Different Risk Profiles for Progression of Nonproliferative Diabetic Retinopathy: A 2-Year Study.

INTRODUCTION: Characterization of 2-year progression of different risk phenotypes in eyes with mild and moderate nonproliferative diabetic retinopathy (NPDR) in type 2 diabetes (T2D). METHODS: A 2-year prospective longitudinal cohort study (CORDIS, NCT03696810) was conducted. Ophthalmological examinations were performed including best corrected visual acuity, color fundus photography and optical coherence tomography (OCT and OCTA). OCT metrics, central retinal thickness and ganglion cell layer + inner plexiform layer (GCL + IPL) thickness were analyzed. OCTA metrics, vessel density (VD), perfusion density (PD) and area of intercapillary spaces (AIS) were obtained from superficial and deep capillary plexus (SCP, DCP). Only phenotype C identified by decreased VD ≥ 2 SD of healthy controls and phenotype B identified by subclinical macular edema with decreased VD < 2 SD of healthy controls were included. RESULTS: One hundred twenty-two eyes from T2D individuals were included in study; 65 eyes (53%) were classified as phenotype B and 57 eyes (47%) as phenotype C. For phenotype B, progression was associated with thinning of the GCL + IPL (ETDRS 35, 1 year p = 0.013, 2 year p < 0.001; ETDRS 43-47, 2 year p = 0.003) and vessel closure involving mainly the DCP for both ETDRS grades (ETDRS 35, 1 year p = 0.025, 2 year p = 0.034; ETDRS 43-47, 1 year p = 0.011). For phenotype C there was also progressive thinning of the GCL + IPL (ETDRS 35, in both years p ≤ 0.001; ETDRS 43-47, 1 year p = 0.002, 2 year p = 0.001), with vessel closure involving mainly SCP (ETDRS 35, 1 year p = 0.012, 2 year p = 0.023 in full-retina), which appeared to stabilize at maximal values in ETDRS grade 43-47 at the end of 2 years. ETDRS severity changes at the end of the 2-year period showed that worsening was associated with phenotype C with changes involving predominantly the SCP (VD, p = 0.005; PD, p = 0.008; AIS, p = 0.005). CONCLUSIONS: Association between ETDRS classification of NPDR severity and identification of different risk phenotypes offers new perspective to predict disease progression in T2D individuals with NPDR.

Swept-source OCTA quantification of capillary closure predicts ETDRS severity staging of NPDR.

PURPOSE: To test whether a single or composite set of parameters evaluated with optical coherence tomography angiography (OCTA), representing retinal capillary closure, can predict non-proliferative diabetic retinopathy (NPDR) staging according to the gold standard ETDRS grading scheme. METHODS: 105 patients with diabetes, either without retinopathy or with different degrees of retinopathy (NPDR up to ETDRS grade 53), were prospectively evaluated using swept-source OCTA (SS-OCTA, PlexElite, Carl Zeiss Meditec) with 15×9 mm and 3×3 mm angiography protocols. Seven-field photographs of the fundus were obtained for ETDRS staging. Eyes from age-matched healthy subjects were also imaged as control. RESULTS: In eyes of patients with type 2 diabetes without retinopathy or ETDRS levels 20 and 35, retinal capillary closure was in the macular area, with predominant alterations in the parafoveal retinal circulation (inner ring). Retinal capillary closure in ETDRS stages 43-53 becomes predominant in the retinal midperiphery with vessel density average values of 25.2±7.9 (p=0.001) in ETDRS 43 and 23.5±3.4 (p=0.001) in ETDRS 47-53, when evaluating extended areas of 15×9 protocol. Combination of acquisition protocols 3×3 mm and 15×9 mm, using SS-OCTA, allows discrimination between eyes with mild NPDR (ETDRS 10, 20, 35) and eyes with moderate-to-severe NPDR (ETDRS grades 43-53). CONCLUSIONS: Retinal capillary closure, quantified by SS-OCTA, can identify NPDR severity progression. It is located mainly in the perifoveal retinal capillary circulation in the initial stages of NPDR, whereas the retinal midperiphery is predominantly affected in moderate-to-severe NPDR.

Efficacy and Safety of Intravitreal Aflibercept Treat and Extend for Polypoidal Choroidal Vasculopathy in the ATLANTIC Study: A Randomized Clinical Trial.

