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Though rare, acute macular neuroretinopathy is a well-described clinical entity. We report for the first time a detailed analysis of macular hyalocyte count and morphology during the acute phase of acute macular neuroretinopathy. We present a case of a 19-year-old man with bilateral acute onset paracentral scotomas in the setting of an antecedent viral infection. Multimodal imaging demonstrated classic features of acute macular neuroretinopathy. Further analysis revealed increased macular hyalocyte count and an activated hyalocyte morphology during the acute phase of the disease course. Multimodal imaging not only allows for greater confidence in a diagnosis and prognosis but also helps to shed light on underlying pathophysiology. The new clinical capability of monitoring cellular behavior, such as hyalocyte count and morphology, in physiological and pathological conditions may prove useful as biomarkers of early disease activity or response to therapy.

We report the case of a 27-year-old monocular woman with a history of sickle cell disease who received intra-arterial tissue plasminogen activator (tPA) after presenting with acute painless vision loss secondary to incomplete central retinal artery occlusion presenting as paracentral acute middle maculopathy in her left eye.Ultrawidefield fundus photography, ultrawidefield fluorescein angiography, en face optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA) were obtained and reviewed, followed by cerebral angiography and infusion of intra-arterial tissue plasminogen activator.A patient with a history of sickle cell disease presented with a new onset of a dense central scotoma, and the visual acuity diminished to 20 of 200 from baseline 20 of 20 in her left eye. Fluorescein angiogram was nondiagnostic. Optical coherence tomography revealed perifoveal hyper-reflective bands in the inner nuclear layer in a pattern characteristic of paracentral acute middle maculopathy. The patient received intra-arterial tissue plasminogen activator through her left ophthalmic artery shortly after presentation, resulting in a gradual restoration of the visual acuity to 20 of 20 in the three months after the procedure.This is the first report describing the use of intra-arterial tissue plasminogen activator to treat incomplete central retinal artery occlusion presenting as a paracentral acute middle maculopathy lesion in a patient with sickle cell disease.

Sickle cell disease (SCD) exists on a phenotypic spectrum with variable genetic expressivity, making it difficult to assess an individual patient’s risk of complications at any particular point in time. Current and emerging SCD treatments, including CRISPR-based gene editing, result in a variable proportion of affected red blood cells (RBCs) still vulnerable to sickling. Clinical serological indicators of disease such as hemoglobin, indirect bilirubin, and reticulocyte count and clinical metrics including number of emergency department visits and hospitalizations over time often fall short in their ability to objectively quantify ischemic disease activity and efficacy of treatments. Clearly, better clinical biomarkers are needed. The rapidly developing field of oculomics leverages the transparent nature of the ocular tissue to directly study the retinal microvasculature in order to characterize the status of systemic diseases. In this case report, we demonstrate the ability of optical coherence tomography angiography (OCT-A) to detect and measure micro-occlusive events within the retinal capillary bed before and after RBC exchange transfusion and following CRISPR-based gene editing, as an indicator of systemic ischemic disease activity and measure of treatment efficacy. The implications of these findings are discussed.

Venous thromboembolic complications have been reported in association with coronavirus disease 2019 (COVID-19) infection. We raised awareness regarding a potential temporal association between COVID-19 infection and retinal vein occlusion (RVO).Multicenter, retrospective, nonconsecutive case series.Patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection, were included. The exclusion criteria were as follows: age50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization.This was a multicenter, retrospective, nonconsecutive case series including patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection. The exclusion criteria were as follows: age50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization.Ophthalmic findings, including presenting and final visual acuity (VA), imaging findings, and clinical course.Twelve eyes of 12 patients with CRVO (9 of 12) or HRVO (3 of 12) after COVID-19 infection were included. The median age was 32 years (range, 18-50 years). Three patients were hospitalized, but none were intubated. The median time from COVID-19 diagnosis to ophthalmic symptoms was 6.9 weeks. The presenting VA ranged from 20/20 to counting fingers, with over half (7 of 12) having a VA of ≥20/40. OCT revealed macular edema in 42% of the eyes; of these, 80% (4 of 5) were treated with anti-VEGF injections. Ninety-two percent (11 of 12) had partial or complete resolution of ocular findings at final follow-up. Four eyes (33%) had retinal thinning, as determined using OCT, by the end of the study interval. The final VA ranged from 20/20 to 20/60, with 11 of the 12 (92%) eyes achieving a VA of ≥20/40 at a median final follow-up period of 13 weeks (range, 4-52 weeks).Although we acknowledge the high seroprevalence of COVID-19 and that a causal relationship cannot be established, we reported this series to raise awareness regarding the potential risk of retinal vascular events due to a heightened thromboinflammatory state associated with COVID-19 infection.

Retinal surface macrophages play key roles in the regulation of immune response, maintenance of vitreous clarity, and tissue repair. We examined the variation of parafoveal surface macrophages in a thyroid eye disease (TED) patient before and after treatment with teprotumumab (Tepezza, Horizon therapeutics). Pre- and posttreatment parafoveal surface macrophages were imaged using clinical en face OCT, and their density was assessed using a novel cell density mapping technique. Pretreatment, surface macrophage cell density was high. Macrophages had a nonuniform spatial distribution, and their appearance was round with few protrusions, consistent with an “activated” state. Posttreatment, cell density decreased. The macrophages were regularly spaced and had a ramified appearance and filopodia-like processes, consistent with a “quiescent” state. Surface macrophage density decreased as the Clinical Activity Score (CAS) decreased with teprotumumab treatment, suggesting a potential association of these cells with an underlying intraocular and retinal inflammatory process previously not described in TED.

