Interleukin 17F Gene Polymorphism as a Potential Protective Factor in the Immunopathology of Ocular Toxoplasmosis.

Ocular toxoplasmosis (OT) is characterised by intraocular inflammation due to Toxoplasma gondii infection. Studies have found that interleukin 17 (IL-17) plays a central role in the pathology of OT. However, nucleotide variability in IL17 and interleukin 17 receptor (IL17R) genes has not been characterised in OT. As cytokine gene polymorphisms may influence the expression of these molecules, the aim of this study was to verify whether IL17A (rs2275913), IL17F (rs763780), IL17RA (rs4819554) and IL17RC (rs708567) polymorphisms are associated with OT in a Brazilian population. This study enrolled 214 patients seropositive for T. gondii (110 with OT and 104 without) and 107 controls. Polymorphisms were identified by PCR-restriction fragment length polymorphism analysis, validated by DNA sequencing with chi-square and multivariate analyses being used to assess possible associations between polymorphisms and OT. Logistic regression under the dominant model revealed a protection factor against OT of the C mutant allele of the IL17F (rs763780) polymorphism. The T/C-C/C genotypes were significantly more common in patients without OT compared to those with OT (p value = 0.0066) and controls (p value = 0.014). Findings from this study suggest that the IL17F polymorphism may have an influence in the immunopathology of OT in Brazilian individuals.

Metagenomic analysis of the ocular toxoplasmosis in children uveitis from Fayoum governorate, Egypt.

Granulomatous anterior uveitis with single or numerous gelatinous nodules was found in children living in rural Egypt. All ocular diseases were originally thought to be water-born and related to digenic flukes. The current study sought to learn more about the causes of anterior granulomatous uveitis in Egyptian youngsters who used to swim in rural water canals. 50 children with eye lesions that had not responded to medical treatment were recruited. Four samples were surgically extracted and examined using real-time PCR, transmission electron microscopy (TEM), and shotgun metagenomic sequencing (SMS). Toxoplasma gondii was detected free within the syncytium's distal section, while the proximal part exhibited active synthesis of a presumably extra-polymeric material, possibly released by the microbial population. Toxoplasma gondii was found in 30 samples. Serologically, distinct anti-Toxoplasma antibodies were not found in 91.6% of patients. SMS showed that the T. gondii ME 49 strain had the greatest percentage (29-25%) in all samples within an Acinetobacter-containing microbial community. These findings suggested that these bacteria entered the body via the exterior route rather than the circulatory route. The lack of genetic evidence for subsequent parasite stages invalidates the prior findings about the assumed trematode stage.

Acquired Ocular Toxoplasmosis: a Case Report and Review of the Literature.

BACKGROUND: Toxoplasmosis is a zoonotic illness caused by Toxoplasma gondii. Ocular infection frequently manifests as acute necrotizing retinal chorioretinitis. In this paper, we describe a case of retinal chorioretinitis caused by Toxoplasma gondii infection, as well as the most recent diagnostic and treatment techniques. METHODS: Serum and vitreous fluid were collected and analyzed, and PCR for Toxoplasma gondii DNA, ELISA for Toxoplasma gondii IgG and Goldmann-Witmer coefficient, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and fundus autofluorescence were done (FAF). RESULTS: Toxoplasma gondii DNA (-), serum and vitreous IgG from Toxoplasma gondii (+) cells, and the Goldmann-Witmer coefficient of Toxoplasma gondii were all considerably enhanced, indicating Toxoplasma gondii infection. Antiparasitic infection in combination with an anti-inflammatory glucocorticoid were given, laser treatment of the fundus was provided, and the patient's condition has been stable with no indication of recurrence to date following conclusion of therapy. CONCLUSIONS: Toxoplasma gondii can infect the whole retina, causing variable degrees of visual impairment; thus, rapid diagnosis and tailored therapy are necessary to enhance prognosis and reduce disease recurrence.

Ocular Toxoplasmosis in Africa: A Narrative Review of the Literature.

