Cerebral/cortical visual impairment (CVI) is a leading cause of pediatric visual impairment in the United States and other developed countries, and is increasingly diagnosed in developing nations due to improved care and survival of children who are born premature or have other risk factors for CVI. Despite this, there is currently no objective, standardized method to quantify the diverse visual impairments seen in children with CVI who are young and developmentally delayed. We propose a method that combines eye tracking and an image-based generative artificial intelligence (AI) model (SegCLIP) to assess higher- and lower-level visual characteristics in children with CVI. We will recruit 40 CVI participants (aged 12 months to 12 years) and 40 age-matched controls, who will watch a series of images on a monitor while eye gaze position is recorded using eye tracking. SegCLIP will be prompted to generate saliency maps for each of the images in the experimental protocol. The saliency maps (12 total) will highlight areas of interest that pertain to specific visual features, allowing for analysis of a range of individual visual characteristics. Eye tracking fixation maps will then be compared to the saliency maps to calculate fixation saliency values, which will be assigned based on the intensity of the pixel corresponding to the location of the fixation in the saliency map. Fixation saliency values will be compared between CVI and control participants. Fixation saliency values will also be correlated to corresponding scores on a functional vision assessment, the CVI Range-CR. We expect that fixation saliency values on visual characteristics that require higher-level processing will be significantly lower in CVI participants compared to controls, whereas fixation saliency values on lower-level visual characteristics will be similar or higher in CVI participants. Furthermore, we anticipate that fixation saliency values will be significantly correlated to scores on corresponding items on the CVI Range-CR. Together, these findings would suggest that AI-enabled saliency analysis using eye tracking can objectively quantify abnormalities of lower- and higher-order visual processing in children with CVI. This novel technique has the potential to guide individualized interventions and serve as an outcome measure in future clinical trials.

BACKGROUND:Optic nerve hypoplasia (ONH), the leading congenital cause of permanent blindness, is characterized by a retinal ganglion cell (RGC) deficit at birth and frequently associated neurologic and endocrine abnormalities. Multifactorial developmental events are hypothesized to underlie ONH; however, environmental influences are unclear, and genetic causes are under-investigated. METHODS:To identify monogenic, disease-causing variants among ONH patients, exomes from 34 ONH subjects and their parents were sequenced and rare variants identified. Inheritance-modelled variants were evaluated using population frequency, pathogenicity predictions, and mutational constraint metrics. Variants with the strongest genetic effect lacked evidence that they are monogenic and causal. All rare variants were filtered using mutational constraint metrics and pathogenicity predictions. The resultant variant-harboring genes were examined for recurrence within the cohort, gene ontology over-representation, RGC expression, and coincidence with neuro developmental disorder (NDD), autism, and previously proposed ONH genes. RESULTS:Mutationally constrained genes with potentially pathogenic mutations were enriched in gene ontologies related to neuro developmental processes, were expressed in RGCs at significantly higher levels than random exome variant genes, and were enriched in autism and NDD-associated genes. Including the genes with strong genetic effect variants, these analyses call attention to 161 genes with potentially pathogenic variants that may contribute polygenic risk for ONH.

Background Cerebral/cortical visual impairment (CVI) is a leading cause of pediatric visual impairment in developed countries and is associated with neurologic conditions that may impair adaptive functioning or skills required to perform everyday tasks (eg, communication, socialization, and daily living skills). Adaptive behavior in children with CVI has not been systematically studied, and the relationship between visual function and adaptive function in CVI is unknown. Methods We prospectively recruited 49 children with CVI (mean age, 4 ± 3 years). Adaptive behavior was evaluated using the Vineland Adaptive Behavior Scale, 3rd edition (VABS-III). Visual acuity was assessed by a pediatric neuro-ophthalmologist using the six-level Visual Behavior Scale (VBS). The relationship between VBS and VABS-III scores was assessed using a Spearman correlation coefficient and a multiple regression model to correct for age, sex, and neurologic and ophthalmologic comorbidities. Results In our cohort, mean adaptive behavior scores in children with CVI were below the 1st percentile on all VABS-III domains and subdomains. Visual acuity, as assessed by VBS, was significantly associated with VABS-III total adaptive behavior composite score (P = 0.04), socialization (P = 0.03) domain, and interpersonal (P = 0.04), play and leisure (P = 0.04), and personal (P = 0.01) subdomains. Conclusions Children with CVI have significantly reduced adaptive functioning. Visual behavior is correlated with socialization and some daily living skills. Future longitudinal studies should evaluate whether adaptive functioning increases as visual acuity improves in children with CVI, which may have prognostic implications.

