Frequency and Distribution of Ophthalmic Surgical Procedures among Patients with Inherited Retinal Diseases.

OBJECTIVE: In this study, we aimed to characterize the frequency and distribution of ocular surgeries in patients with inherited retinal diseases (IRDs) and evaluate associated patient and disease factors. DESIGN: Retrospective cohort. PARTICIPANTS: Subjects aged ≥ 18 years who were followed at the Johns Hopkins Genetic Eye Disease Center. METHODS: We studied a retrospective cohort of patients with an IRD diagnosis to analyze the occurrence of laser and incisional surgeries. Subjects were categorized into 2 groups: central dysfunction (macular/cone/cone-rod dystrophy, "MCCRD group") and panretinal or peripheral dysfunction (retinitis pigmentosa-like, "RP group"). Genetic testing status was recorded. The association of patient and disease factors on the frequency, distribution, and timing of surgeries was analyzed. MAIN OUTCOME MEASURES: Prevalence, prevalence odds ratio (POR), hazard ratio (HR) of ophthalmic procedures by phenotype. RESULTS: A total of 1472 eyes of 736 subjects were evaluated. Among them, 31.3% (n = 230) had undergone ocular surgery, and 78.3% of those (n = 180/230) had a history of more than 1 surgery. A total of 602 surgical procedures were analyzed. Cataract extraction with intraocular lens implantation (CEIOL) was the most common (51.2%), followed by yttrium aluminum garnet capsulotomy, refractive surgery, retinal surgery, and others. Cataract extraction with intraocular lens implantation occurred more frequently in RP than in MCCRD subjects (POR, 2.59; P = 0.002). Retinitis pigmentosa subjects underwent CEIOL at a younger age than patients with MCCRD (HR, 2.11; P < 0.001). CONCLUSIONS: Approximately one-third of patients with IRD had a history of laser or incisional surgery. Cataract extraction with intraocular lens implantation was the most common surgery; its frequency and timing may be associated with the IRD phenotype. This data may inform the design of prospective research. Such efforts may illuminate routine clinical decision-making and contribute to surgical strategy development for cell and gene therapy delivery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Automated identification of fleck lesions in Stargardt disease using deep learning enhances lesion detection sensitivity and enables morphometric analysis of flecks.

PURPOSE: To classify fleck lesions and assess artificial intelligence (AI) in identifying flecks in Stargardt disease (STGD). METHODS: A retrospective study of 170 eyes from 85 consecutive patients with confirmed STGD. Fundus autofluorescence images were extracted, and flecks were manually outlined. A deep learning model was trained, and a hold-out testing subset was used to compare with manually identified flecks and for graders to assess. Flecks were clustered using K-means clustering. RESULTS: Of the 85 subjects, 45 were female, and the median age was 37 years (IQR 25-59). A subset of subjects (n=41) had clearly identifiable fleck lesions, and an AI was successfully trained to identify these lesions (average Dice score of 0.53, n=18). The AI segmentation had smaller (0.018 compared with 0.034 mm2, p<0.001) but more numerous flecks (75.5 per retina compared with 40.0, p<0.001), but the total size of flecks was not different. The AI model had higher sensitivity to detect flecks but resulted in more false positives. There were two clusters of flecks based on morphology: broadly, one cluster of small round flecks and another of large amorphous flecks. The per cent frequency of small round flecks negatively correlated with subject age (r=-0.31, p<0.005). CONCLUSIONS: AI-based detection of flecks shows greater sensitivity than human graders but with a higher false-positive rate. With further optimisation to address current shortcomings, this approach could be used to prescreen subjects for clinical research. The feasibility and utility of quantifying fleck morphology in conjunction with AI-based segmentation as a biomarker of progression require further study.

Association of Sociodemographic Characteristics with Pediatric Vision Screening and Eye Care: An Analysis of the 2021 National Survey of Children's Health.

