BACKGROUND: GAPO syndrome (growth retardation, alopecia, pseudoanodontia, optic atrophy) is a rare, autosomal recessive connective tissue disorder with only 60 reported cases. Ophthalmic manifestations vary and include hypertelorism, optic atrophy, and glaucoma. There have been three reported cases of GAPO syndrome with craniosynostosis. MATERIALS/METHODS: We describe two new siblings with GAPO syndrome and craniosynostosis and the first histopathologic analysis of Tenon's capsule and extraocular muscle in this syndrome. RESULTS: Both siblings presented with papilledema and V-pattern strabismus in addition to the alopecia, brittle eyelashes, growth retardation, and pseudoanodontia that characterize GAPO syndrome. Cranial vault expansion, though successful, was complicated by lack of distinct periosteal layers, thin dural adherence to bone, and extensive venous bleeding. Tenons encountered during strabismus surgery was inelastic and highly vascular. Histopathological analysis revealed hyalinization of Tenon's and a thickened, homogenized, amorphous appearance, similar to the extracellular matrix abnormalities described in skin and other organs Histopathological analysis of extraocular muscle was, in contrast, unremarkable. CONCLUSIONS: GAPO impacts the extracellular matrix of Tenon's resulting in inelasticity and hypervascularity. Ophthalmologists should be mindful of these aberrant characteristics when planning surgery in this population.

Metabolic dysfunction of retinal pigment epithelial cells (RPE) is a key pathogenic driver of retinal diseases such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Since RPE are highly metabolically-active cells, alterations in their metabolic status reflect changes in their health and function. High-resolution respirometry allows for real-time kinetic analysis of the two major bioenergetic pathways, glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), through quantification of the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively. The following is an optimized protocol for conducting high-resolution respirometry on primary human retinal pigment epithelial cells (H-RPE). This protocol provides a detailed description of the steps involved in producing bioenergetic profiles of RPE to define their basal and maximal OXPHOS and glycolytic capacities. Exposing H-RPE to different drug injections targeting the mitochondrial and glycolytic machinery results in defined bioenergetic profiles, from which key metabolic parameters can be calculated. This protocol highlights the enhanced response of BAM15 as an uncoupling agent compared to carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) to induce the maximal respiration capacity in RPE. This protocol can be utilized to study the bioenergetic status of RPE under different disease conditions and test the efficacy of novel drugs in restoring the basal metabolic status of RPE.

PURPOSE: To evaluate the retinal vasculature in pediatric patients with X-linked retinoschisis (XLRS) DESIGN: Retrospective consecutive case series SUBJECTS: Pediatric patients with a diagnosis of XLRS who had undergone wide-field fluorescein angiography (FA). METHODS: The electronic medical records of pediatric patients with XLRS at a tertiary referral eye center were reviewed from January 2015 to December 2021. Fluorescein angiography images were reviewed for anomalies of the retinal vasculature. MAIN OUTCOMES: Vascular anomalies on FA were recorded including capillary dropout/ischemia, terminal supernumerary vessels, vascular leakage, abnormal vascular loops, straightening of vessels, aberrant circumferential vessels, and neovascularization. RESULTS: In total, 29 eyes of 15 patients were included in the study (one patient had a phthisical eye). On FA, the most common findings were capillary dropout/ischemia (21 of 29 eyes, 72.4%), terminal supernumerary vessels (21 eyes, 72.4%), abnormal vascular loops (20 eyes, 69%), and vascular leakage (17 eyes, 58.6%). Of the 17 eyes with leakage, the most posterior zone of involvement was Zone 1 in 11 eyes (64.7%) and Zone 2 in 6 eyes (35.3%). All eyes demonstrated at least one vascular anomaly on FA. Among the 29 eyes, 23 (79.3%) demonstrated peripheral bullous schisis or retinal detachment with a mean of 5.6 clock hours of involvement. The presence of either retinal detachment or bullous retinal schisis was associated with the incidence of capillary dropout (91.3% in schisis/RD eyes vs 0% in non-schisis/RD eyes, p<0.001). Among those with retinal detachment or bullous schisis, a higher degree of involvement correlated with more severe capillary dropout (Pearson 0.49, p=0.025). CONCLUSIONS: The present study demonstrates consistent vascular changes in pediatric patients with XLRS using wide-field FA. While the presence of capillary ischemia was associated with the severity of bullous schisis or retinal detachment, other vascular anomalies were seen in patients both with and without peripheral schisis. Though further research is needed to understand the etiology of these vascular anomalies, FA should be considered in the evaluation of these patients.

