Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality.

PURPOSE: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression. DESIGN: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. PARTICIPANTS: Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer. METHODS: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study. MAIN OUTCOME MEASURES: Overall mortality and CM. RESULTS: Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration. CONCLUSIONS: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Ophthalmic Immune-Related Adverse Events after Anti-CTLA-4 or PD-1 Therapy Recorded in the American Academy of Ophthalmology Intelligent Research in Sight Registry.

PURPOSE: Detailed study of ophthalmic immune-related adverse events (AEs), including determination of incidence and recurrence rates, is of integral importance in cancer immunotherapy to inform management and treatment guidelines. DESIGN: Retrospective registry study. PARTICIPANTS: Patients newly diagnosed with ophthalmic immune-related AEs between January 1, 2013, and December 31, 2017, in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS®) Registry. METHODS: Data were collected from electronic health records of IRIS® Registry participating ophthalmology practices. Patients with select ophthalmic immune-related AEs were identified by International Classification of Diseases diagnosis codes. The primary exposure of interest was prior initiation of immune checkpoint inhibitors (ICIs). MAIN OUTCOME MEASURES: Incidence of ophthalmic immune-related AEs within 1 year after initiation of ICI therapy was determined. Incidence rate ratios (IRRs) were derived by comparing incidence of ophthalmic immune-related AEs after ICIs versus rates of the same ocular complications in patients not taking ICIs in the entire registry population. Rates of ophthalmic immune-related AEs in patients with a past history of ocular inflammation or other specific ophthalmic condition before initiation of ICIs were examined further. RESULTS: A total of 3123 patients who received anti-CTLA-4 or anti-programmed cell death 1 (PD-1) therapy were identified, 112 of whom demonstrated an ophthalmic immune-related AE. Incidence rates for anterior uveitis, the most common ophthalmic immune-related AE, were 8209 per 100 000 for ipilimumab (anti-CTLA-4), 2542 per 100 000 for nivolumab (anti-PD-1), 2451 per 100 000 for pembrolizumab (anti-PD-1), 5556 per 100 000 for ipilimumab plus nivolumab, and 3740 per 100 000 among all ICIs. Rates of ophthalmic immune-related AEs among patients receiving ICI therapy were higher compared with baseline rates in the general registry population (anterior uveitis IRR, 13.9; other uveitis IRR, 43.0; papilledema IRR, 38.3). Patients with a history of uveitis or other ocular inflammatory condition demonstrated high recurrence rates of ophthalmic immune-related AEs after initiating ICIs (up to 51.1%). CONCLUSIONS: For patients initiating ICI therapy, early coordination with ophthalmic subspecialist care is important because rates of ophthalmic immune-related AEs are elevated compared with ocular complication rates in the entire registry population and patients with a history of prior autoimmune ocular disease are at high risk of recurrence of ocular complications.

Masqueraders of multiple evanescent white dot syndrome (MEWDS).

PURPOSE: To describe disorders that can masquerade as multiple evanescent white dot syndrome (MEWDS). DESIGN: Retrospective, multicenter case series. PARTICIPANTS: Patients who presented with clinical findings compatible with a diagnosis of MEWDS but were ultimately diagnosed with an alternative inflammatory, infectious, or neoplastic disorder. METHODS: Clinical records and multimodal imaging findings including fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and OCT angiography (OCTA) were analyzed. MAIN OUTCOME MEASURES: Inclusion criteria to be defined as a masquerade syndrome for MEWDS included the presence of disseminated grayish-white outer retinal spots that were hyperautofluorescent on FAF and associated with ellipsoid zone (EZ) disruption on OCT. RESULTS: Twenty-two eyes of 13 patients were identified. All patients presented with the classic findings of MEWDS listed above. A MEWDS-like presentation was bilateral in nine of 13 patients (69%). Final diagnosis was determined on the basis of additional investigations including serologies and biopsy. These diagnoses included syphilis (three patients), lymphoma (three patients), idiopathic multifocal choroiditis (two patients), idiopathic retinal phlebitis (one patient), idiopathic acute zonal occult outer retinopathy (one patient), sarcoidosis (one patient), tuberculosis (one patient), and cancer-associated retinopathy (one patient). The outer retinal lesions and imaging findings resolved with treatment for the associated systemic disorders. CONCLUSIONS: Widespread grayish-white outer retinal spots associated with hyperautofluorescence on FAF and disruption of the EZ on OCT are not pathognomonic for MEWDS. A high index of suspicion must be maintained for masqueraders of MEWDS, which can include serious inflammatory, infectious, and neoplastic disorders.