PURPOSE: To present a narrative review about ocular toxoplasmosis epidemiology, disease burden and prevalent African parasitic strains. METHODS: An initial search for MeSH terms was conducted with a posterior advanced search in two electronic databases. Full text reading was performed. RESULTS: Animal African studies have identified Toxoplasma gondii type II, type III, Africa 1, and Africa 3 strains. Seroprevalence varies from 6.4% to 74.5%. Nevertheless, there is a scarcity of epidemiology and serotyping information about ocular toxoplasmosis. African studies have demonstrated that uveitis patients present high frequencies of ocular toxoplasmosis. There is a lack of studies describing specific clinical characteristics, which can be related, to environmental and socioeconomic factors, parasite serotype and genotype, and genetic susceptibility of the host. CONCLUSION: As Toxoplasma gondii has more virulent strains in the Southern hemisphere, it is relevant to determine African strain types and the correlation between the infecting strains and the clinical manifestations.

Autoantibodies Against Ubiquitous and Confined Antigens in Patients With Ocular, Neuro-Ophthalmic and Congenital Cerebral Toxoplasmosis.

Toxoplasma gondii infection can trigger autoreactivity by different mechanisms. In the case of ocular toxoplasmosis, disruption of the blood-retinal barrier may cause exposure of confined retinal antigens such as recoverin. Besides, cross-reactivity can be induced by molecular mimicry of parasite antigens like HSP70, which shares 76% identity with the human ortholog. Autoreactivity can be a determining factor of clinical manifestations in the eye and in the central nervous system. We performed a prospective observational study to determine the presence of autoantibodies against recoverin and HSP70 by indirect ELISA in the serum of 65 patients with ocular, neuro-ophthalmic and congenital cerebral toxoplasmosis. We found systemic autoantibodies against recoverin and HSP70 in 33.8% and 15.6% of individuals, respectively. The presence of autoantibodies in cases of OT may be related to the severity of clinical manifestations, while in cases with CNS involvement they may have a protective role. Unexpectedly, anti-recoverin antibodies were found in patients with cerebral involvement, without ocular toxoplasmosis; therefore, we analyzed and proved cross-reactivity between recoverin and a brain antigen, hippocalcin, so the immunological phenomenon occurring in one immune-privileged organ (e.g. the central nervous system) could affect the environment of another (egg. the eye).

Classification Criteria for Toxoplasmic Retinitis.

PURPOSE: To determine classification criteria for toxoplasmic retinitis. DESIGN: Machine learning of cases with toxoplasmic retinitis and 4 other infectious posterior uveitides / panuveitides. METHODS: Cases of infectious posterior uveitides / panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set. RESULTS: Eight hundred three cases of infectious posterior uveitides / panuveitides, including 174 cases of toxoplasmic retinitis, were evaluated by machine learning. Key criteria for toxoplasmic retinitis included focal or paucifocal necrotizing retinitis and either positive polymerase chain reaction assay for Toxoplasma gondii from an intraocular specimen or the characteristic clinical picture of a round or oval retinitis lesion proximal to a hyperpigmented and/or atrophic chorioretinal scar. Overall accuracy for infectious posterior uveitides / panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for toxoplasmic retinitis were 8.2% in the training set and 10% in the validation set. CONCLUSIONS: The criteria for toxoplasmic retinitis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

MACULAR HOLE ASSOCIATED WITH TOXOPLASMOSIS: A SURGICAL CASE SERIES.

