Glucose tolerance and insulin resistance/sensitivity associate with retinal layer characteristics: the LIFE-Adult-Study.

AIMS/HYPOTHESIS: As the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset. METHODS: The LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA1c 5.7-6.4% [39-47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings. RESULTS: In the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised ß=-0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; ß=-0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (ß=0.090; p<0.001 for eGDR) and MZ (ß=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis. CONCLUSIONS/INTERPRETATION: An impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes.

Vision-related quality of life is selectively affected by comorbidities in patients with geographic atrophy.

BACKGROUND: The atrophic late stage of age-related macular degeneration (AMD) is termed geographic atrophy (GA), and affects visual acuity (VA) as well as quality of life (QoL). Previous studies have found that best-corrected VA (BCVA), the standard vision assessment often underrepresents functional deficits. Therefore, the purpose of this study was to evaluate the correlation between atrophic lesion size, VA and QoL measured with the National Eye Institute Visual Function Questionnaire (VFQ-39) in a Danish population. Moreover, we wanted to evaluate the correlation between comorbidities, behavioural factors, and QoL. METHODS: This was prospective clinical study of 51 patients with GA in one or both eyes, of these 45 patients had bilateral GA. Patients were consecutively included between April 2021 and February 2022. All patients filled in the VFQ-39 questionnaire except the subscales "ocular pain" and "peripheral vision." Lesion size was measured from fundus autoflourescense images, and BCVA was assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. RESULTS: We found an overall low score in each VFQ-39 subscale scores reflected by GA. Lesion size and VA were both significantly associated with all VFQ-39 subscale scores except for "general health." VA showed a larger effect on QoL than lesion size. Chronic obstructive pulmonary disease (COPD) was associated with a lower score in the subscale score "general health" but none of the other subscale scores were affected. Cardiovascular disease (CVD) was associated with a lower BCVA as well as in QoL reflected in the subscale scores "poor general vision," "near activities," and "dependency" of VFQ-39. CONCLUSION: Both atrophic lesion size and visual acuity affects QoL in Danish patients with GA, who reports an overall poor QoL. CVD seems to have a negative effect on disease, as well as in VFQ-39 in several subscales, whereas COPD did not affect disease severity or vision-related subscales in VFQ-39.

Evaluation of retinal vascular density and related factors using OCTA in children and adolescents with myopia without maculopathy.

BACKGROUND: Myopia is the most common ophthalmic condition worldwide with a rapidly increasing prevalence. This study aimed to compare the retinal microvasculature in the superficial capillary plexus (SCP) in children and adolescents with mild and moderate/high myopia using optical coherence tomography angiography, determine the relationship between retinal parameters and axial length (AL), and understand the occurrence and progression of myopia in microcirculation. METHODS: This prospective observational study included 39 participants with mild myopia and 33 participants with moderate/high myopia. Vessel density (VD) and perfusion density (PD) in the SCP, the foveal avascular zone (FAZ), and AL were compared between the groups and the relationship between these retinal parameters and AL was assessed. RESULTS: No difference in SCP VD or PD was observed between the two groups. The FAZ did not differ significantly between groups whereas significant differences in age, height, refractive status, and AL were observed. Significantly shorter AL was observed in participants with mild myopia compared with the moderate/high myopia group. Age was positively correlated with height (r = 0.852) and refractive status was negatively correlated with AL (r = -0.588). AL was positively correlated with VD (r = 0.317) and PD (r = 0.308) in the SCP and AL was negatively correlated with the FAZ (r = -0.434). CONCLUSIONS: This study revealed that superficial foveal microvessel density was unaffected in children and adolescents without pathological myopia. However, myopia progression was associated with a change in AL, and an AL increase altered macular blood flow.

Phase 1 Clinical Trial of Elamipretide in Dry Age-Related Macular Degeneration and Noncentral Geographic Atrophy: ReCLAIM NCGA Study.

