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Purpose: To report updated clinical outcomes in subjects undergoing pars plana vitrectomy (PPV) using modern techniques and equipment for the treatment of proliferative diabetic retinopathy-related complications. Pooled analysis of five randomized clinical trials conducted at the same institution and included both study and control subjects from the trials., Methods: There were 943 subjects who prospectively underwent small-gauge PPV with antivascular endothelial growth factor pretreatment for proliferative diabetic retinopathy-related complications and completed 6-month follow-up., Results: The visual acuity of the study population improved from median 2.00 (interquartile range 1.3, 2.3) at baseline to median 1.00 (interquartile range 0.5, 1.3) at 6 months. One hundred and eighty-four patients (19.5%) achieved 20/50 or better acuity, and 652 patients (69.1%) achieved 20/200 or better acuity at 6 months. The vision improved or remained stable in 901 patients (95.5%), and 11 patients (1.2%) developed no light perception at 6 months. Intraoperative complications occurred in 343 cases (36.4%), and 199 cases (21.1%) experienced a postoperative complication. The most common postoperative complication was vitreous hemorrhage in 124 cases (62.3% of all complications). Unplanned secondary PPV was necessary in 86 cases (9.1%)., Conclusion: This study reports updated clinical outcomes in patients undergoing PPV for proliferative diabetic retinopathy-related complications which compares favorably with the age before small-gauge PPV and antivascular endothelial growth factor pretreatment.

Purpose: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration., Design: A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study., Methods: Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks., Main Outcome Measure: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84., Results: The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency., Conclusion: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To quantify the economic incentives associated with the choice of anti-VEGF drugs for retinal diseases., Methods: An economic model was created based on the distribution of use and number of injections of bevacizumab (B), versus aflibercept or ranibizumab (AR); published Medicare reimbursement rates; published rebates; estimated unreimbursed drug use; estimated use of drug company samples; and published costs-of-drugs. Differential economic incentives associated with the choice of drugs were calculated over a range of distributions of drug use., Results: The splits in drug choice ranged from 92% AR/8% B to 31% AR/69% B, and in annual injection numbers from 2000 to 6000 with a median of 4000 in one 5-person retina service. Assumed values for rebates were 1% for drug company rebate, 1% for group purchasing organization rebate, and 5 for number of unreimbursed injections per year. The differential economic incentive of a 92% AR/8% B split compared to a 31% AR/69% B split for the median annual number of injections was $266, 893., Conclusion: Using real-world data, the economic incentive associated with a choice of more expensive anti-VEGF drugs is large. Accounting for unreimbursed drug use and the cost of additional staff required to manage expensive drug inventory does not nullify the incentive. To what degree this financial incentive influences ophthalmologists' choice of drugs is unknown, but not trivial. Financial disclosure of the conflicts of interest in the drugs recommended for treatment should be discussed with patients., Competing Interests: DJB received grant support from the DRCR network, Genentech, Regeneron, Novartis, Apellis, book royalties from Springer, Inc. and has equity ownership in Zeiss Meditec, Inc. (<$25,000). The authors report no other conflicts of interest in this work., (© 2021 Browning and Greenberg.)

