Patient-Reported Outcomes After Ferric Carboxymaltose Treatment for Iron Deficiency Anemia: A Prospective Observational Study.

Background: Iron deficiency anemia (IDA) is a common cause of fatigue and impaired quality of life. The present study aimed to evaluate the impact of intravenous iron supplementation with ferric carboxymaltose (FCM) on fatigue, physical function, and general health among patients with IDA attending routine clinical care. Methods: This was a prospective, single arm, observational study of adult patients prescribed with intravenous FCM for the treatment of IDA during routine clinical care. We used Patient-Reported Outcomes Measurement Information System (PROMIS) instruments to evaluate fatigue (PROMIS Short Form v1.0 13a [FACIT-Fatigue]), general health status (PROMIS Scale v1.2), and physical function (PROMIS Short Form v2.0 4a) before and at 3 and 6 months after FCM treatment. Results: A total of 152 patients were enrolled. Mean age was 47.4 ± 16.0 years and 82.2% were female. Mean serum hemoglobin was 10.2 ± 1.4 g/dL at baseline. All patients were treated with at least one FCM dose at baseline, with 77.6% receiving a two-dose treatment course. The mean baseline FACIT-Fatigue score was 61.0 ± 9.0, improving significantly to 50.2 ± 9.5 at 3 months after FCM treatment. A minimum 5-point improvement, pre-defined as clinically meaningful, was seen in the FACIT-Fatigue, PROMIS Global Physical Health, Global Mental Health and PROMIS Physical Function scores for 72.7%, 52.8%, 41.7% and 39.8% of patients at 3 months (p < 0.0001 for each change from baseline), with statistically significant improvement continuing at 6 months. Mean serum hemoglobin was significantly increased at both 3 and 6 months (12.8 g/dL [N = 44] and 12.4 g/dL [N = 54], respectively). Conclusion: IDA patients attending routine clinical practice reported substantial levels of fatigue and impairments in physical function and global health prior to intravenous iron treatment. Patients experienced significant improvements in fatigue symptoms, physical function, and global health at 3 months after treatment with FCM, which were sustained at 6 months.

Microperimetry and mfERG as functional measurements in diabetic macular oedema undergoing intravitreal ranibizumab treatment.

PURPOSE: To evaluate Microperimetry (MP) and multifocal electroretinogram (mfERG) as whole-macula functional markers of treatment response in naive diabetic macular oedema (DMO) patients undergoing ranibizumab treatment. METHODS: An exploratory sub-analysis of a prospective study (NCT01947881-CHARTRES). Patients received three monthly ranibizumab injections (loading dose) followed by pro re nata (PRN) regimen during 1 year. At baseline, during and after treatment (Months 0, 3, 6 and 12), subjects were tested using BCVA, OCT, MP and mfERG. MP was performed in the central 12°, and retinal sensitivity was measured overall (mean sensitivity (MS)), and in three concentric rings (R1-R3). mfERG P1 amplitude and implicit time were measured over six concentric rings (R1-R6). RESULTS: Thirty-two eyes were included. MP mean and rings sensitivity were significantly lower in DMO (p < 0.001). After loading dose, a significant improvement in retina sensitivity was observed, particularly in good BCVA responders (MS = +2.28 dB; R1 = +2.33 dB, R2 = +2.20 dB, R3 = +2.25 dB; p = 0.049). Overall retinal sensitivity was significantly correlated with BCVA improvement (r = 0.54; p = 0.026) and inversely correlated with OCT central subfield thickness improvement (r = -0.39; p = 0.026). mfERG amplitude and implicit time were also lower in DMO (p < 0.011). An improvement of mfERG P1 amplitude and implicit time in R1 was noted in good responders after ranibizumab loading dose (+16.49 nV/deg2; p = 0.013 and -0.005 ms; p = 0.048, respectively). When changing to PRN treatment regimen, BCVA was maintained during the 12 months of follow-up but worsening of the visual function was detected by MP and mfERG. CONCLUSIONS: Microperimetry and mfERG were able to demonstrate DMO functional improvement after treatment loading dose, as well as early visual changes when treatment regimen was switched to PRN.

