The clinical evaluation of a widefield lens to expand the field of view in optical coherence tomography (OCT-A).

This study aimed to evaluate the clinical benefits of incorporating a widefield lens (WFL) in optical coherence tomography angiography (OCT-A) in patients with retinal vascular diseases in comparison to standard single-shot OCT-A scans. Sixty patients with retinal vascular diseases including diabetic retinopathy (DR) and retinal vein occlusion (RVO) were recruited. OCT-A imaging (PlexElite 9000) with and without WFL was performed in randomized order. The assessment included patient comfort, time, field of view (FoV), image quality and pathology detection. Statistical analysis included paired t-tests, Mann-Whitney U-tests and Bonferroni correction for multiple tests, with inter-grader agreement using the kappa coefficient. Using a WFL did not lead to statistically significant differences in DR and RVO group test times. Patient comfort remained high, with similar responses for WFL and non-WFL measurements. The WFL notably expanded the scan field (1.6× FoV increase), enhancing peripheral retinal visibility. However, image quality varied due to pathology and eye dominance, affecting the detection of peripheral issues in RVO and DR cases. The use of a WFL widens the scan field, aiding vascular retinal disease imaging with minor effects on comfort, time, and image quality. Further enhancements are needed for broader view angles, enabling improved quantification of non-perfused areas and more reliable peripheral proliferation detection.

Confocal microscopy of telangiectatic capillaries (TelCaps) and other features of microvascular remodeling following branch retinal vein occlusion.

Branch retinal vein occlusion (BRVO) is a frequent retinal vascular disease that may cause extensive microvascular remodeling leading to severe visual impairment. Little is known regarding the histology of non-neovascular microvascular remodeling. Here, we examined by confocal microscopy the structure of retinal microvessels of a donor eye with longstanding BRVO. The post-mortem retina of a 91-year-old woman that had superotemporal BRVO for 2 years was examined by confocal microscopy after anti-collagen IV (collIV), alpha-smooth muscle cell (αSMA), and anti-von Willebrand factor (vWf) immunolabeling. In the retinal quadrant affected by BRVO, extensive vascular remodeling affected all vessels, from arterioles to venules, including the foveal avascular zone. Most affected vessels were either irregularly dilated or, on the opposite, reduced to micrometric-size CollIV positive, vWf negative, nuclear-staining negative strings. Telangiectatic capillaries of various sizes and shapes were seen, the largest one (233 µm) being located in the parafoveal area. Some telangiectatic capillaries had a thick, multilayered vWf- and CollIV-positive wall, that often occluded the lumen. Other features included double-channeled arterioles. The majority of microvascular abnormalities were devoid of nuclear staining, suggesting extensive loss of endothelial cells. We describe the spectrum of microvascular abnormalities upstream of a longstanding BRVO. This spectrum comprises a large parafoveal telangiectatic capillary corresponding to what has been previously clinically defined as TelCap. The absence of intraluminal nuclear staining in the majority of abnormal vessels raises the hypothesis that the loss of endothelial cells plays a crucial role in the development of the different manifestations of capillary remodeling. The presence of vWF in de-endothelialized vessels suggests deposition of plasma, hence that they may remain perfused. Our work may help to understand the clinical imaging features of TelCaps.

Comparison of widefield swept-source optical coherence tomography angiography with ultra-widefield fluorescein angiography for the evaluation of lesions in retinal vein occlusion.