Purpose: To describe the rationale for revising the hydroxychloroquine (HCQ) dosing and screening guidelines and to identify the barriers to more effective guidelines in the future., Design: Literature review., Methods: A PubMed query of studies on HCQ dosing and HCQ retinopathy (HCQR) screening was conducted with a selective review of the English language literature., Results: Three iterations of the American Academy of Ophthalmology HCQ dosing and HCQR screening guidelines have been published without including prescribing physicians on the writing committees. This may contribute to prescribing physicians' low adherence to the guidelines. As ancillary tests have improved, asymptomatic HCQR is being detected earlier, leading to a higher reported prevalence of HCQR and a drop in the ceiling for safe dosing. These trends put stricter constraints on prescribers and their patients, who may have had well-controlled autoimmune disease on HCQ doses that were previously considered to be below the high-risk threshold for HCQR. Indeed, stopping HCQ at the earliest sign of HCQR should be reconsidered; for cases of early HCQR, dose reduction and more intensive monitoring for retinopathy may strike a more appropriate balance between HCQ risk and benefits. A prospective study using the Diabetic Retinopathy Clinical Research Retina Network with standardized collection of data, HCQ blood levels, centralized grading of ancillary tests, and community and academic ophthalmologists would provide a stronger evidence base for future HCQ guidelines., Conclusions: The HCQ dosing and screening guidelines should be updated and a prospective study of HCQ dosing and HCQR should be initiated with the joint efforts of ophthalmologists and prescribing physicians., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy., Methods: A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance., Results: Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials., Conclusion: Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and treatment burden are more constrained. Results with subthreshold laser appear promising but will require more rigorous study to establish its role as adjunctive therapy. Evidence to support an optimal integration of the various treatment options is lacking. Central to the widespread adoption of any therapeutic regimen for DR and DME is substantiation of safety, efficacy, and cost-effectiveness by a body of sound clinical trials., Competing Interests: Dr Sam Mansour reports personal fees from Iridex Corporation, Alimera Sciences, Inc., from Chengdu Kanghong Biotech Co., Novartis International AG, and personal non-financial support from Diopsys, Inc. during the conduct of the study, and personal fees from Alcon, outside the submitted work. Dr David Browning reports grants from regeneron, drcr network, novartis, and other from springer and zeiss outside the submitted work. Dr Abdhish Raman Bhavsar reports grants from DRCR and other from Allergay, outside the submitted work. No funding for this work has been received from any public or private entities, including: National Institutes of Health (NIH); Wellcome Trust; Howard and Hughes Medical Institute (HHMI). No author of the present work has any proprietary interest in the subject matter of this manuscript and the authors report no other conflicts of interest in this work., (© 2020 Mansour et al.)

Purpose: The increasing prevalence of obesity over the past 60 years implies the need to reassess the risk of hydroxychloroquine retinopathy (HR) in obese women using the American Academy of Ophthalmology (AAO) 2016 guidelines., Design: Cross-sectional study., Participants: Medical records of 64 patients with HR from the practices of 2 ophthalmologists, 11 of whom were women with body mass index of 30 kg/m 2 or more, were reviewed., Methods: Daily dosing based on real and ideal weight was calculated., Main Outcome Measure: Determine the number (and percentage) of patients given daily dosing according to real-weight and ideal-weight guidelines., Results: In 4 patients (36%), daily dosing was more than 5 mg/kg based on real weight and more than 6.5 mg/kg based on ideal weight. In 4 patients (36%), daily dosing was 5 mg/kg or less based on real weight and 6.5 mg/kg or less based on ideal weight. In 3 patients (27%), daily dosing was 5 mg/kg or less based on real weight and more than 6.5 mg/kg based on ideal weight. No patient had daily dosing of more than 5 mg/kg based on real weight and 6.5 mg/kg or less based on ideal weight., Conclusions: Twenty-seven percent of cases of hydroxychloroquine retinopathy in obese women had ostensibly safe dosing based on 2016 AAO guidelines. Overdosing of obese women by 2016 AAO guidelines is not rare. Daily dosing based on the older 6.5-mg/kg ideal weight threshold is safer in women with a body mass index of 30 kg/m 2 or more., (Copyright © 2019 American Academy of Ophthalmology. All rights reserved.)

Importance: Comparisons of the relative effect of 3 anti-vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment., Objective: To provide additional outcomes from a randomized trial evaluating 3 anti-vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography., Design, Setting, and Participants: Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015., Interventions: Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol., Main Outcomes and Measures: One-year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (≥400 µm) or thinner (250 to 399 µm) CST., Results: In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (-8% to 35%) for aflibercept vs ranibizumab., Conclusions and Relevance: These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients., Trial Registration: clinicaltrials.gov Identifier: NCT01627249.