Purpose: Assess the safety, tolerability, and feasibility of subcutaneous administration of the mitochondrial-targeted drug elamipretide in patients with dry age-related macular degeneration (AMD) and noncentral geographic atrophy (NCGA) and to perform exploratory analyses of change in visual function. Design: Phase 1, single-center, open-label, 24-week clinical trial with preplanned NCGA cohort. Participants: Adults ≥ 55 years of age with dry AMD and NCGA. Methods: Participants received subcutaneous elamipretide 40-mg daily; safety and tolerability assessed throughout. Ocular assessments included normal-luminance best-corrected visual acuity (BCVA), low-luminance BCVA (LLBCVA), normal-luminance binocular reading acuity (NLBRA), low-luminance binocular reading acuity (LLBRA), spectral-domain OCT, fundus autofluorescence (FAF), and patient self-reported function by low-luminance questionnaire (LLQ). Main Outcome Measures: Primary end point was safety and tolerability. Prespecified exploratory end-points included changes in BCVA, LLBCVA, NLBRA, LLBRA, geographic atrophy (GA) area, and LLQ. Results: Subcutaneous elamipretide was highly feasible. All participants (n = 19) experienced 1 or more nonocular adverse events (AEs), but all AEs were either mild (73.7%) or moderate (26.3%); no serious AEs were noted. Two participants exited the study because of AEs (conversion to neovascular AMD, n = 1; intolerable injection site reaction, n = 1), 1 participant discontinued because of self-perceived lack of efficacy, and 1 participant chose not to continue with study visits. Among participants completing the study (n = 15), mean ± standard deviation (SD) change in BCVA from baseline to week 24 was +4.6 (5.1) letters (P = 0.0032), while mean change (SD) in LLBCVA was +5.4 ± 7.9 letters (P = 0.0245). Although minimal change in NLBRA occurred, mean ± SD change in LLBCVA was -0.52 ± 0.75 logarithm of the minimum angle of resolution units (P = 0.005). Mean ± SD change in GA area (square root transformation) from baseline to week 24 was 0.14 ± 0.08 mm by FAF and 0.13 ± 0.14 mm by OCT. Improvement was observed in LLQ for dim light reading and general dim light vision. Conclusions: Elamipretide seems to be well tolerated without serious AEs in patients with dry AMD and NCGA. Exploratory analyses demonstrated possible positive effect on visual function, particularly under low luminance. A Phase 2b trial is underway to evaluate elamipretide further in dry AMD and NCGA.

Retinal and Choroidal Changes in Men Compared with Women with Alzheimer's Disease: A Case-Control Study.

Purpose: To evaluate differences in the retinal microvasculature and structure and choroidal structure among men and women with Alzheimer's disease (AD) compared with age-matched cognitively normal male and female controls. Design: Case-control study of participants ≥ 50 years of age. Participants: A total of 202 eyes of 139 subjects (101 cases and 101 controls). Methods: All participants and controls underwent OCT and OCT angiography (OCTA), and parameters of subjects with AD were compared with those of cognitively normal controls. Main Outcome Measures: The foveal avascular zone (FAZ) area, vessel density (VD), and perfusion density (PD) in the superficial capillary plexus within the 3- and 6-mm circle and ring using Early Treatment Diabetic Retinopathy Study (ETDRS) grid overlay on OCTA; central subfield thickness (CST), retinal nerve fiber layer (RNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, and choroidal vascularity index (CVI) on OCT. Results: No significant sex differences in VD or PD were found in the AD or control cohorts; however, there were greater differences in VD and PD among AD female participants than AD male participants compared with their respective controls. The CST and FAZ area were not different between male and female AD participants. Among controls, men had a thicker CST (P < 0.001) and smaller FAZ area (P = 0.003) compared with women. The RNFL thickness, GCIPL thickness, and CVI were similar among male and female AD participants and controls. Conclusions: There may be a loss of the physiologic sex-related differences in retinal structure and microvasculature in those with AD compared with controls. Further studies are needed to elucidate the pathophysiological basis for these findings.

YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale.

Purpose: Faricimab is a novel anti-angiopoietin-2 and anti-vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME. Design: Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE). Participants: Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus. Methods: These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden. Main Outcome Measures: We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab. Results: YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately. Conclusions: YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.

Equivalent legibility font size for traditional Chinese character compared to early treatment diabetic retinopathy study near visual acuity.

