Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy.

Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 µg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.

PURPOSE: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR. DESIGN: Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom. PARTICIPANTS: Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease. METHODS: A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists). MAIN OUTCOME MEASURES: Primary outcome: sensitivity of the new pathway. SECONDARY OUTCOMES: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings. RESULTS: The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits. CONCLUSIONS: The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).

A 44-year-old Caucasian man presented with seizures and cognitive impairment. He had marked retinal drusen, and MR brain scan showed features of cerebral small vessel disease; he was diagnosed with a leukoencephalopathy of uncertain cause. He died at the age of 46 years and postmortem brain examination showed widespread small vessel changes described as a vasculopathy of unknown cause. Seven years postmortem, whole-genome sequencing identified a homozygous nonsense HTRA1 mutation (p.Arg302Ter), giving a retrospective diagnosis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.

A food-based, low-energy, low-carbohydrate diet for people with type 2 diabetes in primary care: A randomized controlled feasibility trial.

AIM: To examine the feasibility of a food-based, low-energy, low-carbohydrate diet with behavioural support delivered by practice nurses for patients with type 2 diabetes. MATERIALS AND METHODS: People with type 2 diabetes and a body mass index (BMI) of ≥30 kg/m2 were randomized 2:1 to intervention or control (usual care) and assessed at 12 weeks. The intervention comprised an 800-1000 kcal/day, food-based, low-carbohydrate (<26% energy) diet for 8 weeks, followed by a 4-week weight maintenance period and four 15-20-minute appointments with a nurse. Primary outcomes were feasibility of recruitment, fidelity of intervention delivery and retention of participants at 12 weeks. Secondary outcomes included change in weight and HbA1c. Focus groups explored the intervention experience. RESULTS: Forty-eight people were screened, 33 enrolled and 32 followed-up. Mean (±SD) weight loss in the intervention group was 9.5 kg (± 5.4 kg) compared with 2 kg (± 2.5 kg) in the control group (adjusted difference - 7.5 kg [-11.0 to -4.0, P < 0.001]). Mean reduction in HbA1c in the intervention group was 16.3 mmol/mol (± 13.3 mmol/mol) compared with 0.7 mmol/mol (±4.5 mmol/mol) in the control group (difference - 15.7 mmol/mol [-24.1 to -7.3, P < 0.001]). CONCLUSIONS: It is feasible to recruit participants to a food-based, low-energy, low-carbohydrate intervention, for practice nurses to deliver the programme in primary care, and to retain participants in both groups. There is evidence of clinically significant short-term improvements in weight and glycaemic control.

Intralesional Macular Atrophy in Anti-Vascular Endothelial Growth Factor Therapy for Age-Related Macular Degeneration in the IVAN Trial.

PURPOSE: To report on the development and progression of macular atrophy (MA) and its relationship with morphologic and functional measures in study and fellow eyes in the Inhibition of vascular endothelial growth factor (VEGF) in Age-related Choroidal Neovascularisation trial. DESIGN: Reading center analysis of data from a randomized controlled trial. PARTICIPANTS: Participants with previously untreated neovascular age-related macular degeneration (nAMD) in the study eye. METHODS: Color, fluorescein angiography (FA) and OCT images acquired at baseline and during the 2-year follow-up were graded systematically for presence of MA. Regression models were constructed to explore relationships between MA and lesion morphology and vision measures (best-corrected distance and near acuity, reading speed and index, contrast sensitivity). MAIN OUTCOME MEASURES: Primary outcome was development of intralesional MA (≥175 µm greatest linear dimension of choroidal vessels seen on FA and/or color, aided by OCT) lying within the maximum footprint of the neovascular lesion. RESULTS: Study eye data were available for 594 of 610 participants; 57 (9.6%) showed intralesional MA at baseline. Incident intralesional MA occurred in 24.4% by the final visit and extralesional MA in only 1.54%. In fellow eyes, an established nAMD lesion was present at baseline in 248 of whom 42 (16.9%) showed intralesional MA at baseline and 32 (12.9%) developed incident intralesional MA. The odds of incident intralesional MA by final visit were lower in study eyes that had ≥50% classic CNV at baseline (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.19-0.80; P = 0.010), subretinal fluid at final visit (OR, 0.41; 95% CI, 0.25-0.76; P = 0.004), or pigment epithelial detachment at final visit (OR, 0.40; 95% CI, 0.21-0.74; P = 0.004). Secondary analyses of incident or progressed intralesional MA in study eyes supported these findings, with odds increasing if the fellow eye had baseline intralesional MA (OR, 2.43; 95% CI, 1.09-5.44; P = 0.030). No significant associations were observed between development of intralesional MA and any other morphologic or visual function measure. CONCLUSIONS: Macular atrophy frequently develops within an nAMD lesion in eyes receiving anti-VEGF therapy over 2 years. No associations between incident MA and drug or treatment frequency or visual function were detected, providing some reassurance to clinicians; however, the longer-term effects remain unknown.

Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PURPOSE: To understand levels of disease burden and progression in a real-world setting among patients from the United Kingdom with bilateral geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective cohort analysis of a multicenter electronic medical record (EMR) database. PARTICIPANTS: Patients who were aged ≥50 years with bilateral GA and no history of choroidal neovascularization (CNV) and who attended 1 of 10 clinical sites using the EMR. METHODS: A deidentified data set was constructed from the records held at the 10 sites. An algorithm was used to extract cases with a GA diagnosis, of which 1901 had bilateral GA and form the basis of this report. A sample of records randomly selected from each center was used to validate disease definitions. MAIN OUTCOME MEASURES: Progression to blindness (visual acuity [VA] <20 letters or Snellen 3/60 in the better-seeing eye), driving ineligibility (VA ≤70 letters or Snellen 6/12 in the better-seeing eye), progression to CNV, loss of 10 or more letters, and mean change in VA over time. RESULTS: At first record of GA, 7.1% had a VA in the better-seeing eye equal to or lower than the cutoff for blindness registration and 71.1% had a VA that would have rendered them ineligible to drive. Over time, 16% became legally blind (median time to outcome, 6.2 years) and 66.7% became ineligible to drive (median time to outcome, 1.6 years). In the worse-seeing eye, 40.1% lost ≥10 letters in 2.4 years. Among patients with baseline and 24-month VA measurements, mean VA decline was 6.1 letters in the worse-seeing eye (n = 413) and 12.4 letters in the better-seeing eye (n = 414). The rate of progression to CNV in either eye was 7.4% per patient-year. CONCLUSIONS: At initial diagnosis, based on VA in the better-seeing eye, a high proportion of patients with bilateral GA were ineligible to drive and approximately 7% were eligible for UK blindness registration. The subsequent reduction in VA that occurred in the better-seeing eye would render a further two-thirds ineligible to drive. These findings emphasize the severity of the visual disability associated with GA secondary to AMD.

CLINICAL EVIDENCE OF THE MULTIFACTORIAL NATURE OF DIABETIC MACULAR EDEMA.

PURPOSE: To report functional and morphologic outcomes, based on diabetic macular edema (DME) chronicity and baseline best-corrected visual acuity (BCVA), from a subanalysis of the fluocinolone acetonide for macular edema (FAME) trials. METHODS: Patients were categorized by DME duration (nonchronic [ncDME] or chronic [cDME] DME) and three nonexclusive baseline vision strata. Anatomic and visual acuity VA outcomes of these cohorts were compared with treatment assignment. RESULTS: For all patients with ncDME and cDME who received sham control, 27.8% and 13.4%, respectively, gained ≥15 BCVA letters, whereas 22.3% and 34.0% of 0.2 µg/day fluocinolone acetonide (FAc)-treated patients, respectively, gained ≥15 BCVA letters. Among patients with ncDME who received sham control, as baseline vision decreased, the percentage gaining ≥15 BCVA letters increased; however, among those with cDME, the percentage gaining ≥15 BCVA letters did not change as baseline vision decreased. Conversely, among 0.2 µg/day FAc-treated patients, the percentage gaining ≥15 BCVA letters increased with decreasing baseline vision, regardless of DME chronicity. Anatomical outcomes were similar within treatment arms, regardless of the DME duration. CONCLUSION: Patients with cDME and poor baseline vision who were exposed to low-dose FAc experienced BCVA improvements that were not observed in a similar group from the sham-control arm. These data support the multifactorial pathogenesis of cDME.

