Persistent Diabetic Macular Edema Research Articles

Beyond VEGF: Angiopoietin-Tie Signaling Pathway in Diabetic Retinopathy.

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin-Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Retinal OCT biomarkers associated with reading performance in patients with persistent vs. resolved diabetic macular edema.

Recent advancements in imaging technologies, particularly structural optical coherence tomography (OCT), have improved the understanding of diabetic macular edema (DME) pathophysiology and provided valuable biomarkers for disease progression and visual outcomes. This prospective study aimed to investigate the association between specific retinal biomarkers identified through OCT imaging and reading performance metrics in patients with previously treated persistent versus resolved DME and good visual acuity. Forty-nine eyes from 35 patients with a history of DME were enrolled. Reading performance was assessed using the Radner reading charts, which include standardized sentences with geometrically progressing print sizes. Structural alterations in the inner and outer retina, as well as the retinal pigment epithelium (RPE), were graded based on OCT images. Reading performance, measured as maximum reading speed, was associated with specific retinal biomarkers. The disruption of the ellipsoid zone (EZ) in the parafoveal region and the presence of disorganization of the inner retinal layers (DRIL) in the parafovea were correlated with reduced reading speed. These associations were independent of the presence of intraretinal or subretinal fluid. Understanding the relationship between retinal biomarkers and reading performance could contribute to a comprehensive evaluation of visual function and quality of life in patients with DME, leading to better management strategies and treatment outcomes.

Aflibercept vs. dexamethasone implant for recalcitrant diabetic macular edema in pseudophakic eyes - 1-year outcomes from a quazi-randomized study in India.

To assess the safety and efficacy of intravitreal Aflibercept (IVA) versus dexamethasone (DEX) implant for treating recalcitrant diabetic macular edema (DME) in pseudophakic eyes at 1-year follow-up. Retrospective comparative case series. Data of all patients diagnosed with DME between January 2019 and December 2021, who underwent 4-monthly doses of intravitreal ranibizumab but had persistent DME [central macular thickness (CMT) within 10% of baseline value] were extracted from a computerized database. Of these, only pseudophakic eyes that underwent either IVA or DEX implant and had at least 1-year follow-up were included for analysis. DEX implant was preferred before December 2020 and IVA after this time point. In the IVA group, patients were followed up every month while DEX were followed at least every 3 months. Reinjections were considered when vision dropped by at least 1 Snellen's line or CMT increased by at least 10% from the previous visit in both groups. Comparison of change in vision and CMT at 1-year follow-up in DEX versus IVA groups. Eighty-four eyes of 84 patients aged 54.4 + 4.4 years were included, 39 (46%) received DEX and 45 (54%) received IVA. Groups were comparable for baseline vision and CMT. Vision improved equally in both groups from 0.83 + 0.15 logMAR to 0.52 + 0.10 logMAR at 3 months ( P < 0.01) and then stabilized till 1 year. However, eyes in the IVA group were 6.5 times more likely (Odds ratio = 6.45, 95% CI = 1.3 - 31.9) to achieve >3-line improvement in vision. The CMT reduction was also comparable between groups (-169 + 51 in DEX vs. -174 + 49 in IVA, P = 0.67). More eyes in the IVA group required >3 injections (91% vs. 69% in DEX, P = 0.01). The IOP was significantly higher at 6 and 9 months in the DEX group and 5 eyes (13%) required IOP lowering medications. In pseudophakic eyes with recalcitrant DME not responding to ranibizumab, switching to IVA or DEX implant results in equal visual improvement and CMT reduction. Though >3-line improvement occurs more frequently with IVA, this comes at the expense of a greater number of injections and follow-up visits.