BACKGROUND: To compare widefield swept-source optical coherence tomography angiography (SS-OCTA) with ultra-widefield fundus fluorescein angiography (UWF-FA) for detecting retinal vein occlusion (RVO) lesions. METHODS: Thirty-four eyes of 32 patients with treatment-naïve RVO were enrolled at Peking University People's Hospital from September 2021 to March 2022. Patients were imaged with a UWF-FA (200°) and a widefield SS-OCTA using 24 × 20 mm scan single capture. Quantitative assessments of RVO lesions such as foveal avascular zone (FAZ) area and perimeter, non-perfusion areas (NPA), number of microaneurysms (MAs), capillary changes and collateral vessels were performed. RESULTS: The measurement of FAZ area and perimeter were comparable between SS-OCTA and UWF-FA (0.373 (range, 0.277-0.48) mm2 vs. 0.370 (range, 0.277-0.48) mm2, P = 0.818 and 2.480 (range, 2.011-2.998) vs. 2.330 (range, 2.027-2.807) mm, P = 0.536, respectively). Intraclass correlation coefficients (ICCs) of FAZ area and perimeter between SS-OCTA and UWF-FA was high (0.999, [0.997-0.999] and 0.996 [0.991-0.996], respectively), suggesting good agreement. The mean NPA area was larger on SS-OCTA than that on UWF-FA (89.977 ± 78.805 mm2vs. 87.944 ± 77.444 mm2, P = 0.037). The ICC of NPA area was also high (0.999, [0.999-1.000]). The median of total MA count was less on SS-OCTA than on UWF-FA (7 (range, 0-19) vs.12 (range, 0-23), P < 0.001). Agreement in detecting MAs between SS-OCTA and UWF-FA was found to be good (ICC = 0.920, [0.555-0.974]).The total capillary changes and collateral vessels count were less on UWF-FA than SS-OCTA (11 ± 9 vs 6 ± 7, P < 0.001 and 4 (range, 0-6) vs 0 (range, 0-0), P < 0.001, respectively). Agreement in detecting capillary changes and collateral vessels between OCTA and UWF-FA was found to be fair (ICC = 0.733, [0.081-0.905] and 0.564, [0.039-0.805], respectively). CONCLUSION: Compared with UWF-FA, widefield SS-OCTA was found comparable or even superior in detecting FAZ, NPA, capillary changes and collateral vessels except MAs in RVO. Widefield SS-OCTA may offer a more efficient alternative to FA for diagnosis and monitoring RVO.

Parapapillary Choroidal Microvasculature Dropout in Branched Retinal Vein Occlusion and Glaucoma.

Purpose: To investigate parapapillary choroidal microvasculature dropout (MvD) in branch retinal vein occlusion (BRVO) patients and compare them with open-angle glaucoma (OAG) patients using optical coherence tomography angiography (OCT-A). Methods: In total, 85 eyes of BRVO patients and 85 eyes of OAG patients, matched by age, spherical equivalent, and baseline mean deviation (MD) of the visual field (VF), were assessed. MvD was defined as complete loss of microvasculature within the choroidal layer on OCT-A. Linear regression analysis was used to obtain the slope of the MD change of the VF. Results: The presence of MvD on OCT-A was significantly more frequent in OAG eyes (63.1%) compared to BRVO eyes (31.8%). BRVO eyes with MvD showed worse baseline MD of the VF than BRVO eyes without MvD (-10.19 ± 8.50 and -7.77 ± 6.46 dB, respectively; P = 0.045). The presence of MvD was the only factor significantly associated with MD change of the VF in OAG eyes. Lower baseline average RNFL thickness, greater MvD angle, and lower macular superficial vessel density were significantly associated with MD change of the VF in BRVO eyes. Conclusions: OCT-A of the parapapillary area showed choroidal microvasculature impairment in both BRVO and OAG patients. However, the frequency was higher in glaucoma patients with similar degrees of VF damage, which suggests that the glaucomatous process contributes to MvD development. The effect of MvD on VF change was different between BRVO and OAG, suggesting that the underlying pathogenesis may also be different.

Altered White Matter Integrity in Patients with Retinal Vein Occlusion: A Diffusion Tensor Imaging and Tract-Based Spatial Statistics Study.

BACKGROUND: To investigate microstructural alterations of white matter in retinal vein occlusion (RVO) patients by tract-based spatial statistics (TBSS) and diffusion tensor imaging (DTI). Material/Methods. DTI was performed on 14 RVO patients and 14 normal controls (HCs). We measured and recorded fractional anisotropy (FA) and radial diffusivity (RD) of white matter fibers and classified them through the receiver operating characteristic (ROC) curve and correlation analysis, respectively. RESULTS: The mean FA value of white matter in RVO patients is lower than the HCs, and the mean RD value in RVO patients increased, especially in the bilateral posterior thalamic, bilateral sagittal stratum, body of corpus callosum, cingulum, and fornix. The ROC curve of different brain regions showed high accuracy. Moreover, the mean FA and RD values were significantly correlated with visual and psychological disorders. CONCLUSION: TBSS could be regarded as an important method to reveal the alterations of white matter in RVO patients, indicating the underlying neurological mechanism of the RVO.

[Prospects and Challenges of Anti-VEGF Drug Treatment for Pathological Angiogenesis of the Retina].

The number of patients with exudative age-related macular degeneration, diabetic retinopathy and retinal vein occlusion is expected to rise in proportion with the aging of the population and increasing diabetes patients. Also, they are the most common diseases caused by intraocular neovascularization and are often difficult to treat. Currently, anti-vascular endothelial growth factor (VEGF) therapy has been developed and has demonstrated excellent results in treating macular edema, and many patients have avoided blindness. Unfortunately, there are problems with cases that do not respond to the anti-VEGF drugs and complications of administration. It is necessary to deepen the understanding of the physiological and pathological retinal roles of VEGF and to optimize the anti-VEGF therapy. There are also no drugs indicated for the regression of neovascularization itself. The solution to this problem is to develop novel therapies targeting other than VEGF. In this symposium review, we introduce the roles of VEGF in the ischemic retina and anti-angiogenic factors as promising therapeutic targets.

