Non-invasive quantification of corneal vascularization using anterior segment optical coherence tomography angiography.

The presence of corneal vascularization (CV) interferes with the angiogenic and immune privilege of the cornea, risking rejection in eyes following keratoplasty. Pre-operative (lymph)-angioregression is a promising therapeutic approach, but objective monitoring by non-invasive CV imaging is needed. The purpose of this study was to investigate anterior-segment optical coherence tomography angiography (AS-OCTA) for CV visualization and quantification, and to show its superiority over slit-lamp photography in high-risk eyes scheduled for keratoplasty. This institutional pilot study included 29 eyes of 26 patients (51 ± 16 years, 8 female) with significant CV scheduled for keratoplasty that were imaged by slit-lamp photography (Zeiss SL 800) and AS-OCTA (Zeiss Plex Elite 9000). After manual corneal layer segmentation correction, CV maximum/relative depth was measured with the inbuilt software. Slit-lamp photographs and AS-OCTA images were compared for visualization of vascular details. Angiotool software allowed a semi-automated determination of CV-related parameters in the vascular complex of AS-OCTA images. The predominant causes of CV were the herpes simplex virus keratitis (n = 7) and chemical burn (n = 4). Visualization of vascular morphology in AS-OCTA was superior to slit-lamp photography in all except one eye. Vascular metrics including total vessel length, number of junctions/endpoints, junction density, lacunarity, and vessel area/density were defined using Angiotool, with CV depth localization despite scarring and opacification. AS-OCTA proved effective for angioregressive treatment monitoring. AS-OCTA enables non-invasive and objective three-dimensional visualization of corneal vascularization superior to slit-lamp photography, and could be a precious tool for monitoring angioregressive preconditioning prior to keratoplasty.

Long-term outcome of bicuspid aortic valve disease.

AIMS: Bicuspid aortic valve (BAV) is a common congenital condition that is frequently associated with aortic stenosis (AS) and aortic regurgitation (AR), as well as aortic aneurysms, but specific outcome data are scarce. The present study sought to assess outcomes in a large cohort of consecutive patients with BAV. METHODS AND RESULTS: A total of 581 consecutive patients (median age 29 years, 157 female) with BAV were included in the study and followed prospectively in a heart valve clinic follow-up programme. The overall survival rate after 10 years was 94.5%. During follow-up, 158 patients developed an indication for surgery. Event-free survival rates were 97%, 94%, 87%, and 73% at 1, 2, 5, and 10 years, respectively. In the multivariable analysis, event rates were independently predicted by AS [subdistribution hazard ratio (SHR) 2.3 per degree of severity], AR (SHR 1.5 per degree of severity), baseline aortic dilatation ≥ 40 mm (SHR 1.9), and age (SHR 1.3) (P < 0.001). CONCLUSION: BAV disease is associated with a high rate of cardiac events, but state-of-the-art care results in good survival with low rates of infective endocarditis, aortic dissection, and sudden death. Incremental degrees of AS and regurgitation, the presence of aortic dilatation, and age are predictive of cardiac events.

Bilateral corneal perforation in Ipilimumab/Nivolumab - associated peripheral ulcerative keratitis.

Purpose: To present a case of immune checkpoint inhibitor-induced bilateral peripheral ulcerative keratitis that progressed to corneal perforation requiring keratoplasty in both eyes. Observations: We describe the course of a 60-year-old man treated with a combination of Ipilimumab and Nivolumab for metastatic melanoma who presented with foreign body sensation and epiphora in both eyes.Bilateral immune-related peripheral ulcerative keratitis was refractory to topical anti-inflammatory therapy, necessitating repetitive, but unsuccessful cyanoacrylate gluing procedure followed by bilateral lamellar mini-keratoplasty. Conclusions and importance: Combined immune checkpoint inhibition revokes the corneal immune privilege and can lead to auto-immune keratitis with recalcitrant progression to ulceration and perforation.

Identification of Treatment Protocols for Effective Cross-Linking of the Peripheral Cornea: An Experimental Study.