Introduction: Cortical or cerebral visual impairment (CVI) is a leading cause of pediatric visual impairment. However, there are limited data using validated assessments of vision-specific quality of life (VS-QOL) in these patients. The purpose of this study was to assess VS-QOL in children with CVI using the Children's Visual Function Questionnaire (CVFQ). Methods: Children with CVI (ages 12 months to 12 years) were prospectively recruited from a single pediatric neuro-ophthalmology clinic at a children's hospital, where a complete ophthalmologic examination was performed. Age-matched typically developing controls were recruited from a web-based recruitment service. Parents of participants completed the CVFQ. Overall and subscale CVFQ scores were compared between children with CVI and controls. Additionally, CVFQ scores were correlated with clinical findings in children with CVI. Results: Forty-three children with CVI and 20 controls were included in this study. CVFQ overall and all subscale scores were significantly lower in children with CVI (p < .0001). Among CVI participants, there was a borderline association between visual acuity and CVFQ overall and competence subscale (both p = .07) scores. CVI patients with strabismus had significantly worse scores on the family impact subscale than those without strabismus (p = .04). Discussion: CVI profoundly affects VS-QOL in individuals with CVI. Strabismus and CVI may have an additive impact on families. Additional studies are needed to determine whether measures of functional vision correlate with VS-QOL in children with CVI, and also to develop VS-QOL scales that are specific to concerns of families and children with CVI. Implications for Practitioners: All members of the multidisciplinary care team for individuals with CVI should be aware of the effect of this diagnosis on VS-QOL in both the child and family. Ultimately, practitioners and researchers should strive to identify interventions to improve VS-QOL in individuals with CVI.

Purpose:Cerebral/cortical visual impairment (CVI) is a leading cause of pediatric visual impairment and is frequently associated with abnormal ocular motility. Eye tracking has previously been used to characterize oculomotor function in CVI. The purpose of this study was to evaluate the utility of eye tracking in diagnosis, categorization, and prognostication of CVI. Design:Prospective longitudinal study. Participants:Thirty-nine children with CVI and 41 age-matched controls. Methods:Children with CVI underwent 4 eye tracking sessions over 1 year, and age-matched controls completed 1 eye tracking session. Fixations and saccades were labeled by the eye tracking software and used to compute 9 oculomotor features. In children with CVI, unsupervised data-driven clustering analysis using these 9 features was performed to identify 3 CVI eye tracking oculomotor groups. Clinical and demographic characteristics of eye tracking oculomotor groups were compared. Main Outcome Measures:(1) Area under the curve (AUC) for eye tracking oculomotor features in classifying patients with CVI and controls; (2) differences between 3 CVI eye tracking oculomotor groups on clinical and demographic characteristics; and (3) change in visual acuity (VA) over 1 year in 3 CVI eye tracking oculomotor groups. Results:Six oculomotor features (fixation and saccade latency, frequency, and off-screen proportion) had an AUC ≥0.90 in classifying children with CVI and controls (P < 0.0001). Cerebral/cortical visual impairment eye tracking oculomotor groups had significantly different VA (P < 0.0001) and change in VA over 1 year (P = 0.049). Patients in group B, who had the greatest improvement in VA, were younger and had higher rates of term hypoxic ischemic encephalopathy. Conclusions:Eye tracking measures of oculomotor function accurately distinguish between children with CVI and age-matched controls. Clustering analysis revealed 3 CVI eye tracking oculomotor groups with prognostic significance. Eye tracking shows promise as an objective, quantitative measure of oculomotor function in CVI that may in future be useful in both clinical practice (for longitudinal assessment, prognostication, and guiding individualized interventions) and research (as an outcome measure or method to stratify patients in clinical trials). Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

We report a case of torsional diplopia caused by presumed torsional anomalous retinal correspondence after myectomy of previously asymmetrically anteriorized inferior oblique muscles for inferior oblique overaction. Given this patient's experience, it may be prudent to operate with caution on previously anteriorized inferior oblique muscles, especially when anteriorization is performed at a very young age.

