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Background/aimsTo assess foveal avascular zone (FAZ) morphology and parafoveal capillary perfusion in patients with various stages of sickle cell retinopathy (SCR) using optical coherence tomography angiography (OCT-A).MethodsThis is a multi-institutional retrospective study of patients with various stages of SCR compared with healthy controls. Parafoveal OCT-A images obtained using a commercial spectral domain-OCT system were reviewed. Foveal-centred 3×3 mm full vascular slab OCT-As were used for image processing and data analysis. FAZ area, perimeter, and acircularity index were determined on the OCT-A image after manual delineation of the FAZ border. Quadrant-based parafoveal capillary density and per cent area deviating from normal distribution were also measured.ResultsFifty-two patients with SCR (33 non-proliferative and 19 proliferative) and 20 age and race-matched healthy controls were included. One randomly selected eye per study participant was analysed. FAZ perimeter and acircularity index were significantly greater in SCR eyes when compared with the controls. While parafoveal capillary density was significantly lower, per cent area deviated from normal distribution was significantly higher in SCR eyes than that of the control. However, no statistically significant difference between the two SCR stages was observed. In quadrant-based analysis, the temporal quadrant showed greater parafoveal capillary dropout due to SCR, with the most profound effect in patients with proliferative SCR.ConclusionsAbnormal FAZ morphology and altered parafoveal capillary perfusion were found in patients with SCR. Our customised OCT-A image analysis method uniquely highlights significant quantitative alterations in perfusion density mapping in a qualitative display, with minimal obscuration of OCT-A image detail.

Purpose To assess the value of increased perifoveal retinal vascular tortuosity in optical coherence tomography angiography (OCTA) images as a biomarker of early hypertensive retinopathy and compare its clinical sensitivity and accuracy with traditional morphological changes used for Scheie classification. Methods OCTA images of 81 eyes (40 eyes from 20 hypertensive subjects and 41 eyes from 21 control subjects) were obtained retrospectively. Hypertensive retinopathy changes in randomized eyes were graded according to the Scheie classification, and perifoveal vessels were traced in a masked fashion. Tortuosity values of the perifoveal vessels were then calculated along with interobserver agreement in determining the morphometric values. Results There were no differences in perifoveal venular tortuosity between the hypertensive and control groups (Mean = 1.13 ± 0.04 vs. 1.13 ± 0.03), but significant differences existed for arterioles (Mean = 1.14 ± 0.05 vs. 1.11 ± 0.04). Tortuosity measurements demonstrated a significant interobserver agreement ( p  < 0.001), while Scheie ratings had a poor interobserver agreement ( p  = 0.735). There was a significant difference in Scheie classification between the hypertensive and control groups (Mean = 1.06 ± 0.54 vs. 0.50 ± 0.43, p  = 0.005). Conclusions OCTA-based perifoveal retinal arteriolar tortuosity may be a potential reliable biomarker with certain advantages for detecting early hypertensive retinopathy than morphological changes used for the Scheie classification. This may have broad applications and establish important parameters in utilizing OCTA for screening protocols, considering the importance of early detection of systemic hypertension. Key messages What is known • The existing Scheie classification schema for hypertension is subjective in nature with challenges in consistent identification of early hypertensive changes in the retina. What is new • Perifoveal arteriolar tortuosity differs significantly between early hypertensive and control patients. • Arteriolar tortuosity may be a potential biomarker that is useful in identifying patients who have early hypertensive changes in the retina.

