January 2023

In humans and non-human primates (NHPs), motion and stereopsis are processed within fine-scale cortical sites, including V2 thick stripes and their extensions into areas V3 and V3A that are believed to be under the influence of magnocellular stream. However, in both species, the relative functional organization (overlapping vs. none overlapping) of these sites remains unclear. Using high-resolution functional MRI (fMRI), we found evidence for two minimally-overlapping channels within human extrastriate areas that contribute to processing motion and stereopsis. Across multiple experiments that included different stimuli (random dots, gratings, and natural scenes), the functional selectivity of these channels for motion vs. stereopsis remained consistent. Furthermore, an analysis of resting-state functional connectivity revealed stronger functional connectivity within the two channels rather than between them. This finding provides a new perspective toward the mesoscale organization of the magnocellular stream within the human extrastriate visual cortex, beyond our previous understanding based on animal models.

Vaccines against coronavirus disease 2019 (COVID-19) have played an important global role in reducing morbidity and mortality from COVID-19 infection. While the benefits of vaccination greatly outweigh the risks, adverse events do occur. Non-ocular adverse effects of the vaccines have been well-documented, but descriptions of ophthalmic effects remain limited. This systematic review aims to provide an overview of reported cases of corneal adverse events after receiving vaccination against COVID-19 and to compile existing clinical data to bring attention to these phenomena. Our review discusses corneal graft rejection, including proposed mechanisms, herpetic keratitis, and other reported corneal complications. Ophthalmologists and primary care physicians should be aware of such possible associations.

"Blindness upon awakening" occurs in a significant proportion of patients with non-arteritic anterior ischemic optic neuropathy (NAION). This observation has led to a notion that nocturnal hypotension is a significant contributor and, perhaps, the final insult in a multifactorial process leading to the development of NAION, as has been proposed in other ischemic events like strokes, myocardial infarction, and ischemic rest pain. An extension of this concept has led to the recommendation that patients who have experienced NAION avoid taking blood pressure medications at bedtime. However, mounting evidence in the cardiology literature suggests that nocturnal hypertension is associated with increased risk of cardiovascular morbidity. In two prospective blood pressure monitoring studies in 1994 and 1999, Hayreh observed an extreme dipping pattern in nocturnal systolic blood pressure in NAION patients compared to reported normal values. Yet, two subsequent ambulatory blood pressure studies found either normal or non-dipping patterns in NAION patients. The majority of clinical trials published since 1976 that have studied nocturnal administration of antihypertensives have reported enhanced blood pressure control and reduced cardiovascular risk. Most notably, the large, prospective 2020 Hygia Chronotherapy Trial reported a statistically-significant beneficial effect of nocturnal antihypertensive dosing on cardiovascular outcomes and mortality. The controversy regarding nocturnal hypotension and NAION is of increasing relevance as there is new evidence to suggest a beneficial effect of nocturnal antihypertensive dosing in cardiovascular risk. This new information should prompt a re-evaluation of the relevant risk-to-benefit of reducing the risk of NAION on one hand, and the potential increase of cardiovascular risk on the other. Definitive resolution of this question would require a prospective, randomized control study with input from both cardiology and ophthalmology.

The authors describe the clinical and histologic findings of the clear cell variant of syringoma. Three adult female patients (age range 39-76 years old) were found to have multiple, flesh-colored lower eyelid papules, clinically consistent with syringomas, but histologically displaying abundant clear cell change. Two patients had known diagnoses of uncontrolled diabetes.