Purpose: To describe the pharmacokinetics, preclinical studies, and clinical trials of the newly approved anti-vascular endothelial growth factor (VEGF) drug aflibercept (Eylea (VEGF Trap-Eye); Regeneron; and Bayer)., Design: Review with editorial commentary., Methods: A review of the medical literature and pertinent Internet postings combined with analysis of key studies with expert opinion regarding the use of aflibercept for the treatment of exudative age-related macular degeneration., Results: Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity. Preclinical ophthalmologic studies demonstrated that aflibercept suppresses choroidal neovascularization in several animal models. The results of phase 1 and 2 trials showed excellent short-term suppression of choroidal neovascularization in patients with exudative age-related macular degeneration and suggested a longer durability of aflibercept compared with other anti-VEGF drugs. The pivotal phase 3 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration 1 and 2 trials showed that monthly and bimonthly aflibercept were noninferior to monthly ranibizumab at preventing vision loss (< 15-letter loss) with comparable vision gains and safety. Year 2 treatment involved monthly pro re nata injections with required injections every 3 months and maintained vision gains from the first year, with an average of 4.2 injections of aflibercept and 4.7 injections of ranibizumab., Conclusions: Aflibercept promises to deliver excellent visual outcomes for exudative age-related macular degeneration patients while undergoing fewer injections compared with ranibizumab. With a wholesale cost of $1850 per dose, the cost per patient with aflibercept treatment promises to be lower than with ranibizumab., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To estimate the short-term variability of macular thickness in eyes with refractory and regressed diabetic macular edema (DME)., Methods: In this retrospective review of consecutive cases from a retina practice, optical coherence tomography (OCT) measurements of macular thickness were extracted from the clinical charts of patients with refractory DME and regressed DME. Variation in macular thickness was defined as maximal central subfield mean thickness (CSMT) minus minimal CSMT during a period of observation in which clinical macular status did not change., Results: There were 36 eyes of 29 patients in the refractory DME group and 93 eyes of 93 patients in the regressed DME group. Median intervals during which macular status was unchanged and OCTs were collected were 7 months for the refractory DME group and 22 months for the regressed DME group. Baseline CSMTs were 321 μm for the refractory DME group and 217 μm for the regressed DME group. The median variation in CSMT was 89 μm for the refractory DME group and 19 μm for the regressed DME group. Results for total macular volume paralleled those for CSMT., Conclusions: In consonance with eyes having treatment-naïve DME, eyes with refractory DME have short-term fluctuation in macular thickness larger than OCT measurement variability. In eyes with regressed DME, short-term fluctuation is less than in eyes with refractory DME, yet can also exceed measurement variability. This information is clinically important in deciding whether subsequent treatment is indicated.

Purpose: To evaluate vitrectomy for diabetic macular edema (DME) in eyes with at least moderate vision loss and vitreomacular traction., Design: Prospective cohort study., Participants: The primary cohort included 87 eyes with DME and vitreomacular traction based on investigator's evaluation, visual acuity 20/63-20/400, optical coherence tomography (OCT) central subfield >300 microns and no concomitant cataract extraction at the time of vitrectomy., Methods: Surgery was performed according to the investigator's usual routine. Follow-up visits were performed after 3 months, 6 months (primary end point), and 1 year., Main Outcome Measures: Visual acuity, OCT retinal thickening, and operative complications., Results: At baseline, median visual acuity in the 87 eyes was 20/100 and median OCT thickness was 491 microns. During vitrectomy, additional procedures included epiretinal membrane peeling in 61%, internal limiting membrane peeling in 54%, panretinal photocoagulation in 40%, and injection of corticosteroids at the close of the procedure in 64%. At 6 months, median OCT central subfield thickness decreased by 160 microns, with 43% having central subfield thickness <250 microns and 68% having at least a 50% reduction in thickening. Visual acuity improved by > or =10 letters in 38% (95% confidence interval, 28%-49%) and deteriorated by > or =10 letters in 22% (95% confidence interval, 13%-31%). Postoperative complications through 6 months included vitreous hemorrhage (5 eyes), elevated intraocular pressure requiring treatment (7 eyes), retinal detachment (3 eyes), and endophthalmitis (1 eye). Few changes in results were noted between 6 months and 1 year., Conclusions: After vitrectomy performed for DME and vitreomacular traction, retinal thickening was reduced in most eyes. Between 28% and 49% of eyes with characteristics similar to those included in this study are likely to have improvement of visual acuity, whereas between 13% and 31% are likely to have worsening. The operative complication rate is low and similar to what has been reported for this procedure. These data provide estimates of surgical outcomes and serve as a reference for future studies that might consider vitrectomy for DME in eyes with at least moderate vision loss and vitreomacular traction., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the safety, tolerability, maximum tolerated dose, and bioactivity of an intravitreal injection of vascular endothelial growth factor (VEGF) Trap-Eye, a fusion protein of binding domains from human VEGF receptors 1 and 2 with human immunoglobulin-G Fc that binds VEGF family members, in patients with neovascular age-related macular degeneration (AMD)., Design: Dose-escalation, multicenter, interventional clinical trial., Participants: Twenty-one patients (13 female, 8 male) with neovascular AMD (NVAMD) and lesions or=50% active choroidal neovascularization (CNV) with best-corrected visual acuity (BCVA) or=3 lines and 3 patients requiring no adjunctive treatment of any type for 12 weeks. Some showed elimination of fluorescein leakage and reduction in area of CNV., Conclusions: Intravitreal injection of up to 4 mg of VEGF Trap-Eye in patients with NVAMD was well tolerated with no evidence of ocular inflammation. Although the number of patients in each cohort was small, there was evidence of bioactivity, because several patients, especially those receiving 2 or 4 mg of VEGF Trap-Eye, showed substantial improvement in BCVA associated with reductions in foveal thickness. Phase III trials to investigate the efficacy of intraocular VEGF Trap-Eye in patients with NVAMD are under way.