PURPOSE: There are currently limited data addressing the surgical outcomes of pars plana vitrectomy (PPV) in toxoplasmosis-related macular hole (tMH). We aim to report and discuss safety and efficacy of PPV for tMH. METHODS: Surgical case series (n = 11), with minimum postoperative follow-up time of 6 months. Consecutive patients who underwent PPV for tMH from 2013 to 2016 were included. Indications for surgery were: visual acuity ≥ 0.6 logarithm of the minimum angle of resolution (Snellen 20/80 or less), no intraocular inflammation for more than 6 months, extrafoveal toxoplasmosis scar, elevated tMH borders on optical coherence tomography, and patient agreement with surgery. Surgery was performed-PPV with epiretinal (if present) and internal limiting membrane peeling. Safety and efficacy of PPV for tMH were addressed by evaluating: 1) surgery-related complications and 2) visual acuity improvement. RESULTS: A total of 11 patients (6 male), with a mean age of 33.2 ± 11.0 years were studied. Mean preoperative best-corrected visual acuity significantly improved from 1.10 ± 0.24 (Snellen 20/252) to 0.43 ± 0.18 logarithm of the minimum angle of resolution (Snellen 20/54) at last follow-up visit (P < 0.01). The rate of visual acuity improvement (i.e., a gain of at least three lines) and tMH closure was 100% for both. The only reported surgery-related complication was cataract in one case. CONCLUSION: Our results suggest that PPV is a safe and effective option in tMH cases. A controlled, longitudinal study would contribute to confirm these findings.

Driving in Fog without Headlight: Management of a Challenging Case of Presumed Ocular Toxoplasmosis.

Purpose: To describe a case of presumed ocular toxoplasmosis.Method: A retrospective chart review.Result: This case report describes a 35-year-old male who presented hypopyon anterior uveitis in his left eye. Fundus examination revealed severe vitritis which precluded the view of retina. His serum anti-toxoplasma immunoglobulin (Ig)G was significantly raised, with a normal anti-toxoplasma IgM level and PCR from nested primers targeting B1 gene of Toxoplasma gondii was positive. He was started on empirical anti-toxoplasma therapy. Undiluted vitreous specimen collected during lensectomy and diagnostic vitrectomy in left eye was also positive for nested primers targeting B1 gene of T. gondii.Conclusion: Ocular toxoplasmosis without retinochoroiditis, though extremely rare, can occur.

Diffuse Unilateral Subacute Neuroretinitis Evolving With Submacular Granuloma.

DUSN is an infectious ocular disease that can lead to severe visual impairment and blindness. It usually occurs in young healthy individuals and depending on the stage of the disease, clinical presentation may range from mild vitritis and multifocal gray-white lesions in outer retina to optic atrophy.Parasites of different sizes and species have been proposed as the etiological agent of this disease. Thus, it is hypothesized that different infectious worms may be considered as the likely cause of a both autoimmune and toxic form of nematode retinopathy.Most patients present with already severe visual impairment and in the later stages of the disease, where the likelihood of improvement is low, despite therapy. In cases of early diagnosis, prompt treatment, whether with oral antihelmintic or direct photocoagulation of the worm, patients may show considerable visual improvement and have a more favorable prognosis.

Cladosporium Endogenous Endophthalmitis Mimicking Toxoplasma Retinochoroiditis.

Background: Endogenous fungal endophthalmitis is a sight-threatening condition with potentially devastating outcome. Hematogenous spread of the infective seedings is the route of infection. Infected individuals have usually a compromised immune status. The clinical picture of mycotic endogenous endophthalmitis is commonly seen as chorioretinitis. Candida is the most common fungus. Cladosporium causing endogenous endophthalmitis is a rare occurrence, with only a few cases published.Methods: The report includes study and management of a diabetic patient with endogenous cladosporium endophthalmitis mimicking toxoplasma retinochoroiditis.Results: Diagnosis was confirmed as Cladosporium Cladosporioides in vitreous and aqueous aspirate by polymerase chain reaction-based DNA sequencing. Patient was successfully managed with intravitreal and systemic voriconazole.Conclusion: Cladosporium can cause endogenous endophthalmitis and mimic toxoplasma retinochoroiditis. Vitreous biopsy can help in diagnosis in the absence of positive blood culture. Intravitreal voriconazole along with systemic voriconazole shows a good response.

Sulfadiazine plasma concentrations in women with pregnancy-acquired compared to ocular toxoplasmosis under pyrimethamine and sulfadiazine therapy: a case-control study.