VISUAL ACUITY IMPROVEMENT WHEN SWITCHING FROM RANIBIZUMAB TO AFLIBERCEPT IS NOT SUSTAINED.

PURPOSE: To assess whether visual benefits exist in switching to aflibercept in patients who have been chronically treated with ranibizumab for neovascular age-related macular degeneration. METHODS: A multicenter, national, electronic medical record database study was performed. Patients undergoing six continuous monthly ranibizumab injections and then switched to continuous aflibercept were matched to those on continuous ranibizumab therapy. Matching was performed in a 2:1 ratio and based on visual acuity 6 months before and at the time of the switch, and the number of previous ranibizumab injections. RESULTS: Patients who were switched to aflibercept demonstrated transiently significant improvement in visual acuity that peaked at an increase of 0.9 Early Treatment Diabetic Retinopathy Study letters 3 months after the switch, whereas control patients continued on ranibizumab treatment showed a steady decline in visual acuity. Visual acuity differences between the groups were significant (P < 0.05) at 2, 3, and 5 months after the switch. Beginning at 4 months after the switch, the switch group showed a visual acuity decline similar to the control group. CONCLUSION: Transient, nonsustained improvement in visual acuity occurs when switching between anti-vascular endothelial growth factor agents, which may have implications in treating patients on chronic maintenance therapy on one anti-vascular endothelial growth factor medication.

Accommodative Function in Individuals with Autism Spectrum Disorder.

SIGNIFICANCE: Accommodative responses were significantly poorer in individuals with autism spectrum disorder (ASD) compared with age-matched typically developing control subjects, and hypoaccommodation was associated with reduced near visual acuity (NVA) and convergence. PURPOSE: Autism spectrum disorder is a neurodevelopmental disorder with a reported prevalence of 1.1 to 1.5%. Accommodative dysfunction has been noted in other developmental conditions including cerebral palsy and Down syndrome. The aim of this study was to investigate how accommodative accuracy and near visual function in ASD compared with typically developing control subjects. METHODS: This study investigated accommodative function in children with ASD, in conjunction with other vision measures with habitual refractive corrections. Accommodative accuracy was assessed using modified Nott dynamic retinoscopy. Individual accommodative demand and response were calculated incorporating residual refractive error (difference between cycloplegic and habitual refractive state). Near visual measures included NVA, near point of convergence, fusional reserves, and stereoacuity. Cycloplegic autorefraction confirmed refractive error. RESULTS: Accommodative responses were measured from 124 participants with ASD (6 to 17 years old) and 204 age-matched control subjects. There was no significant difference in the magnitude of residual refractive error between groups (P = .10). The prevalence of a clinically significant lag of accommodation was greater in the ASD group compared with control subjects (ASD = 17.4%, control subjects = 4.9%, χ = 13.04, P < .0001). Near visual acuity was significantly reduced in the ASD group with a clinically significant lag of accommodation (P < .01). A few participants (n = 24 control subjects, n = 14 ASD) had uncorrected or undercorrected refractive errors (spherical equivalent refractive error ≥+2.00 D, >1.00 DC), and when these were removed from analysis, there was still an increased prevalence of hypoaccommodation in ASD (14.7%). CONCLUSIONS: Children with ASD were significantly more likely to have accommodative deficits (and associated near visual deficits) in their presenting refractive state than typically developing children. Appraisal of refractive error, accommodation, and NVA should be considered in visual assessment of children with ASD.

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

OBJECTIVE: To 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. DESIGN: Post hoc analysis of data from the 36-month prospective, randomized, FAME A and B trials. PARTICIPANTS: Patients with diabetic macular edema (DME) who received sham control or FAc 0.2 or 0.5 µg/day. METHODS: A 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. MAIN OUTCOME MEASURES: Study eye progression to PDR based on a composite clinical outcome of (1) progression from nonproliferative diabetic retinopathy (NPDR) to PDR based on graded fundus photographs, (2) panretinal photocoagulation (PRP), or (3) pars plana vitrectomy (PPV) for PDR; and study eye changes on the DRSS. RESULTS: In 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. CONCLUSIONS: In subjects with DME, sustained intraocular delivery of FAc slows development of PDR and slows progression of diabetic retinopathy.