Objective: To compare the effects of single-sitting vs 4-sitting panretinal photocoagulation (PRP) on macular edema in subjects with severe nonproliferative or early proliferative diabetic retinopathy with relatively good visual acuity and no or mild center-involved macular edema., Methods: Subjects were treated with 1 sitting or 4 sittings of PRP in a nonrandomized, prospective, multicentered clinical trial. Main Outcome Measure Central subfield thickness on optical coherence tomography (OCT)., Results: Central subfield thickness was slightly greater in the 1-sitting group (n = 84) than in the 4-sitting group (n = 71) at the 3-day (P = .01) and 4-week visits (P = .003). At the 34-week primary outcome visit, the slight differences had reversed, with the thickness being slightly greater in the 4-sitting group than in the 1-sitting group (P = .06). Visual acuity differences paralleled OCT differences., Conclusions: Our results suggest that clinically meaningful differences are unlikely in OCT thickness or visual acuity following application of PRP in 1 sitting compared with 4 sittings in subjects in this cohort. More definitive results would require a large randomized trial. Application to Clinical Practice These results suggest PRP costs to some patients in terms of travel and lost productivity as well as to eye care providers could be reduced., Trial Registration: clinicaltrials.gov Identifier: NCT00687154.

Purpose: To review the available information on classification of diabetic macular edema (DME) as focal or diffuse., Design: Interpretive essay., Methods: Literature review and interpretation., Results: The terms focal diabetic macular edema and diffuse diabetic macular edema frequently are used without clear definitions. Published definitions often use different examination methods and often are inconsistent. Evaluating published information on the prevalence of focal and diffuse DME, the responses of focal and diffuse DME to treatments, and the importance of focal and diffuse DME in assessing prognosis is hindered because the terms are used inconsistently. A newer vocabulary may be more constructive, one that describes discrete components of the concepts such as extent and location of macular thickening, involvement of the center of the macula, quantity and pattern of lipid exudates, source of fluorescein leakage, and regional variation in macular thickening and that distinguishes these terms from the use of the term focal when describing one type of photocoagulation technique. Developing methods for assessing component variables that can be used in clinical practice and establishing reproducibility of the methods are important tasks., Conclusions: Little evidence exists that characteristics of DME described by the terms focal and diffuse help to explain variation in visual acuity or response to treatment. It is unresolved whether a concept of focal and diffuse DME will prove clinically useful despite frequent use of the terms when describing management of DME. Further studies to address the issues are needed.

Objective: To evaluate optical coherence tomography (OCT) measurements and methods of analysis of OCT data in studies of diabetic macular edema (DME)., Design: Associations of pairs of OCT variables and results of 3 analysis methods using data from 2 studies of DME., Participants: Two hundred sixty-three subjects from a study of modified Early Treatment of Diabetic Retinopathy Study (mETDRS) versus modified macular grid (MMG) photocoagulation for DME and 96 subjects from a study of diurnal variation of DME., Methods: Correlations were calculated for pairs of OCT variables at baseline and for changes in the variables over time. Distribution of OCT measurement changes, predictive factors for OCT measurement changes, and treatment group outcomes were compared when 3 measures of change in macular thickness were analyzed: absolute change in retinal thickness, relative change in retinal thickness, and relative change in retinal thickening., Main Outcome Measures: Concordance of results using different OCT variables and analysis methods., Results: Center point thickness correlated highly with central subfield mean thickness (CSMT) at baseline (0.98-0.99). The distributions of changes in CSMT were approximately normally distributed for absolute change in retinal thickness and relative change in retinal thickness, but not for relative change in retinal thickening. Macular thinning in the mETDRS group was significantly greater than in the MMG group when absolute change in retinal thickness was used, but not when relative change in thickness and relative change in thickening were used. Relative change in macular thickening provides unstable data in eyes with mild degrees of baseline thickening, unlike the situation with absolute or relative change in retinal thickness., Conclusions: Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important. Absolute change in retinal thickness is the preferred analysis method in studies involving eyes with mild macular thickening. Relative change in thickening may be preferable when retinal thickening is more severe.