Machine learning and optical coherence tomography-derived radiomics analysis to predict persistent diabetic macular edema in patients undergoing anti-VEGF intravitreal therapy

BackgroundDiabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. This study aimed to develop and evaluate an OCT-omics prediction model for assessing anti-vascular endothelial growth factor (VEGF) treatment response in patients with DME.MethodsA retrospective analysis of 113 eyes from 82 patients with DME was conducted. Comprehensive feature engineering was applied to clinical and optical coherence tomography (OCT) data. Logistic regression, support vector machine (SVM), and backpropagation neural network (BPNN) classifiers were trained using a training set of 79 eyes, and evaluated on a test set of 34 eyes. Clinical implications of the OCT-omics prediction model were assessed by decision curve analysis. Performance metrics (sensitivity, specificity, F1 score, and AUC) were calculated.ResultsThe logistic, SVM, and BPNN classifiers demonstrated robust discriminative abilities in both the training and test sets. In the training set, the logistic classifier achieved a sensitivity of 0.904, specificity of 0.741, F1 score of 0.887, and AUC of 0.910. The SVM classifier showed a sensitivity of 0.923, specificity of 0.667, F1 score of 0.881, and AUC of 0.897. The BPNN classifier exhibited a sensitivity of 0.962, specificity of 0.926, F1 score of 0.962, and AUC of 0.982. Similar discriminative capabilities were maintained in the test set. The OCT-omics scores were significantly higher in the non-persistent DME group than in the persistent DME group (p < 0.001). OCT-omics scores were also positively correlated with the rate of decline in central subfield thickness after treatment (Pearson’s R = 0.44, p < 0.001).ConclusionThe developed OCT-omics model accurately assesses anti-VEGF treatment response in DME patients. The model’s robust performance and clinical implications highlight its utility as a non-invasive tool for personalized treatment prediction and retinal pathology assessment.

Worsening of early DME after cataract surgery. The DICAT II Study report #2.

To analyse the long anatomical and functional outcome of a subgroup of the DICAT II study cohort, consisting of 26 patients undergoing cataract surgery and withdrawn from the study for a clinically significant worsening of early diabetic macular edema (DME). Patients who underwent cataract surgery and withdrawn from the DICAT II study for a clinically significant worsening of early DME with at least 12 months follow-up after the dropout. The study population was divided into two groups according to the clinical evaluation at one-year follow-up: ongoing treatment patients for DME (Treatment group, TG) and patients no longer treated (Non Treatment group, NTG). Central foveal thickness (CFT) at baseline and dropout time were higher in TG than in the NTG, with a statistically significant difference (p < 0.05). In addition, TG patients reported a higher levels of glycated hemoglobin at time baseline compared to NTG patients (7.81 ± 1.15 vs 7.02 ± 0.56; p = 0.048). The linear regression analysis demonstrated a statistically significant relationship between the visual acuity and the ongoing treatment group at one-year follow-up (p = 0.042). The study provides parameters to be considered when assessing the risk of developing persistent DME after cataract surgery in diabetic patients. In particular, CFT at baseline and dropout time have been reported to be an effective and predictable OCT biomarkers when evaluating DME progression. During the evaluation of the systemic disease, similar results were found for the glycated hemoglobin at baseline.

Real-World Evidence of the Long-Term Effectiveness of 0.2 μg/Day Fluocinolone Acetonide Implant in Persistent and Recurrent Diabetic Macular Edema - A Single Center Study.

To report the long-term functional, anatomical and safety outcomes of 0.2 μg/day fluocinolone acetonide 0.19mg in patients with persistent or recurrent diabetic macular edema (DME). Retrospective, observational, single-center study of patients with recurrent or persistent DME. All patients received 0.2 μg/day of fluocinolone acetonide 0.19mg, and data were collected at baseline and months 1, 3, 6, 12, 24 and 36 after implantation. Outcomes measured included best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP), and safety outcomes. A total of 28 eyes from 28 patients were included. The mean age was 66.5 years (95% CI 62.8-70.2) with a mean duration of DME of 8.8 years (95% CI 7.7-10.0). Only two eyes were phakic. Mean follow-up was 25.4 months (95% CI 21.2-29.6). Mean BCVA at baseline was 48.6 ETDRS letters (95% CI 41.3-55.8) and improved as early as month 1 of follow-up with a mean gain in BCVA of 7.8 (95% CI 4.3-11.3) ETDRS letters (p<0.001). Statistically significant improvements in BCVA were also observed at months 6, 12 and 24. At baseline, patients had a mean CMT of 530.5µm (95% CI 463.0-598.0), and a decrease in CMT was observed, starting at the first month of follow-up (mean CMT reduction of -170.5µm, 95% CI -223.8- -117.1; p<0.001). Statistically significant decreases in CMT were also observed at months 6, 12, 24, and 36, with the maximum decrease observed at month 12 (p<0.001). Mean IOP at baseline was 16.4mmHg (95% CI 15.3-17.5) and nine eyes (32.1%) had an IOP ≥21mmHg during follow-up. Our results support the effectiveness and safety profile of fluocinolone acetonide. Although additional long-term real-world evidence is required, fluocinolone acetonide may represent a safe strategy for daily, low-dose, sustained and localized release to the posterior segment of the eye, providing both functional and anatomical benefits in DME.

