Faculty Bibliography

BACKGROUND/UNASSIGNED:In properly selected patients, combined face and whole eye transplantation (FWET) may offer a more optimal aesthetic and potentially functional outcome while avoiding the complications and stigma of enucleation and prosthetics. This study presents the most comprehensive cadaveric assessment for FWET to date, including rehearsal allograft procurement on a brain-dead donor. METHODS/UNASSIGNED:Over a 2-year period, 15 rehearsal dissections were performed on 21 cadavers and one brain-dead donor. After identification of a potential recipient, rehearsals assessed clinical feasibility and enabled operative planning, technical practice, refinement of personalized equipment, and improved communication among team members. Operative techniques are described. RESULTS/UNASSIGNED:Facial allograft procurement closely followed previously described face transplant techniques. Ophthalmic to superficial temporal (O-ST) vessel anastomosis for globe survival was assessed. Craniectomy allowed for maximal optic nerve and ophthalmic vessel pedicle length. Appropriate pedicle length and vessel caliber for O-ST anastomosis was seen. Research procurement demonstrated collateral blood flow to the orbit and surrounding structures from the external carotid system as well as confirmed the feasibility of timely O-ST anastomosis. Personalized cutting guides enabled highly accurate bony inset. CONCLUSIONS/UNASSIGNED:This study formalizes an approach to FWET, which is feasible for clinical translation in judiciously selected patients. O-ST anastomosis seems to minimize retinal ischemia time and allow perfusion of the combined allograft on a single external carotid pedicle. Although restoration of vision likely remains out of reach, globe survival is possible.

In this review we highlight emerging immune regulatory functions of lumican, keratocan, fibromodulin, biglycan and decorin, which are members of the small leucine-rich proteoglycans (SLRP) of the extracellular matrix (ECM). These SLRPs have been studied extensively as collagen-fibril regulatory structural components of the skin, cornea, bone and cartilage in homeostasis. However, SLRPs released from a remodeling ECM, or synthesized by activated fibroblasts and immune cells contribute to an ECM-free pool in tissues and circulation, that may have a significant, but poorly understood foot print in inflammation and disease. Their molecular interactions and the signaling networks they influence also require investigations. Here we present studies on the leucine-rich repeat (LRR) motifs of SLRP core proteins, their evolutionary and functional relationships with other LRR pathogen recognition receptors, such as the toll-like receptors (TLRs) to bring some molecular clarity in the immune regulatory functions of SLRPs. We discuss molecular interactions of fragments and intact SLRPs, and how some of these interactions are likely modulated by glycosaminoglycan side chains. We integrate findings on molecular interactions of these SLRPs together with what is known about their presence in circulation and lymph nodes (LN), which are important sites of immune cell regulation. Recent bulk and single cell RNA sequencing studies have identified subsets of stromal reticular cells that express these SLRPs within LNs. An understanding of the cellular source, molecular interactions and signaling consequences will lead to a fundamental understanding of how SLRPs modulate immune responses, and to therapeutic tools based on these SLRPs in the future.

Many retinal diseases and imaging findings have pathophysiologic underpinnings in the function of the cardiovascular system. Myriad retinal conditions, new imaging biomarkers, and novel image analysis techniques have been investigated for their association with future cardiovascular risk or utility in cardiovascular risk prognostication. An intensive literature search was performed to identify relevant articles indexed in PubMed, Scopus, and Google Scholar for a targeted narrative review. This review investigates the literature on specific retinal disease states, such as retinal arterial and venous occlusions and cotton wool spots, that portend significantly increased risk of future cardiovascular events, such as stroke or myocardial infarction, and the implications for personalized patient counseling. Furthermore, conditions diagnosed primarily through retinal bioimaging, such as paracentral acute middle maculopathy and the newly discovered entity known as a retinal ischemic perivascular lesion, may be associated with future incident cardiovascular morbidity and are also discussed. As ever-more-sophisticated imaging biomarkers and analysis techniques are developed, the review concludes with a focused analysis of optical coherence tomography and optical coherence tomography angiography biomarkers under investigation for potential value in prognostication and personalized therapy in cardiovascular disease.

