Rates of diabetic retinopathy among cluster analysis-identified type 2 diabetic mellitus subgroups.

PURPOSE: To determine whether phenotypic clustering of patients with diabetes mellitus (DM) is associated with more advanced diabetic retinopathy (DR). METHODS: Retrospective cohort study of 495 patients with no prior DR treatment seen at a tertiary care clinic 2014-2020. Four previously identified clusters from Ahlqvist's 2018 paper were reproduced utilizing baseline hemoglobin A1c, body mass index, and age at DM diagnosis. Age-adjusted Cox proportional hazard ratios were used to compare clusters with reference as the lowest risk cluster. RESULTS: All four type 2 DM clusters were replicated with our cohort. There was a significant difference in racial distribution among clusters (p = 0.018) with severe insulin-resistant diabetes (SIRD) having the higher percentage of Caucasians and lower percentage of Hispanics compared to other groups and a higher percentage of African Americans comprising the severe insulin-deficient diabetes (SIDD) cluster than other groups. Rates of proliferative diabetic retinopathy were higher in mild obesity-related diabetes (MOD) (28%), SIDD (24%), mild age-related diabetes (MARD) (20%), and lowest in SIRD (7.9%), overall p = 0.004. Rates of vitreous hemorrhage were higher in MOD (p = 0.032) and MARD (0.005) compared to SIRD. CONCLUSION: Baseline clinical measures may be useful in risk stratifying patients for progression to retinopathy requiring intervention.

Outcomes of chronic macula-off retinal detachment repair.

PURPOSE: There have been disparate outcomes in the few studies that have looked at anatomic success and visual acuity (VA) in chronic retinal rhegmatogenous detachment (RRD) repair. Chronic retinal detachments (RD) without a posterior vitreous detachment (PVD) occur in young myopes often secondary to an atrophic hole. These patients are often asymptomatic, and studies report good surgical anatomic results. However, chronic RD with a PVD is symptomatic but presents late due to patient compliance. This paper aims to evaluate this lesser-studied chronic macula-off RD with PVD. METHODS: After obtaining Institutional Review Board (IRB) approval, patients who had undergone surgical intervention for all diagnosis codes of RD were identified in the Denver Health Medical Center database. Medical records were reviewed, and patients found to have open-globe injuries, tractional RD due to proliferative diabetic retinopathy, macula-on detachments, and RD due to previous ocular surgery were excluded. Similarly, patients without PVD were also excluded. A total of 37 patients with PVD-type chronic macula-off RD were thus identified and preoperative characteristics, surgical intervention, and complications were analyzed. RESULTS: The average patient age was 53.8 years. The length of RRD duration ranged from 30 to 365 days (mean 136.7 days). Twenty-six (70.3% patients had proliferative vitreoretinopathy (PVR) grade C or greater. Initial anatomic success-defined as re-attachment after one surgery-was 54.1%. The final attachment was 94.6%. Fifteen of 37 (40.5%) of the patients had issues with drop adherence, positioning, or missing post-operative appointments. CONCLUSION: Chronic macula-off RD with a PVD should be identified as it is associated with much lower rates of initial re-attachment. Socioeconomic factors likely are the driving factor for patients with PVD-type chronic macula-off RD to present late, struggle with positioning, and have difficulty with follow-up and drop compliance. These extended periods without treatment then lead to high rates of PVR and poor initial anatomic success. However, repair of PVD-type chronic macula-off RD should still be pursued as final anatomic success is high.

Mental health and visual acuity in patients with age-related macular degeneration.

