Sandrina Nunes

Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema

Aim: The study was a prospective randomised controlled double-masked trial performed in two centres to compare sub-threshold micropulse diode laser photocoagulation (MPDL) with conventional green laser photocoagulation (CGL) in the treatment of clinically significant diabetic macular oedema (CSMO). Methods: Fifty-three patients (84 eyes) with diabetic CSMO were randomly assigned to MPDL (n = 44) or CGL (n = 40) according to the modified Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Treatments were performed after baseline and re-treatments were allowed at or after the 4 month visit if necessary. Parameters noted included the best corrected visual acuity (BCVA), colour fundus photographs, central retinal thickness using optical coherence tomography (OCT), vision contrast sensitivity with Pelli–Robson charts and presence of visible laser scars at baseline and at 4 and 12 months. The primary outcome was BCVA at 12 months. Results: All patients completed 12 months of follow-up after treatment at baseline. There were no statistically significant differences in BCVA, contrast sensitivity and retinal thickness between the two laser modalities at 0, 4 and 12 months. We found that laser scarring was much more apparent with CGL than with the sub-threshold approach (MPDL). Laser scars were identified at the 12 month visits in 13.9% of the MPDL-treated eyes compared with 59.0% of the CGL-treated eyes (p<0.001). Conclusion: Sub-threshold micropulse diode laser photocoagulation is equally as effective as CGL treatment for CSMO. Trial registration number: ISTRN 90646644.

Microaneurysm Turnover Is a Biomarker for Diabetic Retinopathy Progression to Clinically Significant Macular Edema: Findings for Type 2 Diabetics with Nonproliferative Retinopathy

Purpose: To examine the relationship between microaneurysm turnover (formation rate), using a new semi-automatic method (MA-Tracker) based on color fundus photographs, and diabetic retinopathy (DR) progression to clinically significant macular edema (CSME). Methods: In total, 113 patients/eyes with nonproliferative DR (NPDR) were followed up every 6 months for 2 years as controls of the DR clinical trials, and by conventional general and ophthalmological care for the next 8 years (over a total of 10 years’ follow-up). Microaneurysm turnover for the 2 first years was computed using the MA-Tracker. Results: The 17 patients that developed CSME over the 10 years of follow-up presented a microaneurysm formation rate of 9.2 ± 18.2 microaneurysms/year (mean ± SD) during the first 2 years, which was statistically higher than the eyes that did not develop CSME (0.5 ± 1.2 microaneurysms/year, p < 0.001). These 17 patients also presented higher HbA1C levels at baseline (8.5 ± 1.2%) compared to the patients who did not develop CSME (7.3 ± 1.2%, p = 0.001). Conclusions: A high microaneurysm formation rate on color fundus photographs appears to be a good biomarker for DR progression to CSME in type 2 diabetic patients with NPDR.

Computer-Assisted Microaneurysm Turnover in the Early Stages of Diabetic Retinopathy

Purpose: To assess the reliability of microaneurysm turnover, computed from color fundus photographs, in evaluating diabetic retinopathy in patients with type 2 diabetes and nonproliferative retinopathy. Methods: A new method (MA-Tracker) was developed to count microaneurysms by mapping their locations through image co-registration. To compute the reliability of microaneurysm turnover, 3 different graders were asked to earmark microaneurysms on the same set of color fundus photographs. Results: The total numbers of microaneurysms earmarked in each of 5 visits suggest that microaneurysms remain stable over time (p ≥ 0.138). However, an analysis of each microaneurysm showed that only 29.4% remained at the same location. By computing the formation and disappearance rates of microaneurysms (2.3 and 1.7 microaneurysms/year, respectively), a significant turnover of microaneurysms was found. Conclusions: The formation and disappearance rates of microaneurysms obtained from color fundus photographs using MA-Tracker show very good agreement between different graders, and can be used as indicators of microaneurysm turnover in the initial stages of diabetic retinopathy.

Microaneurysm Turnover at the Macula Predicts Risk of Development of Clinically Significant Macular Edema in Persons With Mild Nonproliferative Diabetic Retinopathy

OBJECTIVE To examine the relationship between microaneurysm (MA) turnover using automated analysis of fundus photographs (RetmarkerDR; Critical Health SA) and development of clinically significant macular edema (CSME) in nonproliferative diabetic retinopathy (NPDR). RESEARCH DESIGN AND METHODS A prospective, monocenter, observational study was designed to follow eyes/patients with type 2 diabetes and NPDR (Early Treatment Diabetic Retinopathy Study levels 20 and 35) with no prior laser treatment for 2 years or until development of CSME. A total of 410 patients, one eye per patient, fulfilled the inclusion/exclusion criteria and were included in the study. Ophthalmologic examinations including best corrected visual acuity, fundus photography, and optical coherence tomography were performed at baseline, 6 months, and at the last study visit (24 months or before laser treatment). RESULTS A total of 348 eyes/patients performed the 24-month visit or developed CSME. Of these 348 eyes/patients, 26 developed CSME. HbA1c levels at baseline and MA turnover (i.e., the sum of the MA formation and disappearance rates) computed during the first 6 months of follow-up were found to be independently predictive factors for development of CSME. MA turnover was 11.2 ± 11.2 in the 26 eyes/patients that developed CSME and 5.0 ± 5.2 in the remaining 322 (P < 0.001). Higher MA turnover values correlated with earlier development of CSME. MA turnover predictive values for CSME development were, for the positive predictive value, 20% and for the negative predictive value, 96%. CONCLUSIONS MA turnover calculated with the RetmarkerDR predicts development of CSME in eyes with NPDR. Low MA turnover values identify well the eyes that are less likely to develop CSME in a 2-year period.