Avaliação do endotélio corneano através de microscopia especular em participantes com edema macular diabético

Introduction: While the morphological and functional integrity of the corneal endothelium, which is essential for corneal transparency, is affected by diabetes mellitus (DM), its relationship with the severity of diabetic retinopathy and the presence of diabetic macular edema is unclear. Aims: To assess the morphological characteristics of the corneal endothelium in patients with Type 2 Diabetes Mellitus (T2DM) with different therapeutic response profiles to diabetic macular edema (DME). Methods: With a cross-sectional approach, 24 participants with T2DM were divided into 2 groups (without DME versus with DME). Subsequently, the group with DME was subdivided according to the type of therapeutic response (responder versus persistent). Parameters obtained through specular microscopy (endothelial cell density, coefficient of variation, hexagonality, and central corneal thickness) and optical coherence tomography (minimum foveal thickness, central 1mm thickness, macular ganglion cell layer thickness, and peripapillary retinal nerve fiber layer thickness) were analyzed and compared in the different groups. Results: No significant changes were found in the corneal endothelium between the groups with and without DME (p&gt;0.05). However, differences were found in the density of endothelial cells (p=0.04) in participants with persistent DME (1900.3 ± 270.1) compared to participants with responding DME (2307.9 ± 121.2) and control group (2191.7 ± 165.5). Conclusion: There were no differences in the different parameters of the corneal endothelium between participants with and without DME. However, the kind of therapeutic response to DME seems to be associated with a decrease in endothelial cell density.

Real-world experience with fluocinolone acetonide intravitreal implant in patients with diabetic macular edema.

to evaluate long-term effectiveness and safety of fluocinolone acetonide (FAc) implant used as second-line treatment in patients with persistent diabetic macular edema (DME). retrospective data chart review of 241 pseudophakic eyes of 178 patients treated with FAc from July 2017 to December 2021 in 10 medical retinal units in Italy. The primary endpoint was the change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 2 years. A Student's paired t-test was used. Additional therapies for DME and intraocular pressure (IOP)-related events were also evaluated. efficacy of FAc was assessed in a subset of 111 eyes with at least 24 months of follow-up. Mean BCVA increased at 2 years by 5.1 ETDRS letters (95%CI = 2.6-7.5; p < 0.001) while mean CMT decreased by 189 µm (95% CI 151-227; p < 0.001). Thirty-eight of these eyes (34.2%) needed additional intravitreal treatments, mainly anti-VEGF. Safety was evaluated on the entire cohort of 241 eyes treated with FAc. Overall, 66 eyes (27.4%) required emergent IOP-lowering medications (typically within the first-year post FAc) while 14 eyes (5.8%) underwent trabeculectomy, mostly during the second year of follow-up. FAc implant provides a substantial long-term functional and anatomical benefit when used as second-line treatment in eyes with DME. IOP rise can be adequately managed with topical agents although some eyes may require IOP-lowering surgery.

Conversion to faricimab after prior anti-vascular endothelial growth factor therapy for persistent diabetic macular oedema

BackgroundTo assess the anatomical and functional outcomes in eyes with persistent diabetic macular oedema (pDME) on chronic anti-vascular endothelial growth factor therapy switched to intravitreal faricimab.MethodsPatients with pDME on chronic...

