Development and validation of a simple and practical model for early detection of diabetic macular edema in patients with type 2 diabetes mellitus using easily accessible systemic variables.

OBJECTIVE: Diabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetes mellitus (DM). The goal of early detection has not yet achieved due to a lack of fast and convenient methods. Therefore, we aim to develop and validate a prediction model to identify DME in patients with type 2 diabetes mellitus (T2DM) using easily accessible systemic variables, which can be applied to an ophthalmologist-independent scenario. METHODS: In this four-center, observational study, a total of 1994 T2DM patients who underwent routine diabetic retinopathy screening were enrolled, and their information on ophthalmic and systemic conditions was collected. Forward stepwise multivariable logistic regression was performed to identify risk factors of DME. Machine learning and MLR (multivariable logistic regression) were both used to establish prediction models. The prediction models were trained with 1300 patients and prospectively validated with 104 patients from Guangdong Provincial People's Hospital (GDPH). A total of 175 patients from Zhujiang Hospital (ZJH), 115 patients from the First Affiliated Hospital of Kunming Medical University (FAHKMU), and 100 patients from People's Hospital of JiangMen (PHJM) were used as external validation sets. Area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity, and specificity were used to evaluate the performance in DME prediction. RESULTS: The risk of DME was significantly associated with duration of DM, diastolic blood pressure, hematocrit, glycosylated hemoglobin, and urine albumin-to-creatinine ratio stage. The MLR model using these five risk factors was selected as the final prediction model due to its better performance than the machine learning models using all variables. The AUC, ACC, sensitivity, and specificity were 0.80, 0.69, 0.80, and 0.67 in the internal validation, and 0.82, 0.54, 1.00, and 0.48 in prospective validation, respectively. In external validation, the AUC, ACC, sensitivity and specificity were 0.84, 0.68, 0.90 and 0.60 in ZJH, 0.89, 0.77, 1.00 and 0.72 in FAHKMU, and 0.80, 0.67, 0.75, and 0.65 in PHJM, respectively. CONCLUSION: The MLR model is a simple, rapid, and reliable tool for early detection of DME in individuals with T2DM without the needs of specialized ophthalmologic examinations.

Effectiveness of Conventional Digital Fundus Photography-Based Teleretinal Screening for Diabetic Retinopathy and Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

PURPOSE: This American Academy of Ophthalmology Ophthalmic Technology Assessment aims to assess the effectiveness of conventional teleretinal screening (TS) in detecting diabetic retinopathy (DR) and diabetic macular edema (DME). METHODS: A literature search of the PubMed database was conducted most recently in July 2023 to identify data published between 2006 and 2023 on any of the following elements related to TS effectiveness: (1) the accuracy of TS in detecting DR or DME compared with traditional ophthalmic screening with dilated fundus examination or 7-standard field Early Treatment Diabetic Retinopathy Study photography, (2) the impact of TS on DR screening compliance rates or other patient behaviors, and (3) cost-effectiveness and patient satisfaction of TS compared with traditional DR screening. Identified studies then were rated based on the Oxford Centre for Evidence-Based Medicine grading system. RESULTS: Eight level I studies, 14 level II studies, and 2 level III studies were identified in total. Although cross-study comparison is challenging because of differences in reference standards and grading methods, TS demonstrated acceptable sensitivity and good specificity in detecting DR; moderate to good agreement between TS and reference-standard DR grading was observed. Performance of TS was not as robust in detecting DME, although the number of studies evaluating DME specifically was limited. Two level I studies, 5 level II studies, and 1 level III study supported that TS had a positive impact on overall DR screening compliance, even increasing it by more than 2-fold in one study. Studies assessing cost-effectiveness and patient satisfaction were not graded formally, but they generally showed that TS was cost-effective and preferred by patients over traditional surveillance. CONCLUSIONS: Conventional TS is an effective approach to DR screening not only for its accuracy in detecting referable-level disease, but also for improving screening compliance in a cost-effective manner that may be preferred by patients. Further research is needed to elucidate the ideal approach of TS that may involve integration of artificial intelligence or other imaging technologies in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Treatment of Noninfectious Uveitic Macular Edema with Periocular and Intraocular Corticosteroid Therapies: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the effectiveness and complications of periocular and intraocular corticosteroid therapies for noninfectious uveitic macular edema. METHODS: A literature search of the PubMed database was conducted last in December 2021 and a post-assessment search was conducted in March 2023. The searches were limited to articles published in English and no date restrictions were imposed. The combined searches yielded 739 citations; 53 articles were selected for inclusion because the studies (1) evaluated periocular corticosteroid injection, intraocular corticosteroid injection or implant, suprachoroidal corticosteroid injection, or a combination thereof for uveitic macular edema; (2) had outcomes that included visual acuity (VA) or macular edema assessed clinically or imaged by OCT or fluorescein angiography; and (3) included more than 20 patients. RESULTS: This assessment reviewed 23 articles that provided level I or level II evidence from 18 studies on the use of periocular, suprachoroidal, and intravitreal triamcinolone acetonide injections and intravitreal dexamethasone and fluocinolone acetonide implants or inserts in noninfectious uveitic macular edema. These reports consistently demonstrated that all investigated periocular and intraocular corticosteroid therapies improved VA, macular structure, or both. One comparative study showed that intravitreal triamcinolone acetonide injection and the dexamethasone intravitreal implant had effectiveness superior to that of periocular triamcinolone acetonide injection for these outcomes. As a group, the studies highlighted the potential for these therapies to elevate intraocular pressure and to accelerate cataract formation. CONCLUSIONS: The published literature provides high-quality evidence that periocular and intraocular corticosteroid therapies are effective and safe for the treatment of noninfectious uveitic macular edema. However, information on the relative effectiveness and complication rates across the different therapies is limited. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy and Safety of Faricimab for Macular Edema due to Retinal Vein Occlusion: 24-Week Results from the BALATON and COMINO Trials.