BACKGROUND: Visual acuity (VA) loss has been associated with depression in patients with age-related macular degeneration (AMD). However, previous studies did not incorporate subgroups of AMD when correlating VA and mental health. The goal of this study was to describe the relationship between VA and mental health questions in patients with different classifications of AMD, and to identify associations of mental health subscale scores. METHODS: AMD patients classified by multi-modal imaging were recruited into an AMD registry. Habitual VA was obtained by ophthalmic technicians using the Snellen VA at distance. At enrollment, patients completed the NEI-VFQ-25, which includes 25 questions regarding the patient's visual functionality. Median with interquartile-range (IQR) scores on the mental health subscale of the VFQ were calculated by AMD classification and VA groups. Univariate and multivariable general linear models were used to estimate associations between mental health scores and variables of interest. RESULTS: Eight hundred seventy-five patients were included in the study. Patients with bilateral geographic atrophy (GA) or bilateral GA and neovascular (NV) AMD scored lowest on the mental health subscales with a median (IQR) of 58.2 (38-88) and 59.3 (38-88). When stratified by VA, patients with a habitual VA of 20/200 or worse scored the lowest on mental health subscales scores: median of 43.8 (IQR: 31-62). Patients with a VA of 20/20 scored the highest: 87.5 (IQR: 81-94). Habitual VA of the better- and worse-seeing eye and AMD classification were significantly associated with mental health subscale scores (all p < 0.0001 in both the univariate and multivariable analysis, except the VA of the worse-seeing eye in multivariable model p = 0.027). Patients enrolled during the COVID pandemic had mental health scores that were 2.7 points lower than prior to the pandemic, but this difference was not significant in univariate (p = 0.300) or multivariable analysis (p = 0.202). CONCLUSION: There is a significant association between mental health questionnaire scores and AMD classification, as well as VA in both the better and worse-seeing eyes in patients with AMD. It is important for clinicians to recognize feelings of worry/ frustration in these patients, so they can be appropriately referred, screened, and treated for mental health problems.

Vitreous protein binding with nanopore dialysis membrane device.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the industrialized world, affecting over 8 million patients in the United State alone. While the wet (exudative) form of the disease is treated with intraocular injections, there are currently no approved therapies available for the dry (non-exudative) form of the disease which often affects both eyes in patients with AMD. Current research has focused on developing drugs that can be injected into the eye, but the treatment burden associated with monthly injections limits the effectiveness of this approach. Hence, there is a pressing need for a long-term therapeutic solution for patients suffering from this blinding disease. We detail a novel implantable intraocular device, which adsorbs and traps complement factors associated with AMD. In this study, we tested a novel approach by dialyzing proteins from the vitreous using biocompatible implants composed of a nanopore polyacrylonitrile polymer membrane. Preliminary in vitro and in vivo studies demonstrate a high affinity and capacity for complement protein absorption. After a three-month implantation in New Zealand White Cross rabbits, the implant demonstrated good biocompatibility with no inflammation and normal retinal physiology and histology. These studies demonstrate that prolonged CF suppression intraocularly may be accomplished with a nanopore polymer membrane.

Comparison of vitreoretinal disorders in fellow eyes of lamellar macular holes versus epiretinal membrane foveoschisis.

PURPOSE: To evaluate and compare the rate and characteristics of vitreoretinal disorders in fellow eyes of lamellar macular holes (LMH) versus epiretinal membrane foveoschisis (ERMF). METHODS: Included patients in this retrospective study were divided into two groups based on spectral-domain optical coherence tomography (SD-OCT) features of their primary eye: LMH (group A) and ERMF (group B). RESULTS: Ninety-four patients were enrolled: 59 (62.8%) in group A and 35 (37.2%) in group B. Fellow eyes in group A had a higher rate of retinal detachment (8/59 [13.6%] vs. 0/35 [0%], P = 0.024), and full-thickness macular hole (FTMH) (11/59 [18.6%] vs. 2/35 [5.7%], P = 0.079), compared with fellow eyes in group B. In group A, 4/59 patients (6.8%) showed a bilateral LMH while none from group B had a LMH in their fellow eye (0/35 [0%]), P = 0.293. Additionally, epiretinal proliferation was noted in 30/59 (50.8%) fellow eyes in group A versus 3/35 (8.6%) fellow eyes in group B, P < 0.001. Longitudinal data were available for 80/94 patients. Over a mean follow-up of 37.4 ± 29.9 months, 1/48 (2.1%) fellow eyes from group A developed a FTMH and 2/48 (4.2%) developed a LMH, while no FTMH or LMH occurred in fellow eyes of group B. CONCLUSIONS: Fellow eyes of LMH showed a high rate of macular and peripheral vitreoretinal disorders. In addition, epiretinal proliferation was detected in a higher number of fellow eyes of LMH versus ERMF. These findings suggest a bilateral process in eyes of patients with LMH.

