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.

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging.

OBJECTIVE: Systemic activation of the complement system in intermediate age-related macular degeneration (AMD) is understudied. Moreover, links between the presence of reticular pseudodrusen (RPD) and systemic complement dysregulation have not been studied. The aim of this study was to determine if there is a difference in plasma complement factor levels in intermediate AMD compared with controls, and if complement levels are related to the presence of RPD. METHODS AND ANALYSIS: Levels of complement factors C1q (µg/mL), C4 (µg/mL), C2 (µg/mL), Mannose Binding Lectin (ng/mL), C4b (µg/mL), C3 (µg/mL), factor B (µg/mL), factor D (µg/mL), properdin (µg/mL), C3a (ng/mL), iC3b/C3b (ng/mL), Ba (ng/mL), factor H (µg/mL), factor I (µg/mL), C5 (µg/mL), C5a (pg/mL) and SC5b-9 (ng/mL) were measured in plasma. RESULTS: 109 cases and 65 controls were included in the study. Thirty-nine (36%) cases had RPD. Significantly lower systemic levels of: C1q (OR 0.96, 95% CI 0.94 to 0.98), factor B (OR 0.98, 95% CI 0.96 to 0.99), iC3b/C3b (OR 0.97, 95% CI 0.95 to 0.98), factor H (OR 0.99, 95% CI 0.98 to 0.99), factor I (OR 0.83, 95% CI 0.77 to 0.89) and C5 (OR 0.94, 95% CI 0.90 to 0.98) were found in cases versus controls. Significantly elevated levels of: C2 (OR 1.29, 95% CI 1.07 to 1.59), C3a (OR 1.03, 95% CI 1.01 to 1.05) Ba (OR 1.03, 95% CI 1.01 to 1.05) and C5a (OR 1.04, 95% CI 1.02 to 1.07) were found in cases versus controls. Systemic levels of complement factors measured were not related to the presence of RPD. CONCLUSIONS: Levels of several systemic complement pathway factors were found to be altered in intermediate AMD. Systemic levels of complement factors were not related to RPD.

Systemic activation of the complement system in patients with advanced age-related macular degeneration.

PURPOSE: To examine the role of systemic activation of the complement system (assessed by levels of circulating C3a, Ba, and sC5b-9) in patients (n = 122) with advanced age-related macular degeneration, geographic atrophy, and neovascular age-related macular degeneration, compared with cataract controls (n = 27). METHODS: Plasma complement factors were measured using enzyme-linked immunosorbent assays. Statistical analysis included univariate and multivariate logistic regression (p < 0.05). RESULTS: Adjusted for age, the odds ratios of C3a and sC5b-9 for any advanced age-related macular degeneration were 1.78 (95% confidence interval = 1.16-2.73, p < 0.01) and 1.20 (95% confidence interval = 1.04-1.39, p = 0.01), respectively. We found a significantly elevated adjusted odds ratio of C3a (adjusted odds ratio = 1.71, 95% confidence interval = 1.12-2.60, p = 0.01) and sC5b-9 (adjusted odds ratio = 1.22, 95% confidence interval = 1.04-1.43, p = 0.01) for neovascular age-related macular degeneration. Adjusted for age, neither C3a, sC5b-9, nor Ba were associated with geographic atrophy. CONCLUSION: We suggest a role for elevated plasma levels of C3a and sC5b-9 in patients with neovascular age-related macular degeneration. The study's results reinforce the need for more investigation to assess the impact of therapeutic interventions targeted at the complement signaling pathways in age-related macular degeneration.

Hormone Therapy as a Protective Factor for Age-Related Macular Degeneration.