PURPOSE: Vision screening and regular eye care can help detect and treat potentially irreversible vision impairment. This study aims to investigate the associations between sociodemographic and health characteristics and the receipt of eye care among children aged 17 years and younger in the United States. DESIGN: This cross-sectional study used data from the National Survey of Children's Health (NSCH), a nationally representative and population-based survey of randomly sampled households. PARTICIPANTS: Participants were children aged 0 to 17 years, residing in all 50 states and the District of Columbia, whose caregivers or parents answered an address-based survey by mail or online. METHODS: Weighted prevalence calculations were applied to analyze the data, and logistic regression was performed to explore associations between reported eye care and demographic, health, and parent-related variables. MAIN OUTCOME MEASURES: Caregiver-reported vision screenings, referral to an eye doctor after vision screening, eye doctor visits, and prescription of corrective lenses. RESULTS: Caregivers reported that 53.2% of children had a vision screening at least once (if child ≤ 5 years) or within the past 2 years (if child > 5 years). Of those screened, 26.9% were referred to an eye doctor. Overall, 38.6% of all children had a previous eye doctor visit, and among them, 55.4% were prescribed corrective lenses during the visit. Factors associated with decreased odds of vision screening included younger age, lack of health care visits, no insurance coverage, parent education high school or less, and lower household income. Non-White ethnicities, households with a non-English primary language, and lower incomes were more likely to be referred to an eye doctor after vision screening. Lower rates of eye doctor visits were associated with younger age, lack of insurance coverage, and primary household languages other than English. CONCLUSIONS: Children from disadvantaged backgrounds are less likely to receive vision screening and eye care. Targeted strategies are needed to increase vision screening and access to eye care services in these vulnerable groups. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Addressing Health Disparities in Pediatric Eye Care for School-Age Children: A Call to Action.

Disparities in access to pediatric eye care among school-age children pose significant challenges to their health and well-being; addressing these disparities will necessitate coordination across multiple systems. Although vision screenings are mandated in most US states, differences persist in terms of who receives screenings and subsequent follow-up care. Racial, ethnic, and socioeconomic factors exacerbate the issue, with potential ramifications of unaddressed eye problems on learning performance and the risk of widening preexisting educational disparities. To address these challenges, various initiatives and strategic plans have emphasized the need to improve access, enhance diversity in the workforce, and promote health literacy. School-based vision programs (SBVPs) have shown promise in improving access to care and academic outcomes, but issues with integration into the health care system exist. This article explores opportunities to address structural barriers, establish resilient and equitable systems for delivering pediatric eye care to school-age children, and leverage the success of SBVPs to build stronger connections with community providers. Proposed strategies include developing standardized guidelines; establishing referral mechanisms; fostering communication with parents, teachers, and community providers; and promoting eye health literacy across the school community. Collectively, these measures aim to improve health outcomes, address social determinants of health, and reduce disparities in access to care.

Treating patients with geographic atrophy: are we there yet?

Geographic atrophy (GA) is a progressive degenerative disease that significantly contributes to visual impairment in individuals aged 50 years and older. The development of GA is influenced by various modifiable and non-modifiable risk factors, including age, smoking, and specific genetic variants, particularly those related to the complement system regulators. Given the multifactorial and complex nature of GA, several treatment approaches have been explored, such as complement inhibition, gene therapy, and cell therapy. The recent approval by the Food and Drug Administration of pegcetacoplan, a complement C3 inhibitor, marks a significant breakthrough as the first approved treatment for GA. Furthermore, numerous interventions are currently in phase II or III trials, alongside this groundbreaking development. In light of these advancements, this review provides a comprehensive overview of GA, encompassing risk factors, prevalence, genetic associations, and imaging characteristics. Additionally, it delves into the current landscape of GA treatment, emphasizing the latest progress and future considerations. The goal of starting this discussion is to ultimately identify the most suitable candidates for each therapy, highlight the importance of tailoring treatments to individual cases, and continue monitoring the long-term implications of these emerging interventions.

Very Large Cystoid Macular Lesions Identified Using Outlier Analysis of Genetically Confirmed Inherited Retinal Disease Cases.

