Characteristic distribution of microaneurysms and capillary dropouts in diabetic macular edema.

PURPOSE: To investigate the distribution pattern of microaneurysms (MAs) and capillary dropouts (CDOs) related to retinal thickness in patients with diabetic macular edema (DME). METHODS: We designed a cross-sectional observational study in which we manually merged fluorescein angiography and optical coherence tomography (OCT) map and located MAs and CDOs areas. The density of MAs, the width and the length of circumference of CDOs, and the number of MAs adjacent to CDOs were compared between highly thickened (white area (WA) in OCT map) and border areas (red area (RA)). RESULTS: We examined 115 eyes of 115 patients with DME. The density of MAs in RA (1.086 ± 0.616) was significantly higher than that in WA (0.8601 ± 1.086) (p = 0.002). The MA rates adjacent to CDOs in WA and RA were 79.1% and 80.7%, respectively. In the RA, the size of CDO adjacent to MAs was smaller (p = 0.013), but its circumference was longer (p = 0.018), and the number of MAs adjacent to CDOs was larger than those in WA (p = 0.002). The total length of circumference of CDOs was significantly correlated with the number of MAs adjacent to CDOs in WA (p = 0.011, R2 = 0.68) and RA (p = 0.008, R2 = 0.81). CONCLUSION: Smaller but more CDOs with longer circumference adjacent to MAs contribute to the higher density of MAs in the surrounding areas of DME.

Retinal flow density by optical coherence tomography angiography is useful for detection of nonperfused areas in diabetic retinopathy.

PURPOSE: Fluorescein angiography (FA) has been conventionally used for detection of retinal nonperfused area (NPA) in diabetic retinopathy (DR) in spite of its qualitative evaluation. Optical coherence tomography angiography (OCTA) has been recently reported to be useful for the quantification of retinal vascular disorder in DR. In this study, we examined whether retinal flow density (FD) measurement in OCTA was useful for NPA detection in DR. METHODS: The study included 41 eyes from 29 patients with DR who underwent FA and OCTA. Regions surrounded by arteries or veins were extracted in the OCTA image, and the FDs in each region were measured by Image J. Furthermore, each region was classified as NPA or perfused area (PA) in FA. The receiver operating characteristic (ROC) curve was prepared by logistic regression analysis of the FD. The AUC (area under the ROC curve) and cutoff value of FD were also calculated. RESULTS: Two hundred fifty-two regions were analyzed and classified into 38 NPA regions and 214 PA regions using FA. FD of each capillary plexus in NPA was significantly smaller than in PA (p < 0.0001). The AUC of total capillary plexus layers (TCP), superficial capillary plexus layer (SCP), and deep capillary plexus layer (DCP) was 0.975, 0.974, and 0.971, respectively. All areas, where the FD was more than the cutoff value (0.07 in TCP), were diagnosed with PA. Three areas with intraretinal microvascular abnormalities (IRMA) were diagnosed as PA despite being below the cutoff value. CONCLUSIONS: FD measurement in OCTA is useful for NPA detection in DR.

The role of nailfold capillary dropout on mortality in systemic sclerosis.

BACKGROUND: Semi-quantitative wide-field nailfold capillaroscopy (NFC) is a simple technique with proven utility in the early diagnosis of systemic sclerosis (SSc). Its role in prognosis, however, remains uncertain. AIM: To investigate the possible utility of NFC in predicting survival. METHODS: Patients with SSc listed on the South Australian Scleroderma Register (SASR) with prior NFC performed at Flinders Medical Centre from 1991 to 2015 were included in this study. Baseline demographic data, diagnosis, scleroderma antibody status and mortality status were also collected for each patient. RESULTS: The cohort consisted of 99 patients with limited cutaneous SSc, 30 patients with diffuse cutaneous SSc and 23 with an overlap scleroderma syndrome. Fifty-six patients died during the period of study (censured end June 2015). Patients with diffuse scleroderma had significantly greater capillary dropout compared with limited and overlap scleroderma (P < 0.001). In univariate analysis, both capillary dropout scores (log-rank χ2 = 8.75, P = 0.003) and antibody status (log-rank χ2 = 13.94, P = 0.003) were associated with mortality. ANOVA showed a significant association between antibody status and capillary dropout (P < 0.001). In Cox regression, adjustment for capillary dropout attenuated the impact of autoantibody group on survival. CONCLUSIONS: Nailfold capillary dropout was significantly associated with mortality and the severity of dropout attenuates survival dictated by antibody status. Together these observations support the hypothesis that capillary dropout is on the causal pathway between induction of scleroderma associated autoantibodies and mortality.

