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N-of-1 trials are randomized, prospective, controlled, multiple crossover trials in a single patient. Effects of one or more treatments are studied by following individual patients who receive alternative treatments (eg, therapeutic intervention). Such trials may provide a path to assess treatments for rare diseases with rigor equal to or greater than that afforded by parallel group randomized clinical trials provided that the condition is reasonably stable during the trial and has a sign/symptom that responds reversibly to the therapy and that can be measured repeatedly. In this article, the authors propose that N-of-1 trials may improve the feasibility and affordability of clinical trials for patients with rare inherited retinal diseases.

Epidemiologic studies related to the demographics and trends of ocular injury in the pediatric cohort in the last decade are limited. This study describes epidemiologic trends in consumer product–related pediatric ocular injuries from 2010 to 2019. This is a retrospective observational study utilizing data from the National Electronic Injury Surveillance System (NEISS). Inclusion criteria include pediatric patients ages 1–20 presenting to NEISS emergency departments with an ocular injury from January 1, 2010, to December 31, 2019. Outcome measures include prevalence of ocular injury related to consumer products stratified by age group, sex, and injury setting. There were an estimated 636,582 consumer product (CP)–related incidents of ocular injury in children ages 1–20 years with an average age of 9.7 years (SD = 5.92) between 2010 and 2019; 416,378 (65.4%) patients were males with a male-to-female ratio of 1.9:1. The annual incidence of CP-related ocular injury in males decreased from 2010 to 2019 while that in females remained unchanged. The greatest number of injuries occurred in the 1–5-year age group (31%) followed 6–10 group (25%), 16–20 (22%), and 11–15 (21%). Ocular contusion was the most common diagnosis. The most common setting of injury was home (63%). The majority (96%) of patients were treated and released from the ED suggesting a minor injury. Of the 1% of patients admitted to the hospital with ocular injuries, one-fourth were due to an open globe injury. Most ocular injuries occurred in the summer months, and presentation to the ED was more frequent on the weekend than a weekday. Over one-fourth (28%) of injuries were sports-related followed by detergents/chemicals (16%), toys (11%), home workshop equipment (8%), kitchenware (5.0%), and home furniture in (4.4%). The frequency and rate of pediatric ocular injuries in the USA decreased during the last decade. Sports and non-powder guns caused the greatest number of eye injuries in the older pediatric cohorts (11–15- and 16–20-year age groups), while detergents/chemicals accounted for nearly 1/3 of all injuries in younger children (1–5 years). Prophylactic measures targeted to specific age groups will be important in reducing eye injuries further.

PURPOSE To characterize the early retinal microvascular changes in young adults (age: 22.69 ± 3.50 years) with Type 1 diabetes mellitus without clinically detectable diabetic retinopathy using optical coherence tomography angiography and investigate the associated factors. METHODS A total of 36 participants with Type 1 diabetes mellitus (70 eyes) and 34 healthy controls (57 eyes) were retrospectively reviewed. The analyzed optical coherence tomography angiography indices included capillary vessel density, foveal avascular zone area/perimeter/acircularity index, and foveal vascular density, acquired in the 6 × 6-mm2 area centered on the fovea. The generalized estimation equations model was applied to compare the mean values and to study the associated factors. RESULTS In subjects with diabetes, statistically significant decreases were observed in parafoveal vessel density in both superficial and deep capillary plexuses, foveal avascular zone area/perimeter, and foveal vascular density when compared with controls (all P < 0.05). Higher glycated hemoglobin level was independently associated with the decrease of parafoveal vessel density as well as the increase of foveal avascular zone area/perimeter (all P < 0.05). Prepubescent onset of diabetes mellitus was also independently associated with the decrease of superficial parafoveal vessel density, foveal avascular zone area/perimeter, and foveal vascular density (P = 0.015, 0.011, 0.015, and 0.001, respectively). CONCLUSION In young adults with Type 1 diabetes mellitus lacking clinical signs of diabetic retinopathy, optical coherence tomography angiography revealed alterations in retinal microvasculature that were associated with glycated hemoglobin level and onset of diabetes mellitus related to puberty.

Background/aimTo evaluate relationships between subretinal fluid (SRF), macular atrophy (MA) and visual outcomes in ranibizumab-treated neovascular age-related macular degeneration (nAMD).MethodsThis post hoc HARBOR trial (NCT00891735) analysis included ranibizumab-treated (0.5 or 2.0 mg, monthly or as-needed, all treatment arms pooled) eyes with nAMD and baseline (screening, baseline and week 1) SRF. SRF presence, SRF thickness (0, >0–50, >50–100 and >100 µm) and subretinal fluid volume (SRFV) were determined by spectral domain optical coherence tomography (SD-OCT). Best-corrected visual acuity (BCVA) was assessed. MA was identified using fluorescein angiograms and colour fundus photographs, as well as SD-OCT.ResultsSeven hundred eighty-five of 1097 eyes met analysis criteria. In eyes without baseline MA, residual versus no SRF at month (M) 3 was associated with lower MA rates at M12 (5.1% vs 22.1%) and M24 (13.3% vs 31.2%) (both p0–50 µm, 71.2 letters; >50–100 µm, 71.3 letters; >100 µm, 69.2 letters) versus no SRF (63.6 letters), but the change in BCVA from baseline to M12 or M24 was the same for eyes with or without treatment-resistant subretinal fluid (TR-SRF) at M3 or M6.ConclusionTR-SRF was not detrimental to vision outcomes over 2 years, regardless of thickness. MA rates were significantly higher without TR-SRF.