BACKGROUND: Cystoid macular lesions (CML) in inherited retinal diseases (IRDs) can contribute to vision impairment. Studying the morphologic range and outlier presentations of CML may inform clinical associations, mechanistic research, and trial design. Thus, we aim to describe the distribution of optical coherence tomography (OCT) parameters in IRD cases with CML and identify phenotype-genotype associations in very large cystoid macular lesions (VLCML). MATERIALS AND METHODS: This cross-sectional study retrieved clinical information from electronic records from January 2020 to December 2021. VLCML cases were identified using the robust distance (Mahalanobis) of the correlation between central foveal thickness (CFT) and total macular volume (TMV) and a 99.9% probability ellipse. The distribution of OCT parameters was calculated by genotype and phenotype. RESULTS: We included 173 eyes of 103 subjects. The median age was 55.9 (interquartile range [IQR], 37.9, 63.7) and 47.6% (49/103) were females. Patients had disease-causing mutations in 30 genes. The most common genes included USH2A (n = 18), RP1 (n = 12), and ABCA4 (n = 11). Robust distance analysis showed that the prevalence of VLCML was 1.94% (n = 2 patients, 4 eyes). VLCML was seen in cases of NR2E3 (119-2A>C) and BEST1 (1120_1121insG) mutations. The median CFT in cases without VLCML was 269 µm (IQR 209, 318.50) while the median for VLCML cases was 1,490 µm (IQR 1,445.50, 1,548.00) (P < .001). CONCLUSIONS: Subjects with different IRD genotypes may develop VLCMLs. Future studies could consider the range and outlier values of CML foveal thickness when determining inclusion criteria and biostatistical plans for observational and interventional studies.

Pediatric and School-Age Vision Screening in the United States: Rationale, Components, and Future Directions.

Pediatric vision screening detects children at risk for visual conditions with the goal of connecting those in need with an eye care provider for evaluation and treatment. The primary aim for vision screening in younger children is the detection of those at risk for amblyopia, which can result in irreversible vision loss if left untreated. In older children, screening goals broaden to include the detection of risk for uncorrected refractive error. In the United States, professional organization guidelines and state-mandated requirements for vision screening vary widely across both the timing and components of screening. In this article, we describe the goals and components of pediatric vision screenings, current challenges, novel approaches to providing follow-up services through school-based vision programs, and future directions.

Missed Vision Screenings for School-Age Children During The COVID-19 Pandemic: A Survey Based Study of NASN Representatives.

During the 2020-21 academic year, COVID-19-related educational disruptions impacted school-based vision screenings. However, limited information regarding changes in vision screening and the number of students impacted has been reported. Delayed screenings can negatively impact students' referral to eye care providers, which may affect a child's ability to see clearly and academic success. This study aims to describe changes in school-based vision screening practices through a survey of National Association of School Nurses state representatives (n = 49). Among states with vision screenings mandates, participants reported that 23.7% (9/38) states waived screenings, 31.6% (12/38) continued screenings, and 36.8% (14/38) modified requirements, such as grades screened or assessments included (e.g., color vision and stereoacuity screenings). These results suggest that millions of students across the United States missed vision screenings during the 2020-21 academic year. Efforts by education and school health stakeholders should be directed towards addressing the pandemic-related disruption in vision screening.

Pharmacogenetics of taxane-induced neurotoxicity in breast cancer: Systematic review and meta-analysis.

Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.

Risk of Cystoid Macular Edema after Cataract Surgery in Retinitis Pigmentosa: An Analysis of United States Claims from 2010 to 2018.

