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?

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.

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.

Murine neonatal infection provides an efficient model for congenital ocular toxoplasmosis.

Congenital infection is one of the most serious settings of infection with the apicomplexan parasite Toxoplasma gondii. Ocular diseases, such as retinochoroiditis, are the most common sequels of such infection in utero. However, while numerous studies have investigated the physiopathology of acquired toxoplasmosis, congenital infection has been largely neglected so far. Here, we establish a mouse model of congenital ocular toxoplasmosis. Parasite load and ocular pathology have been followed for the first 4 weeks of life. Ocular infection developed slowly compared to cerebral infection. Even after 4 weeks, not all eyes were infected and ocular parasite load was low. Therefore, we evaluated a scheme of neonatal infection to overcome problems associated with congenital infection. Development of infection and physiopathology was similar, but at a higher, more reliable rate. In summary, we have established a valuable model of neonatal ocular toxoplasmosis, which facilitates the research of the underlying physiopathological mechanisms and new diagnostic approaches of this pathology.

Factors of occurrence of ocular toxoplasmosis. A review.

Acquired and congenital toxoplasmosis are frequently complicated by ocular toxoplasmosis. The diagnosis relies on clinical aspects, response to specific treatment and results of biological assays. The incidence and the prevalence of this complication are difficult to establish precisely and depend on the prevalence of the parasite infection in the general population, and are affected by factors such as type of exposure to the parasite, genetic backgrounds of the parasite and the host, and type of immune response elicited by the parasite.

Sensorial strabismus due to congenital toxoplasmosis. Is it an eso- or exotropia?

OBJECTIVE: To examine sensorial strabismus due to congenital toxoplasmosis to elucidate differences and similarities between cases with esotropia (ET) and with exotropia (XT). METHODS: Restrospective analysis of 49 patients treated between 2002 and 2007. Visual acuity, cycloplegic refraction, strabismus patterns, presence of nystagmus, site of scar, surgery performed and strabismus surgical outcome obtained were evaluated. RESULTS: Mean age: 5 years old. 25 patients had bilateral involvement: 10 had ET, 10 XT and 4 were aligned. 15/24 unilateral cases presented with XT, 7 ET and other 2 orthotropia. 6/8 patients with the right eye affected, manifest ET and 14/16 patients with their OS affected had XT. (P=0.01) CONCLUSION: In bilateral cases of ocular toxoplasmosis ET and XT are found in similar proportions; in unilateral cases, XT is more frequent and the left eye is affected in most cases by both the toxoplasmosis and the strabismus. Esotropia appears more frequently in cases where the right eye is so affected, whereas XT predominates in cases where the left eye is affected.

Long-term control of choroidal neovascularization in quiescent congenital toxoplasma retinochoroiditis with photodynamic therapy: 4-year results.

PURPOSE: To evaluate the efficacy and safety of photodynamic therapy (PDT) in the long-term control of subfoveal choroidal neovascularization (CNV) associated with toxoplasmic retinochoroiditis. METHODS: The records of 13 patients with classic subfoveal CNV associated with toxoplasmic retinochoroiditis treated with PDT were reviewed. All patients were followed up for at least 48 months. Postoperative visual acuity was defined as a gain or loss of two or more lines of best-corrected visual acuity (BCVA), respectively. Post-treatment CNV size was dichotomized into "increased" if the major CNV diameter (CMD) had increased by >or=300 microm, and as "stable/reduced" if it had decreased by >or=300 microm or had not changed by >300 microm. RESULTS: Nine patients [four males (44.4%) and five females (55.6%)] with a mean age of 20.1 +/- 4.3 years (range 14-27 years) were enrolled in the study. All had unilateral involvement. The median follow-up was 55 months (minimum 48, maximum 65 months). At the 48-month follow-up, all patients had stable/improved BCVA and a mean stable/reduced CMD (846 +/- 326.5 microm), with the BCVA having improved significantly (p < 0.0001) from 0.29 +/- 0.19 at baseline to 0.54 +/- 0.16 at 48 months. CONCLUSION: Photodynamic therapy seems to be a safe and effective approach to the long-term control of subfoveal CNV associated with toxoplasmic retinochoroiditis. Further trials are needed to validate these findings.

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.

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.

Imaging of congenital toxoplasmosis macular scars with optical coherence tomography.

PURPOSE: The purpose of this study is to document the appearance of macular toxoplasmosis scars with the high-resolution cross-sectional retinal imaging technique of optical coherence tomography (OCT) and investigate whether a correlation exists between the morphology of the toxoplasmosis scars, the OCT images, and visual acuity. METHODS: In this retrospective observational case series, fundus photos were taken of the macular lesions that were also documented by OCT. Photos were digitized for the purpose of sizing lesions. All images were classified by the authors. RESULTS: There were 10 consecutive patients (13 eyes) whose average age is 13.0 years. Macular lesions ranged from 1.6 mm2 to 20.2 mm2. OCT features included retinal thinning, retinal pigment epithelial hyperreflectivity, excavation, intraretinal cysts, and fibrosis. Patients with better than expected vision had either parafoveal lesions or an intact neurosensory layer. CONCLUSION: The most characteristic OCT features in this young population were prominent retinal thinning, retinal pigment epithelium hyperreflectivity, and excavation of varying severity. OCT imaging is helpful in explaining better than expected vision.

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.

Contributions to the history of ocular toxoplasmosis in Southern Brazil.

