Macular Sequelae Following Exudative Retinal Detachment After Laser Photocoagulation for Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVE: To report a series of exudative retinal detachments (ERDs) following laser photocoagulation for retinopathy of prematurity (ROP). PATIENTS AND METHODS: Retrospective case series. RESULTS: Eleven eyes of seven infants were identified who developed ERD following laser. Median gestation age was 25 weeks (interquartile range [IQR]: 24-27 weeks), and median birth weight was 662 grams (IQR: 538-850 grams). Median postmenstrual age at time of laser was 35 weeks (IQR: 33-39 weeks). ERD was diagnosed at a median of 7 days (IQR: 5-7 days) after laser and was managed with steroids. Bevacizumab was also used for certain cases. Time to resolution ranged from 1 to 5 weeks. Macular pigment changes, atrophy, window defect on fluorescein angiography, and photoreceptor loss on optical coherence tomography were noted in some cases following ERD resolution. Excluding one patient who expired at 3 months, median length of follow-up was 10 years (IQR: 9-13.5 years). Overall, only one patient, who presented with less severe ERD, had normal vision. CONCLUSIONS: ERD is an uncommonly reported complication following laser for ROP. Macular changes following ERD resolution may have negative visual consequences. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:698-705.].

Outcomes of hydrocephalus secondary to congenital toxoplasmosis.

OBJECTIVE: Hydrocephalus occurs in children with congenital toxoplasmosis and can lead to severe disability. In these cases, the decision to intervene is often influenced by the expectation of neurological recovery. In this study, clinical responses to neurosurgical intervention in children with hydrocephalus secondary to congenital toxoplasmosis are characterized. METHODS: Sixty-five participants with hydrocephalus due to congenital Toxoplasma gondii infection were evaluated as part of the National Collaborative Chicago-based Congenital Toxoplasmosis Study, and their neuroradiographic findings were reviewed. Clinical outcomes were scored on the basis of cognition and motor skills through the use of IQ scores and Gross Motor Function Classification System (GMFCS) level. Outcomes were then analyzed in relation to approach to management, anatomy of hydrocephalus, and time from diagnosis of hydrocephalus to surgical intervention. RESULTS: There was considerable variation in the outcomes of patients whose hydrocephalus was treated in early life, ranging from normal cognitive and motor function to profound developmental delay and functional limitation. Of the 65 participants included in the study, IQ and GMFCS level were available for 46 (70.8%). IQ and motor score were highly correlated (r = -0.82, p < 0.001). There were people with differing patterns of hydrocephalus or thickness of cortical mantle on initial presentation who had favorable outcomes. Time to neurosurgical intervention data were available for 31 patients who underwent ventriculoperitoneal (VP) shunt placement. Delayed shunt placement beyond 25 days after diagnosis of hydrocephalus was associated with greater cognitive impairment (p = 0.02). Motor impairment also appeared to be associated with shunt placement beyond 25 days but the difference did not achieve statistical significance (p = 0.13). Among those with shunt placement within 25 days after diagnosis (n = 19), the mean GMFCS level was 1.9 ± 1.6 (range 1-5). Five (29.4%) of 17 of these patients were too disabled to participate in formal cognitive testing, after excluding 2 patients with visual difficulties or language barriers that precluded IQ testing. Of the patients who had VP shunt placement 25 or more days after diagnosis (n = 12), the mean GMFCS level was 2.7 ± 1.4 (range 1-4). Of these, 1 could not participate in IQ testing due to severe visual difficulties and 8 (72.7%) of the remaining 11 due to cognitive disability. CONCLUSIONS: VP shunt placement in patients with hydrocephalus caused by congenital toxoplasmosis can contribute to favorable clinical outcomes, even in cases with severe hydrocephalus on neuroimaging. Shunt placement within 25 days of diagnosis was statistically associated with more favorable cognitive outcomes. Motor function appeared to follow the same pattern although it did not achieve statistical significance.

Publisher Correction: Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

When an Orbital Infection Isn't Infectious at All: A Review of Orbital Inflammatory Syndrome.

Orbital inflammatory syndrome (OIS) includes a wide range of clinical manifestations and may initially be misdiagnosed as orbital cellulitis due similar symptoms of fever, periorbital swelling, and pain with eye movements. A diagnosis of OIS requires evaluation for underlying systemic disorders including autoimmune disorders and thyroid disease. Symptoms typically improve rapidly after initiation of steroid therapy, although recurrence can occur. This article presents an illustrative case of a 13-year-old girl with OIS. [Pediatr Ann. 2017;46(11):e433-e436.].

Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer.

One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: "Orbital-deconvolution" elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. "Cluster-deconvolution" revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, "disease-deconvolution" identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer's disease, and cancer. This "reconstruction-deconvolution" logic provides templates of progenitor cells' potentiating effects, and components affecting human brain parasitism and diseases.

