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Purpose: To evaluate the efficacy and safety of intravitreal aflibercept injections for diabetic macular edema (DME) treatment in a tertiary referral center in Greece., Methods: ADMIRE was a prospective, observational cohort study of patients with DME. Efficacy was assessed by change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to month 36 after treatment with intravitreal aflibercept in treatment-naive patients and previously treated patients. Safety was evaluated by recording any patients-reported events., Results: Participants in the study were 94 patients with DME, 70 treatment naive and 24 previously treated with ranibizumab. At month 36 of the follow-up period, the mean change in BCVA was +7.4 letters compared to baseline ( p  < .001). The mean change in BCVA in treatment-naive patients was +8.9 letters and differed significantly compared to previously treated patients (+5.9 letters, p  = .041). In addition, patients who received a loading dose of 5 monthly injections at the initiation of treatment provided better VA outcomes (+11.4 vs. +6.1 letters, p  < .001). Accordingly, the mean CST at month 36 (369.6 ± 72.8 μm) was significantly decreased compared to baseline (479.2 ± 68.3 μm, p  < .001). Overall, the mean number of injections at month 36 was 13.4. Safety analysis showed that the reported ocular adverse events during the 36-month study period were mild and not sight-threatening., Conclusion: Intravitreal aflibercept was found to be safe and effective for the treatment of DME in real-life in a Greek population. Treatment-naive patients and those who received a loading dose of five consecutive monthly injections at initiation of treatment exhibited better outcomes, suggesting that early and effective treatment may prevent vision loss.

Purpose: To investigate the adjunct efficacy and safety of vitamin supplements, including resveratrol, in patients with diabetic macular edema (DME) treated with intravitreal anti-vascular endothelial factor (anti-VEGF) agents., Methods: Participants in this prospective study were 45 patients with DME, who were treated with either intravitreal anti-VEGF injections (n = 23, Group I) or with combination of intravitreal anti-VEGF injections and vitamin supplements, including resveratrol (n = 22, Group II). All patients underwent visual acuity measurement, slit-lamp examination and spectral domain-optical coherence tomography (SD-OCT) at baseline and monthly after the loading phase of three-monthly anti-VEGF injections, following a PRN protocol., Results: There was a statistically significant improvement in visual acuity in both groups at month 12 compared to baseline, although the mean change in visual acuity did not differ between the two groups (p = 0.183). Accordingly, there was a statistically significant decrease in central retinal thickness in both groups at month 12 compared to baseline, while the mean difference in central retinal thickness was significantly greater in the "combination" group. The mean number of intravitreal anti-VEGF injection was less in Group II (6.45 ± 1.12 in Group II vs. 7.39 ± 1.31 in Group I, p = 0.018)., Conclusions: Vitamin supplements with resveratrol was found to be an effective adjunct to intravitreal anti-VEGF injections in patients with DME, offering better anatomic restoration with less injections at the 12-month follow-up.

