2022

Cerebral visual impairment (CVI) is a brain-based disorder associated with the maldevelopment of central visual pathways. Individuals with CVI often report difficulties with daily visual search tasks such as finding a favorite toy or familiar person in cluttered and crowded scenes. We developed two novel virtual reality (VR)-based visual search tasks combined with eye tracking to objectively assess higher order processing abilities in CVI. The first (virtual toybox) simulates a static object search, while the second (virtual hallway) represents a dynamic human search task. Participants were instructed to search for a preselected target while task demand was manipulated with respect to the presence of surrounding distractors. We found that CVI participants (when compared to age-matched controls) showed an overall impairment with visual search on both tasks and with respect to all gaze metrics. Furthermore, CVI participants showed a trend of worsening performance with increasing task demand. Finally, search performance was also impaired in CVI participants with normal/near normal visual acuity, suggesting that reduced stimulus visibility alone does not account for these observations. This novel approach may have important clinical utility in helping to assess environmental factors related to functional visual processing difficulties observed in CVI.

SIGNIFICANCE: Binocular treatment for unilateral amblyopia is an emerging treatment that requires evaluation through a randomized clinical trial. PURPOSE: To compare change in amblyopic eye visual acuity (VA) in children aged 4 to 6 years treated with the dichoptic binocular Dig Rush iPad game plus continued spectacle correction vs. continued spectacle correction alone. METHODS: Children (mean 5.7 years) were randomly assigned to home treatment for 8 weeks with the iPad game (n = 92, prescribed 1 hour/day, 5 days/week or continued spectacle correction alone n = 90) in a multi-center randomized clinical trial. Prior to enrollment, children wearing spectacles were required to have at least 16 weeks of wear or no improvement in amblyopic-eye VA (< 0.1 logMAR) for at least 8 weeks. Outcome was change in amblyopic-eye VA from baseline to 4 weeks (primary) and 8 weeks (secondary) assessed by masked examiner. RESULTS: 182 children with anisometropic (63%), strabismic (16%) (<5[INCREMENT] near, simultaneous prism and cover test), or combined-mechanism (20%) amblyopia (20/40 to 20/200, mean 20/63) were enrolled. After 4 weeks, mean amblyopic VA improved 1.1 logMAR lines with binocular treatment and 0.6 logMAR lines with spectacles alone (adjusted difference = 0.5 lines; 95.1% CI: 0.1 to 0.9). After 8 weeks, results (binocular treatment: mean amblyopic-eye VA improvement = 1.3 logMAR lines vs. 1.0 logMAR lines with spectacles alone, adjusted difference = 0.3 lines; 98.4% CI: -0.2 to 0.8) were inconclusive because the confidence interval included both zero and the pre-defined difference in mean VA change of 0.75 logMAR lines. CONCLUSIONS: In 4- to 6-year-old children with amblyopia, binocular Dig Rush treatment resulted in greater improvement in amblyopic-eye VA over 4 weeks but not 8 weeks. Future work is required to determine if modifications to the contrast increment algorithm or other aspects of the game or its implementation could enhance the treatment effect.

Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.

PURPOSE: To evaluate the relationship between the occurrence of optic disc hemorrhages (DH) and glaucoma progression as determined by multiple glaucoma testing modalities. DESIGN: Prospective cohort study. METHODS: A longitudinal study was undertaken of 124 open-angle glaucoma patients who had yearly disc photography, visual fields (VFs), spectral-domain optical coherence tomography (SD-OCT), retinal nerve fiber layer (RNFL) thickness scans, and optic nerve volume scans (Spectralis), all performed on the same day over a 5-year period. The minimum distance band (MDB) thickness, a 3-dimensional (3D) neuroretinal rim parameter, was calculated from optic nerve volume scans. Patients were classified as glaucoma progressors or glaucoma nonprogressors using event-based analysis. RESULTS: Of 124 open-angle glaucoma patients, 19 (15.3%) had 1 or more DHs on yearly disc photographs. Presence of a DH was associated with localized 3D neuroretinal rim thickness progression (superior MDB progression; odds ratio: 3.96; P = .04) but not with global or inferior MDB progression (P = .14 and .81, respectively), DP progression (P = .08), VF progression (P = .45), or RNFL global, inferior, or superior progression (P = .17, .26, and .76, respectively). In the majority of patients with MDB progression (14/17 or 82%), the progression was noted before or concurrently with the first instance of DH. CONCLUSIONS: Glaucoma progression detected by high-density 3D SD-OCT neuroretinal rim measurements preceded DH occurrence in the majority of patients. These findings support the hypothesis that DHs are indicators of ongoing glaucoma progression rather than discrete events that cause subsequent progression.