Longitudinal Vision-Related Quality of Life for Patients with Noninfectious Uveitis Treated with Fluocinolone Acetonide Implant or Systemic Corticosteroid Therapy.

PURPOSE: To evaluate longitudinal vision-related quality of life (VRQoL) in patients with noninfectious uveitis. DESIGN: Cohort study using randomized controlled trial data. PARTICIPANTS: Patients with active or recently active intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Steroid Treatment Trial and Follow-up Study. METHODS: Data from the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) for the first 3 years after randomization were evaluated semiannually. Analyses were stratified by assigned treatment (129 implants vs. 126 systemic therapies) because of substantial differences in the trajectories of VRQoL. The impact of baseline measurements of visual function (visual acuity and visual field), demographics, and disease characteristics was assessed using generalized estimating equations. MAIN OUTCOME MEASURES: Primary outcome was the NEI-VFQ-25 composite score over 3 years after randomization. RESULTS: Individuals in both treatment groups showed similar improvement in NEI-VFQ-25 scores after 3 years of follow-up (implant: 11.9 points; 95% confidence interval [CI], 8.6-15.2; P < 0.001; systemic: 9.0 points; 95% CI, 5.6-12.3; P < 0.001; P = 0.21 for interaction). Individuals in the implant group showed a substantial improvement during the first 6 months followed by stable scores, whereas individuals in the systemic group showed a steady improvement over the course of follow-up. Worse initial visual acuity and visual fields were associated with lower initial NEI-VFQ-25 scores for both treatment groups. In the systemic group, these differences were maintained throughout follow-up. In the implant group, individuals with initial visual acuity worse than 20/40 showed additional improvement in NEI-VFQ-25 score to come within -7 points (95% CI, -15.0 to 0.9) of those with visual acuity 20/40 or better initially, a clinically meaningful but not statistically significant difference (P = 0.081). Results based on sensitivity analyses showed similar patterns. CONCLUSIONS: Both treatment groups demonstrated significant improvements in NEI-VFQ-25 scores; however, the improvement was immediate for the implant group as opposed to gradual for the systemic group. Poorer visual function was associated significantly with initial differences in NEI-VFQ-25 scores. However, only individuals in the implant group with poor visual acuity were able to overcome their initial deficits by the end of 3 years.

Corneal Endothelium in Patients with Anterior Uveitis.

PURPOSE: To investigate a possible effect of intraocular inflammation on corneal endothelium by describing corneal endothelial cell density (ECD) and morphologic variables in eyes with anterior uveitis, and to investigate factors that may influence these findings. DESIGN: Cross-sectional, observational study. Observers were not masked. PARTICIPANTS: Volunteers with histories of unilateral or bilateral anterior segment inflammation (anterior, intermediate, or panuveitis); included were 52 patients (84 eyes with uveitis). METHODS: Endothelial cell density and morphologic variables of both eyes of all study participants were determined by specular microscopy; central corneal thickness was determined by ultrasound pachymetry. MAIN OUTCOME MEASURES: Central corneal ECD, coefficient of variability, percentage hexagonality, and central corneal thickness. RESULTS: Central ECD was lower among eyes that had undergone cataract or glaucoma surgery or both (n = 28; P = 0.0004). After exclusion of eyes with surgery, variables for eyes with uveitis (n = 56) were compared with 2 historical populations of normal, age-matched controls and with contralateral eyes in individuals with unilateral uveitis. Central ECD was lower in eyes with uveitis than in control eyes for all age groups (P ≤ 0.01 for four of six 10-year age intervals compared with the primary control group). Among patients with unilateral uveitis who had not undergone surgery in either eye (n = 12), central ECD was lower in eyes with uveitis (2324 cells/mm(2) [range, 1543-3289 cells/mm(2)]) than in contralateral eyes (2812.5 cells/mm(2) [range, 1887-3546 cells/mm(2)]; P = 0.0005), and percentage hexagonality was lower in eyes with uveitis (54% [range, 33%-66%]) than in contralateral eyes (58.5% [range, 52%-82%]; P = 0.004). There was no significant difference in central corneal thickness between eyes with and without uveitis (P = 0.27). No eyes had clinically apparent central corneal edema. Relationships remained unchanged after exclusion of eyes with herpetic anterior uveitis. Host and disease-related characteristics were evaluated as risk factors for variations in outcome measures. Central ECD was correlated to the duration of active uveitis (r = -0.41; P < 0.0001), maximum intraocular pressure during the course of disease (r = -0.40; P = 0.0002), and maximum laser flare photometry value (r = -0.26; P = 0.020). CONCLUSIONS: Observed relationships suggest that anterior segment inflammation adversely affects the corneal endothelium. Longitudinal studies are warranted to determine whether long-standing anterior uveitis increases risk of endothelial dysfunction, especially in the setting of intraocular surgery.

