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1.
Capillary density and caliber as assessed by optical coherence tomography angiography may be significant predictors of diabetic retinopathy severity.
Kushner-Lenhoff, S, Kogachi, K, Mert, M, Chu, Z, Shahidzadeh, A, Palejwala, NV, Wolfe, J, Itty, S, Drenser, KA, Capone, A, et al
PloS one. 2022;(1):e0262996
Abstract
PURPOSE To validate retinal capillary density and caliber associations with diabetic retinopathy (DR) severity in different clinical settings. METHODS This cross-sectional study assessed retinal capillary density and caliber in the superficial retinal layer of 3-mm OCTA scans centered on the fovea. Images were collected from non-diabetic controls and subjects with mild or referable DR (defined DR worse than mild DR) between February 2016 and December 2019 at secondary and tertiary eye care centers. Vessel Skeleton Density (VSD), a measure of capillary density, and Vessel Diameter Index (VDI), a measure of vascular caliber, were calculated from these images. Discriminatory performance of VSD and VDI was evaluated using multivariable logistic regression models predicting DR severity with adjustments for sex, hypertension, and hyperlipidemia. Area under the curve (AUC) was estimated. Model performance was evaluated in two different cohorts. RESULTS This study included 594 eyes from 385 subjects. Cohort 1 was a training cohort of 509 eyes including 159 control, 155 mild non-proliferative DR (NPDR) and 195 referable DR eyes. Cohort 2 was a validation cohort consisting of 85 eyes including 16 mild NPDR and 69 referable DR eyes. In Cohort 1, addition of VSD and VDI to a model using only demographic data significantly improved the model's AUC for discrimination of eyes with any DR severity from controls (0.91 [95% CI, 0.88-0.93] versus 0.80 [95% CI, 0.76-0.83], p < 0.001) and eyes with referable DR from mild NPDR (0.90 [95% CI, 0.86-0.93] versus 0.69 [95% CI, 0.64-0.75], p < 0.001). The transportability of this regression model was excellent when implemented in Cohort 2 for the referable DR versus mild NPDR comparison. The odds ratio of having any DR compared to control subjects, and referable DR compared to mild DR decreased by 15% (95% CI: 12-18%), and 13% (95% CI: 10-15%), respectively, for every 0.001 unit increase in VSD after adjusting for comorbidities. CONCLUSION OCTA-derived capillary density has real world clinical value for rapidly assessing DR severity.
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SEVERITY OF DIABETIC MACULAR EDEMA CORRELATES WITH RETINAL VASCULAR BED AREA ON ULTRA-WIDE FIELD FLUORESCEIN ANGIOGRAPHY: DAVE Study.
Fan, W, Uji, A, Wang, K, Falavarjani, KG, Wykoff, CC, Brown, DM, Van Hemert, J, Sagong, M, Sadda, SR, Ip, M
Retina (Philadelphia, Pa.). 2020;(6):1029-1037
Abstract
PURPOSE To quantify retinal nonperfusion area and retinal vascular bed area (RVBA) in mm on ultra-widefield fluorescein angiography in eyes with diabetic macular edema (DME) and explore their relationship with the severity of DME. METHODS Prospective, observational case series. Baseline ultra-widefield fluorescein angiography images of 40 eyes from 29 patients with treatment-naive DME who participated in the DAVE study (NCT01552408) were stereographically projected at Doheny Image Reading Center. The retinal vasculature was automatically extracted to calculate RVBA. Nonperfusion area was manually delineated by two masked certified graders. Retinal vascular bed area and nonperfusion area were computed in mm automatically by adjusting for peripheral distortion and then correlated with the severity of DME. RESULTS The global RVBA for the entire retina in eyes with DME was increased compared with healthy controls (54.7 ± 16.6 mm vs. 37.2 ± 9.9 mm, P < 0.001) and correlated with the severity of DME (P < 0.05). Retinal ischemia (nonperfusion area) was nonuniformly distributed and not related to DME extent (P > 0.05). CONCLUSION Eyes with DME have an increased RVBA compared with healthy controls. The severity of DME appears to be related to global RVBA, but not to retinal ischemia.
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3.
Microvascular retinal changes in pre-clinical diabetic retinopathy as detected by optical coherence tomographic angiography.