Choroidal neovascularization (CNV) causes acute vision loss in neovascular age-related macular degeneration (AMD). Genetic variations of the nuclear receptor RAR-related orphan receptor alpha (RORα) have been linked with neovascular AMD, yet its specific role in pathological CNV development is not entirely clear. In this study, we showed that Rora was highly expressed in the mouse choroid compared with the retina, and genetic loss of RORα in Staggerer mice (Rorasg/sg) led to increased expression levels of Vegfr2 and Tnfa in the choroid and retinal pigment epithelium (RPE) complex. In a mouse model of laser-induced CNV, RORα expression was highly increased in the choroidal/RPE complex post-laser, and loss of RORα in Rorasg/sg eyes significantly worsened CNV with increased lesion size and vascular leakage, associated with increased levels of VEGFR2 and TNFα proteins. Pharmacological inhibition of RORα also worsened CNV. In addition, both genetic deficiency and inhibition of RORα substantially increased vascular growth in isolated mouse choroidal explants ex vivo. RORα inhibition also promoted angiogenic function of human choroidal endothelial cell culture. Together, our results suggest that RORα negatively regulates pathological CNV development in part by modulating angiogenic response of the choroidal endothelium and inflammatory environment in the choroid/RPE complex.

Complementary and alternative medicine is used by approximately 5% of patients with glaucoma, and examples include marijuana, Ginkgo biloba extract, bilberry fruit extract, and acupuncture. Systemic marijuana is not beneficial for glaucoma due to the short duration of action, the lack of evidence that it alters disease progression, and its negative side effect profile. Drops that affect the cannabinoid pathway are still being studied. Ginkgo biloba and bilberry fruit extracts have been shown to decrease oxidative stress and improve perfusion of the optic nerve head. However, these findings are inconsistent throughout the literature and the studies are small, which makes the overall evidence weak. There is no evidence that acupuncture alters glaucoma disease progression or causes a sustained decrease in intraocular pressure. In summary, the literature suggests that there are transient and/or theoretical benefits of complementary and alternative medicine for glaucoma care; however, the overall evidence to support their use is weak.

BACKGROUND/AIMS: Pathological myopia (PM) is a leading cause of blindness worldwide. We aimed to evaluate microvascular and chorioretinal changes in different stages of myopia with wide-field (WF) swept-source (SS) optical coherence tomography angiography (OCTA). METHODS: This prospective cross-sectional observational study included 186 eyes of 122 patients who had undergone imaging between November 2018 and October 2020. Vessel density (VD) and vessel skeletonised density (VSD) of superficial capillary plexus, deep capillary plexus and whole retina, as well as foveal avascular zone parameters, retinal thickness (RT) and choroidal thickness (CT), were calculated. RESULTS: This study evaluated 75 eyes of 48 patients with high myopia (HM), 43 eyes of 31 patients with mild to moderate myopia and 68 eyes of 53 age-matched controls. Controlling for age and the presence of systemic hypertension, we found that HM was associated with decrease in VD and VSD in all layers on 12×12 mm² scans. Furthermore, HM was associated with a VD and VSD decrease in every Early Treatment Diabetic Retinopathy Study grid, with a larger decrease temporally (βVD=-0.39, βVSD=-10.25, p<0.01). HM was associated with decreased RT and CT. Reduction in RT was outside the macular region, while reduction in CT was in the macular region. CONCLUSION: Using WF SS-OCTA, we identified reduction in microvasculature and structural changes associated with myopia. Decrease in VD and VSD was greater in the temporal quadrant, and reductions in RT and CT were uneven across the retina. Further work may help identify risk factors for the progression of PM and associated vision-threatening complications.

Usher syndrome (USH) is the most common form of hereditary deaf-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye. One of the USH1 genes, USH1C, exhibits extensive alternative splicing and encodes numerous harmonin protein isoforms that function as scaffolds for organizing the USH interactome. RNA-seq analysis of human retinae uncovered harmonin_a1 as the most abundant transcript of USH1C. Bulk RNA-seq analysis and immunoblotting showed abundant expression of harmonin in Müller glia cells (MGCs) and retinal neurons. Furthermore, harmonin was localized in the terminal endfeet and apical microvilli of MGCs, presynaptic region (pedicle) of cones and outer segments (OS) of rods as well as at adhesive junctions between MGCs and photoreceptor cells (PRCs) in the outer limiting membrane (OLM). Our data provide evidence for the interaction of harmonin with OLM molecules in PRCs and MGCs and rhodopsin in PRCs. Subcellular expression and colocalization of harmonin correlate with the clinical phenotype observed in USH1C patients. We also demonstrate that primary cilia defects in USH1C patient-derived fibroblasts could be reverted by the delivery of harmonin_a1 transcript isoform. Our studies thus provide novel insights into PRC cell biology, USH1C pathophysiology and development of gene therapy treatment(s).