INCREASED COMPLEMENT LEVELS IN HUMAN VITREOUS ASPIRATES OF PROLIFERATIVE DIABETIC RETINOPATHY AND RETINAL DETACHMENT EYES.

PURPOSE: To evaluate levels of complement factors in human vitreous of eyes with retinal detachments (RDs) and proliferative diabetic retinopathy (PDR) eyes. METHODS: Human vitreous samples were collected from eyes undergoing routine vitrectomy at the University of Colorado Health Eye Center (Aurora, CO). Complement factor D, component C5/C5a, and component C9 levels were measured using enzyme-linked immunosorbent assay and multiplex assays. Retinal detachment and PDR eyes were compared with controls, which were defined as eyes with macular holes or epiretinal membranes. RESULTS: The levels of complement factor D in PDR (mean = 2,110.0 ng/mL, P = 0.001) and RD (mean = 660.9 ng/mL, P = 0.03) eyes were statistically significantly higher than controls (mean = 290.5 ng/mL). The levels of complement component C9 were also more elevated in PDR (P = 0.004) compared with control but not in RD eyes. CONCLUSION: Elevated complement factors, particularly of the alternative pathway, were noted in PDR and RD eyes compared with controls. One potential explanation for this is that the oxidative stress in RD and PDR eyes leads to complement dysregulation and alternative complement upregulation.

Metabolomics Analysis of Human Vitreous in Diabetic Retinopathy and Rhegmatogenous Retinal Detachment.

The vitreous humor is a highly aqueous eye fluid interfacing with the retina and lens and providing shape. Its molecular composition provides a readout for the eye's physiological status. Changes in cellular metabolism underlie vitreoretinal pathologies, but despite routine surgical collection of vitreous, only limited reports of metabolism in the vitreous of human patients have been described. Vitreous samples from patients with rhegmatogenous retinal detachment ( n = 25) and proliferative diabetic retinopathy ( n = 9) were profiled along with control human vitreous samples ( n = 8) by untargeted mass-spectrometry-based metabolomics. Profound changes were observed in diabetic retinopathy vitreous, including altered glucose metabolism and activation of the pentose phosphate pathway, which provides reducing equivalents to counter oxidative stress. In addition, purine metabolism was altered in diabetic retinopathy, with decreased xanthine and elevated levels of related purines (inosine, hypoxanthine, urate, allantoate) generated in oxidant-producing reactions. In contrast, the vitreous metabolite profiles of retinal detachment patients were similar to controls. In total, our results suggest a rewiring of vitreous metabolism in diabetic retinopathy that underlies disease features such as oxidative stress and furthermore illustrates how the vitreous metabolic profile may be impacted by disease.

IQGAP1: a regulator of intracellular spacetime relativity.

Activating and inhibiting receptors of lymphocytes collect valuable information about their mikròs kósmos. This information is essential to initiate or to turn off complex signaling pathways. Irrespective of these advances, our knowledge on how these intracellular activation cascades are coordinated in a spatiotemporal manner is far from complete. Among multiple explanations, the scaffolding proteins have emerged as a critical piece of this evolutionary tangram. Among many, IQGAP1 is one of the essential scaffolding proteins that coordinate multiple signaling pathways. IQGAP1 possesses multiple protein interaction motifs to achieve its scaffolding functions. Using these domains, IQGAP1 has been shown to regulate a number of essential cellular events. This includes actin polymerization, tubulin multimerization, microtubule organizing center formation, calcium/calmodulin signaling, Pak/Raf/Mek1/2-mediated Erk1/2 activation, formation of maestrosome, E-cadherin, and CD44-mediated signaling and glycogen synthase kinase-3/adenomatous polyposis coli-mediated ß-catenin activation. In this review, we summarize the recent developments and exciting new findings of cellular functions of IQGAP1.