The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance. Its relevance to clinicians and basic scientists as a potential therapeutic target in retinal and choroidal vascular diseases is highlighted by recent preclinical and clinical evidence. The Ang/Tie pathway plays an important role in the regulation of vascular stability, in angiogenesis under physiological and pathological conditions, as well as in inflammation. Under physiological conditions, angiopoietin-1 (Ang-1) binds to and phosphorylates the Tie2 receptor, leading to downstream signalling that promotes cell survival and vascular stability. Angiopoietin-2 (Ang-2) is upregulated under pathological conditions and acts as a context-dependent agonist/antagonist of the Ang-1/Tie2 axis, causing vascular destabilisation and sensitising blood vessels to the effects of vascular endothelial growth factor-A (VEGF-A). Ang-2 and VEGF-A synergistically drive vascular leakage, neovascularisation and inflammation, key components of retinal vascular diseases. Preclinical evidence suggests that modulating the Ang/Tie pathway restores vascular stabilisation and reduces inflammation. This review discusses how targeting the Ang/Tie pathway or applying Ang-2/VEGF-A combination therapy may be a valuable therapeutic strategy for restoring vascular stability and reducing inflammation in the treatment of retinal and choroidal vascular diseases.摘要: 本篇文章是关于不同照明条件对原发性开角型青光眼 (POAG) 患者视力和生活质量影响的研究的系统回顾。研究对CINAHL, MEDLINE, PsycARTICLES, PsycINFO, Embase and Ovid Nursing Database六个数据库进行系统文献检索, 截止发表日期为2019年4月。检索内容包括诊断为POAG的患者, 在变换照明设备/光照水平或炫光的情况下评估人群的视功能和生活质量。两名研究者独立筛选符合标准的受试者。从实验设计, 入选者标准, 结果与结论中挑选合格的研究并提取数据。入选研究的质量经过了严格的评估。在8437项研究中, 共有56项研究符合入选标准。在POAG患者中调查光照对以下因素的影响: 生活质量 (18/56),心理物理学干预 (16/56), 功能性视力 (10/56), 日常活动 (10/56) 和定性发现 (2/56)。POAG会影响患者的低亮度对比敏感度, 炫光症状, 暗适应的时间和程度。在视觉生活质量调查问卷中, 根据POAG患者反馈, 照明设备, 炫光和暗适应的问题较其它问题更多见。这些问题随着进行性视野的缺失而严重, 与同年龄对照组相比(AMC), POAG患者在发病的早期在低亮度和不同亮度切换的环境中会面临更多的困难, 这对之前POAG患者早期阶段没有症状的认知进行了挑战。但是, 基于性能方面的研究很少显示POAG参与者和AMC在模拟非最佳照明条件下日常活动方面有显着差异。 需要对较大的样本进行进一步研究, 以优化环境照明和面向任务的照明, 以支持患者适应POAG。未来亟待大样本的研究为POAG患者提供优化环境和适合工作的照明。.

To identify risk factors for endogenous endophthalmitis (EE) in hospitalized adults, under 65 years of age, with a history of intravenous opioid use and non-ocular infection. The National Inpatient Sample Database was used to identify cases of EE with a recent history of intravenous opioid use disorder with associated non-ocular infection. Systemic and ocular comorbidities were identified using codes from the International Classification of Diseases, Ninth Revision (ICD-9). Descriptive and regression analyses were performed to evaluate the risk factors for EE using IBM SPSS 23. Of the 605,859 inpatients, 21–65 years age, who had a history of recent opioid-IVDU and an associated IVDU-associated systemic infection, 363 (0.1%) had EE. Systemic comorbidities such as diabetes mellitus, mitral valve disease, aortic valve disease, history of cardiac valve transplantation, chronic kidney disease/renal failure, cirrhosis, active or previous radiation therapy, and history of solid organ transplantation were significantly more prevalent in patients with EE. A significantly increased risk of EE in intravenous opioid users was noted if they were of male gender (OR = 1.84), Asian/Pacific Islander ethnicity (OR = 4.41), had history of cirrhosis (OR = 2.33), active or history of radiation therapy (OR = 14.74), history of solid organ transplantation (OR = 5.91), candidemia (OR = 15.22), and infectious endocarditis (OR = 4.83). Conversely, concurrent alcohol use disorder (OR = 0.35) decreased the risk of EE. Various demographic variables and systemic comorbidities increased the risk of developing EE in inpatients with a history of intravenous opioid use with associated non-ocular infection.

Retinopathy of prematurity (ROP) is one of the many significant consequences of premature birth and remains one of the leading causes of visual impairment in infants. Originally, cryotherapy was used to prevent the complications of vitreous hemorrhage and retinal detachment. Subsequently, laser photocoagulation, which is at least as effective and possibly safer than cryoretinopexy, was adopted as the primary treatment for type 1 ROP (stage 2 or 3 disease in zone II with plus disease or any stage disease in zone I with plus disease or stage 3 disease in zone I without plus disease). Laser therapy has been proven effective, and has a degree of permanence that is yet to be matched by alternative treatments, but can be associated with significant ocular side effects such as myopia. Treatment of type 1 ROP with anti-vascular endothelial growth factor (VEGF) agents seems to have fewer ocular side effects than laser ablation of the retina, particularly if used to treat type 1 ROP in zone I. However, ROP recurrence is a real threat after anti-VEGF therapy and long-term systemic side effects of this therapy remain under evaluation. This review focuses on the ophthalmic and systemic benefits and risks of anti-VEGF therapies for ROP as compared to retinal photocoagulation. Anti-VEGF therapies have dramatically altered the management of ROP and have also been shown to be beneficial with regard to the visual prognosis of patients with ROP, but patients so treated require frequent short- and long-term follow-up to detect and manage potential complications associated with this form of treatment. Such information also will allow clinicians to characterize the efficacy, side effect profile, and utility of intravitreal anti-VEGF agents for this condition. Prospective studies are needed to identify the optimum anti-VEGF drug and dose. [ J Pediatr Ophthalmol Strabismus . 2020;57(6):351–362.]