Characterization of Disease Progression in the Initial Stages of Retinopathy in Type 2 Diabetes: A 2-Year Longitudinal Study.

Purpose: To characterize 2-year changes occurring in neurodegeneration, edema, and capillary dropout in nonproliferative diabetic retinopathy. Methods: Two-year prospective longitudinal observational cohort of eyes/patients with type 2 diabetes using spectral domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA). Eyes were examined three times with intervals of 1 year. Thickness of the full retina and layer-by-layer measurements were used to identify edema or neurodegeneration. OCTA vessel density maps of the retina were used to identify capillary dropout. Early Treatment Diabetic Retinopathy Study (ETDRS) classification was performed using the seven-field ETDRS protocol. Results: A total of 62 eyes from 62 patients with diabetes were followed for 2 years. After verification for image quality, a total of 44 eyes from 44 patients (30% women) aged 52 to 80 years were retained for data analysis. There were 18 eyes with ETDRS grades 10 to 20, 17 eyes with ETDRS grade 35, and 9 eyes with ETDRS grades 43 to 47. During the 2-year follow-up period, there was a progressive increase in capillary dropout, whereas edema and neurodegeneration remained stable. In multivariate analysis, considering a model adjusted for age, sex, hemoglobin A1C, visual acuity, and diabetes duration, vessel density remained significantly different between Diabetic Retinopathy Severity Scale groups (Wilks' λ = 0.707; P = 0.015) showing association with disease progression. Conclusions: Capillary dropout increased in a period of 2 years in eyes with minimal, mild, and moderate diabetic retinopathy, whereas the presence of edema and neurodegeneration remained stable.

An analysis of the effectiveness outcomes of economic studies evaluating ophthalmic drugs: a systematic review.

PURPOSE: To characterize the effectiveness measures of cost-effectiveness studies (CES) of ophthalmic drugs. METHODS: A systematic review was conducted in PubMed/Embase until October 2019. Cost-effectiveness studies (CES) evaluating ophthalmic drugs were included. Sources of effectiveness measures were extracted. Data on study design and study outcomes were extracted from sources of effectiveness measures. The adequacy of the sample size of the clinical studies used as sources of effectiveness measures was assessed. If CES have retrieved effectiveness data from multiple sources, the appropriateness of the method to combine the results was analysed. RESULTS: Forty-five CES were included. Thirty-one (68.9%) retrieved their effectiveness measures from experimental studies, five (11.1%) from observational studies and nine (20%) from other type of data sources. Eight (17.8%) CES used data from a primary outcome of a study as an effectiveness measure, eight (17.8%) used data from secondary outcomes, seven (15.6%) used data from the both primary and secondary outcomes and for 22 (48.9%) it was not possible to identify the outcomes used. From the 23 (51.1%) CES based on a single clinical study, three (6.7%) included data from clinical studies which had an adequate sample size to detect significant differences in the clinical outcomes used as effectiveness measures. From the 17 (37.8%) CES based on multiple clinical studies, only one (2.2%) used and/or reported an adequate method of quantitative synthesis (meta-analysis). CONCLUSION: A considerable number of CES in ophthalmology were not based on clinical studies with adequate sample sizes and report results from effectiveness measures not assessed as primary outcomes.

OPTICAL COHERENCE TOMOGRAPHY LEAKAGE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Identification of Choroidal Neovascularization Activity by Location and Quantification of Abnormal Fluid Under Anti-Vascular Endothelial Growth Factor Therapy.