Asymmetry of visual sensory mechanisms: Electrophysiological, structural, and psychophysical evidences

Psychophysical visual field asymmetries are widely documented and have been attributed to anatomical anisotropies both at the retinal and cortical levels. This debate on whether such differences originate within the retina itself or are due to higher visual processing may be illuminated if concomitant anatomical, physiological, and psychophysical measures are taken in the same individuals. In the current study, we have focused on the study of objective functional and structural asymmetries at the retinal level and examined their putative correlation with visual performance asymmetries. Forty healthy participants (80 eyes; 13 male and 27 female subjects) were included in this study. Objective functional/structural asymmetries were probed using the multifocal electroretinogram (mfERG) technique and optical coherence tomography (OCT), respectively. A nasal/temporal pattern of asymmetry (nasal visual hemifield disadvantage) was found for all methods (retinal thickness, contrast sensitivity, and mfERG P1 amplitude). Furthermore, superior/inferior asymmetries could be documented only with psychophysics and structural measures. These patterns likely arise at different levels of the retina as inferred by partly independent correlation patterns. We conclude that patterns of structural/functional asymmetries arise at different levels of visual processing with a strong retinal contribution.

Choroidal Thickness In Diabetic Retinopathy: The Influence of Antiangiogenic Therapy

Purpose: To analyze the effect of anti–vascular endothelial growth factor agents (anti-VEGF) in submacular choroidal thickness (CT) of diabetic retinopathy (DR) patients. Methods: Cross-sectional study, which included 25 DR patients (50 eyes) divided in 2 groups, according to DR stage and previous treatments: nonproliferative DR and diffuse diabetic macular edema in both eyes, submitted to macular laser in both eyes and anti-VEGF injection only in 1 eye (nonproliferative diabetic retinopathy + diabetic macular edema group, n = 11); and proliferative DR in both eyes, treated with panretinal photocoagulation in both eyes and anti-VEGF injection only in 1 eye (proliferative diabetic retinopathy group, n = 14). In the study visit, all patients underwent optical coherence tomography with enhanced depth imaging protocol. Choroidal segmentation was performed manually. The medium CT in central macular area (CCT) and the CT in centrofoveal B-scan were obtained automatically. Results: The 25 eyes treated with anti-VEGF showed a reduction on CCT (P = 0.002) and subfoveal CT (P = 0.004), compared with the fellow eyes treated with laser only. Independent evaluation of PDR group revealed similar results (CCT, P = 0.02; subfoveal CT, P = 0.03). In nonproliferative diabetic retinopathy + diabetic macular edema group, CCT was also significantly thinner in eyes treated with anti-VEGF (P = 0.04). A correlation between the number of injections and a thinner CT was found in this group (P = 0.03) and in the evaluation of all eyes together (P = 0.03). Conclusion: Diabetic eyes treated with anti-VEGF agents have reduced CT.

Three different phenotypes of mild nonproliferative diabetic retinopathy with different risks for development of clinically significant macular edema.

PURPOSE To identify different phenotypes of nonproliferative diabetic retinopathy (NPDR) and their progression to clinically significant macular edema (CSME). METHODS A prospective observational study was designed to follow eyes/patients with diabetes type 2 and NPDR with no prior laser treatment for 2 years or until development of CSME. A total of 410 patients, one eye per patient, fulfilled the inclusion/exclusion criteria and were included in the study. Ophthalmological examinations, including BCVA, fundus photography with Retmarker analysis, and optical coherence tomography (OCT), were performed at baseline, month 6 and month 24, or before laser treatment. Hierarchical cluster analysis was used to identify homogeneous subgroups and clinically significant thresholds of the data collected. RESULTS A total of 376 eyes/patients performed the 6-month visit and were considered for cluster analysis. This mathematical method identified three different phenotypes based on statistically significant differences for the microaneurysm (MA) turnover and for the central retinal thickness (RT): phenotype A (low MA turnover and normal RT, 48.1%); phenotype B (low MA turnover and increased central RT, 23.2%); and phenotype C (high MA turnover, 28.7%). From the 348 eyes/patients that reached the study end point or completed the 24-month visit, 26 developed CSME: 3 from phenotype A (1.8%), 7 from phenotype B (8.5%), and 16 from phenotype C (16.2%). Eyes/patients from phenotype C showed a higher risk for CSME development (OR = 3.536; P < 0.001). CONCLUSIONS Hierarchical cluster analysis identifies three different phenotypes of NPDR based on MA turnover and central macular thickness. Eyes/patients from phenotype C show a higher risk for the development of CSME. (ClinicalTrials.gov number, NCT00763802.)