Purpose: To determine the variation in optical coherence tomography (OCT)-measured macular thickness in diabetic eyes without clinical edema and to investigate factors that might influence variation in macular thickness., Design: Retrospective, observational case series from a clinical practice., Methods: Review of clinical charts and longitudinal OCT measurements of a consecutive series of 56 eyes of 56 patients with diabetes but no clinical macular edema. Measured variables include OCT central subfield mean thickness (CSMT), total macular volume (TMV), and logarithm of the minimum angle of resolution (logMAR) visual acuity., Results: Over a median follow-up of 17 months, interquartile range (IQR) (9, 23), the median variation in CSMT was 18 microns, IQR (11, 31), and the median variation in TMV was 0.09 mm(3), IQR (0.06, 0.16). Variation in CSMT did not change significantly with increasing CSMT. Absolute, but not relative, variation in TMV increased with increasing baseline values (P = .0127 and P = .1538 for absolute variation and relative variation in TMV, respectively). The variation in CSMT and TMV did not vary with follow-up time and did not vary with age, gender, race, hypertension status, glycosylated hemoglobin, or retinopathy level., Conclusions: Variation in CSMT and TMV in diabetic eyes without DME over intervals up to 17 months is no greater than OCT measurement variability in eyes without and with DME. A change in the OCT-measured macular thickness greater than 10% of the baseline thickness is likely to represent a true change in the macular thickness and not OCT measurement variability, diurnal variation, or variability occurring over longer time scales.

Purpose: To examine the relationship of optical coherence tomography (OCT) measured macular thickness to retinopathy severity in patients with diabetes and no clinically detectable macular edema., Design: Retrospective observational case series., Participants: Three hundred eighty-three eyes of 383 patients of a private retina practice; including 100 normal eyes of patients without diabetes, 100 eyes of diabetics without retinopathy, 100 eyes of diabetics with mild to moderate retinopathy, 35 eyes of diabetics with severe nonproliferative or proliferative retinopathy, and 48 eyes of diabetics with regressed proliferative retinopathy., Methods: Review of clinical charts and optical coherence tomography measurements., Main Outcome Measures: Central subfield mean thickness (CSMT), inner and outer zone measurements, and total macular volume., Results: Central subfield mean thicknesses (mean +/- standard deviation) were 208+/-22, 198+/-25, 204+/-26, 224+/-38, and 205+/-27 microm for normals, eyes of diabetics without retinopathy, eyes with mild to moderate nonproliferative retinopathy, eyes with severe nonproliferative to proliferative retinopathy, and eyes with regressed proliferative retinopathy, respectively. For all groups, mean CSMT was larger in males than in females. Statistically significant differences by gender were observed for normals, diabetics without retinopathy, and diabetics with mild to moderate nonproliferative retinopathy (mean differences, 12, 14, and 18 microm, respectively; Ps = 0.0057, 0.0057, and 0.0002). For increasing retinopathy severity, the probability of macular thickening detected by OCT but not detected by clinical examination increased. Fifteen percent of eyes with severe nonproliferative or proliferative retinopathy and no clinically detected edema had OCT-measured macular thickening., Conclusions: Because OCT measurements are gender dependent, gender balance or statistical adjustment for gender imbalances of compared groups in OCT studies of diabetic macular edema is important. As retinopathy severity increases, the probability of subclinical edema rises. Except for an individual baseline measurement possibly useful for longitudinal comparison, the data suggest that there is little reason routinely to obtain OCT in eyes with diabetes and no retinopathy or mild to moderate diabetic retinopathy when clinical examination fails to show macular edema.