BACKGROUND: Dosing recommendations for the treatment of pregnancy-acquired toxoplasmosis are empirical and widely based on experimental data. There are no pharmacological data on pregnant women with acute Toxoplasma gondii infection under treatment with pyrimethamine (PY) and sulfadiazine (SA) and our study intends to tighten this gap. METHODS: In this retrospective case-control study, we included 89 pregnant women with primary Toxoplasma infection (PT) treated with PY (50 mg first dose, then 25 mg/day), SA (50 mg/kg of body weight/day), and folinic acid (10-15 mg per week). These were compared to a group of 17 women with acute ocular toxoplasmosis (OT) treated with an initial PY dose of 75 mg, thereafter 25 mg twice a day but on the same SA and folinic acid regimen. The exact interval between drug intake and blood sampling and co-medication had not been recorded. Plasma levels of PY and SA were determined 14 ± 4 days after treatment initiation using liquid chromatography-mass spectrometry and compared using the Mann-Whitney U test at a p < 0.05 level. RESULTS: In 23 PT patients (26%), SA levels were below 20 mg/l. Fifteen of these 23 patients (17% of all patients) in parallel presented with PY levels below 700 µg/l. Both drug concentrations differed remarkably between individuals and groups (PY: PT median 810 µg/l, 95% CI for the median [745; 917] vs. OT 1230 µg/l [780; 1890], p = 0.006; SA: PT 46.2 mg/l [39.9; 54.4] vs. OT 70.4 mg/l [52.4; 89], p = 0.015) despite an identical SA dosing scheme. CONCLUSIONS: SA plasma concentrations were found in the median 34% lower in pregnant women with PT compared to OT patients and fell below a lower reference value of 50 mg/l in a substantial portion of PT patients. The interindividual variability of plasma concentrations in combination with systematically lower drug levels and possibly a lower compliance in pregnant women may thus account for a still not yet supportable transmission risk. Systematic drug-level testing in PT under PY/SA treatment deserves to be considered.

Optical Coherence Tomography Angiography Analysis of Retinal and Choroidal Vascular Networks during Acute, Relapsing, and Quiescent Stages of Macular Toxoplasma Retinochoroiditis.

PURPOSE: To highlight the advantages of optical coherence tomography angiography (OCTA) in delineating the morphological features of the retinal and choroidal vascular network during acute, relapsing, and quiescent stages of macular toxoplasma retinochoroiditis. METHODS: This prospective study included patients presenting with both active and quiescent ocular toxoplasmoses. OCTA was obtained to diagnose and follow the subsequent vascular network changes at diagnosis and six months after acute presentation. RESULTS: Twenty-three eyes of 23 patients were included. In active lesions, OCTA showed extensive, well-delineated areas of intense hyposignal and perifoveal capillary arcade disruption in the parafoveal superficial capillary plexus (pSCP) and less extensive hyposignal in the parafoveal deep capillary plexus (pDCP). Signals of decreased deep capillary density and disorganization were also seen in the choroid. In nonactive lesions, OCTA demonstrated a homogenous and equally attenuated grayish hyposignal of the pSCP and pDCP and a partial restoration of the nonperfused choroidal areas. CONCLUSION: OCTA is a useful technique for vascular network analysis in toxoplasma retinochoroiditis. It allows the visualization of the different network changes and behaviors during the different stages of the infection.

Interferon-γ and IL-10 Release Assay for Patients with Ocular Toxoplasmosis.

Peripheral blood mononuclear cells (PBMC) from patients with ocular toxoplasmosis were challenged with total antigens from Toxoplasma gondii lysate (TATL) in a cytokine release assay (CRA), run during the inactive period of the disease. Increased interferon gamma (IFN-γ) levels were detected after PBMC stimulation with either ME49 reference strain (P = 0.0015) or local TgCkAr-11-9 isolate (P = 0.0012), as compared with those recorded under basal conditions. TATL from TgCkAr11-9 isolate induced a higher release of IFN-γ than ME49 strain in CRA from all tested patients (P = 0.02). The median value of IFN-γ release on TgCkAr-11-9 stimulation (26.03 pg/mL) allowed the classification of patients into high- or low-/non-IFN-γ releasers. Clinical correlations were established with both groups. The results obtained in this study suggest the need to include local strains when performing CRA with TATL.