Purpose To assess choroid vascular characteristics in four subtypes of central serous chorioretinopathy (CSC) eyes under the new classification system. Methods There were 83 subjects in total for analysis including 16 individuals with acute CSC, 13 with non-resolving CSC, 12 with recurrent CSC, 16 with chronic CSC, and 26 healthy control eyes. We utilized the integrated software of SS-OCTA to acquire measurements of the central choroidal thickness (CT), the choriocapillaris perfusion area (CCPA), three-dimensional choroidal vascularity index (CVI) and three-dimensional choroidal vessel volume (CVV). The SNK-q test was conducted for pairwise comparisons among four subgroups of CSC and healthy control eyes. A multiple linear regression model was employed to investigate the relationship between CVI, CCPA and other factors. Results CT, CVI, and CCPA of the chronic CSC subgroup were significantly lower than the other three CSC subgroups. Lower CVI was significantly correlated with the subgroup of chronic CSC (β = -0.140, P = 0.016), lower CT (β = 0.0014, P < 0.01), and higher CCPA (β = -0.141, P < 0.01). Lower CCPA was significantly correlated with the subgroup of chronic CSC (β = -0.937, P < 0.01), diabetes (β = -0.118, P = 0.015), higher CVV (β = -0.414, P = 0.014), and higher CVI (β = -0.764, P < 0.01). Conclusions This is the first study to evaluate the choroidal characteristics of four subtypes of CSC under the new classification system in detail. It seems that chronic CSC displays distinct pathophysiological alterations in choroidal characteristics. Registration number : NCT05687422. Key messages What is known Central serous chorioretinopathy (CSC) has been recognized as a type of pachychoroid spectrum disease. Traditional classification methods for CSC include acute and chronic forms, and a recent definition encompasses acute, non-resolving, recurrent, and chronic CSC. What is new The choroidal thickness, the choriocapillaris perfusion area, and the three-dimensional choroidal vascularity index of the chronic CSC subgroup were significantly lower than acute subgroup, non-resolving subgroup and recurrent subgroup. Three-dimensional choroidal biomarkers are reliable imaging biomarkers to quantify structural alterations of choroidal vasculature, with considerable potential to contribute to the development of a more precise classification system. It seems that chronic CSC displays distinct pathophysiological alterations in choroidal characteristics.

Aims. To confirm the therapeutic efficacy of conbercept for the treatment of macular edema (ME) secondary to retinal vein occlusion (RVO) by using optical coherence tomography angiography (OCTA) and to find out the differences in therapeutic efficacy between ischemic and nonischemic retinal vein occlusion (iRVO or non-iRVO) after conbercept treatment. Methods. In this prospective, randomized, and comparative study, 60 unilateral eyes suffered from RVO combined with macular edema were included and fellow eye as controls. After an initial intravitreal injection of conbercept (IVIC), a pro re nata (PRN) strategy was adopted, and the follow-up time was 6 months. The foveal avascular zone (FAZ), vascular density of superficial capillary plexus (SCP), and vascular density of deep retinal capillary plexus (DCP), nonperfused areas (NPAs) were evaluated with OCTA on baseline and after treatment. Results. The mean intravitreal injection number was 2.9±0.89 times during six months in iRVO patients and 2.1±0.86 times in non-iRVO patients, with statistically significant difference (p<0.05). On baseline, central macular thickness (CMT) and FAZ were significantly thickened and enlarged compared to those of healthy fellow eyes; the vascular density of SCP and DCP were significantly decreased, and the differences were statistically significant (p<0.05). Compared to baseline, after treatment, the best-corrected visual acuity (BCVA) was improved in either iRVO or non-iRVO (−0.601±0.387, −0.241±0.341 logMAR, p<0.05). In iRVO, the improvement was more substantial than that of the non-iRVO group. FAZ in the non-iRVO group had significantly decreased compared to that in iRVO group (−0.044±0.040 versus 0.014±0.043 mm2, p<0.05). CMT, the vascular density of SCP, and DCP had no significant difference. Conclusions. The changes of microvascular structure can be quantitatively evaluated by using OCTA for the patients with RVO. Conbercept had a significant effect on treatment of RVO with macular edema. A more profound effect was achieved in the iRVO group on visual improvement and FAZ reduction in the non-iRVO group after conbercept treatment.