Healthcare Resource Utilization and Costs in an At-Risk Population With Diabetic Retinopathy.

Purpose: Several investigators have suggested the cost-effectiveness of earlier screening, management of risk factors, and early treatment for diabetic retinopathy (DR). We aimed to evaluate the extent of health care utilization and cost of delayed care by insurance type in a vulnerable patient population. Methods: A retrospective analysis of patients with DR was conducted using electronic medical record (EMR) data from January 2014 to December 2020 at Denver Health Medical Center, a safety net institution. Patients were classified by disease severity and insurance status. DR-specific costs were assessed via Current Procedural Terminology (CPT) codes over a 24-month follow-up period. Results: Among the 313 patients, a higher proportion of non-English speaking patients were uninsured. Rates of proliferative DR at presentation differed across insurance groups (62% of uninsured, 42% of discount plan, and 33% of Medicare/Medicaid, P = 0.016). There was a significant difference in the total median cost between discount plan patients ($1258, interquartile range [IQR] = $0 - $5901) and both Medicare patients ($751, IQR = $0, $7148, P = 0.037) and Medicaid patients ($593, IQR = $0 - $6299, P = 0.025). Conclusions: There were higher rates of proliferative DR at presentation among the uninsured and discount plan patients and greater total median cost in discount plan patients compared to Medicare or Medicaid. These findings prioritize mitigating gaps in insurance coverage and barriers to preventative care among vulnerable populations. Translational Relevance: Advanced diabetic disease and increased downstream health care utilization and cost vary across insurance type, suggesting improved access to preventative care is needed in these specific at-risk populations.

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.

Differences in imaging biomarkers between patients with intermediate and advanced non-neovascular age-related macular degeneration (AMD) in the University of Colorado AMD registry.

PURPOSE: To quantify and compare the different prevalence rates of specific retinal imaging biomarkers in patients with intermediate AMD (iAMD) and advanced non-neovascular AMD (nnAMD). METHODS: Cross-sectional study of patients with iAMD and advanced nnAMD. Imaging studies were reviewed for qualitative imaging biomarkers. Choroidal thickness measurements were obtained subfoveally and in 1000 um and 2000 um intervals away from the fovea. The Chi-squared test and Fisher's exact test were used to compare rates of imaging biomarkers among the two cohorts. P-value of <0.05 was considered significant. RESULTS: 376 eyes of 197 patients with iAMD and 187 eyes of 97 patients with advanced nnAMD were recruited. There were significantly lower rates of the following imaging biomarkers in the iAMD compared with the advanced nnAMD cohorts: soft drusen (66.0% vs. 84.2%, p = 0.001), calcified drusen (4.3% vs. 40.0%, p < 0.0001), RPD (26.2% vs. 53.3%, p < 0.0001), ORT (0.5% vs. 46.9%, p < 0.0001), RP (1.1% vs. 46.3%, p < 0.0001), pigment migration (53.2% vs. 100%, p < 0.0001), and iRORA (17.9% vs. 80.2%, p < 0.0001). In the iAMD cohort, choroidal thickness was significantly greater at 188 µm (SD: 60) and 194 µm (SD: 69), compared to the advanced nnAMD with measurements of 153 µm (SD: 68), and 161 µm (SD: 76). This difference was statistically significant (p < 0.0001 and p = 0.0002). CONCLUSIONS: Our results highlight significant differences in imaging biomarkers between both cohorts. Key biomarkers, such as iRORA, RPD, pigment migration, and thinner choroidal thickness, were associated with advanced nnAMD. Identifying these biomarkers early may help target patients who could benefit from new treatments, potentially delaying vision loss.

Association Between Quantitative and Qualitative Imaging Biomarkers and Geographic Atrophy Growth Rate.