PURPOSE: Cataract surgery is commonly performed to improve vision in patients with retinitis pigmentosa (RP). However, the risk of postoperative cystoid macular edema (CME) in RP remains unclear. Here, we leveraged a large multiyear claims database to estimate the risk of CME after cataract surgery in patients with and without RP. DESIGN: Retrospective multicenter cohort. SUBJECTS: Patients aged 18 to 65 years who underwent single-phase cataract surgery between January 1, 2020, and December 31, 2018. Identified using the IBM MarketScan claims database. METHODS: We evaluated the baseline characteristics and outcomes and estimated the hazard ratio (HR) using a multivariable mixed-effects approach. The eyes of patients with RP were categorized as group R1, and those without diagnoses of RP by the time of surgery were categorized as group R0. MAIN OUTCOME MEASURES: Incident postoperative CME in the same eye that underwent cataract extraction within 12 months of the procedure. RESULTS: We included 468 123 patients and 615 645 eyes. This included 124 eyes with RP (R1) and 615 521 without RP (R0). The mean ages were 50.5 ± 9.8 years in R1 and 57.9 ± 6.1 years in R0. The cumulative incidence of CME at 12 months was 5.8% (95% confidence interval [CI] 1.2%-10.3%) in R1, and it was 1.1% (95% CI 1.1%-1.2%) in R0. On average, CME was reported in R1 subjects 3.9 weeks later than in R0 subjects (95% CI 2.04-6.5 weeks; P <0.001). The subjects in R1 had 4.83 (95% CI 2.13-10.93, P <0.001) times the risk of CME compared to the subjects in R0. A stratified analysis showed that epiretinal membrane (ERM) decreased the risk of CME in R1 (HR 0.12 [95% CI 0.48-0.97; P = 0.004]) but increased it in R0 (HR, 4.32 [95% CI 3.13-5.95; P <0.001]). CONCLUSIONS: The cataract surgery-related risk of CME among patients with RP may be >4 times that among people without RP. Men and individuals aged 18 to 34 and 55 to 65 years may be at the greatest risk, whereas ERM may lower the risk. Further study is warranted to stratify the risk by RP genotype and phenotype and illuminate the natural history, angiographic features, and functional consequences of postoperative CME.

Spherophakia and Ectopia Lentis in a Sturge-Weber Patient: A Case Report.

Sturge-Weber syndrome (SWS) is a rare, sporadic neurocutaneous disorder, primarily characterized by port-wine stain (PWS) over the ophthalmic division of the trigeminal nerve (V1) territory (hallmark feature) and glaucoma (in 30-60% of cases). Other ocular manifestations include episcleral involvement of the PWS, choroidal vascular malformations, and iris heterochromia. Two previous reports also associated ectopia lentis concomitantly among these cases. However, here we report spherophakia as a novel ophthalmological finding in SWS. A 56-year-old female previously diagnosed with SWS presented to the outpatient clinic complaining of right-sided decreased visual acuity and pain after a fall. Phenotypically, the patient had a PWS around V1 territory and involvement of both eyelids. Previous relevant ocular history included retinal detachment without macular involvement, ocular hypertension, and phacodonesis. The slit-lamp examination showed anterior lens luxation and elevated intraocular pressure (IOP) of 40 mm Hg by tonometry. Prior to the surgical approach, the patient received hypotensive treatment for elevated IOP. After intracapsular lens extraction, measurements were consistent with spherophakia. Postoperatively, the patient underwent optical coherence tomography (OCT). There was cystic macular edema (CME) by OCT and a detached posterior hyaloid membrane. The patient fully recovered with topical treatment of bromfenac for CME. To the best of our knowledge, this is the first report of concomitant anterior lens luxation and spherophakia (novel association) in a SWS patient. Our findings supplement the differential ocular diagnoses in SWS and should be considered in the routine ocular exam, specifically of the anterior segment. CME occurred similar to otherwise healthy eyes. However, in this case, topical anti-inflammatory medications had a good response and were well-tolerated.

Assessment of CFH and HTRA1 polymorphisms in age-related macular degeneration using classic and machine-learning approaches.

