Serum levels of neurotrophic factors in active toxoplasmic retinochoroiditis

Abstract Toxoplasmic retinochoroiditis (TR) is the most common identifiable cause of posterior uveitis in Brazil. Response to treatment and clinical presentation may vary significantly. We assessed serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin (NT)-3, and NT-4/5 in patients with active TR, before and after TR treatment. Methods: Twenty patients with active lesion and 15 healthy controls were enrolled in the study. Serum concentration of neurotrophic factors was determined by enzyme-linked immunosorbent assay. Results: BDNF levels were significantly higher in patients before treatment when compared with controls (p = 0.0015). There was no significant difference in pro-BDNF, NGF, GDNF, NT-3, and NT-4/5 levels between TR patients and controls. Treatment did not affect the levels of these factors. Conclusion: BDNF may be released in the context of the active TR inflammatory response.

Detection of Toxoplasma gondii DNA in peripheral blood and aqueous humor of patients with Toxoplasmic active focal necrotizing retinochoroiditis using real-time PCR / Detecção de DNA do Toxoplasma gondii no sangue periférico e humor aquoso por PCR em tempo real

ABSTRACT Purpose: To evaluate the ability of real-time quantitative PCR (qPCR) for detectingToxoplasma gondii DNA in the peripheral blood and aqueous humor of patients with toxoplasmic active focal necrotizing retinochoroiditis. Methods: Fifty-five patients with infectious uveitis seen from 2009 to 2013 at the Department of Ophthalmology and Visual Sciences of the Federal University of São Paulo were enrolled in this study. Forty-three patients had toxoplasmic active focal necrotizing retinochoroiditis, and the remaining 12 had non-toxoplasmic infectious uveitis and served as controls. qPCR analysis forT. gondii DNA was performed on the patients' peripheral blood and aqueous humor samples. Results: The qPCR was positive for T. gondii DNA in 37.21% (16/43) of the aqueous humor samples and 2.33% (1/43) of the peripheral blood samples; further, 16.27% (7/43) of the patients had positive results in both their blood and aqueous humor samples. Conclusion: qPCR was able to detect T. gondii DNA in patients with toxoplasmic active focal necrotizing retinochoroiditis in the blood as well as the aqueous humor and can help with the diagnosis of the disease.

RESUMO Objetivo: Analisar o uso do PCR em tempo real (qPCR) na detecção do DNA do T. gondii no sangue periférico e no humor aquoso de pacientes com lesões de retinocoroidite focal, ativa por toxoplasmose. Métodos: Cinquenta e cinco pacientes com uveite infecciosa foram incluídos neste estudo. Os pacientes foram atendidos entre 2009 a 2013, no Departamento de Oftalmologia e Ciências Visuais da Universidade Federal de São Paulo. Quarenta e três pacientes tiveram o diagnóstico de lesões de retinocoroidite focal, ativa por toxoplasmose e, os outros 12 tiveram o diagnóstico de uveíte infecciosa não toxoplásmica e, por isso foram usados como grupo controle. A técnica de qPCR foi utilizada na detecção de DNA do T. gondii em amostras de sangue periférico e humor aquoso. Resultados: O qPCR foi positivo para o DNA do T. gondii em 37,21% (16/43) das amostras de humor aquoso, 2,33% (1/43) nas amostras de sangue periférico e, 16,27% (7/43) em ambas amostras simultaneamente. Conclusão: O qPCR foi capaz de detectar o DNA do T. gondii em pacientes com lesões de retinocoroidite focal, ativa por Toxoplasmose, no sangue bem como, no humor aquoso, podendo ajudar no diagnostico.

Increased serum levels of soluble tumor necrosis factor receptor-2 (sTNFR2) in patients with active toxoplasmic retinochoroiditis

This study aimed to investigate the serum levels of the cytokine TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in patients with toxoplasmosis retinochoroidits (TR) and controls. 37 patients with TR and 30 subjects with positive serology for toxoplasmosis but without history and signs of uveitis were included in this study. Serum concentrations of TNF-α, sTNFR1, and sTNFR2 were determined by ELISA. Serum concentrations of TNF-α and sTNFR1 were similar in controls (mean ± SD median values; 56.57 ± 141.96 and 504.37 ± 163.87, respectively) and TR patients (mean ± SD values, 121.62 ± 217.56 and 511.15 ± 189.30, respectively). Serum concentrations of sTNFR2 were higher in the uveitis group when compared to the control group (respectively, mean ± SD values, 1734.84 ± 379.32 and 1442.75 ± 309.47; p=0.002). There was no association between the serum levels of the molecules and the time of first symptoms, severity of vitreous haze, size or localization of active lesions, levels of visual acuity, and presence of vasculitis. These results suggest that TR is associated with changes in the circulating levels of inflammatory biomarkers, but they are not correlated with local/ocular signs.

