Putative biomarkers for early diagnosis and prognosis of congenital ocular toxoplasmosis.

In the present study we have evaluated the performance of several immunological biomarkers for early diagnosis and prognosis of congenital toxoplasmosis. Our results showed that ex vivo serum levels of CXCL9, and the frequencies of circulating CD4+CD25+ T-cells and T. gondii-specific IFN-γ+CD4+ T-cells measured 30-45 days after birth presented high accuracy to distinguish T. gondii-infected infants from healthy age-matched controls (Global Accuracy/AUC = 0.9; 0.9 and 0.8, respectively). Of note was the enhanced performance (Accuracy = 96%) achieved by using a combined stepwise analysis of CD4+CD25+ T-cells and CXCL9. In addition, high global accuracy (AUC = 0.9) with elevated sensitivity (Se = 98%) was also reached by using the total frequency of in vitro IFN-γ-producing T. gondii-specific T-cells (∑ IFN-γ+ CD4+ & CD8+) as a biomarker of congenital toxoplasmosis. Furthermore, the analysis of in vitro T. gondii-specific IL5+CD4+ T-cells and IFN-γ+NK-cells displayed a high accuracy for early prognosis of ocular lesion in infant with congenital toxoplasmosis (Global Accuracy/AUC = 0.8 and 0.9, respectively). Together, these findings support the relevance of employing the elements of the cell-mediated immune response as biomarkers with potential to endorse early diagnosis and prognosis of congenital ocular toxoplasmosis to contribute for a precise clinical management and effective therapeutic intervention.

Manejo de la membrana neovascular coroidea secundaria a toxoplasmosis ocular / Management of the neovascular choroidal membrane secondary to ocular toxoplasmosis

Paciente de 12 años diagnosticado de toxoplasmosis congénita sin tratamiento sistémico en el momento actual que acude por disminución de la agudeza visual (AV) en su ojo izquierdo (OI). A la exploración se objetiva una AV en su OI de 0,05 y al examen funduscópico un foco de coriorretinitis adyacente a una cicatriz macular pigmentada y una gran hemorragia subretiniana asociada. Tras confirmar el diagnóstico de membrana neovascular coroidea (MNVC) secundaria a toxoplasmosis ocular, se inicia tratamiento con fármacos anti-toxoplásmicos sistémicos y 2 dosis de anti-VEGF intravítreos separadas por un mes de diferencia. Finalmente, alcanza una AV en el OI de 0,4, y se logra una reabsorción de la hemorragia quedando una cicatriz pigmentada macular inactiva. El uso de anti-VEGF intravítreos en cuadros de toxoplasmosis ocular se han asociado a la reactivación de antiguas lesiones, por lo que se recomienda el uso profiláctico de fármacos anti-toxoplásmicos orales en estos casos

A 12-year-old patient diagnosed with congenital toxoplasmosis, with no systemic treatment at the time, who presented with a decreased visual acuity (VA) in his left eye (LE). On examination, VA in the LE was 0.05 and the fundus examination revealed a focus of chorioretinitis adjacent to a pigmented macular scar, as well as a large associated subretinal haemorrhage. After confirming the diagnosis of choroidal neovascular membrane secondary to ocular toxoplasmosis, treatment was started with systemic anti-toxoplasmosis drugs and two anti-VEGF intravitreal injections separated by one month. Finally, the patients had a VA in LE of 0.4, with reabsorption of the haemorrhage, leaving an inactive pigmented macular scar. The use of anti-VEGF intravitreal injections in cases of ocular toxoplasmosis has been associated with a reactivation of old lesions, so the prophylactic use of oral anti-toxoplasmosis drugs is recommended in these cases

Management of the neovascular choroidal membrane secondary to ocular toxoplasmosis. / Manejo de la membrana neovascular coroidea secundaria a toxoplasmosis ocular.

A 12-year-old patient diagnosed with congenital toxoplasmosis, with no systemic treatment at the time, who presented with a decreased visual acuity (VA) in his left eye (LE). On examination, VA in the LE was 0.05 and the fundus examination revealed a focus of chorioretinitis adjacent to a pigmented macular scar, as well as a large associated subretinal haemorrhage. After confirming the diagnosis of choroidal neovascular membrane secondary to ocular toxoplasmosis, treatment was started with systemic anti-toxoplasmosis drugs and two anti-VEGF intravitreal injections separated by one month. Finally, the patients had a VA in LE of 0.4, with reabsorption of the haemorrhage, leaving an inactive pigmented macular scar. The use of anti-VEGF intravitreal injections in cases of ocular toxoplasmosis has been associated with a reactivation of old lesions, so the prophylactic use of oral anti-toxoplasmosis drugs is recommended in these cases.