PURPOSES: To investigate the legibility of a standardized logarithmic print size of traditional Chinese (TC) characters and compare it with Early Treatment Diabetic Retinopathy Study (ETDRS) near chart. MATERIALS AND METHODS: A total of 1243 commonly used TC characters were chosen and divided into three groups according to its stroke complexity: Group A with 2-9 strokes, Group B with 10-17 strokes, and Group C with 18-25 strokes. For each group of characters, near charts were created using randomly chosen characters arranged in decreasing logarithmic size. In a well-illuminated room, healthy controls were fully corrected to test both ETDRS near chart and our set of TC near charts. The smallest legible font sizes (SLFS) in TC near charts were recorded and analyzed. RESULTS: Forty-two healthy eyes (21 participants) (age 29 ± 8.9 years old) were included. The mean near best-corrected visual acuity (nBCVA) in ETDRS chart was 0.06 ± 0.05 logMAR. We found that the mean SLFS in TC charts (0.33 ± 0.09 logMAR) was significantly larger than the nBCVA in ETDRS chart (P < 0.001). The SLFS of Group B and the SLFS of Group C was significantly larger than that of Group A (P < 0.001). CONCLUSION: According to our results, to recognize TC characters, normal-sight readers need a 0.22-0.30 logMAR (1.7-2.0 fold) enlargement of the acuity size measured by ETDRS near chart. The low-stroke TC charts may provide a new method to assess the postsurgical outcomes for comparable functional visual acuity in reading TC characters.

Comparison of different methods of retinal imaging for the screening of diabetic retinopathy: a systematic review.

BACKGROUND: Screening for diabetic retinopathy (DR) is recommended to detect sight-threatening complications prior to visual loss. Early Treatment Diabetic Retinopathy Study (ETDRS) seven standard field (7SF) retinal imaging has traditionally been regarded the gold standard for DR classification, but other methods are often preferred clinically. The purpose of this systematic review was to determine whether 7SF is the most optimal screening method for DR grading, or if similar results can be achieved by other methods using a smaller field of view (<7SF) or ultra-wide field (UWF) imaging. METHODS: Based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, two independent reviewers initially identified 7167 publications in PubMed, Cochrane and Embase databases. Of these, 16 publications were included based on predefined inclusion criteria. RESULTS: 7SF was used as reference standard in 12 studies (compared with < 7SF in five studies and UWF in seven studies), and four studies compared other reference standards. Compared to 7SF, studies using < 7SF and UWF images both reported of similar agreement. A lower rate of ungradable images was reported for mydriatic and non-mydriatic UWF as compared to non-mydriatic < 7SF modalities. CONCLUSION: Retinal imaging of <7SF and UWF both provide acceptable performance compared to 7SF. Given the time-consuming nature of the latter, these methods could be reasonable options in DR screening, even though a high number of ungradable images in non-mydriatic < 7SF may pose a clinical challenge.

Evolving Treatment Patterns and Outcomes of Neovascular Age-Related Macular Degeneration Over a Decade.

PURPOSE: Management of neovascular age-related macular degeneration (nAMD) has evolved over the last decade with several treatment regimens and medications. This study describes the treatment patterns and visual outcomes over 10 years in a large cohort of patients. DESIGN: Retrospective analysis of electronic health records from 27 National Health Service secondary care healthcare providers in the UK. PARTICIPANTS: Treatment-naïve patients receiving at least 3 intravitreal anti-vascular endothelial growth factor (VEGF) injections for nAMD in their first 6 months of follow-up were included. Patients with missing data for age or gender and those aged less than 55 years were excluded. METHODS: Eyes with at least 3 years of follow-up were grouped by years of treatment initiation, and 3-year outcomes were compared between the groups. Data were generated during routine clinical care between September 2008 and December 2018. MAIN OUTCOME MEASURES: Visual acuity (VA), number of injections, and number of visits. RESULTS: A total of 15 810 eyes of 13 705 patients receiving 195 104 injections were included. Visual acuity improved from baseline during the first year, but decreased thereafter, resulting in loss of visual gains. This trend remained consistent throughout the past decade. Although an increasing proportion of eyes remained in the driving standard, this was driven by better presenting VA over the decade. The number of injections decreased substantially between the first and subsequent years, from a mean of 6.25 in year 1 to 3 in year 2 and 2.5 in year 3, without improvement over the decade. In a multivariable regression analysis, final VA improved by 0.24 letters for each year since 2008, and younger age and baseline VA were significantly associated with VA at 3 years. CONCLUSIONS: Our findings show that despite improvement in functional VA over the years, primarily driven by improving baseline VA, patients continue to lose vision after the first year of treatment, with only marginal change over the past decade. The data suggest these results may be related to suboptimal treatment patterns, which have not improved over the years. Rethinking treatment strategies may be warranted, possibly on a national level or through the introduction of longer-acting therapies.

Correlation of macular sensitivity measures and visual acuity to vision-related quality of life in patients with age-related macular degeneration.

