Krawitz BD, Sirinek P, Doobin D, Nanda T, Ghiassi M, Horowitz JD, Liebmann JM, De Moraes CG. The Challenge of Managing Bilateral Acute Angle-closure Glaucoma in the Presence of Active SARS-CoV-2 Infection. J Glaucoma 2021;30(3):e50-e53.Abstract
PURPOSE: To report a case of bilateral acute angle-closure glaucoma associated with hyponatremia in the setting of chlorthalidone use and SARS-CoV-2 infection, and to demonstrate the challenges of managing this patient given her infectious status. METHODS: This was a case report. CASE: A 65-year-old woman taking chlorthalidone for hypertension presented to the emergency room with headache, pain, and blurry vision in both eyes and was found to be in bilateral acute angle closure. On laboratory investigation, she was severely hyponatremic and also tested positive for SARS-CoV-2. B-scan ultrasound demonstrated an apparent supraciliary effusion in the right eye. Following stabilization of her intraocular pressures with medical management, she ultimately underwent cataract extraction with iridectomies and goniosynechiolysis in both eyes. CONCLUSIONS: We report a rare case of bilateral acute angle-closure glaucoma associated with hyponatremia. Chlorthalidone use and perhaps SARS-CoV-2 infection may have contributed to this electrolyte abnormality and unique clinical presentation. In addition, we discuss the challenges of managing this complex patient with active SARS-CoV-2 infection during the pandemic.
Peng C, Wang Y, Ji L, Kuang L, Yu Z, Li H, Zhang J, Zhao J. LncRNA-MALAT1/miRNA-204-5p/Smad4 Axis Regulates Epithelial-Mesenchymal Transition, Proliferation and Migration of Lens Epithelial Cells. Curr Eye Res 2021;46(8):1137-1147.Abstract
MATERIALS AND METHODS: LECs were cultured and induced with TGF-β2 (10 ng/mL). SiRNA against MALAT1 (Si-MALAT1) was transfected into LECs to knockdown the expression of MALAT1. To overexpress or knockdown miR-204-5p, miR-204-5p mimics (miR-204-5p mimics) and anti-miR-204-5p (miR-204-5p inhibitor) were transfected into LECs. We used RNA FISH to identify the location of MALAT1. RNA levels of MALAT1 and miR-204-5p were analyzed by RT-qPCR. Additionally, target protein levels of Smad4, epithelial differentiation and mesenchymal markers were analyzed with Western blot. We employed EdU Labeling to measured cell proliferation and performed Transwell Assay to analyze the cell migration. Dual-luciferase reporter assays in LECs were conducted to verify whether miRNA-204-5p was negatively regulated by MALAT1 and Smad4 was a direct target of miR-204-5p. RESULTS: The expression of MALAT1 was upregulated in PCO specimens. MALAT1 was overexpressed in TGF-β2 induced LECs, and the knockdown of MALAT1 could attenuate TGF-β2 induced EMT. Besides, the upregulation of MALAT1 was correlated with the downregulation of miR-204-5p and upregulation of Smad4. Importantly, MALAT1 was revealed to be located in the cytoplasm of LECs. Furthermore, luciferase reporter assays confirmed that MALAT1 could negatively regulate the expression of miR-204-5p and then regulate its direct target Smad4. Finally, the knockdown of MALAT1 could inhibit the EMT, proliferation, and migration of LECs; however, those can be reversed by anti-miR-204-5p. CONCLUSIONS: Our findings reveal that MALAT1 may regulate EMT, proliferation, and migration of LECs as a ceRNA by "sponging" miR-204-5p and targeting Smad4, and serve as a promising therapeutic target in preventing PCO.