IMPORTANCE: Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed. METHODS: A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin. The main outcome measures were changes in best-corrected visual acuity (BCVA) from baseline to 52 weeks and polyp occlusion at week 52. Data are presented as median (interquartile range [IQR]) for BCVA, number of IVAI, and change in central retinal thickness (CRT). RESULTS: Of the 50 patients included in the study, 48 patients completed the 52 weeks of follow-up. During this period, a significant median (IQR) BCVA gain of 6 [2-12] Early Treatment Diabetic Retinopathy Study letters was observed for all patients (p < 0.001), after 8 (7-9) injections, with a significant reduction of -93.0 [-154.0, -44.0] µm in central macular thickness (p < 0.001). Using indocyanine green angiography, a complete occlusion of polypoidal lesions was documented in 72% of the cases. Still, no significant difference was detected between the sham PDT and the aflibercept PDT arms, at week 52, for BCVA change (6.5 [2-11] vs. 5 [2-13] letters (p = 0.98)), number of IVAIs (8.5 [7-9] vs. 8 [7-9] (p = 0.21)), change in CRT (-143 [-184; -47] vs. -89 [-123; -41.5] µm [p = 0.23]), and rates of complete polyp occlusion: 77 versus 68% (p = 0.53) or presence of fluid: 68 versus 57% (p = 0.56). No serious ocular adverse events were registered in the 2 arms. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first RCT to compare aflibercept T&E monotherapy with aflibercept T&E plus verteporfin PDT in a Caucasian population with PCV. Aflibercept monotherapy in a T&E showed to be effective and safe with a significant median BCVA improvement of 6 letters and a complete occlusion of polypoidal lesions in near 3 quarters of the eyes, at 1 year. As only 22% of the eyes underwent PDT treatment, the benefit of combined treatment for PCV in Caucasian patients could not be definitively elucidated from this study. TRIAL REGISTRATION: The clinical trial was registered in ClinicalTrials.gov Identifier NCT02495181 and the European Union Drug Regulating Authorities Clinical Trials Database EudraCT No. 2015-001368-20.

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.

Changes in reticular pseudodrusen area in eyes that progressed from early to late age-related macular degeneration.

OBJECTIVE: This retrospective cohort study utilized 3 imaging modalities to analyze quantitatively reticular pseudodrusen (RPD) area changes in eyes that progressed from early to late age-related macular degeneration (AMD). METHODS: Subjects with AMD, unilateral choroidal neovascularization (CNV), and early AMD with RPD in the fellow eye (the study eye) were included. The study eyes underwent indocyanine green angiography (ICGA), near-infrared reflectance (NIR-R), and short-wavelength autofluorescence (AF) imaging of the macula at baseline and at follow-up. Study eyes were analyzed for RPD and for the development of late AMD-CNV and/or geographic atrophy (GA). RPD area was measured at baseline and at follow-up as a percentage of the 30-degree field. RESULTS: During the study period (mean follow-up time 23.5 ± 5.0 months), 12/31 study eyes developed CNV and 4/31 developed GA. In the eyes that developed CNV, there was a statistically significant decrease in mean RPD area over the follow-up period as seen on AF (P < 0.01) and NIR-R (P = 0.01), and the decrease in mean RPD area approached statistical significance on ICGA (P = 0.08). CONCLUSION: Using 3 en face imaging techniques, we demonstrate that RPD undergo dynamic spatiotemporal changes in eyes that progress from early AMD to CNV, namely a decrease in the area of lesions detected.

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.

Genetic variants in ICAM1, PPARGC1A and MTHFR are potentially associated with different phenotypes of diabetic retinopathy.

PURPOSE: To explore phenotype-genotype correlations that may contribute to a better understanding of diabetic retinopathy (DR). PROCEDURES: An exploratory association study was performed to identify genetic variants associated with non-proliferative DR (NPDR) in 307 type 2 diabetic patients who were previously stratified into 3 different phenotypes of NPDR progression. The 307 patients were genotyped for 174 single nucleotide polymorphisms of 11 candidate genes (ACE, AGER, AKR1B1, ICAM1, MTHFR, NOS1, NOS3, PPARGC1A, TGFB1, TNF and VEGFA). RESULTS: Significant associations were observed for PPARGC1A rs16874120 with phenotype A (odds ratio, OR = 0.60, 95% confidence interval, CI 0.36-0.99), ICAM1 rs1801714 with phenotype B (OR = 3.32, 95% CI 1.05-10.50) and both PPARGC1A rs10213440 (OR = 2.00, 95% CI 1.07-3.73) and MTHFR rs1801133 (OR = 1.84, 95% CI 1.08-3.11) with phenotype C. CONCLUSIONS: RESULTS indicate that specific gene variants in ICAM1, PPARGC1A and MTHFR are associated with different NPDR phenotypes, being likely candidates to explain different disease mechanisms underlying the different phenotypes. This is the first study to show correlations between specific gene variants and NPDR phenotypes, opening new perspectives on DR.