Point-of-care testing for Toxoplasma gondii IgG/IgM using Toxoplasma ICT IgG-IgM test with sera from the United States and implications for developing countries.

BACKGROUND: Congenital toxoplasmosis is a serious but preventable and treatable disease. Gestational screening facilitates early detection and treatment of primary acquisition. Thus, fetal infection can be promptly diagnosed and treated and outcomes can be improved. METHODS: We tested 180 sera with the Toxoplasma ICT IgG-IgM point-of-care (POC) test. Sera were from 116 chronically infected persons (48 serotype II; 14 serotype I-III; 25 serotype I-IIIa; 28 serotype Atypical, haplogroup 12; 1 not typed). These represent strains of parasites infecting mothers of congenitally infected children in the U.S. 51 seronegative samples and 13 samples from recently infected persons known to be IgG/IgM positive within the prior 2.7 months also were tested. Interpretation was confirmed by two blinded observers. A comparison of costs for POC vs. commercial laboratory testing methods was performed. RESULTS: We found that this new Toxoplasma ICT IgG-IgM POC test was highly sensitive (100%) and specific (100%) for distinguishing IgG/IgM-positive from negative sera. Use of such reliable POC tests can be cost-saving and benefit patients. CONCLUSIONS: Our work demonstrates that the Toxoplasma ICT IgG-IgM test can function reliably as a point-of-care test to diagnose Toxoplasma gondii infection in the U.S. This provides an opportunity to improve maternal-fetal care by using approaches, diagnostic tools, and medicines already available. This infection has serious, lifelong consequences for infected persons and their families. From the present study, it appears a simple, low-cost POC test is now available to help prevent morbidity/disability, decrease cost, and make gestational screening feasible. It also offers new options for improved prenatal care in low- and middle-income countries.

Patterns of Hydrocephalus Caused by Congenital Toxoplasma gondii Infection Associate With Parasite Genetics.

Four anatomical patterns of hydrocephalus secondary to congenital Toxoplasma gondii infection were identified and characterized for infants enrolled in the National Collaborative Chicago-based Congenital Toxoplasmosis Study. Analysis of parasite serotype revealed that different anatomical patterns associate with Type-II vs Not-Exclusively Type-II strains (NE-II) (P = .035).

Clustering of Toxoplasma gondii Infections Within Families of Congenitally Infected Infants.

BACKGROUND: Family clusters and epidemics of toxoplasmosis in North, Central, and South America led us to determine whether fathers of congenitally infected infants in the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS) have a high incidence of Toxoplasma gondii infection. METHODS: We analyzed serum samples collected from NCCCTS families between 1981 and 2013. Paternal serum samples were tested for T. gondii antibodies with immunoglobulin (Ig) G dye test and IgM enzyme-linked immunosorbent assay. Additional testing of paternal serum samples was performed with differential-agglutination and IgG avidity tests when T. gondii IgG and IgM results were positive and serum samples were collected by the 1-year visit of the congenitally infected child. Prevalence of paternal seropositivity and incidence of recent infection were calculated. We analyzed whether certain demographics, maternal parasite serotype, risk factors, or maternal/infant clinical manifestations were associated with paternal T. gondii infection status. RESULTS: Serologic testing revealed a high prevalence (29 of 81; 36%) of T. gondii infection in fathers, relative to the average seropositivity rate of 9.8% for boys and men aged 12-49 years in the United States between 1994 and 2004 (P < .001). Moreover, there was a higher-than-expected incidence of recent infections among fathers with serum samples collected by the 1-year visit of their child (6 of 45; 13%; P < .001). No demographic patterns or clinical manifestations in mothers or infants were associated with paternal infections, except for sandbox exposure. CONCLUSIONS: The high prevalence of chronic and incidence of recent T. gondii infections in fathers of congenitally infected children indicates that T. gondii infections cluster within families in North America. When a recently infected person is identified, family clustering and community risk factors should be investigated for appropriate clinical management.

Postoperative glaucoma following infantile cataract surgery: an individual patient data meta-analysis.

