Higher Levels of Serum Ionic Calcium are Associated with Macular Edema in Patients with Diabetic Retinopathy.

BACKGROUND: The aim was to study the association of serum total calcium, ionic calcium, and magnesium with increases in macular thickness parameters and photoreceptor ellipsoid zone (EZ) disruption in diabetic macular edema (DME). METHODS: This study is a tertiary care center based observational cross-sectional study with sixty-six consecutive cases, divided into 3 groups of 22 cases each with no diabetic retinopathy (No DR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) and a control group of 22 healthy controls. Best corrected visual acuity (BCVA) was measured on logMAR scale. Central subfield thickness (CST), cube average thickness (CAT), and EZ disruption were assessed using spectral-domain optical coherence tomography (SD-OCT). Serum total calcium, ionic calcium, and magnesium were measured using standard protocol. Data was analyzed statistically. RESULTS: Significant correlation was found between the increase in CST and the increase in serum total calcium and serum ionic calcium. Increase in CAT was significantly correlated with an increase in serum total calcium, serum ionic calcium, and a decrease in serum magnesium. Grades of EZ disruption and logMAR BCVA were also found to be significantly positively associated with serum total calcium and ionic calcium and negatively with serum magnesium. CONCLUSIONS: Increased levels of serum ionic calcium and decreased levels of serum magnesium are associated with an increase in macular thickness and EZ disruption in DME.

Effect of Blue Light Filtering Intraocular Lenses on Visual Perception.

Background and Objectives: This retrospective consecutive case control study compares best-corrected visual acuity (BCVA), mesopic contrast sensitivity (CS), color vision, and glare between a group of eyes with blue-light-filtering intraocular lenses and another with UV-light-filtering intraocular lenses. Materials and Methods: We used Early Treatment Diabetic Retinopathy Study charts to compare BCVA, Rabin charts for mesopic CS testing, Oculus HMC Anomaloscope MR to test for chromatic discrimination, and Oculus Mesotest II to measure scotopic CS with glare. For analysis, we used descriptive statistics and compared means with parametric and non-parametric tests. The level of significance was set as α = 0.05. Results: For the group with the blue-light-filtering intraocular lens, the average results were BCVA = 0.96 (SD ± 0.09), CS = 1.78 log (SD ± 0.12), chromatic discrimination results M = 63.91 (SD ± 11.88), R = 60.07 (SD ± 7.89). For mesopic CS with glare, the group achieved on average 2.54 (SD ± 1.50) points out of 4. For the group with the UV-light-filtering intraocular lens, the average results were BCVA = 0.93 (SD ± 0.14), CS = 1.79 log (SD ± 0.13), chromatic discrimination results M = 65.38 (SD ± 17.14), R = 60.79 (SD ± 10.39). For mesopic CS with glare, this group achieved an average of 2.79 (SD ± 1.53) points out of 4. Conclusion: No significant differences (p > 0.05) were found in any of the tested parameters between the analyzed groups. Slight shift in color vision was observed, although not statistically significant.

Hyperglycemia potentiates the effect of ionic calcium in photoreceptor ellipsoid zone disruption in diabetic retinopathy.

PURPOSE: To study the association of serum ionic calcium and glycated hemoglobin (HbA1c) with retinal photoreceptor ellipsoid zone (EZ) disruption in diabetic retinopathy (DR). METHODS: This is a tertiary care center-based observational cross-sectional study. Sixty-three consecutive cases, divided into 21 cases each with no diabetic retinopathy, non-proliferative diabetic retinopathy and proliferative diabetic retinopathy were included. Twenty-one healthy controls were also included. Ellipsoid zone disruption was assessed using spectral-domain optical coherence tomography. Serum ionic calcium and HbA1c were measured using standard protocol. Patient data from cases were divided into two groups according to their HbA1c levels: group 1 (HbA1c < 7, n = 26) and group 2 (HbA1c > 7, n = 37). Data were analyzed statistically. RESULTS: Mean ionic calcium levels in group 1 and group 2 were 1.131 ± 0.073 mmol/dL and 1.170 ± 0.070 mmol/dL, respectively. In group 1, 11 out of 26 had EZ disruption (42.3%). Similarly, in group 2, 29 out of 37 had EZ disruption (78.4%). On logistic regression analysis, as compared to group 1, ellipsoid zone disruption was found to be positively associated with serum ionic calcium (p = 0.01) in group 2 cases. CONCLUSION: Increased levels of serum ionic calcium are associated with increased EZ disruption in patients with HbA1c > 7 in DR.