PURPOSE: To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion. DESIGN: Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192). PARTICIPANTS: Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO. METHODS: Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug. RESULTS: Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs. +17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs. +17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 µm [95.03% CI, -316.4 to -306.4 µm] and -304.4 µm [95.03% CI, -309.3 to -299.4 µm]) and COMINO (-461.6 µm [95.03% CI, -471.4 to -451.9 µm] and -448.8 µm [95.03% CI, -458.6 to -439.0 µm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively). CONCLUSIONS: These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Risk Factors for Meeting Criteria for Switching from Bevacizumab to Aflibercept When Treating Eyes with Diabetic Macular Edema and Visual Acuity of < 20/40.

PURPOSE: To identify factors for meeting prespecified criteria for switching from bevacizumab to aflibercept in eyes with center-involved diabetic macular edema (CI-DME) and moderate vision loss initially treated with bevacizumab in DRCR Retina Network protocol AC. DESIGN: Post hoc analysis of data from a randomized clinical trial. PARTICIPANTS: Two hundred seventy participants with one or both eyes harboring CI-DME with visual acuity (VA) letter score of 69 to 24 (Snellen equivalent, 20/50-20/320). METHODS: Eligible eyes were assigned to receive intravitreal aflibercept monotherapy (n = 158) or bevacizumab followed by aflibercept if prespecified criteria for switching were met between 12 weeks and 2 years (n = 154). MAIN OUTCOME MEASURES: Meeting switching criteria: (1) at any time, (2) at 12 weeks, and (3) after 12 weeks. Associations between meeting the criteria for switching and factors measured at baseline and 12 weeks were evaluated in univariable analyses. Stepwise procedures were used to select variables for multivariable models. RESULTS: In the group receiving bevacizumab first, older participants showed a higher risk of meeting the switching criteria at any time, with a hazard ratio (HR) for a 10-year increase in age of 1.32 (95% confidence interval [CI], 1.11-1.58). Male participants or eyes with worse baseline VA were more likely to switch at 12 weeks (for male vs. female: odds ratio [OR], 4.84 [95% CI, 1.32-17.81]; 5-letter lower baseline VA: OR, 1.30 [95% CI, 1.03-1.63]). Worse 12-week central subfield thickness (CST; 10-µm greater: HR, 1.06 [95% CI, 1.04-1.07]) was associated with increased risk of switching after 12 weeks. The mean ± standard deviation improvement in visual acuity after completing the switch to aflibercept was 3.7 ± 4.9 letters compared with the day of switching. CONCLUSIONS: The identified factors can be used to refine expectations regarding the likelihood that an eye will meet protocol criteria to switch to aflibercept when treatment is initiated with bevacizumab. Older patients are more likely to be switched. At 12 weeks, thicker CST was predictive of eyes most likely to be switched in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy of Faricimab versus Aflibercept in Diabetic Macular Edema in the 20/50 or Worse Vision Subgroup in Phase III YOSEMITE and RHINE Trials.