Lumican is an extracellular matrix proteoglycan known to regulate toll-like receptor (TLR) signaling in innate immune cells. In experimental settings, lumican suppresses TLR9 signaling by binding to and sequestering its synthetic ligand, CpG-DNA, in non-signal permissive endosomes. However, the molecular details of lumican interactions with CpG-DNA are obscure. Here, the 3-D structure of the 22 base-long CpG-DNA (CpG ODN_2395) bound to lumican or TLR9 were modeled using homology modeling and docking methods. Some of the TLR9-CpG ODN_2395 features predicted by our model are consistent with the previously reported TLR9-CpG DNA crystal structure, substantiating our current analysis. Our modeling indicated a smaller buried surface area for lumican-CpG ODN_2395 (1803 Ų) compared to that of TLR9-CpG ODN_2395 (2094 Ų), implying a potentially lower binding strength for lumican and CpG-DNA than TLR9 and CpG-DNA. The docking analysis identified 32 amino acids in lumican LRR1-11 interacting with CpG ODN_2395, primarily through hydrogen bonding, salt-bridges, and hydrophobic interactions. Our study provides molecular insights into lumican and CpG-DNA interactions that may lead to molecular targets for modulating TLR9-mediated inflammation and autoimmunity.

PURPOSE:To investigate alterations in macular perfusion variability due to branch retinal vein occlusion (BRVO) using a novel approach based on optical coherence tomography angiography (OCTA) coefficient of variation (CoV) analysis. METHODS:Thirteen eyes of 13 patients with macular ischemia due to BRVO were studied. Multiple consecutive en face OCTA images were acquired. Bias field correction, spatial alignment, and normalization of intensities across the images were performed followed by pixelwise computation of standard deviation divided by the mean to generate a CoV map. Region of interest-based CoV values, derived from this map, for arterioles, venules, and the microvasculature were compared between regions with macular ischemia and control areas of the same eye. Control areas were regions of the same macula that were not affected by the BRVO and had normal retinal vascular structure as seen on multimodal imaging and normal retinal vascular density measurements as quantified using OCTA. RESULTS:CoV increased by a mean value of 17.6% within the microvasculature of ischemic regions compared to the control microvasculature (P < 0.0001). CoV measurements of microvasculature were consistently greater in the ischemic area of all 13 eyes compared to control. There were no differences in CoV measurements between ischemic and control areas for arterioles (P = 0.13) and venules (P = 1.0). CONCLUSIONS:Greater variability in microvasculature perfusion occurs at sites of macular ischemia due to BRVO. We report a novel way for quantifying macular perfusion variability using OCTA. This technique may have applicability for studying the pathophysiology of other retinal vascular diseases.

PURPOSE/OBJECTIVE:To enable in vivo analysis of drusen composition and lifecycle, we assessed macular nodular and cuticular drusen using histology. METHODS:Median and interquartile range (IQR) of base widths of single (non-confluent) nodular drusen in 3 sources were determined histologically: 43 eyes of 43 clinically undocumented donors, in an online resource; one eye with punctate hyperfluorescence in fluorescein angiography (FA); and two eyes of one patient with bilateral "starry sky" cuticular drusen. All tissues were processed for high-resolution epoxy-resin histology and for cuticular drusen, transmission electron microscopy. RESULTS:All drusen localized between the retinal pigment epithelium basal lamina and inner collagenous layer of Bruch's membrane. They were solid, globular, homogeneously stained with toluidine blue, and uncovered by basal laminar deposit and basal mounds. Median base widths were 13.0 µm (Source 1, N=128 drusen, IQR 7.7, 20.0 µm), 15.3 µm (Source 2, N=87, IQR 10.6, 20.5 µm), and 7.3 µm (Source 3, N=78, IQR 3.9, 14.1 µm). CONCLUSIONS:In three samples, >90% of solitary nodular drusen were <30 µm, the visibility threshold in color fundus photography; these drusen are hyperfluorescent in FA. Whether these progress to soft drusen, known as high-risk from epidemiology studies and hypofluorescent, may be determinable from multimodal imaging datasets that include FA.

Customized photorefractive keratectomy with minimal tissue ablation combined with corneal cross-linking seems to be a long-term safe and effective strategy for anatomical and visual management of keratoconus, postsurgical ectasia, and other ectasia management. Multiple published studies, many with long-term follow-up, have supported the Athens Protocol and its various forms as a means to manage corneal ectatic disorders, which not only stabilize corneal shapes but also improve functional vision.