PURPOSE: To test optical coherence tomography leakage in the identification and quantification of choroidal neovascularization-related fluid, its change after anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration eyes and its relation to functional outcome. METHODS: Prospective analysis of a cohort of neovascular age-related macular degeneration cases treated with 2.0-mg intravitreal aflibercept. Eyes included were analyzed before, 1-week, and 1-month after one injection. Best-corrected visual acuity was assessed using Early Treatment Diabetic Retinopathy Study method. Optical coherence tomography leakage maps depicting low optical reflectivity (LOR) sites were acquired with OCT Cirrus AngioPlex (Zeiss, Dublin, CA). The LOR area ratio was correlated to retinal thickness and best-corrected visual acuity. Optical coherence tomography angiography was simultaneously performed. RESULTS: Twenty-two eyes of 18 patients with neovascular age-related macular degeneration were included. The LOR ratio of the full retina scan and retinal pigment epithelium-Bruch layer decreased from baseline to Month 1 (P < 0.05). Changes in retinal thickness and LOR ratio were positively correlated (P < 0.05). Best-corrected visual acuity change correlated with the outer segment layer LOR change (rho = -0.53, P = 0.014), and LOR was inferior in better responders (P = 0.021). Optical coherence tomography leakage identified eyes with recurrent fluid in the external layers. CONCLUSION: Optical coherence tomography leakage identified and quantified the fluid related to choroidal neovascularization activity. Low optical reflectivity change in the outer segment layer correlates with functional outcome and increasing LOR in the external layers may be a marker of early recurrence. Combining optical coherence tomography angiography and optical coherence tomography leakage allows both for choroidal neovascularization morphology and activity analysis.

Characterization of Initial Stages of Diabetic Macular Edema.

PURPOSE: This study is aimed at characterizing the type of retinal edema in the initial stages of retinopathy in type 2 diabetes. METHODS: In this retrospective cross-sectional study, spectral domain optical coherence tomography (OCT) layer by layer analysis of the retina in association with OCT-Leakage, an algorithm to detect sites of low optical reflectivity, were used to examine eyes with minimal, mild, and moderate diabetic retinopathy (DR). RESULTS: A total of 142 eyes from 142 patients (28% women) aged 52-88 years were imaged. Macular edema, either subclinical (SCME) or central-involved macular edema (CIME), was present in 43% of eyes in group 10-20, 41% of eyes in group 35, and 38% of eyes in group 43-47. The inner nuclear layer (INL) was the layer showing higher and most frequent increases in retinal thickness (79%). The edema was predominantly intracellular in group 10-20 (65%) and extracellular in groups 35 (77%) and 43-47 (69%). CONCLUSIONS: Eyes from diabetic patients in the initial stages of DR with different Early Treatment Diabetic Retinopathy Study gradings show similar prevalence of SCME and CIME, independent of the severity of the retinopathy. Retinal edema is located mainly in the INL and appears to be mostly extracellular except in the earliest stages of diabetic retinal disease where intracellular edema predominates.

Multimodal Imaging of the Initial Stages of Diabetic Retinopathy: Different Disease Pathways in Different Patients.

The objective of this study was to evaluate the prevalence of different disease pathways (ischemia, neurodegeneration, and edema) in the initial stages of diabetic retinopathy. In this retrospective cross-sectional study, eyes were grouped by diabetic retinopathy severity using the 7-field Early Treatment Diabetic Retinopathy Study (ETDRS) protocol (levels 10-20, 35, and 43-47). Neurodegeneration was identified by thinning of the retinal nerve fiber layer and/or ganglion cell layer. Edema was identified by thickening of the inner nuclear layer, outer plexiform layer, or full retina. Ischemia was identified by metrics of retinal vessel density. Imaging was performed in 142 eyes from 142 patients (28% women) aged 52-88 years. Vessel density (ischemia) was significantly different between the ETDRS groups (P < 0.020). On multivariate regression analysis, it remained significantly different between stages of the disease and showed associations with age (P < 0.001), sex (P = 0.028), and metabolic control (P = 0.034). No significant differences between ETDRS groups were found in retinal thinning (neurodegeneration) or retinal thickness (edema). Eyes with the same ETDRS retinopathy grading from different patients with diabetes showed that the prevalence of different disease pathways varies between patients, even within the same severity group. Ischemia (capillary dropout) is the only disease pathway that shows correlation with retinopathy severity and metabolic control.

Microaneurysm turnover is a predictor of diabetic retinopathy progression.