Dexamethasone intravitreal implant (Ozurdex) in phakic patients with diabetic macular oedema resistant to anti‐VEGF therapy: Short‐term visual and anatomical outcomes in a real‐world study

Aims/Purpose: To prospectively study and analyse the clinical effectiveness of using intravitreal dexamethasone (IVO) implant in treatment resistant phakic patients with centre involving diabetic macular oedema (DMO).Methods: Prospective interventional case series of phakic patients with persistent centre‐involving diabetic macular oedema, who received an IVO implant between May 2022 and February 2023 were included. Primary outcome measures include best corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline, 2 months and 6 months. Secondary efficacy outcome measures include, change in level of cataract and change in intraocular pressure (IOP) control requiring topical treatment or interventional procedures.Results: Nine eyes from eight patients were included. Mean age at treatment was 61.87 ± 11.07 years with male preponderance (8:1). There was no statistically significant difference in BCVA at baseline compared to 2 months following IVO (0.291 ± 0.185 vs. 0.287 ± 0.208, respectively, p = 0.919) or comparing BCVA at baseline to BCVA 6 months following IVO (0.291 ± 0.185 vs. 0.347 ± 0.153, respectively, p = 0.063). Reduction in CRT from baseline to 2 months following IVO was highly significant (436.4 ± 65.1 vs. 305.9 ± 58.6, respectively, p = 0.006) and reduction in CRT comparing baseline and 6 months following IVO which remained significant (436.4 ± 65.1 vs. 363.2 ± 96.1, p = 0.041). Mean intraocular pressures was raised in 44.4% eyes with medical management required in 33.3%. Recurrence of maculopathy was noted in 88.9% eyes. Cataract requiring surgery was performed in one eye.Conclusions: This prospective series shows that phakic patients, with persistent DMO following anti‐VEGF therapy undergoing IVO, resulted in a highly statistically significant reduction in CRT at 2 months following IVO which was maintained at 6 months (p = 0.04) although there is high recurrence. BCVA remains stable over the 6‐month period with no statistically significant change.

Intravitreal injection of methotrexate in persistent diabetic macular edema: a 6-month study.

Diabetic macular edema (DME) affects approximately 10% of patients with diabetes mellitus. This condition can cause blurred or distorted vision, which significantly affects the quality of life of these patients. We evaluated the therapeutic effects of intravitreal methotrexate (MTX) injections on persistent DME. This prospective interventional case series included patients with confirmed persistent DME that was unresponsive to previous standard treatments. The patients underwent comprehensive eye examinations and macular imaging with optical coherence tomography (OCT). A single intravitreal MTX injection (400 µg MTX in 0.16 mL solution) was administered, followed by patient assessments at 1, 3, and 6 months after injection. Best-corrected distance visual acuity (BCDVA), intraocular pressure (IOP), macular thickness (MT), and central subfield thickness (CST) were measured at baseline and post-injection to evaluate treatment efficacy. We included 33 eyes of 30 patients with a mean (standard deviation [SD], range) age of 62.7 (8.3, 44 to 77) years, of whom 17 (56.7%) were men and 13 (43.3%) were women. All participants had type 2 diabetes mellitus, with a mean (SD, range) duration of 17.0 (6.8, 10 to 31) years. Most participants (n = 27 eyes, 81.8%) had non-proliferative diabetic retinopathy, and six eyes (18.2%) had regressed proliferative diabetic retinopathy. Four eyes (12.1%) had undergone prior macular laser photocoagulation. The mean (SD) number of prior intravitreal bevacizumab injections was 3.4 (0.8), and 29 eyes (87.8%) had received one intravitreal triamcinolone injection. During the study period, a statistically significant difference was observed in CST (P < 0.05); however, no statistically significant differences were observed in BCDVA, MT, or IOP (P > 0.05). Pairwise comparison revealed a significant decrease in CST at 6 months post-injection compared to the baseline value (P < 0.05). During the investigation period, no side effects of MTX, such as macular edema, retinal tears, vitreous hemorrhage, endophthalmitis, or vision loss, were observed. A single intravitreal MTX injection significantly reduced CST in patients with persistent DME, without relevant safety concerns. However, no significant improvement in functional outcomes was observed. Therefore, there is no strong evidence to recommend its use as a treatment for pDME. Further studies, preferably randomized clinical trials with long-term follow-ups, are warranted to assess the long-term efficacy, safety, and potential benefits of intravitreal MTX for the treatment of persistent DME.