Purpose: To define the course of subclinical diabetic macular edema (DME) and identify any predictors of progression to clinically significant DME., Design: Retrospective, observational case series., Setting: Private retina practice., Patient Population: One hundred and fifty-three eyes of 153 patients with diabetic retinopathy and subclinical DME., Observation Procedures: Clinical charts review and longitudinal optical coherence tomography (OCT) measurements., Main Outcome Measures: Change in OCT values and time to eventual treatment for clinically significant DME., Results: Over a median follow-up of 14 months (interquartile range, seven to 25 months), 48 of 153 eyes (31.4%) progressed to clinically significant DME. The numbers (%) of eyes showing decreased, unchanged, and increased central subfield mean thickness were 16 (10.5%), 117 (76.5%), and 20 (13.1%), respectively. None of the patients or eye variables typically assessed in clinical practice was predictive of progression from subclinical DME to clinically significant DME., Conclusions: Progression from subclinical DME to clinically significant DME may be detected by serial clinical and OCT assessment. Subclinical DME does not inexorably progress over time scales of one to two years, and a substantial fraction of eyes spontaneously improve. Follow-up intervals of four to six months allowed detection of progression to clinically significant DME. In this sample of patients, OCT did not help in predicting which eyes with subclinical DME would progress to clinically significant DME.

Purpose: To evaluate optical coherence tomography (OCT) reproducibility in patients with diabetic macular edema (DME)., Design: Prospective 1-day observational study., Participants: Two hundred twelve eyes of 107 patients with DME involving the macular center by clinical examination and OCT central subfield thickness of > or =225 microm., Methods: Retinal thickness was measured with the OCT3 system, and scans were evaluated by a reading center. Reproducibility of retinal thickness measurements was assessed, and 95% confidence intervals (CIs) for a change in thickness were estimated., Main Outcome Measures: Reproducibility of OCT-measured central subfield thickness., Results: Reproducibility was better for central subfield thickness than for center point thickness (half-width of the 95% CI for absolute change, 38 microm vs. 50 microm, and for relative change, 11% vs. 17%, respectively; P<0.001). The median absolute difference between replicate measurements of the central subfield was 7 microm (2%). Half-widths of the 95% CI for a change in central subfield thickness were 22, 23, 33, and 56 microm for scans with central subfield thicknesses of <200, 200 to <250, 250 to <400, and > or =400 microm, respectively. When expressed as percentage differences between 2 measurements, half-widths of the 95% CI for a change in central subfield thickness were 10%, 10%, 10%, and 13% for scans with central subfield thicknesses of <200, 200 to <250, 250 to <400, and > or =400 microm, respectively. We were unable to identify an effect on reproducibility of central subfield measurements with respect to the presence of cystoid abnormalities, subretinal fluid, vitreomacular traction, or reduced visual acuity. Reproducibility was better when both scans had a standard deviation (SD) of the center point of <10.0% (half-width of the 95% CI for change, 33 microm vs. 56 microm; P<0.001)., Conclusions: Reproducibility is better for central subfield thickness measurements than for center point measurements, and variability is less with retinal thickness when expressed as a percent change than when expressed as an absolute change. A change in central subfield thickness exceeding 11% is likely to be real. Scans with an SD of the center point of > or =10.0% are less reproducible and should be viewed with caution when assessing the validity of an observed change in retinal thickness in patients with DME.

Objective: To compare optical coherence tomography (OCT)-measured retinal thickness and visual acuity in eyes with diabetic macular edema (DME) both before and after macular laser photocoagulation., Design: Cross-sectional and longitudinal study., Participants: Two hundred ten patients (251 eyes) with DME enrolled in a randomized clinical trial of laser techniques., Methods: Retinal thickness was measured with OCT and visual acuity was measured with the electronic Early Treatment of Diabetic Retinopathy procedure., Main Outcome Measures: Optical coherence tomography-measured center point thickness and visual acuity., Results: The correlation coefficients for visual acuity versus OCT center point thickness were 0.52 at baseline and 0.49, 0.36, and 0.38 at 3.5, 8, and 12 months after laser photocoagulation. The slope of the best fit line to the baseline data was approximately 4.4 letters (95% confidence interval, 3.5-5.3) of better of visual acuity for every 100-mum decrease in center point thickness at baseline with no important difference at follow-up visits. Approximately one third of the variation in visual acuity could be predicted by a linear regression model that incorporated OCT center point thickness, age, hemoglobin A1C, and severity of fluorescein leakage. The correlation between change in visual acuity and change in OCT center point thickening 3.5 months after laser treatment was 0.44, with no important difference at the other follow-up times. A subset of eyes showed paradoxical improvements in visual acuity with increased center point thickening (7%-17% at the 3 time points) or paradoxical worsening of visual acuity with a decrease in center point thickening (18%-26% at the 3 time points)., Conclusions: There is modest correlation between OCT-measured center point thickness and visual acuity, and modest correlation of changes in retinal thickening and visual acuity after focal laser treatment for DME. However, a wide range of visual acuity may be observed for a given degree of retinal edema. Thus, although OCT measurements of retinal thickness represent an important tool in clinical evaluation, they cannot substitute reliably as a surrogate for visual acuity at a given point in time. This study does not address whether short-term changes on OCT are predictive of long-term effects on visual acuity.