PURPOSE: Diabetic Retinopathy Clinical Research Network Protocol T suggests that the response to treatment among patients with diabetic macular edema (DME) may vary depending on baseline best-corrected visual acuity (BCVA). We evaluated the efficacy of faricimab 6 mg versus aflibercept 2 mg over 2 years in patients with DME and baseline BCVA of 20/50 or worse enrolled in faricimab phase III trials. DESIGN: YOSEMITE and RHINE were identically designed, multicenter, randomized, double-masked, active comparator-controlled, noninferiority trials. PARTICIPANTS: Adults ≥18 years of age with center-involving macular edema secondary to type 1 or 2 diabetes. METHODS: Patients were randomized to faricimab every 8 weeks (Q8W), faricimab personalized treat-and-extend (T&E) regimen, or aflibercept Q8W. Post hoc subgroup analyses were conducted using the intention-to-treat population with baseline BCVA of 20/50 or worse. MAIN OUTCOME MEASURES: Changes in ETDRS BCVA and central subfield thickness (CST) from baseline to years 1 and 2 were compared between treatment arms using mixed-model repeated measures analyses. RESULTS: In YOSEMITE and RHINE, respectively, 220 and 217 patients in the faricimab Q8W arm, 220 and 219 patients in the faricimab T&E arm, and 219 and 214 patients in the aflibercept Q8W arm showed baseline BCVA of 20/50 or worse. In both trials, mean change in ETDRS BCVA was comparable between treatments across trials at years 1 and 2. In YOSEMITE, adjusted mean change from baseline in CST (µm) at year 1 was greater with faricimab Q8W (-232.8; P < 0.0001) and faricimab T&E (-217.4; P = 0.0004) ) versus aflibercept Q8W (-190.4). In RHINE, this was faricimab Q8W (-214.2; P = 0.0006) and faricimab T&E (-206.6; P = 0.0116) versus aflibercept Q8W (-186.6). In both trials, change from baseline in CST at year 2 was greater with faricimab Q8W versus aflibercept. The median time to first CST of <325 µm and first absence of intraretinal fluid was shorter in the faricimab arms versus the aflibercept arm, with fewer injections on average. CONCLUSIONS: In patients with DME and baseline ETDRS BCVA of 20/50 or worse, faricimab treatment resulted in comparable visual acuity, greater reduction in retinal thickness, and fewer injections compared with aflibercept. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Stroke incidence increases with diabetic retinopathy severity and macular edema in type 1 diabetes.

BACKGROUND: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. METHODS: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. RESULTS: During median 18.0 (14.1-19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no-very mild (ETDRS 10-20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02-3.15) in non-proliferative (ETDRS 35-53), and 1.69 (1.02-2.82) in proliferative (ETDRS 61-85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91-3.10) in non-proliferative and 1.35 (0.77-2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66-12.28) in non-proliferative and 4.31 (1.16-16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). CONCLUSIONS: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.

Development of high-performance point-of-care aqueous VEGF detection system and proof-of-concept validation in RVO patients.