PurposeRecent studies of glaucoma, age-related macular degeneration, and diabetic retinopathy have demonstrated that flavoprotein fluorescence (FPF) can be utilized non-invasively as an indicator of mitochondrial oxidative stress in the retina. However, a comprehensive assessment of the validity and reliability of FPF in differentiating between healthy and diseased eyes across multiple disease states is lacking. Here, we evaluate the sensitivity and specificity of FPF in discriminating between healthy and diseased eyes in four leading causes of visual impairment worldwide, one of which has not been previously evaluated using FPF. We also evaluate the association between FPF and visual acuity.MethodsA total of 88 eyes [21 eyes of 21 unaffected controls, 20 eyes from 20 retinal vein occlusion (RVO) patients, 20 eyes from 20 diabetic retinopathy (DR) patients, 17 eyes from 17 chronic exudative age-related macular degeneration (exudative AMD) patients, and 10 eyes from 10 central serous retinopathy (CSR) patients] were included in the present cross-sectional observational study. Eyes were imaged non-invasively using a specially configured fundus camera OcuMet Beacon® (OcuSciences, Ann Arbor, MI). The macula was illuminated using a narrow bandwidth blue light (455 – 470 nm) and fluorescence was recorded using a narrow notch filter to match the peak emission of flavoproteins from 520 to 540 nm. AUROC analysis was used to determine the sensitivity of FPF in discriminating between diseased eyes and healthy eyes. Nonparametric Kruskal-Wallis Tests with post-hoc Mann Whitney U tests with the Holm-Bonferroni correction were performed to assess differences in FPF intensity, FPF heterogeneity, and best corrected visual acuity (BCVA) between the five groups. Spearman rank correlation coefficients were calculated to assess the relationship between FPF and BCVA.ResultsAUROC analysis indicated that FPF intensity is highly sensitive for detecting disease, particularly for exudative AMD subjects (0.989; 95% CI = 0.963 – 1.000, p=3.0 x 107). A significant difference was detected between the FPF intensity, FPF heterogeneity, and BCVA in all four disease states compared to unaffected controls (Kruskal-Wallis Tests, p = 1.06 x 10-8, p = 0.002, p = 5.54 x 10-8, respectively). Compared to healthy controls, FPF intensity values were significantly higher in RVO, DR, exudative AMD, and CSR (p < 0.001, p < 0.001, p < 0.001, and p = 0.001, respectively). Spearman rank correlation coefficient between FPF intensity and BCVA was ρ = 0.595 (p = 9.62 x 10-10).ConclusionsDespite variations in structural retinal findings, FPF was found to be highly sensitive for detecting retinal disease. Significant FPF elevation were seen in all four disease states, with the exudative AMD patients exhibiting the highest FPF values compared to DR, CSR, and RVO subjects. This is consistent with the hypothesis that there is elevated oxidative stress in all of these conditions as previously demonstrated by blood studies. FPF intensity is moderately correlated with the late-in disease-marker BCVA, which suggests that the degree of FPF elevation can be used as a metabolic indicator of disease severity.

While plasmapheresis is well known to significantly improve both retinal findings and systemic manifestations associated with Waldenstrom macroglobulinemia, few reports exist documenting changes in optical coherence tomography angiography (OCT-A). The authors present a case of a patient with Waldenstrom macroglobulinemia who had resolution of white-centered peripheral retinal lesions and parafoveal outer nuclear layer hyperreflective material following plasmapheresis. Applying image analysis software to before and after OCT-A images, the authors were able to show an objective decrease in retinal capillary and large vessel density following plasmapheresis. This technique can be used to guide treatment and surveillance for patients with hyperviscosity-related retinopathy.

The main purpose of this study was to investigate the presence of retinal autofluorescence findings in COVID-19 patients. Observational study conducted in São Paulo in 2020. Demographic, medical history, and concomitant events, as well as medications used, hospitalization details, and laboratory test results, were obtained. Patients underwent eye examination and multimodal imaging, including color, red-free, autofluorescence fundus photography and optical coherence tomography. Eighteen patients had autofluorescence findings (6 females; average age 54 years, range 31 to 86 years; 26 eyes). Hyper-autofluorescence findings were present in 6 patients, Hypo-autofluorescence in 14 patients, and 6 patients had mixed pattern lesions. Retinal autofluorescence abnormalities were present in COVID-19 patients and may be secondary to primary or secondary changes caused by the SARS-CoV-2.

INTRODUCTION: Hyalocytes are sentinel macrophages residing within the posterior vitreous cortex anterior to the retinal inner limiting membrane (ILM). Following anomalous PVD and vitreoschisis, hyalocytes contribute to paucicellular (vitreo-macular traction syndrome, macular holes) and hypercellular (macular pucker, proliferative vitreo-retinopathy, proliferative diabetic vitreo-retinopathy) diseases. AREAS COVERED: Studies of human tissues employing dark-field, phase, and electron microscopy; immunohistochemistry; and in vivo imaging of human hyalocytes. EXPERT OPINION: Hyalocytes are important in early pathophysiology, stimulating cell migration and proliferation, as well as subsequent membrane contraction and vitreo-retinal traction. Targeting hyalocytes early could mitigate advanced disease. Ultimately, eliminating the role of vitreous and hyalocytes may prevent proliferative vitreo-retinal diseases entirely.

Vitreous cortex hyalocytes (VCH) are resident macrophage cells that provide immunosurveillance, respond to tissue injury and inflammation, and help maintain the transparency of the media. In this case report we demonstrate the use ofA 38-year-old female with no known medical history presented with complaints of visual disturbances in the right eye. OCT revealed hyperreflective bands in the IPL and INL nasal to the fovea. A diagnosis of PAMM was made. Work-up revealed elevated titers of antiphospholipid antibodies.Our findings suggest that monitoring changes in the distribution and morphology of VCH could have a potential clinical utility for assessing disease severity, predicting recovery, and early recognition of treatment response in various inflammatory ocular pathologies such as PAMM.

