Computational investigation of blood cell transport in retinal microaneurysms.

Microaneurysms (MAs) are one of the earliest clinically visible signs of diabetic retinopathy (DR). MA leakage or rupture may precipitate local pathology in the surrounding neural retina that impacts visual function. Thrombosis in MAs may affect their turnover time, an indicator associated with visual and anatomic outcomes in the diabetic eyes. In this work, we perform computational modeling of blood flow in microchannels containing various MAs to investigate the pathologies of MAs in DR. The particle-based model employed in this study can explicitly represent red blood cells (RBCs) and platelets as well as their interaction in the blood flow, a process that is very difficult to observe in vivo. Our simulations illustrate that while the main blood flow from the parent vessels can perfuse the entire lumen of MAs with small body-to-neck ratio (BNR), it can only perfuse part of the lumen in MAs with large BNR, particularly at a low hematocrit level, leading to possible hypoxic conditions inside MAs. We also quantify the impacts of the size of MAs, blood flow velocity, hematocrit and RBC stiffness and adhesion on the likelihood of platelets entering MAs as well as their residence time inside, two factors that are thought to be associated with thrombus formation in MAs. Our results show that enlarged MA size, increased blood velocity and hematocrit in the parent vessel of MAs as well as the RBC-RBC adhesion promote the migration of platelets into MAs and also prolong their residence time, thereby increasing the propensity of thrombosis within MAs. Overall, our work suggests that computational simulations using particle-based models can help to understand the microvascular pathology pertaining to MAs in DR and provide insights to stimulate and steer new experimental and computational studies in this area.

Artificial intelligence velocimetry and microaneurysm-on-a-chip for three-dimensional analysis of blood flow in physiology and disease.

Understanding the mechanics of blood flow is necessary for developing insights into mechanisms of physiology and vascular diseases in microcirculation. Given the limitations of technologies available for assessing in vivo flow fields, in vitro methods based on traditional microfluidic platforms have been developed to mimic physiological conditions. However, existing methods lack the capability to provide accurate assessment of these flow fields, particularly in vessels with complex geometries. Conventional approaches to quantify flow fields rely either on analyzing only visual images or on enforcing underlying physics without considering visualization data, which could compromise accuracy of predictions. Here, we present artificial-intelligence velocimetry (AIV) to quantify velocity and stress fields of blood flow by integrating the imaging data with underlying physics using physics-informed neural networks. We demonstrate the capability of AIV by quantifying hemodynamics in microchannels designed to mimic saccular-shaped microaneurysms (microaneurysm-on-a-chip, or MAOAC), which signify common manifestations of diabetic retinopathy, a leading cause of vision loss from blood-vessel damage in the retina in diabetic patients. We show that AIV can, without any a priori knowledge of the inlet and outlet boundary conditions, infer the two-dimensional (2D) flow fields from a sequence of 2D images of blood flow in MAOAC, but also can infer three-dimensional (3D) flow fields using only 2D images, thanks to the encoded physics laws. AIV provides a unique paradigm that seamlessly integrates images, experimental data, and underlying physics using neural networks to automatically analyze experimental data and infer key hemodynamic indicators that assess vascular injury.

Microaneurysm density in residual oedema after anti-vascular endothelial growth factor therapy for diabetic macular oedema.

PURPOSE: To investigate the relationship between microaneurysm (MA) density and residual oedema after intravitreal injection of an anti-vascular endothelial growth factor agent for the treatment of diabetic macular oedema (DMO). METHODS: Patients with DMO were divided into those with residual oedema (RO) and those with no residual oedema (NRO) by the presence and absence of oedema at 1 month after intravitreal injection of either aflibercept or ranibizumab. We then compared MA density, best corrected visual acuity (BCVA), central retinal thickness (CRT) and size of the severely thickened area, as indicated by a white area (WA) on optical coherence tomography. RESULTS: We examined 48 eyes in the RO group and 25 eyes in the NRO group (n = 73). In both groups, the CRT and WA size significantly decreased and BCVA improved at 1 month and thereafter. CRT was significantly higher and BCVA was poor in the RO group at 1 and 3 months, while WA size was larger at 1, 3 and 6 months compared with the NRO group (p < 0.05). The number of injections in the RO group (3.62 ± 1.75) was larger than the NRO group (1.89 ± 0.97; p < 0.0001). At 1 and 6 months, the MA density in the area with persistent oedema was significantly higher than in the area with improved oedema (1 month: p = 0.0001, 6 months: p = 0.029). CONCLUSION: High MA density and extensive swelling may be characteristic of RO following treatment for DMO with intravitreal injection of either aflibercept or ranibizumab.