OBJECTIVES: To develop a sensitive point-of-care testing (POCT) aqueous vascular endothelial growth factor (VEGF) detection system, and assess its role for predicting the response to anti-VEGF treatment in macular edema secondary to retinal vein occlusion (RVO-ME) patients. METHODS: An automatic point-of-care aqueous humor Magnetic Particle Chemiluminescence Enzyme Immuno-Assay (MPCLEIA) VEGF detection system was developed. The predictive values of aqueous cytokine levels, in combination with imaging parameters, on anatomical treatment response (ATR, the relative central macular thickness change [ΔCMT/bl-CMT]) were analyzed. RESULTS: The automatic MPCLEIA system was able to provide results in 45 min with only 20 µL sample. Among the 57 eyes with available pre- and post-treatment evaluation, ATR significantly correlated with levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and VEGF measured by Luminex xMAP platform, and VEGF measured by MPCLEIA. Optimal cut-off values for these biomarkers were 13.26 ng/L, 23.57 ng/L, 1,110.12 ng/L, 105.52 ng/L, and 85.39 ng/L, respectively. Univariate analysis showed significant associations between ATR category (good response if ATR≤-25 % or poor response otherwise) and IL-6, IL-8, MCP-1, VEGF-xMAP, and VEGF-MPCLEIA (p<0.05). Multivariate logistic regression revealed that ATR category was significantly associated with aqueous VEGF-MPCLEIA (p=0.006) and baseline(bl)-CMT (p=0.008). Receiver operating characteristics analysis yielded an AUC of 0.959 for the regression model combining VEGF-MPCLEIA and bl-CMT, for predicting ATR category. CONCLUSIONS: Our novel MPCLEIA-based automatic VEGF detection system enables accurate POCT of aqueous VEGF, which shows promise in predicting the treatment response of RVO-ME to anti-VEGF agents when combined with bl-CMT.

Novel artificial intelligence for diabetic retinopathy and diabetic macular edema: what is new in 2024?

PURPOSE OF REVIEW: Given the increasing global burden of diabetic retinopathy and the rapid advancements in artificial intelligence, this review aims to summarize the current state of artificial intelligence technology in diabetic retinopathy detection and management, assessing its potential to improve care and visual outcomes in real-world settings. RECENT FINDINGS: Most recent studies focused on the integration of artificial intelligence in the field of diabetic retinopathy screening, focusing on real-world efficacy and clinical implementation of such artificial intelligence models. Additionally, artificial intelligence holds the potential to predict diabetic retinopathy progression, enhance personalized treatment strategies, and identify systemic disease biomarkers from ocular images through 'oculomics', moving towards a more precise, efficient, and accessible care. The emergence of foundation model architectures and generative artificial intelligence, which more clearly reflect the clinical care process, may enable rapid advances in diabetic retinopathy care, research and medical education. SUMMARY: This review explores the emerging technology of artificial intelligence to assess the potential to improve patient outcomes and optimize personalized management in healthcare delivery and medical research. While artificial intelligence is expected to play an increasingly important role in diabetic retinopathy care, ongoing research and clinical trials are essential to address implementation issues and focus on long-term patient outcomes for successful real-world adoption of artificial intelligence in diabetic retinopathy.

SGLT2 inhibitors and diabetic retinopathy progression.

PURPOSE: To evaluate whether sodium-glucose co-transporter 2 (SGLT2) inhibitors affect progression of non-proliferative diabetic retinopathy (NPDR) compared to standard of care. METHODS: A retrospective cohort study compared subjects enrolled in a commercial and Medicare Advantage medical claims database who filled a prescription for a SGLT2 inhibitor between 2013 and 2020 to unexposed controls, matched up to a 1:3 ratio. Patients were excluded if they were enrolled for less than 2 years in the plan, had no prior ophthalmologic exam, had no diagnosis of NPDR, had a diagnosis of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR), had received treatment for vision-threatening diabetic retinopathy (VTDR), or were younger than 18 years. To balance covariates of interest between the cohorts, an inverse probability treatment weighting (IPTW) propensity score for SGLT2 inhibitor exposure was used. Multivariate Cox proportional hazard regression modeling was employed to assess the hazard ratio (HR) for VTDR, PDR, or DME relative to SGLT2 exposure. RESULTS: A total of 6065 patients who initiated an SGLT2 inhibitor were matched to 12,890 controls. There were 734 (12%), 657 (10.8%), and 72 (1.18%) cases of VTDR, DME, and PDR, respectively, in the SGLT2 inhibitor cohort. Conversely, there were 1479 (11.4%), 1331 (10.3%), and 128 (0.99%) cases of VTDR, DME, and PDR, respectively, among controls. After IPTW, Cox regression analysis showed no difference in hazard for VTDR, PDR, or DME in the SGLT2 inhibitor-exposed cohort relative to the unexposed group [HR = 1.04, 95% CI 0.94 to 1.15 for VTDR; HR = 1.03, 95% CI 0.93 to 1.14 for DME; HR = 1.22, 95% CI 0.89 to 1.67 for PDR]. CONCLUSION: Exposure to SGLT2 inhibitor therapy was not associated with progression of NPDR compared to patients receiving other diabetic therapies.