BACKGROUND: Visual acuity is commonly used as a functional outcome measure in patients with age-related macular degeneration (AMD), despite having a weak correlation with self-perceived visual quality of life. Microperimetry is a useful method of detecting loss of macular function. We wanted to investigate the relationship between these two objective visual outcome measures and subjective vision-related quality of life, finding out which objective measure is more patient-relevant. METHODS: Fifty-one consecutive patients with AMD were recruited to the study. Participants were required to complete the Visual Function Questionnaire 39, the Early Treatment Diabetic Retinopathy Study visual acuity examination and a microperimetry assessment using the Micro Perimeter 3. One patient withdrew consent and seven patients dropped out due to cooperation difficulties under microperimetry. Forty-three patients with AMD were included in the study: twenty-eight patients with late AMD (exudative AMD) and fifteen patients with early (non-exudative) AMD. The right eye was included as standard, as was the eye with the best-corrected visual acuity. RESULTS: There was a higher correlation between vision-related quality of life and macular sensitivity (r = 0.458; p = 0.014) than between vision-related quality of life and visual acuity (r = 0.446; p = 0.018) in patients with late AMD. There was a positive correlation between vision-related quality of life and macular sensitivity in patients with early AMD (r = 0.542; p = 0.037) while the correlation between vision-related quality of life and visual acuity in these patients was not statistically significant. Composite score (r = 0.469; p = 0.012) correlated highest with the nasal outer macular sub-region and near-distance activities score (r = 0.652; p < 0.001) correlated highest with the nasal inner macular sub-region in patients with late AMD. Correlations between composite score and macular sub-regions in patients with early AMD were not significant, but near-distance activities score correlated with the nasal outer macular sub-region in these patients (r = 0.469; p = 0.012). CONCLUSIONS: Macular sensitivity as measured using microperimetry correlates with vision-related quality of life in early AMD and in late AMD, showing it to be a patient-relevant outcome measure. Furthermore, the nasal sub-regions of the macula appear to be preferred retinal loci in patients with AMD. (338 words).

Shortening the Early Treatment Diabetic Retinopathy Study visual acuity test utilizing a novel computer software: reproducibility in control and patient eyes.

PURPOSE: To describe and compare a method of computerized visual acuity (VA) testing software to the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. METHODS: Setting: Single tertiary institution. STUDY POPULATION: Prospective study including right eyes of volunteers (N = 109) and patients (N = 126). INTERVENTION: Subjects were tested in a random order twice with the ETDRS chart and twice with the VA software. For ETDRS, we calculated the final VA separately for each run, using four different test termination criteria (1-miss in a row, 2-miss in a row, 50% miss and per-letter). For software testing, we calculated final VA with a variety of number of letters presented. MAIN OUTCOME MEASURES: The main outcome measures were reproducibility and number of letters required to exceed ETDRS reproducibility. RESULTS: For ETDRS, the average number of letters presented was 55.1 ± 9, 54.3 ± 10, 53.1 ± 10 and 70 for the 1-miss, 2-miss, 50% termination and per-letter criterion. The test-retest variability (TRV) of ETDRS was 0.29, 0.42, 0.17 and 0.141 for the 1-miss in a row, 2-miss in a row, 50% and per-letter termination criteria. For the software VA test, TRV was 0.202, 0.138 and 0.112 after presenting 6, 11 and 20 letters. The reproducibility of the software was equal to the ETDRS at 11 letters and thereafter surpassed. Similar results were achieved in the patient group. CONCLUSIONS: This study demonstrates that by utilizing a VA testing software, based on advanced threshold testing algorithms we were able to duplicate, and surpass, the reproducibility of the ETDRS chart while presenting much fewer letters.

Macular Vascular Geometry Changes With Sex and Age in Healthy Subjects: A Fundus Photography Study.