The Impact of Hyperglycemia on VEGF Secretion in Retinal Endothelial Cells.

BACKGROUND: Diabetic retinopathy is a serious sight-threatening complication which is manifested by excessive angiogenesis in diabetic patients. AIM: We hypothesize that cultured Rhesus monkey retinal endothelial cells (RhRECs) respond to high glucose with a change in cell proliferation and vascular endothelial growth factor (VEGF) secretion. MATERIALS AND METHODS: In our study, 20 000 cells per well were treated without glucose or with 5.5 mM, 18.5 mM and 30 mM glucose for 24 hours. Viable cells were counted using trypan blue dye exclusion method. VEGF concentrations were measured in cell media by ELISA method. RESULTS: The number of viable cells incubated with 5.5 mM glucose increased significantly by 53.7% after 24 hours. In comparison, the number of viable cells decreased by 2.8% at 18.5 mM of glucose and by 20.4% at 30 mM of glucose after 24 hours of incubation. In contrast to this effect of glucose on the number of viable cells, a significant increase in VEGF levels (pg/mL) in the cell media with a glucose concentration of 0 mM compared to 5.5 mM of glucose was found. VEGF secretion in cell medium with 18.5 and 30 mM of glucose increased non-significantly in comparison with euglycemic levels. CONCLUSION: Our results show that viability of retinal endothelial cells and VEGF release are highly responsive to changes in glucose concentration. Such glucose-induced changes in retinal endothelial cells may negatively impact the integrity of the microvasculature in the diabetic retina leading to angiogenesis and microaneursym.

Understanding Loss to Follow-Up in AMD Patients Receiving VEGF Inhibitor Therapy: Associated Factors and Underlying Reasons.

BACKGROUND: In patients with wet age-related macular degeneration (AMD), loss to follow-up (LTFU) leads to unplanned interruptions in therapy and the risk of visual loss. METHODS: This retrospective and prospective case-control cohort study compared AMD patients with (LTFU YES) and without (LTFU NO) LTFU during anti-VEGF treatment over 12 years. LTFU was defined as missing any treatment or monitoring visits, or not scheduling follow-ups for six months. RESULTS: Significant differences between LTFU NO (n = 298) and LTFU YES (n = 174) groups were age, treatment phase, baseline and final best-corrected visual acuity (BCVA), type of anti-VEGF drug, treatment switch, commuting distance, and escort during commuting. A multivariate logistic regression analysis identified the need for an escort during the commuting and treatment phase as the only significant difference. The four most common reasons for LTFU were general health worsening (21.8%), patient-missed appointments (16.7%), COVID-19-related issues (14.9%), and treatment dissatisfaction (8.6%). CONCLUSIONS: The factors associated with increased LTFU rates were older age, inactive treatment phase, lower baseline and final BCVA, bevacizumab treatment, monotherapy, longer travelling distance, and commuting with an escort. According to the multivariate logistic regression analysis, only the escort during the commuting and treatment phases was significant. These findings could direct research to explore social support in treatment adherence and highlight the importance of treatment phases in practice.

Efficacy and Safety of Brolucizumab for Diabetic Macular Edema: The KINGFISHER Randomized Clinical Trial.

Importance: Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME). Objective: To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME. Design, Participants, and Setting: This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021. Intervention: Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks. Main Outcomes and Measures: Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52. Results: A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 µm; aflibercept, -196.5 µm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion. Conclusions and Relevance: In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03917472.

Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial.

