Faculty Bibliography

SIGNIFICANCE:Although von Willebrand disease is the most common inherited bleeding disorder, there are only a few published reports of ocular complications. To our knowledge, this is the first case of peripheral retinal ischemia and retinal neovascularization in a patient with von Willebrand disease. PURPOSE:This study aimed to demonstrate the value of multispecialty care when exploring a diagnosis for bilateral retinopathy. CASE REPORT:A 55-year-old African American woman presented with peripheral retinal hemorrhages on routine examination. She was asymptomatic and did not have any personal or family history of bleeding disorders. Blood work was ordered, and she was referred to a retinal specialist who found peripheral telangiectasia, retinal ischemia, and leakage on fluorescein angiography, consistent with retinal neovascularization. Laser photocoagulation was performed while numerous specialists were consulted to determine the cause for her retinopathy. Laboratory testing confirmed low-grade type 1 von Willebrand disease. She was monitored without systemic treatment. She remained stable and asymptomatic, but her retinal neovascularization did not regress fully, so laser treatment was repeated. CONCLUSIONS:This case described a new finding of peripheral retinal ischemia and retinal neovascularization in von Willebrand disease. It was discovered in an asymptomatic patient who did not have a history of bleeding but presented with bilateral retinal hemorrhages. Diagnosis was challenging because of the high degree of variation in this bleeding disorder, requiring extensive testing and careful consideration of the individual's clinical profile. Most people with von Willebrand disease do not know they have the disease because symptoms are mild or absent, so most cases are unreported. The von Willebrand factor is poorly recognized in ocular disease, but given its role in angiogenesis, it may be a valuable target to consider in future research.

Blindness from age-related macular degeneration (AMD) is an escalating problem, yet AMD pathogenesis is incompletely understood and treatments are limited. The intestinal microbiota is highly influential in ocular and extraocular diseases with inflammatory components, such as AMD. This article reviews data supporting the role of the intestinal microbiota in AMD pathogenesis. Multiple groups have found an intestinal dysbiosis in advanced AMD. There is growing evidence that environmental factors associated with AMD progression potentially work through the intestinal microbiota. A high-fat diet in apo-E-/- mice exacerbated wet and dry AMD features, presumably through changes in the intestinal microbiome, though other independent mechanisms related to lipid metabolism are also likely at play. AREDS supplementation reversed some adverse intestinal microbial changes in AMD patients. Part of the mechanism of intestinal microbial effects on retinal disease progression is via microbiota-induced microglial activation. The microbiota are at the intersection of genetics and AMD. Higher genetic risk was associated with lower intestinal bacterial diversity in AMD. Microbiota-induced metabolite production and gene expression occur in pathways important in AMD pathogenesis. These studies suggest a crucial link between the intestinal microbiota and AMD pathogenesis, thus providing a novel potential therapeutic target. Thus, the need for large longitudinal studies in patients and germ-free or gnotobiotic animal models has never been more pressing.

Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.

PURPOSE/OBJECTIVE:To describe the presentation and management of a patient with epithelial versus fibrous downgrowth following trabeculectomy surgery and review relevant literature regarding this complication after intraocular surgery. OBSERVATIONS/METHODS:A 52-year-old monocular African-American woman was referred for management of presumed epithelial versus fibrous downgrowth following trabeculectomy surgery. The patient was initially treated with intracameral injections of 5-fluorouracil (x2) and bevacizumab (x1). Cataract extraction, membranectomy, and a third intracameral 5-fluorouracil injection were performed. Intraocular pressure (IOP) elevation was subsequently managed with a superotemporal Ahmed FP7 glaucoma drainage device in the sulcus, followed by an inferonasal Baerveldt 350 glaucoma drainage device in the sulcus. The downgrowth has not progressed and the intraocular pressure remains controlled at the most recent follow-up. CONCLUSIONS:This case underscores the risk of this complication following trabeculectomy, the role of a combined medical and surgical approach to management, and the possible need for multiple surgical interventions to control IOP. A review of the literature regarding epithelial and fibrous downgrowth after intraocular surgery was conducted, which highlighted the aggressive nature of these conditions and the range of therapeutic approaches that have been described.