Purpose: To characterize the sex- and age-related alterations of the macular vascular geometry in a population of healthy eyes using fundus photography. Methods: A cross-sectional study was conducted with 610 eyes from 305 healthy subjects (136 men, 169 women) who underwent fundus photography examination and was divided into four age groups (G1 with age ≤ 25 years, G2 with age 26-35 years, G3 with age 36-45 years, and G4 with age ≥ 46 years). A self-developed automated retinal vasculature analysis system allowed segmentation and separate multiparametric quantification of the macular vascular network according to the Early Treatment Diabetic Retinopathy Study (ETDRS). Vessel fractal dimension (Df), vessel area rate (VAR), average vessel diameter (Dm), and vessel tortuosity (τn) were acquired and compared between sex and age groups. Results: There was no significant difference between the mean age of male and female subjects (32.706 ± 10.372 and 33.494 ± 10.620, respectively, p > 0.05) and the mean age of both sexes in each age group (p > 0.05). The Df, VAR, and Dm of the inner ring, the Df of the outer ring, and the Df and VAR of the whole macula were significantly greater in men than women (p < 0.001, p < 0.001, p < 0.05, respectively). There was no significant change of τn between males and females (p > 0.05). The Df, VAR, and Dm of the whole macula, the inner and outer rings associated negatively with age (p < 0.001), whereas the τn showed no significant association with age (p > 0.05). Comparison between age groups observed that Df started to decrease from G2 compared with G1 in the inner ring (p < 0.05) and Df, VAR, and Dm all decreased from G3 compared with the younger groups in the whole macula, inner and outer rings (p < 0.05). Conclusion: In the healthy subjects, macular vascular geometric parameters obtained from fundus photography showed that Df, VAR, and Dm are related to sex and age while τn is not. The baseline values of the macular vascular geometry were also acquired for both sexes and all age groups.

Association of Dyslipidemia with Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients: A Hospital-Based Study.

BACKGROUND: Dyslipidemia is an important risk factor that can lead to the progression of retinopathy (DR). Diabetic dyslipidemia with low high-density lipoprotein (HDL) and increased triglycerides (TGs) are seen frequently among Type 2 diabetic mellitus. AIMS AND OBJECTIVES: (1) To assess the level of serum lipids (total cholesterol, TGs, HDL, and low-density lipoprotein [LDL]) among type 2 diabetes patients. (2) To determine the association between serum lipid levels and DR. MATERIALS AND METHODS: This was a hospital-based cross-sectional study conducted in a tertiary care hospital in Salem from September 2018 to March 2020 with a sample size of 200. Details of their diabetic history were obtained. Patients were evaluated for their HbA1C levels, hypertension, and lipid profile status. Early treatment DR Study system was used to classify DR. Low density lipoprotein cholesterol was calculated by Freidewald's equation. RESULTS: This study showed a significant association among DR and LDL cholesterol. DR with raised LDL, TGs levels, and lowered HDL on adjusted analysis. There was strong association between DR and serum cholesterol in unadjusted analysis; however, there was no association when adjusted for factors such as age, gender, duration of diabetes, and glycemic control. Majority of participants were males (57.5%) with a male: female = 1.35:1. The mean age of the patients in our study was 57.8 (5.8) years and 54.4 (6.6) years in patients with DR and patients without retinopathy, and it was found to be statistically significant. There was a significant difference in the duration of diabetes with the presence of DR and the patients with DR were having longer duration of diabetes (7.9 vs. 6.2 years; P < 0.001). Moderate nonproliferative diabetic retinopathy (NPDR) was found to be present in 41.0% of eyes followed by mild NPDR (20.5% eyes). Proliferative diabetic retinopathy was present only in 9.5%, and the severity of retinopathy was associated only with the HDL level, and there was no association found with total cholesterol, TG, and LDL cholesterol. CONCLUSION: A statistically significant correlation was found between dyslipidemia and the severity of DR among Type 2 diabetic patients.

Validation of a Standardized Home Visual Acuity Test for Teleophthalmology.

Purpose: The recent exponential growth in teleophthalmology has been limited in part by the lack of a validated method to measure visual acuity (VA) remotely. We investigated the validity of a self-administered Early Treatment Diabetic Retinopathy Study (ETDRS) home VA test. We hypothesized that a home VA test with a printout ETDRS chart is equivalent to a standard technician-administered VA test in clinic. Design: Prospective cohort study. Participants: Two hundred nine eyes from 108 patients who had a scheduled in-person outpatient ophthalmology clinic visit at an academic medical center. Methods: Enrolled patients were sent a .pdf document consisting of instructions and a printout ETDRS vision chart calibrated for 5 feet. Patients completed the VA test at home before the in-person appointment, where their VA was measured by an ophthalmic technician using a standard ETDRS chart. Survey questions about the ease of testing and barriers to completion were administered. For the bioequivalence test with a 5% nominal level, the 2 1-sided tests procedure was used, and an equivalent 90% confidence interval (CI) was constructed and compared with the prespecified 7-letter equivalence margin. Main Outcome Measures: The primary outcome was the mean adjusted letter score difference between the home and clinic tests. Secondary outcomes included the unadjusted letter difference, absolute letter difference, and survey question responses. Results: The mean adjusted VA letter score difference was 4.1 letters (90% CI, 3.2-4.9 letters), well within the 7-letter equivalence margin. Average unadjusted VA scores in clinic were 3.9 letters (90% CI, 3.1-4.7 letters) more than scores at home. The absolute difference was 5.2 letters (90% CI, 4.6-5.9 letters). Ninety-eight percent of patients agreed that the home test was easy to perform. Conclusions: An ETDRS VA test self-administered at home following a standardized protocol was equivalent to a standard technician-administered VA test in clinic in the examined population.