Case report: North Carolina macular dystrophy misdiagnosed as congenital ocular toxoplasmosis.

Purpose: This report discusses a case of North Carolina macular dystrophy (NCMD) in a 7-year-old boy initially diagnosed as congenital toxoplasmosis. Genetic testing was performed on the child and his family after the suspicion of NCMD was raised by the treating ophthalmologist. This case report highlights the similarities between congenital toxoplasmosis and NCMD. Methods: DNA was collected from the family with consent and underwent comparative genomic hybridization and Sanger sequencing. Results: Genetic testing identified a previously reported single base substitution (chromosome 6: 99,593,111 (G>C) NC_000006.11(GRCh38):g.100040987G>C), which confirms a diagnosis of NCMD. Conclusions: We believe this is the first confirmed case of NCMD in Australia. This case highlights the similarities between NCMD and more commonly recognized conditions, such as ocular toxoplasmosis, and raises the question; How many other cases are misdiagnosed as ocular toxoplasmosis?

Psicofísica visual em caso de toxoplasmose ocular congênita / Visual psychophysics of congenital ocular toxoplasmosis case

Resumo A toxoplasmose ocular congênita é uma manifestação da infecção pelo parasita Toxoplasma gondii que ocorrer por meio placentário. Essa doença pode provocar importantes sequelas visuais. Este trabalho descreve um estudo de caso que utilizou avaliação psicofísica visual para descrever alterações funcionais decorrentes da toxoplasmose ocular congênita. A avaliação foi realizada em paciente de 30 anos, sexo masculino, residente em São Luís (MA), hígido com histórico da mãe ter apresentado infecção por toxoplasmose no período gestacional. Somente aos 26 anos foi feita uma avaliação médica detalhada que descreveu lesão na fóvea do olho direito. Na avaliação clínica clássica e na avaliação psicofísica visual, o paciente apresentou visão normal para o olho esquerdo. O olho direito apresentou baixa acuidade visual (valor decimal: 0,028), campo visual com escotomas localizados até 20º de ângulo visual e alteração da visão de cor. O estudo fornece informações médicas seguras e relevantes para o diagnóstico de toxoplasmose ocular congênita utilizando testes eficazes, de baixo custo e boa portabilidade, possibilitando uma alternativa de diagnóstico funcional para ser aplicada em locais de difícil acesso pelo interior do Brasil.

Abstract Congenital ocular toxoplasmosis is a manifestation of infection by the parasite Toxoplasma gondii that occurs through the placenta. This disease can lead to important visual sequelae. This paper describes a case report that uses visual psychophysics for the alterations of congenital ocular toxoplasmosis. The evaluation was performed in a 30-year-old man, a resident of São Luís (MA), with a history of his mother have had toxoplasmosis in the gestational period. Only at 26 years-old he did the detailed medical evaluation that described a lesion the fovea of the right eye. In the classic clinical examination and in visual psychophysical evaluation, the patient presented normal vision for the left eye. The right eye had low visual acuity (decimal value: 0.028), visual field with scotomas up to 20º of visual angle and alteration of color vision. The study offers safe and relevant medical information for the diagnosis of congenital ocular toxoplasmosis using a low-cost evaluation and with good portability, allowing a functional diagnostic alternative to be applied in places difficult to access in the interior of Brazil.

Can the route of Toxoplasma gondii infection affect the ophthalmic outcomes?

Ocular toxoplasmosis is the most common cause of retinochoroiditis worldwide in humans. Some studies highlighted the idea that ocular lesions differ according to the route of infection but none of them mimicked the natural route. The current study aimed to investigate the ophthalmic outcomes in congenital and oral routes of infection with Toxoplasma in experimental animals. Mice were divided into three groups; group I: congenital infection, group II: acquired oral infection and group III: non-infected. We used Me49 chronic low-virulence T. gondii strain. We found that retina is the most affected part in both modes of infections. However, the retinal changes are different and more pronounced in case of congenital infection. The congenitally infected mice showed retinal lesions e.g. total detachment of retinal pigment epithelium from the photoreceptor layer and irregular arrangement of retinal layers. More severe damage was observed in mice infected early in pregnancy. While the postnatal orally infected mice showed fewer changes. In conclusion, the routes of Toxoplasma infection affect the ophthalmic outcomes and this may be the case in human disease. Although both are vision threatening, it seems that the prognosis of postnatal acquired ocular toxoplasmosis is better than that of congenital disease.