Photodynamic therapy for chronic central serous chorioretinopathy: a 4-year follow-up study.

PURPOSE: To evaluate the efficacy and safety of standard photodynamic therapy with verteporfin at 48 months in patients with chronic central serous chorioretinopathy. METHODS: A retrospective, multicenter, interventional case series analysis in patients with chronic central serous chorioretinopathy, treated with standard photodynamic therapy, and with ≥4 years of follow-up. Evaluations were performed every 3 months in the first year, every 6 months in the second year, and thereafter annually. Optical coherence tomography was performed in all visits. Fluorescein angiography and indocyanine green angiography were performed at baseline and thereafter as necessary. Retinal thickness on optical coherence tomography was measured manually, evaluating central macular thickness and neural retina thickness. Main outcomes included the evolution of best-corrected visual acuity, the resolution of subretinal fluid, documented with optical coherence tomography, the number of treatments, and the evaluation of neural retina thickness during the 48 months of follow-up. RESULTS: The study included 46 eyes of 42 patients, 38 men (90.4%) and 4 women (9.5%), with mean age of 49.19 ± 9.9 years (range, 32-70 years), and the minimal follow-up period was 48 months (mean, 56.8 ±10.3 months). Subretinal fluid was observed in all the included eyes at baseline, and 10 eyes (21.7%) had intraretinal diffuse or cystoid fluid. Concerning the mean best-corrected visual acuity, a statistically significant improvement (P < 0.01, Student t-test) was registered from 58.8 ± 18.3 letters at baseline to 66.9 ± 18.6 letters at 48th month. A complete resolution of subretinal fluid was achieved in 93.4%, and resolution of intraretinal fluid occurred in all 10 cases at 48 months. Neural retina thickness remained stable during the 48 months of follow-up (163.8 ± 47 µm at baseline and 163.8 ± 46 µm at 48 months). The mean number of treatments was 1.08 ± 0.3. No systemic or ocular side effects were registered. CONCLUSION: Standard photodynamic therapy with verteporfin was effective and safe in chronic central serous chorioretinopathy treatment with a significant improvement in the long term, both anatomic and visual, without inducing additional retinal atrophy or systemic adverse effects.

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.

Early markers of choroidal neovascularization in the fellow eye of patients with unilateral exudative age-related macular degeneration.

OBJECTIVE: To identify morphological and/or functional early markers of choroidal neovascularization (CNV) development in fellow eyes of patients with exudative age-related macular degeneration (AMD). DESIGN: This is a single-center, prospective, observational, longitudinal 2-year study. PATIENTS: Patients were enrolled with the diagnosis of neovascular AMD in 1 eye and early age-related maculopathy (ARM) in the fellow eye. Intervention or Methods: All patients completed the baseline assessment and were followed up for up to 24 months with repeated ophthalmic and imaging assessments performed at 6-month intervals. MAIN OUTCOME MEASURES: Each patient underwent a detailed ocular and medical history, a complete ophthalmologic examination with color fundus photography, fluorescein angiography, indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging and retinal leakage analysis (RLA). RESULTS: Sixty-two patients were enrolled in the study. Large or intermediate drusen were present in 100% of the study eyes and hyperpigmentation in 46% (24 eyes). Fifty-two patients completed the 2-year study follow-up. Large soft drusen (>125 µm) were observed in 15 out of 17 eyes (88%) that converted and developed CNV during the study and in 25 out of 35 eyes (71.4%) that did not develop CNV. Among the 17 eyes that developed CNV, 9 (53%) showed abnormal findings before conversion, on ICG. No particular FAF pattern was found to be correlated with conversion to wet AMD. OCT was able to document the presence of intra- or subretinal fluid at the time of conversion in all 17 eyes that developed CNV during the study. Alterations of the blood-retinal barrier were identified by RLA before conversion in 76% of the eyes that converted and 23% of the eyes that did not convert during the study. CONCLUSIONS: Characterization of early ARM phenotypes is challenging. By combining different imaging modalities of the macula and correlating this information, we were able to determine the presence of functional macular alterations in the fellow eye of patients with this disease before development of CNV.

Short-term efficacy and safety of intravitreal ranibizumab for myopic choroidal neovascularization.