Purpose: The purpose of this study was to determine if the use of menopausal hormone therapy (HT) is related to the development of neovascular (NV) age-related macular degeneration (AMD), geographic atrophy (GA) and/or early/intermediate AMD.Methods: A case-control study was conducted from patients prospectively recruited from July 2014 to June 2019. Cases were females with AMD recruited into a registry and controls were females with age-related cataract and no AMD. Age-related macular degeneration was categorized into NV-AMD, GA, and early/intermediate. Hormone therapy (historic and current) was self-reported by the patient and categorized as ever/never use. Adjusted odds ratios (ORs) from multinomial logistic regressions are presented for each AMD group.Results: Female AMD case patients (n = 409) and controls (n = 132) were included in the analytic database. Almost half (45.5%) of the female AMD patients had NV-AMD, 14.9% had GA, and 39.6% had early/intermediate AMD. Among all study participants, 285 (52.7%) reported historic and/or current use of HT. Controls were significantly more likely to have any HT use (71.2%), compared to 43.0% (p ≤ 0.001) of NV-AMD patients, 47.5% (p = .002) of GA patients, and 50.6% (p ≤ 0.001) of early/intermediate AMD patients. Adjusted for potential confounders of age and Caucasian race, cases were significantly more likely to have lower HT use compared to controls: NV-AMD, OR = 0.31 (95%CI: 0.18-0.54), GA, OR = 0.40 (95%CI: 0.20-0.80), and early/intermediate AMD, OR = 0.36 (95%CI: 0.22-0.61).Conclusion: Our case-control study found that the use of HT was associated with a lower odds of all AMD stages studied: NV-AMD, GA and early/intermediate.

Is subretinal surgery feasible for a non-responsive juxtafoveal type 2 choroidal neovascular membrane?

PURPOSE: To describe the long-term outcome of a patient with multifocal choroiditis, who underwent surgical removal of a type 2 choroidal neovascular membrane employing 23 G pars plana vitrectomy. OBSERVATIONS: A 50-year-old man was treated with 3 monthly intravitreal bevacizumab injections, but despite treatment, visual acuity continued to worsen from 20/40 to 20/100, and bleeding was not receding. A minimal invasive pars plana vitrectomy was performed for surgical removal of the neovascular complex without any complicating incident. Subsequent visual acuity was 20/25 for more than eleven years. CONCLUSIONS AND IMPORTANCE: Surgical removal of choroidal neovascular membranes employing minimal invasive surgery in addition to anti-VEGF therapy, and OCT evaluation can be a viable approach for selected cases of juxtafoveal type 2 CNV.

Driving and Visual Acuity in Patients with Age-Related Macular Degeneration.

PURPOSE: To assess driving status, habitual visual acuity (VA) in the better-seeing eye, and self-reported driving difficulty among patients diagnosed with age-related macular degeneration (AMD). DESIGN: Cross-sectional cohort study of 553 AMD patients' habitual VA, self-reported driving status, and driving difficulty at time of interview. PARTICIPANTS: Patients diagnosed with AMD and recruited into the University of Colorado registry. METHODS: Measurement of habitual VA by median logarithm of the minimum angle of resolution (logMAR) and Snellen equivalent, as well as 3 categories: 20/40 or better, 20/50 or 20/60, and worse than 20/60. Driving difficulty was self-reported on the 25-item National Eye Institute Visual Function Questionnaire. MAIN OUTCOME MEASURES: Self-reported driving status and driving difficulty. RESULTS: A total of 394 patients (71.2%) reported currently driving at time of study interview. Drivers were significantly younger than nondrivers (mean age, 76.7 years vs. 83.9 years; P < 0.0001) and were more likely to be men (42.6% vs. 25.8%; P = 0.0002). Median habitual VA in the better-seeing eye was better among drivers: 0.097 logMAR (Snellen equivalent, 20/25) versus 0.301 logMAR (Snellen equivalent, 20/40) for nondrivers (P < 0.0001). Among drivers, habitual VA was 20/40 or better for 87.6% of patients, 20/50 to 20/60 for 9.6% of participants, and worse than 20/60 for 2.8% of participants. Driving patients with habitual VA in the better-seeing eye of 20/40 or better reported less difficulty driving compared with patients with 20/50 or worse VA. CONCLUSIONS: In our study, most patients with AMD who were currently driving had at least 20/40 VA in the better-seeing eye. However, 12.4% of patients had VA of 20/50 or worse and reported more difficulties with driving. As the aging population continues to grow with increasing lifespan, the number of patients with AMD will increase, and discussion of driving and VA will become more clinically and legally pertinent.