UK Age-Related Macular Degeneration Electronic Medical Record System (AMD EMR) Users Group Report IV: Incidence of Blindness and Sight Impairment in Ranibizumab-Treated Patients.

PURPOSE: To study the incidence of blindness and sight impairment in treatment-naive patients receiving ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) in the United Kingdom (UK) National Health Service. DESIGN: Multicenter nAMD database study. PARTICIPANTS: A total of 11 135 patients who collectively received 92 976 treatment episodes to 12 951 eyes. METHODS: Data were extracted from 14 UK centers using the same electronic medical record system (EMR). The EMR-mandated collection of a data set (defined before first data entry) including: age, Early Treatment Diabetic Retinopathy Study visual acuity letter score (VA) for both eyes at all visits, and injection episodes. Participating centers used overwhelmingly a pro re nata re-treatment posology at intended monthly follow-up visits following a loading phase of 3 monthly injections. MAIN OUTCOME MEASURES: Incidence of blindness and sight impairment (VA in the better-seeing eye <38 letters [≤20/200 Snellen, approximately], and <68 letters [≤20/50 Snellen, approximately] at 2 consecutive visits, or 1 visit if no further follow-up data) in each year after initiating treatment. RESULTS: Information from >300 000 clinic visits (2.8 million data points) collected over 5 years was collated from 14 centers. Mean age at first treatment was 79.7 years (standard deviation = 9.19 years), with a female preponderance (63%). The mean (median) VA at baseline in the better-seeing eye was 67.2 (72.0) letters, 20/40- (20/40+) approximate Snellen conversion. The cumulative incidence of new blindness and sight impairment in patients with treated nAMD in at least 1 eye at years 1 to 4 after first injection were 5.1%, 8.6%, 12% and 15.6% for new blindness and 29.6%, 41.0%, 48.7%, and 53.7% for new sight impairment, but with significant reductions in the rates between year cohorts initiating treatment (blindness [P = 4.72 × 10-08], sight impaired [P = 3.27 × 10-06]). CONCLUSIONS: To the best of our knowledge, this is the first multicenter real-world study on the incidence of blindness and sight impairment based on VA data in patients treated with ranibizumab for nAMD, and its results show low incidences of both blindness and sight impairment, which both declined during the study period.

Previous Intravitreal Therapy Is Associated with Increased Risk of Posterior Capsule Rupture during Cataract Surgery.

PURPOSE: To investigate if previous intravitreal therapy is a predictor of posterior capsule rupture (PCR) during cataract surgery. DESIGN: Multicenter, national electronic medical record (EMR) database study with univariate and multivariate regression modeling. PARTICIPANTS: A total of 65 836 eyes of 44 635 patients undergoing cataract surgery. METHODS: Anonymized data were extracted for eyes undergoing cataract surgery from 20 hospitals using the same EMR for cases performed between 2004 and 2014. Variables included as possible risk indicators for PCR were age, sex, number of previous intravitreal injections, indication for intravitreal therapy, grade of healthcare professional administering intravitreal therapy, advanced cataract, and cataract surgeon grade. MAIN OUTCOME MEASURES: Presence or absence of posterior capsular rupture during cataract surgery. RESULTS: Data were available on 65 836 cataract operations, of which 1935 had undergone previous intravitreal therapy (2.9%). In univariate regression analyses, patient age, advanced cataract, junior cataract surgeon grade, and number of previous intravitreal injections were significant predictors of PCR. By considering the number of previous intravitreal injections as a continuous variable, the odds ratio for PCR per intravitreal injection was 1.04 (P = 0.016) after adjusting for age, advanced cataract, and cataract surgeon grade. Repeat analysis considering intravitreal injections as a categoric variable showed 10 or more previous injections were associated with a 2.59 times higher likelihood of PCR (P = 0.003) after again adjusting for other significant independent predictors. CONCLUSIONS: Previous intravitreal therapy is associated with a higher likelihood of PCR during cataract surgery. This study provides data to help inform surgeons and patients about the risk of complications when undergoing cataract surgery after multiple prior intravitreal injections. Further investigation is required to determine the cause behind the increased PCR risk.