PURPOSE: Exogenous silicone has been reported to migrate to anatomic sights far from an initial injection or implantation site; this phenomenon has been rarely described in the ocular adnexa, especially in the eyelids. We document 3 additional cases of distant migration of silicone implanted elsewhere in the body to the eyelids and review the prior literature on this uncommon event. METHODS: A retrospective chart review of 3 patients was conducted along with analysis of diagnostic histopathology. A comprehensive review of the literature regarding dissemination or migration of silicone to the eyelids in patients with either silicone breast implants or silicone facial filler use was performed. RESULTS: Cases of silicone migrating to the eyelids from silicone breast implants and silicone-based facial filler are outlined in Tables 1 and 2, respectively. There are 4 total reports of women with silicone breast implants, including the 2 described here, with evidence of migration of silicone to the eyelid. Similarly, 5 cases of silicone-based facial filler with resultant migration of filler to the eyelids were identified, including 2 of the cases presented in this report (1 patient had both silicone breast implants and silicone facial filler). CONCLUSION: Silicone is chemically inert, but is known to travel throughout the body, causing a resultant foreign body response in tissue that can adversely affect even the eyelids. Silicone has a relatively characteristic histologic appearance and diagnosis of silicone granuloma highlights the importance of obtaining a thorough clinical history, particularly regarding prior cosmetic injections or breast enhancement surgery. Foreign material/foreign body granuloma is important to consider in patients with deep eyelid nodules of unclear etiology.

PURPOSE: To assess the effect of corneal scarring location on corneal nerve regeneration in patients with herpes simplex virus (HSV) keratitis in their affected and contralateral eyes over a 1-year period by in vivo confocal microscopy (IVCM), and to correlate these findings to corneal sensation measured by Cochet-Bonnet Esthesiometer. METHODS: Prospective, longitudinal, case-control study. Bilateral corneal nerve density and corneal sensation was analyzed centrally and peripherally in 24 healthy controls and 23 patients with unilateral HSV-related corneal scars using IVCM. RESULTS: In the central scar (CS) group, total nerve density in the central cornea remained significantly lower compared to controls at follow-up (11.05 ± 1.97mm/mm2, p < 0.001), and no significant nerve regeneration was observed (p = 0.090). At follow-up, total nerve density was not significantly different from controls in the central and peripheral cornea of peripheral scar (PS) group (all p > 0.05), and significant nerve regeneration was observed in central corneas (16.39 ± 2.39mm/mm2, p = 0.007) compared to baseline. In contralateral eyes, no significant corneal nerve regeneration was observed in central or peripheral cornea of patients with central scars or peripheral scars at 1-year follow-up, compared to baseline (p > 0.05). There was a positive correlation between corneal nerve density and sensation in both central (R = 0.53, p < 0.0001) and peripheral corneas (R = 0.27, p = 0.0004). In the CS group, the corneal sensitivity was <4 cm in 4 (30.8%) and 7 (53.8%) patients in the central and peripheral corneas at baseline, and in 5 (38.5%) and 2 subjects (15.4%) at follow-up, whereas in the PS group only 1 patient (10%) showed a corneal sensation < 4cm in the central cornea at baseline, and only 1 (10.0%), 3 (30.0%) and 1 (10.0%) patients at follow-up in the central, affected and opposite area of the cornea, respectively. CONCLUSION: The location of HSV scarring in the cornea affects the level of corneal nerve regeneration. Eyes with central corneal scar have a diminished capacity to regenerate nerves in central cornea, they show a more severe reduction in corneal sensation in the central and peripheral cornea that persist at follow-up, and they have a reduced capability to restore the corneal sensitivity above the cut-off of 4 cm. Thus, clinicians should be aware that CS patients would benefit from closer monitoring for potential complications associated with neurotrophic keratopathy, as they have a lower likelihood for nerve regeneration.

