Charles C. Wykoff

Diabetic Retinopathy: A Position Statement by the American Diabetes Association.

Diabetic retinopathy diagnostic assessment and treatment options have improved dramatically since the 2002 American Diabetes Association Position Statement (1). These improvements include the widespread adoption of optical coherence tomography to assess retinal thickness and intraretinal pathology and wide-field fundus photography to reveal clinically silent microvascular lesions. Treatment of diabetic macular edema is now achieved by intravitreous injection of anti–vascular endothelial growth factor agents, and the same drugs are now used for proliferative diabetic retinopathy. Improvements in medications and devices for the systemic therapy of diabetes have also improved the ability of patients to optimize their metabolic control. This Position Statement incorporates these recent developments for the use of physicians and patients.nnDiabetic retinopathy is a highly specific neurovascular complication of both type 1 and type 2 diabetes, the prevalence of which strongly correlates to both the duration of diabetes and level of glycemic control. A pooled meta-analysis involving 35 studies conducted worldwide from 1980 to 2008 estimated global prevalence of any diabetic retinopathy and proliferative diabetic retinopathy (PDR) among patients to be 35.4% and 7.5%, respectively (2). Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20–74 years in developed countries. Glaucoma, cataracts, and other disorders of the eye occur earlier and more frequently in people with diabetes.nnIn addition to diabetes duration, factors that increase the risk of or are associated with retinopathy include chronic hyperglycemia (3,4), nephropathy (5), hypertension (6), and dyslipidemia (7). Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy (8,9).nnLowering blood pressure has been shown to decrease retinopathy progression in people with type 2 diabetes, although tight targets (systolic blood pressure <120 mmHg) do …

Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical Characteristics of 36 Eyes

PURPOSEnTo expand understanding of presentation, diagnosis, and outcomes of hemorrhagic occlusive retinal vasculitis (HORV).nnnDESIGNnRetrospective case series.nnnPARTICIPANTSnThirty-six eyes of 23 patients.nnnMETHODSnThe American Society of Cataract and Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment, and outcomes. An online registry was established on both societies web sites. Surveys were e-mailed to members of both societies soliciting cases of suspected HORV. A literature search was performed to uncover additional cases.nnnMAIN OUTCOME MEASURESnHistorical data including intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes.nnnRESULTSnCharacteristic findings of HORV included unremarkable postoperative day 1 undilated examination, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes of 23 patients were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), via intravitreal injection (1/36), or through the irrigation bottle (2/36). Patients sought treatment with HORV 1 to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61%) had 20/200 or worse visual acuity and 8 of 36 eyes (22%) had no light perception (NLP). Neovascular glaucoma developed in 20 of 36 eyes (56%). Seven eyes received additional intravitreal vancomycin after surgery; 5 of these 7 eyes had NLP visual acuity at the most recent examination. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70, and hand movements.nnnCONCLUSIONSnHemorrhagic occlusive retinal vasculitis is a rare, potentially devastating condition that can develop after cataract surgery or intraocular injection. All cases in this series were associated with intraocular vancomycin. Disease course and findings suggest that HORV is caused by a delayed hypersensitivity reaction to vancomycin. Early treatment with corticosteroids likely is beneficial. Subsequently, anti-vascular endothelial growth factor injections and panretinal photocoagulation are important to prevent neovascular glaucoma, a common complication. Avoidance of additional intravitreal vancomycin is recommended if HORV is suspected.

Randomized Trial of Treat and Extend Ranibizumab with and without Navigated Laser for Diabetic Macular Edema: TREX-DME 1 Year Outcomes