Proteomic Profiles in Advanced Age-Related Macular Degeneration Using an Aptamer-Based Proteomic Technology.

PURPOSE: To explore top-ranked plasma proteins related to neovascular age-related macular degeneration (AMD) and geographic atrophy (GA), and explore pathways related to neovascular AMD and GA. METHODS: We conducted a pilot study of patients with neovascular AMD (n = 10), GA (n = 10), and age-matched cataract controls (n = 10) who were recruited into an AMD registry. We measured 4001 proteins in ethylenediaminetetraacetic acid plasma samples using an aptamer-based proteomic technology. Relative concentrations of each of 4001 proteins were log (base 2) transformed and compared between cases of neovascular AMD and GA versus controls using linear regression. Pathway analysis was conducted using pathways downloaded from Reactome. RESULTS: In this pilot study, higher levels of vinculin and lower levels of CD177 were found in patients with neovascular AMD compared with controls. Neuregulin-4 was higher and soluble intercellular adhesion molecule-1 was lower in patients with GA compared with controls. For neovascular AMD, cargo trafficking to the periciliary membrane, fibroblast growth factor receptor 3b ligand binding and activation, and vascular endothelial growth factor-related pathways were in the top ranked pathways. The top-ranked pathways for GA included several related to ErbB4 signaling. CONCLUSIONS: We found different proteins and different pathways associated with neovascular AMD and GA. Vinculin and some of the top-ranked pathways have been previously associated with AMD, whereas others have not been described. TRANSLATIONAL RELEVANCE: Biomarkers identified in plasma likely reflect systemic alterations in protein expression and may improve our understanding of the mechanisms leading to AMD.

COLORADO AGE-RELATED MACULAR DEGENERATION REGISTRY: Design and Clinical Risk Factors of the Cohort.

PURPOSE: To study new and existing risk factors related to age-related macular degeneration (AMD) phenotypes in a Colorado cohort. METHODS: Age-related macular degeneration was categorized into early, intermediate, or advanced forms. Controls (n = 180) were patients with cataract and no AMD. Demographic and clinical data were gathered by patient interview and verified by chart review. Image data were reviewed by vitreoretinal specialists. Statistical analysis included univariable and multivariate logistic regression analysis (P < 0.05). RESULTS: Among the 456 patients with AMD, 157 (34.4%), 80 (17.6%), and 219 (48.0%) had the early/intermediate, geographic atrophy, and neovascular forms of the disease, respectively. Adjusted for age, African-American race was associated with a reduced risk of early/intermediate (adjusted odds ratio [AOR] = 0.08, confidence interval [CI] = 0.01-0.67) and neovascular AMD (AOR = 0.15, CI = 0.03-0.72). A family history of AMD was a risk factor for early/intermediate (AOR = 4.08, CI = 2.30-7.25), geographic atrophy (AOR = 8.62, CI = 3.77-19.7), and neovascular AMD (AOR = 3.76, CI = 2.16-6.56). A history of asthma was related to the early/intermediate form of AMD (AOR = 2.34, CI = 1.22-4.46). CONCLUSION: Studying AMD in specific populations may reveal novel risk factors such as our finding of a relationship between asthma history and AMD.

Cytomegalovirus Retinitis in Pediatric Stem Cell Transplants: Report of a Recent Cluster and the Development of a Screening Protocol.