OBJECTIVE:We assessed the utility of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging to differentiate benign and malignant orbital tumours by oculoplastic surgeons in the clinical setting and sought to validate observed ADC cut-off values. DESIGN AND PARTICIPANTS:Retrospective review of patients with benign or malignant biopsy-confirmed orbital tumours. METHODS:/s) using the Region of Interest tool. OUTCOME MEASURES:Nonradiologist measurements were compared with each other to assess reliability and with an expert neuroradiologist measurement and final pathology to assess accuracy. RESULTS:/s (sensitivity 1, specificity 0.9). Inter-rater reliability was excellent (intraclass correlation coefficient = 0.92; 95% CI, 0.86-0.96). Our 3 graders had a combined accuracy of 84.5% (92.3%, 92.3%, and 65.4%). CONCLUSIONS:/s for benign and malignant orbital tumours agrees with previously established values in literature. Without priming with instructions, training, or access to patient characteristics, most tumours were correctly classified using rapid ADC measurements. Surgeons without radiologic expertise can use the ADC tool to quickly risk stratify orbital tumours during clinic visits to guide patient expectations and further work-up.

INTRODUCTION/BACKGROUND:To evaluate the ability of artificial intelligence (AI) software to quantify proptosis for identifying patients who need surgical drainage. METHODS:We pursued a retrospective study including 56 subjects with a clinical diagnosis of subperiosteal orbital abscess (SPOA) secondary to sinusitis at a tertiary pediatric hospital from 2002 to 2016. AI computer software was developed to perform 3D visualization and quantitative assessment of proptosis from computed tomography (CT) images acquired at the time of hospital admission. The AI software automatically computed linear and volume metrics of proptosis to provide more practice-consistent and informative measures. Two experienced physicians independently measured proptosis using the interzygomatic line method on axial CT images. The AI software and physician proptosis assessments were evaluated for association with eventual treatment procedures as standalone markers and in combination with the standard predictors. RESULTS:To treat the SPOA, 31 of 56 (55%) children underwent surgical intervention, including 18 early surgeries (performed within 24 h of admission), and 25 (45%) were managed medically. The physician measurements of proptosis were strongly correlated (Spearman r = 0.89, 95% CI 0.82-0.93) with 95% limits of agreement of ± 1.8 mm. The AI linear measurement was on average 1.2 mm larger (p = 0.007) and only moderately correlated with the average physicians' measurements (r = 0.53, 95% CI 0.31-0.69). Increased proptosis of both AI volumetric and linear measurements were moderately predictive of surgery (AUCs of 0.79, 95% CI 0.68-0.91, and 0.78, 95% CI 0.65-0.90, respectively) with the average physician measurement being poorly to fairly predictive (AUC of 0.70, 95% CI 0.56-0.84). The AI proptosis measures were also significantly greater in the early as compared to the late surgery groups (p = 0.02, and p = 0.04, respectively). The surgical and medical groups showed a substantial difference in the abscess volume (p < 0.001). CONCLUSION/CONCLUSIONS:AI proptosis measures significantly differed from physician assessments and showed a good overall ability to predict the eventual treatment. The volumetric AI proptosis measurement significantly improved the ability to predict the likelihood of surgery compared to abscess volume alone. Further studies are needed to better characterize and incorporate the AI proptosis measurements for assisting in clinical decision-making.

Glaucoma causes progressive visual field deterioration and is the leading cause of blindness worldwide. Glaucomatous damage is irreversible and greatly impacts quality of life. Therefore, it is critically important to detect glaucoma early and closely monitor progression to preserve functional vision. Glaucoma is routinely monitored in the clinical setting using optical coherence tomography (OCT) for derived measures such as the thickness of important visual structures. There is not a consensus of what measures represent the most relevant biomarkers of glaucoma progression. Further, despite the increasing availability of longitudinal OCT data, a quantitative model of 3D structural change over time associated with glaucoma does not exist. In this paper we present an algorithm that will perform hierarchical geodesic modeling at the imaging level, considering 3D OCT images as observations of structural change over time. Hierarchical modeling includes subject-wise trajectories as geodesics in the space of diffeomorphisms and population level (glaucoma vs control) trajectories are also geodesics which explain subject-wise trajectories as deviations from the mean. Our preliminary experiments demonstrate a greater magnitude of structural change associated with glaucoma compared to normal aging. Our algorithm has the potential application in patient-specific monitoring and analysis of glaucoma progression as well as a statistical model of population trends and population variability.