PURPOSE:Compelling new evidence reveals a close link between the gut microbiome and the pathogenesis of neovascular age-related macular degeneration (nAMD). Germ-free (GF) animal models are the current gold standard for studying host the microbe interactions in vivo; yet, no GF animal models of nAMD are available today. This protocol describes gnotobiotic operations and assembly for a laser-induced choroidal neovascularization (CNV) model in GF mice to study the gut microbiome in neovascular AMD. METHODS:We developed a step-wise approach to performing retinal laser photocoagulation in GF C57BL/6J mice that were bred and maintained at the gnotobiotic facility. Following a strict sterility protocol, we administered laser photocoagulation via an Argon 532-nm laser attached to a customized slit-lamp delivery system. Sterility was confirmed by weekly fecal cultures and reverse transcriptase-polymerase chain reaction. RESULTS:The experiment was repeated twice at different time points using seven mice (14 eyes). Stool cultures and RT-PCR remained negative for 14 days post-procedure in all mice. Lectin immunostaining performed on choroidal flatmounts confirmed the presence of CNV lesions 2 weeks after laser treatment. CONCLUSIONS:We established a GF mouse model of nAMD with detailed guidelines to deliver retinal laser in GF mice maintaining sterility after the laser procedure. TRANSLATIONAL RELEVANCE:To our knowledge, this is the first protocol that describes a GF murine model of laser-induced CNV. In addition to nAMD, this animal model can be used to investigate host-microbial interactions in other eye diseases with laser-induced mouse models such as glaucoma and retinal vein occlusion.

The relationship between retinal disease, diet, and the gut microbiome has shown increasing importance over recent years. In particular, high-fat diets (HFDs) are associated with development and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy. However, the complex, overlapping interactions between diet, gut microbiome, and retinal homeostasis are poorly understood. Using high-throughput RNA-sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) mice on a regular diet (ND) and HFD to investigate transcriptomic changes without influence of gut microbiome. After correction of raw data, 53 differentially expressed genes (DEGs) were identified, of which 19 were upregulated and 34 were downregulated in GF-HFD mice. Key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Enrichment analysis revealed that the top 3 biological processes affected were regulation of blood vessel diameter, inflammatory response, and negative regulation of endopeptidase. Molecular functions altered include endopeptidase inhibitor activity, protease binding, and cysteine-type endopeptidase inhibitor activity. Human and mouse pathway analysis revealed that the complement and coagulation cascades are significantly affected by HFD. This study demonstrates novel data that diet can directly modulate the retinal transcriptome independently of the gut microbiome.

This study compared macular capillary parameters between healthy black and white subjects using optical coherence tomography angiography (OCTA). We measured vessel density (VD) of superficial (SCP), intermediate (ICP), and deep (DCP) capillary plexuses and choriocapillaris blood flow area (BFA) of the fovea, parafovea and total 3 mm-diameter circular area centered on the fovea, as well as the foveal avascular zone (FAZ) parameters, controlling for axial length. Black subjects had lower foveal and parafoveal VD in the SCP (p = 0.043 and p = 0.014) and the ICP (p = 0.014 and p = 0.002). In the DCP, black subjects had a trend toward lower foveal and parafoveal VD. Black subjects had decreased choriocapillaris BFA in the total 3 mm area (p = 0.011) and the parafovea (p = 0.033), larger FAZ area (p = 0.006) and perimeter (p = 0.014), and a higher capillary density in a 300 μm wide region around the FAZ (FD-300) (p = 0.001). There was no significant difference in FAZ acircularity index. To our knowledge, this is the first report analyzing the three distinct retinal capillary plexuses and identifying differing baseline VD, choriocapillaris and FAZ parameters in healthy young black compared to white subjects. Larger studies are needed to validate these findings and better understand racial differences in vulnerability to ocular diseases.