Continuous glucose monitoring metrics following sub-Tenon's injection of triamcinolone acetonide for diabetic macular edema.

PURPOSE: This pilot study aims to comprehensively evaluate the effects of sub-Tenon's injection of triamcinolone acetonide (STTA) on glycemic control in patients with diabetic macular edema (DME) using professional continuous glucose monitoring (CGM). METHODS: This retrospective study analyzed changes in glycemic control in 20 patients with type 2 mellitus and DME following single STTA (20 mg/0.5 mL) using The FreeStyle Libre Pro system. Professional CGM provides core CGM metrics such as the percentage of time that glucose levels fall within a target range and include the time in range (TIR) (70-180 mg/dL), time above range (TAR) (> 180 mg/dL), and time below range (TBR) (< 70 mg/dL). Outcome measures were the changes in CGM metrics (TIR, TAR and TBR) and the percentage of patients in whom TAR increased by at least 10 percentage points (ppt) 4 days before to 4 days after STTA administration. RESULTS: The mean CGM metrics (TIR/TAR/TBR) were 75.5%/19.9%/4.4% 4 days before STTA and 73.7%/22.4%/3.5% 4 days after STTA; the metrics 4 days before and 4 days after STTA were not significantly different (P = 0.625 for TIR, P = 0.250 for TAR, and P = 0.375 for TBR). TAR increased by more than 10 ppt in four (20%) patients treated with sulfonylurea and/or insulin. CONCLUSION: Although there were no significant changes in the CGM metrics, four patients developed CGM-measured hyperglycemia after STTA for DME.

Relationship between ischemic index, leakage index, and macular edema in branch retinal vein occlusion.

PURPOSE: To investigate the combined association of the ischemic index and leakage index with macular edema on ultra-widefield fluorescein angiography (UWFFA) in patients with branch retinal vein occlusion (BRVO). METHODS: Retrospective image analysis study. The leakage index and ischemic index were calculated using Fiji after aligning early and late UWFFA images. Differences in the ischemic index, leakage index, and central macular thickness (CMT) between ischemic and non-ischemic BRVO were compared. Moreover, the association between the ischemic index, leakage index, and macular edema was analyzed. RESULTS: Eighty-three patients with BRVO were enrolled, including 53 non-ischemic BRVO and 30 ischemic BRVO patients. No significant differences were observed in leakage index and CMT between ischemic BRVO and non-ischemic BRVO (all P > 0.05). In all included patients, CMT correlated with the panretina and all subregion leakage indexes (all P < 0.01), but not with the ischemic index (all P > 0.05). In the ischemic BRVO group, CMT showed a correlation with the leakage index in several regions, but not with the ischemic index. After adjusting for the ischemic index and other clinical features, CMT remained significantly correlated with the leakage index in all regions. CONCLUSION: The leakage index may be a more effective biomarker for monitoring BRVO-associated macular edema compared to the ischemic index. Further follow-up studies are warranted to validate these findings.

Subthreshold micropulse laser combined with anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis.

PURPOSE: To evaluate the effects of subthreshold micropulse laser (SML) in addition to anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were systematically searched for studies that compared anti-VEGF with SML and anti-VEGF monotherapy for DME. Outcome measures were best-corrected visual acuity (BCVA), central macular thickness (CMT), and the number of anti-VEGF injections. RESULTS: Eight studies including 493 eyes were selected. Four studies were randomized controlled, and the other four were retrospective. Meta-analysis showed that there was no significant difference in BCVA (mean difference [MD] -0.04; 95%CI -0.09 to 0.01 logMAR; P = 0.13;). CMT was thinner in the group of anti-VEGF with SML (MD -11.08; 95%CI -21.04 to -1.12 µm; P = 0.03); however, it was due to a single study that weighed higher, and the sensitivity and subcategory analyses did not support the finding. The number of anti-VEGF injections was significantly decreased in the group of anti-VEGF with SML (MD -2.22; 95%CI -3.02 to -1.42; P < 0.0001). CONCLUSION: Current evidence indicates that adding SML to anti-VEGF therapy could significantly reduce the number of anti-VEGF injections compared to anti-VEGF monotherapy, while achieve similar BCVA and CMT.

