Classification of Diabetic Retinopathy from Fluorescein Angiograms: ETDRS Report Number 11
Abstract
The Early Treatment Diabetic Retinopathy Study included use of nonsimultaneous stereoscopic fluorescein angiography to assess severity of characteristics such as capillary loss and fluorescein leakage and to guide treatment of macular edema. Two 30° photographic fields were taken, extending along the horizontal meridian from about 25° nasal to the disc to about 20° temporal to the macula, and a classification system was constructed to allow assessment of selected characteristics. This classification system relies on comparisons with standard and example photographs to evaluate the presence and severity of capillary loss and dilatation, arteriolar abnormalities, leakage of fluorescein dye (including characterization of source), abnormalities of the retinal pigment epithelium, cystoid changes, and several other features. The classification is described and illustrated and its reproducibility between graders assessed by calculating percentages of agreement and kappa statistics for duplicate gradings of baseline angiograms. Agreement was substantial (weighted kappa, 0.61 to 0.80) for severity of fluorescein leakage and cystoid spaces, and moderate (weighted kappa, 0.41 to 0.60) for capillary loss, capillary dilatation, narrowing/pruning of arteriolar side branches, staining of arteriolar walls, and source of fluorescein leakage (microaneurysms versus diffusely leaking capillaries).
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Cited by (433)
En Face Optical Coherence Tomography Illustrates the Trizonal Distribution of Drusen and Subretinal Drusenoid Deposits in the Macula
2024, American Journal of OphthalmologyTo analyze the topographic distribution of macular drusen and subretinal drusenoid deposits (SDDs) using single-capture en face spectral domain optical coherence tomography (SD-OCT) imaging.
Retrospective case series.
Analysis of 33 eyes of 20 patients with evidence of SDDs. Structural en face OCT images were reconstructed using a 40-µm-thick slab positioned from 48 to 88 µm above the Bruch membrane. The Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and a rod/cone density map were overlaid on the en face OCT images, and the distribution of different subtypes of SDDs and macular drusen were assessed.
A total of 31 eyes (94%) showed a trizonal distribution pattern of drusen and SDDs. Whereas small to large drusen tended to aggregate in the central circle, dot SDDs predominated in the inner ring and the inner portion of the outer ring of the ETDRS grid and ribbon SDDs localized to the outer ring and outside the ETDRS grid. Of note, drusen colocalized to the region of greatest cone density, whereas ribbon SDDs colocalized to the area of greatest rod density. The dot SDDs mapped to the intermediate region with mixed rod and cone representation.
Dot and ribbon subtypes of SDDs and macular drusen show a characteristic trizonal distribution. The locations of these lesions colocalize according to the different densities of the cones and rods in the retina and may reflect varying pathophysiological activities of these photoreceptor subtypes.
Ocular and Systemic Risk Factors for Disease Worsening Among Patients with NPDR: Post Hoc Analysis of the PANORAMA Trial
2024, Ophthalmology RetinaIdentify baseline systemic and ocular characteristics associated with nonproliferative diabetic retinopathy (NPDR) worsening and the impact of intravitreal aflibercept injection (IAI) on these associations.
Post hoc analysis of PANORAMA.
Patients with moderately severe to severe NPDR enrolled in the prospective PANORAMA phase III trial.
Associations between baseline systemic and ocular factors with events indicative of NPDR worsening at week 100 were evaluated by multivariable analysis in sham-treated eyes. Nonproliferative diabetic retinopathy worsening was defined as the development of (1) vision-threatening complications (VTCs; comprising proliferative diabetic retinopathy and/or anterior segment neovascularization), (2) center-involved diabetic macular edema (CI-DME), or (3) ≥ 2-step Diabetic Retinopathy Severity Scale (DRSS) worsening. The impact of IAI on identified baseline factors was evaluated using univariable analysis in combined IAI groups.