OCTA characterisation of microvascular retinal alterations in patients with central serous chorioretinopathy.

PURPOSE: This study aimed to describe the characteristics of microvascular retinal alterations in eyes with chronic central serous chorioretinopathy (CSC) employing optical coherence tomography angiography (OCTA) analysis. METHODS: We collected data from 472 eyes with chronic CSC from 336 patients who had OCTA obtained. Each OCTA image was graded by two readers to assess the presence of microvascular retinal alterations, including regions of vascular rarefaction/retinal hypoperfusion, enlargement of the foveal avascular zone (FAZ) and presence of telangiectasias or microaneurysms. Volume spectral domain optical coherence tomography (SD-OCT) scans were obtained through the macula and the OCT was correlated with the OCTA findings in eyes with retinal vascular alterations. RESULTS: OCTA displayed microvascular retinal alterations in 18 out of 474 eyes (3.6%) from 14 patients (13 male and 1 female; mean±SD age was 54.7±11.1 years). One eye displayed the presence of retinal telangiectasias, while 17 out of 18 eyes were graded as having areas of retinal vascular rarefactions, and 3 out of 17 eyes were also characterised by an enlargement of the FAZ. The parafoveal region was the location most involved by retinal vascular changes (66,7%), followed by foveal (22,2%) and perifoveal (11.1%) regions, respectively. CONCLUSION: Although CSC is known to represent a choroidal disorder, retinal vascular alterations may be present in these eyes and OCTA may represent a useful tool to identify and describe them.

Quantitative Ultra-Widefield Angiography and Diabetic Retinopathy Severity: An Assessment of Panretinal Leakage Index, Ischemic Index and Microaneurysm Count.

PURPOSE: To investigate the relationship between the diabetic retinopathy (DR) severity and quantitative ultra-widefield angiographic metrics, including leakage index, ischemic index, and microaneurysm count. DESIGN: Retrospective image analysis study. METHODS: Eyes with DR that had undergone ultra-widefield fluorescein angiography (UWFA) with associated color photography were identified. All eyes were laser-naive and had not received any intravitreal pharmacotherapy within 6 months of UWFA. Each eye was graded for DR severity. Quantitative angiographic parameters were evaluated with a semiautomated analysis platform with expert reader correction, as needed. Angiographic parameters included panretinal leakage index, ischemic index, and microaneurysm count. Clinical characteristics analyzed included age, gender, race, hemoglobin A1C level, hypertension, systolic blood pressure, diastolic blood pressure, and smoking history. MAIN OUTCOME MEASURES: Association of DR severity with panretinal leakage index, ischemic index, and microaneurysm count. RESULTS: Three hundred thirty-nine eyes were included with mean age of 62±13 years. Forty-two percent of eyes were from women and 57.5% were from men. Distribution of DR severity was as follows: mild NPDR in 11.2%, moderate NPDR in 23.9%, severe NPDR in 40.1%, and PDR with 24.8%. Panretinal leakage index [mild NPDR (mean = 0.51%), moderate NPDR mean = 1.20%, severe NPDR (mean = 2.75%), and PDR (mean = 5.84%); P<2×10-16], panretinal ischemic index [mild NPDR (mean = 0.95%, moderate NPDR (mean = 1.37%), severe NPDR (mean = 2.80%), and PDR (mean = 9.53%); P<2×10-16], and panretinal microaneurysm count [mild NPDR (mean = 36), moderate NPDR (mean = 129), severe NPDR (mean = 203), and PDR (mean = 254); P<5×10-7] were strongly associated with DR severity. Multivariate analysis demonstrated that ischemic index and leakage index were the parameters associated most strongly with level of DR severity. CONCLUSIONS: Panretinal leakage index, panretinal ischemic index, and panretinal microaneurysm count are associated with DR severity. Additional research is needed to understand the clinical implications of these parameters related to progression risk, prognosis, and implications for therapeutic response.