Biomarkers determining treatment interval of diabetic macular edema after initial resolution by anti-vascular endothelial growth factor.

PURPOSE: To identify predictive factors that help determine the interval of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection after the initial resolution of diabetic macular edema (DME). METHODS: This retrospective case-control study enrolled treatment-naïve DME patients who had achieved DME resolution after intravitreal anti-VEGF injections. Patients were classified into the recurrence and no-recurrence groups, depending on the development of recurrent DME after deferring intravitreal anti-VEGF injection. The demographics and clinical features, including optical coherence tomography findings, were compared between the two groups. RESULTS: We enrolled 105 eyes. Sixty eyes (57.1%) belonged to the no-recurrence group, and 45 (42.9%), belonged to the recurrence group. The severity of diabetic retinopathy at baseline was related to early DME recurrence (P = 0.009). At the treatment deferring point, the non-recurrence group had both thinner central subfield thickness (289.5 ± 27.2 µm vs. 307.0 ± 38.2 µm, P = 0.011) and thinner central retinal thickness (214.9 ± 41.4 µm vs. 231.8 ± 41.2 µm, P = 0.043) compared to the recurrence group. Intraretinal cyst was observed in 34 eyes (56.7%) in the no-recurrence group and 42 eyes (93.3%) in the recurrence group at the deferring point (P < 0.001). CONCLUSION: A low risk of early DME recurrence is anticipated in the eyes with foveal thinning and no intraretinal cyst when anti-VEGF injection is deferred. These predictive biomarkers can be useful for patient monitoring and determining treatment strategies for DME patients.

Optical coherence tomography angiography macular biomarkers of peripheral retinal ischemia in diabetic macular edema: secondary endpoints from the clinical study "FOVEA".

PURPOSE: To investigate the relationship between the macular values of fractal dimension (FD) and lacunarity (LAC) on optical coherence tomography angiography (OCTA) images and the presence of peripheral retina non-perfusion areas (NPAs) on fluorescein angiography (FA) in patients with treatment-naïve diabetic macular edema (DME). METHODS: Fifty patients with treatment-naïve DME underwent a full ophthalmic examination, including best-corrected visual acuity measurement, FA, spectral-domain optical coherence tomography, and OCTA. Specifically, FA was performed to detect the presence of retinal NPAs, whereas fractal OCTA analysis was used to determine macular FD and LAC values at the level of the superficial and deep capillary plexus (SCP and DCP). FA montage frames of the posterior pole and peripheral retina, as well as macular OCTA slabs of the SCP and DCP, were obtained. RESULTS: Thirty (60%) eyes with FA evidence of peripheral retinal NPAs in at least one quadrant showed significantly lower FD and higher LAC in both SCP and DCP, when compared with eyes presenting a well-perfused peripheral retina. Furthermore, macular FD and LAC values were found to be significantly associated with the extent of retinal NPAs. CONCLUSIONS: Macular FD and LAC of both SCP and DCP seem to be strongly associated with the extent of peripheral retinal NPAs, thus suggesting that may be useful predictive biomarkers of peripheral ischemia in treatment-naïve DME eyes.

Flare levels after intravitreal injection of brolucizumab for diabetic macular edema.