Aims/hypothesis Fractal analysis of the retinal vasculature provides a global measure of the complexity and density of retinal vessels summarised as a single variable: the fractal dimension. We investigated fractal dimensions as long-term predictors of microvasculopathy in type 1 diabetes. Methods We included 180 patients with type 1 diabetes in a 16 year follow-up study. In baseline retinal photographs (from 1995), all vessels in a zone 0.5–2.0 disc diameters from the disc margin were traced using Singapore Institute Vessel Assessment-Fractal image analysis software. Artefacts were removed by a certified grader, and fractal dimensions were calculated using the box-counting method. At follow-up (in 2011), diabetic neuropathy, nephropathy and proliferative retinopathy were assessed and related to baseline fractal dimensions in multiple regressions adjusted for sex and baseline age, diabetes duration, HbA 1c , BP, BMI, vibration perception threshold, albuminuria, retinopathy and vessel diameters. Results Mean baseline age and diabetes duration were 21.0 and 13.4 years, respectively, and of patients 50.0% were males. The mean fractal dimension was 1.3817. The 16 year incidences of neuropathy, nephropathy and proliferative retinopathy were 10.8%, 8.0% and 27.9%, respectively. Multiple regression analyses showed a lower fractal dimension to significantly predict incident neuropathy (OR 1.17 per 0.01 fractal dimension decrease [95% CI 1.01, 1.36]), nephropathy (OR 1.40 per 0.01 fractal dimension decrease [95% CI 1.10, 1.79]) and proliferative retinopathy (OR 1.22 per 0.01 fractal dimension decrease [95% CI 1.09, 1.37]). Conclusions/interpretation The retinal vascular fractal dimension is a shared biomarker of diabetic microvasculopathy, thus indicating a possible common pathogenic pathway. Retinal fractal analysis therefore is a potential tool for risk stratification in type 1 diabetes.

Background/Objective Adolescents with type 1 diabetes have early macrovascular changes (increased intima‐media thickness [IMT]) and early retinal changes that predict clinical disease in adulthood. We hypothesized that early changes in the macrovascular and retinal microvascular beds develop in parallel before retinopathy develops. We therefore aimed to investigate the relationship between changes in atherosclerosis (carotid and aortic IMT) and retinal vascular geometry cross‐sectionally and longitudinally in adolescents with type 1 diabetes. Methods Ninety adolescents with type 1 diabetes (41 boys, aged 13.6 ± 3.5 years) who were enrolled in a randomized controlled trial had evaluations at baseline; 41 randomized to placebo were also investigated at 12 months for carotid and aortic IMT using ultrasound and retinal vascular geometry was measured from retinal photographs. Results There were significant associations between thicker mean/maximum carotid IMT and wider retinal arteriolar and venular calibers; for every 0.1 mm increase in mean carotid IMT, retinal arteriolar caliber increased by 7.90 μm (95% confidence interval [CI] 4.50, 11.30, P < 0.0001) and venular caliber by 9.61 μm (95% CI 4.16, 15.06, P = 0.0008). Increased mean aortic IMT was associated with increased arteriolar tortuosity (2.61, 95% CI 0.50, 4.71, P = 0.02). Conclusions The early changes of atherosclerosis are associated with retinal microvascular changes in adolescents with type 1 diabetes. This supports parallel adverse changes in the macro and microvascular circulations from early adolescence in type 1 diabetes, and highlights the importance of early intervention.

Aims/hypothesisWe examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes.MethodsA cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as ‘high-risk’ for future albuminuria and the lower two tertiles were deemed ‘low-risk’. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1–Q5) for associations with log10 ACR and ACR risk groups.ResultsGreater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2–Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1–Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control.Conclusions/interpretationHigher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.

To report the incidence and features of retinal microvascular abnormalities (MVAs) occurring secondary to stereotactic radiotherapy (SRT) in a randomised double-masked sham-controlled clinical trial at 21 European sites. Two hundred and thirty participants with neovascular age-related macular degeneration (AMD) treated with at least three intravitreal antivascular endothelial growth factor (anti-VEGF) injections prior to enrolment, and demonstrating a continuing need for re-treatment. 16 Gy, 24 Gy or sham SRT. All three groups received pro re nata anti-VEGF injections if the lesion was judged to be active at review visits. Colour fundus images from baseline and 6 months and fluorescein angiograms from baseline and annual visits were graded for measures of morphological outcome and safety using a prespecified protocol with accompanying definitions to distinguish RT-related MVA from non-specific retinal vessel abnormalities that are known to occur in neovascular AMD. The main outcome measure was MVA detected by months 12, 24 and 36 after enrolment. The frequency of MVAs in the combined SRT arms was 0% in year 1, 13.1% in year 2 and 30.3% in year 3. The area of MVA was small and the mean change in visual acuity in year 2 was similar in a subset of SRT eyes with MVAs, versus those without MVAs. MVA was considered to have possibly contributed to vision loss in 2 of 18 cases with MVA in year 2, and 5 of 37 cases in year 3. Treatment with SRT is associated with development of subtle MVAs that have little or no impact on visual outcome. These findings can help clinicians recognise the retinal MVAs that occur in response to SRT.