Ocular toxoplasmosis in the United States: recent and remote infections.

We tested all samples from patients with ocular toxoplasmosis sent to the Palo Alto Medical Foundation Toxoplasma Reference Laboratory from June 2004 through August 2010 for serologic evidence of recent Toxoplasma gondii infection. Of 205 patients aged 10-96 years, 11.7% had recent infection. Many people develop ocular disease soon after T. gondii infection.

Incidence and long-term outcomes of the human immunodeficiency virus neuroretinal disorder in patients with AIDS.

PURPOSE: Patients with AIDS have an abnormality of retina/optic nerve function, manifested as decreased contrast sensitivity (in the absence of ocular opportunistic infections or media opacity), abnormalities on automated perimetry, and loss of retinal nerve fiber layer, even among those with good visual acuity, termed the "human immunodeficiency virus (HIV) neuroretinal disorder." The objectives of this study were to determine the prevalence, incidence, risk factors, and outcomes of HIV neuroretinal disorder. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 1822 patients with AIDS without ocular infections or media opacities. METHODS: Patients with HIV neuroretinal disorder were identified by a contrast sensitivity <1.50 log units in either eye in the absence of ocular opportunistic infections or media opacity. MAIN OUTCOME MEASURES: Incidence of HIV neuroretinal disorder, mortality, visual impairment (visual acuity ≤20/50), and blindness (≤20/200) on logarithmic visual acuity charts. RESULTS: Sixteen percent of participants had HIV neuroretinal disorder at enrollment. The estimated cumulative incidence by 20 years after AIDS diagnosis was 51% (95% confidence interval [CI], 46-55). Human immunodeficiency virus neuroretinal disorder was more common in women and African Americans. Risk factors for HIV neuroretinal disorder included hepatitis C infection, low CD4+ T cells, and detectable HIV RNA in the blood. Patients with HIV neuroretinal disorder had a 70% excess mortality versus those without it, even after adjusting for CD4+ T cells and HIV load (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1; P < 0.0001). Patients with HIV neuroretinal disorder had increased risks of bilateral visual impairment (HR, 6.5; 95% CI, 2.6-10.6; P < 0.0001) and blindness (HR, 5.9; 95% CI, 2.8-13.7; P = 0.01) versus those without HIV neuroretinal disorder. CONCLUSIONS: Human immunodeficiency virus neuroretinal disorder is a common finding among patients with AIDS, and it is associated with an increased mortality and an increased risk of visual impairment. Successful antiretroviral therapy decreases but does not eliminate the risk of HIV neuroretinal disorder.

Outcome of Treatment of Uveitic Macular Edema: The Multicenter Uveitis Steroid Treatment Trial 2-Year Results.

