in the Colombian population. Our data concord with those obtained from the genotyping of other isolates from Europe and South America. We demonstrated that, despite some limitation due to antigen and/or antibody specificity, serotyping is a promising assay to investigate the relationship between type of strain and severity of the disease.
To determine the incidence of new chorioretinal lesions in patients with congenital toxoplasmosis who were treated throughout their first year of life.
Prospective longitudinal observation of a cohort.
One hundred thirty-two children were studied as part of the longitudinal observation.
One hundred thirty-two children were treated during their first year of life with pyrimethamine, sulfadiazine, and leucovorin. They had eye examinations at prespecified intervals.
New chorioretinal lesions on fundus examination and fundus photographs.
The mean age (+/- standard deviation) is 10.8+/-5.1 years (range, 0.2-23). One hundred eight children have been evaluated for new chorioretinal lesions. Thirty-four (31%; 95% confidence interval, 23%-41%) of 108 children developed at least one chorioretinal lesion that was previously undetected. These occurred at varying times during their follow-up course. Fifteen children (14%) developed new central lesions, and 27 (25%) had newly detected lesions peripherally. Ten (9%) had more than one occurrence of new lesions developing, and 13 (12%) had new lesions in both eyes. Of those who developed new lesions, 14 children (41%) did so at age 10 or later.
New central chorioretinal lesions are uncommon in children with congenital toxoplasmosis who are treated during their first year of life. This finding contrasts markedly with earlier reports in the literature for untreated children or those treated for only 1 month near birth, in whom new lesions were much more prevalent (>/=82%). Our observation that 14 (41%) of the 34 children with new chorioretinal lesions had occurrences when they were 10 years or older indicates that long-term follow-up into the second decade of life is important in assessing the efficacy of treating toxoplasmosis during infancy.
Reliable information is needed to counsel parents of children with congenital toxoplasmosis regarding the long-term risk of visual impairment resulting from ocular toxoplasmosis.
Prospective cohort study of children with congenital toxoplasmosis identified by prenatal or neonatal screening.
After three years of age, ophthalmologists reported the site of retinochoroidal lesions and visual acuity and parents reported visual impairment. An ophthalmologist predicted the child's vision based on the last retinal diagram. Selection biases were minimized by prospective enrollment and data collection, high rates of follow-up, and exclusion of referred cases.
Two hundred and eighty-one of 284 infected children who underwent ophthalmic examinations were followed up to a median age of 4.8 years. One in six children (49/281; 17%) had at least one retinochoroidal lesion, two-thirds of whom (32/49; 65%) had a lesion at the posterior pole. In children with retinochoroiditis who had visual acuity measured after 3 years of age, 94% (31/33) had normal vision in the best eye (6/12 Snellen or better), as did 91% of those with a posterior pole lesion (21/23). Analyses based on affected eyes showed that 42% (29/69) had a posterior pole lesion, of which just more than half (15/29, 52%) had normal vision, as did 84% (16/19) of eyes with a peripheral lesion alone. Vision predicted by the ophthalmologist was moderately sensitive (59%) but overestimated impairment associated with posterior pole lesions. Of 44 children with information on acuity, four (9%) had bilateral visual impairment worse than 6/12 Snellen.
Severe bilateral impairment occurred in 9% of children with congenital toxoplasmic retinochoroiditis. Half the children with a posterior pole lesion and one in six of those with peripheral lesions alone were visually impaired in the affected eye.
Unlabelled:
Perceptual visual filling-in of toxoplasmic retinochoroiditis chronic scotomas was studied in 13 patients. Although there is deficit of visual inputs, patients with such chronic lesions perceive the region in the visual field uninterrupted. Targets were programmed to appear just outside the edge of the retinal lesion, and healthy retinal areas in the same eye. The results showed no significant difference in perceptual filling-in latencies (P>0.05).
Conclusions:
(i) neural mechanisms of filling-in at the blind spot are probably involved explaining this perceptual phenomenon; (ii) any neuronal changes occurring at the edge of the lesion only affected filling-in within the scotoma area.
Retinochoroiditis is the main complication of congenital toxoplasmosis. Its risk factors have rarely been investigated and were the object of this study.
A retrospective study was conducted on 300 infants with congenital toxoplasmosis born between July 1, 1996 and December 31, 2002 and treated with pyrimethamine and sulfonamide for at least 12 months. Results of eye tests were collected up to 24 months. Risk factors associated with first retinochoroiditis were identified by univariate then multivariate analyses (Cox model).
One hundred forty-nine boys and 151 girls were included. Maternal infection dated from the first trimester in 34 cases, the second in 97 cases, and the last in 169 cases. At birth, 22 infants had cerebral calcifications. During the first 2 years of life, first retinochoroiditis was diagnosed in 36 infants (12%). In multivariate analysis, 3 factors were significantly associated with first retinochoroiditis before the age of 2 years: a delay of >8 weeks between maternal seroconversion and first treatment [hazard ratio, 2.54; 95% confidence interval (CI), 1.14-5.65], female gender (hazard ratio, 2.02; 95% CI, 1.01-4.1), and cerebral calcifications at birth (hazard ratio, 4.3; 95% CI, 1.9-10). There was no correlation between gestational age at the time of maternal infection and risk for retinochoroiditis.
A delay of >8 weeks between maternal seroconversion and the beginning of treatment, female gender, and especially cerebral calcifications are risk factors for retinochoroiditis during the first 2 years of life in infants treated for congenital toxoplasmosis.