AIM: To analyse retinopathy phenotypes and microaneurysm (MA) turnover in mild non-proliferative diabetic retinopathy (NPDR) as predictors of progression to diabetic central-involved macular oedema (CIMO) in patients with type 2 diabetes mellitus (DM) in two different ethnic populations. METHODS: 205 patients with type 2 DM and mild NPDR were followed in a prospective observational study for 2 years or until development of CIMO, in two centres from different regions of the world. Ophthalmological examinations, including best-corrected visual acuity (BCVA), fundus photography with RetmarkerDR analysis, and optical coherence tomography (OCT), were performed at baseline and 6 12 and 24 months. RESULTS: 158 eyes/patients reached either the study endpoint, CIMO (24) or performed the last study visit (24-month visit) without developing CIMO (134). From the eyes/patients in analysis, 27 eyes (17.1%) progressed to more advanced ETDRS (Early Treatment Diabetic Retinopathy Study) levels: 6 progressed to mild NPDR (level 35), 15 progressed to moderate NPDR (level 43), 5 progressed to moderately severe NPDR (level 47) and 1 progressed to high risk PDR (level 71). Worsening in ETDRS level is associated with phenotype C (p=0.005). From the 130 eyes/patients with a low MA turnover, 18 (13.8%) eyes/patients had an increase in ETDRS level, and from the 19 eyes/patients with a high MA turnover, 9 (47.4%) had an increase in ETDRS level (p<0.001). CONCLUSION: Eyes in the initial stages of diabetic retinopathy show different phenotypes with different risks for progression to CIMO. In phenotype C, MA turnover correlates with ETDRS grading worsening and development of CIMO.

MEASUREMENTS OF RETINAL FLUID BY OPTICAL COHERENCE TOMOGRAPHY LEAKAGE IN DIABETIC MACULAR EDEMA: A Biomarker of Visual Acuity Response to Treatment.

PURPOSE: To evaluate the effects of anti-vascular endothelial growth factor treatment on retinal fluid in patients with diabetic macular edema by using optical coherence tomography leakage (OCT-L), a new method of quantifying sites of lower than normal optical reflectivity (LOR) in OCT, and to correlate these findings with best-corrected visual acuity (BCVA) response. METHODS: Prospective analysis of 21 eyes with diabetic macular edema, naive to anti-vascular endothelial growth factor treatment. Macular cube 512 × 128 and OCT angiography 6 × 6-mm scans (CIRRUS AngioPlex; ZEISS, Dublin, CA) were acquired in all eyes before the first ranibizumab injection (V1) and 1 week after treatment (V2). Optical coherence tomography leakage analysis was performed with Angioplex raw scan data used to calculate LOR map ratios. Lower optical reflectivity ratios at baseline and differences from V1 to V2 and other OCT morphological features such as central retinal thickness measurements, disorganization of the inner retinal layers, and disruption of ellipsoid zone were compared with BCVA response 1 month after the first intravitreal injection. RESULTS: After the first intravitreal injection of ranibizumab, eight patients (38%) were identified as good responders, 5 (24%) as moderate, and 8 (38%) as poor. There were no significant BCVA differences at baseline. Significant differences were found in LOR ratio changes between the different treatment response groups after 1 week of treatment, especially in outer segment and outer plexiform layer (outer segment-good responders: -53%, responders: -12%, and poor responders: 7% [P = 0.026]; outer plexiform layer-good responders: -49%, responders: 18%, and poor responders: 5% [P = 0.010]). Lower optical reflectivity ratios differences after 1 week of treatment predict better the BCVA treatment response at 1 month than changes of central retinal thickness, disorganization of the inner retinal layer, and ellipsoid zone disruption, especially in the outer segment and outer plexiform layer (area under the curve = 0.82 and 0.73, respectively). CONCLUSION: Optical coherence tomography leakage changes after anti-vascular endothelial growth factor treatment of diabetic macular edema, identifying the degree of decrease in retinal fluid in the outer layers of the retina is a more robust biomarker of BCVA recovery than central retinal thickness, disorganization of the inner retinal layer, or ellipsoid zone disruption changes.