Analysis of quantitative correlations between microaneurysm, ischaemic index and new vessels in ultrawide-field fluorescein angiography images using automated software.

BACKGROUND/AIM: To analyse ultrawide-field fluorescein angiography (UWF-FA) images of diabetic retinopathy using a novel software that automatically calculates microaneurysm (MA) and non-perfusion area. METHODS: Two hundred UWF-FA images of treatment-naïve diabetic retinopathy (38 proliferative diabetic retinopathy and 162 non-proliferative diabetic retinopathy) from 120 patients (mean age 54.22; 80 male) were analysed using novel software to determine the number of MAs, area of capillary non-perfusion (ischaemic index) and number of neovascularisations. Each result was compared according to its retinal regions. RESULTS: For the total retina, the mean number of MAs was 292.02 (±175.57) and the ischaemic index was 59.42% (±14.78%). Most MAs were located in the mid-peripheral retina (80.54%); however, the density of MAs was highest in the posterior pole (p<0.001). The ischaemic index was highest in the peripheral retina (89.19%), followed by mid-periphery (50.65%) and posterior pole (1.85%). Patients with diabetic macular oedema (DME) presented more MA and a greater ischaemic index (p<0.001, each) than those without DME. CONCLUSION: The automated software allowed prompt and quantitative analysis of UWF-FA images of DMR. MAs were most frequent in the nasal and mid-peripheral retina, with their density being highest in the posterior pole and nasal retina. Ischaemic index increased with distance from the posterior pole, showing strong correlation with central foveal thickness in all retinal areas except the posterior pole.

Structural and Functional Analyses of Retinal Ischemia in Eyes with Retinal Vein Occlusion: Relationship with Macular Edema or Microaneurysm Formation.

PURPOSE: To study the structural and functional changes of retinal ischemia and investigate their association with macular edema (ME) or microaneurysm (MA) formation in eyes with retinal vein occlusion (RVO). METHODS: Sixty eyes of 30 patients (27 eyes with branch [b]RVO, 3 with central RVO, and 30 fellow eyes) were retrospectively reviewed. Optical coherence tomography (OCT), OCT angiography (OCTA), and microperimetry were performed simultaneously to measure retinal thickness and sensitivity. The presence of ME or MA was also assessed using OCT and fluorescein angiography. RESULTS: The mean retinal sensitivity in the nonperfused areas (NPAs) deteriorated, and this was significantly (r = -0.379, p = 0.0391*) and inversely correlated with duration from disease onset. ME and MA were unlikely to be observed around the area where the retinal sensitivity decreased. In the NPAs, the mean retinal thickness of the superficial capillary plexus (SCP) (p < 0.0001), deep capillary plexus (DCP) (p = 0.0323), and outer retina (p = 0.0008) were significantly thinner than those in the fellow eyes, respectively. Multivariate regression analysis revealed that the thicknesses of the DCP (ß: 0.3107, p = 0.0007) and outer retina (ß: 0.3482, p = 0.0001) were the independent correlative factors of the retinal sensitivity, but that SCP thickness was not. CONCLUSION: Deep retinal thinning in NPAs was correlated significantly with a decreased retinal sensitivity, which might be a negative predictor of ME and MA in eyes with RVO.

Effect of Leaking Foveal Microaneurysms on the Treatment of Center-Involving Diabetic Macular Edema: A Pilot Study.