PURPOSE: Investigate associations between geographic atrophy (GA) growth rate and multimodal imaging biomarkers and patient demographics in patients with advanced non-neovascular age-related macular degeneration (nnAMD). DESIGN: Prospective cohort study. METHODS: One hundred twenty-one eyes of 66 patients with advanced nnAMD with GA enrolled in the University of Colorado AMD Registry from August 2014 to June 2021, with follow-up through June 2023. Multimodal images were reviewed by two graders for imaging biomarkers at enrollment. GA growth rate and square-root transformed (SQRT) GA growth rate were measured between enrollment and final visit. Associations between the outcome SQRT GA growth rate and imaging biomarkers, baseline GA lesions characteristics, and patient demographics were evaluated. RESULTS: Average GA growth rate was 1.430 mm2/year and SQRT GA growth rate was 0.268 mm/year over a mean of 3.7 years. SQRT GA growth rate was positively associated with patient age (P = .010) and female sex (0.035), and negatively associated with body mass index (0.041). After adjustment for these demographic factors, SQRT GA growth rate was positively associated with presence of non-exudative subretinal fluid (P < .001), non-exudative subretinal hyperreflective material (P = .037), and incomplete retinal pigment epithelium and outer retina atrophy (P = .022), and negatively associated with subfoveal choroidal thickness (P = .031) and presence of retinal pseudocysts (P = .030). Larger baseline GA size at enrollment was associated with faster GA growth rate (P = .002) but not SQRT GA growth rate. CONCLUSIONS: Select patient demographic factors and basic clinically-relevant imaging biomarkers were associated with GA growth rate. These biomarkers may guide patient selection when considering treating GA patients with novel therapeutics.

Risk Factors and Outcomes of Delayed Presentation of Diabetic Retinopathy Patients to a County Hospital.

Purpose: To identify risk factors and evaluate outcomes of patients with delayed presentation and advanced diabetic retinopathy in our safety-net county hospital population. Methods: A retrospective study was performed on 562 patients who presented with a new diagnosis of diabetic retinopathy (DR). Delayed presentation was defined as moderate or severe nonproliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) at the initial visit. Comparisons between patient groups were performed with chi-square or Fisher's exact test for categorical variables and multinomial logistic regression for multivariable analysis. Linear and logistic regression modeling with general estimating equations to account for patients having two eyes was used to compare eye-level outcomes. Results: Lack of a primary care provider (PCP) was highest in patients who presented initially with PDR (28.8%), compared to 14.3% in moderate/severe NPDR, 12.4% in mild NPDR, and 7.6% in no DR groups (P < 0.001). Only 69.4% of patients with a PCP had an ophthalmology screening referral. Highest lack of referral (47.2%) was seen in the PDR group (P = 0.002). Patients with PDR were more likely to be uninsured (19.2%) compared to no and mild DR groups, with rates of 7.6% and 9.0%, respectively (P = 0.001). The PDR group had worse initial and final visual acuities (P < 0.001). Conclusions: Several risk factors were noted for delayed DR presentation, including lack of PCP, lack of screening referral, and uninsured/underinsured status. Patients with advanced DR at presentation had worse final visual outcomes despite aggressive treatment. Translational Relevance: Screening programs targeting populations with identified risk factors are essential for improving outcomes.

RANTES (CCL5) in Patients With Geographic Atrophy Age-Related Macular Degeneration.

Purpose: A previous study from our research group showed significantly lower levels of RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in patients with intermediate age-related macular degeneration (AMD) compared to control patients with no AMD. The primary aim of this study was to assess levels of RANTES in a cohort of patients with a more advanced form of the disease, geographic atrophy (GA), in comparison with controls. Methods: The study was conducted on a cohort of patients with GA recruited into a Colorado AMD registry. Cases and controls were defined with multimodal imaging. Plasma levels of the chemokine RANTES were measured using a multiplex assay. A nonparametric (rank-based) regression model was fit to RANTES with a sex by AMD category interaction. Results: The plasma levels of RANTES were significantly higher in the control group in comparison to the GA AMD group (median [interquartile range]): 10,204 [5799-19,554] pg/mL vs. 5435 [3420-9177] pg/mL, respectively, P < 0.01). When moderated by sex, there was no statistical difference between the male and female GA AMD or the male and female controls. Conclusions: We found lower level of RANTES in patients with GA AMD compared with controls. This finding is consistent with the findings from our previous intermediate AMD study. However, in contrast to the results of our previous research, when moderated by sex there was no statistical difference between male and female GA patients. Translational Relevance: The biomarker RANTES is significantly lower in GA AMD patients compared to controls.