ILUVIEN® in diabetic macular edema that persists or recurs despite treatment: Results from the Retina.pt® RIVER audit.

Persistent diabetic macular edema (DME) remains a problem in clinical practice, with many patients having a suboptimal response to the standard of care (SOC). Evidence supports the long-term efficacy of intravitreal fluocinolone acetonide (FAc) implant (ILUVIEN®) in patients that have responded sub-optimally, although there is still scarce data from real-world Portuguese practices. We aimed to monitor the current SOC in selected Portuguese practices prior to FAc implantation and then assess the long-term effectiveness and safety of the FAc implant. The study included patient data from five Portuguese public hospitals. This was a non-interventional, multicenter audit of data collected from Retina.pt registry from patients with persistent or recurrent DME despite treatment. Outcome measures included changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP). Results were compared at regular times over 36 months. This study included 222 eyes from 152 patients. A significant decrease in BCVA (P < 0.001) and a significant increase in CMT (P = 0.013) were observed prior to FAc. A significant increase in BCVA was registered at 6 months after FAc implant administration (P < 0.001), which was maintained during follow-up. No relevant changes in IOP were observed. Treatment burden was reduced as a result of treatment with FAc (P < 0.001 for anti-VEGF, corticosteroids, or both treatments) in the full population. In Portuguese practice, data showed that pre-FAc implantation, some patients did not respond to SOC treatment and/or they were undertreated. Following FAc implant administration, there were rapid, sustained, long-term visual and anatomical improvements, and a marked reduction in treatment burden.

Switching to Conbercept in Diabetic Macular Edema After Unsatisfactory Response to Previous Intravitreal Injection of Ranibizumab.

To assess the functional and anatomical effects of transitioning to conbercept intravitreal injection (IVC) treatment in patients with diabetic macular edema (DME) who had inadequate responses to prior anti-vascular endothelial growth factor (anti-VEGF) injections. We retrospectively included eyes with persistent DME after at least 3 injections of intravitreal ranibizumab (IVR). The analysis included the assessment of best corrected visual acuity (BCVA) and central macular thickness (CMT) during 6 months after the switch. A total of 30 patients (30 eyes) were included. CMT dropped sharply from 437.8±40.67μm at baseline to 363.59±45.09,312.52 ± 39.15, 278.51 ± 37.92, and 292.59 ± 38.09 after 1, 2, 3 and 6 months of IVC, respectively (p <0.001). BCVA in log MAR units was significantly improved from 0.73±0.15 at baseline to 0.50±0.09,0.46±0.72, 0.40±0.06 and 0.48±0.04 after 1, 2, 3 and 6 months, respectively (p <0.001). Switching to Conbercept effectively improved visual and anatomical structure in DME patients who had not responded satisfactorily to previous anti-VEGF injections.

Retinal changes after fluocinolone acetonide implant (ILUVIEN®) for DME: SD-OCT imaging assessment using ESASO classification.