Purpose: To investigate potential laboratory and imaging biomarkers as treatment response predictors to intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents in patients with diabetic macular edema (DME)., Methods: The study included 36 treatment naïve patients with DME, treated with intravitreal anti-VEGF agents and followed-up for 12 months. At baseline, all participants underwent best-corrected visual acuity (BCVA) measurement, dilated fundoscopy, optical coherence tomography, color fundus photography and fluorescein angiography, while full blood count and biochemical analysis of various parameters was also performed. At month 12, treatment response was examined and classified as "favorable" or "non-response". Potential associations between laboratory/imaging biomarkers and treatment response were assessed., Results: Univariate analysis showed that favorable response at month 12 after initiation of anti-VEGF treatment was correlated with baseline central subfield thickness (CST)≤405 μm ( p < .001), absence of subretinal fluid ( p = .034), absence of exudates ( p = .041), absence of disorganization of the inner retinal layers ( p = .037), intact ellipsoid zone (EZ) and external limiting membrane (ELM) ( p < .001 and p = .002, respectively), absence of epiretinal membrane (ERM) ( p = .040) and absence of macular ischemia ( p = .042), while increased lipoprotein(a) was associated with no treatment response ( p = .025). At the multivariate analysis, CST was found to be independent predictor of treatment response, while EZ, ELM and ERM were found to predict treatment response perfectly and they could not be entered in the model., Conclusion: Intact EZ and ELM, absence of ERM and CST≤405 μm at baseline can predict favorable treatment response in patients with treatment naïve DME, while no correlation with baseline laboratory parameters was found.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM) and the leading cause of blindness in patients with DM. In the pathogenesis of DR, chronic hyperglycemia leads to biochemical and structural alterations in retinal blood vessels' wall, resulting in hyperpermeability and non-perfusion. Since vascular endothelial growth factor (VEGF) has been found to play a significant role in the pathogenesis of DR, this review sheds light on the effect of intravitreal anti-VEGF agents on retinal non-perfusion in patients with DR. Based on the existing literature, anti-VEGF agents have been shown to improve DR severity, although they cannot reverse retinal ischemia. The results of the published studies are controversial and differ based on the location of retinal non-perfusion, as well as the imaging modality used to assess retinal non-perfusion. In cases of macular non-perfusion, most of studies showed no change in both fundus fluorescein angiography (FFA) and optical coherence tomography (OCTA) in patients with DR treated with intravitreal anti-VEGF agents, while few studies reported worsening of non-perfusion with enlargement of foveal avascular zone (FAZ). Regarding peripheral ischemia, studies using wide-field-FFA demonstrated an improvement or stability in non-perfusion areas after anti-VEGF treatment. However, the use of wide-field-OCTA revealed no signs of re-perfusion of retinal vessels post anti-VEGF treatment. Further prospective studies with long follow-up and large sample size are still needed to draw solid conclusions., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: To investigate the potential association between peripheral blood biomarkers and morphological characteristics of retinal imaging in patients with diabetic macular edema (DME)., Methods: Participants in this cross-sectional study were 36 consecutive patients (36 eyes) with treatment-naïve DME, who underwent spectral domain-optical coherence tomography (SD-OCT), fundus photography, and fundus fluorescein angiography (FFA). In addition, peripheral blood samples were taken to evaluate full blood count and biochemical parameters. Correlation between imaging characteristics and laboratory parameters was examined., Results: Eyes with central subfield thickness greater than 405  μ m presented significantly higher neutrophils/lymphocytes ( p = 0.043) and higher lipoprotein (a) compared to eyes with CST < 405  μ m ( p = 0.003). Presence of hyperreflective foci on SD-OCT was associated with significantly higher white blood cell count ( p = 0.028). Ellipsoid zone disruption was associated with significantly lower hematocrit ( p = 0.012), hemoglobin ( p = 0.009), and red blood cell count ( p = 0.026), as well as with higher lipoprotein (a) ( p = 0.015). Macular ischemia on FFA was associated with significantly higher monocytes ( p = 0.027) and monocytes/HDL ( p = 0.019). No significant associations were found between laboratory parameters and subretinal fluid, intraretinal fluid, exudates, cysts, disorganization of inner retinal layers, epiretinal membrane, and external limiting membrane condition., Conclusion: Specific imaging morphological characteristics were found to be associated with laboratory parameters in patients with DME. These findings may shed light on the pathophysiology of DME and its correlation with the development of specific clinical signs., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Eleni Dimitriou et al.)

Purpose: To evaluate the morphological characteristics in patients with diabetic macular edema (DME), either with co-existent non-proliferative diabetic retinopathy (NPDR) or with PDR., Methods: Retrospective study includes 138 treatment naïve patients with DME, either with NPDR (n = 96) or in combination with PDR (n = 42). All patients underwent best corrected visual acuity (BCVA) measurement, spectral domain-optical coherence tomography (SD-OCT) and fluorescein angiography, while demographic characteristics were also recorded. Specific clinical and morphological characteristics were analyzed and compared between the two groups., Results: Patients with DME and PDR presented higher central retinal thickness and mixed type of edema, with predominantly cystoid component and large cysts, extending in the foveal, peri- and para-foveal area, compared to patients with DME and NPDR. The presence of non-perfusion areas in patients with DME and PDR led to additional ellipsoid zone and external limiting membrane disruption in a higher percentage, accompanied with worse visual acuity compared to patients with DME and NPDR. Patients with DME and PDR had also higher vitreomacular traction percentage and higher HbA1c levels than those with DME and NPDR., Conclusion: Variations in morphological characteristics of DME on SD-OCT existed between patients with NPDR and those with PDR. These differences may explain the alterations in visual acuity and prognosis.