Purpose:This work describes the characteristics, treatment, and outcomes of endogenous endophthalmitis (EE) cases over 13 years at a tertiary care hospital.Methods:This retrospective case series included EE cases from 2006 to 2018. Eyes were categorized by cultured organism and initial treatment status.Results:Forty-five eyes of 38 patients were identified with EE. Mean age was 48 ± 12 years and approximately three-fourths were male. Mean visual acuity (VA) at presentation was logMAR 1.86 ± 0.83. More than 50% of patients had a history of intravenous drug use. In a quarter of patients, no systemic source of infection was identified; 90% of these patients had a history of intravenous drug use. Bilateral infections occurred in 18% of participants. Of positive cultures, 29%, 56%, and 13% were fungal, gram-positive, and gram-negative in etiology, respectively. Eyes with fungal infections had a better presenting VA and were more likely to have better than 20/100 final VA vs those with bacterial infections. All patients received IV antibiotics; additionally 29% of eyes underwent initial combined pars plana vitrectomy with intravitreal antibiotic injection while 51% of eyes initially received bedside intravitreal antibiotic injection. There was no significant difference in final VA with respect to initial mode of treatment.Conclusions:Initial treatment of intravitreal antibiotics with or without pars plana vitrectomy did not show any difference in the average final VA in eyes with EE. Eyes with fungal infections had more favorable visual outcomes than those with bacterial infections. Almost 1 in 5 EE eyes were enucleated.

Purpose: The objective of our project is to use the National Inpatient Sample Database to identify risk factors for endophthalmitis in cases of open-globe injury (OGI). Methods: This is a cross-sectional observational study of 48 627 cases of OGI from the National Inpatient Sample Database. We performed regression analysis using IBM SPSS Statistics 23. Codes from the International Classification of Disease, Ninth Revision were used to identify ocular findings and conditions. Variables with P values less than .05 on univariate analysis were included in the multivariable regression model; Bonferroni correction was applied to these results. Results: Of the 48 627 cases of OGI, 37 440 (77.0%) occurred in the adult group (21 years and older). Overall, 1018 (2.1%) cases developed posttraumatic endophthalmitis, with 74.5% cases in the adult group. Endophthalmitis developed in 293 (4.5%) eyes with an intraocular foreign body (IOFB). Results of binary logistic regression showed the clinical findings of traumatic cataracts, hypopyon, vitreous inflammation, corneal ulcers, or IOFBs were associated with an increased risk of developing endophthalmitis after OGI. Conversely, orbital fractures, rupture-type injuries, and intraocular tissue prolapse were associated with a decreased likelihood of being diagnosed with endophthalmitis. Conclusions: Endophthalmitis developed in 2.4% of pediatric OGIs and 2.0% of adult OGIs. Traumatic cataract, hypopyon, vitreous inflammation, corneal ulcer, keratitis, retinal detachment, IOFB, and diabetes increased the risk of post-open-globe endophthalmitis.

Trauma is the leading cause of enucleations in the USA. Current information regarding open globe injuries (OGI) is based mainly on data from individual tertiary care centers across the country which might skew the findings towards the population served by these level-one trauma centers. The aim of this study is to evaluate the demographics, characteristics, and risk factors of traumatic enucleations in a large data sample. Descriptive cross-sectional observational study using the National Inpatient Sample (NIS) Database from 2002 to 2013. Inpatients with traumatic enucleations were identified using ICD-9 codes. Chi-square and logistic regression analyses were used to identify differences between the enucleated and non-enucleated cohorts and to evaluate the predictive factors of enucleation in OGIs. Enucleations were performed in 3020 (6.2%) of 48,563 OGIs identified. The average age in the enucleated cohort for males vs. females was 44.7 vs. 62.2 years. In the USA, the highest number of traumatic enucleations occurred in the 21–40 group (41.8%) and the fewest in the 80+ age group (11.8%). The risk of enucleation decreased across the age groups significantly. Compared with the 21–40 age group, the risk of undergoing enucleation was 15% lower in patients 41 to 60 years of age, 35% in patients 61 to 80, and 40% lower in patients over 80. In total, 5.1% OGIs in women and 6.7% of OGIs in men were enucleated. The risk of enucleation was 29% higher in men than in women. The highest absolute number of enucleations was seen in Whites. Compared with Whites, Blacks had a 63% higher risk of enucleation following an OGI. OGIs with rupture-type injury, endophthalmitis, or phthisis were significantly higher odds to be enucleated. The risk of enucleation following traumatic OGI significantly increased for patients who were in the 21–40 age group, of Black race, or of male gender; the risk also increased if the injury was a rupture-type or associated with endophthalmitis or phthisis. The risk of depression was 75% higher in enucleated patients versus non-enucleated patients.

Importance Limited data exist on the real-world safety outcomes of patients with neovascular age-related macular degeneration treated with brolucizumab (Beovu). Objective To determine the real-world incidence of intraocular inflammation (IOI), including retinal vasculitis (RV) and/or retinal vascular occlusion (RO), for patients with neovascular age-related macular degeneration who underwent brolucizumab treatment. Additionally, potential risk factors associated with these adverse events were evaluated. Design, setting, and participants This cohort study included patients with neovascular age-related macular degeneration in the Intelligent Research in Sight (IRIS) Registry and Komodo Healthcare Map. Patients initiating and receiving 1 or more brolucizumab injections from October 8, 2019, to June 5, 2020, with up to 6 months of follow-up were included. Intervention Brolucizumab injections. Main outcome and measures Incidence of IOI (including RV) and/or RO and RV and/or RO and risk stratification for the identified risk factors. Results Of 10 654 and 11 161 included eyes (from the IRIS Registry and Komodo Health database, respectively), the median follow-up times were 97 and 95 days. Most eyes switched from another anti-vascular endothelial growth factor agent (9686 of 10 654 [90.9%] and 10 487 of 11 161 [94.0%], respectively), most commonly aflibercept (7160 of 9686 [73.9%] and 7156 of 10 487 [68.2%]), and most were from women (6105 of 10 654 [57.3%] and 6452 of 11 161 [57.8%]). The overall incidence of IOI and/or RO was 2.4% (255 of 10 654 eyes) and 2.4% (268 of 11 161 eyes) for the IRIS and Komodo groups, respectively, and RV and/or RO, 0.6% (59 of 10 654 eyes and 63 of 11 161 eyes), respectively. Patients with a history of IOI and/or RO in the 12 months before brolucizumab initiation had an increased observed risk rate (8.7% [95% CI, 6.0%-11.4%] and 10.6% [95% CI, 7.5%-13.7%]) for an IOI and/or RO event in the 6 months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2.0% in both data sets). There was an increased estimated incidence rate in women (2.9% [95% CI, 2.5%-3.3%] and 3.0% [95% CI, 2.6%-3.4%]) compared with men (1.3% [95% CI, 1.0%-1.7%] and 1.4% [95% CI, 1.0%-1.7%]), but this risk was not as large as that of a prior IOI and/or RO. Similar findings were observed for patients with RV and/or RO events. Conclusions and relevance The incidence rate of IOI and/or RO was approximately 2.4%. Patient eyes with IOI and/or RO in the 12 months prior to first brolucizumab injection had the highest observed risk rate for IOI and/or RO in the early months after the first brolucizumab treatment. However, given study limitations, the identified risk factors cannot be used as predictors of IOI and/or RO events, and causality with brolucizumab cannot be assessed.