PURPOSE: To evaluate the safety and efficacy of intravitreal ranibizumab in the treatment of choroidal neovascularization (CNV) secondary to pathologic myopia (PM). METHODS: Retrospective, multicenter, consecutive, nonrandomized, interventional case series. PARTICIPANTS: Twenty-six eyes of 26 patients with CNV secondary to pathologic myopia; 11 eyes with previous photodynamic therapy; and 15 eyes with no previous treatment. FOLLOW-UP: 3 or more months. Best-corrected visual acuity (BCVA), ocular coherence tomography, and the presence of metamorphopsia were assessed monthly. RESULTS: At 1 month, 31% of the eyes had an improvement in visual acuity of 3 or more lines. Twenty-six eyes completed 3 months of follow-up, and nine eyes completed 6 months of follow-up. Visual acuity improved significantly from 20/100 at baseline to 20/80 at 1 month (P = 0.003) to 20/63 at 3 months (P < 0.001), and 20/50 at 6 months (P = 0.01). A significant reduction in ocular coherence tomography central thickness was observed at 1, 3, and 6 months. No cases of severe visual acuity loss occurred, and no systemic or ocular side effects were registered during the follow-up. CONCLUSION: Short-term results of intravitreal ranibizumab for myopic CNV are encouraging. Further prospective long-term studies are necessary to evaluate safety and efficacy of intravitreal ranibizumab in the treatment of myopic CNV.

Effect of calcium dobesilate on progression of early diabetic retinopathy: a randomised double-blind study.

BACKGROUND: The study was carried out to confirm the effect of calcium dobesilate (CaD) compared to placebo (PLA) on the blood-retinal barrier (BRB) permeability in early diabetic retinopathy (DR). METHODS: Adults with type II diabetes and early diabetic retinopathy (below level 47 of ETDRS grading and PVPR between 20 and 50x10(-6)/ min, plasma-free fluorescein) were included in this double-blind placebo-controlled study. Treatment was 2 g daily for 24 months. The primary parameter, posterior vitreous penetration ratio (PVPR), was measured every 6 months by fluorophotometry. Secondary parameters were fundus photography, fluorescein angiography and safety assessments. Metabolic control was performed every 3 months. RESULTS: A total of 194 patients started the treatment (98 CaD, 96 PLA) and 137 completed the 24-month study (69 CaD, 68 PLA). Both treatment groups were comparable at baseline, with ETDRS level 10 in about 59% of patients. Mean PVPR change from baseline after 24 months was significantly (P=0.002) lower in the CaD group [-3.87 (SD 12.03)] than in the PLA group [+2.03 (SD 12.86)], corresponding to a 13.2% decrease in the CaD group and a 7.3% increase in the PLA group. PVPR evolution was also analysed by HbA1c classes (<7%, between 7 and 9%, > or =9%) and results confirmed the superiority of CaD independently of the diabetes control level. A highly significant difference [CaD: -3.38 (SD 13.44) versus PLA: +3.50 (SD 13.70)] was also obtained in a subgroup of patients without anti-hypertensive and/or lipid-lowering agents (P=0.002 at 24 months). A further analysis of the secondary parameters showed significant changes in favour of CaD in the evolution from baseline to the last visit of haemorrhages (P=0.029), DR level (P=0.0006) and microaneurysms (P=0.013). Regarding safety, only 2.5% (n=5 patients/ events) of all adverse events reported were assessed as possibly or probably related to the test drug, while all serious adverse events were reported as unlikely. There was no statistical difference between groups. CONCLUSION: Calcium dobesilate 2 g daily for 2 years shows a significantly better activity than placebo on prevention of BRB disruption, independently of diabetes control. Tolerance was very good.

Medical treatment of retinopathy of type-2 diabetes.

The medical treatment of retinopathy in type-2 diabetes should be considered as a major component in the overall management of diabetic retinal disease. It is clear that specific and timely interventions, such as glycemic and blood pressure control, are the basis for good management of diabetic retinopathy. The American Diabetes Association has developed specific recommendations concerning diabetic retinopathy for the primary care physician and diabetologist. The ophthalmologist must be aware of these recommendations and establish efficient communication channels with the colleagues who follow their patients and the progression of diabetes closely. The challenge for the ophthalmologist is to make sure that, when signs of retinopathy are detected, information regarding the status of the retina, prognostic factors and the rate of progression must be given to the primary care physician and diabetologist. Under these circumstances, excellent glycemic control, aggressive management of blood pressure and normalization of lipids are all needed, and the goals to be achieved must be shared between the ophthalmologist and the primary care physician or diabetologist. Appropriate medical management of diabetic retinopathy is fundamental to reduce the risk of blindness. This goal can only be achieved if the ophthalmologist is fully aware of the role of medical management and establishes an efficient flow of communication with the primary care physician or diabetologist, particularly for the diabetic patients whose eyes show signs of risk for rapid progression of their retinopathy.