PURPOSE: To evaluate the 2-year outcomes of uveitic macular edema. DESIGN: Longitudinal follow-up of a randomized cohort. PARTICIPANTS: At baseline, 148 eyes of 117 patients enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial had macular edema, and 134 eyes of 108 patients completed 2-year follow-up. METHODS: Patients enrolled in the study were randomized to either systemic immunosuppression or intravitreal fluocinolone acetonide implant therapy. Macular edema was defined as thickening of the retina (center point thickness≥240 µm) on time-domain optical coherence tomography (OCT) of macula. MAIN OUTCOME MEASURES: Improvement in macular edema (≥20% reduction in central point thickness on OCT), resolution of macular edema (normalization of thickness on OCT), and best-corrected visual acuity (BCVA). RESULTS: Between randomization and 2-years' follow-up, 62% and 25% of eyes in the systemic and implant groups, respectively, received at least 1 supplemental regional corticosteroid injection. By 2-years' follow-up, macular edema improved in 71% of eyes and resolved in 60%. There were no differences between treatment groups in the proportion of eyes with macular edema improving (systemic therapy vs. implant, 65% vs. 77%; P=0.20) and resolving (52% vs. 68%; P=0.28), but eyes randomized to implant had more improvement in macular thickness (median decrease of 180 vs. 109 µm in the systemic therapy group; P=0.04). Eyes with baseline fluorescein angiographic leakage were more likely to improve than those without (76% vs. 58%; P=0.03). Overall, there was a mean 5-letter (1 line) improvement in BCVA at 2 years. Mean changes in BCVA from baseline at 2 years by macular edema response status were: resolution, +10 letters; improvement without resolution, +10 letters (P=0.92); little to no change, 6 letters (P=0.19); and worsening, -16 letters (worsening acuity; P=0.0003). CONCLUSIONS: About two thirds of eyes with uveitic macular edema were observed to experience improvement in the edema and visual acuity with implant or systemic treatment. Fluocinolone acetonide implant therapy was associated with a greater quantitative improvement in thickness. Fluorescein angiography leakage was associated with a greater likelihood of improvement in macular edema.

Relationship between Human Immunodeficiency Virus Neuroretinal Disorder and Vision-Specific Quality of Life among People with AIDS.

PURPOSE: Some human immunodeficiency virus (HIV)-infected individuals have evidence of optic nerve or retinal dysfunction that manifests as decreased contrast sensitivity, even with good best-corrected visual acuity (BCVA). This condition, termed HIV-related neuroretinal disorder (HIV-NRD), is a risk factor for vision impairment (BCVA <20/40), blindness (BCVA ≤20/200), and increased mortality. We investigated the effect of HIV-NRD on vision-specific quality of life (QOL). DESIGN: Cross-sectional analysis of data from a prospective, observational study. PARTICIPANTS: Individuals from the Longitudinal Study of the Ocular Complications of AIDS cohort who completed the National Eye Institute 25-item Visual Function Questionnaire (VFQ-25), had BCVA of 20/40 or better, and had no evidence of ocular opportunistic infection or cataract. METHODS: We compared QOL by HIV-NRD status, adjusting for potential confounding variables, using multiple linear regression. Among those with HIV-NRD, we assessed the relationship between VFQ-25 and the logarithm of contrast sensitivity (logCS), using Spearman correlation. We defined a minimum clinically important difference (MCID) as 1 standard error of measurement from a well-characterized, historical population of individuals with a variety of ophthalmic disorders. MAIN OUTCOME MEASURES: Subscales and composite VFQ-25 scores (0 = worst, 100 = best). RESULTS: A total of 813 individuals met study criteria. Those with HIV-NRD (n = 39 [4.8%]) had a lower mean composite score than those without HIV-NRD (81 vs. 89; P = 0.0002) and lower mean scores in the following subscales: near activities (77 vs. 86; P = 0.004), distance activities (85 vs. 91; P = 0.01), social functioning (89 vs. 96; P = 0.0005), mental health (75 vs. 87; P = 0.0001), dependency (81 vs. 94; P < 0.0001), driving (75 vs. 85; P = 0.02), color vision (90 vs. 97; P < 0.0001), and peripheral vision (85 vs. 91; P = 0.0496). Score differences for each of these subscales met criteria for MCID. Among those with HIV-NRD, there was a positive correlation between logCS and composite score (r = 0.36; 95% confidence interval, 0.04-0.60). CONCLUSIONS: HIV-NRD has a statistically significant and clinically meaningful association with decreased vision-specific QOL among people with AIDS and good BCVA.

Uveitis in human immunodeficiency virus-infected persons with CD4+ T-lymphocyte count over 200 cells/mL.