Purpose: The purpose of this study was to investigate retinal layers' changes in patients with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (anti-VEGF) agents and to evaluate if these changes may affect treatment response., Methods: Participants in this prospective study were 110 treatment-naïve patients with center involved DME, who were treated with anti-VEGF agents and followed up for at least 12 months. A qualitative and quantitative analysis of retinal layers that can affect visual acuity was performed. Patients with persistent DME were defined, and factors which could affect this outcome were determined., Results: Visual acuity was significantly improved, while there was also a statistically significant reduction in central retinal thickness and in all separate retinal layers' thickness at month 12 compared to baseline (p < 0.001). Visual acuity was associated with central retinal thickness and outer retinal layers' thickness;51.8% of the patients presented with persistent DME at month 12, which was found to be significantly associated with baseline visual acuity and HbA1C levels., Conclusions: Anti-VEGF treatment is effective in reducing retinal thickness as a whole and in all separate retinal layers at 12-month follow-up in patients with DME. Changes in central retinal thickness and in outer retinal layers were found to affect visual acuity. HbA1c was the most significant factor to determine persistence of DME at month 12., (© 2020 S. Karger AG, Basel.)

Purpose: To analyze photoreceptors' condition after intravitreal ranibizumab treatment according to the pattern of diabetic macular edema (DME) on spectral-domain optical coherence tomography (SD-OCT)., Methods: Retrospective study includes 58 treatment naïve patients with DME, treated with intravitreal ranibizumab injections and followed up for at least 12 months. Patients were classified based on DME morphology on SD-OCT into: diffuse macular edema, cystoid macular edema (CME) and serous retinal detachment with CME (SRD/CME). The DME morphology was analyzed, while quantitative measurement of ellipsoid zone (EZ) defect, as well as qualitative assessment of the condition of external limiting membrane (ELM) and interdigitation zone (IZ) at foveal area, was taken before and after treatment., Results: Before treatment, patients with CME presented worse ELM and IZ condition and greater EZ defect than patients with diffuse macular edema or SRD/CME. After treatment, the restoration of EZ defect and IZ was more evident in patients with CME than in diffuse macular edema or SRD/CME., Conclusion: Patients with DME presented significant photoreceptors' restoration after intravitreal ranibizumab injections at the 12-month follow-up. The improvement in EZ defect size and IZ was dependent on the pattern of DME on SD-OCT.

Aims: To compare intravitreal ranibizumab as monotherapy or in combination with panretinal photocoagulation (PRP) in patients with proliferative diabetic retinopathy (PDR) and coexistent diabetic macular edema (DME) in a long-term follow-up of 24 months., Methods: Participants in this prospective study were 47 patients with PDR and concurrent DME, who were randomized at baseline into two groups: (i) the "ranibizumab alone" group (n = 23), which was treated with at least 3 intravitreal ranibizumab injections as a loading phase, and (ii) the "combination" group (n = 24), which was treated with PRP and at least 3 intravitreal ranibizumab injections. Thereafter, all patients were followed up at a pro re nata (PRN) basis, with regular monthly monitoring for 24 months. At each visit, best corrected visual acuity (BCVA) and spectral domain-optical coherence tomography were performed, while regression of neovascularization was also recorded., Results: The "combination" group had better control of neovascularization and less events of vitreous hemorrhage than ranibizumab alone through the 2 years. BCVA did not differ significantly between the two groups at months 12 and 24 of the follow-up. The "ranibizumab" alone group presented greater reduction in central retinal thickness at month 12, which did not reach significance at month 24 compared to "combination" group. Greater number of injections was needed in the monotherapy group (mean 14 injections) compared to "combination" group (mean 11 injections) through month 24., Conclusions: Both intravitreal ranibizumab alone or in combination with PRP could be used effectively for the treatment of PDR and coexistent DME. Even though there was no difference in BCVA and CRT at the 24-month follow-up between the two groups, the combination group presented greater regression of neovascularization with less injections.

Purpose: To evaluate peripapillary retinal nerve fiber layer (RNFL) changes in patients with diabetes mellitus (DM) and compare them with those of normal population. In addition, this study aims to determine potential factors, affecting RNFL changes in patients with DM., Methods: Participants in this study were 107 patients (211 eyes) with DM and 100 healthy controls (200 eyes). Diabetic patients were further classified into four groups depending on severity of diabetic retinopathy (no retinopathy, mild, moderate, severe nonproliferative diabetic retinopathy, and proliferative diabetic retinopathy, while presence of macular edema was also assessed. All participants underwent spectral-domain optical coherence tomography (SD-OCT) to measure RNFL thickness, while demographic and clinical characteristics of the participants were also recorded., Results: Patients with DM with or without DR presented significantly decreased peripapillary RNFL thickness in all quadrants. In the diabetic group, the multivariate analysis showed a significant association between decreased average RNFL thickness and increased HbA1c ( p < 0.001), longer DM duration ( p = 0.007), and more severe diabetic retinopathy status ( p = 0.016), while presence of DME, age, gender, hypertension, and hyperlipidemia were not found to be associated with RNFL thickness decrease., Conclusion: Diabetes mellitus seems to affect RNFL thickness, suggesting that early neurodegenerative changes may occur, potentially before microvascular alterations. Since duration of disease, DR severity, and HbA1c levels were associated with RNFL thinning, modifying glycemic control seems to be important to potentially prevent the development of DM complications.