PURPOSEnTo compare monthly dosing with a treat and extend algorithm using ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation for center-involving diabetic macular edema (DME).nnnDESIGNnMulticenter, prospective, randomized clinical trial.nnnPARTICIPANTSnA total of 150 eyes from 116 subjects were randomized into 3 cohorts: Monthly (nxa0= 30), TReat and EXtend without macular laser photocoagulation (TREX; nxa0= 60), and treat and extend with angiography-GuIded macular LAser photocoagulation (GILA; nxa0= 60).nnnMETHODSnMonthly cohort eyes received ranibizumab 0.3 mg every 4 weeks. Eyes in the TREX and GILA cohorts received 4 monthly injections of ranibizumab 0.3 mg followed by a treat and extend algorithm based on disease activity. Eyes in the GILA cohort also received angiography-guided macular laser photocoagulation at month 1 and again every 3 months for microaneurysm leakage.nnnMAIN OUTCOME MEASURESnChange in mean best-corrected visual acuity (BCVA), mean central retinal thickness (CRT), number of injections from baseline to 1 year, and percentage gaining/losing 2 and 3 lines of vision.nnnRESULTSnBaseline demographics were well balanced among the cohorts. A total of 137 eyes (91%) completed the 1-year end point visit. At 1 year, the mean BCVA improved by 8.6, 9.6, and 9.5 letters in the Monthly, TREX, and GILA cohorts, respectively (Pxa0= 0.8). There was no significant difference between the cohorts in the percentage gaining/losing 2 and 3 lines of vision. The CRT improved by 123 μm, 146 μm, and 166 μm in thexa0Monthly, TREX, and GILA cohorts, respectively (Pxa0= 0.47). The mean number of macular laser treatments in thexa0GILA cohort at 1 year was 2.9 (range, 1-4). The number of injections was significantly reduced in both the TREX (10.7) and GILA (10.1) cohorts compared with the Monthly cohort (13.1, P < 0.001). There were no cases of endophthalmitis, and the total incidence of Anti-Platelet Trialists Collaboration events was 4.7%.nnnCONCLUSIONSnThis prospective, randomized trial found that treat and extend dosing of ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation significantly decreased the number of injections given while providing similar visual and anatomic outcomes compared with monthly dosing at 1 year. Adding angiography-guided laser photocoagulation to this dosing algorithm did not significantly improve outcomes at 1 year.

Long-term Effects of Intravitreal 0.19 mg Fluocinolone Acetonide Implant on Progression and Regression of Diabetic Retinopathy

OBJECTIVEnTo investigate the effects of fluocinolone acetonide (FAc) on the progression to proliferative diabetic retinopathy (PDR) and the impact of FAc on changes in Early Treatment Diabetic Retinopathy Study (ETDRS) diabetic retinopathy (DR) severity scale (DRSS) grade during the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) A and B Phase III clinical trials.nnnDESIGNnPost hoc analysis of data from the 36-month prospective, randomized, FAME A and B trials.nnnPARTICIPANTSnPatients with diabetic macular edema (DME) who received sham control or FAc 0.2 or 0.5 μg/day.nnnMETHODSnA masked reading center (University of Wisconsin-Madison) determined DRSS grade and retinal perfusion status using standard 7-field stereo fundus photography and fluorescein angiography, respectively. Retinopathy changes over time were determined by DRSS step differences from baseline to month 36. Pairwise comparisons between the 3 treatment groups were performed using a log-rank test without adjustment for covariates, with the primary comparison between sham control and 0.2 μg/day FAc.nnnMAIN OUTCOME MEASURESnStudy eye progression to PDR based on a composite clinical outcome of (1)xa0progression from nonproliferative diabetic retinopathy (NPDR) to PDR based on graded fundus photographs, (2)xa0panretinal photocoagulation (PRP), or (3) pars plana vitrectomy (PPV) for PDR; and study eye changes on the DRSS.nnnRESULTSnIn the integrated FAME data set, compared with sham control-treated subjects, time to first PDR event was significantly delayed in subjects treated with FAc (P < 0.001), and this effect was confirmed in subgroups with more severe DR and chronic DME at baseline. In addition, subjects with retinal nonperfusion at baseline showed greater reduction in progression to PDR with FAc treatment. Both FAc dosages demonstrated statistically significant improvements in mean DR severity compared with sham treatment at months 6, 12, and 18. Numerically more subjects who received FAc experienced 2-or-more- or 3-or-more-step improvements in DR severity compared with subjects who received sham; conversely, fewer subjects treated with FAc experienced 2-or-more- or 3-or-more-step worsening in DR severity. The 3-or-more-step improvement with 0.5 μg/day FAc was statistically significantly different from sham control.nnnCONCLUSIONSnIn subjects with DME, sustained intraocular delivery of FAc slows development of PDR and slows progression of diabetic retinopathy.