Population-based reports regarding bacterial endogenous endophthalmitis (BEE) are scarce in the literature. Our study sought to investigate the incidence of BEE, relative risk of comorbid conditions, and treatment patterns using a nationally representative database, the National Inpatient Sample (NIS).Retrospective cross-sectional study.Inpatients with bacteremia with and without BEE in the NIS database between 2002 and 2013.Demographic and comorbid medical conditions were evaluated in bacteremic patients who demonstrated BEE and in those who did not; furthermore, logistic regression was performed to predict the relative risk of comorbid conditions in BEE developing. Chi-square analysis was used to determine if certain organisms were more likely to cause BEE and their role in treatment method. Statistical analysis was performed using SPSS software version 22 (IBM, Armonk, NY).Comorbidities, associated microorganisms, and surgical management.Among 3 907 204 bacteremic inpatients, 1793 (0.05%) were found to have BEE. Patients were more likely to demonstrate BEE in the presence of endocarditis (P 0.001), bacterial meningitis (P0.001), pyogenic arthritis (P0.001), internal organ abscess (P0.001), osteomyelitis (P0.001), prostatitis (P0.001), diabetic retinopathy (P0.001), and vascular catheter placement or infection (P0.001). Diabetes mellitus without complications was not associated with an increased risk of BEE. Methicillin-resistant Staphylococcus aureus (MRSA), streptococcal, and pneumococcal bacteremia were found to significantly increase the risk of BEE (P0.001 for all), and the incidences of BEE associated with these organisms were 0.19%, 0.09%, and 0.07%, respectively. Fewer than 10% of patients with BEE underwent vitrectomy, and 1.6% of BEE patients underwent enucleation.Bacterial endogenous endophthalmitis was observed in approximately 1 in 2000 inpatients with bacteremia in this large cohort of NIS inpatients. It was seen more commonly with MRSA, streptococcal, and pneumococcal species. Endocarditis, meningitis, prostatitis, osteomyelitis, infected vascular catheter, internal organ abscess, and diabetic retinopathy showed a significant risk (P0.001) of being associated with BEE.

PURPOSE: To describe the characteristics, outcomes and complications of eyes after silicone oil removal. METHODS: Retrospective case series of eyes that underwent oil removal between 2012 and 2016 at The Institute of Ophthalmology and Visual Science. Visual acuity (VA), intraocular pressure (IOP) and rates of retinal re-detachment, hypotony, ocular hypertension, corneal decompensation, cystoid macular edema (CME) and cataract progression were evaluated. RESULTS: Totally, 101 eyes of 99 patients (65% male, average age 47.2 years) were identified. Oil tamponade had been used for retinal detachment (RD) repair in all eyes; 15 eyes had also undergone an open globe repair previously. The most common vitreous substitutes used after oil removal were balanced salt solution (BSS) and air in 90% of eyes. The average time of oil tamponade before removal was 9.46 months. The average logMAR VA before oil removal was 1.7 which improved to an average of 1.4 post-operatively. The average IOP pre-operatively was 16.1 mm Hg, which decreased to an average of 14.8 mm Hg post-operatively. Complications after oil removal, included retinal re-detachment (6.9%), hypotony (7.9%), ocular hypertension (12.9%), corneal decompensation (9.9%), CME (2%) and cataract progression (68%). CONCLUSION: This study showed an overall improvement in VA and decrease in IOP after oil removal. Cataract progression was the most common complication.

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or “wet” form of AMD, no therapy is successful for the non-neovascular or “dry” form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy., No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.

Purpose A simulated switching study assessed the effects of continuing the same anti–vascular endothelial growth factor (VEGF) treatment among patients who typically are considered for a therapy switch. Post hoc analysis of data from HARBOR was undertaken. Patients with neovascular age-related macular degeneration who demonstrated a suboptimal response after 3 or 6 months of ranibizumab treatment were identified as switching candidates. Rather than switching, however, patients continued on ranibizumab treatment, and visual and anatomic outcomes from the point of the hypothetical switch were examined. Design Post hoc analysis of the phase 3 HARBOR clinical trial. Participants Patients were included in 3- and 6-month switcher analyses if they received 3 of 3 initial monthly ranibizumab doses and 5 of 6 initial monthly ranibizumab doses, respectively, and met all the following: 5-letter or fewer gain from baseline, best-corrected visual acuity (BCVA) 20/40 or worse, and intraretinal or subretinal fluid with central foveal thickness (CFT) equal to or greater than central subfield thickness. Methods Patient data were examined at months 3 and 6 to identify those who met predetermined switching criteria. Best-corrected visual acuity and CFT were examined from the point at which switching criteria were met through months 6, 12, 18, and 24 of HARBOR and compared with those who did not meet the criteria. Main Outcome Measures Outcome measures included mean BCVA and CFT change over time from the point (month 3 or 6) at which switching criteria were met. Results By months 3 and 6, only 44 of 1059 patients (4.2%) and 37 of 769 patients (4.8%), respectively, met the inclusion criteria for hypothetical switching. Patients who met switching criteria at month 3 gained, on average, 5.3 letters from months 3 to 12 and 2.7 letters from months 3 to 24. Month 6 switchers gained, on average, 1.6 letters from months 6 to 12 and 1.8 letters from months 6 to 24. Both groups experienced significant CFT reductions over 24 months. Conclusions Month 3 hypothetical switchers achieved vision and anatomic improvement while continuing their original ranibizumab treatment. Month 6 switcher outcomes replicated those commonly reported in published anti-VEGF switching studies: stable vision or nominal improvements in vision with continued substantial anatomic improvement.