Choi EY, Li D, Fan Y, Pasquale LR, Shen LQ, Boland MV, Ramulu P, Yousefi S, De Moraes CG, Wellik SR, Myers JS, Bex PJ, Elze T, Wang M. Predicting Global Test-Retest Variability of Visual Fields in Glaucoma. Ophthalmol Glaucoma 2021;4(4):390-399.Abstract
PURPOSE: To model the global test-retest variability of visual fields (VFs) in glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Test-retest VFs from 4044 eyes of 4044 participants. METHODS: We selected 2 reliable VFs per eye measured with the Humphrey Field Analyzer (Swedish interactive threshold algorithm 24-2) within 30 days of each other. Each VF had fixation losses (FLs) of 33% or less, false-negative results (FNRs) of 20% or less, and false-positive results (FPRs) of 20% or less. Stepwise linear regression was applied to select the model best predicting the global test-retest variability from 3 categories of features of the first VF: (1) base parameters (age, mean deviation, pattern standard deviation, glaucoma hemifield test results, FPR, FNR, and FL); (2) total deviation (TD) at each location; and (3) computationally derived archetype VF loss patterns. The global test-retest variability was defined as root mean square deviation (RMSD) of TD values at all 52 VF locations. MAIN OUTCOME MEASURES: Archetype models to predict the global test-retest variability. RESULTS: The mean ± standard deviation of the root mean square deviation was 4.39 ± 2.55 dB. Between the 2 VF tests, TD values were correlated more strongly in central than in peripheral VF locations (intraclass coefficient, 0.66-0.89; P < 0.001). Compared with the model using base parameters alone (adjusted R2 = 0.45), adding TD values improved prediction accuracy of the global variability (adjusted R2 = 0.53; P < 0.001; Bayesian information criterion [BIC] decrease of 527; change of >6 represents strong improvement). Lower TD sensitivity in the outermost peripheral VF locations was predictive of higher global variability. Adding archetypes to the base model improved model performance with an adjusted R2 of 0.53 (P < 0.001) and lowering of BIC by 583. Greater variability was associated with concentric peripheral defect, temporal hemianopia, inferotemporal defect, near total loss, superior peripheral defect, and central scotoma (listed in order of decreasing statistical significance), and less normal VF results and superior paracentral defect. CONCLUSIONS: Inclusion of archetype VF loss patterns and TD values based on first VF improved the prediction of the global test-retest variability than using traditional global VF indices alone.
Jafari A, von Sneidern M, Lehmann AE, Shen SA, Shishido S, Freitag SK, Bleier BS. Exclusively endoscopic endonasal resection of benign orbital tumors: a systematic review and meta-analysis. Int Forum Allergy Rhinol 2021;11(5):924-934.Abstract
BACKGROUND: The Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) classification system was developed to standardize prospective outcome analysis following orbital cavernous hemangioma (OCH) resection. The goal of this study was to retroactively apply the CHEER system to all prior existing reports of endoscopic resection of primary benign orbital tumors (BOTs) to: (1) compare patient presentations, perioperative characteristics, and outcomes between OCH and other BOTs; and (2) determine whether the CHEER categorization regime could be expanded to other BOTs. METHODS: A systematic review of studies reporting exclusively endoscopic resections of OCH and other BOTs (eg, solitary fibrous tumor, schwannoma, and meningioma) was performed. Patient, tumor characteristics, and operative outcomes were recorded. All tumors with adequate reporting were retrospectively assigned a CHEER stage. Outcomes were compared using chi-square or Fisher's exact tests. RESULTS: Ninety-three studies met inclusion criteria, and sufficient data were available in 36 studies, comprising 105 tumors (n = 87 OCHs; n = 18 other BOTs). Baseline patient and tumor characteristics, as well as intraoperative and short-term postoperative outcomes were not significantly different between OCHs and other BOTs. Long-term outcomes (eg, visual deficits, diplopia, eye position, and recurrence) also did not differ when controlling for CHEER stage. CONCLUSION: This review represents the largest collection of outcomes data following exclusively endoscopic endonasal resection of BOTs. Short-term and long-term outcomes appear similar between OCHs and other BOTs. These results suggest that exclusively endoscopic resection of orbital tumors may be effective in a range of benign pathologies. Furthermore, these results support a broader application of the CHEER system to other benign primary orbital tumors.
Gonzalez-Buendia L, Delgado-Tirado S, An M, O'Hare M, Amarnani D, Whitmore HAB, Zhao G, Ruiz-Moreno JM, Arboleda-Velasquez JF, Kim LA. Treatment of Experimental Choroidal Neovascularization via RUNX1 Inhibition. Am J Pathol 2021;191(3):418-424.Abstract
Choroidal neovascularization (CNV) is a prevalent cause of vision loss in patients with age-related macular degeneration. Runt-related transcription factor 1 (RUNX1) has been identified as an important mediator of aberrant retinal angiogenesis in proliferative diabetic retinopathy and its modulation has proven to be effective in curbing pathologic angiogenesis in experimental oxygen-induced retinopathy. However, its role in CNV remains to be elucidated. This study demonstrates RUNX1 expression in critical cell types involved in a laser-induced model of CNV in mice. Furthermore, the preclinical efficacy of Ro5-3335, a small molecule inhibitor of RUNX1, in experimental CNV is reported. RUNX1 inhibitor Ro5-3335, aflibercept-an FDA-approved vascular endothelial growth factor (VEGF) inhibitor, or a combination of both, were administered by intravitreal injection immediately after laser injury. The CNV area of choroidal flatmounts was evaluated by immunostaining with isolectin B4, and vascular permeability was analyzed by fluorescein angiography. A single intravitreal injection of Ro5-3335 significantly decreased the CNV area 7 days after laser injury, and when combined with aflibercept, reduced vascular leakage more effectively than aflibercept alone. These data suggest that RUNX1 inhibition alone or in combination with anti-VEGF drugs may be a new therapy upon further clinical validation for patients with neovascular age-related macular degeneration.