PURPOSE: To develop an internationally standardized and validated tool to assess skill in performing tube shunt surgery. DESIGN: A panel of 6 glaucoma surgeons developed a tool for assessing tube shunt surgery using a modified Dreyfus scale for skill acquisition. The tool was reviewed by a panel of 10 international content experts, and their comments were incorporated into the final rubric. PARTICIPANTS: A different panel of 8 international glaucoma specialists independently graded videos of surgical procedures performed by 6 surgeons at various levels of ophthalmic training. MAIN OUTCOME MEASURES: Inter-rater reliability for each step in the rubric was calculated. RESULTS: The tube shunt rubric contained 13 steps specific to tube shunt surgery and 7 global indices. The Cronbach α statistic, a measure of internal reliability, ranged from 0.75 to 0.97, indicating strong internal reliability for all 13 steps. CONCLUSIONS: The tube shunt assessment tool has face validity, content validity, and interobserver reliability, and can be used to assess tube shunt surgery skills. Further studies are required to determine predictive and construct validity.

Corneal transplantation, or penetrating keratoplasty (PK), is the most common form of solid-organ transplantation performed worldwide. Here, we evaluated the indications for PK and rates of transplant survival around the world by geographic region. We conducted a literature search of PubMed, MEDLINE, and Google Scholar databases and identified 155 relevant studies from 41 countries published between 1987 and 2021. The most common indications for PK were keratoconus in Europe, Africa, the Middle East, Australia, New Zealand, and Central and South America, bullous keratopathy in North America, and corneal scarring in Asia. The overall global mean graft survival rates at 1-, 2-, 3-, 5-, and 10-years were 88.6%, 81.2%, 78.9%, 72.8%, and 61.2%, respectively. Through this systematic analysis of PK by region, we hope to bring a new perspective to the corneal transplantation literature and to potentially highlight global differences and unmet needs in patient care.

Models of object recognition have mostly focused upon the hierarchical processing of objects from local edges up to more complex shape features. An alternative strategy that might be involved in pattern recognition centres around coarse-level contrast features. In humans and monkeys, the use of such features is most documented in the domain of face perception. Given prior suggestions that, generally, rodents might rely upon contrast features for object recognition, we hypothesized that they would pick up the typical contrast features relevant for face detection. We trained rats in a face-nonface categorization task with stimuli previously used in computer vision and tested for generalization with new, unseen stimuli by including manipulations of the presence and strength of a range of contrast features previously identified to be relevant for face detection. Although overall generalization performance was low, it was significantly modulated by contrast features. A model taking into account the summed strength of contrast features predicted the variation in accuracy across stimuli. Finally, with deep neural networks, we further investigated and quantified the performance and representations of the animals. The findings suggest that rat behaviour in visual pattern recognition tasks is partially explained by contrast feature processing.

PURPOSE: To determine the sensitivity and specificity of syphilis antibody tests in vitreous samples and to propose an algorithm using vitreous syphilis antibody as a supplementary test to confirm syphilitic uveitis (SU). METHODS: A prospective case-control study was conducted at the Retina and Uveitis Clinic from May 2017 to January 2020. Initially, patients were classified based on syphilis serology into group 1 (positive testing) and group 2 (negative testing). Group 1 was further divided into 2 subgroups (group 1A and 1B) depending on their relevant clinical manifestations and clinical improvement. Group 2 served as a control group. RESULTS: Thirty-eight patients were enrolled in the study: 14 in group 1A, 5 in group 1B, and 19 in group 2B. No patient was assigned to group 2A. All patients in group 1A, representing definite SU, completed syphilis test (rapid plasma reagin [RPR], enzyme immunoassay [EIA], and fluorescent treponemal antibody-absorption [FTA-ABS]) for vitreous, and all vitreous samples yielded positive results. Of the 5 subjects in group 1B, 3 cases were considered to be not SU with different conditions, and 2 were indeterminate for SU. They presented with different features not typical of SU, and they had variable and fewer positive syphilis antibody responses. The most sensitive test for detecting syphilis antibodies in vitreous was EIA (90.9%), followed by RPR (80.0%) and FTA-ABS IgG (78.9%). EIA and FTA-ABS had the highest specificity, detecting 100% of the syphilis antibody. CONCLUSIONS: Vitreous analysis of syphilis antibody can serve as a supplementary test to confirm SU in selected cases as the proposed algorithm.