Purpose: To identify best clinical practices for macular degeneration imaging. Methods: We reviewed best clinical practices for imaging patients with age-related macular degeneration. These recommendations are based on different levels of evidence (I-III). Results: The type of imaging needed depends to some degree on the clinical scenario: first visit vs follow-up visit vs poorly responsive patient. Conclusions: Imaging technologies that may be useful include optical coherence tomography, fundus photography, fundus autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and optical coherence tomography angiography.

Purpose: This article describes the characteristics, management, and etiology of retinal artery occlusions (RAOs) in young patients. Methods: A retrospective chart review of patients Results: Seventeen eyes of 15 patients younger than 50 (mean age, 34±8 years; 71% male, 29% female) with RAOs were identified. AOs included: 8 (47%) central RAOs (CRAOs), 5 (29%) branch RAOs (BRAOs), 3 (18%) ophthalmic AOs (OAOs), and 1 (6%) combined CRAO and vein occlusion (CRAO/CRVO). Logarithm of the minimum angle of resolution visual acuity (VA) at presentation was 2.6±4 (Snellen range 20/15 to no light perception). Systemic diseases in patients with BRAO included Susac disease (n = 1), sickle cell disease (n = 2), patent foramen ovale (PFO) (n = 1), and HIV (n = 1). CRAO was diagnosed in 4 patients after invasive surgery (3 after neurosurgery and 1 after cardiac surgery). Other patients had hypertension (n = 3), hypercoagulability due to uterine cancer (n = 1), and PFO (n = 1). OAOs were noted in 1 patient with Saturday night retinopathy and in 1 with ruptured internal carotid aneurysm at the level of the ophthalmic artery. Two eyes with CRAO were treated with tissue plasminogen activator (1 intraophthalmic artery through catheterization and 1 intravenously) without any change in final VA. In these patients, VA remained poor (VA hand motions – counting fingers) at 6 months or greater follow-up visits. Conclusion: RAO in young patients is uncommon. In this series, one-fourth of occlusions were seen during the perioperative period. A significant number of patients had concurrent uncontrolled hypertension. Other associated systemic findings included PFO, hypercoagulability, sickle cell disease, Susac disease, and HIV.

Retinal cell therapy can have the objectives of rescue (i.e., modulation of metabolic abnormalities primarily for sight preservation) as well as replacement (i.e., replace cells lost due to injury or disease for sight restoration as well as preservation). The first clinical trials of retinal pigment epithelium (RPE) transplantation for vision-threatening complications of age-related macular degeneration (AMD) have begun with some preliminary signs of success (e.g., improvement in vision in some patients, anatomic evidence of transplant-host integration with some evidence of host photoreceptor recovery, long-term survival of autologous induced pluripotent stem cell-derived RPE transplants without immune suppression) as well as limitations (e.g., limited RPE suspension survival in the AMD eye, limited tolerance for long-term systemic immune suppression in elderly patients, suggestion of uncontrolled cell proliferation in the vitreous cavity). RPE survival on aged and AMD Bruch’s membrane can be improved with chemical treatment, which may enhance the efficacy of RPE suspension transplants in AMD patients. Retinal detachment, currently used to deliver transplanted RPE cells to the subretinal space, induces disjunction of the first synapse in the visual pathway: the photoreceptor-bipolar synapse. This synaptic change occurs even in areas of attached retina near the locus of detachment. Synaptic disjunction and photoreceptor apoptosis associated with retinal detachment can be reduced with Rho kinase inhibitors. Addition of Rho kinase inhibitors may improve retinal function and photoreceptor survival after subretinal delivery of cells either in suspension or on scaffolds.

Purpose: To use the National Inpatient Sample (NIS) Database to describe trends in demographics, types, and incidence of pediatric open globe injuries in the United States. Methods: A retrospective, cross-sectional, observational study was conducted of 8,943 acute cases of pediatric open globe injury (age < 21 years) obtained from the NIS Database, between 2002 and 2014. Weighted analysis was performed using IBM SPSS Statistics 25 software (IBM Corporation). Codes from the International Classification of Disease , Ninth Revision, Clinical Modification were used to identify pediatric open globe injury cases. Results: In the United States, 8,943 pediatric cases of acute open globe injuries were identified between 2002 and 2014. Males comprised 78% of the acute pediatric open globe injury cases. Penetrating open globe injuries without intraocular foreign bodies (IOFBs) were the most common type of injury ( P < .001). The proportion of injuries that were penetrating open globe injuries decreased with age, whereas the proportion of IOFBs and globe ruptures increased. The proportion of open globe injuries with IOFB in boys was twice as high as in girls. The incidence of open globe injuries by age, race, and gender was highest in the 16 to 20 years age group, in Blacks and Native Americans, and in boys, respectively. Conclusions: The incidence of open globe injuries in pediatric patients (age < 21 years) was estimated to be 7.93 per 1,000,000 individuals and varied by race, gender, and age. The proportion of different types of open globe injury varied significantly by age, race, and gender. The mean duration of hospital stay for open globe injury management was 2.2 days, and 17.5% of patients lacked medical insurance. [ J Pediatr Ophthalmol Strabismus . 2021;58(4):232–239.]