PURPOSE: Artificial intelligence (AI) methods are changing all areas of research and have a variety of capabilities of analysis in ophthalmology, specifically in visual fields (VFs) to detect or predict vision loss progression. Whereas most of the AI algorithms are implemented in Python language, which offers numerous open-source functions and algorithms, the majority of algorithms in VF analysis are offered in the R language. This paper introduces PyVisualFields, a developed package to address this gap and make available VF analysis in the Python language. METHODS: For the first version, the R libraries for VF analysis provided by vfprogression and visualFields packages are analyzed to define the overlaps and distinct functions. Then, we defined and translated this functionality into Python with the help of the wrapper library rpy2. Besides maintaining, the subsequent versions' milestones are established, and the third version will be R-independent. RESULTS: The developed Python package is available as open-source software via the GitHub repository and is ready to be installed from PyPI. Several Jupyter notebooks are prepared to demonstrate and describe the capabilities of the PyVisualFields package in the categories of data presentation, normalization and deviation analysis, plotting, scoring, and progression analysis. CONCLUSIONS: We developed a Python package and demonstrated its functionality for VF analysis and facilitating ophthalmic research in VF statistical analysis, illustration, and progression prediction. TRANSLATIONAL RELEVANCE: Using this software package, researchers working on VF analysis can more quickly create algorithms for clinical applications using cutting-edge AI techniques.

IMPORTANCE: Electronic clinical decision support systems apply clinical guidelines in real time and offer a new approach to improve referral and utilization of low vision rehabilitation (LVR) care. OBJECTIVE: To characterize patients and factors associated with LVR service utilization with and without the use of an electronic health record (EHR) clinical decision support system (CDSS) alert. DESIGN, SETTING, AND PARTICIPANTS: Quality improvement study using EHR data to compare patients who did and did not utilize LVR service after referral between November 6, 2017, and October 5, 2019, (primary) and to assess overall service utilization rate from September 1, 2016, to April 2, 2021, regardless of referral status (secondary). Participants in the primary analysis were patients at a large ophthalmology department in an academic medical center in the US who received an LVR referral recommendation from their ophthalmologist according to the CDSS alert. The secondary analysis included patients with best documented visual acuity (BDVA) worse than 20/40 before, during, and after the CDSS implementation. Data were analyzed from August 2021 to April 2022. EXPOSURES: Number and locations of referral recommendations for LVR service according to the CDSS alert in the primary analysis; active CDSS implementation in the secondary analysis. MAIN OUTCOMES AND MEASURES: LVR service utilization rate was defined as the number of patients who accessed service among those who were referred (primary) and among those with BDVA worse than 20/40 (secondary). EHR data on patient demographics (age, sex, race, ethnicity) and ophthalmology encounter characteristics (numbers of referral recommendations, encounter location, and BDVA) were extracted. RESULTS: Of the 429 patients (median [IQR] age, 71 [53 to 83] years; 233 female [54%]) who received a CDSS-based referral recommendation, 184 (42.9%) utilized LVR service. Compared with nonusers of LVR, users were more likely to have received at least 2 referral recommendations (12.5% vs 6.1%; χ21 = 5.29; P = .02) and at an ophthalmology location with onsite LVR service (87.5% vs 78.0%; χ21 = 6.50; P = .01). Onsite LVR service (odds ratio, 2.06; 95% CI, 1.18-3.61) persisted as the only statistically significant factor after adjusting for patient demographics and other referral characteristics. Among patients whose BDVA was worse than 20/40 before, during, and after the CDSS implementation regardless of referral status, the LVR service utilization rate was 6.1%, 13.8%, and 7.5%, respectively. CONCLUSIONS AND RELEVANCE: In this quality improvement study, ophthalmologist referral recommendations and onsite LVR services at the location where patients receive other ophthalmic care were significantly associated with service utilization. Ophthalmology CDSSs are promising tools to apply clinical guidelines in real time to improve connection to care.