IMPORTANCE: Infantile cataract surgery bears a significant risk for postoperative glaucoma, and no consensus exists on factors that may reduce this risk. OBJECTIVE: To assess the effect of primary intraocular lens implantation and timing of surgery on the incidence of postoperative glaucoma. DATA SOURCES: We searched multiple databases to July 14, 2013, to identify studies with eligible patients, including PubMed, MEDLINE, EMBASE, ISI Web of Science, Scopus, Central, Google Scholar, Intute, and Tripdata. We also searched abstracts of ophthalmology society meetings. STUDY SELECTION: We included studies reporting on postoperative glaucoma in infants undergoing cataract surgery with regular follow-up for at least 1 year. Infants with concurrent ocular anomalies were excluded. DATA EXTRACTION AND SYNTHESIS: Authors of eligible studies were invited to contribute individual patient data on infants who met the inclusion criteria. We also performed an aggregate data meta-analysis of published studies that did not contribute to the individual patient data. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: Time to glaucoma with the effect of primary implantation, additional postoperative intraocular procedures, and age at surgery. RESULTS: Seven centers contributed individual patient data on 470 infants with a median age at surgery of 3.0 months and median follow-up of 6.0 years. Eighty patients (17.0%) developed glaucoma at a median follow-up of 4.3 years. Only 2 of these patients had a pseudophakic eye. The risk for postoperative glaucoma appeared to be lower after primary implantation (hazard ratio [HR], 0.10 [95% CI, 0.01-0.70]; P = .02; I(2) = 34%), higher after surgery at 4 weeks or younger (HR, 2.10 [95% CI, 1.14-3.84]; P = .02; I(2) = 0%), and higher after additional procedures (HR, 2.52 [95% CI, 1.11-5.72]; P = .03; I(2) = 32%). In multivariable analysis, additional procedures independently increased the risk for glaucoma (HR, 2.25 [95% CI, 1.20-4.21]; P = .01), and primary implantation independently reduced it (HR, 0.10 [95% CI, 0.01-0.76]; P = .03). Results were similar in the aggregate data meta-analysis that included data from 10 published articles. CONCLUSIONS AND RELEVANCE: Although confounding factors such as size of the eye and surgeon experience are not accounted for in this meta-analysis, the risk for postoperative glaucoma after infantile cataract surgery appears to be influenced by the timing of surgery, primary implantation, and additional intraocular surgery.

ALOX12 in human toxoplasmosis.

ALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a nonheme lipoxygenase family of dioxygenases. ALOX12 catalyzes the addition of oxygen to arachidonic acid, producing 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which can be reduced to the eicosanoid 12-HETE (12-hydroxyeicosatetraenoic acid). 12-HETE acts in diverse cellular processes, including catecholamine synthesis, vasoconstriction, neuronal function, and inflammation. Consistent with effects on these fundamental mechanisms, allelic variants of ALOX12 are associated with diseases including schizophrenia, atherosclerosis, and cancers, but the mechanisms have not been defined. Toxoplasma gondii is an apicomplexan parasite that causes morbidity and mortality and stimulates an innate and adaptive immune inflammatory reaction. Recently, it has been shown that a gene region known as Toxo1 is critical for susceptibility or resistance to T. gondii infection in rats. An orthologous gene region with ALOX12 centromeric is also present in humans. Here we report that the human ALOX12 gene has susceptibility alleles for human congenital toxoplasmosis (rs6502997 [P, <0.000309], rs312462 [P, <0.028499], rs6502998 [P, <0.029794], and rs434473 [P, <0.038516]). A human monocytic cell line was genetically engineered using lentivirus RNA interference to knock down ALOX12. In ALOX12 knockdown cells, ALOX12 RNA expression decreased and levels of the ALOX12 substrate, arachidonic acid, increased. ALOX12 knockdown attenuated the progression of T. gondii infection and resulted in greater parasite burdens but decreased consequent late cell death of the human monocytic cell line. These findings suggest that ALOX12 influences host responses to T. gondii infection in human cells. ALOX12 has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical role ALOX12 plays in T. gondii infection in humans.

Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981-2009).

BACKGROUND: Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types. METHODS: ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined. RESULTS: Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment. CONCLUSIONS: Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment. CLINICAL TRIALS REGISTRATION: NCT00004317.

Spinal Cord Lesions in Congenital Toxoplasmosis Demonstrated with Neuroimaging, Including Their Successful Treatment in an Adult.

Neuroimaging studies for persons in the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS) with symptoms and signs referable to the spinal cord were reviewed. Three infants had symptomatic spinal cord lesions, another infant a Chiari malformation, and another infant a symptomatic peri-spinal cord lipoma. One patient had an unusual history of prolonged spinal cord symptoms presenting in middle age. Neuroimaging was used to establish her diagnosis and response to treatment. This 43 year-old woman with congenital toxoplasmosis developed progressive leg spasticity, weakness, numbness, difficulty walking, and decreased visual acuity and color vision without documented re-activation of her chorioretinal disease. At 52 years of age, spinal cord lesions in locations correlating with her symptoms and optic atrophy were diagnosed with 3 Tesla MRI scan. Treatment with pyrimethamine and sulfadiazine decreased her neurologic symptoms, improved her neurologic examination, and resolved her enhancing spinal cord lesions seen on MRI.

Clinical manifestations of ocular toxoplasmosis.