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

Visual symptoms are common after concussion in children and adolescents, making it essential for clinicians to understand how to screen, identify, and initiate clinical management of visual symptoms in pediatric patients after this common childhood injury. Although most children and adolescents with visual symptoms after concussion will recover on their own by 4 weeks, for a subset who do not have spontaneous recovery, referral to a specialist with experience in comprehensive concussion management (eg, sports medicine, neurology, neuropsychology, physiatry, ophthalmology, otorhinolaryngology) for additional assessment and treatment may be necessary. A vision-specific history and a thorough visual system examination are warranted, including an assessment of visual acuity, ocular alignment in all positions of gaze, smooth pursuit (visual tracking of a moving object), saccades (visual fixation shifting between stationary targets), vestibulo-ocular reflex (maintaining image focus during movement), near point of convergence (focusing with both eyes at near and accommodation (focusing with one eye at near because any of these functions may be disturbed after concussion. These deficits may contribute to difficulty with returning to both play and the learning setting at school, making the identification of these problems early after injury important for the clinician to provide relevant learning accommodations, such as larger font, preprinted notes, and temporary use of audio books. Early identification and appropriate management of visual symptoms, such as convergence insufficiency or accommodative insufficiency, may mitigate the negative effects of concussion on children and adolescents and their quality of life.

Much of what we know about astrocyte form and function is derived from the study of gray matter protoplasmic astrocytes, whereas white matter fibrous astrocytes remain relatively unexplored. Here, we used the ribotag approach to isolate ribosome-associated mRNA and investigated the transcriptome of uninjured fibrous astrocytes from three regions: unmyelinated optic nerve head, myelinated optic nerve proper, and corpus callosum. Astrocytes from each region were transcriptionally distinct and we identified region-specific astrocyte genes and pathways. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as key differentiators of astrocyte populations. Optic nerve astrocytes expressed higher levels of neuroinflammatory pathways than corpus callosum astrocytes and we further identified CARTPT as a new marker of optic nerve head astrocytes. These previously uncharacterized transcriptional profiles of white matter astrocyte types reveal their functional diversity and a greater heterogeneity than previously appreciated.

In this study, a one-step electrochemical aptasensor was developed to detect the biomarker vascular endothelial growth factor (VEGF), an important protein in the pathogenesis of many retinal diseases, including age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion. The aptamer has a good affinity and can rapidly identify and capture VEGF based on its unique structure. We designed a VEGF aptasensor based on the aptamer recognition and complex metallo nanoenzyme particles as an electron exchange center and bridge between capture DNA and electrode. The aptamers maintained the hairpin structure to avoid nonspecific surface adsorption and expose the capture sequence outwards when the target was inexistent. Conversely, the aptamers opened the hairpin structure to release space to accomplish binding between VEGF and DNA, resulting in increased impedance. The performance of the electrochemical aptasensor is detected by electrochemical impedance spectroscopy (EIS). The limit of detection by EIS was as low as 8.2 pg ml-1, and the linear range was 10 pg ml-1-1 μg ml-1. The electrochemical aptasensor also showed high specificity and reproducibility.