Yang, JY, Wang, Q, Yan, YN, Zhou, WJ, Wang, YX, Wu, SL, Yuan, MX, Wei, WB, Jonas, JB
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2020;(3):513-520
Abstract
PURPOSE To investigate microvascular abnormalities in diabetic patients without conventional clinical signs of diabetic retinopathy (DR). METHODS In this cross-sectional observational cohort study, the study group included randomly chosen participants of a community-based cohort with diabetes type 2 without DR, and the control group consisted of non-diabetic individuals from a population-based study. All participants underwent optical coherence tomographic angiography (OCTA). RESULTS Upon OCTA, 118 (40.4%) eyes of the study group (n = 292 eyes) showed microvascular abnormalities including foveal avascular zone erosion (95 (32.5%) eyes), non-perfusion areas in the superficial and deep retinal layers (39 (13.4%) eyes and 19 (6.5%) eyes, respectively), and microaneurysms in the superficial and deep retinal layers (22 (7.5%) eyes and 31 (10.6%) eyes, resp.). None of these abnormalities was detected in the control group (n = 80). The study group showed a lower vessel density in the superficial retinal vascular layer in all regions except for the foveal region (P < 0.001), and higher vessel density in the parafoveal region in the deep retinal vascular layer (P = 0.01). Higher diabetes prevalence was associated with lower superficial retinal vascular density (P = 0.005) in multivariable analysis. A lower radial peripapillary capillary flow density was correlated (regression coefficient r, 0.62) with higher fasting blood concentration of glucose (P < 0.001) in multivariable analysis. CONCLUSIONS OCTA revealed microvascular abnormalities in 40% of eyes of diabetic patients without ophthalmoscopically detectable diabetic fundus changes in a community-based population. The early stage of DR may be re-defined upon OCTA.
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RETINAL LEAKAGE INDEX DYNAMICS ON ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY IN EYES TREATED WITH INTRAVITREAL AFLIBERCEPT FOR PROLIFERATIVE DIABETIC RETINOPATHY IN THE RECOVERY STUDY.
Babiuch, AS, Wykoff, CC, Srivastava, SK, Talcott, K, Zhou, B, Hach, J, Hu, M, Reese, JL, Ehlers, JP
Retina (Philadelphia, Pa.). 2020;(11):2175-2183
Abstract
PURPOSE Characterization of leakage indices on ultra-widefield fluorescein angiography in proliferative diabetic retinopathy treated with intravitreal aflibercept. METHODS Prospective study enrolling subjects for treatment of proliferative diabetic retinopathy randomized 1:1 to receive 2-mg intravitreal aflibercept every 4 weeks (2q4) or every 12 weeks (2q12). Ultra-widefield fluorescein angiography images obtained at baseline, 24, and 48 weeks were analyzed using a semiautomated leakage segmentation platform. Panretinal and zonal leakage indices were calculated. RESULTS Forty eyes of 40 subjects were included, and mean age was 48 ± 12.1 years. Mean number of injections was 11 ± 1.7 in the 2q4 arm and 4 ± 0.4 in the 2q12 arm. Median baseline leakage index in the 2q4 and 2q12 groups was 5.1% and 4.3%, respectively (P = 0.28). At 24 and 48 weeks, the 2q4 group significantly improved to 1.1% (-79%, P < 0.0001). At Week 24, the 2q12 group demonstrated nonsignificant improvement (3.4%; -21%, P = 0.47); by Week 48, improvement was significant (1.4%; -68%, P = 0.02). The 2q4 group resulted in lower leakage index compared with the 2q12 group at 24 weeks (1.1% vs. 3.4%, respectively; P = 0.008), but by 48 weeks, leakage index was similar between both groups (1.1% vs. 1.4%, respectively; P = 0.34). CONCLUSION Proliferative diabetic retinopathy treated with intravitreal aflibercept demonstrated significant leakage index reductions at 1 year. Monthly dosing provided more rapid reduction in leakage index compared with quarterly dosing. TRIAL REGISTRATION RECOVERY study (NCT02863354); https://clinicaltrials.gov/ct2/show/NCT02863354.