INTRODUCTION: The purpose was to compare two flexible regimens of intravitreal aflibercept (IVT-AFL) with fixed dosing every 8 weeks, beyond the first year of treatment, in patients with diabetic macular edema (DME). VIOLET was a 100-week, randomized, Phase IIIb, non-inferiority study in patients with center-involving DME previously treated with IVT-AFL for ≥ 1 year according to the European label. METHODS: Patients received an initial dose of IVT-AFL at study baseline and were randomly assigned (1:1:1) to treat-and-extend (T&E), pro re nata (PRN), or fixed regimens. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline (randomization) to Week 52. RESULTS: Full analysis set comprised 458 patients (baseline mean BCVA: 72.5, 71.0, and 72.7 letters in the T&E, PRN, and fixed-dose groups, respectively). Patients received a mean (min-max) of 10.0 (2-14; T&E), 11.5 (1-25; PRN), and 12.3 (3-13; fixed) injections over 100 weeks, with 13.3 (4-23), 25.0 (3-29), and 16.1 (5-25) clinic visits, respectively. At Week 52, mean (± standard deviation) BCVA changes from baseline were + 0.5 ± 6.7 (T&E), + 1.7 ± 6.8 (PRN), and + 0.4 ± 6.7 (fixed-dosing) letters (least squares mean difference [95% confidence interval]: T&E 0.01 [- 1.46, 1.47] and PRN 0.95 (- 0.52, 2.42) letters versus fixed dosing; p < 0.0001 for both non-inferiority tests [4-letter margin]). The IVT-AFL safety profile was consistent with previous studies. CONCLUSION: The treatment burden associated with intravitreal injections for DME is lowest with T&E regimens, but there are a range of flexible IVT-AFL dosing regimens, allowing physicians to adopt an individualized treatment plan. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818998.

Analysis of biometric parameters of 2340 eyes measured with optical biometer Lenstar LS900 in a Caucasian population.

OBJECTIVES: To describe the pattern and mutual relationships between basic biometric characteristics of the eye in a Central European Caucasian population. METHODS: A single-centre retrospective study of 2340 patients (965 males, 1375 females) scheduled for cataract surgery between 2014 and 2016. Measurements using laser interferometry included AL (axial length), K (average corneal curvature), ACD (anterior chamber depth), LT (lens thickness), CCT (central corneal thickness), AST (astigmatism) and WTW (white to white). Subjects were stratified by gender and controlled for age. Descriptive, correlation and regression analyses were performed on the data. RESULTS: The mean AL was 23.33 ± 1.01 mm - higher in males (23.59 ± 0.99 mm), in comparison to females (23.15 ± 0.99 mm). The elderly had lower ACD and higher LT, while males had higher AL independent of age. Furthermore, LT and K decreased with AL, while ACD decreased with LT and increased with AL independent of age and gender. CONCLUSIONS: The estimates of the biometrics are obtained on a large sample of subjects and can serve as normative values for Lenstar LS900 in the Central European Caucasian population.

Retinal photoreceptor apoptosis is associated with impaired serum ionized calcium homeostasis in diabetic retinopathy: An in-vivo analysis.

PURPOSE: The aim of this work was to study the association of serum ionized calcium with retinal photoreceptor apoptosis on spectral domain optical coherence tomography (SD-OCT) in diabetic retinopathy (DR). METHODS: Sixty consecutive cases with Type 2 diabetes mellitus were categorized into three groups: no diabetic retinopathy; non-proliferative DR; proliferative DR. The eye with more severe form of the disease was considered. Twenty healthy controls were also included. Best corrected visual acuity (BCVA) was measured on logMAR scale. Retinal photoreceptor apoptosis was defined as disruption of retinal photoreceptor ellipsoid zone (EZ). Ellipsoid zone disruption was assessed using SD-OCT. Serum levels of total and ionized calcium were measured using standard protocol. RESULTS: EZ disruption was found to be positively associated with serum total calcium and ionized calcium. Also, EZ disruption was found to be positively associated with logMAR BCVA. CONCLUSION: Increased serum ionized calcium induces retinal photoreceptor apoptosis resulting in increased EZ disruption in DR.

Vision-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Intravitreal Aflibercept: The AQUA Study.

PURPOSE: To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). DESIGN: AQUA was a multicenter, open-label, single-arm, phase 4 study. PARTICIPANTS: Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. METHODS: Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. MAIN OUTCOME MEASURES: The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. RESULTS: A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 µm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was -175.38 µm (SD, 132.62 µm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. CONCLUSIONS: Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.

Disorganization of retinal inner layers correlates with ellipsoid zone disruption and retinal nerve fiber layer thinning in diabetic retinopathy.