Adherence to a Mediterranean diet, lifestyle and age-related macular degeneration: the Coimbra Eye Study - report 3.

PURPOSE: To characterize the lifestyle and nutritional risk profile associated with the Mediterranean diet in a Portuguese population with and without age-related macular degeneration (AMD). METHODS: Nested case-control study (n = 883) within the Coimbra Eye Study, including 434 subjects with AMD and 449 age- and sex-matched subjects without AMD. All enrolled subjects underwent a full risk assessment, including lifestyle-related risk factors and a thorough food frequency questionnaire. This allowed us to build an adherence score to the Mediterranean diet (mediSCORE, range 0-9) constructed from individual food intakes. Food intake was also further analysed by conversion to micronutrient consumption. RESULTS: Our results suggest that physical activity has a protective role in AMD [p = 0.018 after multivariate adjustment, OR: 0.69 (0.51-0.93)]. High (mediSCORE ≥6) was also found to be protective [p = 0.041, OR: 0.62 (95% CI: 0.38-0.97)]. Food group analysis unveiled a specific protective role for increased fruits consumption (p = 0.029). Finally, micronutrient analysis revealed a protective role associated with increased consumption of caffeine, fibres, beta-carotene, vitamin C and vitamin E (p < 0.05). CONCLUSION: High mediSCORE appears to confer protection against the development of AMD in a Mediterranean population. This effect is driven by increased consumption of fruits and some antioxidant micronutrients, which emerged as statistically significant protective factors. Further studies are required to establish dietary recommendations with clinical application.

Subclinical Macular Edema as a Predictor of Progression to Central-Involved Macular Edema in Type 2 Diabetes.

PURPOSE: The aim of this study was to examine the relationship between subclinical diabetic macular edema (SCME) and the development of central-involved macular edema (CIME) in patients with diabetes mellitus type-2 and mild nonproliferative diabetic retinopathy (NPDR), from 2 populations of different ethnicities. METHODS: Two hundred and five patients with diabetes mellitus type-2 and mild NPDR with no prior laser or intravitreal treatment were followed for 2 years or until the development of CIME. Ophthalmological examinations, including BCVA, fundus photography with RetmarkerDR analysis, and optical coherence tomography were performed at baseline and months 6, 12, and 24. RESULTS: One hundred and fifty eight eyes/patients reached either the study endpoint, CIME (n = 24), or performed the 24-month visit without developing CIME (n = 134). Fifty eyes/patients had SCME at baseline (31.6%). Of these 50 eyes, 16 (32.0%) developed CIME, whereas of the 108 eyes with normal retinal thickness (RT) at baseline, only 8 (7.4%) developed CIME (p < 0.001). Patients with increased RT in the central subfield at baseline showed a 12-fold risk of progression to CIME compared with patients without SCME. CONCLUSIONS: In patients with mild NPDR, the presence of SCME is a good predictor of progression to CIME.

Adherence to a Mediterranean diet and its association with age-related macular degeneration. The Coimbra Eye Study-Report 4.

OBJECTIVES: This study aimed to characterize the association of lifestyle and nutritional risk profiles with age-related macular degeneration (AMD) in two subpopulations with differing AMD prevalence. METHODS: This case-control study (n = 1992) included 768 patients with AMD and 1224 age- and sex-matched participants without AMD with a single visit at a primary health care unit. Enrolled participants completed a validated lifestyle and food frequency questionnaire. A score to measure adherence to the Mediterranean diet (mediSCORE; Range, 0-9) was constructed from individual food intakes, which were further analyzed by conversion to nutrient consumption. RESULTS: Higher adherence to the Mediterranean diet (mediSCORE ≥6) was significantly associated with no AMD (odds ratio [OR] = 0.73; P = 0.009). The subpopulation with lower AMD prevalence presented significantly higher adherence to the Mediterranean diet in relation to all individual food groups that comprised the mediSCORE (P < 0.014) with the exception of cereals. Food group analysis showed significant associations between the increased consumption of vegetables (OR = 0.63; P < 0.001) and fruit and nuts (OR = 0.78; P = 0.010) with no AMD. Nutrient analysis revealed that an increased ingestion of water, fibers, total fat, monounsaturated and polyunsaturated fatty acids, linoleic acid, vitamins A and C, carotene, alpha-tocopherol, folate, magnesium, iron, and zinc were significantly associated with no AMD (P < 0.0013). Finally, regular physical activity was associated with no AMD (P = 0.003). CONCLUSIONS: High adherence to a Mediterranean diet and regular physical activity seem to be protective factors for AMD in a Portuguese population. The effect of the diet is likely driven by the increased consumption of vegetables, fruits, and nuts.

Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).

PURPOSE: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN: Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS: Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.

Different Phenotypes of Mild Nonproliferative Diabetic Retinopathy with Different Risks for Development of Macular Edema (C-TRACER Study).

PURPOSE: To evaluate diabetic retinopathy (DR) progression in patients with diabetes mellitus type 2 in 2 populations of different ethnicity. METHODS: A prospective observational study was designed to follow eyes/patients with mild nonproliferative DR, for 2 years or until the development of central-involved macular edema (CIME), in 2 centers from different regions of the world. A total of 205 eyes/patients fulfilled the inclusion/exclusion criteria and were included in this study. Ophthalmological examinations, fundus photography with RetmarkerDR analysis, and optical coherence tomography were performed at baseline and at 6, 12 and 24 months. RESULTS: Of the 158 eyes/patients that completed this study, 24 eyes developed CIME and 134 eyes were present at the last study visit. Eighty-eight eyes (56.4%) were classified as phenotype A, 49 (31.4%) as phenotype B, and 19 (12.2%) as phenotype C. Phenotype A is associated with a very low risk for development of CIME in comparison with phenotypes B and C. The OR for development of CIME was 19.0 for phenotype B and 25.1 for phenotype C. CONCLUSION: Eyes in the initial stages of DR show different phenotypes with different risks of progression to ME. The phenotypes associated with increased risks of progression show different distributions in patients of different ethnicities.

OPTICAL COHERENCE TOMOGRAPHY BASELINE PREDICTORS FOR INITIAL BEST-CORRECTED VISUAL ACUITY RESPONSE TO INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT IN EYES WITH DIABETIC MACULAR EDEMA: The CHARTRES Study.

PURPOSE: To identify baseline optical coherence tomography morphologic characteristics predicting the visual response to anti-vascular endothelial growth factor therapy in diabetic macular edema. METHODS: Sixty-seven patients with diabetic macular edema completed a prospective, observational study (NCT01947881-CHARTRES). All patients received monthly intravitreal injections of Lucentis for 3 months followed by PRN treatment and underwent best-corrected visual acuity measurements and spectral domain optical coherence tomography at Baseline, Months 1, 2, 3, and 6. Visual treatment response was characterized as good (≥10 letters), moderate (5-10 letters), and poor (<5 or letters loss). Spectral domain optical coherence tomography images were graded before and after treatment by a certified Reading Center. RESULTS: One month after loading dose, 26 patients (38.80%) were identified as good responders, 19 (28.35%) as Moderate and 22 (32.83%) as poor responders. There were no significant best-corrected visual acuity and central retinal thickness differences at baseline (P = 0.176; P = 0.573, respectively). Ellipsoid zone disruption and disorganization of retinal inner layers were good predictors for treatment response, representing a significant risk for poor visual recovery to anti-vascular endothelial growth factor therapy (odds ratio = 10.96; P < 0.001 for ellipsoid zone disruption and odds ratio = 7.05; P = 0.034 for disorganization of retinal inner layers). CONCLUSION: Damage of ellipsoid zone, higher values of disorganization of retinal inner layers, and central retinal thickness decrease are good predictors of best-corrected visual acuity response to anti-vascular endothelial growth factor therapy.

A Nonrandomized, Open-Label, Multicenter, Phase 4 Pilot Study on the Effect and Safety of ILUVIEN® in Chronic Diabetic Macular Edema Patients Considered Insufficiently Responsive to Available Therapies (RESPOND).