INTRODUCTION: This study aimed to test and evaluate modified corneal cross-linking (CXL) protocols regarding improved treatment effects on the peripheral cornea in terms of tissue stability and cellular response. METHODS: Peripheral CXL (pCXL) was performed within a ring of 9-11 mm of 36 human donor corneas with variations in applied energy (5.4, 7.2, and 10 J/cm2) at 9 mW/cm2 irradiance. Each energy level was additionally modulated regarding the oxygen level surrounding the cornea during treatment (21%; 100%). Stress-strain tests with endpoints at 12% strain and collagenase A-assisted digestions to complete digestion were performed to evaluate the rigidity and resistance of treated and control tissue. Further, corneas were processed histologically via TUNEL assay and H&E staining to demonstrate the effects on stromal cells during treatment under varying CXL conditions. RESULTS: Increases in energy dosage achieved significant increases in resistance to stress in all variations except when comparing protocols A and B under normoxic conditions. Supplemental oxygen significantly increased rigidity in protocols B (p < 0.01) and C (p = 0.018). Hyperoxic conditions significantly increased resistance to digestion in all protocols. The number of DNA strand breaks in TUNEL assay staining showed significant increases in all increases in energy as well as with oxygen supplementation. CONCLUSIONS: Increases in energy and supplemental oxygen improved the effect of CXL, though endothelial safety could not be verified with confidence in high-fluence CXL with supplemental oxygen. Results suggest that CXL protocols using 7.2 J/cm2 with 100% O2 or 10 J/cm2 without supplemental oxygen prove most effective without anticipated risk of endothelial damage.

Corneal Toxicity Associated With Belantamab Mafodotin Is Not Restricted to the Epithelium: Neuropathy Studied With Confocal Microscopy.

PURPOSE: The purpose of this study was to investigate epithelial and neuronal changes in patients with refractory/relapsed multiple myeloma (RRMM) before/during belantamab mafodotin (belamaf) treatment using confocal microscopy. DESIGN: Retrospective case series. METHODS: RRMM patients underwent best-corrected visual acuity (BCVA) testing and slitlamp examination/photography, followed by corneal confocal microscopy (CCM), to evaluate the epithelium and subbasal nerve plexus (SNP) to measure corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) before and during belamaf treatment. RESULTS: In 14 eyes of 7 patients (4 female, 68 ± 10 years of age) with complete follow-up (4 ± 2 months), the median BCVA dropped from 20/25 (20/25-20/20) to 20/40 (20/200-20/32) in the worse eye at the end of follow-up. Microcystic epithelial changes and ocular surface disease were demonstrated biomicroscopically. CCM showed "grape-like" hyperreflective spots in the central basal epithelium that changed to polymorphous-structured cysts in the superficial epithelium, with no pathology detected at the(peri-)limbal structures. The baseline, normal SNP morphology with a mean CNFD, CNBD, and CNFL of 20.25 ± 7.06/mm2, 19.49 ± 12.34/mm2, and 11.8 ± 3.74mm/mm2 respectively, showed severe fiber fragmentation during follow-up, and an observed complete loss of the SNP at the end of follow-up in all eyes. CONCLUSIONS: This study is the first to illustrate neurotoxic effects of belamaf on the human cornea.

Atezolizumab induced immune-related adverse event mimicking conjunctival metastatic disease.

Purpose: To describe a case of an immune-related adverse event associated with Atezolizumab therapy which was aggravated by ocular surgery. Observations: A 59-year-old man treated with Atezolizumab for metastatic non-small-cell lung cancer developed a conjunctival hypertrophic lesion mistaken for metastatic tissue. Biopsy surgery induced fulminant and multifocal granulomatous conjunctival tissue growth and sterile corneal ulceration. The immune-related adverse event was refractory to topical therapy, with curative success only after introduction of systemic prednisone. Conclusions: Atezolizumab use may be associated with severe and recalcitrant ocular surface inflammation with potential exacerbation after surgical interventions.

Comparison of early diabetic retinopathy staging in asymptomatic patients between autonomous AI-based screening and human-graded ultra-widefield colour fundus images.

INTRODUCTION: Comparison of diabetic retinopathy (DR) severity between autonomous Artificial Intelligence (AI)-based outputs from an FDA-approved screening system and human retina specialists' gradings from ultra-widefield (UWF) colour images. METHODS: Asymptomatic diabetics without a previous diagnosis of DR were included in this prospective observational pilot study. Patients were imaged with autonomous AI (IDx-DR, Digital Diagnostics). For each eye, two 45° colour fundus images were analysed by a secure server-based AI algorithm. UWF colour fundus imaging was performed using Optomap (Daytona, Optos). The International Clinical DR severity score was assessed both on a 7-field area projection (7F-mask) according to the early treatment diabetic retinopathy study (ETDRS) and on the total gradable area (UWF full-field) up to the far periphery on UWF images. RESULTS: Of 54 patients included (n = 107 eyes), 32 were type 2 diabetics (11 females). Mean BCVA was 0.99 ± 0.25. Autonomous AI diagnosed 16 patients as negative, 28 for moderate DR and 10 for having a vision-threatening disease (severe DR, proliferative DR, diabetic macular oedema). Based on the 7F-mask grading with the eye with the worse grading defining the DR stage 23 patients were negative for DR, 11 showed mild, 19 moderate and 1 severe DR. When UWF full-field was analysed, 20 patients were negative for DR, while the number of mild, moderate and severe DR patients were 12, 21, and 1, respectively. CONCLUSIONS: The autonomous AI-based DR examination demonstrates sufficient accuracy in diagnosing asymptomatic non-proliferative diabetic patients with referable DR even compared to UWF imaging evaluated by human experts offering a suitable method for DR screening.