PURPOSE: To study the correlation between disorganization of inner retinal layer (DRIL) and macular thickness parameters, ellipsoid zone (EZ) disruption and retinal nerve fiber layer (RNFL) thickness on spectral domain optical coherence tomography (SD-OCT) in diabetic retinopathy (DR), for the first time. METHODS: A tertiary care center-based cross-sectional study was undertaken. One hundred and four consecutive study subjects of type 2 diabetes mellitus were included: diabetes mellitus with no retinopathy (No DR) (n = 26); non-proliferative DR (NPDR) (n = 26); proliferative DR (PDR) (n = 26) and healthy controls (n = 26). Best Corrected Visual Acuity (BCVA) was measured on the logarithm of the minimum angle of resolution (logMAR) scale. Clinician-friendly, SD-OCT based, grading systems were created for DRIL and EZ disruption, within the macular cube. DRIL was graded as: grade 0, DRIL absent; and grade 1, DRIL present. EZ disruption was graded as; Grade 0: Intact EZ; Grade 1: Focal disruption and Grade 2: Global disruption. Every study subject underwent RNFL thickness analysis. RESULTS: DRIL was significantly associated with increase in severity of DR.Pearson correlation analysis showed significant positive correlation between DRIL and CST CAT and grades of EZ disruption . However, a significant negative correlation was found between DRIL and RNFL thickness . CONCLUSION: Presence of DRIL correlates with severity of DR, EZ disruption and RNFL thinning.

Prevalence of Age-Related Macular Degeneration in Slovakia and Associated Risk Factors: A Mobile Clinic-Based Cross-Sectional Epidemiological Survey.

PURPOSE: Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly population. Although there are prevalence studies for AMD in Europe, data are scarce for the Slovakian population. METHODS: This was a prospective, multicenter, non-interventional, mobile clinic-based cross-sectional study that assessed age-specific prevalence of AMD in the Slovakian population and risk factors associated with AMD. The type of AMD was graded based on the international age-related maculopathy grading system; optical coherence tomography (OCT) was used for the differential diagnosis. Overall, 3,278 patients were screened; the fundus photographs, OCT scans, and self-reports were collected at the mobile clinic in a single visit. RESULTS: The prevalence of AMD in the study population was 8.99% (wet AMD 1.01%; dry AMD 7.85%), whereas the extrapolated estimate in the entire Slovakian population was 3.3% (wet AMD 0.3%; dry AMD 3.0%). Age, smoking, and hypertension were risk factors associated with AMD; however, contrary to reports in the literature, no gender-specific association was observed. CONCLUSION: Based on the results of this study, mobile clinics may be an effective way to extend health care access to a larger population. Early diagnosis of AMD will assist in early treatment and effective disease management of the population at risk.

A noninterventional study to monitor patients with diabetic macular oedema starting treatment with ranibizumab (POLARIS).

PURPOSE: Antivascular endothelial growth factor agents are increasingly used in diabetic macular oedema (DME); however, there are few studies exploring their use in DME in real-world settings. METHODS: POLARIS was a noninterventional, multicentre study to monitor 12-month outcomes in patients starting ranibizumab treatment in routine practices. The primary outcome was mean change in visual acuity (VA) from baseline to month 12 (last observation carried forward approach). Other outcomes included mean change in central retinal thickness (CRT) and resource utilization. Visual acuity (VA) outcomes were also stratified by country, baseline visual acuity score (VAS), sex, age and injection frequency. RESULTS: Outcomes were analysed from all treated patients (n = 804) and from first-year completers (patients who had a visual acuity assessment at 12 months; n = 568). The mean (SD) baseline VAS was 59.4 (15.9) letters, and the mean change in visual acuity was 4.4 letters (95% confidence interval: 3.3-5.4) at month 12 (study eye; first-year completers). The mean number of injections (study eye) was 4.9, and the mean number of all visits (any eye) was 10 (58% were injection visits) over 12 months (first-year completers). The mean (SD) baseline CRT was 410.6 (128.8) µm, and the mean change in CRT was -115.2 µm at month 12 (study eye; first-year completers). Visual acuity (VA) outcomes were generally comparable across most countries and subgroups and were greatest in patients with the lowest baseline VAS (≤60 letters). CONCLUSION: POLARIS showed that real-world outcomes in DME patients starting treatment with ranibizumab were lower than those observed in clinical studies, in spite of extensive monitoring.