PURPOSE: The aim of this study was to assess the effectiveness and safety of ILUVIEN® in patients with chronic diabetic macular edema (DME) who were insufficiently responsive to prior therapies. METHODS: This is a prospective, nonrandomized, multicenter, open-label, phase 4 pilot study assessing the effectiveness and safety of ILUVIEN® involving 12 patients insufficiently responsive to available therapies. Assessments were performed at screening, baseline, week 1, and months 1, 3, 6, 9, and 12. Demographics, medical/ophthalmic history, prior laser, anti-VEGF, and steroid treatments, and lab tests were recorded at screening. A complete ophthalmic examination and SD-OCT were performed at screening and at all follow-up visits. RESULTS: The patients showed improvements in best-corrected visual acuity (+3.7 letters), with greater improvement among pseudophakic patients (+6.8 letters) compared with phakic patients (-2.5 letters) 12 months after ILUVIEN®. The mean central subfield thickness decrease from baseline to month 12 was statistically significant, with a rapid reduction in the first week. Regarding safety, only 2 patients showed an intraocular pressure (IOP) increase over 25 mm Hg during the study, and the rise in IOP was well managed with eye drops only. CONCLUSIONS: This prospective and pilot study suggests that ILUVIEN® is safe and may be considered effective for chronic DME patients insufficiently responsive to other available therapies as it showed a rapid and sustained improvement of macular edema obtained after treatment with ILUVIEN®.

OCT-Leakage: A New Method to Identify and Locate Abnormal Fluid Accumulation in Diabetic Retinal Edema.

Purpose: To identify retinal extracellular fluid changes and their correlation with increased retinal thickness (RT) in eyes with subclinical and clinical macular edema in diabetes type 2. Methods: A cohort of 48 eyes from 48 type 2 diabetic patients with mild or moderate nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study levels 20/35) were classified as having normal RT (10), subclinical macular edema (30), or clinical macular edema (8). They were examined with Cirrus spectral-domain optical coherence tomography (OCT) at baseline visits (ClinicalTrials.gov number, NCT01145599) in the Coimbra center. Results from automated analysis of the retinal extracellular space, using our OCT-Leakage algorithm to identify sites of low optical reflectivity, were compared with those from a control group of 25 healthy eyes. Results: The highest increases in RT in the eyes with subclinical and clinical macular edema were found in the inner nuclear layer (INL). These increases were, on average, 49.9% in subclinical macular edema and 104.7% in clinical macular edema. Extracellular space increases in the INL that were identified with the OCT-Leakage algorithm showed a strong positive correlation with the increases in RT in the central subfield (r = 0.71, P < 0.001). Conclusions: Increases in number of sites with lower optical reflectivity positively correlate with the increase in RT in the initial stages of macular edema in diabetes type 2. Diabetic macular edema is represented mainly by extracellular fluid accumulation that preferentially involves the INL of the retina.

Age-related macular degeneration in Portugal: prevalence and risk factors in a coastal and an inland town. The Coimbra Eye Study - Report 2.