PURPOSE: The purpose of this study was to describe the genetic relationship between smoking and glaucoma. METHODS: We used summary-level genetic data for smoking initiation, smoking intensity (cigarettes per day [CPD]), intraocular pressure (IOP), vertical cup-disc ratio, and open-angle glaucoma (OAG) to estimate global genetic correlations (rg) and perform two-sample Mendelian randomization (MR) experiments that explored relations between traits. Finally, we examined associations between smoking genetic risk scores (GRS) and smoking traits with measured IOP and OAG in Rotterdam Study participants. RESULTS: We identified weak inverse rg between smoking- and glaucoma-related traits that were insignificant after Bonferroni correction. However, MR analysis revealed that genetically predicted smoking initiation was associated with lower IOP (-0.18 mm Hg per SD, 95% confidence interval [CI] = -0.30 to -0.06, P = 0.003). Furthermore, genetically predicted smoking intensity was associated with decreased OAG risk (odds ratio [OR] = 0.74 per SD, 95% CI = 0.61 to 0.90, P = 0.002). In the Rotterdam Study, the smoking initiation GRS was associated with lower IOP (-0.09 mm Hg per SD, 95% CI = -0.17 to -0.01, P = 0.04) and lower odds of OAG (OR = 0.84 per SD, 95% CI = 0.73 to 0.98, P = 0.02) in multivariable-adjusted analyses. In contrast, neither smoking history nor CPD was associated with IOP (P ≥ 0.38) or OAG (P ≥ 0.54). Associations between the smoking intensity GRS and glaucoma traits were null (P ≥ 0.13). CONCLUSIONS: MR experiments and GRS generated from Rotterdam Study participants support an inverse relationship between smoking and glaucoma. TRANSLATIONAL RELEVANCE: Understanding the genetic drivers of the inverse relationship between smoking and glaucoma could yield new insights into glaucoma pathophysiology.

Avascular peripheral retina in an infant is a common characteristic of numerous pediatric retinal vascular disorders and often presents a diagnostic challenge to the clinician. In this review, key features of each disease in the differential diagnosis, from retinopathy of prematurity, familial exudative vitreoretinopathy, Coats disease, incontinentia pigmenti, Norrie disease, and persistent fetal vasculature, to other rare hematologic conditions and telomere disorders, will be discussed by expert ophthalmologists in the field.

PURPOSE: The aim of this study was to compare outcomes between cases of Acanthamoeba keratitis (AK) diagnosed and treated with or without the use of in vivo confocal microscopy (IVCM). METHODS: We performed a retrospective comparative case series of 26 eyes of 23 patients diagnosed with AK at the Massachusetts Eye and Ear Infirmary over a 5-year period. The characteristics of all identified cases were summarized. We compared the time from presentation to diagnosis of AK (primary outcome), visual acuity, and rates of therapeutic penetrating keratoplasty between eyes diagnosed by culture-only group (n = 8) and by IVCM to diagnose AK (n = 9) and later confirmed by culture (IVCM/C group). RESULTS: The diagnostic delay was significantly longer in the culture only group (25 ± 29 days) compared with the IVCM/C group (3 ± 3 days, P < 0.01). At 6 months, there was a significant difference in best-corrected visual acuity between the culture-only group (1.46 ± 1.07, n = 7) and the IVCM/C group (0.22 ± 0.22, n = 8), after adjusting for initial baseline visual acuity (P = 0.02). Therapeutic penetrating keratoplasty was performed in 50% of culture-only (n = 7) and 11% of IVCM/C group eyes (n = 9), but this was not statistically significant (P = 0.13). CONCLUSIONS: IVCM can expedite the diagnosis of AK, and its use as an adjunct tool in the diagnosis of AK may result in better patient outcomes compared with basing treatment decisions on corneal cultures alone.

PURPOSE: To evaluate the long-term visual acuity (VA) outcome of cataract surgery in inflammatory eye disease. SETTING: Tertiary care academic centres. DESIGN: Multicentre retrospective cohort study. METHODS: A total of 1741 patients with non-infectious inflammatory eye disease (2382 eyes) who underwent cataract surgery while under tertiary uveitis management were included. Standardised chart review was used to gather clinical data. Multivariable logistic regression models with adjustment for intereye correlations were performed to evaluate the prognostic factors for VA outcomes. Main outcome measure was VA after cataract surgery. RESULTS: Uveitic eyes independent of anatomical location showed improved VA from baseline (mean 20/200) to within 3 months (mean 20/63) of cataract surgery and maintained through at least 5 years of follow-up (mean 20/63). Eyes that achieved 20/40 or better VA at 1 year were more likely to have scleritis (OR=1.34, p<0.0001) or anterior uveitis (OR=2.2, p<0.0001), VA 20/50 to 20/80 (OR 4.76 as compared with worse than 20/200, p<0.0001) preoperatively, inactive uveitis (OR=1.49, p=0.03), have undergone phacoemulsification (OR=1.45 as compared with extracapsular cataract extraction, p=0.04) or have had intraocular lens placement (OR=2.13, p=0.01). Adults had better VA immediately after surgery, with only 39% (57/146) paediatric eyes at 20/40 or better at 1 year. CONCLUSIONS: Our results suggest that adult and paediatric eyes with uveitis typically have improved VA following cataract surgery and remain stable thereafter for at least 5 years.