Assessment of capillary dropout in the superficial retinal capillary plexus by optical coherence tomography angiography in the early stage of diabetic retinopathy.

BACKGROUND: To assess capillary dropout in the superficial retinal capillary plexus (SCP) by optical coherence tomography angiography (OCTA) in the early stage of diabetic retinopathy (DR). METHODS: This study was a cross-sectional observational study. Patients that underwent OCTA examinations in our hospital between November 2015 and May 2016 were included in the study. The subjects were divided into two groups: A) normal controls (41 eyes of 41 subjects) and B) the DR patients (49 eyes of 49 patients with mild non-proliferative DR (NPDR)). The retinal thickness and SCP vessel density were analyzed using built-in software in nine sections of the macular area; whole scan area; fovea; parafovea; and sub-sections of the parafovea, superior-hemi, inferior-hemi, temporal, superior, nasal, and inferior. The correlation between vessel density and retinal thickness was also analyzed. RESULTS: The SCP density was significantly lower (P < 0.05) in mild NPDR patients than in normal controls in all areas, with the exception of the fovea (P > 0.05). In the parafovea, superior-hemi, inferior-hemi, temporal, and nasal sectors of group B, the SCP density was negatively correlated with the corresponding retinal thickness (P < 0.05). Specifically, as the SCP density decreased, retinal thickness increased. CONCLUSIONS: In the early stage of NPDR, retinal capillary dropout and retinal thickness changes can be clearly captured and analyzed by OCTA. The results confirm a negative correlation between vessel density and retinal thickness in diabetic patients. This noninvasive technique could be applied for DR detection and monitoring. Further study with a larger sample size is warranted.

Delineation of capillary dropout in the deep retinal capillary plexus using optical coherence tomography angiography in a patient with Purtscher's retinopathy exhibiting normal fluorescein angiography findings: a case report.

BACKGROUND: Fat embolism in the deep retinal capillary plexus is one of the reported mechanisms underlying central/paracentral scotoma in patients with Purtscher's retinopathy. Here we report the clear delineation of capillary dropout in the deep capillary plexus using optical coherence tomography angiography (OCTA) in a chronic case of unexplained scotoma that developed after femoral fracture. The patient exhibited normal fluorescein angiography (FA) findings and a normal retinal appearance. CASE PRESENTATION: A 42-year-old Japanese man with a history of bilateral, unexplained paracentral scotoma that developed after femoral fracture and pulmonary fat embolism due to a car accident 20 years ago was referred to our outpatient clinic. Initial ophthalmological examination revealed unremarkable retinal findings. Goldmann perimetry, FA, and full field electroretinography showed no pathological changes. Although fat embolism in the retinal vasculature was suspected, psychosomatic visual field defects could not be ruled out. We performed OCTA, which clearly delineated capillary dropout in the deep retinal capillary plexus. A final diagnosis of paracentral acute middle maculopathy secondary to Purtscher's retinopathy was made on the basis of this finding. CONCLUSIONS: Our findings suggest that OCTA clearly and noninvasively delineates the deep retinal capillary plexus and the superficial capillary plexus. Because conventional FA provides limited depth resolution, capillary dropout restricted within the deep capillary plexus cannot be detected, particularly when the superficial capillary plexus is well preserved. Thus, OCTA can be a useful tool for the detection of capillary dropout in the deep retinal capillary plexus.

Retinal Ischaemia in Diabetic Retinopathy: Understanding and Overcoming a Therapeutic Challenge.