PURPOSE: This study aimed to evaluate anterior flare intensity (AFI) after intravitreal injection of brolucizumab (IVBr) in patients with diabetic macular edema (DME), and to identify the factors associated with the change of AFI after IVBr. METHODS: This prospective multicenter study was conducted at five sites in Japan for patients with DME who underwent a single IVBr. AFI and central retinal thickness (CRT) were measured using a laser flare meter and spectral-domain optical coherence tomography, respectively, at weeks 0 and 6. RESULTS: Sixty-five patients (phakia, 37 eyes; pseudophakia, 28 eyes) were enrolled. Six weeks after IVBr, CRT and best-corrected visual acuity significantly improved (p < 0.0001). AFI (p = 0.0003) and age (p = 0.0054) were significantly higher in patients with pseudophakic eyes than those with phakic eyes. The AFI of the phakic eyes decreased after IVBr (p = 0.043). As the AFI before injection is higher (p = 0.0363) and the age is lower (p = 0.0016), the AFI decreases after IVBr. There was a significant positive correlation between the rates of change in CRT and AFI (p = 0.024). CONCLUSION: After IVBr, AFI decreases in phakic eyes but not in pseudophakic eyes. The age, AFI and CRT before injection and changes of CRT are involved in the change in AFI after IVBr.

Switching to subtenon triamcinolone acetonide does not jeopardize the functional and anatomic outcomes of dexamethasone implant treated eyes with diabetic macular edema.

BACKGROUND: Intraocular dexamethasone implant (DEXi) is an efficient treatment for diabetic macular edema (DME). However, it may be unavailable or contraindicated. Triamcinolone acetonide is another corticosteroid that has proved to be safe and effective in treating macular edema complicating various diseases including diabetes. The purpose of this study is to evaluate the outcomes of a switch from DEXi to subtenon triamcinolone acetonide (STTA) and back, in eyes with DME. METHODS: Retrospective study. DME eyes that had been treated with DEXi and switched to STTA between October 2018 and February 2019 (stock shortage of DEXi) were included. The functional and anatomical outcomes of the switch and switch-back were studied. RESULTS: 26 eyes of 17 patients (mean age 67.1 ± 8.2 years) were considered. The mean baseline visual acuity (VA) was 0.35 ± 0.17 decimals remaining stable after DEXi, STTA and switch-back to DEXi. The mean central macular thickness (CMT) was 492.7 ± 32.8 µm initially, decreasing to 294.3 ± 133.4 µm after DEXi, 369.9 ± 182.3 µm after STTA and 297.6 ± 72.0 µm after switching back to DEXi (all p < 0.05 versus baseline). Compared to baseline, the CMT reduction was numerically better after DEXi and switching back to DEXi than after STTA (mean reduction: -200.4 µm, -167.7 µm, and -95.08 µm respectively, p = 0.13). Intraocular pressure was comparable after DEXi and STTA. CONCLUSION: DEXi is the steroid of choice in DME. However, STTA can be a cost-effective alternative when DEXi is unavailable or contraindicated. This study suggests that STTA may be used in the context of a step therapy in DME.

Efficacy of anti-VEGF monotherapy versus anti-VEGF therapy with subthreshold micropulse laser (SML) in the management of diabetic macular oedema (DMO): a systematic review and meta-analysis.

BACKGROUND: Intravitreal injection anti-vascular endothelial growth factor (IVI anti-VEGF) therapy serves as the primary treatment for centre involving diabetic macular oedema (DMO). Conventional laser therapy (CLT) adjunct has proven beneficial; however, it is not widely used due to significant risks of retinal scarring. Subthreshold micropulse laser (SML) therapy has, however, emerged as a comparable alternative to combination therapy, offering a distinct advantage by mitigating the risk of retinal scarring. METHODS: A search of six databases was conducted. A meta-analysis of mean differences was performed including subgroup analyses where appropriate. Primary outcome was the number of injections at 12-14 months; secondary outcomes were changes in central macular thickness (CMT) and best corrected visual acuity (BCVA) at 6-8 months and 12-14 months. RESULTS: A total of ten papers including six randomised clinical trials and four retrospective clinical studies were included in our study, capturing 563 eyes of 478 patients. Overall, the risk of bias was moderate for these studies. Significantly fewer anti-VEGF therapy injections were administered in the combination therapy versus anti-VEGF monotherapy patients at 12-14 months who had poor visual acuity (6/18 Snellen or worse) at baseline, mean difference - 2.25 (95% CI; - 3.35, - 1.15; p < 0.05). Combination therapy was not associated with significantly fewer intravitreal injections in patients with a higher visual acuity (6/15 Snellen or better) at baseline. Our analysis also showed significant improvements to both BCVA and CMT were reached at 6 - 8 month post-baseline at the 95% confidence intervals: - 1.13 (- 2.09, - 0.16) and - 4.04 (- 7.59, - 0.50). These improvements remained statistically significant at 12-14 months: - 0.94 (- 1.67, - 0.20) and - 1.92 (- 3.52, - 0.32) respectively with combination therapy. CONCLUSION: Our findings demonstrate that combination therapy (SML + IVI anti-VEGF) is associated with fewer intravitreal injections. We report a better BCVA and a reduction in CMT at 6 and 12 months from baseline with combination treatment compared to the IVI anti-VEGF monotherapy comparator. SML is a proven non-scarring cost-effective therapy for DMO that should be readily available in the medical retinal therapy as it may reduce the burden of care.