The evolution of knowledge regarding ocular toxoplasmosis over the last 30 years is described based on studies and observations performed in Southern Brazil. The isolation of Toxoplasma gondii established the definitive diagnosis of the disease. It was proven that in most cases, the disease was acquired after birth, a concept supported by the description of numerous familial cases and observation of the disease many years after primary infection. Epidemiological studies showed important regional variations in the prevalence of the disease due to different factors, including the types of strains involved, of which type I predominates. The large number of patients also enabled detailed study of the different forms of clinical presentation of the disease and its complications. New parameters have been established for the use of steroids and the management of pregnant women with active lesions. Studies on the epidemiology of toxoplasmic infection in pregnant women and newborns showed a high prevalence of infection. The different factors of exposure to infection have also been studied. Gradually, preventive actions have been developed in the sphere of public health, although they have not been sufficiently effective. Trends for future research over the next few years are also outlined.

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.

Longitudinal study of new eye lesions in children with toxoplasmosis who were not treated during the first year of life.

PURPOSE: To determine the incidence of new chorioretinal lesions in children with toxoplasmosis diagnosed after, and therefore not treated during, their first year. DESIGN: Prospective longitudinal cohort study. METHODS: Thirty-eight children were evaluated in Chicago between 1981 and 2005 for new chorioretinal lesions. Thirty-eight children and mothers had serum IgG antibody to Toxoplasma gondii. RESULTS: Twenty-eight of 38 children had one of the following: diagnosis with serum antibody to T. gondii indicative of chronic infection at age 24 months, central nervous system calcifications, hydrocephalus, illness compatible with congenital toxoplasmosis perinatally but not diagnosed at that time. Twenty-five returned for follow-up during 1981 to 2005. Their mean (range) age at last exam was 10.9 +/- 5.7 (range, 3.5 to 27.2) years and mean follow-up was 5.7 +/- 2.9 years. Eighteen (72%) children developed at least one new lesion. Thirteen (52%) had new central lesions, 11 (44%) had new peripheral lesions, and six (24%) had both. Thirteen (52%) had new lesions diagnosed at age > or =10 years. New lesions were found at more than one visit in four (22%), and bilateral new lesions developed in seven (39%) of 18 children who developed new lesions. Of 10 additional children with eye findings and serologic tests indicative of chronic infection, six returned for follow-up, four (67%) developing new lesions at > or =10 years of age. CONCLUSIONS: More than 70% developed new chorioretinal lesions. New lesions were commonly diagnosed after the first decade of life.

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.

Ocular toxoplasmosis signs in mice embryo.

Ocular toxoplasmosis is present in 20% of infected immunocompetent individuals. Toxoplasmosis is the most common cause of posterior uveitis in immunocompetent subjects and congenital toxoplasmosis transmission was the first parasite to be linked to human lesions in the eye. An experimental model for congenital ocular toxoplasmosis was developed in C57BL/6 mice with the purpose to evaluate Toxoplasma induced ocular pathology during fetal life. Toxoplasma gondii, ME-49 strain, was used to infect pregnant females. Histological analysis of pre-natal fetal eyes from infected female mice, did not show parasite infestation, however, alterations were observed in the outer nuclear layer (ONL) and in the inner nuclear layers (INL) of the retina. Edema was also observed, characterized by the increase of interstitial spaces forming lacunae between the ONL and INL cells and a net of vessels associated with an intense inflammatory infiltrate. These histological observations suggest that ocular lesions are not delayed manifestations of toxoplasmosis. The eye was affected in the initial phase of disease, and these alterations were of similar nature as those observed in mice at later stages of infection.

Severe sulfadiazine hypersensitivity in a child with reactivated congenital toxoplasmic chorioretinitis.

A 7-year-old with congenital toxoplasmosis who took pyrimethamine and sulfadiazine for reactivated chorioretinitis developed fever, severe cutaneous involvement, swelling, abdominal pain and transaminitis, persisting weeks after withholding medicines. Symptoms resolved when systemic corticosteroids were administered. This case underscores problems in clinical management with sulfadiazine hypersensitivity, potential immunosuppression from corticosteroids and selection of medications for recurrences of toxoplasmic chorioretinitis.

Toxoplasmic retinochoroiditis presenting in childhood: clinical findings in a UK survey.

AIM: To compare the clinical findings in children with symptomatic toxoplasmic ocular lesions attributable to infection acquired before or after birth. METHODS: Cases were prospectively ascertained for 24 months through national surveillance units and reference laboratories in the British Isles. Age and presenting symptoms, site of lesion and visual impairment in children who were classified as acquiring infection either before or after birth on the basis of clinical and serological findings were compared. RESULTS: 31 children had toxoplasmic retinochoroiditis, 15 had congenital infection and all but three of these presented before the age of 4 years. The remaining 16 children acquired toxoplasmosis postnatally, and 14 of 16 presented after the age of 10 years. A further four children had retinochoroiditis due to other causes. The presence of bilateral, multiple or posterior pole lesions did not distinguish between the two groups, but most children (16/19; 84%) presenting with acute ocular symptoms had postnatally acquired infection. Unilateral visual impairment (Snellen < or =6/18) was equally prevalent in the two groups (4/9 before birth v 7/16 after birth; p>0.5). Only two children had bilateral visual impairment, both of whom had congenital infection. No child was blind. CONCLUSIONS: About 50% of children with ocular lesions due to toxoplasmosis had postnatal infection. Retinochoroidal lesions due to infection before and after birth were indistinguishable. The prognosis for bilateral visual function was good, regardless of when infection was acquired.

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.