September 2021

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Seto B, Singh MK, Lemire CA, Arroyo JG. Anterior versus posterior endoscopic cyclophotocoagulation: comparison of indications, populations, and outcomes. Int Ophthalmol 2021;41(9):3021-3028.Abstract
PURPOSE: To examine how indications, patient characteristics, and outcomes differ between anterior and posterior approaches of endoscopic cyclophotocoagulation (ECP) in the treatment of glaucoma. METHODS: This is a retrospective chart review of 9 anterior and 20 posterior ECP cases (n = 29). RESULTS: Posterior ECP cases were typically associated with a dramatic increase in intraocular pressure (IOP), whereas the anterior ECP was associated with chronically elevated pressures. The initial IOPs in mm Hg of posterior ECP cases (26.8 non-NVG; 35.2 NVG) were much greater than anterior ECP cases (17.8), and a greater overall reduction in IOP was observed in the posterior versus anterior ECP cases (10.3 posterior non-NVG; 21.3 posterior NVG; 3.6 anterior, P < .001). With procedural success defined as 6-month post-operative IOP falling within normal ranges and a decrease in either IOP or number of prescribed glaucoma medications, the success rate of ECP was 92% for posterior NVG, 89% for anterior and 75% for posterior non-NVG cases (P = .34), similar to the previous literature. Of the four unsuccessful cases, two resulted in a normal IOP but lacked a drop in pressure or reduction in medication burden, one resulted in a 6-point drop in IOP but remained at 23 mm Hg, and one resulted in phthisis bulbi (3%) from an initial pressure above 40 mm Hg. CONCLUSION: Endoscopic cyclophotocoagulation is an effective and safe procedure for severe glaucoma cases from both an anterior and posterior approach. Ophthalmologists should consider this procedure as part of their glaucoma treatment arsenal.
Sobrin L, Yu Y, Han S, Susarla G, Kempen JH, Hubbard RA, VanderBeek BL. Decreased risk of non-infectious anterior uveitis with statin therapy in a large healthcare claims database. Graefes Arch Clin Exp Ophthalmol 2021;259(9):2783-2793.Abstract
PURPOSE: The purpose of this study is to determine if statin therapy decreases the incidence of non-infectious uveitis (NIU) using a retrospective cohort study. METHODS: Patients enrolled in a national insurance plan who initiated statin (n = 711,734, statin cohort) or other lipid-lowering therapy (n = 148,044, non-statin cohort) were observed for NIU development. Incident NIU in the primary analysis was defined as a new diagnosis code for NIU followed by a second instance of a NIU code within 120 days. For the secondary outcome definition, a corticosteroid prescription or code for an ocular corticosteroid injection within 120 days of the NIU diagnosis code was used instead of the second NIU diagnosis code. Estimation of NIU incidence used multivariable Cox proportional hazards regression. The proportional hazards assumption was satisfied by creating two time periods of analysis, ≤ 150 and > 150 days. Subanalyses were performed by anatomic subtype. RESULTS: Overall, the primary outcome occurred 541 times over 690,465 person-years in the statin cohort and 103 times over 104,301 person-years in the non-statin cohort. No associations were seen in the ≤ 150-day analyses (p > 0.20 for all comparisons). However, after 150 days, the statin cohort was less likely to develop any uveitis [hazard ratio (HR) = 0.70, 95% confidence interval (CI): 0.51-0.97, P = 0.03] in the primary outcome analysis, but did not meet significance for the secondary outcome (HR = 0.85, 95% CI: 0.63-1.15, P = 0.30). Similarly, in the anatomic subtype analysis, after 150 days, the statin cohort was less likely to develop anterior uveitis (HR = 0.67, 95% CI: 0.47-0.97, P = 0.03) in the primary analysis, but the association did not reach significance for the secondary outcome (HR = 0.82, 95% CI: 0.56-1.20, P = 0.31). CONCLUSION: Our results suggest that statin therapy for > 150 days decreases the incidence of NIU.