Purpose: The objective of this study was to identify the prevalence of CMV ocular disease in children and to identify associated risk factors for ocular involvement. Design: Retrospective multicenter, cross-sectional study. Methods: Setting: Hospitalized patients screened for CMV viremia by PCR between 2005 and 2018 at four pediatric referral centers. Participants: Seven-hundred and ninety-three children showed CMV viremia (>135 copies/mL by polymerase chain reaction; PCR). Main Outcomes and Measures: (1) Occurrence of ophthalmologic examination. (2) Presence of CMV ocular disease, defined as retinitis, vasculitis, hemorrhage, optic nerve atrophy, or anterior uveitis in the setting of CMV viremia without other identifiable causes. Results: A total of 296/793 (37%) underwent ophthalmologic examination following CMV viremia. A total of23/296 patients (8%) had ocular symptoms prompting evaluation while the rest had eye exams for baseline screening unrelated to CMV viremia. Of these, 13 cases (4% of those with an eye exam) with ocular disease were identified (three congenital CMV, five severe combined immunodeficiency disorder (SCID) status post-stem cell transplantation, three hematologic malignancy status post-stem cell transplantation for two of them, one Evans syndrome status post-stem cell transplantation, and one medulloblastoma status post-bone marrow transplantation). No patients with solid organ transplantation developed CMV ocular disease in our cohort. Conclusion: CMV ocular disease was a rare occurrence in this cohort without an identifiable pattern across sub-groups. Excluding the three congenital CMV cases, nine out of ten patients with CMV ocular disease were status post-stem cell transplantation. We provide integrated screening guidelines based on the best available evidence for this rare condition.

PRCIS: In this prospective interventional case series that included 474 patients, there were no significant differences in visual field (VF) parameters between fields from patients tested one-at-a-time and simultaneously, except for fixation losses. PURPOSE: To test for differences in reliability and performance parameters of patients taking VF tests while using a remote patient monitoring system to supervise 1 or 2 test sessions simultaneously. METHODS: In a prospective interventional case series, 861 eyes of 474 consecutive patients undergoing automated perimetry during a 6-month period were monitored during the test using an audio/video-enabled remote monitoring system. Two patients were simultaneously tested (simultaneous test) by a single technician if they were ready for testing at the same time. Patients were otherwise tested individually (single test). Performance and reliability parameters including false negatives, false positives, fixation losses, mean deviation, pattern standard deviation, VF index, and test duration were compared between patients undergoing simultaneous tests and single tests. Patients undergoing remotely monitored testing, for whom a prior VF could be found, had performance and reliability parameters compared with those prior tests. VFs were analyzed separately for 2 test strategies: SITA Standard 24-2 and SITA Faster 24-2C. RESULTS: No significant parameter differences were observed among SITA Standard 24-2 VFs between single and simultaneous tests, except for fixation losses (single: 16.8±19.7%, simultaneous: 22.5±25.0%, P=0.01). Similarly, there were no significant differences observed among SITA Faster 24-2C tests. Paired analyses comparing remotely monitored VFs with prior traditionally monitored VFs showed no significant differences for any parameters, except for fewer fixation losses with remote monitoring (traditional: 23.6±27.5%, remote 17.7±20.8%, P=0.003). CONCLUSIONS: Remote patient monitoring of VF testing enabled technicians to supervise testing of 2 patients simultaneously with preserved performance and reliability.

PURPOSE: To determine global current practice patterns for the management of open globe injuries and identify areas of variation. DESIGN: Cross-sectional survey. METHODS: An online survey assessed global management paradigms for open globe injuries from August 2020 to January 2021. Responses were collected from experts at eye trauma centers and emergency departments worldwide who manage ≥1 open globe injury per month. The survey assessed the use/selection of antibiotics and steroids, procedural and imaging decisions, and admission practices for open globe injuries. RESULTS: Responses were received from representatives of 36 of 42 institutions (85.7%), of which 33 (78.6%) had sufficient trauma volume to be included. Included responses were distributed across North America (n=12, 36.4%), Asia (n=12, 36.4%), South America (n=4, 12.1%), Africa (n=3, 9.1%), Europe (n=1, 3.0%), and Australia (n=1, 3.0%). Preoperative systemic antibiotics for open globe injuries were administered by 75.8% (n = 25/33) of institutions, while 30.3% (n = 10/33) administered preoperative topical antibiotics. Intraoperative ophthalmic antibiotics for open globe injuries were used by 54.5% (n = 18/33) of experts. Most institutions also administered postoperative systemic antibiotics (n = 23 [69.7%]) and topical steroids (n = 29 [87.9%]), although specific medication choices diverged. At 19 responding centers (61.3% of the 31 that had trainees), residents participated in surgical repairs. Many institutions discharged patients after repair, but 54.5% (n = 18/33) of locations routinely admitted them for observation. CONCLUSIONS: Preferred management practices for open globe injuries vary widely. To ensure the highest standard of care for all patients, evidence-based international guidelines for the treatment of these injuries are needed.

Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

AIM: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. METHODS: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. RESULTS: We studied 383 children born at a median of 23.3 (range 21.9-23.9) weeks, with a median birthweight of 565 (range 340-874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). CONCLUSION: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.

Purpose: To report a case of systemic diffuse large B cell lymphoma presenting with ocular manifestations and neurologic findings resembling Vogt-Koyanagi-Harada syndrome. Observations: A 51-year-old Caucasian man presented with headache, ear pain, and blurry vision in both eyes. He was found to have bilateral exudative retinal detachments. After a short period of initial improvement with high dose systemic corticosteroid, his condition significantly worsened. An extensive work-up, including a kidney biopsy, led to a diagnosis of systemic diffuse large B cell lymphoma. He had excellent recovery following treatment with appropriate chemotherapy. Conclusions and Importance: Systemic malignancy may present with ocular manifestations and may masquerade as another diagnosis. An unexpected clinical course may suggest an alternative diagnosis. A broad systemic work-up including an evaluation for malignancy should be considered for patients presenting with unexplained exam or systemic findings.

Purpose: To evaluate efficacy of a novel risk stratification system in minimizing resident surgical complications and to evaluate whether the system could be used to safely introduce cataract surgery to earlier levels of training. Materials and Methods: This is a retrospective cross-sectional study on 530 non-consecutive cataract cases performed by residents at Columbia University. Risk scores, preoperative best corrected visual acuity (BCVA), intraoperative complications, postoperative day 1 (POD1), and month 1 (POM1) exam findings were tabulated. The relationship between risk scores and POD1 and POM1 BCVA was modeled using linear regression. The relationship between risk scores and complication rates was modeled using logistic regression. Logistic regression was used to model the rates of complications across different levels of training. Rates of complications were compared between diabetic versus non-diabetic patients using t-tests. Results: Risk scores did not have significant association with intraoperative complications. Risk scores were predictive of corneal edema (OR = 1.36, p = 0.0032) and having any POM1 complication (OR = 1.20, p = 0.034). Risk scores were predictive of POD1 (β = 0.13, p < 0.0001) and POM1 (β = 0.057, p = 0.00048) visual acuity. There was no significant association between level of training and rates of intraoperative (p = 0.9) or postoperative complications (p = 0.06). Rates of intraoperative complication trended higher among diabetic patients but was not statistically significant (p = 0.2). Conclusion: Higher risk scores were predictive of prolonged corneal edema but not risk of intraoperative complications. Our risk stratification system allowed us to safely introduce earlier phacoemulsification surgery.

OBJECTIVE: There are unmet needs for refractive correction in the pediatric population, especially in high-poverty communities. We reported the impact of refractive correction on vision outcomes over a 2-year follow-up in the Baltimore Reading and Eye Disease Study. DESIGN: Prospective, school-based cohort study. PARTICIPANTS: Students of second and third grades who were prescribed glasses during baseline assessment. METHODS: We conducted baseline eye exams in 12 Baltimore public schools during the fall of school year 2014-15 with follow-up visits in the spring of school year 2014-15 (first follow-up) and school year 2015-16 (second follow-up). Visual acuity (VA) was measured at distance and near with correction. Refractive status was determined based on the eye with the larger refractive error and categorized as myopia, hyperopia, and astigmatism. MAIN OUTCOME MEASURES: VA in better-seeing and worse-seeing eye at first and second follow-up, and acuity improvement from baseline. RESULTS: In the 206 students (84% African American) who completed the first follow-up, both distance (from 0.14 ± 0.20 to 0.05 ± 0.10 logMAR) and near presenting VA (from 0.08 ± 0.16 to 0.03 ± 0.06 logMAR) improved from the baseline assessment; children with more severe hyperopia showed improvement in near VA by 0.05 ± 0.16 logMAR. Children who were prescribed glasses through a school-based research study had improved vision, which was sustained into the following school year. CONCLUSIONS: Many second and third graders in Baltimore Schools needed refractive correction and benefited from provision of glasses with sustained vision improvement over the 2-year observation.