Cytokine Signatures Associated With Early Onset, Active Lesions and Late Cicatricial Events of Retinochoroidal Commitment in Infants With Congenital Toxoplasmosis.

BACKGROUND: Ocular toxoplasmosis is a prominent and severe condition of high incidence in Brazil. The current study provides new insights into the immunological events that can be associated with retinochoroiditis in the setting of congenital toxoplasmosis in human infants. METHODS: Flow cytometry of intracytoplasmic cytokines in leukocyte subsets following in vitro short-term antigenic recall in infants with congenital T. gondii infection. RESULTS: Our data demonstrates that whereas neutrophils and monocytes from T. gondii-infected infants display a combination of proinflammatory and regulatory cytokine profiles, natural killer cells showed a predominantly proinflammatory profile upon in vitro T. gondii stimulation. The proinflammatory response of CD4(+) and CD8(+) T cells, characterized by the production of interferon γ (IFN-γ) and interleukin 17 in patients with an active retinochoroidal lesion, revealed the presence of IFN-γ and tumor necrosis factor α during early and late immunological events. This specific proinflammatory pattern is associated with early events and active retinochoroidal lesion, whereas a robust monocyte-derived interleukin 10-mediated profile is observed in children with cicatricial ocular lesions. CONCLUSIONS: These findings support the existence of a progressive immunological environment concomitant with the initial, apical, and cicatricial phases in the process of retinochoroidal lesion formation in infants with congenital toxoplasmosis that may be relevant in the establishment of stage-specific clinical management.

Severe ocular sequelae of congenital toxoplasmosis: huge macular scar.

Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. Ophthalmologists are rarely able to distinguish between toxoplasmic retinochoroiditis due to infection acquired before or after birth, unless other clinical or serological indications are present. This article reports a case of a 3-year-old boy with abnormalities suggestive of congenital toxoplasmosis. The clinical and complementary examinations are discussed. The education of pregnant women is crucial for the prevention of congenital toxoplasmosis. Awareness of antenatal and postnatal presenting signs and symptoms is important for clinicians, because early diagnosis and treatment may minimize sequelae. Untreated, the majority of affected infants will develop chorioretinitis, deafness and/or neurological symptoms.

Müller cell activation and photoreceptor depletion in a mice model of congenital ocular toxoplasmosis.

Müller glial cells are critically involved in retinal inflammatory processes. Here, we investigate the activation of Müller cells in a model of congenital ocular toxoplasmosis (OT). Four weeks after infection, retinal sections were studied immunohistochemically using the markers glial fibrillary acidic protein (GFAP) and vimentin. Müller cells showed strong up-regulation of both markers, as well as a deteriorated morphology in all infected retinas. Moreover, cell density and color intensity of the outer nuclear layer (ONL) of photoreceptors were decreased. Our results indicate that the severe retinal damage and loss of vision observed in human OT may be not only directly caused by infection but rather mediated by infection induced reactive gliosis.

[Congenital toxoplasmosis: long-term ophthalmologic follow-up praised by patients]. / Toxoplasmose congénitale; le suivi ophtalmologique à long terme plébiscité par les patients.

INTRODUCTION: Ocular lesions of congenital toxoplasmosis may occur and relapse unpredictably even a long time after birth. There is no consensus concerning the necessity or timing of ophthalmologic follow-up for these patients. We surveyed adults with congenital toxoplasmosis followed regularly since birth, in order to learn their perceptions of this follow-up. The goal of this study was to provide doctors with patient-reported information on how they perceived the long-term monitoring of their disease. METHODS: Enrolled patients were given a two-question questionnaire addressing the way they perceived the long-term follow-up and their attitudes toward continuing it. Eligible patients had to be 18 years or older and to have undergone ophthalmologic follow-ups, including funduscopy, every year since birth. The last ophthalmologic examination had to be within one year of the patient's inclusion in the study. RESULTS: Of the 102 patients finally included in the study, 98% stated that the follow-up was useful and 92% reassuring. Among the 11% of patients who found the follow-ups frightening, the proportion of patients with low visual acuity and low score on the visual function test was significantly higher than among the others. All patients except two wished to continue with regular follow-up. CONCLUSION: Without general agreement or guidelines on how patients with congenital toxoplasmosis should be monitored, the patient's wishes are important in making a decision. Our study brought out a clear fact; the majority of patients found long-term follow-up useful and reassuring and wished to continue.