Singh N, Singh R, Bowen RC, Abdel-Rahman MH, Singh AD. Uveal Melanoma in BAP1 Tumor Predisposition Syndrome: Estimation of Risk. Am J Ophthalmol 2021;224:172-177.Abstract
PURPOSE: To estimate point prevalence of uveal melanoma in the patients with germline BAP1 pathogenic variant. DESIGN: Cohort study with risk assessment using Bayesian analysis. METHODS: The point prevalence estimate was obtained by Bayes's rule of reverse conditional probabilities. The probability of uveal melanoma given that BAP1 mutation exists was derived from the prevalence of uveal melanoma, prevalence of germline BAP1 pathogenic variants, and the probability of germline BAP1 pathogenic variant given that uveal melanoma is present. Confidence intervals (CIs) for each variable were calculated as the mean of Bernoulli random variables and for the risk estimate, by the delta method. The age at diagnosis and the gender of the uveal melanoma patients with BAP1 germline pathogenic variants obtained from previous publications or from authors' unpublished cohort was compared with those in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The point prevalence of uveal melanoma in patients with the germline BAP1 pathogenic variants in the US population was estimated to be 2.8% (95% CI, 0.88%-4.81%). In the SEER database, the median age at diagnosis of uveal melanomas was 63 (range 3-99 years) with a male-to-female ratio of 1.01:1. In comparison, uveal melanoma cases with BAP1 germline pathogenic variants from the US population (n = 27) had a median age at diagnosis of 50.5 years (range 16-71). CONCLUSIONS: Quantification of the risk of developing uveal melanoma can enhance counseling regarding surveillance in patients with germline BAP1 pathogenic variant.
Sokol JT, Schechet SA, Komati R, Eliott D, Vavvas DG, Kaplan RI, Ittiara ST, Farooq AV, Sheth VS, MacCumber MW, Ke R, Gentile RC, Skondra D. Macular Hole Closure with Medical Treatment. Ophthalmol Retina 2021;5(7):711-713.
Freedman SF, Beck AD, Nizam A, VanderVeen DK, Plager DA, Morrison DG, Drews-Botsch CD, Lambert SR, Lambert SR. Glaucoma-Related Adverse Events at 10 Years in the Infant Aphakia Treatment Study: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol 2021;139(2):165-173.Abstract
Importance: Glaucoma-related adverse events constitute serious complications of cataract removal in infancy, yet long-term data on incidence and visual outcome remain lacking. Objective: To identify and characterize incident cases of glaucoma and glaucoma-related adverse events (glaucoma + glaucoma suspect) among children in the Infant Aphakia Treatment Study (IATS) by the age of 10.5 years and to determine whether these diagnoses are associated with optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) assessment. Design, Setting, and Participants: Analysis of a multicenter randomized clinical trial of 114 infants with unilateral congenital cataract who were aged 1 to 6 months at surgery. Data on long-term glaucoma-related status and outcomes were collected when children were 10.5 years old (July 14, 2015, to July 12, 2019) and analyzed from March 30, 2019, to August 6, 2019. Interventions: Participants were randomized at cataract surgery to either primary intraocular lens (IOL), or aphakia (contact lens [CL]). Standardized definitions of glaucoma and glaucoma suspect were created for IATS and applied for surveillance and diagnosis. Main Outcomes and Measures: Development of glaucoma and glaucoma + glaucoma suspect in operated-on eyes up to age 10.5 years, plus intraocular pressure, axial length, RNFL (by optical coherence tomography), and ONH photographs. Results: In Kaplan-Meier analysis, for all study eyes combined (n = 114), risk of glaucoma after cataract removal rose from 9% (95% CI, 5%-16%) at 1 year, to 17% (95% CI, 11%-25%) at 5 years, to 22% (95% CI, 16%-31%) at 10 years. The risk of glaucoma plus  glaucoma suspect diagnosis after cataract removal rose from 12% (95% CI, 7%-20%) at 1 year, to 31% (95% CI, 24%-41%) at 5 years, to 40% (95% CI, 32%-50%) at 10 years. Risk of glaucoma and glaucoma plus glaucoma suspect diagnosis at 10 years was not significantly different between treatment groups. Eyes with glaucoma (compared with eyes with glaucoma suspect or neither) had longer axial length but relatively preserved RNFL and similar ONH appearance and visual acuity at age 10 years. Conclusions and Relevance: Risk of glaucoma-related adverse events continues to increase with longer follow-up of children following unilateral cataract removal in infancy and is not associated with primary IOL implantation. Development of glaucoma (or glaucoma suspect) after removal of unilateral congenital cataract was not associated with worse visual acuity outcomes at 10 years. Trial Registration: Identifier: NCT00212134.