The blood-retinal barriers system. Basic concepts and clinical evaluation.

Morphological studies demonstrating the presence in the retinal vessels of 'zonulae occludente' between the endothelial cells and physiological studies examining diffusion gradients in the vitreous after systemic or intravitreal administration of fluorescein, performed under the guidance of David Maurice, established the basis of the Blood-Retinal Barrier (BRB) concept. The BRB system is briefly reviewed as well as its role in health and disease. Regulation of the microenvironment of the retina is fundamental for appropriate retinal function and vision. The diffusional characteristics and transport functions of the BRB system may be evaluated and followed by vitreous fluorometry. Its clinical use has shown the importance of BRB alterations in a variety of retinal diseases but has been restricted by the lack of disease specificity. A recent development, the Retinal Leakage Analyzer, maps BRB alterations and has opened new perspectives for multimodal macula mapping and improved evaluation of newly available drugs that show promise for stabilizing the BRB.

Macular alterations after small-incision cataract surgery.

PURPOSE: To characterize macular edema that occurs after uneventful cataract surgery. SETTING: Centre of Ophthalmology, University Hospital, Institute of Biomedical Research on Light and Image, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. METHODS: Thirty-two eyes of 32 patients had uneventful phacoemulsification with implantation of a foldable intraocular lens. Postoperatively, patients were examined at 3, 6, 12, and 30 weeks. The examinations included retinal leakage analysis (Zeiss CSLO), optical coherence tomography (Humphrey Instruments), and retinal thickness analysis (Talia Technology, Ltd.). Results were compared with those in a control group comprising healthy subjects. RESULTS: Increases in retinal thickness (ie, over the mean +/- 2 SD in the control group) reached a maximum at 6 weeks in 13 of 32 eyes (41%), after which recovery was progressive. At 30 weeks, all eyes had good visual acuity, but 7 eyes (22%) still had macular edema. The edema was located primarily in the central macular region. Leaking sites involving the vascular areas of the macula, which indicated areas of abnormal blood-retinal barrier permeability, were a frequent finding. The number of sites remained relatively stable during the first 12 weeks (88%) and decreased to 68% at 30 weeks, indicating a trend toward recovery. CONCLUSION: Macular edema after cataract surgery occurred primarily in the central region of the macula and was associated with the presence of leaking sites, which were located predominantly in the vascular regions of the central macula.

Stabilization of visual acuity with photodynamic therapy in eyes with chorioretinal anastomoses.

PURPOSE: (1) To evaluate, in a non-randomized, institutional, prospective study, the efficacy of photodynamic therapy with Visudyne (PDT) in neovascular age-related macular degeneration (AMD) eyes with chorioretinal anastomoses (CRA). (2) To review, in a retrospective study and for comparison, the natural evolution of neovascular AMD eyes with CRA. METHODS: Prospective clinical and angiographic study of 17 consecutive eyes with CRA, treated with PDT. Retrospective clinical and angiographic study of the natural course of 17 consecutive patients with CRA. Masked best-corrected visual acuity (VA) and angiographic features at baseline and during the period of one year were evaluated. RESULTS: The two groups presented similar characteristics at baseline regarding age, sex, initial VA, duration of follow-up and angiographic features. PDT-treated eyes showed, at 1-year follow-up, VA stabilization or improvement in 73.3% of the eyes, no cases with very severe VA loss, and no fluorescein leakage in 46.6% of the eyes. In contrast, at 1-year follow-up the natural evolution of CRA was characterized by severe or very severe VA loss in 69% of the eyes and statistically significant mean VA loss (P=0.001) with persistence of fluorescein leakage in all cases. CONCLUSION: The natural history of AMD eyes with CRA leads to progressive and dramatic VA loss, which is associated with blindness in most of the cases. PDT with verteporfin can offer some benefit to these patients, allowing VA stabilization or improvement in more than two thirds of the cases, at one year.

Three-year follow-up study of blood-retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative diabetic retinopathy.