Unilateral Acute Macular Toxoplasmic Chorioretinitis Associated with White Dot-Like Choroidal Involvement Demonstrated on Indocyanine Green Angiography

A 9-year-old otherwise healthy boy was examined due to a 4-day history of visual decline in his right eye. Ophthalmological examination revealed an area of active retinochoroiditis in the right macula. Indocyanine green angiography (ICGA) demonstrated multiple hypocyanescent dots surrounding the active lesion extending 360 degrees towards the equator. Optical coherence tomography angiography (OCTA) exhibited dark dots on the choriocapillaris slab over areas corresponding to the hypocyanescent dots detected with ICGA. Full systemic examination and laboratory investigations were carried out. Toxoplasma gondii serology was positive. The diagnosis of toxoplasmic chorioretinitis with white dot-like choroidal involvement was made. Trimethoprim/sulfamethoxazole, azithromycin, and oral prednisolone were administered orally. On repeated ICGA 2 weeks later, the scattered hypocyanescent dots were significantly fewer in number. A month later, right visual acuity was improved, the macular chorioretinitis focus had become inactive, an epiretinal membrane had formed, and the dark dots on the choriocapillaris slab of OCTA were markedly diminished. ICGA may be helpful to observe possible, subtle choroidal involvement in patients with toxoplasmic chorioretinitis.

Toxoplasma gondii SAG2 type III in an atypical presentation of ocular toxoplasmosis in Indonesia.

OBJECTIVE: This study aimed to perform genotyping of Toxoplasma gondii strain or variant causing atypical toxoplasmic uveitis in Indonesian patients. METHODS: Ocular fluid samples originating from 46 uveitis patients with non-specific ocular manifestations were analysed for Toxoplasma infection by PCR of the B1 locus. The clonal type was determined by amplification, sequencing and phylogenetic analysis of SAG2 and GRA6 loci in B1-positive samples. Clinical data were obtained from the medical records. RESULTS: Pan uveitis was the most frequent manifestation (65.2%) and mostly unilateral (76.1%). PCR of the B1 locus identified eight positive subjects (12.5%); six had panuveitis and two of these had diabetes mellitus. Phylogenetic analysis with maximum likelihood of the SAG2 locus in the B1-positive samples resulted in Toxoplasma gondii SAG2 type III allele. No positive result was obtained from the PCR of GRA6 locus. CONCLUSION: Toxoplasma gondii SAG2-type III allele was identified in an atypical presentation of toxoplasmic uveitis in Indonesia.

Long-term Results of Trimethoprim-Sulfamethoxazole Versus Placebo to Reduce the Risk of Recurrent Toxoplasma gondii Retinochoroiditis.

PURPOSE: To compare the effects of 1 year of treatment with trimethoprim-sulfamethoxazole (TMP-SMZ) vs placebo in reducing the risk of recurrence of toxoplasmic retinochoroiditis during a 6-year follow-up period. DESIGN: Randomized, double-masked clinical trial. METHODS: This cohort included 141 subjects recruited in Campinas, Brazil. The inclusion criterion was unilateral active recurrent toxoplasmic retinochoroiditis. All subjects were treated with 1 dose of TMP-SMZ (160 mg/800 mg) twice daily for 45 days, and all lesions healed after this treatment. After this initial treatment, subjects were randomly assigned to group 1 (1 TMP-SMZ dose every other day for 311 days) or group 2 (1 identical placebo tablet containing starch with no active ingredients every other day for 311 days). Between the second and sixth years of follow-up appointments, none of the subjects received treatment unless a new recurrence episode had occurred. The primary outcomes were recurrent toxoplasmic retinochoroiditis within the first year of follow-up and recurrent toxoplasmic retinochoroiditis in the 6 years of follow-up. RESULTS: The cumulative probability of recurrence 1, 2, 3, 4, 5, and 6 years after the initial infection was, respectively, 13.0% (9/69), 17.4% (12/69), 20.3% (14/69), 23.2% (16/69), 26.1% (18/69), and 27.5% (19/69) in the placebo group and 0%, 0%, 0%, 0%, 0%, and 1.4% (1/72) in the TMP-SMZ group (P < .001; log-rank test). There were 3 cases (3/69; 4.3%) of multiple recurrences in the same individual in the placebo group. No treatment-limiting toxicity or side effects were observed in either group. New recurrences were more frequent among female subjects. CONCLUSIONS: TMP-SMZ may be used safely for prophylaxis of recurrent toxoplasmic retinochoroiditis and may provide long-term benefits.