BACKGROUND: Introduction of highly active antiretroviral therapy has altered the course of disease for persons infected with human immunodeficiency virus by elevating CD4+ T-lymphocyte levels. Changes in the spectrum of systemic diseases encountered in human immunodeficiency virus-positive individuals are reported in the general medical literature. DESIGN: Retrospective case series. PARTICIPANTS: Sixty-one individuals infected with human immunodeficiency virus, who presented with uveitis when the peripheral CD4+ T-lymphocyte count was over 200 cells/µL. METHODS: Standardized data collection at seven tertiary-referral inflammatory eye disease clinics. MAIN OUTCOME MEASURES: Standardization of Uveitis Nomenclature anatomic classification and descriptors, cause of uveitis, and visual acuity RESULTS: Peripheral CD4+ T cell counts varied between 207 and 1777 (median = 421) cells/µL at the time of diagnosis of uveitis. Uveitis was classified anatomically as anterior (47.5%), intermediate (6.6%), anterior/intermediate (16.4%), posterior (14.8%) and pan (14.8%). Specific causes of uveitis included infections (34.4%), with syphilis responsible for 16.4% of all cases, and defined immunological disorders (27.0%); no cause for the inflammation was identified in 34.4% of persons. Visual acuity was better than 6/15 in 66.7% and 6/60 or worse in 11.8% of 93 eyes at presentation, and better than 6/15 in 82.4% and 6/60 or worse in 8.8% of 34 eyes at 1 year of follow-up. CONCLUSIONS: Both infectious and non-infectious forms of uveitis occur in individuals who are infected with human immunodeficiency virus and have preserved or restored peripheral CD4+ T cell levels. Individuals who are human immunodeficiency virus-positive and present with uveitis should be evaluated in the same way all patients with uveitis are assessed.

Burden of HIV-related cytomegalovirus retinitis in resource-limited settings: a systematic review.

BACKGROUND: Cytomegalovirus (CMV) is a late-stage opportunistic infection in people living with human immunodeficiency virus (HIV)/AIDS. Lack of ophthalmological diagnostic skills, lack of convenient CMV treatment, and increasing access to antiretroviral therapy have all contributed to an assumption that CMV retinitis is no longer a concern in low- and middle-income settings. METHODS: We conducted a systematic review and meta-analysis of published and unpublished studies reporting prevalence of CMV retinitis in low- and middle-income countries. Eligible studies assessed the occurrence of CMV retinitis by funduscopic examination within a cohort of at least 10 HIV-positive adult patients. RESULTS: We identified 65 studies from 24 countries, mainly in Asia (39 studies, 12 931 patients) and Africa (18 studies, 4325 patients). By region, the highest prevalence was observed in Asia with a pooled prevalence of 14.0% (11.8%-16.2%). Almost a third (31.6%, 95% confidence interval [CI], 27.6%-35.8%) had vision loss in 1 or both eyes. Few studies reported immune status, but where reported CD4 count at diagnosis of CMV retinitis was <50 cells/µL in 73.4% of cases. There was no clear pattern of prevalence over time, which was similar for the period 1993-2002 (11.8%; 95% CI, 8%-15.7%) and 2009-2013 (17.6%; 95% CI, 12.6%-22.7%). CONCLUSIONS: Prevalence of CMV retinitis in resource low- and middle-income countries, notably Asian countries, remains high, and routine retinal screening of late presenting HIV-positive patients should be considered. HIV programs must ensure capacity to manage the needs of patients who present late for care.

Bilateral uveitis associated with fluoroquinolone therapy.

CONTEXT: Retrospective case series, database study and literature review. Forty case reports are described. OBJECTIVE: To report a possible association between fluoroquinolones and uveitis. MATERIALS AND METHODS: Spontaneous reports from the National Registry of Drug-Induced Ocular Side effects, World Health Organization, and Food and Drug Administration were collected on uveitis associated with systemic fluoroquinolone therapy. A literature review was performed using keywords "uveitis", "fluoroquinolones", and each individual fluoroquinolone name. Additional case reports were collected from the practices of six uveitis subspecialists and one neuro-ophthalmologist. MAIN OUTCOME MEASURES: Data garnered from the reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of uveitis, concomitant drugs, systemic disease, dechallenge and rechallenge data. RESULTS: A total of 40 case reports of uveitis associated with fluoroquinolones were identified including 12 men, 27 women, and 1 case in which the gender was not specified. The median age was 54 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 13 days (range 0-20 days). Thirteen patients were 60 years or older, and one patient was taking systemic anti-inflammatory steroids. There were five positive dechallenge case reports. DISCUSSION: According to World Health Organization criteria, the relationship between fluoroquinolone therapy and uveitis is "possible". Causality assessments are based on the time relationship of drug administration, uveitis development, and dechallenge data. CONCLUSIONS: Clinicians should be aware of a possible bilateral fluoroquinolone-associated uveitis, particularly the finding of iris transillumination and pigment dispersion.