Soeken TA, Ross AE, Kohane DS, Kuang L, Legault GL, Caldwell MC, Brundridge WL, Merkley MB, Ciolino JB, Townley RJ. Dexamethasone-Eluting Contact Lens for the Prevention of Postphotorefractive Keratectomy Scar in a New Zealand White Rabbit Model. Cornea 2021;40(9):1175-1180.Abstract
PURPOSE: To evaluate the safety and efficacy of an experimental dexamethasone-eluting contact lens (DCL) for the prevention of postphotorefractive keratectomy (PRK) corneal haze in a New Zealand White (NZW) rabbit model. METHODS: Both eyes of 29 NZW rabbits underwent PRK. The rabbits were randomized to one of the 5 study arms for 4 weeks: tarsorrhaphy only, tarsorrhaphy and bandage contact lens (BCL) replaced weekly, tarsorrhaphy and BCL for 1 week plus topical 0.1% dexamethasone ophthalmic solution (drops) for 4 weeks, tarsorrhaphy and BCL replaced weekly plus topical dexamethasone for 4 weeks, and tarsorrhaphy and DCL changed weekly for 4 weeks. Each week for 4 consecutive weeks postoperatively, the tarsorrhaphies were opened, the eyes underwent evaluation and imaging, and the tarsorrhaphies were replaced. Contact lenses were cultured on removal. Central corneal haze was assessed weekly with corneal densitometry. After 4 weeks, the animals were killed, and the eyes were enucleated for histopathologic analysis. RESULTS: The tarsorrhaphy only group displayed more haze with a greater change in optical densitometry from pre-op compared with the other treatment groups. There was no difference between the DCL group and the groups receiving a BCL and dexamethasone drops in densitometry or histopathology. No NZW rabbits developed clinical signs of infection, and cultures from DCLs and BCLs grew similar organisms. CONCLUSIONS: In the post-PRK rabbit model, DCLs worn weekly for 4 weeks were safe and as effective at preventing corneal haze as 0.1% dexamethasone drops applied 4 times a day for 4 weeks.
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Townes-Anderson E, Halasz E, Wang W, Zarbin M. Coming of Age for the Photoreceptor Synapse. Invest Ophthalmol Vis Sci 2021;62(12):24.Abstract
Purpose: To discuss the potential contribution of rod and cone synapses to the loss of visual function in retinal injury and disease. Methods: The published literature and the authors' own work were reviewed. Results: Retinal detachment is used as a case study of rod spherule and cone pedicle plasticity after injury. Both rod and cone photoreceptors terminals are damaged after detachment although the structural changes observed are only partially overlapping. For second-order neurons, only those associated with rod spherules respond consistently to injury by remodeling. Examination of signaling pathways involved in plasticity of conventional synapses and in neural development has been and may continue to be productive in discovering novel therapeutic targets. Rho kinase (ROCK) inhibition is an example of therapy that may reduce synaptic damage by preserving normal synaptic structure of rod and cone cells. Conclusions: We hypothesize that synaptic damage contributes to poor visual restoration after otherwise successful anatomical repair of retinal detachment. A similar situation may exist for patients with degenerative retinal disease. Thus, synaptic structure and function should be routinely studied, as this information may disclose therapeutic strategies to mitigate visual loss.
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Uemura A, Fruttiger M, D'Amore PA, De Falco S, Joussen AM, Sennlaub F, Brunck LR, Johnson KT, Lambrou GN, Rittenhouse KD, Langmann T. VEGFR1 signaling in retinal angiogenesis and microinflammation. Prog Retin Eye Res 2021;84:100954.Abstract
Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, -C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
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Whitman MC. Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders. Annu Rev Vis Sci 2021;7:827-850.Abstract
Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: (a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or (b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.