Near full thickness macular hole with an intact overlying internal limiting membrane following resolution of fulminant acquired toxoplasma retinitis -A unique finding.

A 43-year-old immunocompetent male presented with focal macular retinitis with overlying vitritis in the right eye. His BCVA was counting fingers close to face. OCT showed increased intraretinal thickness at the area of retinitis with adjacent hypo reflectivity of the choroid. Serology was positive for IgM and IgG antibodies for toxoplasma. He received oral clindamycin 300 mg 4 times/day for 8 weeks. At 6 weeks, his BCVA was CF 2 metres. Fundus showed complete resolution of retinitis with formation of near, full thickness macular hole with intact overlying ILM. A small hyper reflective scar was seen at the base of the macular hole.

Model Systems for Studying Mechanisms of Ocular Toxoplasmosis.

The most common human disease caused by infection with Toxoplasma gondii is ocular toxoplasmosis, which typically is manifest as recurrent attacks of necrotizing retinal inflammation with subsequent scarring. The multilayered retina contains specialized cell populations, including endothelial cells, epithelial cells, neurons and supporting cells, all of which may be involved in this condition. In vitro investigations of basic mechanisms operating in human ocular toxoplasmosis use cellular and molecular methods that are common to the study of many pathological processes, and the novel aspect of this research is the use of human retinal cell subsets. Most in vivo research on ocular toxoplasmosis is conducted in the laboratory mouse. Experimental models involve local or systemic inoculation of parasites to induce acute disease, or sequential systemic and local parasite inoculations to trigger recurrent disease. We present methods for in vitro and in vivo studies of ocular toxoplasmosis, including dissection of the human eye, and culture and infection of differentiated cell populations from the retina, as well as induction of mouse ocular toxoplasmosis by intraocular, or sequential systemic and intraocular, inoculations, and imaging of toxoplasmic retinal lesions.

Chorio-retinal toxoplasmosis: treatment outcomes, lesion evolution and long-term follow-up in a single tertiary center.

BACKGROUND: Ocular toxoplasmosis is a common cause of ocular inflammation worldwide. The aim of this study is to characterize the clinical outcomes and lesion evolution of patients with ocular toxoplasmosis and to compare the primary and reactivation subgroups. METHODS: A retrospective population-based cohort study at one uveitis-specialized tertiary referral center. Patients presenting with active ocular toxoplasmosis between the years 2007-2016 were included. Primary ocular toxoplasmosis and reactivations were compared. RESULTS: Included were 22 patients, 64% female with a mean age of 29 ± 18 years, 59% (n = 13) were primary, 9% (n = 2) congenital and 32% (n = 7) reactivations. Visual acuity improved from 0.38 ± 0.44 to 0.20 ± 0.27 LogMAR (P = 0.026) after a mean of 37 ± 33 months. Initial lesion size was 2.38 ± 1.1 optic disc areas, reducing to 1.56 ± 1.24 following 2 months (34% reduction, P = 0.028) and to 1.17 ± 0.87 disc areas following one year (51% reduction, P = 0.012). Patients with macula-threatening lesions had worse visual acuity (0.50 ± 0.46 vs. 0.05 ± 0.07 LogMAR, P = 0.047). Primary and reactivation subgroups had similar presentations, visual outcomes and recurrence rates (all P > 0.05). CONCLUSIONS: In this population, primary ocular toxoplasmosis was the most common presentation. Lesion size reduced during the initial months with limited change thereafter and a third of cases recurred. Macula-threatening lesions were associated with worse visual acuity, and no significant differences were seen between the primary and reactivation subgroups.