A detailed understanding of the anatomical and structural changes occurring in the retina following intravitreal fluocinolone acetonide implantation may help improve the management and prognosis of persistent or recurrent diabetic macular edema (DME). Overall, 45 eyes (from 35 patients) with refractory center-involved DME received an intravitreal fluocinolone acetonide implant. They were monitored at baseline and at 6, 12, 24, and 36 months for best-corrected visual acuity (BCVA), central foveal thickness (CFT), and the seven retinal parameters used in the classification of diabetic maculopathy recently developed at the European School for Advanced Studies in Ophthalmology (ESASO). Within 6 months of implantation, significant improvements were evident in BCVA, CFT, maculopathy stage, and the percentage of eyes with: intraretinal cysts; CFT > 30% above the upper normal value; and disrupted or absent ellipsoid zone (EZ) and/or external limiting membrane (ELM). Significant improvements were still maintained at 36 months post-implantation. At month 36, early treatment with the implant (i.e., after < 6 previous intravitreal injections for DME) trended toward being more effective than later treatment in improving BCVA, CFT, maculopathy stage, and the percentage of eyes with CFT > 30% above the upper normal value. However, statistical significance was not achieved. In persistent or recurrent DME, fluocinolone acetonide implantation can be effective in improving maculopathy stage and reducing the percentage of eyes with: intraretinal cysts; CFT > 30% above the upper normal value; and disrupted or absent EZ and/or ELM. It can also increase BCVA and reduce CFT.

Serum apolipoprotein A1 and B are associated with 6-month persistent and incident diabetic macular oedema in type 2 diabetes

AimsTo investigate the associations of baseline apolipoprotein A1 (ApoA1) and B (ApoB) levels with persistent and incident diabetic macular oedema (DMO) after 6 months of follow-up.MethodsThis is a prospective cohort...

Combined Treatment of Persistent Diabetic Macular Edema with Aflibercept and Triamcinolone Acetonide in Pseudophakic Eyes.

Background and Objectives: The main cause of the vision loss in diabetics is the development of diabetic macular edema, regardless of the stage of diabetic retinopathy. The paper aimed to examine whether the additional intravitreal application of triamcinolone acetonide to continuous anti-vascular endothelial growth factor therapy could improve therapeutic outcomes for pseudophakic eyes with persistent diabetic macular edema. Materials and Methods: twenty-four pseudophakic eyes with refractory diabetic macular edema, that had appeared despite three previously administered intravitreal injections of aflibercept, were divided into two groups (twelve eyes in each group). The first group continued to have aflibercept administered according to a fixed dosing regimen (once in two months). Triamcinolone acetonide 10 mg/0.1 mL (administered once per four months) was included for the second group, i.e., their treatment continued with a combination of aflibercept + triamcinolone acetonide. Results: The reduction in central macular thickness was higher in the eyes treated with combined therapy (aflibercept + triamcinolone acetonide) compared with the use of aflibercept alone during the entire 12-month follow-up period (3rd month p = 0.019; 6th month p = 0.023; 9th month p = 0.027; 12th month p = 0.031). As was evident from the p-values, the differences were statistically significant. No statistically significant difference was recorded for visual acuity: 3rd month p = 0.423; 6th month p = 0.392; 9th month p = 0.413; 12th month p = 0.418. Conclusions: Combined anti-vascular endothelial growth factor and steroid therapy leads to a better anatomical outcome of persistent diabetic macular edema in pseudophakic eyes, but does not lead to a more significant improvement in visual acuity than continuous anti-VEGF therapy alone.

Combined intravitreal dexamethasone and bevacizumab injection for the treatment of persistent diabetic macular edema (DexaBe study): a phase I clinical study

PurposeThe aim of this study is to investigate the safety of combined intravitreal injection of dexamethasone aqueous-solution (IVD) and bevacizumab (IVB) in patients with refractory diabetic macular edema (DME) and its effect on intraocular pressure (IOP), best-corrected visual acuity (BCVA) and central subfield thickness (CSFT).MethodsThis prospective study included 10 patients (10 eyes) with DME refractory to laser photocoagulation and/or anti-vascular endothelial growth factor (anti-VEGF) therapy. A complete ophthalmological examination was performed at baseline, during the first week of treatment, and monthly through week 24. Therapy consisted of monthly injections of combined IVD and IVB “pro re nata” (PRN) if CST > 300 µm. We investigated the impact of the injections on intraocular pressure (IOP), cataract development, Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA), and central sub-foveal thickness (CSFT) measured by spectral-domain optical coherence tomography (OCT).ResultsEight patients (80%) completed 24 weeks of follow-up. Compared to baseline, mean IOP increased significantly (p < 0.05) and anti-glaucomatous eye drops were necessary for 50% of the patients, CSFT was significantly reduced at all follow-up visits (p < 0.05), although mean BCVA showed no significant improvement. One patient developed dense cataract progression and another showed vitreoretinal traction at week 24. No inflammation or endophthalmitis was observed.ConclusionTreatment of DME refractory to laser and/or anti-VEGF therapy with combined PRN IV dexamethasone aqueous solution and bevacizumab was associated with adverse effects related to the use of corticosteroids. However, there was a significant improvement in CSFT meantime best-correct visual acuity remained stable or improved in 50% of patients.