The choroidal vascularity index (CVI) is a relatively new parameter, calculated off optical coherence tomography (OCT) images, for the quantitative evaluation of choroid vascularity. It is defined as the ratio of vascular area to the total choroidal area, presented as a percentage. The choroid is an important vascular bed, often implicated in ocular and systemic conditions. Since the introduction of CVI, multiple studies have evaluated its efficacy as a tool for disease prognostication and monitoring progression, with promising results. The CVI was born out of the need for more robust and accurate evaluations of choroidal vasculature, as prior parameters such as choroidal thickness and choroidal vessel diameter had their limitations. In this review, we summarise current literature on the CVI, explain how the CVI is derived and explore its potential integration into future research and translation into clinical care. This includes the application of CVI in various disease states, and ongoing attempts to produce an automated algorithm which can calculate CVI from OCT images.

Purpose: Several risk factors have been identified for central retinal vein occlusion (CRVO) in older population. CRVO in young is uncommon, and the risk factors for this group are unclear. This large retrospective, cross-sectional study used the National Inpatient Sample (NIS) database to evaluate the risk factors for CRVO in patients 18 to 40 years of age. Methods: The 2002 to 2014 NIS database was used. All patients 18 to 40 years of age with a primary diagnosis of CRVO were identified. Age- and gender-matched non-CRVO controls were randomly selected. The primary outcome was identification of risk factors for CRVO. Chi-square analysis and Firth logistic regression were performed with IBM SPSS 23 and R packages versions 3.4.3, respectively. p Results: A total of 95 weighted young CRVO patients were identified. The average age was 31.44 ± 6.41 years with no gender predilection. Systemic and ocular conditions found to have statistically significant associations with CRVO included primary open-angle glaucoma (POAG) (OR 836.72, p Conclusion: The most significant risk factors for CRVO in young adults were POAG, retinal vasculitis, and pseudotumor cerebri. Hypercoagulable states and DVT/PE were also associated with CRVO in this population. Systemic inflammatory conditions were not associated with CRVO. Traditional risk factors such as hypertension and diabetes did not pose significant risks, whereas hyperlipidemia was deemed a significant risk factor.

To use the 2002 through 2014 National Inpatient Sample (NIS) database to identify risk factors for endogenous endophthalmitis (EE) in hospitalized patients with candidemia.Retrospective, cross-sectional study.Hospitalized patients sampled in the NIS database.The NIS database (2002-2014) was used to identify patients with candidemia and EE and their comorbidities. Descriptive analysis was performed with chi-square testing, and risk factors for EE were identified using logistic regression analysis. Chi-square testing and regression analysis were performed using IBM SPSS software version 23 (IBM Corp, Armonk, NY) and R package software version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria), respectively.Diagnosis of EE in hospitalized patients with candidemia.We identified 98 783 hospitalized patients with candidemia; 529 patients (0.5%) had concurrent EE. Men constituted 48.0% of patients who did not demonstrate EE and 45.1% of those who did (P = 0.186). The average age of fungemia patients with EE was 54.6 years and of those without EE was 58.2 years (P0.001). Most EE cases (58.6%) occurred in patients 21 to 64 years of age. Hispanic (odds ratio [OR], 1.58), Asian or Pacific Islander (OR, 3.51), and Native American (OR, 5.22) patients with candidemia were at an increased risk of EE developing compared with White patients. Candida endocarditis (OR, 1.84), cirrhosis (OR, 1.93), diabetes with chronic complications (OR, 1.96), intravenous drug use (OR, 3.12), radiation therapy (OR, 5.28), and solid organ transplantation (OR, 2.48) increased the risk of seeding the infection into the eye. Conversely, chronic kidney disease (OR, 0.53) and invasive mechanical intubation (OR, 0.43) were associated with a decreased risk of EE. The mortality of inpatients with candidemia was significantly lower in the EE group (2.8% vs. 15.6%; P0.001).Systemic comorbidities that increased the risk of EE in candidemia included endocarditis, cirrhosis, diabetes with chronic complications, intravenous drug use, radiation therapy, and solid organ transplantation. Racial disparity was observed with Hispanics, Asians and Pacific Islanders, and Native Americans at a higher risk than Whites of being diagnosed with EE in the setting of Candida fungemia.

This is an Editorial and does not have an abstract.

Purpose of review Retinal detachment initiates a series of events that lead to degenerative changes in retinal synaptic architecture as well as the well-known phenomena of gliosis and photoreceptor apoptosis. Retinal reattachment does not always result in complete visual recovery, even if the fovea is not directly involved in the detachment. Rho-kinase (ROCK) inhibitors may mitigate some of these deleterious changes including disruption of synaptic architecture, photoreceptor apoptosis, and initiation of the epithelial-mesenchymal transition that characterizes proliferative vitreoretinopathy (PVR). This review focuses on the use of ROCK inhibitors to modulate synaptic disjunction. Recent findings ROCK inhibition prevents retinal detachment-induced photoreceptor synaptic terminal retraction (i.e., synaptic disjunction), thereby diminishing the damage of the first synapse in the visual pathway. ROCK inhibition also reduces retinal detachment-induced photoreceptor apoptosis and suppresses PVR progression in preclinical models. Summary Inhibition of ROCK may help to optimize visual recovery after retinal detachment surgery or iatrogenic detachments during cell transplantation or viral subretinal injection and might play a role in reducing the risk of PVR after retinal detachment surgery.