BACKGROUND:Optic nerve hypoplasia (ONH), the leading congenital cause of permanent blindness, is characterized by a retinal ganglion cell (RGC) deficit at birth. Multifactorial developmental events are hypothesized to underlie ONH and its frequently associated neurologic and endocrine abnormalities; however, environmental influences are unclear and genetic underpinnings are unexplored. This work investigates the genetic contribution to ONH RGC production and gene expression using patient induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs). MATERIALS AND METHODS:iPSCs produced from ONH patients and controls were differentiated to ROs. RGC genesis was assessed using immunofluorescence and flow cytometry. Flow-sorted BRN3+ cells were collected for RNA extraction for RNA-Sequencing. Differential gene expression was assessed using DESeq2 and edgeR. PANTHER was employed to identify statistically over-represented ontologies among the differentially expressed genes (DEGs). DEGs of high interest to ONH were distinguished by assessing function, mutational constraint, and prior identification in ONH, autism and neurodevelopmental disorder (NDD) studies. RESULTS:RGC genesis and survival were similar in ONH and control ROs. Differential expression of 70 genes was identified in both DESeq2 and edgeR analyses, representing a ~ 4-fold higher percentage of DEGs than in randomized study participants. DEGs showed trends towards over-representation of validated NDD genes and ONH exome variant genes. Among the DEGs, RAPGEF4 and DMD had the greatest number of disease-relevant features. CONCLUSIONS:ONH genetic background was not associated with impaired RGC genesis but was associated with DEGs exhibiting disease contribution potential. This constitutes some of the first evidence of a genetic contribution to ONH.

PURPOSE:To identify clinical and sociodemographic factors associated with disparities in amblyopia treatment outcomes. DESIGN:Retrospective chart review. PARTICIPANTS:Children ≤ 8 years of age diagnosed and treated for unilateral refractive or strabismic amblyopia at our institution from 2012 to 2022. METHODS:Children with amblyopia were categorized by outcome: resolved amblyopia (< 0.2 logarithm of the minimum angle of resolution [logMAR] interocular difference [IOD] in visual acuity [VA] or no fixation preference in nonverbal patients) or persistent amblyopia. Demographic and clinical data were recorded from the medical record. Zip codes were used to calculate Childhood Opportunity Index (COI) scores, estimated annual household income, and distance to hospital. MAIN OUTCOME MEASURES:Sociodemographic and clinical factors were compared between children with resolved and persistent amblyopia. Factors significant at P < 0.10 on univariate analysis were included in a multivariable regression model. RESULTS:A total of 168 patients met inclusion criteria, and 131 patients (78%) had resolved amblyopia. Demographic factors associated with resolution of amblyopia were younger age at diagnosis (3.3 ± 1.7 years vs. 4.5 ± 1.9 years; P = 0.0009), English as the primary language (79.4% vs. 62.2%; P = 0.04), higher estimated annual income ($83 315.93 ± $29 276.64 vs. $71 623.00 ± $26 842.56; P = 0.03), higher COI scores (50.9 ± 27.3 vs. 40.0 ± 26.4; P = 0.03), and living farther from our institution (28.6 ± 37.6 miles vs. 14.9 ± 12.7 miles; P = 0.003). Patients with resolved amblyopia also had higher rates of treatment compliance (83.2% ± 25.0% vs. 75.6% ± 24.4%; P = 0.009) and shorter delays in follow-up (40.1 ± 76.8 days vs. 61.1 ± 90.4 days; P = 0.02). Amblyopia persistence was borderline associated with governmental insurance and higher presenting IOD in VA (both P = 0.06). On multivariate analysis, only younger age at amblyopia diagnosis (P = 0.0010) remained significantly associated with amblyopia resolution. CONCLUSIONS:Our findings suggest that disparities in amblyopia outcomes are related to differences in age at diagnosis. Interventions to lower the age at which amblyopia is diagnosed, such as programs to improve vision screening rates and access to pediatric eye care in at-risk groups, may directly address inequities in rates of amblyopia resolution. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found after the references.