Baseline systemic and ocular factors associated with events indicative of NPDR worsening at week 100. The cumulative incidence and risk of developing such events at week 100 among sham versus IAI-treated eyes.
Using multivariable analyses among sham-treated eyes, 5 baseline factors associated with increased risk of NPDR worsening were identified: fluorescein leakage, retinal nonperfusion area, thicker central subfield thickness, eosinophil level, and proteinuria. Considering baseline fluorescein leakage area as a prognostic indicator in detail, the risk of developing VTCs alone, VTCs and/or CI-DME, or ≥ 2-step DRSS worsening increased with increasing fluorescein leakage area in the sham group (all P < 0.05). Considering baseline retinal nonperfusion area as a prognostic indicator in detail, the risk of developing VTCs alone, CI-DME alone, or VTCs and/or CI-DME increased with increasing baseline retinal nonperfusion area in the sham group (all P < 0.05). In contrast, among IAI-treated eyes, increasing baseline fluorescein leakage or retinal nonperfusion areas did not increase the risks of NPDR worsening.
Within the PANORAMA trial, increased areas of fluorescein leakage and retinal nonperfusion at baseline were identified as key ocular biomarkers associated with events indicative of NPDR worsening among sham-treated patients. Intravitreal aflibercept injection treatment seemed to mitigate the effect of these baseline risk factors and reduced the likelihood of NPDR worsening.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Efficacy and Safety of Faricimab for Macular Edema due to Retinal Vein Occlusion: 24-Week Results from the BALATON and COMINO Trials
2024, OphthalmologyTo evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion.
Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192).
Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO.
Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks.
Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug.
Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7–18.1 letters] vs. +17.5 letters [95.03% CI, 16.3–18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4–18.3 letters] vs. +17.3 letters [95.03% CI, 15.9–18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (−311.4 μm [95.03% CI, −316.4 to −306.4 μm] and −304.4 μm [95.03% CI, −309.3 to −299.4 μm]) and COMINO (−461.6 μm [95.03% CI, −471.4 to −451.9 μm] and −448.8 μm [95.03% CI, −458.6 to −439.0 μm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively).
These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topographic Correlation of Microperimetry With Structural Characteristics in Diabetic Macular Ischemia
2024, American Journal of OphthalmologyThis study aimed to determine the threshold for defining abnormal retinal sensitivity (RS) that correlates with structural changes in diabetic macular ischemia (DMI) patients with stable treated proliferative diabetic retinopathy (PDR).
Prospective cross-sectional study.
In a single center, we recruited 85 eyes (67 patients) with stable treated PDR with best-corrected visual acuity (BCVA) ≥54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent 20/80) and optical coherence tomography angiography evidence of DMI. The function–function and function–structure correlation were assessed. Two preselected thresholds in overall RS (oRS), 25 decibels (dB) and age-matched normative data (AMND), were tested on their ability to reflect abnormal anatomy in DMI. Finally, a multivariable regression model was established to depict the relationship between the oRS and various parameters.
The oRS showed only a modest correlation with BCVA and low-luminance visual acuity (LLVA). The whole-image deep vessel density (wiDVD) was the most reliable vascular metric correlated with RS. For every 1% decline in the wiDVD, the oRS decreased by 0.37 dB (P < .001) after multivariable adjustment. Furthermore, both a reduction of oRS to <25 dB or below AMND could differentiate eyes with FAZ ≥0.5 mm2, whole image superficial vessel density (wiSVD) <37.7%, wiDVD <41.9%, and the presence of disorganization of the retinal inner layers (DRIL) from their counterparts.
The absolute value of 25 dB in oRS is worth considering as a trial endpoint, because it does not require complex calculation and closely reflects the structural abnormalities in DMI.