Atrophy Expansion Rates in Stargardt Disease Using Ultra-Widefield Fundus Autofluorescence.

Purpose: To investigate atrophy expansion rate (ER) using ultra-widefield (UWF) fundus autofluorescence (FAF) in Stargardt disease (STGD1). Design: Retrospective, longitudinal study. Participants: Patients with biallelic ABCA4 mutations who were evaluated with UWF FAF and Heidelberg 30° × 30° and 55° × 55° FAF imaging. Methods: Patients with atrophy secondary to STGD1 were classified into genotype groups: group A, biallelic severe or null-like variants with early-onset disease; group B, 1 intermediate variant in trans with severe or null-like variant; and group C, 1 mild variant in trans with severe or null-like variant or late-onset disease. The boundaries of definitely decreased autofluorescence (DDAF) were outlined manually and areas (in square millimeters) were recorded at baseline and follow-up. Bland-Altman analysis was conducted to examine agreement between observers and devices. Linear mixed modeling was used to evaluate predictors of ER in DDAF area and square root area (SRA). Main Outcome Measures: Patient and ocular predictors of DDAF area ER and DDAF SRA ER included age at onset, duration of symptoms, genotype group, baseline visual acuity, and baseline atrophy size. Results: A total of 138 eyes from 69 patients (33 men [47%]; mean age ± standard deviation, 41 ± 20 years; range, 10-83 years) carrying 61 unique ABCA4 variants were recruited. Ultra-widefield FAF measurements were equivalent to Heidelberg 30° × 30° imaging. Baseline DDAF area was the only significant predictor of DDAF area ER (P < 0.001). Age at baseline and genotype group were predictors for DDAF SRA ER. Definitely decreased autofluorescence area ER ranged from 4.65 mm2/year (group A) to 0.62 mm2/year (group C). Conclusions: Ultra-widefield FAF is a feasible and reliable method for assessing atrophy ER in STGD1. The value of ABCA4 mutation severity in predicting atrophy ER warrants further investigation.

Progression of Atrophy and Visual Outcomes in Extensive Macular Atrophy with Pseudodrusen-like Appearance.

Purpose: To report visual outcomes and rate of retinal pigment epithelium (RPE) atrophy progression in patients with extensive macular atrophy with pseudodrusen-like appearance (EMAP). Design: Retrospective, observational study. Participants: Patients with EMAP and symptom onset before 55 years of age, at least 12 months of follow-up using Spectralis blue-light fundus autofluorescence (BAF) and OCT and with no other ocular or systemic conditions. Methods: Best-corrected visual acuity (BCVA), BAF, and OCT images were reviewed at baseline and at each annual visit until the last available follow-up. Atrophy was measured by 2 graders using the region finder software on Heidelberg Explorer and confirmed using OCT scans covering the entire atrophic lesion. The following imaging biomarkers were analyzed at each visit: foveal atrophy, vitreomacular traction, outer retinal tubulations, choroidal caverns and subfoveal choroidal thickness, border autofluorescence pattern (hyper-autofluorescent or iso-autofluorescent), and border irregularity as expressed by circularity index (CI). Main Outcome Measures: Primary outcomes were annual rate of atrophy enlargement and BCVA loss in EMAP patients. Secondary outcomes included the assessment of potential factors able to predict disease progression. Results: Thirty-six eyes from 18 patients with EMAP (6 men [33%]; mean age at symptom onset, 48.1 ± 1.7 years) were included. Mean follow-up lasted 32.8 ± 14.3 months. RPE atrophy increased from 10.8 ± 6.3 mm2 at baseline to 18.1 ± 8.3 mm2 at the end of follow-up, with a rate of 2.91 ± 1.09 mm2/year. Faster progression was associated with smaller CI at baseline (P = 0.02) and with iso-autofluorescent lesion borders (P = 0.01). Visual acuity declined progressively at a rate of 7.4 ± 5.8 letters per year, with 57% of eyes showing vision of 20/200 Snellen or worse at the 4-year follow-up. Worse visual outcomes were observed in patients with early foveal involvement at baseline (P = 0.02). Conclusions: Patients affected by EMAP present a rapid expansion of RPE atrophy that is comparable with the diffuse-trickling form of geographic atrophy. More irregular and iso-autofluorescent lesion borders seem to predict faster progression. Our findings may provide relevant information for patient counseling and future interventional approaches to select the best candidates and proper clinical outcomes.