Ung L, Jonas JB, Lietman TM, Chodosh J. COVID-19 and the Unfinished Agenda of VISION 2020. Am J Ophthalmol 2021;224:30-35.Abstract
PURPOSE: To critically evaluate the potential impact of the coronavirus disease (COVID-19) pandemic on global ophthalmology and VISION 2020. DESIGN: Perspective supplemented with epidemiologic insights from available online databases. METHODS: We extracted data from the Global Vision Database (2017) and Global Burden of Disease Study (2017) to highlight temporal trends in global blindness since 1990, and provide a narrative overview of how COVID-19 may derail progress toward the goals of VISION 2020. RESULTS: Over 2 decades of VISION 2020 advocacy and program implementation have culminated in a universal reduction of combined age-standardized prevalence of moderate-to-severe vision impairment (MSVI) across all world regions since 1990. Between 1990 and 2017, low-income countries observed large reductions in the age-standardized prevalence per 100,000 persons of vitamin A deficiency (25,155 to 19,187), undercorrected refractive disorders (2,286 to 2,040), cataract (1,846 to 1,690), onchocerciasis (5,577 to 2,871), trachoma (506 to 159), and leprosy (36 to 26). Despite these reductions, crude projections suggest that more than 700 million persons will experience MSVI or blindness by 2050, principally owing to our growing and ageing global population. CONCLUSIONS: Despite the many resounding successes of VISION 2020, the burden of global blindness and vision impairment is set to reach historic levels in the coming years. The impact of COVID-19, while yet to be fully determined, now threatens the hard-fought gains of global ophthalmology. The postpandemic years will require renewed effort and focus on vision advocacy and expanding eye care services worldwide.
Marmamula S, Barrenkala NR, Khanna RC, Challa R, Bhakki M, Kumbham TR, Modepalli SB, Yellapragada R, Friedman DS. Near vision impairment among the elderly in residential care-the Hyderabad Ocular Morbidity in Elderly Study (HOMES). Eye (Lond) 2021;35(8):2310-2315.Abstract
BACKGROUND/OBJECTIVE: To report on the prevalence and risk factors for near vision impairment (NVI) among the elderly in residential care in Telangana State in India. METHODS: Individuals aged ≥60 years were recruited from 41 'home for the aged' centres in Hyderabad, India. All participants had complete eye examinations including presenting and best-corrected visual acuity assessment for distance and near. NVI was defined as binocular presenting near vision worse than N8 (6/15) among those who had a normal presenting distance visual acuity of 6/18 in the better eye. RESULTS: Of the 826 participants, the mean age was 74.4 years (standard deviation-8.4 years), 525 (63.6%) were women, 715 (86.6%) had at least school education. The prevalence of NVI was 51.2% (95% CI: 47.7-54.7) based on presenting vision. On applying multiple logistic regression analysis, the odds of NVI were higher in 80 years and older age (OR: 2.17; 95% CI: 3.44-13.6). Those with school education (OR: 0.58: 95% CI: 0.36-0.94) and higher education (OR: 0.38; 95% CI: 0.21-0.69) had lower odds for NVI. Similarly, those with self-reported diabetes (OR: 0.69; 95% CI: 0.49-0.97), those using spectacles (OR: 0.09; 95% CI: 0.05-0.16), and those who had undergone cataract surgery (OR: 0.51; 95% CI: 0.36-0.74) had lower odds for NVI. CONCLUSIONS: NVI was common among the elderly in residential care in homes for the aged in Hyderabad, India. As most of this NVI is correctable, a routine screening programme and dispensing of spectacles can be undertaken to address this vision loss.