PURPOSE: To determine the age- and sex-specific prevalence of early and late age-related macular degeneration (AMD) in two Portuguese population-based samples and to identify its risk factors. POPULATION: A population of 6023 adults aged ≥55 years was recruited from two Portuguese primary healthcare units in the central region of Portugal - one from a coastal (n = 3000) and another from an inland town (n = 3023). METHODS: Cross-sectional population-based study. Participants were enrolled in the two locations between August 2009 and October 2013. Responders underwent standardized interviews and ophthalmologic examination, including digital fundus imaging. All fundus photographs were graded according to an International Classification and Grading System. The main outcome measures consisted of age- and sex-adjusted prevalence of early and late AMD. Potential epidemiologic risk factors were also evaluated using logistic regression analysis. RESULTS: Of the 6023 subjects enrolled, 5996 had gradable fundus images and were included in the analysis. The crude prevalence of early and late AMD was 6.99 and 0.67%, respectively, for the coastal town and 15.39 and 1.29% for the inland town. Age- and sex-adjusted prevalence of any AMD for the Portuguese population was 12.48% (95% CI: 11.61-13.33) with late AMD accounting for 1.16% (95% CI: 0.85-1.46). Neovascular AMD (NV-AMD) and geographic atrophy (GA) accounted for 0.55% (95% CI: 0.36-0.75) and 0.61% (95% CI: 0.37-0.84) of individuals, respectively. After adjusting for possible confounding factors, prevalence of early and late AMD increased with increasing age (OR = 1.35; 95% CI: 1.23-1.49 for early and OR = 3.01; 95% CI: 2.22-4.08 for late AMD, per each decade of age increase, p < 0.001). After adjustment for age, sex, family history, smoking history, hypertension, diabetes and BMI, subjects from the inland town presented a significantly higher OR of early and late AMD than subjects from the coastal town (OR = 2.57, 95% CI: 2.12-3.12, p < 0.001 for early and OR = 2.06, 95% CI: 1.07-3.95, p = 0.029 for late AMD). CONCLUSIONS: The prevalence of early and late AMD in this Portuguese population was similar to other large-scale population-based cohorts. After controlling for confounders, age and study site of inclusion were significant independent predictors for both early and late forms of the disease. Further analysis will be needed to completely unravel the underlying reasons for this difference regarding geographic location.

Relevance of Retinal Thickness Changes in the OCT Inner and Outer Rings to Predict Progression to Clinical Macular Edema: An Attempt of Composite Grading of Macular Edema.

PURPOSE: To characterize the relevance of macular thickness changes in the inner and outer rings in the progression of macular edema in eyes/patients with diabetes type 2. METHODS: A total of 374 type 2 diabetic patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20-35) were included in a 12-month prospective observational study to identify retinopathy progression. Retinal thickness analyses were performed in 194 eyes/patients using Cirrus SD- OCT and 166 eyes/patients using Spectralis SD-OCT. The DRCR.net classification of subclinical and clinical macular edema was used. A composite grading of macular edema is proposed in this study. RESULTS: A total of 317 eyes/patients completed the study. SD-OCT identified clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema in 104 eyes/patients (28.9%) at baseline. Increased thickness of the central subfield is the best predictor for the development of clinical macular edema, with 85.7% sensitivity and 71.9% specificity (OR: 2.57, 95% CI: 0.82-7.99). However, the involvement of the inner and outer rings is a cumulative predictor of progression to clinical macular edema (OR: 8.69, 95% CI: 2.85-26.52). CONCLUSIONS: A composite OCT grading of macular edema taking into account the retinal thickness changes in the inner and outer macular rings offers a simple way to characterize macular edema, with added clinical value.

Retinal layer location of increased retinal thickness in eyes with subclinical and clinical macular edema in diabetes type 2.

PURPOSE: To identify the retinal layer predominantly affected in eyes with subclinical and clinical macular edema in diabetes type 2. METHODS: A cohort of 194 type 2 diabetic eyes/patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20/35) were examined with Cirrus spectral-domain optical coherence tomography (OCT) at the baseline visit (ClinicalTrials.gov identifier: NCT01145599). Automated segmentation of the retinal layers of the eyes with subclinical and clinical macular edema was compared with a sample of 31 eyes from diabetic patients with normal OCT and an age-matched control group of 58 healthy eyes. RESULTS: From the 194 eyes in the study, 62 had subclinical macular edema and 12 had clinical macular edema. The highest increases in retinal thickness (RT) were found in the inner nuclear layer (INL; 33.6% in subclinical macular edema and 81.8% in clinical macular edema). Increases were also found in the neighboring layers. Thinning of the retina was registered in the retinal nerve fiber, ganglion cells and inner plexiform layers in the diabetic eyes without macular edema. CONCLUSIONS: The increase in RT occurring in diabetic eyes with macular edema is predominantly located in the INL but extends to neighboring retinal layers indicating that it may be due to extracellular fluid accumulation.