Comparison between indocyanine green angiography and optical coherence tomography angiography for the detection of nonexudative macular neovascularization.

PURPOSE: Patients with unilateral treatment-naïve exudative neovascular age-related macular degeneration (nAMD) were examined for the presence of nonexudative macular neovascularization (neMNV) in their fellow eye using a multimodal imaging approach. This is intended to determine the sensitivity of individual imaging methods, namely, indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA). METHODS: In this retrospective cross-sectional study, ICGA images of the nonexudative eye were analyzed for the presence of plaques. SS-OCTA outer retinal segmentations were evaluated for neovascular flow in en-face scans and/or color-coded flow in B-scans. The findings were matched with a double-layer sign (DLS) or pigment epithelium detachment (PED) on conventional OCT. RESULTS: In total, neMNV was diagnosed in the fellow eye of 40 of 241 patients (17%) using a multimodal imaging approach employing both ICGA and SS-OCTA. 25 eyes (10%) showed neMNV in both modalities, while 7 (3%) were only detected by ICGA and 8 (3%) by OCTA alone. The sensitivities of ICGA therefore were 80% (32/40) and 83% (33/40) for OCTA. Of the 40 eyes with neMNV, OCT revealed DLS in 25/40 (63%) and PED in 17/40 (43%) of the cases. CONCLUSION: None of the modalities alone could detect all neMNV in the partner eye of Caucasians with unilateral treatment-naïve exudative nAMD. ICGA and OCTA showed comparable sensitivity. The combination of ICGA, OCTA, and OCT provides the most comprehensive screening for this AMD subtype.

OPTICAL COHERENCE TOMOGRAPHY AND OCT ANGIOGRAPHY CHARACTERISTICS OF INDOCYANINE GREEN ANGIOGRAPHIC PLAQUES IN NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To describe characteristics of indocyanine green (ICG) angiographic plaques in the nonexudative fellow eye of White patients with unilateral treatment-naïve exudative neovascular age-related macular degeneration through optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: In this retrospective cross-sectional study, nonexudative eyes with ICG angiographic plaques were analyzed by OCT B-scans for the sensitivity of a double-layer sign, a pigment epithelium detachment, outer retinal atrophy, hyperreflective dots, and subretinal hyperreflective material (SRHM). The ICG angiographic plaque was matched with a macular neovascularization in OCTA en face scans and color-coded B scans. RESULTS: In total, 35 ICG angiographic plaques in 33 of 291 (11%) nonexudative eyes were diagnosed. OCT revealed 27 double-layer sign (78%), eight pigment epithelium detachment (23%), 8 outer retinal atrophy (23%), eight hyperreflective dots (23%), and one subretinal hyperreflective material (3%). OCTA confirmed a macular neovascularization in 28 plaques (80%): 7 (20%) in en face scans, 3 (9%) in color-coded B scans, and 18 (51%) in both. The area size in OCTA was significantly smaller than that of ICG angiography ( P = 0.002). CONCLUSION: The diagnosis of an ICG angiographic plaque in nonexudative fellow eyes of Whites with unilateral treatment-naïve exudative neovascular age-related macular degeneration was highly suggestive of a typical macular neovascularization type 1 as characterized by OCT and OCTA.

The Impact of the COVID-19 Pandemic on the Quality of Care of Treatment-Naïve Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept. / Die Auswirkungen der COVID-19-Pandemie auf die Versorgungsqualität von therapienaiven PatientInnen mit neovaskulärer altersbedingter Makuladegeneration unter intravitrealer Aflibercept-Therapie.