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Topical Treatment With Brimonidine and Somatostatin Causes Retinal Vascular Dilation in Patients With Early Diabetic Retinopathy From the EUROCONDOR.
Grauslund, J, Frydkjaer-Olsen, U, Peto, T, Fernández-Carneado, J, Ponsati, B, Hernández, C, Cunha-Vaz, J, Simó, R, ,
Investigative ophthalmology & visual science. 2019;(6):2257-2262
Abstract
PURPOSE Structural retinal microvascular changes have been identified as risk markers of diabetic retinopathy (DR). In order to estimate the retinal response of neuroprotective eye drops, we aimed to evaluate the effect of topical retinal neuroprotection on retinal microvascular changes in early DR. METHODS Patients with type 2 diabetes with no or early DR were randomized 1:1:1 to topical treatment with placebo, brimonidine, or somatostatin in a 96-week prospective, phase II to III, European multicenter trial. Retinal vascular calibers were measured semiautomatically in digital fundus images by certified graders at baseline and follow-up and summarized as central retinal arteriolar and venular equivalent (CRAE and CRVE). RESULTS Of 449 patients originally included, 297 completed the study with gradable retinal images. Median age and duration of diabetes was 64.5 and 9.9 years, and 65.7% were male. At baseline, Early Treatment Diabetic Retinopathy Study levels were 10 (no DR, 42.8%), 20 (minimal DR, 28.3%), and 35 (mild DR, 29.0%), and CRAE and CRVE did not differ between groups. As opposed to patients with no or minimal DR at baseline, patients with mild DR in the active groups developed a larger retinal arteriolar (brimonidine: +6.2 μm, P = 0.006; somatostatin: +7.2 μm, P = 0.006) and venular (brimonidine: +13.9 μm, P = 0.01; somatostatin: +14.3 μm, P = 0.0001) caliber in contrast to those in the placebo group. CONCLUSIONS Topical treatment with brimonidine and somatostatin causes retinal arteriolar and venular dilation in patients with type 2 diabetes and preexisting early DR. Upcoming studies should elaborate on the potential of these findings in arresting early DR.
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Efficacy of Ranibizumab in Eyes with Diabetic Macular Edema and Macular Nonperfusion in RIDE and RISE.
Reddy, RK, Pieramici, DJ, Gune, S, Ghanekar, A, Lu, N, Quezada-Ruiz, C, Baumal, CR
Ophthalmology. 2018;(10):1568-1574
Abstract
PURPOSE To determine whether there are baseline characteristics that distinguish patients with diabetic macular edema (DME) with coexisting macular nonperfusion (MNP) at baseline and assess these patients' potential to achieve favorable visual acuity (VA), anatomic, and diabetic retinopathy (DR) outcomes over 24 months. DESIGN Post hoc analysis of RIDE/RISE, 2 phase 3, parallel, randomized, multicenter, double-masked trials (ClinicalTrials.gov: NCT00473382; NCT00473330). PARTICIPANTS Study eyes with best-corrected VA (BCVA)/fluorescein angiogram (FA) data at baseline. METHODS To measure MNP, the Early Treatment for Diabetic Retinopathy Study (ETDRS) grid was overlaid on FAs of the macula. The MNP area was calculated by estimating the percentage of capillary loss in the central, inner, and outer subfields and converting into disc areas (DAs) using a software algorithm. Summary statistics and P values, respectively, were provided for all outcomes and comparisons of interest. MAIN OUTCOME MEASURES Baseline characteristics; MNP area, BCVA, and central subfield thickness (CST) at months 12 and 24; and incidence of study eyes with ≥2-step DR improvement at months 3, 6, 12, 18, and 24. RESULTS Baseline MNP was detected in 28.2%, 25.8%, and 26.3% of study eyes in the ranibizumab 0.3 mg (n = 213), ranibizumab 0.5 mg (n = 225), and sham (n = 228) arms, respectively. At baseline, patients with MNP were younger and had shorter diabetes duration, worse vision, increased CST, and worse DR severity (P values < 0.01 vs. those without MNP). In the ranibizumab 0.3 mg arm, eyes with baseline MNP had lower mean baseline BCVA (53.4 vs. 57.2 ETDRS letters for those without baseline MNP; P = 0.05), but mean BCVA gain at month 24 was comparable (+15.6 vs. +13.4 ETDRS letters, respectively; P = 0.2). Eyes with baseline MNP had increased CST at baseline, but experienced a greater decrease in CST by month 24. The proportion of eyes with ≥2-step DR improvement was greater for eyes with versus without baseline MNP in each ranibizumab arm. CONCLUSIONS Despite having worse vision/increased CST versus those without baseline MNP, eyes with concurrent DME and baseline MNP entering RIDE/RISE experienced robust VA and anatomic improvement with ranibizumab and therefore should not be excluded from therapy.