Clinical manifestations of ocular toxoplasmosis are reviewed. Findings of congenital and acute acquired ocular toxoplasmosis include retinal scars, white-appearing lesions in the active phase often associated with vitritis. Complications can include fibrous bands, secondary serous or rhegmatogenous retinal detachments, optic neuritis and neuropathy, cataracts, increased intraocular pressure during active infection, and choroidal neovascular membranes. Recurrences in untreated congenital toxoplasmosis occur in teenage years. Manifestations at birth are less severe, and recurrences are fewer in those who were treated promptly early in the course of their disease in utero and in the first year of life. Severe retinal involvement is common at diagnosis of symptomatic congenital toxoplasmosis in the United States and Brazil. Acute acquired infections also may be complicated by toxoplasmic retinochoroiditis, with recurrences most common close to the time of acquisition. Suppressive treatment can reduce recurrent disease.

Lesões coriorretinianas em mães de crianças com toxoplasmose congênita no national collaborative Chicago-based, toxoplasmosis study / Chorioretinal lesions in mothers of children with congenital toxoplasmosis in the national collaborative Chicago-based, congenital toxoplasmosis study

Aims: To determine whether mothers of children with congenital toxoplasmosis have chorioretinal lesions consistent with toxoplasmosis. Methods: Prospective cohort study. Ophthalmologists in our study have examined 173 children with congenital toxoplasmosis in a hospital outpatient setting. These children were referred to us by their primary care physicians. One hundred and thirty mothers of these children had retina examinations of both eyes at least once. Main outcome measure was lesion(s) consistent with ocular toxoplasmosis. Results: Of 130 mothers examined between 1991-2005, 10 (7.7%, 95% Confidence Interval 3.8%, 13.7%) had chorioretinal lesions which likely represent resolved toxoplasmic chorioretinitis. Most of these were small peripheral chorioretinal lesions. None reactivated between 1991-2005. Conclusions: Chorioretinal lesions consistent with quiescent ocular toxoplasmosis occur in mothers of children with congenital toxoplasmosis in the United States.

Chorioretinal lesions in mothers of children with congenital toxoplasmosis in the National Collaborative Chicago-based, Congenital Toxoplasmosis Study.

AIMS: To determine whether mothers of children with congenital toxoplasmosis have chorioretinal lesions consistent with toxoplasmosis. METHODS: Prospective cohort study. Ophthalmologists in our study have examined 173 children with congenital toxoplasmosis in a hospital outpatient setting. These children were referred to us by their primary care physicians. One hundred and thirty mothers of these children had retina examinations of both eyes at least once. Main outcome measure was lesion(s) consistent with ocular toxoplasmosis. RESULTS: Of 130 mothers examined between 1991-2005, 10 (7.7%, 95% Confidence Interval 3.8%, 13.7%) had chorioretinal lesions which likely represent resolved toxoplasmic chorioretinitis. Most of these were small peripheral chorioretinal lesions. None reactivated between 1991-2005. CONCLUSIONS: Chorioretinal lesions consistent with quiescent ocular toxoplasmosis occur in mothers of children with congenital toxoplasmosis in the United States.

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.

Longitudinal study of new eye lesions in treated congenital toxoplasmosis.

OBJECTIVE: To determine the incidence of new chorioretinal lesions in patients with congenital toxoplasmosis who were treated throughout their first year of life. DESIGN: Prospective longitudinal observation of a cohort. PARTICIPANTS: One hundred thirty-two children were studied as part of the longitudinal observation. METHODS: 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. MAIN OUTCOME MEASURES: New chorioretinal lesions on fundus examination and fundus photographs. RESULTS: 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. CONCLUSION: 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.

Cataracts in congenital toxoplasmosis.

PURPOSE: To determine the incidence and natural history of cataracts in children with congenital toxoplasmosis. METHODS: Children referred to the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS) between 1981 and 2005 were examined by ophthalmologists at predetermined times according to a specific protocol. The clinical course and treatment of patients who developed cataracts were reviewed. RESULTS: In the first year of life, 134 of 173 children examined were treated with pyrimethamine, sulfadiazine, and leukovorin, while the remaining 39 were not treated. Cataracts occurred in 27 eyes of 20 patients (11.6%, 95% confidence interval [7.2%, 17.3%]). Fourteen cataracts were present at birth and 13 developed postnatally. Locations of the cataracts included anterior polar (three eyes), anterior subcapsular (six eyes), nuclear (five eyes), posterior subcapsular (seven eyes), and unknown (six eyes). Thirteen cataracts were partial, nine total, and five with unknown complexity. Twelve cataracts remained stable, 12 progressed, and progression was not known for 3. Five of 27 eyes had cataract surgery, with 2 of these developing glaucoma. Sixteen eyes of 11 patients had retinal detachment and cataract. All eyes with cataracts had additional ocular lesions. CONCLUSIONS: In the NCCCTS cohort, 11.6% of patients were diagnosed with cataracts. There was considerable variability in the presentation, morphology, and progression of the cataracts. Associated intraocular pathology was an important cause of morbidity.