OBJECTIVE: The aim of this study was to compare the quality of care received by treatment-naïve patients with neovascular age-related macular degeneration (nAMD) who received intravitreal aflibercept therapy before the coronavirus disease 2019 (COVID-19) pandemic with patients who received the same therapy during the pandemic. METHODS: Data, including best corrected visual acuity (BCVA) as the logarithm of the minimum angle of resolution (logMAR) and anatomical outcomes at diagnosis and at each follow-up, was collected on 297 treatment-naïve patients who received intravitreal aflibercept. Therapy-naïve patients who started therapy at least 24 months prior to the first pandemic-related lockdown and were thus treated exclusively prior to the pandemic (n = 123) were compared with patients who started therapy within 12 months prior to the first lockdown and were thus treated during the pandemic (n = 174). Both groups were followed over a two-year period. RESULTS: In patients treated before the COVID-19 pandemic, VA remained stable (0.58 ± 0.41 logMAR) compared to baseline (0.54 ± 0.34 logMAR; p = 0.228) until the end of the observation period. In patients treated during the COVID-19 pandemic, BCVA dropped below the baseline (0.56 ± 0.35 logMAR) within 24-month of follow-up (0.79 ± 0.43 logMAR; p = 0.010). Compared to the patients treated prior to the COVID-19 pandemic, the latter group showed a significantly worse VA at the 6-month (p = 0.041), 12-month (p = 0.040), 18-month (p = 0.024), 21-month (p = 0.035), and 24-month (p = 0.004) follow-up. Additionally, the group treated during the COVID-19 pandemic received significantly fewer aflibercept injections (3,94 ± 1,9 vs. 3,30 ± 1,6; p = 0,007) and fewer follow-up examinations (2,71 ± 1,2 vs. 2,16 ± 0,9; p < 0,001) in the second year compared to the group that was treated before the COVID-19 pandemic. CONCLUSION: We confirmed significantly worse VA outcomes in the group of nAMD patients treated during the COVID-19 pandemic. Impeded access to care could be attributed to the restrictions imposed owing to the COVID-19 pandemic.

CHANGES IN SYSTEMIC LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AFTER INTRAVITREAL INJECTION OF AFLIBERCEPT OR BROLUCIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To analyze and compare the effects of intravitreal brolucizumab versus aflibercept on systemic vascular endothelial growth factor (VEGF)-A levels in patients with neovascular age-related macular degeneration. METHODS: In this prospective interventional case series study, brolucizumab (6.0 mg/50 µL) or aflibercept (2.0 mg/50 µL) was injected intravitreally in 30 patients each. Blood samples were drawn at baseline and 7 days and 28 days after the first injection. Systemic VEGF-A levels were measured using enzyme-linked immunosorbent assay. Thirty healthy individuals served as controls. RESULTS: The median baseline systemic VEGF-A levels in the brolucizumab, aflibercept, and control groups were 10.8 (8.0-13.2), 12.0 (8.0-18.5), and 10.0 (8.0-15.1) pg/mL, respectively (P = 0.315). In the brolucizumab group, VEGF-A levels significantly decreased to 8.0 (8.0-11.5) pg/mL on Day 7 (P = 0.0254) and to 8.0 (8.0-8.0) pg/mL on Day 28 (P < 0.001). In the aflibercept group, VEGF-A levels significantly decreased to 8.0 (8.0-8.0) pg/mL on Day 7 (P < 0.001) but returned to the baseline level, 12.5 (8.5-14.6) pg/mL, on Day 28 (P = 0.120). Vascular endothelial growth factor-A levels were significantly different between the treatment groups after 28 days (P < 0.001). CONCLUSION: Intravitreal brolucizumab resulted in a sustained reduction of systemic VEGF-A levels until 28 days posttreatment, which raises concerns regarding its safety and long-term effects.

Long-term persistence with aflibercept therapy among treatment-naïve patients with exudative age-related macular degeneration in a universal health care system: a retrospective study.