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Retinal vascular calibre changes after intravitreal bevacizumab or dexamethasone implant treatment for diabetic macular oedema.
Wickremasinghe, SS, Fraser-Bell, S, Alessandrello, E, Mehta, H, Gillies, MC, Lim, LL
The British journal of ophthalmology. 2017;(10):1329-1333
Abstract
PURPOSE To compare changes in retinal vascular calibre after 2 years of treatment with intravitreal bevacizumab (BVZ) or dexamethasone implant (DEX) in patients with centre-involving diabetic macular oedema (DMO). METHODS At baseline, 88 eyes of 61 patients with DMO were recruited in a prospective, multicentre, randomised, single-masked clinical trial. Of these subjects, 22 BVZ-treated (52%) and 22 DEX-treated (48%) eyes of 34 patients (56%) had gradable retinal photographs at both the baseline and 24-month visits. Retinal vascular calibre was measured from digital fundus photographs and summarised as central retinal artery (CRAE) and vein (CRVE) equivalents in all gradable eyes at baseline and 24 months. RESULTS At 24 months, 40.9% of BVZ and 45.5% of DEX eyes gained 10 or more letters (p=0.77). There was concurrent reduction in mean central macular thickness, -157.7 μm in BVZ and -192.5 μm in DEX-treated eyes (p=0.40). DEX-treated eyes showed a statistically significant reduction in CRVE compared with BVZ-treated eyes, with a mean change from baseline of -31.78 to +4.34 µm, respectively (p<0.001). CRAE showed a non-statistically significant trend towards reduction over time in DEX-treated eyes compared with BVZ-treated eyes, with a mean change from baseline of -6.09 and +1.66, respectively (p=0.077). CONCLUSIONS DEX had a significant narrowing effect on venular diameter in eyes with DMO not seen with BVZ. The changes in retinal vascular calibre suggest that these agents have a differing actions effects retinal vasculature and thereby suggest a potentially different mechanism of action on reducing DMO. TRIAL REGISTRATION NUMBER NCT01298076.
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Correlation between Retinal Vessel Calibre and Neurodegeneration in Patients with Type 2 Diabetes Mellitus in the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR).
Frydkjaer-Olsen, U, Soegaard Hansen, R, Simó, R, Cunha-Vaz, J, Peto, T, Grauslund, J, ,
Ophthalmic research. 2016;(1):10-6
Abstract
PURPOSE To investigate the correlation between retinal vessel calibre and measurements of neurodegeneration in patients with type 2 diabetes (T2D) and no or early diabetic retinopathy (DR). METHODS Baseline data on 440 patients with T2D from the EUROCONDOR clinical trial were used. DR was graded according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale, and patients with ETDRS levels 10-35 were included. Retinal vessel diameters were measured by semi-automatic software. Calibres were summarized into central retinal artery and vein equivalents (CRAE and CRVE). RESULTS Median age and diabetes duration were 64.0 and 10.3 years, respectively. ETDRS levels were 10 (42.3%), 20 (27.5%) and 35 (30.2%). The median CRAE and CRVE were 146.7 and 215.3 µm, respectively. CRAE did not differ according to ETRDS level (p = 0.12), but wider CRVE were found in patients with higher ETDRS levels (p = 0.04). In a multivariable linear regression model, CRAE was associated with macular ganglion cell layer thickness (coefficient 0.27 per micrometre, p < 0.01), and CRVE was correlated with macular retinal thickness (coefficient -0.07 per micrometre, p = 0.04) and retinal nerve fibre layer thickness at the optic disc (coefficient 0.32 per micrometre, p < 0.01). CONCLUSION Retinal vessel calibre was independently associated with structural changes of the neuroretina in patients with no or early DR.