Niu L, Fang Y, Yao X, Zhang Y, Wu J, Chen DF, Sun X. TNFα activates MAPK and Jak-Stat pathways to promote mouse Müller cell proliferation. Exp Eye Res 2021;202:108353.Abstract
Mouse Müller cells, considered as dormant retinal progenitors, often respond to retinal injury by undergoing reactive gliosis rather than displaying neural regenerative responses. Tumor necrosis factor alpha (TNFα) is a key cytokines induced after injury and implicated in mediating inflammatory and neural regenerative responses in zebrafish. To investigate the involvement of TNFα in mouse retinal injury, adult C57BL/6J mice were subjected to light damage for 14 consecutive days. TNFα was elevated in the retina of mice exposed to light damage, which induced Müller cell proliferation in vitro. Affymetrix microarray showed that, in Müller cells, TNFα induces up-regulation of inflammatory and proliferation-related genes, including NFKB2, leukemia inhibitory factor, interleukin-6, janus kinase (Jak) 1, Jak2, signal transducer and activator of transcription (Stat) 1, Stat2, mitogen-activated protein kinase (MAPK) 7, and MAP4K4 but down-regulation of neuroprogenitor genes, including Sox9, Ascl1, Wnt2 and Hes1. Blocking the Jak/Stat and MAPK pathways attenuated TNFα-induced Müller cell proliferation. These results suggest that TNFα may drive the proliferation and inflammatory response, rather than the neural regenerative potential, of mouse Müller cells.
Hildebrandt C, Fulton A, Rodan LH. Homozygous deletion of 21q22.2 in a patient with hypotonia, developmental delay, cortical visual impairment, and retinopathy. Am J Med Genet A 2021;185(2):555-560.Abstract
21q22 contains several dosage sensitive genes that are important in neurocognitive development. Determining impacts of gene dosage alterations in this region can be useful in establishing contributions of these genes to human development and disease. We describe a 15-month-old girl with a 1,140 kb homozygous deletion in the Down Syndrome Critical Region at 21q22.2 including 4 genes; B3GALT5, IGSF5, PCP4, DSCAM, and a microRNA (MIR4760). Clinical singleton genome sequencing did not report any candidate gene variants for the patient's phenotype. She presented with hypotonia, global developmental delay, cortical visual impairment, and mild facial dysmorphism. Ophthalmological exam was suggestive of retinopathy. We propose that the absence of DSCAM and PCP4 may contribute to the patient's neurological and retinal phenotype, while the role of absent B3GALT5 and IGSF5 in her presentation remain unclear at this time.
Rossin EJ, Szypko C, Giese I, Hall N, Gardiner MF, Lorch A. Factors Associated With Increased Risk of Serious Ocular Injury in the Setting of Orbital Fracture. JAMA Ophthalmol 2021;139(1):77-83.Abstract
Importance: Orbital fractures are common in ocular trauma, and there is a need to develop predictive tools to estimate risk of concurrent ocular injury. Objective: To identify clinical and radiographic features that are associated with increased risk of substantial ocular injury in the setting of orbital fracture. Design, Setting, and Participants: Retrospective consecutive case series of patients who sustained orbital fractures between 2012 and 2018. Examinations were done at 1 of 2 level 1 trauma centers in the emergency or inpatient setting. A total of 430 consecutive patients (500 eyes) between 2012 and 2017 met inclusion criteria for the training sample. After building a predictive model, 88 additional consecutive patients (97 eyes) between 2017 and 2018 who met inclusion criteria were collected as a test sample. Main Outcomes and Measures: The primary outcome measure was substantial ocular injury distinct from orbital fracture. Results: The mean age of our patient population was 53.5 years (range, 16-100 years). The overall rate of substantial ocular injury was 20.4%, and the rate of injury requiring immediate ophthalmic attention was 14.4%. Five variables were found to be associated with increased risk of substantial ocular injury: blunt trauma with a foreign object (odds ratio [OR], 19.4; 95% CI, 6.3-64.1; P < .001), inability to count fingers (OR, 10.1; 95% CI, 2.8-41.1; P = .002), roof fracture (OR, 9.1; 95% CI, 2.8-30.0; P = .002), diplopia on primary gaze (OR, 6.7; 95% CI, 1.7-25.1; P = .003), and conjunctival hemorrhage or chemosis (OR, 4.2; 95% CI, 2.2-8.5; P < .001). The results were translated into a bedside tool that was tested in an independent group of eyes (n = 97) and found to be associated with substantial ocular injury with a 95% sensitivity (95% CI, 77.2-99.9), 40% specificity (95% CI, 28.9-52.0), 31.8% positive predictive value (95% CI, 27.5-36.5), and 96.8% negative predictive value (95% CI, 81.3-99.5). Conclusions and Relevance: A minority of patients with an orbital fracture had a substantial ocular injury. Certain radiographic and clinical findings were associated with substantial ocular injury. Testing of the algorithm in prospective longitudinal settings appears warranted.