PURPOSE: Evaluate the effect of foveal leaking microaneurysms (MAs) on the required number of intravitreal ranibiz-umab (IVR) injections in the treatment of center-involving diabetic macular edema (DME) when treated with focal/grid laser. DESIGN: A pilot study of prospective, nonrandomized, multicenter clinical trial. METHODS: This study enrolled 21 eyes with DME for which pro re nata IVR injections were combined with short-pulse focal/grid laser. At 12 months, best-corrected visual acuity (BCVA), central subfield macular thickness (CMT), and the required number of IVRs to maintain CMT < 300 µm were compared between eyes with or without foveal leaking MAs, termed the MA(+) and MA(-) groups, respectively. RESULTS: Significant CMT improvements (p < 0.0001) and increased BCVA of 4.0 ± 8.5 letters were observed at 12 months. The MA(-) group required significantly fewer IVRs than did the MA(+) group (mean: 4.9 ± 3.0 vs. 8.6 ± 3.0; p = 0.0306). In the latter 6 months of the 1-year follow-up, 50% (4/8) of MA(-) eyes did not require any IVR administration to sustain CMT < 300 µm. CONCLUSIONS: A combination therapy of short-pulse focal/grid laser and reduced IVR injections appeared noninferior to previous reports of IVR monotherapy. Further large-scale investigations are warranted.

Endovascular Management of Microcerebral Aneurysms with Diameter Smaller than 3 mm: Is It Feasible and Safe?

BACKGROUND: The neurosurgical management of microcerebral aneurysms with diameter smaller than 3 mm remains a great challenge as many complications can occur. AIM: Our target was to assess the efficacy and usefulness of endovascular treatment of these lesions. METHODS: We did a prospective and retrospective gathering of the results of endovascular treatments for a group of 16 patients with 16 microcerebral aneurysms. Four patients were treated by direct coil embolization, and 12 patients were managed by remodeling techniques. RESULTS: Coil embolization was technically accessible in all cases. Initial complete occlusion is achieved in 12 patients. We did not face major technical complications such as aneurysmal rupture or coil migration during the endovascular management in 15 patients. Only in 1 case the second and last coil (2/1 mm) migrated distally and could not be retrieved. In this case clinical evidence of neurologic deterioration and weakness in left lower limb due to right anterior cerebral artery territory stroke was evidenced in the follow-up computed tomography scan. Follow-up clinical and radiological studies were available for 9 of 12 surviving patients and showed complete occlusion in 7 cases, and in 1 case aneurysm tiny recanalization was demonstrated after 1 year, which was retreated with complete occlusion, and in another case tiny aneurysm recanalization at the neck appeared after 2 years, which was left under observation. CONCLUSIONS: Endovascular treatment is a beneficial and effective therapeutic alternative to microsurgery for microaneurysms. The long-term assessment of endovascular management for these lesions was not included in that study.

Laws of physics help explain capillary non-perfusion in diabetic retinopathy.

The purpose is to use laws of physics to elucidate the mechanisms behind capillary non-perfusion in diabetic retinopathy. In diabetic retinopathy, loss of pericytes weakens capillary walls and the vessel dilates. A dilated capillary has reduced resistance to flow, therefore increased flow in that vessel and decreased in adjoining capillaries. A preferential shunt vessel is thus formed from the dilated capillary and the adjacent capillaries become non-perfused. We apply the laws of Laplace and Hagen-Poiseuille to better understand the phenomena that lead to capillary non-perfusion. These laws of physics can give a foundation for physical or mathematical models to further elucidate this field of study. The law of Laplace predicts that a weaker vessel wall will dilate, assuming constant transmural pressure. The Hagen-Poiseuille equation for flow and the Ostwald-de Waele relationship for viscosity predict that a dilated vessel will receive a higher portion of the fluid flow than the adjoining capillaries. Viscosity will decrease in the dilated vessel, furthering the imbalance and resulting in a patch of non-perfused capillaries next to the dilated 'preferential' shunt vessel. Physical principles support or inspire novel hypotheses to explain poorly understood phenomena in ophthalmology. This thesis of pericyte death and capillary remodelling, which was first proposed by Cogan and Kuwabara, already agrees with histological and angiographical observations in diabetic retinopathy. We have shown that it is also supported by classical laws of physics.

Higher skin autofluorescence in young people with Type 1 diabetes and microvascular complications.