center dot PURPOSE: To compare eye tracking and Teller acuity cards (TAC) for assessment of visual acuity in children center dot METHODS: We recruited 41 children with CVI from a single academic pediatric neuro-ophthalmology clinic. All children performed eye tracking to measure visual acuity, and 26 children completed TAC assessment by a masked examiner. Additionally, 2 pediatric neuroophthalmologists graded visual behavior using the 6-level Visual Behavior Scale (VBS). Eye tracking and TAC were performed at baseline and at 1 month. Test-retest reliability of eye tracking and TAC were assessed using and TAC visual acuities were correlated with one another and VBS scores using the Spearman correlation coefficient. center dot RESULTS: Test-retest reliability was excellent for eye tracking measurement of visual acuity (ICC = 0.81, P < .0001). For pediatric CVI, TAC test-retest reliability was fair (ICC = 0.42, P = .04). There was a moderate correlation between eye tracking and TAC ( r = 0.43, P = .03) and between TAC and VBS score ( r = 0.50, P = .009), and a strong correlation between eye tracking grating acuity and VBS score ( r = 0.72, P < .0001). center dot CONCLUSIONS: In our cohort of children with CVI, grating acuity measured by eye tracking demonstrated higher test-retest reliability and stronger correlation with pediatric neuro-ophthalmologic assessment of visual behavior than Teller acuity. Objective determination of gaze direction by an eye tracking camera may be more accurate than human assessment in this population. Future research is needed to determine the optimal methods of longitudinal assessment of visual function and functional vision in children with CVI. (Am J Ophthalmol 2024;260: 115-121. (c) 2023 Elsevier Inc. All rights reserved.)

Abstract BACKGROUND NF1-OPGs are amorphous tumors involving either single or multiple locations (optic nerve, chiasm, tract) along the anterior visual pathway (AVP). In this prospective study, we investigated how volumetric MRI measures of the AVP as well as other clinical variables are associated with treatment decisions in children with newly diagnosed NF1-OPGs. METHODS Children with newly diagnosed NF1-OPG whose MRI included a T1-weighted volumetric sequence without significant artifact at their enrollment visit were eligible for inclusion. All subjects underwent a quantitative ophthalmic exam to determine if visual acuity (VA) was normal. The neuro-oncologist/NF1 expert determined whether the subject would be observed or undergo treatment at that baseline visit. Volumetric MRI analysis was automatically performed using a deep learning network that measured AVP volume (mm3). Non-parametric group comparisons and multivariable logistic regression models evaluated the impact of age at enrollment, sex, NF1 inheritance type, AVP volume, and VA on the decision for immediate treatment with chemotherapy versus observation. RESULTS One-hundred twenty-three subjects met inclusion criteria. Subjects assigned to observation (N=112, 44% female) and subjects immediately treated with chemotherapy (N=11, 80% female) at enrollment were of similar age (2.7 and 2.8 years, respectively) and inheritance (p > 0.05). Abnormal VA was present more often in the treatment group (46%) compared to the observation group (17%, p <0.001). AVP volume was significantly greater in the treatment group (4,181.1mm3) compared to the observation group (1,819.8mm3, p <0.001). AVP volume, sex, and VA reached significance in univariable regression, however, in the multivariable regression model only the AVP volume (p < 0.001) was significantly associated with treatment initiation. DISCUSSION Children with greater NF1-OPG AVP volumes are treated more often compared with those with lower volumes. Volumetric measures of NF1-OPGs are a valuable metric in understanding treatment patterns and are positioned to help inform clinical decision making.