Elevated tumor necrosis factor alpha and vascular endothelial growth factor in intermediate age-related macular degeneration and geographic atrophy.

Introduction: Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine implicated in pathological changes to the retinal pigment epithelium that are similar to changes in geographic atrophy (GA), an advanced form of age related macular degeneration (AMD). TNF-α also modulates expression of other cytokines including vascular endothelial growth factor (VEGF), leading to choroidal atrophy in models of AMD. The purpose of this study was to investigate systemic TNF-α and VEGF in patients with GA and intermediate AMD (iAMD) compared to controls without AMD. Methods: We examined plasma levels of TNF-α and VEGF in patients with GA, iAMD, and controls without AMD from the University of Colorado AMD registry (2014 to 2021). Cases and controls were characterized by multimodal imaging. TNF-α and VEGF were measured via multiplex immunoassay and data were analyzed using a non-parametric rank based linear regression model fit to plasma biomarkers. Results: There were 97 GA, 199 iAMD patients and 139 controls. TNF-α was significantly increased in GA (Median:9.9pg/ml, IQR:7.3-11.8) compared to iAMD (Median:7.4, IQR:5.3-9.1) and in both GA and iAMD compared to controls (Median:6.4, IQR:5.3-7.8), p<0.01 for all comparisons. VEGF was significantly increased in iAMD (Median:8.9, IQR:4.8-14.3) compared to controls (Median:7.7, IQR:4.6-11.1), p<0.01. There was a significant positive correlation between TNF-α and VEGF in GA (0.46, p<0.01), and iAMD (0.20, p=0.01) with no significant interaction between TNF-α and VEGF in any group. Discussion: These findings suggest TNF-α and VEGF may contribute to systemic inflammatory processes associated with iAMD and GA. TNF-α and VEGF may function as systemic biomarkers for disease development.

A Surgical Kit for Stem Cell-Derived Retinal Pigment Epithelium Transplants: Collection, Transportation, and Subretinal Delivery.

Transplantation of stem cell-derived retinal pigment epithelium (RPE) cells is a promising potential therapy for currently incurable retinal degenerative diseases like advanced dry age-related macular degeneration. In this study, we designed a set of clinically applicable devices for subretinal implantation of RPE grafts, towards the overarching goal of establishing enabling technologies for cell-based therapeutic approaches to regenerate RPE cells. This RPE transplant kit includes a custom-designed trephine for the production of RPE transplants, a carrier for storage and transportation, and a surgical device for subretinal delivery of RPE transplants. Cell viability assay confirmed biocompatibility of the transplant carrier and high preservation of RPE transplants upon storage and transportation. The transplant surgical device combines foldable technology that minimizes incision size, controlled delivery speed, no fluid reflux, curved translucent tip, usability of loading and in vivo reloading, and ergonomic handle. Furthermore, the complementary design of the transplant carrier and the delivery device resulted in proper grasping, loading, and orientation of the RPE transplants into the delivery device. Proof-of-concept transplantation studies in a porcine model demonstrated no damage or structural change in RPE transplants during surgical manipulation and subretinal deployment. Post-operative assessment confirmed that RPE transplants were delivered precisely, with no damage to the host retina or choroid, and no significant structural change to the RPE transplants. Our novel surgical kit provides a comprehensive set of tools encompassing RPE graft manufacturing to surgical implantation rendering key enabling technologies for pre-clinical and clinical phases of stem cell-derived RPE regenerative therapies.

Plasma C-C Chemokine Concentrations in Intermediate Age-Related Macular Degeneration.

Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory pathways associated with age-related macular degeneration. Methods: The concentrations of CCL2, CCL3, CCL4, and CCL5 were measured using multiplex assays in plasma collected from 210 patients with iAMD and 102 control individuals with no macular degeneration as defined by multi-modal imaging. Non-inflammatory data included in the analysis were: age, sex, family history of AMD, history of smoking, body mass index, presence of reticular pseudo-drusen and cardiovascular disease. Median concentrations as well as a cutoff value for each chemokine were compared between the two groups. Results: The median concentrations of CCL2 and CCL4 did not differ between control and iAMD groups, however, CCL2 was elevated in iAMD when a cutoff comparison was used (p < 0.05). Median CCL3 and CCL5 concentrations were significantly decreased in the macular degeneration group compared with controls (p < 0.001) as well as when a cutoff value comparison was used. CCL3 and CCL5 were negatively correlated in cases and positively correlated in controls. Conclusions: Plasma CCL3 and CCL5 concentrations were significantly decreased and CCL2 concentrations were increased in patients with iAMD compared with controls, suggesting a role for C-C chemokines in the systemic inflammatory processes associated with disease development.

Increased Systemic C-Reactive Protein Is Associated With Choroidal Thinning in Intermediate Age-Related Macular Degeneration.

Purpose: C-reactive protein (CRP) and decreased choroidal thickness (CT) are risk factors for progression to advanced age-related macular degeneration (AMD). We examined the association between systemic levels of CRP and CT in patients with intermediate AMD (iAMD). Methods: Patients with iAMD in the Colorado AMD Registry were included. Baseline serum samples and multimodal imaging including spectral domain-optical coherence tomography (SD-OCT), fundus photography, and autofluorescence were obtained. Medical and social histories were surveyed. CT was obtained by manual segmentation of OCT images. High-sensitivity CRP levels were quantified in serum samples. Univariate and multivariable linear regression models accounting for the intrasubject correlation of two eyes were fit using log-transformed CT as the outcome. Results: The study included 213 eyes from 107 patients with a mean age of 76.8 years (SD, 6.8). Median CT was 200.5 µm (range, 86.5-447.0). Median CRP was 1.43 mg/L (range, 0.13-17.10). Higher CRP was associated with decreased CT in the univariate model (P = 0.01). Older age and presence of reticular pseudodrusen (RPD) were associated with decreased CT (P < 0.01), whereas gender, body mass index, and smoking were not associated with CT. Higher CRP remained significantly associated with decreased CT after adjustment for age and RPD (P = 0.01). Conclusions: Increased CRP may damage the choroid, leading to choroidal thinning and increased risk of progression to advanced AMD. Alternatively, CRP may be a marker for inflammatory events that mediate ocular disease. The results of this study further strengthen the association between inflammation and AMD. Translational Relevance: Increased CRP is associated with choroidal thinning, a clinical risk factor for AMD.

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration.

Purpose: To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD. Methods: Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database. Results: Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3-48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03-49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-ß family members. Conclusions: We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD. Translational Relevance: Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD.

CONCURRENT ENDOPHTHALMITIS AND ANTERIOR SEGMENT ISCHEMIA AFTER STRABISMUS SURGERY.

BACKGROUND/PURPOSE: To report a case of simultaneous endophthalmitis and anterior segment ischemia (ASI) that occurred in a patient after strabismus surgery. This is the first known case of both complications occurring at the same time. METHODS: Case report. RESULTS: A 60-year-old woman presented with eye pain and loss of vision 6 days after uncomplicated strabismus surgery for thyroid eye disease. On examination, she had corneal edema, anterior segment fibrin, an atonic iris, and no view to the posterior segment. On fluorescein angiography of the anterior segment, a large portion of the iris was nonperfused. Posterior segment ultrasound showed dense vitritis and a choroidal abscess. Intraoperative cultures grew methicillin-resistant Staphylococcus aureus. CONCLUSIONS: Endophthalmitis and anterior segment ischemia are both exceedingly rare complications of strabismus surgery. It is possible that each one occurred independently, but more likely one process potentiated the other. One possible mechanism is inflammation-induced thrombosis.

The influence of needle gauge and infection source on vitreous aspirate cultures.