Efficacy of 190 mcg fluocinolone acetonide intravitreal implant: microperimetry and OCT real-life data.

Fluocinolone acetonide is a valid alternative treatment for patients with chronic diabetic macular edema (DME) with poor response to anti-vascular endothelial growth factor (VEGF) therapy. The purpose of this study is to report the efficacy and safety of ILUVIEN® implant in pseudophakic eyes with persistent DME. This is a single-centre pilot-study of 8 patients with persistent DME treated with the ILUVIEN implant, despite previous anti-vascular endothelial growth factor and/or steroid treatment. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT) central retinal thickness, intraocular pressure (IOP) and microperimetric data were evaluated at baseline and month 1, 3 and 6 post treatment. All data are presented as mean and standard deviation. At baseline, 1, 3 and 6 months, we had BCVA of 0.26±0.22, 0.38±0.27, 0.48±0.27 and 0.46±0.24; IOP of 15.00±2.67, 15.50±3.16, 14.88±2.42 and 15.63±2.67 mmHg; macular thickness of 652±231, 487±278, 475±287 and 413±211 µm; macular sensitivity of 6.83±4.20, 6.13±3.72, 7.68±3.40 and 7.71±3.33 dB; bivariate contour elliptic area (BCEA) 95.4% 3.8±3.42, 6.06±10.06, 3.05±2.46 and 2.59±2.19°2. According to the results of our study, fluocinolone acetonide (FAc) is a valid therapy option despite some limitations. It has been evidenced that FAc is more effective in patients with mild central macular thickening, while in those with modest to severe central macular thickness (CMT), different therapy strategies should be considered.

Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications.

Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.

Foveal eversion patterns in diabetic macular edema

The aim of the present study was to describe foveal eversion patterns in diabetic macular edema (DME) and to assess their relationship with the course of the disease and the outcome. The study was designed as prospective, observational, with two years of follow-up. DME patients were divided in two groups, one treated by combined anti-VEGF injections and dexamethasone (DEX) implants, and the other treated by fluocinolone acetonide (FAc) implant with additional anti-VEGF retreatments if needed. Main outcome measures were foveal eversion prevalence, foveal eversion patterns, best-corrected visual acuity (BCVA), central macular thickness (CMT), structural OCT metrics, number of intravitreal injections. One hundred and forty-six eyes (146 patients; 80 males; mean age 67 ± 8 years) affected by already treated DME, with 84 eyes treated with anti-VEGF/DEX treatments (mean of 10 ± 3 injections) and 62 treated with FAc implant. Looking at the treatments administered before the inclusion into the study, 84 eyes (58%) were treated with anti-VEGF injections, whereas 62 eyes (42%) underwent a combination of anti-VEGF and corticosteroids implants. DME eyes showed statistically significant improvements of LogMAR BCVA and CMT over the 2-year follow-up. Foveal eversion was found in 83 eyes (57%), categorized as follows: Pattern 1a (16;19%); Pattern 1b (22;27%) and Pattern 2 (45;54%). BCVA improvement was detected in all the subgroups, excepting for Pattern 2, which showed also significantly worse structural OCT parameters. Pattern 1b and Pattern 2 were characterized by significantly higher prevalence of persistent DME (64% and 89% of cases, respectively). Foveal eversion patterns were correlated with progressively worse DME outcome. Foveal eversion may be associated to the loss of foveal homeostasis, with consequent poor response to intravitreal treatments and worse DME outcome.