Purpose: The purpose of this study is to describe the patient characteristics, management, and outcomes of bleb-related endophthalmitis (BRE). Methods: A retrospective chart review was conducted of patients who presented to a tertiary care facility from 2001 to 2016 with BRE. Collected data included demographics, medical and ocular history, visual acuity (VA), intraocular pressure (IOP), presence of hypopyon, treatment, microbiology, visual outcomes particularly of VA and IOP, and complications. Results: Thirty-six eyes (36 patients: 21 females, mean 66.8 years old, 78% with primary open-angle glaucoma) presented an average of 4.5 years (range, 2 days-33 years) after glaucoma surgery (30 trabeculectomies with mitomycin C, 6 tube shunts) with endophthalmitis. Mean VA and IOP at presentation were hand motion (HM; logMAR 2.1) and 19.9 mmHg, respectively, with 82% displaying hypopyon and 87% with purulent blebitis. Eighteen (50%) eyes (mean VA HM) underwent vitreous tap and injection (T/I) of intravitreal antibiotics (vancomycin 1 mg/0.1 cc and ceftazidime 2.25 mg/0.1 cc), and 18 (50%) eyes (mean VA HM) underwent pars plana vitrectomy (PPV) with intravitreal antibiotic injection. Eight (45%) eyes initially treated with T/I required a subsequent PPV, and 5 (28%) eyes treated initially with PPV underwent a second PPV. All patients also received systemic antibiotics (33 intravenous [IV] and 3 oral) and topical medications. Average time to documented resolution was 15 days, with mean VA of HM and IOP of 13.6 mmHg. Thirty-one (86%) eyes had vision worse than 20/200 at resolution, and those presenting with light perception or no light perception (NLP) vision (n = 6) had worse vision final VA (logMAR 2.6) than those with initial vision of HM or better (final VA logMAR 1.7). Three (8.6%) eyes were enucleated, with 4 worsening to NLP during the course of the infection. Conclusions: BRE is a visually devastating infection requiring prompt diagnosis and management. Despite aggressive treatment with antibiotics, visual prognosis is poor.

Topic This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance Intravitreal anti–vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists’ Collaboration (APTC). Results The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72–1.88) for ATE, 1.33 (0.59–2.97) for MI, 1.43 (0.54–3.77) for stroke excluding TIA, 1.25 (0.61–2.55) for stroke or TIA, 0.57 (0.18–1.78) for vascular death, and 1.12 (0.64–1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit–risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses.

Purpose: To study the treatment effect of antivascular endothelial growth factor (anti-VEGF) injections on eyes with iris neovascularization (NVI). Methods: Retrospective study of patients who underwent intravitreal anti-VEGF for the treatment of NVI at the Rutgers-Institute of Ophthalmology and Visual Sciences between January 1, 2007 and March 30, 2017. Results: Twenty-eight eyes (mean age, 63 ± 13 years old, 12 [43%] males) were identified. All patients had NVI, and 23 patients had concurrent neovascular glaucoma. The etiology of anterior segment ischemia was proliferative diabetic retinopathy in 20 eyes (71%), central retinal vein occlusion in 7 eyes (25%), and branch retinal vein occlusion in 1 eye (4%). Corneal edema in 25 eyes (89%), hyphema in 11 (39%), visually significant cataract in 25 (86%), and vitreous hemorrhage in 15 (54%) precluded an adequate view to the fundus to perform panretinal photocoagulation (PRP). All patients initially received anti-VEGF therapy; PRP was provided in some eyes ( n = 7) with persistent NVI if the view to the fundus improved. On average, 1.66 (median, 1; standard deviation [SD], 1.64) anti-VEGF injections were performed before complete NVI regression was achieved. Complete regression of rubeosis iridis took an average of 42 (median, 40; SD, 48) days from the first injection. Ten eyes (36%) had recurrence of rubeosis at 198 (median, 126; SD, 165) days after complete regression of NVI. Conclusions: NVI regression was noted in all eyes. Anti-VEGF may be a good supplement for initial NVI management in eyes when PRP cannot be initiated.

Purpose To describe the characteristics of open-globe injuries with posterior segment intraocular foreign bodies (IOFBs). Design Retrospective chart review study. Participants Patients treated for posterior segment IOFB injuries. Methods Retrospective analysis of all patients with posterior segment IOFBs from 2003 to 2014 was conducted. Data including demographics, mechanism of injury, type of IOFB, method of diagnosis, presenting examination, medical and surgical treatment, visual outcomes, and complications were recorded. Main Outcome Measures Visual acuity (VA); anatomically successful retinal reattachment; need for additional surgery; frequency of post-traumatic complications, such as sympathetic ophthalmia (SO), endophthalmitis, and enucleations; and accuracy of Ocular Trauma Score (OTS). Results Thirty-one patients (28 male; mean age, 36.6 years; 42% Hispanic) had posterior segment IOFB injuries, 23 (74%) of which were construction work related. Twenty-five IOFBs (81%) were metallic. Twenty-four IOFBs (77%) had Zone I entry. Computed tomography (CT) scan detected an IOFB in 21 of 22 eyes in which it was performed, with 1 scan highly suspicious for an IOFB. Average size of the IOFB was 10 mm3; size or initial VA did not have any correlation with final VA. The OTS had 60% accuracy in predicting final VA (n = 20). The majority of patients had traumatic cataract and vitreous hemorrhage (VH) on presentation (77% and 61%, respectively); 65% had a retinal tear or retinal detachment (RD), and these patients had worse final VA than those with no retinal pathology. Average time from injury to IOFB removal was 3 days because of the delay in presentation to our facility; 27 of 31 patients (87%) had IOFBs removed within 24 hours of presentation with pars plana vitrectomy (PPV) and either gas or silicone oil tamponade. Patients were admitted for an average of 4 days of intravenous antibiotics. The most common complication was recurrent RD in 11 patients (35%), which portended worse final VA. One patient (3%) developed SO. There were no cases of postoperative endophthalmitis or enucleation. Conclusions Open-globe injuries with posterior segment IOFBs have a guarded visual prognosis, particularly when associated with RD. Increased awareness of the importance of eye protection can help minimize the occurrence of these injuries.