BACKGROUND: This study aimed to analyse the persistence rates of treatment-naïve patients with neovascular age-related macular degeneration (nAMD) who received intravitreal aflibercept therapy in a universal health care system. METHODS: In this single-centre retrospective cohort study, we audited data of 918 treatment-naïve patients who received exclusively intravitreal aflibercept therapy for nAMD between September 2015 and May 2021. The primary outcome measures were the rates of treatment nonpersistence (gap in ophthalmological care > 6 months) and long-term nonpersistence (> 12 months). RESULTS: The rates of nonpersistence and long-term nonpersistence were 12.3% and 3.4% after one year; 22.4% and 9.5% after two years; and 38.3% and 19.3% after five years, respectively. Logistic regression analysis revealed that older age (p = 0.045), male sex (p = 0.039), requirement for caretakers or ambulance (p = 0.001), and low visual acuity of the study eye (p = 0.010) or fellow eye (p = 0.029) were independent risk factors for long-term nonpersistence. Patients aged > 80 and > 85 years (p = 0.013 and p = 0.022, respectively) had more than twice the risk for being nonpersistent to therapy within two years of follow-up compared with younger patients. Male patients (p = 0.033), patients requiring a caretaker (p = 0.038), and patients living > 60 km from the clinic (p = 0.029) had a 2 × higher risk of being persistently nonpersistent to therapy. CONCLUSIONS: Patients with nAMD who were treated with aflibercept had lower nonpersistence rates than those reported in current literature. Multiple independent risk factors were correlated with long-term nonpersistence, early nonpersistence, or complete loss to follow-up. Considering the possible consequences of reduced compliance, further strategies are urgently needed for patients at risk of nonpersistence to therapy.

Impact of submacular fluid volume on visual outcome in macula-off rhegmatogenous retinal detachment using automated optical coherence tomography volumetric quantification.

BACKGROUND: We investigated effects of submacular fluid volume (SMFV) on visual outcomes following surgery for macula-off primary rhegmatogenous retinal detachment (RRD) using automated fluid volumetric quantification with optical coherence tomography (OCT). METHODS: We analysed 127 eyes that were surgically treated for macula-off RRDs. We obtained preoperative images following the spectral domain (SD)-OCT dense volume protocol, applied automated retinal segmentation and used an automated algorithm to quantify each eye's SMFV. We used multivariate models to identify various risk factors for impaired visual outcome. RESULTS: Linear regression showed that preoperative SMFV (ß = 0.013; P = .005) was significantly associated with a reduced visual outcome 12 months after the treatment of macula-off RRDs. SMFV was negatively correlated with 12-month postoperative (r = .311; P = .001) visual acuity (VA). The group with low preoperative SMFV (≤9.0 mm3 ) showed an increasing VA up to 12 months postoperatively (P < .001), while the VA did not increase in the group with high SMFV (>9.0 mm3 ) beyond 3 months of follow-up. Patients with a high SMFV were 8.0 times more likely to have worse visual outcomes after 12 months of follow-up (P = .018). CONCLUSIONS: SMFV was negatively correlated with visual outcomes after the surgical treatment of macula-off RRDs. Patients with SMFV <9.0 mm3 12 months after surgery had an 8.0 times greater chance for better visual recovery than patients with high preoperative SMFV. Our findings highlight the efficacy of automated SMFV quantification in predicting surgical outcomes in patients with RRDs, which could be useful in future clinical practice and the development of research models.

[Patient Mobility and Journey Distance as Risk Factors for Severe Visual Impairment: Real-Life Data Analysis of Treatment-naïve Patients with nAMD under Intravitreal Aflibercept Therapy]. / PatientInnen-Mobilität und Anreisedistanz als Risiko für höhergradige Sehbehinderung: Real-Life-Daten therapienaiver AMD-PatientInnen unter intravitrealer Aflibercept-Therapie.

OBJECTIVE: The aim of this study is to describe the effectiveness of aflibercept in treatment-naive patients with neovascular age related macular degeneration (nAMD) and the impact of patients' residential distance to the clinic and patients' mobility on therapy in a pro re nata regime. METHODS: A retrospective dataset analysis of 483 treatment-naive patients with nAMD was performed. The main outcomes were best corrected visual acuity (BCVA), central foveal thickness (CFT), bilateral visual impairment, distance and type of transport to the clinic. Secondary outcomes were injection rate, numbers and reasons of loss to follow-up. RESULTS: Patients received 4.91 ± 1.9 injections in their first year and 7.06 ± 3.6 after the period of 25 months (m). Initially the BCVA improved significantly after a loading dose from 0.72 logMAR (± 0.44) to 0.63 logMAR (± 0.45; p = 0.03). However, the BCVA significantly decreased after 2 years to 0.82 (± 0.48; p < 0.001). The proportion of patients with higher visual impairment and patients needing assistance with transport increased with the distance of their residence to the clinic (both p < 0.001). The LTFU rate was 3% and showed a correlation with greater age (p = 0.019). CONCLUSION: The presented data show that aflibercept is effective for the treatment of nAMD. Although a good increase in visual acuity is initially achieved in the majority of patients, the initial success of treatment is not maintained throughout the course of the disease. Compared to controlled clinical studies, the presented data show reduced therapeutic success and lower injection frequencies. The rising demand for patient transport aid and increased visual impairment with increased distance indicate potential problems within the healthcare system.