Purpose To report a case of macular vortex vein imaged with indocyanine green angiography, spectral domain optical coherence tomography, and optical coherence tomography angiography. Methods Observational case report. Results A 51-year-old myopic man presented with the complaint of a floater in his left eye for the previous 2 weeks. His visual acuity was 20/25 in the right eye and 20/40 in the left eye. Biomicroscopy was normal. Retinoscopy revealed lattice degeneration and posterior vitreous detachment of both eyes with dilated submacular vasculature in the right eye and submacular hemorrhage in the left eye. Spectral domain optical coherence tomography demonstrated dilated vessels in the choroid of the right eye and a choroidal neovascular membrane in the left eye. Fluorescein angiography and indocyanine green angiography showed a macular vortex vein in the right eye. Optical coherence tomography angiography demonstrated normal vessel densities in the superficial and deep capillary plexuses. No abnormalities were detected in the outer retina or choriocapillaris. Optical coherence tomography angiography delineated the macular vortex vein with a relative flow void in the right eye. His vision remained stable in the right eye. Conclusion Macular vortex veins may be a prominent, albeit rare, incidental finding in highly myopic eyes. Further studies with application of newer optical coherence tomography angiography modalities, such as swept-source optical coherence tomography angiography, are recommended to improve our understanding and monitoring of these structures.

Purpose: Lipopolysaccharide (LPS) can activate Toll-like receptor 4 (TLR4) and increase the expression of CXCL1 and CXCL2, the potent neutrophils chemoattractants, in various cell types. These effects have not been previously reported in the uveal melanocytes. This study was designed to investigate the effects of LPS on the activation of TLR4 and expression of CXCL1/CXCL2 in cultured human uveal melanocytes and the relevant signal pathways.Methods: Effects of LPS on the expression of TLR4 were tested using real-time PCR, flow cytometry and fluorescence immunostaining. Effects of LPS-induced expression/secretion of CXCL1/CXCL2 were studied using real-time PCR in cell lysates and ELISA in conditioned media of cultured uveal melanocytes. Activated NF-κB and phosphorylated MAPK signals were tested in cells with and without LPS treatment using flow cytometry. Effects of various signal inhibitors on p38, ERK1/2, JNK1/2 and NF-κB on the secretion of CXCL1/CXCL2 were tested by ELISA. The effects of neutralized antibodies of CXCL1/CXCL2 on the severity of LPS-induced uveitis were tested in a mouse model.Results: LPS stimulation increased the expression of TLR4 mRNA and protein in culture uveal melanocytes. Constitutive secretion of CXCL1/CXCL2 was detected in uveal melanocytes and was significantly increased dose- and time-dependently by LPS stimulation. LPS mainly increased the activated NF-κB and phosphorylated JNK1/2. LPS-induced expression of CXCL1/CXCL2 was blocked by NF-κB and JNK1/2 inhibitors. The severity of LPS-induced uveitis was significantly inhibited by neutralizing antibody to CXCL1/CXCL2Conclusions: This is the first report on the LPS-induced expression of CXCL1 and CXCL2 by uveal melanocytes via the activation of TLR4. These results suggest that uveal melanocytes may play a role in the immune reaction that eliminates the invading pathogens. Conversely, an excessive LPS-induced inflammatory reaction may also lead to the development of inflammatory ocular disorders, such as non-infectious uveitis.

Ethan K Sobol,1,2 Yu Sakai,3 Danielle Wheelwright,3 Carl S Wilkins,1,2 Amanda Norchi,1 Michael G Fara,4 Christopher Kellner,3 James Chelnis,1 J Mocco,3 Richard B Rosen,1,2 Reade A De Leacy,3 Gareth MC Lema1,2 1Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; 2Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, 10003, USA; 3Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; 4Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USACorrespondence: Gareth MC LemaDepartment of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USATel +1 212-241-0939Fax +1 212-824-2325Email gareth.lema@mssm.eduPurpose: To investigate the benefit of early intra-arterial tissue plasminogen activator (IAT) for treatment of central retinal artery occlusion (CRAO).Patients and Methods: Fifteen eyes of 15 patients presenting with acute CRAO were included in this retrospective consecutive interventional case series. Patients were excluded if treatment with IAT was not initiated within 12 hours. The diagnosis was confirmed by an ophthalmologist. IAT was performed via a transfemoral arterial approach. Tissue plasminogen activator (tPA) was infused into the ophthalmic artery in aliquots up to 3mg to a maximum of 22mg. Paracentesis was done at the ophthalmologist’s discretion. The primary outcome measure was visual acuity after three weeks. Adverse events were recorded during treatment and follow-up visits.Results: After treatment with IAT, there was a statistically significant improvement in visual acuity, with a mean change of − 0.76 (SD 0.91; range − 2.4 to 0.85) logMAR (p=0.006). Vision improved by 3 or more lines in 53%, and of these, the mean Snellen visual acuity improvement was > 6 lines. Notably, 4 patients (27%) improved from CF or worse to 20/80 or better. The mean dose of tPA used was 17mg and the mean time to treatment was 8.83 hours (range: 5.5 to 12 hours). There were no statistically significant differences based on time to treatment, dose of tPA, or use of a paracentesis. No major adverse events were recorded.Conclusion: IAT was safe and showed significant visual improvement in this small uncontrolled study. Larger studies and efforts to decrease time to treatment should be initiated to optimize outcomes.Keywords: CRAO, tPA, intervention, treatment, ophthalmic artery

The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA’s globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique “fingerprint” or “biomarker” vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.

Acute retinal necrosis is a rare yet devastating disease, with significant ocular morbidity. Over the past several decades, initial treatment regimens have shifted from intravenous antivirals requiring hospital admission to the routine use of oral antivirals with intravitreal antivirals for immediate local control. Given the rarity of this disease process and a lack of large-scale research trials, debate continues over recommended practice guidelines. In this paper, we review current diagnostic criteria and recommend a treatment algorithm based on available evidence.