Central retinal thickness measured with HD-OCT shows a weak correlation with visual acuity in eyes with CSME

Aims To investigate the correlation between increased retinal thickness (RT) measured with spectral domain high-definition optical coherence tomography (OCT) (Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, California, USA)) and best-corrected visual acuity (BCVA) in eyes with clinically significant macular oedema (CSME) and type 2 diabetes. Methods Seventy eyes with CSME were included in this observational study. Sixty-two eyes were considered for analysis and were classified as having/not having retinal thickening in the central fovea (central 500-μm-diameter circle) by Cirrus HD-OCT. RT measurements were computed and correlated with BCVA. For comparison purposes, the Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA) central point thickness was also obtained in these eyes. Results In the 19 eyes with CMSE identified by Cirrus HD-OCT without increased RT in the central fovea (500-μm-diameter circle), no correlation was found between RT and BCVA (R=0.062; 95% CI −0.404 to 0.502). In the 43 eyes where the Cirrus HD-OCT identified an increased RT in the central fovea (central 500-μm-diameter circle), only a moderate correlation between RT and BCVA was found (R=−0.459; 95% CI −0.667 to −0.184). Conclusion Correlations between RT and BCVA in CSME are only present when the central 500-μm-diameter circle is involved. However, even in this circumstance, a correlation was found in only 48.8% of the cases. RT cannot, therefore, be used as a surrogate outcome for visual acuity changes.

Age-Related Macular Degeneration and Risk Factors for the Development of Choroidal Neovascularisation in the Fellow Eye: A 3-Year Follow-Up Study

Introduction: The presence of large-sized drusen (≧125 µm), soft indistinct drusen, pigmentary changes, a large area of drusen and a choroidal neovascular membrane in one eye have been found to be predictive risk factors of late exudative age-related macular degeneration (AMD). Multimodal imaging potentially increases the possibility of indentifying further potential risk factors of developing wet AMD. Purpose: To identify morphological and/or functional baseline risk factors for the development of choroidal neovascularization (CNV) in a multimodal set of images from fellow eyes of patients with exudative AMD. Methods: Single-center, prospective, observational, longitudinal 2-year plus 1-year extension study of 62 patients with neovascular AMD in one eye (the nonstudy eye) and early age-related maculopathy (ARM) in the fellow eye (study eye). Best-corrected ETDRS visual acuity, fluorescein angiography (FA) and indocyanine green angiography (ICG), fundus photography, retinal leakage analysis, fundus autofluorescence imaging and optical coherence tomography (OCT Stratus 4.0.2, Carl Zeiss Meditech Inc.) were performed at baseline and every 6 months in order to identify both conversion to CNV as well as possible predictive features present before conversion. A semiautomated computer-assisted grading system was used for classifying fundus color images. Only eyes with 3 years of follow-up were considered for statistical analysis. Results: Fifty-two patients completed the 3-year study follow-up: 26 men and 26 women aged from 56 to 92 years (mean ± SD: 76 ± 6 years). CNV confirmed with FA developed in 46% of the 52 study eyes during the 3-year follow-up (24 converted eyes: 7 in the first year, 11 in the second and 6 in the third). A significantly higher risk for conversion to wet AMD was found only for leakage on a retinal leakage analyzer (odds ratio, OR = 5.0; 95% confidence interval, CI = 1.5–16.4; p = 0.006) detected at least in one visit before the onset of exudative lesions, for baseline ICG hot spots (OR = 7.2; 95% CI = 2.0–25.7; p = 0.002), baseline late ICG hot spots (OR = 4.7; 95% CI = 1.4–15.4; p = 0.009) and baseline early ICG hypofluorescent spots (OR = 3.7; 95% CI = 1.2–12.1; p = 0.025). The total area of drusen, the area of drusen in subfield 1, inner circle or outer circle, the total number of drusen and the number of drusen ≧125 µm, fundus autofluorescence patterns, OCT findings and the severity of ARM at baseline did not show any correlation with an increased risk of conversion to wet AMD. Conclusion: At 3 years, progression from early to late exudative AMD was superior to the expected rate (44%). ICG early and late hyperfluorescent spots or areas, ICG early hypofluorescent spots or areas and early leakage detected with the retinal leakage analyzer, but not pigmentary changes, large drusen, number and area of drusen at any location or a greater severity of ARM at baseline, showed to be a predictive parameter of conversion to wet AMD.

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.