BACKGROUND: Retinal ischaemia is present to a greater or lesser extent in all eyes with diabetic retinopathy (DR). Nonetheless, our understanding of its pathogenic mechanisms, risk factors, as well as other characteristics of retinal ischaemia in DR is very limited. To date, there is no treatment to revascularise ischaemic retina. METHODS: Review of the literature highlighting the current knowledge on the topic of retinal ischaemia in DR, important observations made, and underlying gaps for which research is needed. RESULTS: A very scarce number of clinical studies, mostly cross-sectional, have evaluated specifically retinal ischaemia in DR. Interindividual variability on its natural course and consequences, including the development of its major complications, namely diabetic macular ischaemia and proliferative diabetic retinopathy, have not been investigated. The in situ, surrounding, and distance effect of retinal ischaemia on retinal function and structure and its change over time remains also to be elucidated. Treatments to prevent the development of retinal ischaemia and, importantly, to achieve retinal reperfusion once capillary drop out has ensued, are very much needed and remain to be developed. CONCLUSION: Research into retinal ischaemia in diabetes should be a priority to save sight.

Nonperfusion Area and Other Vascular Metrics by Wider Field Swept-Source OCT Angiography as Biomarkers of Diabetic Retinopathy Severity.

Purpose: To study the wider field swept-source optical coherence tomography angiography (WF SS-OCTA) metrics, especially non-perfusion area (NPA), in the diagnosing and staging of DR. Design: Cross-sectional observational study (November 2018-September 2020). Participants: 473 eyes of 286 patients (69 eyes of 49 control patients and 404 eyes of 237 diabetic patients). Methods: We imaged using 6mm×6mm and 12mm×12mm angiograms on WF SS-OCTA. Images were analyzed using the ARI Network and FIJI ImageJ. Mixed effects multiple regression models and receiver operator characteristic analysis was used for statistical analyses. Main Outcome Measures: Quantitative metrics such as vessel density (VD); vessel skeletonized density (VSD); foveal avascular zone (FAZ) area, circularity, and perimeter; and NPA in DR and their relative performance for its diagnosis and grading. Results: Among patients with diabetes (median age 59 years), 51 eyes had no DR, 185 eyes (88 mild, 97 moderate-severe) had non-proliferative DR (NPDR); and 168 eyes had proliferative DR (PDR). Trend analysis revealed a progressive decline in superficial capillary plexus (SCP) VD and VSD, and increased NPA with increasing DR severity. Additionally, there was a significant reduction in deep capillary plexus (DCP) VD and VSD in early DR (mild NPDR), but the progressive reduction in advanced DR stages was not significant. NPA was the best parameter to diagnose DR (AUC:0.96), whereas all parameters combined on both angiograms efficiently diagnosed (AUC:0.97) and differentiated between DR stages (AUC range:0.83-0.97). The presence of diabetic macular edema was associated with reduced SCP and DCP VD and VSD within mild NPDR eyes, whereas an increased VD and VSD in SCP among moderate-severe NPDR group. Conclusions: Our work highlights the importance of NPA, which can be more readily and easily measured with WF SS-OCTA compared to fluorescein angiography. It is additionally quick and non-invasive, and hence can be an important adjunct for DR diagnosis and management. In our study, a combination of all OCTA metrics on both 6mm×6mm and 12mm×12mm angiograms had the best diagnostic accuracy for DR and its severity. Further longitudinal studies are needed to assess NPA as a biomarker for progression or regression of DR severity.

Longer Interscan Times in OCT Angiography Detect Slower Capillary Flow in Diabetic Retinopathy.