First-Year Visual Acuity Outcomes of Providing Aflibercept According to the VIEW Study Protocol for Age-Related Macular Degeneration.

PURPOSE: Aflibercept has the potential advantage of reducing capacity problems by allowing 2 monthly visits for patients with neovascular macular degeneration (nAMD) compared with monthly pro re nata regimens that are the most commonly used in the United Kingdom. This study aimed to report the visual outcomes achieved in routine clinical practice using the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) protocol at 1 year and compare with trials data and other real-world reports. DESIGN: Retrospective data analysis from an electronic medical record. PARTICIPANTS: Consecutive series of treatment-naïve patients initiated on aflibercept for nAMD at least 1 year before data extraction. METHODS: Data were anonymized and remotely extracted from 16 centers in the United Kingdom that use the same electronic medical record (EMR) system (Medisoft Ophthalmology; Medisoft Limited, Leeds, UK). MAIN OUTCOME MEASURES: The minimum data set defined before first data entry and mandated by the EMR included age, gender, visual acuity, injection episodes, and complications. RESULTS: The mean age was 80.0 years (median, 81.0 years) and 63.7% were women. During the first year of treatment with aflibercept, 1840 treatment-naïve eyes of 1682 patients received a median of 8 (mean, 7.0) injections at a median of 8 (mean, 7.3) visits. The mean baseline visual acuity was 53.7 letters, improving to 58.8 letters (+5.1-letter gain) at 1 year. In first-treated eyes, the respective figures were 52.7 letters at baseline and 58.2 letters at 1 year, a gain of +5.5 letters. The proportion achieving 70 letters or more increased from 16.4% at baseline to 33.7% at 1 year, and 92% avoided moderate visual loss at 1 year. CONCLUSIONS: The visual acuity outcomes are comparable to randomized trials and better than many previous real-world data collections, with a mean +5.1-letter gain at 1 year compared with +8.4 letters in the integrated analysis of the VIEW 1 and VIEW 2 studies. Early visual gains were maintained through the year. Collection of outcomes beyond clinical trials can have limitations but better reflect the full pool of patients actually treated and are important to determine whether a particular treatment is performing as expected. Such data also have the potential to improve services by setting up a mechanism to compare sites.

A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema.

PURPOSE: To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. DESIGN: Randomized, double-masked, 36-week, 3-period crossover clinical trial. PARTICIPANTS: Fifty-six subjects with DME involving the center of the macula in one or both eyes. METHODS: Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). MAIN OUTCOME MEASURES: Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. RESULTS: Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 µm for bevacizumab and -137 µm for ranibizumab (difference, 48 µm; P < 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 µm (95% CI, -155 to -100) for bevacizumab and -176 µm (95% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next. CONCLUSIONS: This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME.

Profile of refractive errors in European Caucasian children with Autistic Spectrum Disorder; increased prevalence and magnitude of astigmatism.

PURPOSE: Autistic Spectrum Disorder (ASD) is a common neurodevelopmental disorder characterised by impairment of communication, social interaction and repetitive behaviours. Only a small number of studies have investigated fundamental clinical measures of vision including refractive error. The aim of this study was to describe the refractive profile of a population of children with ASD compared to typically developing (TD) children. METHODS: Refractive error was assessed using the Shin-Nippon NVision-K 5001 open-field autorefractor following the instillation of cyclopentolate hydrochloride 1% eye drops. RESULTS: A total of 128 participants with ASD (mean age 10.9 ± 3.3 years) and 206 typically developing participants (11.5 ± 3.1 years) were recruited. There was no significant difference in median refractive error, either by spherical equivalent or most ametropic meridian between the ASD and TD groups (Spherical equivalent, Mann-Whitney U307 = 1.15, p = 0.25; Most Ametropic Meridian, U305 = 0.52, p = 0.60). Median refractive astigmatism was -0.50DC (range 0.00 to -3.50DC) for the ASD group and -0.50DC (Range 0.00 to -2.25DC) for the TD group. Magnitude and prevalence of refractive astigmatism (defined as astigmatism ≥1.00DC) was significantly greater in the ASD group compared to the typically developing group (ASD 26%, TD 8%, magnitude U305 = 3.86, p = 0.0001; prevalence (χ12=17.71 , p < 0.0001). CONCLUSIONS: This is the first study to describe the refractive profile of a population of European Caucasian children with ASD compared to a TD population of children. Unlike other neurodevelopmental conditions, there was no increased prevalence of spherical refractive errors in ASD but astigmatic errors were significantly greater in magnitude and prevalence. This highlights the need to examine refractive errors in this population.