Wiegand I, Wolfe JM. Target value and prevalence influence visual foraging in younger and older age. Vision Res 2021;186:87-102.Abstract
The prevalence and reward-value of targets have an influence on visual search. The strength of the effect of an item's reward-value on attentional selection varies substantially between individuals and is potentially sensitive to aging. We investigated individual and age differences in a hybrid foraging task, in which the prevalence and value of multiple target types was varied. Using optimal foraging theory measures, foraging was more efficient overall in younger than older observers. However, the influence of prevalence and value on target selections was similar across age groups, suggesting that the underlying cognitive mechanisms are preserved in older age. When prevalence was varied but target value was balanced, younger and older observers preferably selected the most frequent target type and were biased to select another instance of the previously selected target type. When value was varied, younger and older observers showed a tendency to select high-value targets, but preferences were more diverse between individuals. When value and prevalence were inversely related, some observers showed particularly strong preferences for high-valued target types, while others showed a preference for high-prevalent, albeit low-value, target types. In younger adults, individual differences in the selection choices correlated with a personality index, suggesting that avoiding selections of low-value targets may be related to reward-seeking behaviour.
Wishart TFL, Flokis M, Shu DY, Das SJ, Lovicu FJ. Hallmarks of lens aging and cataractogenesis. Exp Eye Res 2021;210:108709.Abstract
Lens homeostasis and transparency are dependent on the function and intercellular communication of its epithelia. While the lens epithelium is uniquely equipped with functional repair systems to withstand reactive oxygen species (ROS)-mediated oxidative insult, ROS are not necessarily detrimental to lens cells. Lens aging, and the onset of pathogenesis leading to cataract share an underlying theme; a progressive breakdown of oxidative stress repair systems driving a pro-oxidant shift in the intracellular environment, with cumulative ROS-induced damage to lens cell biomolecules leading to cellular dysfunction and pathology. Here we provide an overview of our current understanding of the sources and essential functions of lens ROS, antioxidative defenses, and changes in the major regulatory systems that serve to maintain the finely tuned balance of oxidative signaling vs. oxidative stress in lens cells. Age-related breakdown of these redox homeostasis systems in the lens leads to the onset of cataractogenesis. We propose eight candidate hallmarks that represent common denominators of aging and cataractogenesis in the mammalian lens: oxidative stress, altered cell signaling, loss of proteostasis, mitochondrial dysfunction, dysregulated ion homeostasis, cell senescence, genomic instability and intrinsic apoptotic cell death.
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Zabaleta N, Dai W, Bhatt U, Hérate C, Maisonnasse P, Chichester JA, Sanmiguel J, Estelien R, Michalson KT, Diop C, Maciorowski D, Dereuddre-Bosquet N, Cavarelli M, Gallouët A-S, Naninck T, Kahlaoui N, Lemaitre J, Qi W, Hudspeth E, Cucalon A, Dyer CD, Pampena BM, Knox JJ, LaRocque RC, Charles RC, Li D, Kim M, Sheridan A, Storm N, Johnson RI, Feldman J, Hauser BM, Contreras V, Marlin R, Tsong Fang RH, Chapon C, van der Werf S, Zinn E, Ryan A, Kobayashi DT, Chauhan R, McGlynn M, Ryan ET, Schmidt AG, Price B, Honko A, Griffiths A, Yaghmour S, Hodge R, Betts MR, Freeman MW, Wilson JM, Le Grand R, Vandenberghe LH. An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates. Cell Host Microbe 2021;29(9):1437-1453.e8.Abstract
The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans and does not elicit cross-reactivity to common AAVs used in gene therapy. Vector genome persistence and expression wanes following injection. The single low-dose requirement, high-yield manufacturability, and 1-month stability for storage at room temperature may make this technology well suited to support effective immunization campaigns for emerging pathogens on a global scale.
Zebardast N, Sekimitsu S, Wang J, Elze T, Gharahkhani P, Cole BS, Lin MM, Segrè AV, Wiggs JL, Wiggs JL. Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank. Ophthalmology 2021;128(9):1300-1311.Abstract
PURPOSE: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs). METHODS: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG). MAIN OUTCOME MEASURES: Penetrance of glaucoma. RESULTS: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG. CONCLUSIONS: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.

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