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Quantifying Microvascular Density and Morphology in Diabetic Retinopathy Using Spectral-Domain Optical Coherence Tomography Angiography.
Kim, AY, Chu, Z, Shahidzadeh, A, Wang, RK, Puliafito, CA, Kashani, AH
Investigative ophthalmology & visual science. 2016;(9):OCT362-70
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Abstract
PURPOSE To quantify changes in retinal microvasculature in diabetic retinopathy (DR) by using spectral-domain optical coherence tomography angiography (SD-OCTA). METHODS Retrospective, cross-sectional, observational study of healthy and diabetic adult subjects with and without DR. Retinal microvascular changes were assessed by using SD-OCTA images and an intensity-based optical microangiography algorithm. A semiautomated program was used to calculate indices of microvascular density and morphology in nonsegmented and segmented SD-OCTA images. Microvascular density was quantified by using skeleton density (SD) and vessel density (VD), while vessel morphology was quantified as fractal dimension (FD) and vessel diameter index (VDI). Statistical analyses were performed by using the Student's t-test or analysis of variance with post hoc Tukey honest significant difference tests for multiple comparisons. RESULTS Eighty-four eyes with DR and 14 healthy eyes were studied. Spearman's rank test demonstrated a negative correlation between DR severity and SD, VD, and FD, and a positive correlation with VDI (ρ = -0.767, -0.7166, -0.768, and +0.5051, respectively; P < 0.0001). All parameters showed high reproducibility between graders (ICC = 0.971, 0.962, 0.937, and 0.994 for SD, VD, FD, and VDI, respectively). Repeatability (κ) was greater than 0.99 for SD, VD, FD, and VDI. CONCLUSIONS Vascular changes in DR can be objectively and reliably characterized with SD, VD, FD, and VDI. In general, decreasing capillary density (SD and VD), branching complexity (FD), and increasing average vascular caliber (VDI) were associated with worsening DR. Changes in capillary density and morphology were significantly correlated with diabetic macular edema.
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Spectrum of Retinal Vascular Diseases Associated With Paracentral Acute Middle Maculopathy.
Chen, X, Rahimy, E, Sergott, RC, Nunes, RP, Souza, EC, Choudhry, N, Cutler, NE, Houston, SK, Munk, MR, Fawzi, AA, et al
American journal of ophthalmology. 2015;(1):26-34.e1
Abstract
PURPOSE To evaluate the spectrum of retinal diseases that can demonstrate paracentral acute middle maculopathy and isolated ischemia of the intermediate and deep capillary plexus. DESIGN Retrospective, multicenter, observational case series. METHODS This is a retrospective case series review of 9 patients (10 eyes) from 5 centers with paracentral acute middle maculopathy lesions and previously unreported retinal vascular etiologies. Case presentations and multimodal imaging, including color photographs, near-infrared reflectance, fluorescein angiography, spectral-domain optical coherence tomography (SD OCT), and orbital color Doppler imaging, are described. Baseline and follow-up findings are correlated with clinical presentation, demographics, and systemic associations. RESULTS Five men and 4 women, aged 27-66 years, were included. Isolated band-like hyperreflective lesions in the middle retinal layers, otherwise known as paracentral acute middle maculopathy, were observed in all patients at baseline presentation. Follow-up SD OCT analysis of these paracentral acute middle maculopathy lesions demonstrated subsequent thinning of the inner nuclear layer. Novel retinal vascular associations leading to retinal vasculopathy and paracentral acute middle maculopathy include eye compression injury causing global ocular ischemia, sickle cell crisis, Purtscher's retinopathy, inflammatory occlusive retinal vasculitis, post-H1N1 vaccine, hypertensive retinopathy, migraine disorder, and post-upper respiratory infection. CONCLUSION Paracentral acute middle maculopathy lesions may develop in a wide spectrum of retinal vascular diseases. They are best identified with SD OCT analysis and may represent ischemia of the intermediate and deep capillary plexus. These lesions typically result in permanent thinning of the inner nuclear layer and are critical to identify in order to determine the cause of unexplained vision loss.