Regulatory Factors Influencing Usage of Retinal Pharmaceuticals: A Look Both Home and Abroad

E XUDATIVE RETINAL DISEASES, INCLUDING AGErelated macular degeneration (AMD), diabetic retinopathy, and venous occlusive disease, are major contributors to vision loss globally. Fortunately, many ocular-specific treatments have been developed over the last decade and many more are in advanced-phase clinical trials with anticipated market release over the next 5 years. Although the specifics in bringing a novel pharmaceutical to market vary among countries, 2 key regulatory steps are often employed that influence the clinical availability and usage of these pharmacologic therapies.

Comparison of Early Treatment Diabetic Retinopathy Study Standard 7-Field Imaging With Ultrawide-Field Imaging for Determining Severity of Diabetic Retinopathy

Importance Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials. Objective To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging. Design, Setting, and Participants This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017. Main Outcomes and Measures Agreement between UWF images, UWF images masked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using &kgr; statistics. Results A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted &kgr;, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; &kgr;, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%). Conclusions and Relevance Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.

Ultra-Wide-Field Fluorescein Angiography–Guided Normalization of Ischemic Index Calculation in Eyes With Retinal Vein Occlusion

PurposenThe purpose of this study was to compare the use of central and montaged ultra-wide-field fluorescein angiography (UWFFA) images for calculating the area of nonperfusion (NP) and ischemic index (ISI) in patients with retinal vein occlusion (RVO) and macular edema (ME) and to correlate these measurements with best-corrected visual acuity (BCVA) and central macular thickness (CMT).nnnMethodsnThirty eyes of 30 RVO patients with recurrent ME were enrolled. Baseline UWFA images were sent to the Doheny Image Reading Center for quantitative analysis by certified graders. The association between ISI from the various zones and BCVA and CMT was examined by Spearman rank correlation and compared. Generalized linear models (GLMs) were used to analyze associations between BCVA and disease status.nnnResultsnThe NP area and ISI for central and montaged images were not significantly different for any retinal zone. A modest but statistically significant negative linear correlation was observed between BCVA and ISI, ranging from r = -0.3825 in the perimacular area (PMA) to r = -0.584 in the far peripheral area (FPA). On GLM analysis, both PMA (β = -1.059; 95% confidence interval: -1.74 to -0.378) and FPA (β = -0.505; 95% confidence interval: -0.988 to -0.021) were significant independent predictors of BCVA. We found no correlation between ISI from the various zones and CMT in this cohort.nnnConclusionsnMontaging of UWFFA images may not be required to adequately quantify and represent areas of NP in eyes with RVO. NP in both the PMA and peripheral retina appear relevant to visual function, highlighting the importance of evaluating the retinal periphery in these individuals.

Intravitreal aflibercept for proliferative diabetic retinopathy

www.thelancet.com Vol 390 November 11, 2017 2141 group, the conclusion of the study is that PRP alone was associated with a 3-letter vision loss. What was the cause of this loss? If it is diabetic macular oedema—the authors state that “no patients were offered antiVEGF treatment for macular oedema in the PRP group”—many reports show the efficacy of anti-VEGF therapy in improving vision. We are strong advocates for anti-VEGF therapy for diabetic macular oedema and proliferative diabetic retinopathy but we believe there is potentially a role for combining it with PRP, especially in eyes with proliferative diabetic retinopathy.

Erratum. Diabetic Retinopathy: A Position Statement by the American Diabetes Association. Diabetes Care 2017;40:412–418

After duration of diabetes, hyperglycemia has been the most consistently associated risk factor for retinopathy. A large and consistent set of observational studies and clinical trials document the association of poor glucose control and retinopathy. The Diabetes Control and Complications Trial (DCCT), a randomized controlled clinical trial of intensive glycemic control versus conventional glycemic control in people with type 1 diabetes, demonstrated that intensive therapy reduced the development or progression of diabetic retinopathy by 34–76% (51). In addition, the DCCT demonstrated a definitive relationship between hyperglycemia and diabeticmicrovascular complications, including retinopathy (18). Early treatmentwith intensive therapy was most effective. In addition, intensive therapy had a substantial beneficial effect over the entire range of retinopathy. A 10% reduction in HbA1c, for example from 10 to 9% or from 8 to 7.2%, reduces the risk of retinopathy progression by 43% (52).