Association between capillary congestion and macular edema recurrence in chronic branch retinal vein occlusion through quantitative analysis of OCT angiography.

This study aims to quantitatively investigate the optical coherence tomographic angiography (OCTA) findings of capillary congestion and its association with macular edema (ME) recurrence in chronic branch retinal vein occlusion (BRVO). We retrospectively reviewed the medical records of 115 consecutive patients with major ischemic BRVO who reached stable macula (without ME for two consecutive visits) at baseline (the first visit within the stable period). All patients were classified into a recurrence or non-recurrence groups depending on ME recurrence. Capillary congestion of deep capillary plexuses (DCP-C) and other abnormal capillary lesions were segmented, and their areas, vascular densities, and mean retinal thicknesses (MRT) were calculated. The main outcomes were differences between the two groups and risk factors for recurrence among baseline and OCTA parameters. A total of 76 eyes were included, of which 22 (28.9%) recurred. DCP-C existed in all eyes at baseline. MRT of DCP-C (p = 0.006) was greater in the recurrence group. Greater MRT of DCP-C (OR: 1.044; p = 0.002) and more frequent intravitreal injections (OR: 1.803; p < 0.001) were associated with a higher risk of relapsing ME. DCP-C may contribute to the anatomical stability of chronic BRVO and simultaneously be the source of ME.

Role of the choroidal vascularity index in branch retinal vein occlusion (BRVO) with macular edema.

PURPOSE: To assess choroidal vasculature changes in eyes with branch retinal vein occlusion (BRVO) and macular edema (ME) using the choroidal vascularity index (CVI) and evaluate the effectiveness of CVI as a prognostic biomarker. METHODS: 35 patients with monocular BRVO and ME were analyzed retrospectively. Luminal and stromal areas in choroids of swept-source optical coherence tomography were calculated using the image binarization technique. The CVI was calculated as the ratio of the luminal to total choroidal area. The CVI of BRVO and ME eyes were compared with that of the unaffected fellow and post anti-vascular endothelial growth factor (VEGF) injected eyes. A regression analysis was performed on the choroidal parameters, logMAR visual acuity (VA) two years post disease onset and central macula thickness (CMT). RESULTS: The CVI of BRVO and ME eyes was significantly lower than the fellow and post-injected eyes (p<0.05). The regression analysis showed a strong association between two years after logMAR VA and the CVI of fellow eyes (R2 = 0.433, p<0.001). Remarkable correlations were observed in the CVI and subfoveal choroidal thickness of BRVO and ME eyes (R2 = 0.189, 0.155, respectively, p<0.05). The CMT of diseased eyes were also significantly associated with the CVI of unaffected fellow eyes (R2 = 0.113, p<0.05). CONCLUSIONS: The alteration of CVI in BRVO and ME suggests that choroidal vasculature might be affected by extracellular fluid shift and VEGF changes. The fellow eye CVI could be a useful supplementary prognostic biomarker.

HDC-Net: A hierarchical dilation convolutional network for retinal vessel segmentation.

The cardinal symptoms of some ophthalmic diseases observed through exceptional retinal blood vessels, such as retinal vein occlusion, diabetic retinopathy, etc. The advanced deep learning models used to obtain morphological and structural information of blood vessels automatically are conducive to the early treatment and initiative prevention of ophthalmic diseases. In our work, we propose a hierarchical dilation convolutional network (HDC-Net) to extract retinal vessels in a pixel-to-pixel manner. It utilizes the hierarchical dilation convolution (HDC) module to capture the fragile retinal blood vessels usually neglected by other methods. An improved residual dual efficient channel attention (RDECA) module can infer more delicate channel information to reinforce the discriminative capability of the model. The structured Dropblock can help our HDC-Net model to solve the network overfitting effectively. From a holistic perspective, the segmentation results obtained by HDC-Net are superior to other deep learning methods on three acknowledged datasets (DRIVE, CHASE-DB1, STARE), the sensitivity, specificity, accuracy, f1-score and AUC score are {0.8252, 0.9829, 0.9692, 0.8239, 0.9871}, {0.8227, 0.9853, 0.9745, 0.8113, 0.9884}, and {0.8369, 0.9866, 0.9751, 0.8385, 0.9913}, respectively. It surpasses most other advanced retinal vessel segmentation models. Qualitative and quantitative analysis demonstrates that HDC-Net can fulfill the task of retinal vessel segmentation efficiently and accurately.