Genetic polymorphism for IFNγ +874T/A in patients with acute toxoplasmosis / Polimorfismo genético para IFNγ +874T/A em pacientes com toxoplasmose aguda

INTRODUCTION: A single nucleotide polymorphism (SNP) in the gene encoding gamma interferon influences its production and is associated with severity of infectious diseases. This study aimed to evaluate the association of IFNγ+874T/A SNP with duration of disease, morbidity, and development of retinochoroiditis in acute toxoplasmosis. METHODS: A case-control study was conducted among 30 patients and 90 controls. RESULTS: Although statistical associations were not confirmed, A-allele was more common among retinochoroiditis cases and prolonged illness, while T-allele was more frequent in severe disease. CONCLUSIONS: Despite few cases, the results could indicate a relation between IFNγ+874T/A single nucleotide polymorphism and clinical manifestations of toxoplasmosis.

INTRODUÇÃO: Um polimorfismo de nucleotideo único (SNP) no gene codificante para interferon gama influencia a sua produção e pode estar associado à gravidade de diversas doenças infecciosas. O objetivo deste estudo foi avaliar a associação entre SNP para IFNγ+874T/A com a duração da doença, a morbidade e o desenvolvimento de retinocoroidite na toxoplasmose aguda. MÉTODOS: Estudo de caso-controle incluindo 30 pacientes e 90 controles. RESULTADOS: Apesar da ausência de associação estatística, o alelo A foi mais comum entre os casos com retinocoroidite e doença prolongada e o alelo T nas formas mais severas. CONCLUSÕES: Os dados encontrados sugerem uma relação entre o polimorfismo de base única em IFNγ+874T/A com a morbidade e com o desenvolvimento de retinocoroidite por toxoplasmose.

Retinocoroidite toxoplásmica em pacientes com AIDS e neurotoxoplasmose / Toxoplasmic retinochoroiditis in patients with AIDS and neurotoxoplasmosis

OBJETIVO: A neurotoxoplasmose é a alteração do sistema nervoso central mais frequente observada em pacientes com AIDS. A ocorrência de toxoplasmose ocular em neurotoxoplasmose ainda é pouco estudada. O objetivo deste estudo foi de investigar a ocorrência de retinocoroidite toxoplásmica, típica ou provável, em pacientes com AIDS e neurotoxoplasmose. MÉTODOS: Foi desenvolvido estudo prospectivo, tipo série de casos incluindo 70 pacientes, de ambos os sexos, com idade variando de 20 a 63 anos, internados nas enfermarias de três hospitais públicos da cidade do Recife, Pernambuco, com tais diagnósticos firmados segundo os critérios do CDC (1992), no período de janeiro a outubro de 2008. Os pacientes caracterizavam-se por: primeiro episódio de neurotoxoplasmose (65; 92,9 por cento) ou recidiva (5; 7,1 por cento); desconhecimento de ter AIDS (23; 32,9 por cento), contagem média de linfócitos T CD4 de 139,8 ± 3,04 células/mm³ e carga viral média igual a 137.080 ± 39.380 cópias/mL. Todos os pacientes foram submetidos a exame oftalmológico, consistindo de: inspeção ocular; aferição da acuidade visual; investigação da função muscular extrínseca ocular e fundoscopia, empregando oftalmoscópio indireto binocular (modelo OHN 3.5 (Eyetec®) e lente externa de 20 dioptrias (Volk®). RESULTADOS: Foram diagnosticados 4 (5,7 por cento) pacientes com lesões cicatriciais de retinocoroidite, características de toxoplasmose ocular, sendo típica em 3 (75 por cento) pacientes e bilateral em 1. Não houve qualquer caso de retinocoroidite ativa, típica ou provável. As lesões oculares ativas foram raras comparadas às lesões cicatriciais, as quais se associam à presença de cistos na retina. CONCLUSÃO: Recomenda-se que mesmo lesões cicatriciais sejam valorizadas em pacientes com AIDS.