Aim To test our hypothesis that activation of protein kinase A (PKA) signal pathway by β-adrenergic agonist plays an important role in the protecting of cultured retinal pigment epithelial (RPE) cells against the hydroxychloroquine (HCQ) toxicity. Methods Cultured human RPE cells were treated with 1) HCQ, 2) HCQ with salbutamol (a β2-adrenergic receptor agonist), and 3) HCQ with salbutamol and a PKA inhibitor, and compared these to 4) untreated cells (controls). After treated for 24h, cell vacuolation, cells viability, PKA and PKA kinase activity levels were determined by the measurement of the size of vacuoles using Image J software, the cell counting with a dye-exclusion testing, Western blot and PKA kinase detection, respectively. Results Cell vacuolation and cell death of cultured RPE cells were significantly increased by the treatment of HCQ. Salbutamol significantly elevated PKA and PKA activity levels and this was associated with the inhibition of the vacuolation and cell death. The PKA inhibitor significantly decreased the PKA levels and eliminated the protective effects of salbutamol on HCQ-treated RPE cells. Conclusion The PKA pathway plays an important role in the protective effects of β2-adrenergic agonist on the RPE cells against HCQ toxicity. These findings reveal a novel potential strategy against HCQ retinopathy by treatment with PKA activating medications.

Purpose: To report a new modification of an illuminated endolaser to facilitate safe endophotocoagulation during chandelier-assisted scleral buckling surgery. Methods: This case series comprised phakic patients with rhegmatogenous retinal detachments (RRDs) who had primary scleral buckling with chandelier endoillumination, external drainage, and endophotocoagulation using the modified endolaser instrument. Results: All 6 patients had successful outcomes after primary scleral buckling for RD repair without significant intraoperative or postoperative complications. Conclusions: The new modified endolaser instrument can be safely used in a nonvitrectomized eye during chandelier scleral buckling.

Soft drusen and subretinal drusenoid deposits (SDDs) characterize two pathways to advanced age-related macular degeneration (AMD), with distinct genetic risks, serum risks, and associated systemic diseases.One hundred and twenty-six subjects with AMD were classified as SDD (with or without soft drusen) or non-SDD (drusen only) by retinal imaging, with serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke.There were 62 subjects with SDD and 64 non-SDD subjects, of whom 51 had CVD or stroke. SDD correlated significantly with lower mean serum high-density lipoprotein (61 ± 18 vs. 69 ± 22 mg/dL, P = 0.038, t-test), CVD and stroke (34 of 51 SDD, P = 0.001, chi square), ARMS2 risk allele (P = 0.019, chi square), but not with CFH risk allele (P = 0.66). Non-SDD (drusen only) correlated/trended with APOE2 (P = 0.032) and CETP (P = 0.072) risk alleles (chi square). Multivariate independent risks for SDD were CVD and stroke (P = 0.008) and ARMS2 homozygous risk (P = 0.038).Subjects with subretinal drusenoid deposits and non-SDD subjects have distinct systemic associations and serum and genetic risks. Subretinal drusenoid deposits are associated with CVD and stroke, ARMS2 risk, and lower high-density lipoprotein; non-SDDs are associated with higher high-density lipoprotein, CFH risk, and two lipid risk genes. These and other distinct associations suggest that these lesions are markers for distinct diseases.

Alexander Pinhas,1,2 Jorge S Andrade Romo,1 Giselle Lynch,1,3 Davis B Zhou,1,3 Maria V Castanos Toral,1 Phillip A Tenzel,1 Oscar Otero-Marquez,1 Shoshana Yakubova,1,4 Alexander Barash,1 David Della Rocca,1 Robert Della Rocca,1 Toco YP Chui,1 Richard B Rosen,1 Harsha S Reddy1 1Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA; 2Department of Ophthalmology, State University of New York Downstate Medical Center, Brooklyn, NY, USA; 3Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Department of Biology, Macaulay Honors College at City University of New York Queens College, Flushing, NY, USACorrespondence: Harsha S Reddy, Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, 310 E 14th St, New York, NY, 10003, USA, Tel +1 212-979-4284, Fax +1 212-966-6295, Email hreddy@nyee.eduPurpose: Hemodynamic changes surrounding the optic nerve head are known to occur in thyroid-related orbitopathy (TRO). This pilot study explores the capillary and non-capillary peripapillary perfusion changes of the retina in TRO eyes without dysthyroid optic neuropathy (DON) using optical coherence tomography angiography (OCT-A).Methods: Non-capillary and capillary peripapillary perfusion densities were calculated using single 4.5 × 4.5mm en face “RPC layer” OCT-A scans of 8 TRO patients without DON (8 eyes, mean age 40.6 years, range 23– 69 years). Results were compared to a previously published dataset of 133 healthy controls (133 eyes, mean 41.5 years, range 11– 83 years). The strength of association was measured between OCT-A perfusion densities and clinical measures of TRO.Results: Non-capillary peripapillary perfusion density in TRO eyes was found to be significantly decreased compared to healthy controls (TRO group 15.4 ± 2.9% vs controls 21.5 ± 3.1%; p < 0.0001). Capillary peripapillary perfusion densities showed no significant difference (TRO group 42.5 ± 1.8% vs controls 42.5 ± 1.5%; p = 1.0). Clinical measures of disease did not correlate well with OCT-A perfusion densities (p> 0.05).Conclusion: These findings may represent decreased blood flow and subclinical ischemia to the optic nerve. We discuss possible pathogenic mechanisms of thyroid-related vasculopathy, including vessel wall thickening due to immunologically-induced media enlargement.Keywords: thyroid-related orbitopathy, optical coherence tomography angiography, peripapillary microvasculature, thyroid-related vasculopathy