PURPOSE: To evaluate demographic trends of open globe injuries (OGIs) using a large dataset representative of United States population. METHODS: Retrospective cross-sectional observational study using the National Inpatient Sample (NIS) database from 2002 to 2013. Only patients with a primary admitting diagnosis of OGI were included. Data included age (in years), gender, race, type of OGI, death rate and length and cost of stay. RESULTS: During the 12-year period, 27,467 adults (age > 20) with acute OGIs were admitted to the US hospitals. The incidence of OGIs in the adult US population was 10.6 cases per 1,000,000 persons. The mean age was 50.4 years (SD 21.52); the average ages of men and women were 44.34 (SD 17.63) and 65.69 (SD 22.77), respectively. Men accounted for 71% of all cases, with 84% of patients under 60. A decrease in the number of OGIs was seen with advancing age in men, whereas the opposite was true for women. Men, elderly over 80 and Blacks were at the highest risk of sustaining an OGI. The most and least common types of injuries were penetrating injuries (73%) and IOFBs (11%), respectively. Over half of young adults in the 21–40 cohort and 43% of men were uninsured (p

Age-related macular degeneration (AMD) involves progressive degeneration of the central retina, termed the macula, which provides high-acuity vision needed to recognize faces, drive, etc. AMD is the leading cause of blindness in the aging population. A plethora of paradigm-shifting perspectives regarding AMD's multifaceted pathophysiology is emerging. This review will endeavor to gather novel insights and attempts to identify translational implications and new areas of research. The concept of aberrant inflammation being at the center of age-related diseases, particularly AMD, is being received with increasing credence. Retinal angiogenesis, at the forefront of the neovascular complications of AMD (nAMD), is now being understood as an imbalance between trophic factors released by retinal cells secretome. Additionally, mechanisms involving oxidative stress and inflammatory complement pathways have also been identified, along with genetic and other risk factors that play a key role in AMD's onset and progression. Associations have been drawn with AMD and other degenerative deposit diseases such as Alzheimer's disease, atherosclerosis, and glomerulonephritis, which are providing further insight into this maculopathy.

Intraocular foreign body injuries may result in a wide range of intraocular pathology and visual outcomes based on the mechanism of injury, type of foreign body, and subsequent complications. We have reviewed the literature to describe the epidemiology and mechanisms of such injuries; types of foreign bodies; imaging tools for diagnosis; current trends in management, presurgical, and surgical interventions; as well as visual prognosis and potential complications. The purpose of this review is to familiarize clinicians with the recent advances in diagnosis and management of such injuries.

Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections.

Retinal stem cell therapy is under investigation in several registered phase I/II clinical trials as a potential means to preserve or restore vision in various retinal degenerative conditions such as age-related macular degeneration (AMD), retinitis pigmentosa, and Stargardt macular dystrophy. The therapeutic cellular substrates include retinal pigment epithelium (RPE) cells derived from embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC). Other trials involve the subretinal or intravitreal transplantation of allogeneic cells such as umbilical stem cells and fetal-derived retinal progenitor cells. Delivery methods include cell suspension transplantation or cellular sheet transplantation in which synthetic scaffolds are used to support the cell patch as a preformed monolayer. Overall, encouraging safety data indicate the absence of significant adverse effects related to the cells or scaffolds; however, several safety concerns have arisen from the surgical procedure(s) used for stem cell delivery. Additionally, severe complications have arisen following the delivery of unregulated direct-to-consumer products, and there has been a call for greater regulatory oversight to protect patients. Retinal stem cell therapy holds great promise as a treatment for patients with retinal degenerative diseases. Further development of the various approaches is warranted.

Advantages of the eye as a target organ for cell-based therapy are as follows. The anatomy and physiology of the retina have been characterized in detail. Surgical access to the vitreous cavity and the subretinal space are well established with an excellent safety record. The eye is an immune privileged organ, particularly the subretinal space, which may reduce the need for long-term immune suppression of transplant recipients. High-resolution noninvasive imaging technology permits visualization and functional assessment of the transplanted cells in situ. These imaging and monitoring capabilities permit development of an iterative pathway to successful transplant paradigms in human patients as well as precise modulation of immunotherapy should it be needed.

The availability of noninvasive high-resolution imaging technology, the immune-suppressive nature of the subretinal space, and the existence of surgical techniques that permit transplantation surgery to be a safe procedure all render the eye an ideal organ in which to begin cell-based therapy in the central nervous system. A number of early stage clinical trials are underway to assess the safety and feasibility of cell-based therapy for retinal blindness. Cell-based therapy using embryonic stem cell-derived differentiated cells (e.g., retinal pigment epithelium (RPE)), neural progenitor cells, photoreceptor precursors, and bone marrow-derived hematopoietic stem/progenitor cells has demonstrated successful rescue and/or replacement in preclinical models of human retinal degenerative disease. Additional research is needed to identify the mechanisms that control synapse formation/disjunction (to improve photoreceptor transplant efficacy), to identify factors that limit RPE survival in areas of geographic atrophy (to improve RPE transplant efficacy in eyes with age-related macular degeneration), and to identify factors that regulate immune surveillance of the subretinal space (to improve long-term photoreceptor and RPE transplant survival).

Blockade of vascular endothelial growth factor (VEGF) signaling, whether via sequestration of free VEGF or via inhibition of the tyrosine kinases activated by VEGF, is associated with decreased nitric oxide (NO) and prostaglandin-I 2 (PG-I 2) production along with vascular endothelial cell death. Systemic administration of drugs that block VEGF signaling (eg, for cancer treatment) is associated with systemic complications such as hypertension and thrombosis. Evidence regarding the risk of systemic serious adverse events after intravitreal injection of anti-VEGF agents in patients with diabetic macular edema or neovascular age-related macular degeneration is inconsistent, in part because of study design limitations (eg, bias of ascertainment through strict enrollment criteria and/or inadequate power to identify the risk of low frequency events). Studies involving patients at high risk of arteriothrombotic events (eg, patients with diabetic macular edema) who have high exposure to intravitreal anti-VEGF therapy (eg, monthly aflibercept or ranibizumab injection) demonstrate an increased risk of all-cause mortality compared with randomized controls. The pharmacokinetics of anti-VEGF drug clearance from the systemic circulation and the documented sustained reduction in free plasma VEGF levels after intravitreal aflibercept and bevacizumab injection are consistent with these findings. Although the frequency of systemic serious adverse events after intravitreal anti-VEGF therapy is low, some patients may be at higher risk (eg, those with recent stroke or multiple strokes), and physicians may wish to take special measures with these patients to minimize the risk of systemic complications.