PURPOSE: The incidence of cytomegalovirus (CMV) retinitis in the pediatric allogeneic hematopoietic stem cell transplant (HSCT) population is unknown. We report a cluster of 5 pediatric patients with CMV retinitis diagnosed in a 12-month period and compare this to the rate of CMV viremia and retinitis in the 4 years prior. Presented is the ophthalmic screening protocol developed in response to this experience. DESIGN: Retrospective cross-sectional study. METHODS: A retrospective chart review was performed on patients at Children's Hospital of Colorado (CHCO) who received allogeneic HSCT between January 2010 and December 2014. Fisher exact test was used to compare the proportion of CMV viremia and CMV retinitis in patients transplanted between January 2010 and December 2013 with those transplanted in 2014. RESULTS: A total of 101 patients underwent allogeneic HSCT from January 2010 to December 2013; 32 (32%) tested positive for CMV viremia. No cases of CMV retinitis were identified. From January 2014 to December 2014, 28 patients underwent allogeneic HSCT; 13 patients (46%) had CMV viremia, not a statistically significant increase (P = .18). There were 5 cases of CMV retinitis diagnosed in those transplanted in 2014, a statistically significant increase compared with those transplanted in 2010-2013 (P = .0004). A multidisciplinary team was formed to review the literature and an ophthalmic screening protocol was developed. CONCLUSION: Our recent cluster of CMV retinitis in pediatric allogeneic HSCT patients may suggest a rise in incidence of CMV retinitis. We propose an ophthalmic screening protocol to diagnose retinitis in pediatric HSCT patients in the early, often asymptomatic stage.

Consistent pattern in positional instability of polyfocal full-optics accommodative IOL.

PURPOSE: We describe cases of dislocation or subluxation of the WIOL-CF® polyfocal full-optics intraocular lens (IOL) and suggest a consistent pattern and possible mechanism for the IOL instability. METHODS: This is a retrospective case series of five consecutive eyes in three patients with WIOL-CF® IOL instability at Keimyung University Dongsan Medical Center and Kimkisan Eye Center from 2012 to 2014. The medical records and ocular exam data for these patients were analyzed. RESULTS: A 50-year-old male had uneventful phacoemulsification in both eyes with WIOL-CF® IOL implantation. At 27 months after surgery, the patient was referred to our clinic with a dislocated IOL in the left eye. The IOL in the right eye was dislocated in the same pattern 38 months after cataract surgery. Another 50-year-old male, who had phacoemulsification and WIOL-CF® IOL implantation in both eyes, was referred to our clinic following diagnosis of a subluxated IOL. Both IOLs were well centered; however, the infranasal aspect of the IOLs tilted posteriorly, and the supratemporal portion the IOLs tilted anteriorly, with overlying iris atrophy in a symmetric pattern. The inferonasal continuous curvilinear capsulorrhexis (CCC) edge was dragged superotemporally, and the supratemporal CCC edge was identified on the posterior surface of the IOL. A 16-year-old female had uneventful phacoemulsification and WIOL-CF® IOL implantation to treat a cataract in the right eye, and 3 years later, the IOL tilted with the same pattern as the previous case. CONCLUSIONS: Years after uncomplicated phacoemulsification, an implanted WIOL-CF® IOL may tilt and dislocate in the absence of trauma, in a consistent and characteristic pattern.

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.

Enhanced High-Density Line Spectral-Domain Optical Coherence Tomography Imaging of the Vitreoretinal Interface: Description of Selected Cases.

PURPOSE: We introduce a new method to observe the morphologic features of the vitreous with spectral-domain optical coherence tomography (SD-OCT) by evaluating and describing the posterior vitreous structure of various selected cases using enhanced high-density (HD) line mode. METHODS: This is a descriptive case series of SD-OCT images with enhanced HD line at Denver Health Medical Center, University of Colorado School of Medicine, in 2014. The medical records with ocular images for these patients were analyzed. RESULTS: Enhanced HD line in vitreoretinal mode with SD-OCT offered wide images with well-visible vitreoretinal interface. The posterior precortical vitreous pocket (PPVP), often mistaken as a posterior vitreous detachment on standard retina-based cross line mode, was easily identified. Vitreomacular adhesion and traction, absence or presence of connecting channels between PPVP and Cloquet's canal, liquefied vitreous lacuna, and emulsified silicone oil droplet-layer could be observed. CONCLUSIONS: SD-OCT using enhanced HD line in vitreoretinal mode enables clear visualization of the posterior vitreous structure and often reclassifies patients previously thought to have a posterior vitreous detachment.

Red cell exchange transfusion halts progressive proliferative sickle cell retinopathy in a teenaged patient with hemoglobin SC disease.