Purpose Pain after an intravitreal injection (IVI) can last up to 7 days and negatively impacts the patient’s experience, potentially reducing treatment compliance. We prospectively evaluated topical nepafenac 0.3% suspension and patching for the reduction of pain after IVI. Design Randomized controlled trial. Participants Sixty patients receiving an IVI of bevacizumab, aflibercept, or triamcinolone acetonide in 1 eye. Methods Participants were randomized equally to receive either a single drop of nepafenac 0.3%, a pressure patch for 2 hours, or a single drop of preservative-free artificial tears (control group). A single-blinded placebo-controlled design was used to mask the topical treatment used. Pain was assessed using the Numeric Pain Rating Scale that ranged from 0 to 10 (horizontal pain scale). Because pain scores were not normally distributed, statistical analysis was performed using a nonparametric randomization-based analysis of covariance. Main Outcome Measure Pain scores. Results Fifty-six and 53 patients of the 60 patients enrolled completed the 6- and 24-hour follow-ups, respectively. Numeric Pain Rating Scale scores at 6 and 24 hours after IVI were lower in the nepafenac group (0.8±0.3 and 0.1±0.1, respectively; n = 18) and the patching group (1.3±0.4 and 0.4±0.2, respectively; n = 19) compared with the control group (2.5±0.6 and 0.9±0.4, respectively; n = 19). After controlling for age, gender, number of prior injections, and physician administering the injection, patients in the nepafenac group reported significantly lower pain scores than those in the control group at 6 hours (1.3±0.6 less; P = 0.047) and 24 hours (0.7±0.3 less; P = 0.047). Although the patching group reported lower pain scores than the control group, this was not statistically significant (6 hours, P = 0.24; 24 hours, P = 0.29). Conclusions Nepafenac 0.3% was effective as a single drop in reducing pain at 6 and 24 hours after IVI compared with placebo. Limited patching was associated with lower pain scores than placebo, but the difference was not statistically significant. Additional studies are needed to determine the most effective method to maximize the patient’s experience after an IVI without sacrificing outcomes.

Purpose To summarize the results of a consensus meeting aimed at defining terminology for widefield imaging across all retinal imaging methods and to provide recommendations for the nomenclature used to describe related images. Design An international panel with expertise in retinal imaging was assembled to define consensus terminology for widefield imaging and associated terminology. Participants A panel of retina specialists with expertise in retinal imaging. Methods Before the consensus meeting, a set of 7 images acquired with a range of imaging methods and representing both healthy and diseased eyes was circulated to the expert panel for independent assignment of nomenclature for each example. The outputs were assembled and used as the starting point for discussions occurring at a subsequent roundtable meeting. The anatomic location, field of view, and perspective provided by each image example was reviewed. A process of open discussion and negotiation was undertaken until unanimous terminology for widefield imaging was achieved. Main Outcome Measures Definitions of widefield imaging applicable to multiple imaging methods. Results Across a range of different imaging methods, the expert panel identified a lack of uniform terminology being used in recent literature to describe widefield images. The panel recommended the term widefield be limited to images depicting retinal anatomic features beyond the posterior pole, but posterior to the vortex vein ampulla, in all 4 quadrants. The term ultra widefield was recommended to describe images showing retinal anatomic features anterior to the vortex vein ampullae in all 4 quadrants. The definitions were recommended over other device-specific terminology. Conclusions A consistent nomenclature for widefield imaging based on normal anatomic landmarks that is applicable to multiple retinal imaging methods has been proposed by the International Widefield Imaging Study Group. The panel recommends this standardized nomenclature for use in future publications.

Purpose: We describe the features of niacin maculopathy in a 61-year old man using ocular coherence tomography (OCT), fluorescein angiography, and electroretinography (ERG). Methods: A case report is presented. Results: A 61-year-old male presented with decreased visual acuity. Cirrus OCT revealed bilateral cystic macular edema, without leakage on fluorescein angiography. Dark-adapted maximal-flash ERG demonstrated an absent b-wave. Light-adapted flicker responses revealed diminished amplitude and delayed implicit time (IT). Multifocal ERG demonstrated diffusely decreased amplitudes. Two months after discontinuation of niacin, OCT demonstrated complete resolution of the macular edema. Dark-adapted maximal-flash ERG showed improvement in the b-wave. Light-adapted flicker responses improved in amplitude and decreased IT. Conclusions: To the best of the authors’ knowledge, this case is the first to demonstrate a reduced b-wave in niacin maculopathy. Discontinuation of niacin led to an improved b-wave response suggesting that niacin maculopathy is caused by niacin induced muller cell dysfunction.

Previous studies examining the association of retinal vein occlusion (RVO) and cardiovascular events have been inconsistent and have mostly focused on stroke and myocardial infarction. The goal of this study is to use meta-analysis to examine the available evidence examining the association of RVO with incident cardiovascular events and mortality.Systematic review and meta-analysis of all longitudinal cohort studies published in PubMed, Embase, and the Cochrane Library from inception to April 7, 2018, that evaluated the association of baseline RVO and incident cardiovascular events and/or mortality, that provided multivariate-adjusted risk estimates with 95% confidence intervals (95% CIs), and that had average follow-up ≥1 year. The Newcastle-Ottawa scale was used to assess study quality. Multivariate-adjusted risk estimates with 95% CI along with study characteristics were extracted from each study, and pooled risk ratios (RRs) with 95% CI were generated using a random-effects model with inverse-variance weighting to account for heterogeneity. Main outcomes were incident stroke (fatal or nonfatal), myocardial infarction, heart failure, peripheral arterial disease, all-cause mortality, and cardiovascular mortality.Fifteen cohort studies with a total of 474,466 patients (60,069 with RVO and 414,397 without RVO) were included. Each study had Newcastle-Ottawa scale score ≥6, indicating moderate-to-high quality. Retinal vein occlusion was associated with increased risk of stroke (RR = 1.45; 95% CI, 1.31-1.60), myocardial infarction (RR = 1.26; 95% CI, 1.17-1.37), heart failure (RR = 1.53; 95% CI, 1.22-1.92), peripheral arterial disease (RR = 1.26; 95% CI, 1.09-1.46), and all-cause mortality (RR = 1.36; 95% CI, 1.02-1.81), but was not associated with increased risk of cardiovascular mortality (RR = 1.78; 95% CI, 0.70-4.48).This review suggests patients with RVO have an increased risk of cardiovascular events and all-cause mortality. More studies are needed to determine the highest risk periods for cardiovascular events and mortality after RVO and whether immediate cardiovascular evaluation and intervention will improve outcomes.