Phase 1 Study of THR-687, a Novel, Highly Potent Integrin Antagonist for the Treatment of Diabetic Macular Edema.

Purpose: To evaluate the safety and preliminary efficacy of THR-687 in patients with center-involved diabetic macular edema (DME). Design: Phase 1, open-label, multicenter, 3 + 3 dose-escalation study with 3-month follow-up. Participants: Patients 18 years of age or older with visual impairment resulting from DME. Methods: Single intravitreal injection of THR-687 (0.4 mg, 1.0 mg, or 2.5 mg). Main Outcome Measures: The primary outcome measure was the incidence of dose-limiting toxicities (DLTs). The secondary outcome measure was the incidence of adverse events (AEs), including the occurrence of laboratory abnormalities. Exploratory outcome measures included changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), assessments of ischemia and leakage on fluorescein angiography, and THR-687 levels in plasma. Results: Twelve patients were treated: 3 patients received 0.4 mg of THR-687, 3 patients received 1.0 mg of THR-687, and 6 patients received 2.5 mg of THR-687. Most patients were men (9/12 patients). Their mean age was 57.8 years. No DLTs or serious AEs were reported at any of the dose levels tested. Overall, 9 AEs in the study eye were reported for 5 of 12 patients. Of those, 4 AEs in 3 of 12 patients were deemed treatment related by the investigator, all of which were mild, started on the day of the injection, and had resolved within 28 days without treatment. Overall, mean gains from baseline in BCVA were observed at all study visits with a rapid onset (7.2 Early Treatment Diabetic Retinopathy Study [ETDRS] letters at day 7) and a durability up to the end of the study (8.3 ETDRS letters at month 3). A mean decrease in CST was observed up to month 1. Overall, the mean BCVA gains and CST decreases were highest at the highest THR-687 dose level tested. THR-687 was undetectable in plasma at 7 days after the injection. Conclusions: At all dose levels tested, a single intravitreal injection of THR-687 was safe and well tolerated. Preliminary efficacy was observed by a rapid gain in BCVA with 3 months' durability and a decrease in CST up to 1 month after the injection.

Quantitative Parameters from OCT Angiography in Patients with Diabetic Retinopathy and in Those with Only Peripheral Retinopathy Compared with Control Participants.

Purpose: To describe the differences in a range of quantitative OCT angiography (OCTA) metrics across early stages of diabetic retinopathy (DR), providing robust effect estimates as well as sensitivity and specificity. Design: Cross-sectional study with population-based sampling. Participants: Four hundred forty-one eyes from 296 individuals: 328 control eyes (no diabetes mellitus [DM] and no DR), 55 eyes with DM and no DR, and 58 eyes with early nonproliferative DR. Methods: Multimodal retinal imaging included color fundus photography, color Optomap ultra-widefield imaging, and spectral-domain OCT (Spectralis OCT2; Heidelberg Engineering GmbH) with the OCTA module. All images were graded for the presence and severity of DR features. OCTA images were assessed manually for inclusion based on quality. Binary OCTA metrics were assessed after 3-dimensional projection artifact removal including from the nerve fiber layer vascular plexus, superficial vascular plexus (SVC), and deep vascular plexus (DVC) by Early Treatment Diabetic Retinopathy Study (ETDRS) grid, foveal avascular zone (FAZ) area, FAZ minimum and maximum diameter, perimeter length, and circularity. Main Outcome Measures: Diabetes mellitus and DR status and presence or absence of DR in the retinal periphery. Results: The reduction in vessel densities in participants with DM and manifest DR compared with control participants tended to be twice that of those with DM, but no DR, compared with control participants. Some evidence of spatial heterogeneity in vessel reductions was found in those yet to develop DR, whereas those with manifest DR had significant reductions across the ETDRS grid. The FAZ perimeter and circularity were impacted most significantly by DM, and those with DR showed decreased multispectral fractal dimensions compared with control participants. Eyes with peripheral DR had reduced vessel density compared with those with DM and no DR only in the superior outer, temporal inner, and temporal outer regions in the DVC and SVC. The area under the receiver operating characteristic curve ranged between 0.48 and 0.73. Conclusions: Significant differences in OCTA metrics can be found in those with DM before manifest DR using commercially available equipment with minimal image postprocessing. Although diagnostic performance was poor, these metrics may be useful for measuring change over time in clinical trials.