Association between macrophage-like cell density and ischemia metrics in diabetic eyes
2023, Experimental Eye ResearchWe previously showed that macrophage-like cells (MLCs) are increased in eyes with advanced diabetic retinopathy (DR). Here, we hypothesized that MLC density was correlated with ischemia using optical coherence tomography angiography (OCTA) and ultra-widefield fluorescein angiography (UWF-FA). Treatment-naïve diabetic eyes were prospectively imaged with repeated OCTA (average 5.3 scans per eye) and UWF-FA imaging. OCTA images were registered and averaged to generate a superficial capillary plexus (SCP), deep capillary plexus (DCP), and MLC slab. We calculated geometric perfusion deficit (GPD), vessel length density, and vessel density for the SCP and DCP. MLC density was quantified by two masked graders and averaged. Ischemia on UWF-FA was measured to generate a non-perfusion area (NPA) and index (NPI). Since MLC density was non-parametrically distributed, MLC density was correlated with ischemia metrics using Spearman correlations. Forty-five treatment-naïve eyes of 45 patients (59 ± 12 years of age; 56% female) were imaged. We included 6 eyes with no DR, 7 eyes with mild non-proliferative DR (NPDR), 22 moderate NPDR, 4 severe NPDR, and 6 PDR eyes. MLC density between graders was highly correlated (r = 0.9592, p < 0.0001). MLC density was correlated with DCP GPD (r = 0.296, p = 0.049), but no other OCTA ischemia metrics. MLC density was also correlated with UWF-FA NPA (r = 0.330, p = 0.035) and NPI (r = 0.332, p = 0.034). MLC density was correlated with total ischemia on UWF-FA and local DCP GPD. Since both UWF-FA and DCP non-perfusion are associated with higher risk for DR progression, MLC density could be another potential biomarker for DR progression.
Evaluation of Posterior Ocular Blood Flow in Diabetic Retinopathy Patients Without Macular Edema Using Optical Coherence Tomography Angiography
2023, Photodiagnosis and Photodynamic TherapyThe objective of this study is to investigate and compare the superficial and deep vascular structures of the retina, as well as the changes in the choriocapillaris (CC) and optic disc microvasculature, using optical coherence tomography angiography (OCTA) in patients diagnosed with diabetes mellitus (DM) without diabetic retinopathy (DR), patients with non-proliferative and proliferative DR, and healthy individuals.
This prospective study conducted between July 2020 and July 2021 included patients diagnosed with type 2 DM without DR, as well as patients with mild nonproliferative, moderate nonproliferative, and proliferative DR without macular oedema. A control group of 25 age- and gender-matched healthy individuals was also included. OCTA parameters of the patients were examined.
In the DR groups, compared to the control group, there was a significant decrease in macular superficial, deep, and CC perfusion areas as the severity of DR increased (p<0.001). The vascular density (VD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) exhibited a statistically significant decrease in all quadrants of the DR group compared to the control group (p = 0.033 for SCP in the fovea, p<0.001 for all other quadrants). The superficial and deep FAZs showed a significant expansion in the DR group compared to the control group (p = 0.003 for superficial FAZ, p<0.001 for deep FAZ). As the severity of DR increased, there was a statistically significant decrease in the perfusion areas of the optic nerve head (ONH), radial peripapillary capillary (RPC), and vitreous segments (p<0.001 for ONH, p = 0.031 for RPC, p<0.001 for vitreous). There was a statistically significant decrease in RPC VD in all quadrants as the severity of DR increased. Moreover, as the severity of DR increased, a statistically significant decrease in the VD of the ONH was observed in all quadrants except for the inferior nasal (p = 0.094), inferior temporal (p = 0.111), superior temporal (p = 0.18), and temporal (p = 0.284) quadrants.
Our study demonstrated the involvement of macular and optic nerve perfusion areas (PA) and VD in diabetic patients. OCTA proved to be a valuable and noninvasive imaging modality, providing an easy and repeatable assessment of posterior segment vascular changes in patients with DR.
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A list of the ETDRS Research Group Investigators appears at the end of ETDRS report number 7 in this supplement to Ophthalmology.