OBJECTIVE: To examine the 3-year alterations of the blood-retinal barrier and changes in retinal thickness occurring in the macular region in 14 eyes of 14 patients with type 2 diabetes mellitus (DM) and mild nonproliferative diabetic retinopathy. METHODS: We classified 14 eyes of 14 patients with type 2 DM and mild nonproliferative diabetic retinopathy, as having disease levels 20 (microaneurysms only) or 35 (microaneurysm plus retinal hemorrhage[s] and/or hard exudates) of Wisconsin Card-Sorting Test grading, by using 7-field stereoscopic fundus photographs. We examined them 7 times at 6-month intervals, using fundus photography, fluorescein sodium angiography, the retinal leakage analyzer (RLA)-modified confocal scanning laser ophthalmoscope, and the retinal thickness analyzer. The retinal leakage and retinal thickness maps were aligned and integrated into 1 image. Data from the group of individuals with type 2 DM were compared with those of a healthy control population (n = 14; mean age, 48 years; age range, 42-55 years) to establish reference maps for the RLA and retinal thickness analyzers. RESULTS: Areas of abnormally increased fluorescein leakage were detected in all eyes examined at baseline. The sites of increased fluorescein leakage reached values as high as 483% above normal levels, but in 20 of the total 95 examinations performed, fluorescein leakage returned to normal levels. Every eye that showed reversal to normal levels of fluorescein leakage showed stabilization or a decrease in glycosylated hemoglobin A(1c) values at the same visit. When comparing the RLA-leaking sites among the 7 examinations, they remained, in general, in the same locations, but there was a clear fluctuation in the percentage of increases. No clear correlation was observed among the location of areas of increased retinal thickness and RLA-leaking sites, the number of microaneurysms, or the glycosylated hemoglobin A(1c) values. Microaneurysms on fundus photographs showed different cumulative incidences throughout the follow-up period in the different eyes. Associations between these different abnormalities suggest specific patterns of evolution of type 2 DM-related retinal disease. CONCLUSIONS: The dominant alteration in the retina of patients with type 2 DM and mild nonproliferative retinopathy is the presence of RLA-leaking sites. This damage seems to be reversible and directly associated with variations in glycemic metabolic control. Together with the intensity and persistence of RLA-leaking sites, the rates of microaneurysm accumulation and alterations of the foveal avascular zone may characterize different genetically based phenotypes of diabetic retinopathy.

Multimodal macula mapping: a new approach to study diseases of the macula.

Multimodal macula mapping is presented as a combination of a variety of diagnostic tools and techniques to examine the macular region in order to obtain information on its structure and function in a clinical environment. Foundations of macular mapping are reviewed and discussed. New methodologies for multimodal macula mapping based on a combination of scanning laser angiography, retinal leakage analysis, retinal thickness analysis, and visual field testing are presented, demonstrating the potential of macula mapping. Other available detection devices are briefly reviewed considering their potential to be included and utilized in future developments of multimodal macula mapping. Multimodal macula mapping appears to offer unique perspectives and insights that are expected to contribute to improved diagnosis and better understanding of macular diseases.

Retinal thickness in eyes with mild nonproliferative retinopathy in patients with type 2 diabetes mellitus: comparison of measurements obtained by retinal thickness analysis and optical coherence tomography.

OBJECTIVE: To compare measurements of retinal thickness in eyes with mild nonproliferative retinopathy in patients with type 2 diabetes mellitus using 2 different techniques: the retinal thickness analyzer (RTA) and optical coherence tomography (OCT). METHODS: Twenty-eight eyes from 28 patients with type 2 diabetes mellitus and mild nonproliferative retinopathy were classified according to the Wisconsin grading system by 7-field stereoscopic fundus photography. Ten eyes were classified as level 10 (absence of visible lesions) and 18 as level 20 or 35 (minimal retinopathy). All eyes were examined by the RTA and OCT. Healthy populations were used to establish reference maps for the RTA (n = 14; mean age, 48 years; age range, 42-55 years) and OCT (n = 10; mean age, 56 years; age range, 43-68 years). Reference maps were computed using the means + 2 SDs of the values obtained for each location. Increases in thickness were computed as a percentage of increase over these reference maps. RESULTS: The RTA detected increases in thickness in 1 or more locations in 24 of the 28 diabetic eyes examined, whereas OCT detected increases in only 3 eyes. The percentages of increase detected by the RTA ranged from 0.3% to 73.5%, whereas OCT detected percentages of increase of 0.3% to 4.8%. CONCLUSION: Optical coherence tomography is less sensitive than the RTA in detecting localized increases in retinal thickness in the initial stages of diabetic retinal disease.