Purpose: To investigate the detection of slower retinal capillary blood flow using commercial OCT angiography (OCTA) with a longer interscan time in diabetic retinopathy (DR). Design: Observational, prospective, cross-sectional study. Participants: A total of 62 eyes from 39 subjects with diabetes mellitus and 10 eyes from 9 healthy subjects. Methods: Commercial spectral domain-OCT was used to obtain 3 × 3-mm fovea-centered OCTA images of all eyes with 3 different interscan times (4.3, 5.7, and 8.6 ms). For each interscan time, OCTA imaging was performed 5 consecutive times, and a ×5 averaged image was obtained. Capillary flow density and visualization of retinal capillaries in the superficial and deep capillary plexuses (SCPs and DCPs, respectively) were compared between the 3 averaged images from the 3 different interscan times. Main Outcome Measures: Capillary flow density and visualization of foveal capillaries in 3 images with different interscan times. Results: Forty-five eyes of 34 patients were analyzed. There was no significant difference in the flow density of the SCP and DCP between the 3 images with different interscan times in all the DR stages. Some capillaries including microaneurysms that could not be observed at 4.3 ms could be observed at 5.7 or 8.6 ms. There were significantly more capillaries with difference points between the 3 images in the group with DR than in the group without DR (P < 0.01). The morphology of some microaneurysms also changed with longer interscan times. Conclusions: OCTA with longer interscan times revealed slower flow points in capillaries and more accurate visualization and morphology of microaneurysms in DR.

Phenotypic Differences in a PRPH2 Mutation in Members of the Same Family Assessed with OCT and OCTA.

Choroidal dystrophies comprise a group of chorioretinal degenerations. However, the different findings observed among these patients make it difficult to establish a correct clinical diagnosis. The objective of this study was to characterize new clinical findings by optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) in these patients. Four family members with a PRPH2 gene mutation (p.Arg195Leu) were included. OCT was performed at the macula, and the thickness of the outer and inner retina, total retina, and choroid was measured. The features of the vascular network were analyzed by OCTA. Patients showed a decreased outer nuclear layer in the avascular area compared with the controls. Two patients presented greater foveal and parafoveal degeneration of the outer retina, whereas the most degenerated area in the rest was the perifovea. Disruption of the third outer band at the foveola is one of the first-altered outer bands. Slow blood flow areas or capillary dropout were main signs in the deep capillary plexus. Microaneurysms were frequently observed in less degenerated retinas. Vascular loops and intraretinal microvascular abnormalities (IRMAs) were present in the superficial plexus. Extensive degeneration of the choriocapillaris was detected. Phenotypic differences were found between patients: two showed central areolar choroidal dystrophy and the rest had extensive chorioretinal atrophy. These signs observed in OCT and OCTA can help to more appropriately define the clinical disease in patients with choroidal dystrophies.

Capillary Dropout: A Novel Fluorescein Angiography Finding in Primary Vitreoretinal Lymphoma.

Tissue diagnosis with vitreous and/or retinal biopsy usually confirms the diagnosis of primary vitreoretinal lymphoma. Multiple imaging modalities like fundus fluorescein angiography, fundus autofluorescence, and optical coherence tomography have been used to support the diagnosis of vitreoretinal lymphoma. We report a case of a 74-year-old lady diagnosed with primary vitreoretinal lymphoma showing a novel fluorescein angiographic finding of capillary dropout. We hypothesize that this clinical finding on the fluorescein angiogram may be due to the occlusion of the retinal vasculature by the malignant tumor cells. This finding also suggests the possible intraocular invasion of the malignant lymphomatous cells into the inner retinal layers.

Assessment of Ischemic Index in Retinal Vascular Diseases Using Ultra-Wide-Field Fluorescein Angiography: Single Versus Summarized Image.

BACKGROUND AND OBJECTIVE: To compare a single image with a computer-generated summarized image from the ultra-wide-field fluorescein angiogram (UWFFA) sequence for evaluation of ischemic index (ISI). MATERIALS AND METHODS: UWFFA sequences from patients with diabetic retinopathy (DR) (n=5), branch retinal vein occlusion (BRVO) (n=5), and central retinal vein occlusion (CRVO) (n=5) were evaluated by six graders. A single image best illustrating retinal non-perfusion was compared to a summarized image generated by computerized superimposition of angiograms. Non-perfused and ungradable retinal areas were outlined and the ISI between the single and summarized images was compared. RESULTS: The mean ISI in the single versus (vs) summarized images was 17% vs 15% in BRVO (p=0.12), 48% vs 48% in CRVO (p=0.67), and 25% vs 23% in DR (p=0.005). Inter-grader agreement of ISI in single versus summarized images was 0.43 vs 0.40 in BRVO, 0.69 vs 0.71 in CRVO, and 0.53 vs 0.34 in DR. CONCLUSION: Computer-generated summarized images were similar to single images for grading ISI in BRVO and CRVO, but underestimated it in DR.