Objective: To evaluate diurnal variation in retinal thickness measured with optical coherence tomography (OCT) in patients with center-involved diabetic macular edema., Methods: Serial OCT3 measurements were performed in 156 eyes of 96 subjects with clinically diagnosed diabetic macular edema and OCT central subfield retinal thickness of 225 microm or greater at 8 am. Central subfield thickness was measured from OCT3 retinal thickness maps at 6 points over a single day between 8 am and 4 pm. A change in central subfield thickening (observed thickness minus mean normal thickness) of at least 25% and of at least 50 microm at 2 consecutive points or between 8 am and 4 pm was considered to have met the composite outcome threshold., Results: At 8 am, the mean central subfield thickness was 368 microm and the mean visual acuity was 66 letters (approximately 20/50). The mean change in relative central subfield retinal thickening between 8 am and 4 pm was a decrease of 6% (95% confidence interval, -9% to -3%) and the mean absolute change was a decrease of 13 microm (95% CI, -17 to -8). The absolute change was significantly greater in retinas that were thicker at 8 am (P<.001) but the relative change was not (P = .14). The composite threshold of reduction in central subfield thickening (as defined above) was observed in 5 eyes of 4 subjects (3% of eyes; 95% CI, 1% to 8%) while 2 eyes of 2 subjects (1%; 95% CI, 0% to 5%) had an increase in central subfield thickening of this same magnitude. The maximum decrease was observed at 4 pm in all 5 eyes., Conclusion: Although on average there are slight decreases in retinal thickening during the day, most eyes with diabetic macular edema have little meaningful change in OCT central subfield thickening between 8 am and 4 pm.

Background and Objective: To provide a tool for analyzing optical coherence tomography data in patients with diabetic macular edema., Patients and Methods: Retrospective series of 206 patients with diabetic macular edema involving at least one eye and receiving focal laser photocoagulation, intravitreal triamcinolone acetonide injection, or vitrectomy, membrane peeling, and intravitreal triamcinolone acetonide injection, and of untreated fellow eyes without diabetic macular edema. Main outcome measures included foveal subfield mean thickness and thickening relative to normal (microns), total macular volume and its increase relative to normal (mm3), visual acuity (Snellen decimal), and intraocular pressure (mm Hg)., Results: The authors demonstrate a graphical display of data based on a spreadsheet template for the longitudinal management of diabetic macular edema. Complex relationships of ocular response and interventions are concisely displayed., Conclusion: A graphical display of optical coherence tomography, visual acuity, and intraocular pressure data is a practical aid in the management of diabetic macular edema.

Purpose: To define regional patterns of macular thickening in diabetic macular edema (DME)., Design: Retrospective case series., Setting: Retina practice., Patient Population: Fifty-two normal eyes of 48 patients and 100 eyes of 80 patients with DME., Experimental Procedure: We measured retinal thickness for nine zones and total macular volume using the 3.5-mm display of an optical coherence tomograph (OCT). We determined the normal ranges of values for zones, and then normal ranges of values for the difference in thickness between each pair of zones, termed comparisons. main outcome measures: Frequencies of increased zonal thickness, increased total macular volume, and abnormalities in zonal comparisons., Results: We found the following abnormalities: increased total macular volume 49% (49/100), increased foveal zone thickness 46% (46/100), increased inner parafoveal zone thickness (average 42.2% for the four zones), and increased outer zone thickness (average 34.3% for the four zones). Abnormal two-zone comparisons were found in 1027 of the 7200 possible comparisons (14.3%). Of these abnormal comparisons, the fovea was thicker relative to another zone in 26%; the four inner parafoveal zones were thicker relative to other zones in 8.7% to 15.2% (average 13.0%); and the four outer zones were thicker relative to other zones in 3.9% to 7.6% (average 6%). Eighty-eight percent (88/100) of the eyes chosen on clinical grounds as needing focal laser photocoagulation were detected., Conclusion: A broader concept of OCT abnormality, which includes abnormalities in zonal relationships, may improve automated detection of DME compared with clinical judgment.