Purpose: To compare prospectively intravitreal ranibizumab treatment and pars plana vitrectomy (PPV) in patients with recurrent vitreous haemorrhage (VH) due to proliferative diabetic retinopathy (PDR), who were previously treated with PPV., Methods: Participants in this prospective study were 37 patients (37 eyes) with PDR, previously treated with PPV. All patients presented recurrent VH and were treated with either ranibizumab (n = 18) or PPV (n = 19). All participants were examined at week 2 post-treatment and every month thereafter for 1 year. Main outcomes were the need of PPV, the rate of recurrence of VH and the change in visual acuity by the end of the 12-month follow-up., Results: At month 12, there was statistically significant improvement in visual acuity in both groups compared to baseline, but the two groups did not differ regarding the change in visual acuity. In ranibizumab group, two patients presented recurrent VH during the follow-up and one patient needed PPV to clear the VH by month 12. In PPV group, two patients had mild recurrent VH, which cleared itself. No statistically significant difference was noticed regarding the rate of recurrent VH and the need of PPV between the two groups., Conclusion: Intravitreal ranibizumab seems to be a safe and effective treatment alternative in patients with recurrent VH secondary to PDR, who had been previously treated with PPV.

Purpose: The purpose of this study was to evaluate refractive changes after intravitreal ranibizumab injections for the treatment of diabetic macular oedema., Methods: Participants in this retrospective study were 35 patients (35 eyes) with diabetic macular oedema, who received intravitreal ranibizumab injections. Spherical equivalent refractive power was evaluated before treatment and at least one month after the last injection where no fluid existed. Demographic characteristics, visual acuity, central retinal thickness and the number of injections were recorded and analysed., Results: The spherical equivalent refractive power did not differ significantly pre- or post-injections. Changes in visual acuity and central retinal thickness were statistically significant before and after injections., Conclusions: Intravitreal ranibizumab injections did not seem to affect the refractive power of patients with diabetic macular oedema. Therefore, appropriate spectacle correction can be prescribed any time during ongoing treatment with ranibizumab injections., (© 2017 Optometry Australia.)

Objective: Because many patients with diabetic macular edema (DME) do not respond to focal/grid laser photocoagulation, the only currently approved treatment, alternatives are needed. Based on encouraging preliminary findings, we aimed to assess efficacy and safety of the anti-tumor necrosis factor (TNF) monoclonal antibody infliximab in this condition., Research Design and Methods: This was a single-center, double-blind, randomized, placebo-controlled, crossover study. Eleven patients with sight-threatening DME persisting after two sessions of laser photocoagulation received infliximab (5 mg/kg) intravenously at weeks 0, 2, 6, and 14, followed by placebo at weeks 16, 18, 22, and 30, or vice versa. Blinding was maintained to week 32, when the final assessments were performed. Best corrected visual acuity evaluated by a mixed-models approach for imbalanced crossover design using the percentage difference as the outcome variable was the primary study end point. Data were analyzed on an intention-to-treat basis., Results: Early Treatment of Diabetic Retinopathy Study (ETDRS) scores dropped from 31.6 +/- 5.1 (mean +/- SD) letters read at baseline to 28.8 +/- 11.6 letters read at week 16 in six placebo-treated eyes and improved to 35.4 +/- 11.2 letters read after infliximab. In contrast, visual acuity improved from 23.5 +/- 10.3 at baseline to 30.4 +/- 13.4 letters read at week 16 in eight infliximab-treated eyes and was sustained at completion of placebo treatment (31.4 +/- 12.1 letters read). The excess visual acuity in infliximab-treated eyes was greater by 24.3% compared with that in placebo-treated eyes (95% CI 4.8-43.7; P = 0.017). Infliximab treatment was well tolerated., Conclusions: The positive results of this small phase III study suggest that larger and longer term trials should be conducted to assess the efficacy of systemic or intravitreal anti-TNF agent administration for primary treatment of DME.