Tipping the balance from angiogenesis to fibrosis in CKD.

Chronic progressive renal fibrosis leads to end-stage renal failure many patients with chronic kidney disease (CKD). Loss of the rich peritubular capillary network is a prominent feature, and seems independent of the specific underlying disease. The mechanisms that contribute to peritubular capillary regression include the loss of glomerular perfusion, as flow-dependent shear forces are required to provide the survival signal for endothelial cells. Also, reduced endothelial cell survival signals from sclerotic glomeruli and atrophic or injured tubule epithelial cells contribute to peritubular capillary regression. In response to direct tubular epithelial cell injury, and the inflammatory reaction that ensues, capillary pericytes dissociate from their blood vessels, also reducing endothelial cell survival. In addition, direct inflammatory injury of capillary endothelial cells, for instance in chronic allograft nephropathy, also contributes to capillary dropout. Chronic tissue hypoxia, which ensues from the rarefaction of the peritubular capillary network, can generate both an angiogenic and a fibrogenic response. However, in CKD, the balance is strongly tipped toward fibrogenesis. Understanding the underlying mechanisms for failed angiogenesis in CKD and harnessing endothelial-specific survival and pro-angiogenic mechanisms for therapy should be our goal if we are to reduce the disease burden from CKD.

Importance of 3-D image reconstruction of spectral-domain OCT on outcome of grid laser photocoagulation for diffuse diabetic macular edema.

AIM: To present the outcome of modified grid laser photocoagulation (GLP) in diffuse diabetic macular edema (DDME) in eyes without extrafoveal and/or vitreofoveal traction. METHODS: Inclusion criteria for the retrospective study were DDME eyes of patients with type II diabetes mellitus that had ≥4 months of follow-up following GLP. Only one eye per patient was analyzed. Using 3-D spectral-domain optical coherence tomography (3-D SD-OCT), eyes that had either extrafoveal or vitreofoveal traction, or had been previously treated by an intravitreal medication(s) were excluded. Treated DDME eyes were divided into 4 groups: A) "Classic" DDME that involved the central macula; B) edema did not involve the macular center; C) eyes associated with central epiretinal membrane (ERM); D) DDME that was associated with macular capillary dropout ≥2 disc-diameter (DD). RESULTS: GLP outcome in 35 DDME eyes after 4-24 (mean, 13.1±6.9) months was as follows: Group A) 18 eyes with "classic" DDME. Following one or 2 (mean, 1.2) GLP treatments, best-corrected visual acuity (BCVA) improved by 1-2 Snellen lines in 44.4% (8/18) of eyes, and worsened by 1 line in 11.1% (2/18). Central macular thickness (CMT) improved by 7%-49% (mean, 26.6%) in 77.8% (14/18) of eyes. Causes of CMT worsening (n=4) were commonly explainable, predominantly (n=3) associated with emergence of extrafoveal traction, 5-9 months post-GLP. Group B) GLP(s) in DDME that did not involve the macular center (n=6) resulted in improved BCVA by 1-2 lines in 2 eyes. However, the central macula became involved in the edema process after the GLP in 3 (50%) eyes, associated with an emergence of extrafoveal traction in one of these eyes 4 months following the GLP. Group C) GLP failed in all 5 eyes associated with central ERM. Group D) GLP was of partial benefit in 2 of 6 treated eyes with macular capillary dropout ≥2DD. CONCLUSION: Eyes with DDME that involved the macular center were found to achieve favourable outcomes after GLP(s) during mid-term follow-up, unless complicated pre-GLP or post-GLP by vitreoretinal interface abnormalities, often extrafoveal traction or ERM, or by capillary dropout ≥2DD. Prospective studies with larger cohorts are required.