Limited English Proficiency Is Associated With Diabetic Retinopathy in Patients Presenting for Cataract Surgery.

Purpose: To investigate the relationship between limited English proficiency (LEP) and diabetic retinopathy (DR) in patients presenting for cataract surgery. Methods: This is a retrospective observational study of patients who underwent cataract surgery between January 2014 and February 2020. Patients who self-identified as needing or preferring an interpreter were defined as having LEP. Differences in demographics, characteristics, and outcomes including history of type 2 diabetes (T2DM), DR, preoperative best corrected visual acuity (BCVA), macular edema, and anti-vascular endothelial growth factor injections were analyzed. Statistical comparisons were assessed using logistic regression with generalized estimating equations. Results: We included 13,590 eyes. Of these, 868 (6.4%) were from LEP patients. Patients with LEP were more likely to be Hispanic (P < 0.001), female sex (P = 0.008), or older age (P = 0.003) and have worse mean BCVA at presentation (P < 0.001). Patients with LEP had a significantly higher rate of T2DM (P < 0.001), macular edema (P = 0.033), and DR (18.1% vs. 5.8%, P < 0.001). Findings remained significant when controlling for age, sex, race/ethnicity, and type of health insurance. Patients with LEP and DR were more likely to have had later stages of DR (P = 0.023). Conclusions: Patients with LEP presenting for cataract surgery had a higher rate of DR and associated complications compared to patients with English proficiency. Further studies are needed to understand how language disparities influence health and what measures could be taken to improve healthcare in this vulnerable population. Translational Relevance: Our study highlights healthcare disparities within ophthalmology and emphasizes the importance of advocating for improved healthcare delivery for patients with LEP.

Interleukin-4 Plasma Levels Stratified by Sex in Intermediate Age-Related Macular Degeneration and Geographic Atrophy.

Purpose: Chronic local inflammation underlies the pathogenesis of age-related macular degeneration (AMD) causing damage to the neurosensory retina. However, there is minimal research on systemic cell-mediated inflammation in AMD. Interleukin-4 (IL-4) is an immunoregulatory cytokine with an important role in modulating inflammation in chronic immune mediated disease. The purpose of this study was to: (1) investigate the role of systemic IL-4 in patients with intermediate AMD (iAMD) and in geographic atrophy (GA), an advanced form of AMD, compared to controls without AMD, and (2) determine if IL-4 levels are moderated by sex. Methods: We examined plasma levels of IL-4 in patients with iAMD, GA, and controls without AMD included in the University of Colorado AMD registry (August 2014 to June 2021). Cases and controls were defined by multimodal imaging. IL-4 was measured by multiplex immunoassay. Data were analyzed using a nonparametric rank based linear regression model fit to IL-4. Results: There were 199 patients with iAMD, 97 patients with GA, and 139 controls, with a percentage of female patients 61%, 55%, and 66%, respectively. We demonstrated significantly higher median IL-4 levels in GA (35.3; interquartile range [IQR] = 22.8-50.5) compared to iAMD (6.1; IQR = 2.2-11.3, P < 0.01) and controls (10.7; IQR = 5.0-16.8, P < 0.01). There were no significant differences in levels of IL-4 for cases and controls when stratified by sex. Conclusions: These findings demonstrate a systemic immunological difference between iAMD and GA, indicating IL-4 may be a systemic biomarker for GA development. Translational Relevance: The plasma biomarker IL-4 is significantly elevated in patients with GA.

SPONTANEOUS LAMELLAR MACULAR HOLES CLOSURE.