PURPOSE: Neurotoxoplasmosis is the most common central nervous system disorder in patients with AIDS. The occurrence of ocular toxoplasmosis in neurotoxoplasmosis is not well studied. The objective of this study was to investigate the occurrence of typical or probable toxoplasmic retinochoroiditis in patients with AIDS and neurotoxoplasmosis. METHODS: A prospective case series was performed, including 70 patients of both genders, aged from 20 to 63 years, hospitalized in three public hospitals in Recife, Pernambuco, with such diagnosis according to the CDC criteria (1992), from January to October, 2008. RESULTS: Patients were characterized by first neurotoxoplasmosis episode (65, 92.9 percent) or relapse (5, 7.1 percent), ignorance of AIDS diagnosis (23, 32.9 percent), mean CD4 T lymphocytes count of 139.8 ± 3.04 cells/mm³ and mean viral load of 137,080 ± 39,380 copies/mL. All patients underwent ophthalmologic examination, consisting of ocular inspection, visual acuity measurement, investigation of ocular extrinsic muscle function and fundoscopy, using binocular indirect ophthalmoscope (model OHN 3.5 (Eyetec®) and 20 diopters external lens (Volk®). Four (5.7 percent) patients presented retinochoroiditis scar lesions, characteristic of ocular toxoplasmosis, typical in 3 (75 percent) of them and bilateral in one. There was no case of typical or probable active retinochoroiditis. Active ocular lesions were rare compared to scarring, which are associated with the presence of retinal cysts. CONCLUSION: Scarring lesions should be valued in patients with AIDS.

Toxoplasmose congênita em filho de mãe cronicamente infectada com reativação de retinocoroidite na gestação / Congenital toxoplasmosis from a chronically infected woman with reactivation of retinochoroiditis during pregnancy an underestimated event?

Objetivo: Apresentar um caso raro de toxoplasmose congênita de uma mãe imunocompetente com infecção crônica que teve reativação da doença ocular durante a gestação. Descrição: O recém-nascido estava assintomático no nascimento e foi identificado através de triagem neonatal (IgM anti-Toxoplasma gondii em sangue seco) entre outros 190 bebês com toxoplasmose congênita durante um período de 7 meses. Sua mãe tinha tido um episódio não tratado de reativação de retinocoroidite toxoplásmica durante a gestação, com títulos de IgG estáveis e resultados negativos para IgM. Os resultados de IgM e IgG no soro do recém-nascido e o teste de immunoblotting para IgG foram positivos, e detectou-se lesões retinocoroideanas ativas na periferia da retina. O recém-nascido foi tratado com sulfadiazina, pirimetamina e ácido folínico. Aos 14 meses de vida, a criança permanecia assintomática, com regressão das lesões retinocoroideanas e persistência de IgG. Comentários: É possível que a triagem neonatal sistemática em áreas com alta prevalência de infecção possa identificar esses casos.

Objectives: To report a rare case of congenital toxoplasmosis from an immunocompetent mother with chronic infection who had reactivation of ocular disease during pregnancy. Descriptions:The newborn was asymptomatic at birth and identified by neonatal screening (IgM anti-Toxoplasma gondii in dried blood) among other 190 infants with congenital toxoplasmosis during a 7-month period. His mother had had a non-treated episode of reactivation of toxoplasmic retinochoroiditis during pregnancy, with stable IgG titers and negative IgM results. Results of IgM and IgG in the newborn’s serum, as well as IgG immunoblotting were positive and active retinochoroidal lesions were detected in his peripheral retina. The neonate was treated with sulfadiazine, pyrimethamine and folinic acid. At 14 months of life, the child remained asymptomatic, with regression of retinochoroidal lesions and persistence of IgG. Comments: It is possible that systematic neonatal screening in areas with high prevalence of infection may identify these cases.

The IFN-γ +874T/A polymorphism is associated with retinochoroiditis toxoplasmosis susceptibility

Toxoplasmosis is a worldwide zoonosis that generally produces an asymptomatic infection. In some cases, however, toxoplasmosis infection can lead to ocular damage. The immune system has a crucial role in both the course of the infection and in the evolution of toxoplasmosis disease. In particular, IFN-γ plays an important role in resistance to toxoplasmosis. Polymorphisms in genes encoding cytokines have been shown to have an association with susceptibility to parasitic diseases. The aim of this work was to analyse the occurrence of polymorphisms in the gene encoding IFN-γ (+874T/A) among Toxoplasma gondii seropositive individuals, including those with ocular lesions caused by the parasite, from a rural population of Santa Rita de Cássia, Barra Mansa, state of Rio de Janeiro, Brazil. Further, we verified which of these polymorphisms could be related to susceptibility to the development of ocular toxoplasmosis. This study included 34 individuals with ocular toxoplasmosis (ocular group) and 134 without ocular lesions (control group). The differences between A and T allele distributions were not statistically significant between the two groups. However, we observed that a higher frequency of individuals from the ocular group possessed the A/A genotype, when compared with the control group, suggesting that homozygocity for the A allele could enhance susceptibility to ocular toxoplasmosis in T. gondii infection.