The longitudinal follow-up of a newly proposed OCTA imaging finding (SSPiM) and the importance of it as a new biomarker for treatment response in diabetic macular edema.

PURPOSE: This study aimed to evaluate the frequency of SSPiM (suspended scattering particles in motion), systemic risk factors, ocular findings, progression characteristics, and treatment response in diabetic retinopathy (DR) patients. METHODS: In this prospective study, a total of 109 eyes of 109 patients with diabetic macular edema (DME) were included. Demographic characteristics and systemic data of the patients were recorded. In addition to a detailed ophthalmological examination, optical coherence tomography (OCT) and OCT angiography (OCTA) imaging were performed. According to the OCTA images, the patients were divided into two categories: SSPiM detected (SSPiM +) and undetected (SSPiM -). The patients were followed up at 0, 3, and 6 months. Treatment responses at 6 months in treatment-administered patients with and without SSPiM were examined. RESULTS: The frequency of SSPiM in DME cases was found to be 34.9%. No significant correlation was found between SSPiM and demographic characteristics, systemic, and biochemical parameters (p > 0.05). It was observed that SSPIM was most frequently localized in the outer nuclear layer adjacent to the outer plexiform (81.6%). SSPiM appearance disappeared in 7 (19.4%) of 36 patients with SSPiM who had regular follow-up for 6 months. In 4 (11.1%) of these seven patients, hard exudate plaques developed in the areas where SSPiM disappeared. Regarding treatment response at 6 months, the decrease in CMT was statistically significantly lower in the SSPiM group compared to cases without SSPiM. CONCLUSION: SSPiM is a finding seen in approximately one-third of DME patients and may adversely affect the response to the treatment.

ESASO classification relevance in the diagnosis and evolution in diabetic macular edema patients after dexamethasone implant treatment.

PURPOSE: To assess the clinical relevance of The European School for Advanced Studies in Ophthalmology (ESASO) classification in patients with diabetic macular edema (DME) after their first dexamethasone implant (DEXI) treatment. METHODS: Retrospective real-world study conducted on consecutive DME patients who underwent DEXI treatment and were controlled at month-2. Subjects were initially classified according to the ESASO classification stages. The outcomes were anatomical biomarkers with spectral-domain optical coherence tomography (SD-OCT) and best-corrected visual acuity (BCVA). RESULTS: A total of 128 patients were classified according to ESASO classification stages as early (7; 5.5%), advanced (100; 78.1%), and severe (21; 16.4%). At baseline, there were significant differences between stages in BCVA, central macular thickness (CMT), and tomography anatomical biomarkers (p < 0.05). Initial BCVA (logMAR) was 0.33 ± 0.10, 0.58 ± 0.34, and 0.71 ± 0.35 in the early, advanced, and severe stages, respectively (p < 0.05). At month-2, BCVA was 0.17 ± 0.15, 0.46 ± 0.29, and 0.69 ± 0.27 in those classified as early, advanced, and severe stages, respectively. At month-2, DME was resolved or improved in 6 (85.7%), 60 (60%), and 12 (60%) patients classified as early, advanced, and severe stages, respectively. CONCLUSIONS: There was a good correlation between BCVA and ESASO classification stages. Patients in the severe stage did not achieve visual acuity improvement over the study period.