Total venous nature of retinal deep capillary plexus inferred by continuity of prominent middle limiting membrane sign in optical coherence tomography.

This study aimed to theoretically identify the vascular nature of the deep capillary plexus (DCP) by examining patients presenting with both paracentral acute middle maculopathy (PAMM) and prominent middle limiting membrane (p-MLM) sign and p-MLM sign alone in spectral-domain optical coherence tomography (SD-OCT). A retrospective review of the medical records of patients with retinal vein or artery occlusion from two tertiary medical centers was performed. Consecutive patients with a clinical diagnosis of all categories of retinal artery occlusion (RAO) and retinal vein occlusion (RVO) (branch or central and ischemic or non-ischemic) who had undergone SD-OCT imaging from January 2015 to May 2020 were recruited and their p-MLM signs and PAMM lesions were assessed. We included 118 patients who presented with p-MLM sign with or without PAMM lesions. Amon them, 40 were female and 78 were male, with a mean age of 61.1 years. Of the 109 patients with both p-MLM sign and PAMM lesions, 23 had branch RAO, two had branch RVO, 67 had central RAO, 13 had central RVO, and four had a combination of central RAO and central RVO. All nine patients with the p-MLM sign alone had central RVO accompanied by cystoid macular edema. In all the enrolled patients, the hyperreflective lines of the p-MLM sign were continuous, regardless of the type of PAMM lesions. In conclusion, when PAMM and p-MLM sign are examined together, further proof regarding the possible complete venous nature of the vasculature of the retinal DCP might be speculated.

Smooth borders between inner nuclear layer and outer plexiform layer predict fewer macular edema recurrences in branch retinal vein occlusion.

We hypothesized the smoothness of the border between the inner nuclear layer (INL) and outer plexiform layer (OPL) associates with the frequency of macular edema (ME) recurrences secondary to branch retinal vein occlusion (BRVO). Thirty-seven consecutive eyes with BRVO treated with anti-vascular endothelial growth factor (VEGF) injections at 1-year follow-up were included. We manually traced the border between the INL and OPL within the 1.5-mm vertical line from the fovea on optical coherence tomography (OCT) images at the initial visit. The jagged ratio (JR), the border length divided by the spline curve length, was calculated. We performed univariate and multivariate regression analyses, including JR, patient characteristics, number of cystoid spaces in the INL, INL area, and outer retina area. Multivariate regression analysis showed JR significantly correlates with the total number of anti-VEGF injections (P < 0.0001). Moreover, the mean JR was significantly lower in the nine eyes receiving two or fewer injections than in the 28 eyes receiving three or more injections (1.02 ± 0.01 vs. 1.13 ± 0.06, P < 0.0001). A smooth border between the INL and the OPL on OCT images at the initial visit may be a biomarker for fewer ME recurrences in eyes with BRVO.

Changes in peripapillary and subfoveal choroidal thickness in patients with central retinal vein occlusion.

PURPOSE: We sought to evaluate changes of mean peripapillary choroidal thickness (PCT) and subfoveal choroidal thickness (SFCT) over 12 months in patients with unilateral central retinal vein occlusion (CRVO). METHODS: Our retrospective, observational study included 19 patients with treatment-naïve, unilateral CRVO who completed at least 12 months of follow-up period. Mean PCT and mean SFCT in CRVO-affected eyes and unaffected contralateral eyes were measured at each follow-up visit, and then compared. Differences between baseline and 12 months (ΔSFCT and ΔPCT) and percentage changes (ΔSFCT or ΔPCT/baseline×100%) were determined. We also investigated the predictive factors for visual outcome in the CRVO-affected eyes. RESULTS: In the CRVO-affected eyes, mean PCT was 146.7±41.9 µm at baseline, and 106.5±24.2 µm at 12 months (P < 0.001). Mean PCT of the contralateral eyes was 129.8±42.6 µm at baseline and 124.6±39.7 µm at 12 months (P = 0.089). Mean SFCT of CRVO-affected eyes was 225.8±77.9 µm at baseline, and 199.4±66.6 µm at 12 months (P = 0.009). Mean SFCT of the contralateral eyes was 218.4±83.0 µm at baseline, and 208.4±78.1 µm at 12 months (P = 0.089). Δ PCT was -41.6±25.3 µm in the CRVO-affected eyes, and -5.2±5.8 µm in the contralateral eyes (P<0.001). % PCT was -24.9±14.0% in the CRVO-affected eyes, and -4.0±0.4% in the contralateral eyes (P = 0.001). Δ SFCT was -26.4±24.6 µm in the CRVO-affected eyes, and -9.5±16.7µm in the contralateral eyes (P = 0.016). % SFCT was -10.4±9.8% in the CRVO-affected eyes, and -3.4±6.4% in the contralateral eyes (P = 0.015). Among the various factors, BCVA at baseline (ß = 0.797, P = 0.001) and % SFCT (ß = 0.712, P = 0.001) were significantly associated with visual outcome at 12 months in the CRVO-affected eyes. CONCLUSION: Both peripapillary and subfoveal choroidal thickness reduced significantly over 12 months in the CRVO-affected eyes, but not in the contralateral eyes. In addition, the absolute reduction amount and reduction ratio of PCT and SFCT were significantly greater in the CRVO-affected eyes than the contralateral eyes.

Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis.

The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.

Fatty acid-binding protein 4 is an independent factor in the pathogenesis of retinal vein occlusion.

The main objective of current study was to identify the fatty acid-binding protein 4 (FABP4) expressed in both adipocytes and macrophages in vitreous fluid from patients with retinal vein occlusion (RVO). Patients with RVO (n = 14, CRVO; central RVO n = 5, BRVO; branch RVO n = 9) and non-RVO (macular hole or epiretinal membrane, n = 18) were surgically treated by a 25 or 27G vitrectomy. Undiluted vitreous fluid samples obtained as the result of surgery were subjected to enzyme-linked immunosorbent assays to measure the levels of FABP4 and vascular endothelial growth factor A (VEGFA).Data including ocular blood flow by laser speckle flow graphy (LSFG), height and weight, systemic blood pressures and several blood biochemistry values were collected. Among the LSFG mean blur rate (MBR) values of the optic nerve head (ONH) at baseline, MA (MBR of all area), MV (MBR of the vascular area), and MV-MT (MBR of the tissue area) were significantly decreased in patients with CRVO. The levels of V-FABP4 and V-VEGFA were relatively or significantly (P< 0.05) higher in the BRVO or CRVO patients compared to the non-RVO patients, respectively. A positive correlation (r = 0.36, P = 0.045) or a negative correlation (r = -0.51, P = 0.006) was observed between Log V-FABP4 and Log V-VEGF, or Log V-FABP4 and MV-MT at post-operative 1-week, respectively. Furthermore, neither of these factors were affected with respect to sex, body mass index and several clinical parameters that were collected, except that a positive correlation was observed for Log V-FABP4 with blood urea nitrogen. Stepwise multivariable regression analyses indicated that MV-MT at post-operative 1week was independently associated with Log V-FABP4 after adjustment for age and gender, and gender and Log V-FABP4 were independently associated with Log V-VEGFA after adjustment for age. The findings reported herein suggest that an independent factor, FABP4 may be synergistically involved in the pathogenesis of RVO with VEGFA.

Ocular side effects of novel anti-cancer biological therapies.

To examine the ocular side effects of selected biological anti-cancer therapies and the ocular and systemic prognosis of patients receiving them. We retrospectively reviewed all medical records of patients who received biological anti-cancer treatment from 1/2012 to 12/2017 and who were treated at our ocular oncology service. The following data was retrieved: primary malignancy, metastasis, type of biological therapy, ocular side effects, ophthalmic treatment, non-ocular side effects, and ocular and systemic disease prognoses. Twenty-two patients received biological therapies and reported ocular side effects. Eighteen patients (81.8%) had bilateral ocular side effects, including uveitis (40.9%), dry eye (22.7%), and central serous retinopathy (22.7%). One patient (4.5%) had central retinal artery occlusion (CRAO), and one patient (4.5%) had branch retinal vein occlusion (BRVO). At the end of follow-up, 6 patients (27.27%) had resolution of the ocular disease, 13 patients (59.09%) had stable ocular disease, and 3 patients (13.64%) had progression of the ocular disease. Visual acuity improved significantly at the end of follow-up compared to initial values. Eighteen patients (81.8%) were alive at study closure. Biological therapies can cause a wide range of ocular side effects ranging from dry eye symptoms to severe pathologies that may cause ocular morbidity and vision loss, such as uveitis, CRAO and BRVO. All patients receiving biological treatments should be screened by ophthalmologists before treatment, re-screened every 4-6 months during treatment, and again at the end of treatment. Patients on biological treatment who have ocular complaints should be urgently referred to ocular consultation for early identification and early intervention.