Quantification of Anterior Chamber Cells in Children With Uveitis Using Anterior Segment Optical Coherence Tomography.

PURPOSE: To evaluate the feasibility of anterior segment optical coherence tomography (AS-OCT) for measuring anterior chamber (AC) cells in children with uveitis and to compare different AS-OCT acquisition modes. DESIGN: Validity and reliability analysis. METHODS: We enrolled children younger than 18 years who had uveitis involving the anterior segment and children without eye disease as controls. All underwent clinical grading of AC cells. AC images of each eye were obtained using the Optovue Avanti RTVue XR AS-OCT. Two acquisition modes were used: a single cross-sectional line scan and an 8-line radial scan in an asterisk pattern. Two independent, masked graders counted cells manually on AS-OCT images. Rater agreement was assessed using intraclass correlation (ICC). RESULTS: Included were 30 children (59 eyes) with uveitis (median age 13.0 years, range 3-17 years) and 20 control children (40 eyes, median age 10.5 years, range 4-17 years). The number of eyes assigned each clinical grade of cells were as follows: none, 32 (54%); 0.5+, 12 (20.3%); 1+, 5 (8.5%); 2+, 8 (13.6%); 3+, 2 (3.4%). ICC of graders for line and radial scan protocols were 0.87 and 0.90. There was no significant difference between acquisition modes for pooled grader results (95% CI for difference: -0.04 to 0.14). ICC of cell counts between line and radial scan protocols was 0.85 (95% CI: 0.69-0.90). No control eyes had cells on AS-OCT images. CONCLUSIONS: Quantification of AC cell in children with uveitis is feasible with AS-OCT and has excellent reliability between different graders and acquisition modes.

Prospective, Randomized Trial Comparing Simulator-based versus Traditional Teaching of Direct Ophthalmoscopy for Medical Students.

OBJECTIVE: To compare results of simulator-based vs traditional training of medical students in direct ophthalmoscopy. DESIGN: Randomized controlled trial. METHODS: First-year medical student volunteers completed 1 hour of didactic instruction regarding direct ophthalmoscopes, fundus anatomy, and signs of disease. Students were randomized to an additional hour of training on a direct ophthalmoscope simulator (n = 17) or supervised practice examining classmates (traditional method, n = 16). After 1 week of independent student practice using assigned training methods, masked ophthalmologist observers assessed student ophthalmoscopy skills (technique, efficiency, and global performance) during examination of 5 patient volunteers, using 5-point Likert scales. Students recorded findings and lesion location for each patient. Two masked ophthalmologists graded answer sheets independently using 3-point scales. Students completed surveys before randomization and after assessments. Training groups were compared for grades, observer- and patient-assigned scores, and survey responses. RESULTS: The simulator group reported longer practice times than the traditional group (P = .002). Observers assigned higher technique scores to the simulator group after adjustment for practice time (P = .034). Combined grades (maximum points = 20) were higher for the simulator group (median: 5.0, range: 0.0-11.0) than for the traditional group (median: 4.0, range: 0.0-9.0), although the difference was not significant. The simulator group was less likely to mistake the location of a macular scar in 1 patient (odds ratio: 0.28, 95% confidence interval: 0.056-1.35, P = .013). CONCLUSIONS: Direct ophthalmoscopy is difficult, regardless of training technique, but simulator-based training has apparent advantages, including improved technique, the ability to localize fundus lesions, and a fostering of interest in learning ophthalmoscopy, reflected by increased practice time.

Assessing the Validity and Reliability of the Effects of Youngsters' Eyesight on Quality of Life Questionnaire Among Children With Uveitis.