PURPOSE: To report two cases of spontaneous closure of lamellar macular holes with epiretinal proliferation (ERP). METHODS: Observational cases report. RESULTS: Two patients affected with lamellar macular hole showed progressive and spontaneous closure of the hole associated with ERP development. At presentation, both patients presented with irregular foveal contour, and foveal cavitation with apparent loss of retinal tissue. In both cases, ERP, also called "lamellar hole-associated epiretinal proliferation", was present and increased in size over time. This proliferation progressively developed across the hole with apparent restoration of the foveal contour and preservation of visual acuity. CONCLUSION: This report describes two cases of lamellar macular hole in which ERP increased over time, resulting in lamellar macular hole closure. Such observations may suggest a spontaneous healing process driven by glial cell proliferation.

Gender Differences in Visual Functioning Questionnaire Scores among Patients with Age-Related Macular Degeneration.

PURPOSE: To examine gender differences in visual functioning using the National Eye Institute Visual Functioning Questionnaire-25 (VFQ-25) in a Colorado cohort of patients with age-related macular degeneration (AMD). METHODS: A retrospective cohort study was conducted using a registry of AMD patients who attended the Sue Anschutz-Rodgers Eye Center (2014 to 2019). Demographic, clinical, and image data were collected, and AMD was categorized as Early/Intermediate AMD, or unilateral/bilateral neovascular (NV) AMD, geographic atrophy (GA), or Both Advanced using the Beckman Classification. Each patient completed the VFQ-25, which evaluates visual functioning, generating a composite score and subscale scores for vision-specific activities. Univariate and multivariable general linear models were used to estimate the associations between gender and VFQ-25 scores with parameter estimates (PE) and standard errors (SE). RESULTS: Among 739 patients with AMD, 294 (39.8%), 115 (15.6%), 168 (22.7%), and 162 (21.9%) were diagnosed with Early/Intermediate AMD, GA, NV AMD, and Both Advanced, respectively. Adjusted for AMD classification, age and habitual visual acuity in the better-seeing and worse-seeing eyes, female gender was not significantly associated with lower composite VFQ-25 scores (PE (SE): -1.2 (0.9), p = .193), and was significantly associated with reportedly worse ocular pain and driving subscale scores (PE (SE): -4.6 (1.0), p < .0001 and -9.1 (2.1), p < .0001, respectively). CONCLUSION: Gender plays a role in reported driving activities and ocular pain among patients with AMD. This may need to be accounted for in future research related to the use of VFQ-25 for AMD.

Clinical and Morphologic Characteristics of Perivenular Fernlike Leakage on Ultrawide-field Fluorescein Angiography.

PURPOSE: To analyze the spectrum of the perivenular fernlike leakage on ultrawide-field fluorescein angiography (UWFA) and discuss its potential implications in the current understanding of the retinal venous outflow. DESIGN: Retrospective, observational case series. PARTICIPANTS: Eyes presenting with fernlike patterns of dye leakage on UWFA were included in this study. METHODS: Analysis of the clinical characteristics and multimodal imaging findings using UWFA and wide-angle swept-source OCT-angiography (SS-OCTA). MAIN OUTCOME MEASURES: The disease spectrum, anatomic origin, and clinical implications of this fernlike leakage. RESULTS: Multimodal retinal images from 40 eyes of 29 patients with fernlike leakage on UWFA were studied. The underlying etiologies included a wide range of inflammatory disorders, including pars planitis (18 eyes) and central retinal vein occlusion (2 eyes). On UWFA, the fernlike leakage originated from the retinal capillaries and venules directly adjacent to the veins and spared the periarterial zone. This perivenular fernlike leakage involved the far periphery in all cases and progressed more diffusely and centripetally in cases with more severe intraocular inflammation. On wide-angle SS-OCTA, the impairment of deep capillary plexus (DCP) flow signals precisely colocalized with the perivenular fernlike leakages identified on UWFA. CONCLUSIONS: The fernlike leakage on UWFA refers to the distinctive perivenular dye leakage that originates from the retinal capillaries and venules. Multimodal imaging correlation suggests that the predominant impairment is at the level of the DCP. The axial symmetry of the fernlike leakage with the veins and sparing of the periarterial zone may support the dominant venous role of the DCP.