Prevalence of Vitreoretinal Interface Disorders in an Australian Population: The Blue Mountains Eye Study.

Purpose: To describe the prevalence, risk factors, and associations of vitreoretinal interface (VRI) abnormalities in a population-based study of older adults. Design: Cross-sectional analysis of cohort study participants. Participants: Of the 1149 participants (mean age, 76.1 ± 6.9 years) in the 15-year Blue Mountains Eye Study follow-up examination from 2007 through 2009, 905 (1791 eyes) had gradable time-domain or spectral-domain OCT scans of the macula from at least 1 eye. Methods: OCT scans were graded according to the International Vitreomacular Traction Study Group classification system of VRI abnormalities. Best-corrected visual acuity (BCVA) was recorded. Main Outcome Measures: Prevalence of VRIs. Results: Overall, 451 participants showed any VRI abnormality (49.8%). Prevalence of VRI abnormality by person was: vitreomacular adhesion (VMA), 33.6%; vitreomacular traction (VMT), 1.6%; epiretinal membrane (ERM), 21.4%; full-thickness macular hole (FTMH), 0.7%; and lamellar macular hole (LMH), 0.7%. Twenty-two percent of VMAs were focal, and 78% were broad based; 76% of VMTs were focal, and 24% were broad based. All FTMHs observed were large (>400 µm), with mean aperture size of 573 µm (range, 459-771 µm). Increased age was associated with higher ERM and lower VMA prevalence (P < 0.001 for both). Pseudophakia and myopia were associated with ERM (age- and sex-adjusted odds ratios [ORs], 1.48 [95% confidence interval (CI), 1.01-2.17] and 1.72 [95% CI, 1.05-2.81], respectively). Moderate or severe ERM and FTMH were associated with worse BCVA of 9.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% CI, 3.4-15.0 ETDRS letters; P = 0.008) and 26.0 ETDRS letters (95% CI, 10.9-41.1 ETDRS letters; P = 0.001), respectively. Conclusions: The prevalence of VRI abnormalities is high in older individuals. Epiretinal membrane was associated with increasing age, pseudophakia, and myopia. Epiretinal membrane and FTMH may account for significant visual loss in the affected eye. This study provided useful population-based data on the prevalence of VRI abnormalities in older individuals.

Comparison of Ultra-Widefield Imaging and Standard Imaging in Assessment of Early Treatment Diabetic Retinopathy Severity Scale.

Purpose: To compare Early Treatment Diabetic Retinopathy Study (ETDRS) severity levels between standard 7-field imaging and ultra-widefield (UWF) imaging and to incorporate peripheral diabetic retinopathy (DR) lesions into the ETDRS grading system. Design: Cross-sectional Study. Participants: Paired images from 192 eyes (189 participants) with diabetic retinopathy were included. Methods: The ETDRS levels were determined by masked graders in 3 ways: standard 7-field imaging, UWF within the 7-field region (7-field UWF imaging), and the entire UWF image (global ETDRS imaging). Main Outcome Measures: Percentage agreement between 7-field and UWF imaging for ETDRS levels. Results: Of the 166 paired images evaluated, exact agreement was found in 48.8% of eyes between standard 7-field and 7-field UWF ETDRS levels with a weighted κ value of 0.59 (95% confidence interval [CI], 0.5-0.68). Agreement rates varied with DR severity and were least in early DR (30.8%) and moderate nonproliferative DR (26.5%) groups. In 156 eyes with 7-field UWF ETDRS and global UWF ETDRS levels, exact agreement was found in 143 eyes (92%), with a weighted κ value of 0.9 (95% CI, 0.9-0.98). The peripheral lesions contributed to a higher DR severity in 8% and changed the eye to a proliferative DR level in 2%. Reproducibility of the 3 ETDRS evaluations was comparable with a weighted κ value of 0.57 with standard 7-field imaging, 0.65 with 7-field UWF imaging, and 0.60 with global ETDRS scale imaging. Conclusions: Moderate agreement was found in the ETDRS DR severity scale between standard 7-field and UWF imaging, indicating caution in interchanging data from the 2 methods. Both methods showed good reproducibility for clinical trial outcome of 2-step change. The global ETDRS scale provides a comprehensive score to incorporate peripheral changes into the ETDRS scale. The implications of the global scale on progression rate are yet to be determined.