Background/AimsQuantifying microaneurysms (MAs) turnover may be an objective measure for therapeutic response in diabetic retinopathy. This study assesses changes in MA counts on ultra-widefield fluorescein angiography (UWFA) in subjects undergoing treatment with intravitreal aflibercept injection (IAI) for proliferative diabetic retinopathy (PDR) in the Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy(RECOVERY) study using an automated MA detection platform.MethodsRECOVERY is a prospective study that enrolled 40 subjects with PDR randomised 1:1 to receive 2 mg IAI every 4 weeks(q4wk) or every 12 weeks (q12wk). UWFA images were obtained at baseline, 6 months and 1 year. Images were analysed using an automated segmentation platform to detect and quantify MAs. Zones 1, 2 and 3 correspond to the macula, mid-periphery and far-periphery, respectively.ResultsThe q4wk cohort demonstrated a significant decline in MAs in all zones and panretinally at baseline versus month 6, baseline versus year 1, and month 6 versus year 1 (−20.0% to −61.8%; all p<0.001). In the q12wk cohort, baseline versus month 6 showed a significant decline panretinally (mean: −34.2%; p<0.001) and in zone 3 (mean −44.18%; p<0.001). Addiitonally, baseline to year 1 in the q12wk group demonstrated significant decline panretinally (mean: −47.7%; p<0.001) and in zone 3 (mean: −59.8%; p<0.001). All zones demonstrated significantly decline from month 6 to year 1 in the q12wk group.ConclusionTherapy with IAI demonstrates significantly reduced panretinal MA counts in PDR at 1 year in both treatment groups. The use of automated platforms to detect and quantify MAs may provide a novel imaging marker for evaluating disease activity and therapeutic impact.Trial registration numberNCT02863354.

PurposeTo investigate the diagnostic values of intereye or intraeye asymmetry of retinal perfused vessel density and neural structure parameters for detection of glaucoma.MethodsIn total, 152 healthy subjects and 72 bilateral primary open-angle glaucoma (POAG) patients were enrolled. Total POAG group contains all glaucoma patients. Early to moderate POAG group contains patients whose binocular mean defect values were larger than −12 dB. The retinal perfused vessel densities were acquired using optic coherence tomography angiography. The neural structure parameters include RNFL, GCC thickness and its derivative indices like focal loss volume percentage (FLV%) and global loss volume percentage (GLV%). Intereye asymmetry equaled to the absolute difference of parameters between paired eyes. Intraeye asymmetry was defined as absolute difference between the inferior and superior hemisphere values from one random selected eye. The areas under the receiver operating characteristic curves (AUROCs) were calculated to evaluate diagnostic ability.ResultsFrom pairwise comparison analysis of ROC curves, the intereye asymmetric parameters with the largest diagnostic accuracy were FLV and GLV% (AUROC = 0.944), which were significantly superior to the intereye asymmetry of perfused vessel density in peripapillary area and parafoveal area (P < 0.05). Particularly, the intereye asymmetry of FLV% (AUROC = 0.926) and GLV% (AUROC = 0.950) showed excellent diagnostic precision for detecting early to moderate glaucoma patients. However, the intraeye asymmetry of microvascular parameters and neural structure parameters showed fair diagnostic ability for identifying POAG patients.ConclusionsThe intereye asymmetry of neural structure parameters, particularly the FLV% and GLV%, outperformed the microvascular parameters for identifying POAG patients.