BACKGROUND: CFH and HTRA1 are pivotal genes driving increased risk for age-related macular degeneration (AMD) among several populations. Here, we performed a hospital-based case-control study to evaluate the effects of three single nucleotide polymorphisms (SNPs) among Hispanics from Mexico. MATERIALS AND METHODS: 122 cases and 249 controls were genotyped using Taqman probes. Experienced ophthalmologists diagnosed AMD following the American Association of Ophthalmology guidelines. We studied CFH (rs1329428, rs203687) and HTRA1 (rs11200638) SNPs thoroughly by logistic regression models (assuming different modes of inheritance) and machine learning-based methods (ML). RESULTS: HTRA1 rs11200638 is the most significant polymorphism associated with AMD in our studied population. In a multivariate regression model adjusted for clinically and statistically meaningful covariates, the A/G and A/A genotypes increased the odds of disease by a factor of 2.32 and 7.81, respectively (P < .05) suggesting a multiplicative effect of the polymorphic A allele. Furthermore, this observation remains statistically meaningful in the allelic, dominant, and recessive models, and ML algorithms. When stratifying by phenotype, this polymorphism was significantly associated with increased odds for geographic atrophy (GA) in a recessive mode of inheritance (12.4, p < .05). CONCLUSIONS: In sum, this work supports a strong association between HTRA1 genetic variants and AMD in Hispanics from Mexico, especially with GA. Moreover, ML was able to replicate the results of conventional biostatistics methods unbiasedly.

Microspherophakia in a 47, XYY Syndrome Patient: A Case Report.

47, XYY syndrome affects males with variable phenotypic expression. Around 80-99% of affected individuals present low-set ears, malar flattening, motor delay, and tall stature. Yet, some cases lack signs or symptoms or are barely noticeable. There are four reports of ocular involvement among these individuals - one with unusual multiple retinal atrophic holes in the posterior pole, other with coloboma, an association with morning glory syndrome, and a case of congenital cataract. Here, we describe a plausible new ocular sign in a 4-year-old male with 47, XYY syndrome who was brought to the outpatient clinic for vision loss. After a complete assessment, we diagnosed a right-sided phacomorphic glaucoma and microspherophakia treated with phacoemulsification and aspiration with posterior capsulotomy and anterior vitrectomy, followed by an Ahmed valve implant for intraocular pressure control. Even though there is a low prevalence of ocular involvement in 47, XYY syndrome cases, this might reflect the rarity of the full expression of the disease leading to an underdiagnosis, added to the scarcity of cases. Microspherophakia and phacomorphic glaucoma among four others previously reported ocular findings could be looked for in 47, XYY syndrome patients.

Significant Association Between Variant in SGCD and Age-Related Macular Degeneration.

CFH and HTRA1 genes are traditional markers of increased risk of age-related macular degeneration (AMD) across populations. Recent findings suggest that additional genes-for instance, in the dystrophin-associated protein complex-might be promising markers for AMD. Here, we performed a case-control study to assess the effect of SGCD single nucleotide polymorphisms (SNPs), a member of this protein family, on AMD diagnosis and phenotype. We performed a case-control study of an under-studied population from Hispanics in Mexico City, with 134 cases with 134 unpaired controls. Cases were 60 years or older (Clinical Age-Related Maculopathy Staging (CARMS) grade 4⁻5, as assessed by experienced ophthalmologists following the American Association of Ophthalmology (AAO) guidelines), without other retinal disease or history of vitreous-retinal surgery. Controls were outpatients aged 60 years or older, with no drusen or retinal pigment epithelium (RPE) changes on a fundus exam and a negative family history of AMD. We examined SNPs in the SGCD gene (rs931798, rs140617, rs140616, and rs970476) by sequencing and real-time PCR. Genotyping quality checks and univariate analyses were performed with PLINK v1.90b3.42. Furthermore, logistic regression models were done in SAS v.9.4 and haplotype configurations in R v.3.3.1. After adjusting for clinical covariates, the G/A genotype of the SGCD gene (rs931798) significantly increases the odds of being diagnosed with AMD in 81% of cases (1.81; 95% CI 1.06⁻3.14; p = 0.031), especially the geographic atrophy phenotype (1.82; 95% CI 1.03⁻3.21; p = 0.038) compared to the G/G homozygous genotype. Moreover, the GATT haplotype in this gene (rs931798, rs140617, rs140616, and rs970476) is associated with lower odds of AMD (adjusted odds ratio (OR) 0.13; 95% CI 0.02⁻0.91; p = 0.041). SGCD is a promising gene for AMD research. Further corroboration in other populations is warranted, especially among other Hispanic ethnicities.