BACKGROUND/AIMS: While the Endophthalmitis Vitrectomy Study (EVS) included only post-cataract surgery patients, the methods and data from that study are widely applied in the management of endophthalmitis of all types. We sought to examine how our experience with in-office vitreous aspiration differed from the EVS in two ways: first, by reviewing microbiological culture yields from vitreous aspirates obtained using 30-gauge needles versus 25-27-gauge needles and second, by reviewing culture yields in cases of endogenous versus non-endogenous endophthalmitis. METHODS: Cases of endophthalmitis over a 14-year period were reviewed when vitreous tap was the initial diagnostic procedure. The data included infection source, needle size used to obtain a vitreous aspirate, organism cultured and rates of unsuccessful attempts at vitreous aspiration or dry taps. RESULTS: 10 cases were endogenous endophthalmitis, while 36 cases were a mix of postoperative, post-traumatic, post-intravitreal injection and miscellaneous patients. A positive microbiological culture was obtained in 11/36 (31%) of vitreous taps using a 25-27-gauge needle and in 8/10 (80%) taps using a 30-gauge needle (p<0.01). A positive vitreous culture was obtained in 18/36 (50%) of all non-endogenous cases, while a positive result was obtained in 0/10 (0%) cases of endogenous endophthalmitis (p<0.01). CONCLUSIONS: The use of a smaller needle in obtaining vitreous samples in endophthalmitis did not lower the microbiological yield. A positive microbiological yield was significantly less likely in cases of endogenous endophthalmitis compared with non-endogenous cases. Vitreous tap as a method for identifying the causative organism in endogenous endophthalmitis was of limited utility.

Spectral domain optical coherence tomographic analysis of healthy retina in branch retinal vein occlusion and its response to antiangiogenic therapy.

PURPOSE: To propose a model that measures the effect of intravitreal bevacizumab (IVB) on relatively healthy retina. The purpose is to analyze the remote effect of a branch retinal vein occlusion in the healthy retina, to determine the response it may have to IVB, and to determine if IVB has an atrophic effect on the healthy retina. METHODS: Retrospective, longitudinal comparative analysis of patients with branch retinal vein occlusion treated with IVB. Eyes were divided into experimental (branch retinal vein occlusion eye) and control (contralateral eye) groups. Each eye was analyzed for thickness and area. Thickness measurements were performed for total retinal thickness, inner retina thickness, and outer retina thickness. Area was measured for photoreceptors, choroid, and total retina. RESULTS: Eighteen eyes of 9 patients. For thickness analysis, 1,050 scans were studied, and 126 measurements were performed on 42 scans for area analysis. No difference was observed for thickness, except for inner retina thickness. No difference was observed for area. No difference was observed when analyzing a cumulative exposure to IVB. CONCLUSION: There is no evidence to suggest an atrophic effect caused by IVB when analyzing thickness or area in this experiment. This model could be used to analyze the long-term safety of IVB in larger studies.

Reversal of paracentral occlusive retinopathy in a case of sickle cell disease using exchange transfusion.

Paracentral occlusive retinopathy is an uncommon manifestation of sickle cell disease. If macular ischemia is not reversed, permanent vision loss can result. The authors report the successful use of exchange transfusion to treat unilateral paracentral occlusive retinopathy secondary to sickle cell disease in a 23-year-old man with hemoglobin SS disease. Initial presentation demonstrated arteriolar occlusion, perivenous hemorrhages, vessel tortuosity, and areas of retinal ischemia. Visual acuity was count fingers, and the patient noted a paracentral scotoma. Following transfusion, there was restoration of arteriolar flow as documented with fluorescein angiogram, and visual acuity returned to 20/20.

VZV multifocal vasculopathy with ischemic optic neuropathy, acute retinal necrosis and temporal artery infection in the absence of zoster rash.

We describe a 54-year-old diabetic woman who developed ischemic optic neuropathy followed by acute retinal necrosis and multiple areas of focal venous beading. Vitreous fluid contained amplifiable VZV DNA but not HSV-1, CMV or toxoplasma DNA. The clinical presentation was remarkable for jaw claudication and intermittent scalp pain, prompting a temporal artery biopsy that was pathologically negative for giant cell arteritis, but notable for VZV antigen. The current case adds to the clinical spectrum of multifocal VZV vasculopathy. The development of acute VZV retinal necrosis after ischemic optic neuropathy supports the notion that vasculitis is an important additional mechanism in the development of VZV retinal injury.