Purpose: To investigate the hemostatic effects of SF6 gas in preventing postoperative vitreous hemorrhage in diabetic vitrectomy., Methods: A prospective, randomized study of 33 diabetic eyes with vitreous hemorrhage, treated by vitrectomy. In 17 of our cases SF6 20% was injected into the eye at the end of the operation, while in 16 cases BSS remained in the vitreous cavity., Results: The incidence of vitreous hemorrhage recurrence was 17.6% for the SF6 group and 12.5% for the BSS group (statistically not significant). Progression of lens opacities was observed in 23.5% of the SF6 group, and in 18.8% of the BSS group (statistically not significant, with a higher incidence in the SF6 group)., Conclusions: SF6 gas did not show hemostatic effects in the cases studied. Furthermore, it may have contributed to cataract progression. Therefore we suggest that the use of SF6 is not recommended as a treatment modality in preventing new vitreous hemorrhage after diabetic vitrectomy.

Cataract surgery may exacerbate preexisting diabetic retinopathy. Especially diabetics with active retinal neovascularisation are at high risk of rubeosis iridis after intracapsular cataract extraction. Thirty-five eyes previously treated with panretinal photocoagulation underwent extracapsular cataract extraction with posterior chamber lens implantation. Twenty-eight eyes with retinal neovascularisation required further Argon laser PRP after surgery. Fourteen eyes required YAG-laser capsulotomy. From the group of eyes without YAG-laser capsulotomy none developed neovascular glaucoma. From the YAG laser capsulotomy group six eyes developed rubeosis iridis and neovascular glaucoma. Our results indicate that eyes in which PRP has been performed, have an excellent prognosis after ECCE with posterior chamber lens implantation only if YAG Laser posterior capsulotomy is not performed.

Fifty eyes of 42 patients with background diabetic retinopathy and diffuse macular edema were included in a prospective, randomized, clinical study to determine the long-term visual results of modified grid laser photocoagulation compared with the natural course of the disease. At the end of the three annual follow-up visits there were more eyes with improved visual acuity in the treatment group and more eyes with worse visual acuity in the control group. However, statistical analysis of the data showed that only at the end of the first and the second year was there a significant statistical difference between the two groups. At the end of the third year no statistically significant difference was found. These results suggest that modified grid laser photocoagulation is not an effective procedure for the long-term management of diffuse diabetic macular edema compared with the natural course of the disease.

The prospective study reported here was based on 105 diabetic eyes with "new vessels elsewhere" (NVE), treated exclusively by panretinal laser application and followed up for 2.5 to 4 years. Fundus angiography was performed before treatment. The eyes were then classified in four categories according to the extent and location of capillary nonperfusion responsible for the NVE, namely 1) generalized ischemia (Type A); 2) extensive midperipheral ischemia (Type B); 3) moderate midperipheral ischemia (Type C); and 4) peripheral ischemia (Type D). Analysis of the neovascularization distribution pattern showed that NVE alone existed only in Type D, whereas in the other three types the neovascularization was present either only in the retina or in both the retina and the optic disk. This mixed vascularization was 100% in Type A, 71% in Type B, 31% in Type C, and nonexistent in Type D. Statistical analysis revealed a significant correlation between the type of ischemia and the location of the new vessels. The therapeutic results 3-4 months, 1 year, and 2.5-4 years after intervention showed a significant trend toward an increase in the number of eyes with recurrences when moving from Type D to Type A. This means that the prognosis of NVE after panretinal laser coagulation depends mainly on the type of retinal ischemia. The poorest prognosis is that for generalized ischemia (Type A), followed in descending order by Types B, C, and D. The critical period for increased recurrence in cases which initially responded positively to treatment is primarily in the first 3-4 months following the intervention.

This study comprises 53 eyes, divided into two groups A and B, with proliferative diabetic retinopathy which were treated with panretinal photocoagulation (PRP). Its purpose is to investigate the alterations in the central 15 degrees and 30 degrees of the visual field and in each quadrant separately. In both groups A and B, PRP covered the periphery and mid-periphery. In group A, it stopped 2 disc diameters (DD) from the upper temporal and lower margin of the fovea including the papillomacular bundle, while in group B, PRP stopped 3 DD from the upper temporal and lower margin of the fovea and 1 DD of the nasal margin of the optic disc. The investigation revealed, in group B after PRP, an improvement of the retinal sensitivity in the central 15 degrees of the visual field (p less than 0.01). In the 30 degrees of the visual field a deterioration after PRP was noted in both groups A and B, the deterioration being however much more prominent in group A. Comparing the results between groups B and A after PRP, a difference in the retinal sensitivity in favour of group B at 15 degrees and 30 degrees of the visual field was found. As regards regression of neovascularization and visual acuity, no statistically significant difference has been observed between the two groups.