Ocular toxoplasmosis: an update and review of the literature

Ocular toxoplasmosis is the most common cause of posterior uveitis worldwide. The infection can be acquired congenitally or postnatally and ocular lesions may present during or years after the acute infection occur. Current treatment controls ocular infection and inflammation, but does not prevent recurrences. We present a review and update on ocular toxoplasmosis and address misconceptions still found in the current medical literature.

Ocular toxoplasmosis: the influence of patient age

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.

Acute acquired toxoplasmosis: clinical-laboratorial aspects and ophthalmologic evaluation in a cohort of immunocompetent patients

Most cases of acute acquired toxoplasmosis (AAT) are oligosymptomatic and self-limited. Therefore, these infections rarely indicate treatment. Prospective studies of AAT patients are rare in the medical literature. The frequency of systemic manifestations has not been sufficiently studied. In order to search for risks factors for systemic and ocular involvement, 37 patients were submitted to a diagnostic investigative protocol. The most frequent findings were lymph node enlargement (94.6 percent), asthenia (86.5 percent), headache (70.3 percent), fever (67.6 percent) and weight loss (62.2 percent). Hepatomegaly and/or splenomegaly were present in 21.6 percent of cases (8/37). Liver transaminases were elevated in 11 patients (29.7 percent) and lactic dehydrogenase in 17 patients (45.9 percent). Anaemia was found in four patients (10.8 percent), leucopoenia in six patients (16.2 percent), lymphocytosis in 14 patients (37.8 percent) and thrombocytopenia in one patient (2.7 percent). Fundoscopic examination revealed retinochoroiditis in four patients (10.8 percent). No statistical association was found between any one morbidity and retinochoroiditis. Nevertheless, a significant association was found between the presence of more than eight morbidity features at evaluation and long-lasting disease. An ideal diagnostic protocol for AAT would include evidence of systemic involvement. Such a protocol could be used when planning treatment.

Tratamento clínico da neurorretinite subaguda difusa unilateral com albendazol / Clinical treatment of diffuse unilateral subacute neuroretinitis with albendazole

OBJETIVO: Descrever a evolução de uma série de casos de neurorretinite subaguda difusa unilateral (NSDU) tratados com albendazol. MÉTODOS: Relato de série de casos intervencionista. Os autores desenvolveram protocolo de ensaio clínico não controlado, para estudar a evolução clínica de casos de neurorretinite subaguda difusa unilateral tratados com albendazol. Segundo os critérios do protocolo, foram selecionados seis pacientes até o momento desta publicação, que serão descritos separadamente. RESULTADOS: Dos seis pacientes estudados, quatro apresentavam larva. Todos os seis pacientes tratados com a droga anti-helmíntica apresentaram melhora da acuidade visual e das lesões coriorretinianas multifocais. As larvas identificadas nos pacientes foram inativadas com o tratamento. Nenhum efeito colateral foi observado. CONCLUSÕES: A terapia anti-helmíntica com albendazol parece ser benéfica e segura para pacientes com neurorretinite subaguda difusa unilateral. Mais estudos são necessários para avaliar a eficácia do albendazol no tratamento da neurorretinite subaguda difusa unilateral.

PURPOSE: To describe the evolution of a series of cases of diffuse unilateral subacute neuroretinitis (DUSN) treated with albendazole. METHODS: Interventional case series. The authors developed a non-randomized clinical trial protocol to investigate the clinical evolution of diffuse unilateral subacute neuroretinitis cases treated with albendazole. According to protocol criteria up to now, six patients were selected that will be described separately. RESULTS: Of the six studied patients, four presented the worm. All six patients treated with the antiparasitic drug showed improvement of visual acuity and of chorioretinal scars. During the weeks of treatment, evidence of worm inactivation was documented for the four patients with visible worms. No adverse drug side effects were observed. CONCLUSIONS: The antiparasitic drug albendazole seems to be beneficial and safe in patients with diffuse unilateral subacute neuroretinitis. More studies are necessary to evaluate the effectiveness of albendazole in the treatment of diffuse unilateral subacute neuroretinitis.

Toxoplasmic retinochoroiditis and hydrocephalus.

A child presenting with hydrocephalus with extensive inactive retinochoroiditis and his mother with a healed toxoplasmic scar is being discussed. Maternal ocular examination in each case of hydrocephalus is recommended, as uveitis work up of the child is often unrewarding.