The prevalence of asteroid hyalosis in adults ≥ 40 years old was 0.6–0.8% in the 2005–2008 National Health and Nutrition Examination Survey (NHANES). Older age and elevated serum creatinine were associated with the presence of asteroid hyalosis.

Cases of reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported worldwide. We investigated reinfection cases in a set of more than 30,000 samples, and the SARS-CoV-2 genomes from selected samples from four patients with at least two positive diagnoses with an interval ≥ 45 days between tests were sequenced and analyzed. Comparative genomic and phylogenetic analysis confirmed three reinfection cases and suggested that the fourth one was caused by a virus of the same lineage. Viral sequencing is crucial for understanding the natural course of reinfections and for planning public health strategies for management of COVID-19.

It is well known that humans have a massive memory for pictures and scenes.1,2,3,4 They show an ability to encode thousands of images with only a few seconds of exposure to each. In addition to this massive memory for "what" observers have seen, three experiments reported here show that observers have a "spatial massive memory" (SMM) for "where" stimuli have been seen and a "temporal massive memory" (TMM) for "when" stimuli have been seen. The positions in time and space for at least dozens of items can be reported with good, if not perfect accuracy. Previous work has suggested that there might be good memory for stimulus location,5,6 but there do not seem to have been concerted efforts to measure the extent of this memory. Moreover, in our method, observers are recalling where items were located and not merely recognizing the correct location. This is interesting because massive memory is sometimes thought to be limited to recognition tasks based on sense of familiarity.

Abnormal angiogenesis is associated with myriad human diseases, including proliferative diabetic retinopathy (PDR). Signaling transduction through phosphoinositide 3-kinases (PI3Ks) plays a critical role in angiogenesis. Herein, we showed that p110δ, the catalytic subunit of PI3Kδ, was highly expressed in pathological retinal vascular endothelial cells (ECs) in a mouse model of oxygen-induced retinopathy (OIR) and in fibrovascular membranes from patients with PDR. To explore novel intervention with PI3Kδ expression, we developed a recombinant dual adeno-associated viral (rAAV) system for delivering CRISPR/Cas9 in which Streptococcus pyogenes (Sp) Cas9 expression was driven by an endothelial specific promoter of the intercellular adhesion molecule 2 (pICAM2) to edit genomic Pik3cd, the gene encoding p110δ. We then demonstrated that infection of cultured mouse vascular ECs with the dual rAAV1s of rAAV1-pICAM2-SpCas9 and rAAV1-SpGuide targeting genomic Pik3cd resulted in 80% DNA insertion/deletion in the locus of genomic Pik3cd and 70% depletion of p110δ expression. Furthermore, we showed that in the mouse model of OIR editing retinal Pik3cd with the dual rAAV1s resulted in not only a significant decrease in p110δ expression, and Akt activation, but also a dramatic reduction in pathological retinal angiogenesis. These findings reveal that Pik3cd editing is a novel approach to treating abnormal retinal angiogenesis.

Black patients are more affected by glaucoma and suffer from more advanced disease. Diagnostic challenges among black patients with glaucoma include lower rates of diagnostic testing and thinner average central corneal thickness, the latter of which affects intraocular pressure measurement. Treatment challenges include poor follow-up, medication adherence, and trust in providers. Black patients undergoing trabeculectomy have higher rates of failure compared to white patients. Race is not a definitive factor affecting success for tube shunts, laser trabeculoplasty, cyclophotocoagulation, and micro-invasive glaucoma surgeries, but the body of evidence is limited by low inclusion of black patients in these studies. Future steps should include increased attention toward improving trust between patients and providers, improving access to care, and increased representation of black patients in glaucoma research to better understand factors affecting racial disparities in glaucoma management and outcomes in this population disproportionately affected by the disease.