INTRAVITREAL CORTICOSTEROIDS IN DIABETIC MACULAR EDEMA: PHARMACOKINETIC CONSIDERATIONS.

PURPOSE: To review the relationship between kinetics, efficacy, and safety of several corticosteroid formulations for the treatment of diabetic macular edema. METHODS: Reports of corticosteroid use for the treatment of diabetic macular edema were identified by a literature search, which focused on the pharmacokinetics, efficacy, and safety of these agents in preclinical animal models and clinical trials. RESULTS: Available corticosteroids for diabetic macular edema treatment include intravitreal triamcinolone acetonide, dexamethasone, and fluocinolone acetonide. Because of differences in solubility and bioavailability, various delivery mechanisms are used. Bioerodible delivery systems achieve higher maximum concentrations than nonbioerodible formulations. There is a relationship between visual gains and drug persistence in the intravitreal compartment. Safety effects were more complex; level of intravitreal triamcinolone acetonide exposure is related to development of elevated intraocular pressure and cataract; this does not seem to be the case for dexamethasone, where two different doses showed similar mean intraocular pressure and incidence of cataract surgery. With fluocinolone acetonide, rates of intraocular pressure elevations requiring surgery seem to be dose related; rates of cataract extraction were similar regardless of dose. CONCLUSION: Available corticosteroids for diabetic macular edema exhibit different pharmacokinetic profiles that impact efficacy and adverse events and should be taken into account when developing individualized treatment plans.

Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema.

PURPOSE: To present the safety and efficacy of intravitreal implants releasing 0.2 µg/day fluocinolone acetonide (FAc) in patients with chronic versus nonchronic diabetic macular edema (DME). To assess ocular characteristics, anatomic changes, and re-treatment and ancillary therapies that may explain the differential treatment effect seen with intravitreal implants releasing FAc 0.2 µg/day in patients with chronic and nonchronic DME. An overall benefit-to-risk assessment for the FAc 0.2-µg/day and FAc 0.5-µg/day doses has been reported previously. DESIGN: Preplanned subgroup analysis of chronic (duration of diagnosis, ≥3 years) and nonchronic (duration of diagnosis, <3 years) DME in patients from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Patients with persistent DME despite 1 or more macular laser treatment were randomized 1:2:2 to sham injection (n = 185), FAc 0.2 µg/day (n = 375), or FAc 0.5 µg/day (n = 393). METHODS: Patients received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on re-treatment criteria, additional masked study drug could be given after 1 year. MAIN OUTCOME MEASURES: Percentage of patients with improvement of 15 letters or more from baseline. Secondary outcomes included other parameters of visual function and foveal thickness. RESULTS: At month 36, the difference between FAc 0.2 µg/day and sham control in the percentage of patients who gained 15 letters or more was significantly greater in chronic DME patients (FAc 0.2 µg/day, 34.0% vs. sham, 13.4%; P<0.001), compared with patients with nonchronic DME (FAc 0.2 µg/day, 22.3% vs. sham, 27.8%; P = 0.275). The greater response in patients with chronic DME was not associated with baseline ocular characteristics, changes in anatomic features, or differences in re-treatment or ancillary therapies. The ocular adverse event profile for FAc 0.2 µg/day was similar regardless of DME duration. CONCLUSIONS: This is the first published analysis correlating duration of diagnosis of DME with treatment effect. In patients with chronic DME, FAc 0.2 µg/day provides substantial visual benefit for up to 3 years and would provide an option for patients who do not respond to other therapy.