PurposeSoft drusen and subretinal drusenoid deposits (SDD) aka reticular macular disease (RMD) characterize two pathways to advanced age-related macular degeneration (AMD). We propose these pathways are distinct diseases, with distinct genetic risks, serum risks and associated systemic diseases.Methods126 Subjects with AMD had: retinal imaging for RMD status, serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke.Results62 subjects had RMD, 64 were nonRMD (drusen only), 51 had CVD or Stroke. RMD correlated significantly with: ARMS2 risk allele (p= 0.019); lower mean serum HDL (61±18 vs. 69±22 mg/dl, p= 0.038, t test); CVD and troke (34/51 RMD, p= 0.001).NonRMD correlated/trended with APOE2 (p= 0.032) and CETP (p= 0.072) risk alleles. 97 subjects total had some drusen, which correlated with CFH risk (p= 0.016). Multivariate independent risks for RMD were: CVD and Stroke (p= 0.008), and ARMS2 homozygous risk (p= 0.038).ConclusionThe RMD and soft drusen AMD pathways have distinct systemic associations, serum and genetic risks. RMD is associated with CVD and stroke, ARMS2 risk, and lower HDL; drusen with CFH risk and two lipid risk genes. These pathways appear to be distinct diseases leading to advanced AMD.Summary StatementTwo phenotypes of age-related macular degeneration, soft drusen and reticular macular disease (the combination of subretinal drusenoid deposits and choriocapillaris insufficiency), are shown here to have distinct systemic vascular, serum, and genetic risks. These findings support the concept that these phenotypes actually represent distinct disease processes.

ImportanceHigh-risk vascular diseases (HRVs) may remain undetected until catastrophe ensues. Detection from non-invasive retinal imaging would be highly significant.ObjectiveTo demonstrate that certain lesions of Age-Related Macular Degeneration (AMD) found on retinal imaging correlate with co-existing HRVs.DesignCross-sectional cohort study. Two years. Retinal image graders blinded to HRV status.Setting2 retina referral clinics.Participants151 consecutive AMD patients, ages 50-90, 97 females, 54 males, with lesions of soft drusen and/or subretinal drusenoid deposits (SDD). 12 others approached, 10 refused, 2 excluded.MethodsPatients were classified by retinal imaging into SDD (SDD present, +/- drusen) or nonSDD (soft drusen only), and by history into HRV (cardiac pump defect (myocardial infarction (MI), coronary artery bypass grafting (CABG), congestive heart failure (CHF)), valve defect, and carotid stroke) or nonHRV, with serum risk factors and medical histories.Main Outcome MeasuresCorrelations of HRV with SDD and other covariates (Univariate chi-square and multivariate regression). Performance of Machine Learning predicting HRV.Results75 SDD subjects; 76 nonSDD subjects; HRV prevalence 19.2% (29/151).High density lipoprotein (HDL) < 62 mg/Dl was found in 24/29 HRV, 42/122 nonHRV, OR 12.40, 95% Confidence Interval (CI) 5.125-30.014; p= 0.0002.15 Pump defects, 14/15 SDD, 8 Valve defects, 6/8 SDD (4 severe aortic stenosis), 6 carotid strokes, 5/6 SDD. Total HRVs 29, 25/29 SDD, OR 9.0, 95% CI 2.95-27.46; p= 0.000012.Adjusted multivariate correlations. HRV with SDD (p= 0.000333). SDD and HDL < 62 with HRV (p= 0.000098 and 0.021).Machine Learning prediction of HRVs from SDD status and HDL level: specificity 87.4%, sensitivity 77.4%, accuracy 84.9%; 95% CIs(%) 79.0-93.3, 58.0-90.4, 77.5-90.7, respectively.Conclusions and RelevanceHigh-risk vascular diseases were accurately identified in a cohort of AMD patients from the presence of characteristic deposits (SDDs) on imaging and HDL levels. The SDDs are directly consequent to inadequate ocular perfusion resulting from the systemic vasculopathies. Further validation in larger cohorts of both vasculopathic and AMD subjects could bring this system into widespread medical practice, to reduce mortality and morbidity from vascular disease, particularly in women, where undiagnosed cardiac disease remains a serious issue.Key PointsQuestionWhat is the relationship and driving mechanism between High Risk Vascular Diseases (HRVs) and Age-Related Macular Degeneration (AMD)?FindingsThe specific AMD lesions of Subretinal Drusenoid Deposits (SDDs) were found to be highly correlated with and directly consequent to the inadequate ocular perfusion resulting from the HRVs of severe cardiac pump insufficiency or valve defect, and carotid occlusion, These vasculopathies could be predicted from the presence of SDDs on spectral domain optical coherence tomography (SD-OCT) imaging and serum HDL.MeaningScreening for SDDs with SD-OCT imaging could reduce mortality and morbidity from severe vascular disease, particularly in women, where undiagnosed cardiac disease remains a serious issue.

Purpose Lafora disease is a genetic neurodegenerative metabolic disorder caused by insoluble polyglucosan aggregate accumulation throughout the central nervous system and body. The retina is an accessible neural tissue, which may offer alternative methods to assess neurological diseases quickly and noninvasively. In this way, noninvasive imaging may provide a means to characterize neurodegenerative disease, which enables earlier identification and diagnosis of disease and the ability to monitor disease progression. In this study, we sought to characterize the retina of individuals with Lafora disease using non-invasive retinal imaging. Methods One eye of three individuals with genetically confirmed Lafora disease were imaged with optical coherence tomography (OCT) and adaptive optics scanning light ophthalmoscopy (AOSLO). When possible, OCT volume and line scans were acquired to assess total retinal thickness, ganglion cell-inner plexiform layer thickness, and outer nuclear layer + Henle fiber layer thickness. OCT angiography (OCTA) scans were acquired in one subject at the macula and optic nerve head (ONH). AOSLO was used to characterize the photoreceptor mosaic and examine the retinal nerve fiber layer (RNFL). Results Two subjects with previous seizure activity demonstrated reduced retinal thickness, while one subject with no apparent symptoms had normal retinal thickness. All other clinical measures, as well as parafoveal cone density, were within normal range. Nummular reflectivity at the level of the RNFL was observed using AOSLO in the macula and near the ONH in all three subjects. Conclusions This multimodal retinal imaging approach allowed us to observe a number of retinal structural features in all three individuals. Most notably, AOSLO revealed nummular reflectivity within the inner retina of each subject. This phenotype has not been reported previously and may represent a characteristic change produced by the neurodegenerative process.