OBJECTIVE: The Effects of Youngsters' Eyesight on Quality of Life (EYE-Q) questionnaire measures vision-related functioning (VRF) and vision-related quality of life (VRQoL) in children with uveitis. Our aim was to revise the alpha version of the EYE-Q to refine VRF and VRQoL subscales and to assess the validity of the EYE-Q. METHODS: Children with juvenile idiopathic arthritis (JIA), JIA-associated uveitis, and other noninfectious uveitis were enrolled. Patients and parents completed the EYE-Q, Pediatric Quality of Life Inventory (overall quality of life), and Childhood Health Assessment Questionnaire (physical functioning). The development site completed the alpha version of the EYE-Q, and the composite sites completed the beta version. We compared item-subscale correlations, internal consistency, and construct and discriminant validity among the different versions. RESULTS: Of the 644 patients enrolled, 61.6% completed the alpha version, and 38.4% the beta version of the EYE-Q. Mean ± SD patient age was 11.1 ± 4.2 years, and 70% were female. Fewer White patients (73.5%) completed the alpha version compared to the beta version (86.2%; P < 0.001). With the exception of patient-reported VRF, both versions had similar item-subscale correlations. Version comparisons on scale internal consistencies indicated significant differences for parent- and patient-reported VRF, but each scale had a Cronbach's α of >0.80 beta. When data were combined, the EYE-Q showed significant differences between JIA-only and uveitis patients on all parent and patient scores, except for patient-reported VRF. CONCLUSION: The EYE-Q appears to be a valid measure of VRF and VRQoL in pediatric uveitis. Our results suggest it may be used as an outcome measure in multicenter pediatric uveitis studies.

Comprehensive Assessment of Quality of Life, Functioning, and Mental Health in Children With Juvenile Idiopathic Arthritis and Noninfectious Uveitis.

OBJECTIVE: Pediatric uveitis can lead to sight-threatening complications and can impact quality of life (QoL) and functioning. We aimed to examine health-related QoL, mental health, physical disability, vision-related functioning (VRF), and vision-related QoL in children with juvenile idiopathic arthritis (JIA), JIA-associated uveitis (JIA-U), and other noninfectious uveitis. We hypothesized that there will be differences based on the presence of eye disease. METHODS: A multicenter cross-sectional study was conducted at four sites. Patients with JIA, JIA-U, or noninfectious uveitis were enrolled. Patients and parents completed the Pediatric Quality of Life Inventory (PedsQL; health-related QoL), the Revised Childhood Anxiety and Depression Scale (RCADS; anxiety/depression), the Childhood Health Assessment Questionnaire (C-HAQ; physical disability), and the Effects of Youngsters' Eyesight on Quality of Life (EYE-Q) (VRF/vision-related QoL). Clinical characteristics and patient-reported outcome measures were compared by diagnosis. RESULTS: Of 549 patients, 332 had JIA, 124 had JIA-U, and 93 had other uveitis diagnoses. Children with JIA-U had worse EYE-Q scores compared to those with JIA only. In children with uveitis, those with anterior uveitis (JIA-U and uveitis only) had less ocular complications, better EYE-Q scores, and worse C-HAQ and PedsQL physical summary scores compared to those with nonanterior disease. In children with anterior uveitis, those with JIA-U had worse PedsQL physical summary and C-HAQ scores than anterior uveitis only. Further, EYE-Q scores were worse in children with bilateral uveitis and more visual impairment. There were no differences in RCADS scores among groups. CONCLUSION: We provide a comprehensive outcome assessment of children with JIA, JIA-U, and other uveitis diagnoses. Differences in QoL and function were noted based on underlying disease. Our results support the addition of a vision-specific measure to better understand the impact of uveitis.

Identification of an atypical strain of toxoplasma gondii as the cause of a waterborne outbreak of toxoplasmosis in Santa Isabel do Ivai, Brazil.

Multilocus DNA sequencing has identified a nonarchetypal strain of Toxoplasma gondii as the causal agent of a waterborne outbreak in Brazil in 2001. The strain, isolated from a water supply epidemiologically linked to the outbreak, was virulent to mice, and it has previously been identified as BrI. Using a serologic assay that detects strain-specific antibodies, we found that 13 (65%) of 20 individuals who were immunoglobulin (Ig) M positive during the outbreak possessed the same serotype as mice infected with the purported epidemic strain. The remaining 7 individuals, plus additional IgM-negative, IgG-positive individuals, possessed 1 of 4 novel serotypes, the most common of which matched the serotype of mice infected with strains isolated from chickens foraging near the outbreak site. The latter strains likely reflect the genetic diversity of T. gondii circulating in highly endemic regions of Brazil. The serotyping assay proved a useful tool for identification of specific individuals infected with the outbreak agent.