Epidemiology of ocular toxoplasmosis.

Retinal infection with Toxoplasma gondii is the most important cause of posterior uveitis, whereby prevalence and incidence of ocular symptoms after infection depend on socio-economic factors and the circulating parasite genotypes. Ocular toxoplasmosis is more common in South America, Central America, and the Caribbean and parts of tropical Africa as compared to Europe and Northern America, and is quite rare in China. Ocular disease in South America is more severe than in other continents due to the presence of extremely virulent genotypes of the parasite. Drinking untreated water is considered the major source of Toxoplasma infection in developing countries, whereas in the Western world the consumption of raw or undercooked meat (products) is the most important cause. Since acquired infection with T. gondii is currently a more important cause of ocular toxoplasmosis compared to congenital infection, prevention should be directed not only toward pregnant women but toward the general population.

Long-term ocular outcome in congenital toxoplasmosis: a prospective cohort of treated children.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Ocular findings in children with congenital toxoplasmosis]. / Achados oculares em crianças com toxoplasmose congênita.

PURPOSE: This study aimed to know the most common ocular findings in children with congenital toxoplasmosis. METHODS: This is a retrospective study carried out from a historical cohort, with a quantitative approach. We evaluated children referred to a pediatric infectious disease service and included only those with confirmed diagnosis of congenital toxoplasmosis. The ophthalmologic evaluation included regular fundus examination under pupil dilation. RESULTS: Of 58 children presumably exposed to risk of the disease during the pregnancy, 20 had ocular lesions during the first year of life (34 eyes). Of these, 12 were asymptomatic at birth. Strabismus was noted in 14 children (70%). In one child there was ptosis, and another had decrease in the palpebral fissure (microphthalmia). Retinochoroiditis was the most common complication, present in all 20 children. Seven children (35%) showed unilateral changes and 13 children showed bilateral changes (65%), with emphasis on the location in the posterior pole and macula. CONCLUSION: Retinochoroiditis and strabismus were outstanding as important sequelae of congenital toxoplasmosis.

Achados oculares em crianças com toxoplasmose congênita / Ocular findings in children with congenital toxoplasmosis

OBJETIVO: Conhecer as lesões oculares mais frequentes encontradas em crianças expostas à toxoplasmose congênita. MÉTODOS: Trata-se de um estudo retrospectivo, a partir de uma coorte histórica, de abordagem quantitativa. Foram avaliadas crianças encaminhadas de um serviço de infectologia pediátrica e inseridas apenas aquelas com diagnóstico confirmado de toxoplasmose congênita. A avaliação oftalmológica incluiu o mapeamento de retina sequencial, sob dilatação pupilar. RESULTADOS: Das 58 crianças presumivelmente expostas ao risco de doença durante a gestação, 20 apresentaram lesões oftalmológicas ao longo do primeiro ano de vida (34 olhos). Destas, 12 estavam assintomáticas ao nascimento. Estrabismo foi registrado em 14 crianças (70 por cento). Em uma criança observou-se ptose palpebral e em outra diminuição da fenda palpebral (microftalmia). Retinocoroidite foi a complicação mais frequente, presente em todas as 20 crianças. Sete crianças apresentaram alterações unilaterais (35 por cento) e 13 crianças apresentaram alterações bilaterais (65 por cento), prevalecendo a localização no polo posterior e mácula. CONCLUSÃO: Retinocoroidite e estrabismo destacaram-se como importantes sequelas da toxoplasmose congênita.

PURPOSE: This study aimed to know the most common ocular findings in children with congenital toxoplasmosis. METHODS: This is a retrospective study carried out from a historical cohort, with a quantitative approach. We evaluated children referred to a pediatric infectious disease service and included only those with confirmed diagnosis of congenital toxoplasmosis. The ophthalmologic evaluation included regular fundus examination under pupil dilation. RESULTS: Of 58 children presumably exposed to risk of the disease during the pregnancy, 20 had ocular lesions during the first year of life (34 eyes). Of these, 12 were asymptomatic at birth. Strabismus was noted in 14 children (70 percent). In one child there was ptosis, and another had decrease in the palpebral fissure (microphthalmia). Retinochoroiditis was the most common complication, present in all 20 children. Seven children (35 percent) showed unilateral changes and 13 children showed bilateral changes (65 percent), with emphasis on the location in the posterior pole and macula. CONCLUSION: Retinochoroiditis and strabismus were outstanding as important sequelae of congenital toxoplasmosis.