Age-related macular degeneration (AMD) remains a leading cause of modifiable vision loss in older adults. Chronic oxidative injury and compromised antioxidant defenses represent essential drivers in the development of retinal neurodegeneration. Overwhelming free radical species formation results in mitochondrial dysfunction, as well as cellular and metabolic imbalance, which becomes exacerbated with increasing age. Thus, the depletion of systemic antioxidant capacity further proliferates oxidative stress in AMD-affected eyes, resulting in loss of photoreceptors, neuroinflammation, and ultimately atrophy within the retinal tissue. The aim of this systematic review is to examine the neuroprotective potential of the xanthophyll carotenoids lutein, zeaxanthin, and meso-zeaxanthin on retinal neurodegeneration for the purpose of adjunctive nutraceutical strategy in the management of AMD. A comprehensive literature review was performed to retrieve 55 eligible publications, using four database searches from PubMed, Embase, Cochrane Library, and the Web of Science. Epidemiology studies indicated an enhanced risk reduction against late AMD with greater dietary consumption of carotenoids, meanwhile greater concentrations in macular pigment demonstrated significant improvements in visual function among AMD patients. Collectively, evidence strongly suggests that carotenoid vitamin therapies offer remarkable synergic protection in the neurosensory retina, with the potential to serve as adjunctive nutraceutical therapy in the management of established AMD, albeit these benefits may vary among different stages of disease.

To investigate the presence of flavoprotein fluorescence (FPF) at the optic nerve head (ONH) rim as a marker of mitochondrial dysfunction in primary open-angle glaucoma (POAG) and control eyes.Retrospective cross-sectional study of patients recruited from the New York Eye and Ear Infirmary of Mount Sinai.A total of 86 eyes (50 eyes of 30 patients with POAG and 36 eyes of 20 control participants) were enrolled. The presence of POAG was defined by circumpapillary retinal nerve fiber layer thickness (cpRNFLT) of less than the bottom fifth percentile of the normative database, glaucomatous ONH changes, and visual field defects on 24-2 tests.Primary open-angle glaucoma and control eyes were imaged using the OcuMet Beacon. A 23° × 23° infrared scan was obtained, and an FPF scan was performed within a capture field spanning 13° in diameter. The ONH margins on the infrared image were identified by software algorithms. Then, FPF was measured within an elliptical annulus around the ONH rim, with the inner and outer boundaries corresponding to 0.5 to 1.1 times the ONH rim size.Flavoprotein fluorescence at the OHN rim in POAG and control eyes.Differences in FPF between POAG and control eyes were characterized through mixed-effects logistic regression, adjusted for age and interocular pressure. Flavoprotein fluorescence was significantly higher in POAG versus control eyes, with a mean ± SD of 46.4 ± 27.9 versus 28.0 ± 11.7 (P0.001), respectively. Among POAG eyes, FPF showed correlation to visual field mean deviation (P0.001), visual field pattern standard deviation (P = 0.003), and cpRNFLT (P = 0.001) on linear mixed-effects models.Higher FPF in POAG versus control eyes suggests the presence of mitochondrial dysfunction at the ONH rim in eyes with glaucomatous damage. The degree of FPF corresponds to disease severity, as measured by visual field and nerve fiber layer thickness metrics. Thus, FPF may represent a metabolic indicator of disease status that reveals the extent of injury in glaucoma.

The main purpose of this study was to investigate ocular clinical findings in patients with confirmed COVID-19 infection, of various levels of disease severity, who required mechanical ventilation and admission to intensive care units or specialized wards. Longitudinal, observational study conducted from March 2020 to June 2020. Color fundus and red-free photography were performed in both eyes following pupillary dilation. 104 participants were recruited from 2 different centers: 60 (58%) from the Hospital Municipal de Barueri intensive care unit (ICU) and 44 (42%) from specialized wards for patients with COVID-19 at the Hospital Sao Paulo. 21.9% presented with eye lesions, in 3% these lesions were vision compromising. Our results have shown similar rate of intraocular lesions in patients in both the ward or intensive care unit, regardless of medication use, including anticoagulant drugs.

Purpose Fundus albipunctatus is an inherited cause of congenital stationary night blindness. The objective of this report is to describe structural changes occurring in a macular phenotype of a novel RDH5 mutation producing fundus albipunctatus using high-resolution in vivo imaging. A 62-year-old male with longstanding night blindness underwent imaging and genetic evaluation. High-resolution images of the photoreceptor mosaic were compared to those of a healthy subject. Results of a comprehensive ophthalmic evaluation and genetic testing with imaging including fundus photography, spectral-domain optical coherence tomography (OCT), fluorescein angiography (FA), OCT angiography (OCT-A), and adaptive optics scanning light ophthalmoscopy (AOSLO) are described. Observations The patient presented with visual acuity of 20/25 in both eyes and longstanding poor dark adaptation. Anterior segment examination was unremarkable. Fundoscopy revealed well circumscribed bilateral perifoveal mottling and atrophy in both eyes. Discrete white-yellow flecks were present beyond the vascular arcades extending to the far periphery. Genetic testing revealed a novel compound heterozygous RDH5 mutation (c.388C > T, p.Gln130*; c.665T > C, p.Leu222Pro). OCT demonstrated perifoveal photoreceptor and outer retinal irregularities, which corresponded to a window defect with late staining on FA. OCT-A demonstrated normal retinal vasculature with patchy areas of non-perfusion in the choriocapillaris. Macular abnormalities in both eyes were imaged using AOSLO to assess cone and rod photoreceptor architecture. While clinical features are consistent with a primary rod disorder, confocal AOSLO showed a paucity of normal cones with a small spared central island in both eyes. Rods appeared larger and more irregular throughout the macula. Non-confocal split detection AOSLO imaging revealed the presence of cone inner segments in dark regions of confocal imaging, indicating some degree of photoreceptor preservation. Conclusions and Importance The AOSLO imaging of this particular macular phenotype of fundus albipunctatus demonstrates some of the structural photoreceptor abnormalities that occur in this condition, adding insight to the variable presentation of RDH5 retinopathy. The presence of preserved inner segment architecture suggests the possibility that gene therapy could play a future role in treating this condition.