Longitudinal analysis of microvascular perfusion and neurodegenerative changes in early type 2 diabetic retinal disease.

AIM: To prospectively monitor subclinical changes in capillary perfusion and retinal layer thickness in patients with type 2 diabetes and early diabetic retinal disease over 2 years. METHODS: In this longitudinal study we performed biannual retinal vascular imaging using optical coherence tomography angiography (RTVue) to analyse the foveal avascular zone (FAZ) area, perimeter, acircularity index (AI) and parafoveal superficial/deep vessel density (VD). Spectral-domain optical coherence tomography (Spectralis) was used to measure the thickness of nine macular layers and the peripapillary nerve fibre layer. RESULTS: Among 117 eyes (58 left) of 59 patients (21 female), 105 had no diabetic retinopathy (DR), 6 mild and 6 moderate non-proliferative DR at baseline. We found DR progression in 13 eyes at year 2. The FAZ area (+0.008±0.002 mm2/year, p<0.0001), perimeter (+0.036±0.010 mm/year, p=0.006) and AI (+0.005±0.002/year, p=0.0280) increased significantly. A pronounced decrease was found in the superficial (-1.425±0.290%/year, p<0.0001) but not the deep VD. Inner neuroretinal loss was confined to the ganglion cell (-0.539±0.150 µm/year, p=0.0004) and the inner plexiform layer (-0.361±0.127 µm/year, p=0.0045). In the outer retina, we observed a statistically significant decrease in thickness in the outer plexiform, photoreceptor layer and pigment epithelium of -0.921±0.161 µm/year, -0.325±0.139 µm/year and -0.385±0.084 µm/year, respectively. CONCLUSION: Subclinical signs of microangiopathy and neurodegeneration appear in parallel and are highly progressive even in the earliest stages of diabetic retinal disease. Trial registration number EudraCT20156000239634.

Identification of Subclinical Microvascular Biomarkers in Coronary Heart Disease in Retinal Imaging.

Purpose: Cardiovascular disease and foremost coronary heart disease (CHD) are the worldwide leading causes of death. The aim of this study was to use non-invasive, multimodel retinal imaging to define microvascular features in patients with and without coronary angiography (CA)-confirmed CHD. Methods: In this prospective, cross-sectional pilot study we included adult patients who presented to a tertiary referral center for elective CA due to suspected CHD. All patients underwent widefield fundus photography for retinopathy grading. Optical coherence tomography angiography was used to measure vessel density (VD) of the individual capillary plexuses in 6 × 6-mm macular volume scans. Adaptive optics imaging was performed to assess the first-order arteriolar lumen diameter (LD), total diameter (TD), wall-to-lumen ratio (WLR), and wall cross-section area, as well as to qualitatively describe vessel morphology. Results: Of the included 45 patients (13 females; 65 ± 10 years old), 27 were confirmed with CHD in elective CA. The most prevalent retinal vascular pathologies were arteriovenous nickings, focal arterial narrowings, and microaneurysms. VD in the superficial capillary plexus, deep capillary plexus, and choriocapillaris was lower in CHD patients, although the odds ratios were not significantly different from 1 (P = 0.06-0.92). Median arterial LD, TD, and WLR values were 98.3 µm (interquartile range [IQR] = 13.0), 122.9 µm (IQR = 17.6), and 0.26 µm (IQR = 0.07), respectively, with a trend toward a higher WLR in CHD patients. Conclusions: In a cardiovascular risk population, high-resolution quantitative and qualitative microvascular phenotyping in the retina may provide valuable subclinical indicators for coronary artery impairment, although larger clinical trials are needed. Translational Relevance: Subclinical retinal microvascular changes may serve as non-invasive, cost-effective biomarkers for risk stratification of patients with CHD.