AIM: To test the hypothesis that non-invasive skin autofluorescence, a measure of advanced glycation end products, would provide a surrogate measure of long-term glycaemia and be associated with early markers of microvascular complications in adolescents with Type 1 diabetes. METHODS: Forearm skin autofluorescence (arbitrary units) was measured in a cross-sectional study of 135 adolescents with Type 1 diabetes [mean ± sd age 15.6 ± 2.1 years, diabetes duration 8.7 ± 3.5 years, HbA1c 72 ± 16 mmol/mol (8.7 ± 1.5%)]. Retinopathy, assessed using seven-field stereoscopic fundal photography, was defined as ≥1 microaneurysm or haemorrhage. Cardiac autonomic function was measured by standard deviation of consecutive RR intervals on a 10-min continuous electrocardiogram recording, as a measure of heart rate variability. RESULTS: Skin autofluorescence was significantly associated with age (R2 = 0.15; P < 0.001). Age- and gender-adjusted skin autofluorescence was associated with concurrent HbA1c (R2 = 0.32; P < 0.001) and HbA1c over the previous 2.5-10 years (R2 = 0.34-0.43; P < 0.002). Age- and gender-adjusted mean skin autofluorescence was higher in adolescents with retinopathy vs those without retinopathy [mean 1.38 (95% CI 1.29, 1.48) vs 1.22 (95% CI 1.17, 1.26) arbitrary units; P = 0.002]. In multivariable analysis, retinopathy was significantly associated with skin autofluorescence, adjusted for duration (R2 = 0.19; P = 0.03). Cardiac autonomic dysfunction was also independently associated with skin autofluorescence (R2 = 0.11; P = 0.006). CONCLUSIONS: Higher skin autofluorescence is associated with retinopathy and cardiac autonomic dysfunction in adolescents with Type 1 diabetes. The relationship between skin autofluorescence and previous glycaemia may provide insight into metabolic memory. Longitudinal studies will determine the utility of skin autofluorescence as a non-invasive screening tool to predict future microvascular complications.

Retinal Image Enhancement Using Robust Inverse Diffusion Equation and Self-Similarity Filtering.

As a common ocular complication for diabetic patients, diabetic retinopathy has become an important public health problem in the world. Early diagnosis and early treatment with the help of fundus imaging technology is an effective control method. In this paper, a robust inverse diffusion equation combining a self-similarity filtering is presented to detect and evaluate diabetic retinopathy using retinal image enhancement. A flux corrected transport technique is used to control diffusion flux adaptively, which eliminates overshoots inherent in the Laplacian operation. Feature preserving denoising by the self-similarity filtering ensures a robust enhancement of noisy and blurry retinal images. Experimental results demonstrate that this algorithm can enhance important details of retinal image data effectively, affording an opportunity for better medical interpretation and subsequent processing.

Relationship between Functional and Structural Changes in Diabetic Vessels in Optical Coherence Tomography Angiography.

The decorrelation signals in optical coherence tomography angiography (OCTA) are derived from the flow of erythrocytes and concomitantly delineate the retinal vasculature. We compared the structural and functional characteristics of vascular lesions visualized in fluorescein angiography (FA), OCTA, and en-face OCT images in 53 eyes (28 patients) with diabetic retinopathy (DR). The foveal avascular zone (FAZ) areas in OCTA images in the superficial layer almost corresponded to those in FA images. The FAZ areas in the en-face OCT images in the superficial layer were smaller than those in the FA images and correlated with each other, which agreed with the finding that en-face OCT images often delineated the vascular structure in the nonperfused areas in FA images. Microaneurysms appeared as fusiform, saccular, or coiled capillaries in OCTA images and ringed, round, or oval hyperreflective lesions in en-face OCT images. OCTA and en-face OCT images detected 41.0 ± 16.1% and 40.1 ± 18.6%, respectively, of microaneurysms in FA images, although both depicted only 13.9 ± 16.4%. The number of microaneurysms in FA images was correlated with that in OCTA and en-face OCT images. Comparisons of these modalities showed the associations and dissociations between blood flow and vascular structures, which improves the understanding of the pathogenesis of DR.