PURPOSE OF REVIEW: In this article, the current use and limitations of existing retinal tamponades are discussed. Potential novel developments that address those limitations are subsequently highlighted, along with areas of future improvements. RECENT FINDINGS: While retinal tamponades have existed for decades and improved the treatment of retinal detachments, many problems still exist with their use, including inadequate tamponade of the inferior retina, toxicity from retained heavy liquids, glaucoma, and keratopathy, among others. New advancements in the components of heavy liquids and vitreous substitutes aim to mitigate those issues. SUMMARY: Existing retinal tamponades, including perflurocarbon heavy liquids, fluorinated gases, and silicone oil, have specific limitations that cause potentially avoidable morbidity. New developments, such as heavy silicone oil, novel vitreous gels, and future avenues of approach, such as potentially reabsorbing heavy liquids may help increase our ability to treat retinal detachments with fewer complications.

Background: Some patients with diabetic macular edema (DME) fail to completely respond to anti-vascular endothelial growth factor (VEGF) therapy. These patients have a high treatment burden in the absence of significant improvement. We investigate the role of intravitreal dexamethasone insert (IDI) in eyes with super-refractory DME. Methods: A non-randomized interventional study was performed among eyes with super-refractory DME refractory to anti-VEGF therapy. Eyes were treated with IDI after failing clinical response to anti-VEGF, with a minimum of 15 prior. Failure to respond was defined as failure of vision to improve at least one line on Snellen Acuity chart, central subfield thickness (CST) greater than 320 μm, or failure of CST to improve by 10% or more. Eyes with glaucoma or prior uncontrolled steroid-responsive ocular hypertension were excluded. Patient outcomes were analyzed at weeks 6, 12, 24, and year 1. Results: Six eyes of four patients were identified. All patients had failed aflibercept. The mean number of prior anti-VEGF injections was 34.5. Eyes received an average of 2.92 dexamethasone injections per person-year (PY) and required breakthrough anti-VEGF injection at 1.95/PY. Mean pre-treatment visual acuity was 0.475 LogMAR, improving to 0.342 at week 6, and 0.375 at 1 year. Mean CST pre-injection was 386.5 mm, improving to 315 mm at 1 year. No glaucoma developed. Conclusions: Intravitreal dexamethasone insert appears effective in eyes with super-refractory DME. IDI resulted in excellent anatomic improvement on SD-OCT as well as modest visual improvement. Injection burden was reduced in those who may otherwise receive years of monthly treatments.

Epiretinal membranes (ERM) are a collection of glial or RPE cells and collagenous cells that can form a contractile fibrocellular scaffold. This contractile scaffold can lead to reduced vision and metamorphopsia. Epiretinal membranes can occur idiopathically or may be associated with uveitis, posterior vitreous detachments, retinal tears, retinal detachments, and vitreous hemorrhage. ERMs have been called by a variety of different names including macular pucker, cellophane maculopathy, preretinal macular fibrosis, epimacular membranes, and preretinal gliosis. Ocular coherence tomography (OCT) can help identify the presence of an ERM and elucidate characteristics of retinal thickening or distortion and the extent of the ERM. Prior to a surgical intervention, it is important to establish that the ERM is in fact the cause of the patient’s visual disturbance.

Focal laser photocoagulation was the first treatment proven effective for reducing diabetic macular edema established by the Early Treatment Diabetic Retinopathy Study (ETDRS). The purpose of focal laser photocoagulation is to reduce the progression of diabetic macular edema and to stabilize visual function. Focal laser treatment is targeted at leaking microaneurysms identified by fluorescein angiography or by fundoscopic exam over areas of retinal thickening. Grid pattern photocoagulation can be applied over areas of diffuse leakage. Since the early 2000s, intravitreal injections of anti-vascular endothelial growth factor (VEGF) have revolutionized the management of diabetic macular edema. The treatment of diabetic macular edema often involves a multimodal approach combining the use of intravitreal anti-VEGF injections, with or without focal laser treatment, with or without intravitreal steroid injections.

Introduction. We present a case of serpiginous choroidopathy (SC) with novel OCTA and en face OCT reflectance findings which help identify subclinical disease progression. Case Presentation. En face OCT reflectance images demonstrated outer retinal tubules (ORT) at the serpiginous lesion margins of affected and unaffected retina on multimodal imaging. OCTA findings demonstrate variable dropout of choriocapillaris in “normal” retina beyond lesion borders which was not visible on standard imaging and which demonstrated a clear transition zone beyond the ORT. Discussion. This is the first report of choriocapillaris atrophy identified on OCTA not identified on traditional multimodal imaging in serpiginous choroidopathy. Damage to vasculature only visible with OCTA may help characterize the distribution of inflammation, aiding in monitoring of suppression not illustrated by traditional imaging and which may threaten the central macula. ORT in SC suggest death and reorganization of outer segments from dysfunction of the choriocapillaris and RPE, as well as serve to demarcate the area of chronic or old inflammation, supporting the hypothesis that the choriocapillaris is the primary site of inflammation in SC. Based on these findings, we recommend OCTA on all patients with serpiginous choroidopathy to monitor underlying state of inflammation and help determine immunosuppressive threshold.