A male with sickle SC disease presented at age 8 years with proliferative sickle cell retinopathy (PSCR) and bilateral vitreous hemorrhage which spontaneously resolved, then recurred at 13 years of age. Despite conventional therapy with repeated pan-retinal photocoagulation and pars plana vitrectomy, he developed progressive PSCR and recurrent vitreous hemorrhage over the next 30 months. We describe the successful use of chronic red cell exchange transfusion (RCE) to preserve his vision and stabilize the retinopathy.

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.

Positioning-related complications of minimally invasive radical prostatectomies.

BACKGROUND AND PURPOSE: Because of recent advances in minimally invasive surgical techniques, robot-assisted radical prostatectomy (RARP) has become the primary treatment option in prostate cancer. RARP, however, necessitates patients to be placed in a steep Trendelenberg position, which presents multiple opportunities for complications relating to the positioning of the patient. Our study aims to study the prevalence and demographic predictors of these positioning complications and assess their impacts on length of stay (LOS) and total cost. PATIENTS AND METHODS: We included patients who underwent RP from 2008 to 2009 using data extracted from the Nationwide Inpatient Sample database. Positioning complications (eye, nerve, compartment syndrome/rhabdomyolysis) were identified using patient-level diagnosis and procedural International Classification of Disease, 9th edition, Clinical Modification codes. Logistic regression models assessed relationships between demographic factors and occurrence of complications and the effects of them on prolonged LOS and total inpatient cost. RESULTS: Positioning complications occurred in 0.4% of cases with eye complications contributing the most to this frequency. Laparoscopic RP procedure (odds ratio [OR]=2.88, P<0.01) and comorbidities (OR=2.34, P<0.01) were highly associated with increased odds of positioning complication occurrence, whereas RARP procedures (OR=0.93, P>0.4) were not associated with positioning complications. Having positioning complications increased a patient's odds of having increased inpatient costs and extended LOS by almost 400% and 300%, respectively. CONCLUSION: The steep Trendelenberg position used in RARP was not shown to be associated with patient positioning-related complications in this sample. The occurrence of positioning-related complications, however, places huge burdens on total inpatient costs and LOS.

Downbeat nystagmus secondary to familial hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis is a rare autosomal recessive disorder characterized by severe inflammation induced by defective natural killer cell function, which triggers a state of highly stimulated but ineffective immune response. This disorder can affect multiple organ systems, and neurologic manifestations include irritability, seizures, impaired consciousness, meningismus, and cranial nerve palsies. We describe a unique case of hemophagocytic lymphohistiocytosis in which downbeat nystagmus developed due to cerebellar swelling with compression of the cervicomedullary junction.

Comparison of fundus autofluorescence between fundus camera and confocal scanning laser ophthalmoscope-based systems.

BACKGROUND AND OBJECTIVE: To compare fundus autofluorescence (FAF) imaging via fundus camera (FC) and confocal scanning laser ophthalmoscope (cSLO). PATIENTS AND METHODS: FAF images were obtained with a digital FC (530 to 580 nm excitation) and a cSLO (488 nm excitation). Two authors evaluated correlation of autofluorescence pattern, atrophic lesion size, and image quality between the two devices. RESULTS: In 120 eyes, the autofluorescence pattern correlated in 86% of lesions. By lesion subtype, correlation rates were 100% in hemorrhage, 97% in geographic atrophy, 82% in flecks, 75% in drusen, 70% in exudates, 67% in pigment epithelial detachment, 50% in fibrous scars, and 33% in macular hole. The mean lesion size in geographic atrophy was 4.57 ± 2.3 mm(2) via cSLO and 3.81 ± 1.94 mm(2) via FC (P < .0001). Image quality favored cSLO in 71 eyes. CONCLUSION: FAF images were highly correlated between the FC and cSLO. Differences between the two devices revealed contrasts. Multiple image capture and confocal optics yielded higher image contrast with the cSLO, although acquisition and exposure time was longer.

Spontaneous resolution of unilateral vitreomacular traction.

Vitreomacular traction (VMT) caused visual symptoms in two healthy young adults but spontaneously resolved within four weeks without any sequelae. Optical coherence tomography (OCT) and fundus photographs proved vital in documenting the rare complete resolution of VMT. It is prudent to monitor for spontaneous resolution of VMT in young healthy adults.