Treatment compliance and adherence among patients with diabetic retinopathy and age-related macular degeneration treated by anti-vascular endothelial growth factor under universal health coverage.

PURPOSE: To analyze and compare loss to follow-up (LTFU) rates between patients with diabetic retinopathy (DR) and those with neovascular age-related macular degeneration (nAMD) in patients, receiving treatment with anti-vascular endothelial growth factor (VEGF), under universal health coverage. METHODS: We retrospectively analyzed the relevant data of 1264 patients receiving anti-VEGF therapy, in this cohort study. The observation period ranged from September 01, 2015 to December 31, 2018. Intervals between each procedure and the subsequent follow-up examination were measured. Demographic data, visual acuity (VA), the type of transport for treatment access, and distance between the residence and clinic were evaluated as risk factors for LTFU. RESULTS: We collected data for 841 patients with nAMD (age, 81.0 (± 8.1 years)) and 423 patients with DR (age, 67.7 (± 12.1 years)). The rate of LTFU, for at least 6 months, was 28.8% and 2.9% for patients with DR and nAMD, respectively (p < 0.001). In the DR group, 18.9% patients were lost to follow-up exceeding > 12 months. Multivariate regression analysis showed that advanced age, lack of mobility, and need for assisted transport, poor final VA despite treatment, and decrease in vision during the observational period were independent risk factors for LTFU exceeding 12 months (p < 0.05). CONCLUSIONS: We found a high long-term LTFU rate for patients with DR, despite treatment under universal health coverage. Considering the risk of disease progression, particularly in patients with chronic DR, strategies for better compliance and adherence to therapy should be considered for optimized patient care.

IN VITRO FLOW ANALYSIS OF NOVEL DOUBLE-CUTTING, OPEN-PORT, ULTRAHIGH-SPEED VITRECTOMY SYSTEMS.

PURPOSE: To analyze the performance and flow characteristics of novel double-cutting, open-port, 23-, 25-, and 27-gauge ultrahigh-speed vitrectomy systems. METHODS: In vitro fluidic measurements were performed to assess the volumetric aspiration profiles of several vitrectomy systems in basic salt solution and egg white. RESULTS: Double-cutting open-port vitrectomy probes delivered stable aspiration flow rates that were less prone to flow variation affected by the cutting speed. Increase in cutting frequency to the maximum level resulted in flow reduction of less than 10% (0.0%-9.5%). Commercially available 23-, 25-, and 27-G double-cutting probes exhibited higher egg-white and basic salt solution flow rates at all evaluated cut rates, with aspirational efficiencies being 1.1 to 2.9 times the flow rates of standard single-blade vitrectomy probes of the same caliber at the maximum preset vacuum. The highest relative differences were observed at faster cut rates. CONCLUSION: The newly introduced double-cutting open-port vitrectomy probes delivered stable aspiration flow rates that were less prone to flow variation affected by the cutting speed. The fluidic principle of constant flow even at the highest cut rates and low vacuum levels might impact surgical strategies, especially when performing manipulations close to the retina.

[Surgical Methods in the Treatment of Uveal Melanoma]. / Chirurgische Methoden in der Behandlung des Aderhautmelanoms.

Significant advancements have been made in the last decades in the treatment of uveal melanoma. Radiation therapy can achieve, depending on the method, local tumour control in up to 98% of cases. Surgical modalities have been implemented in the ocular therapy for uveal melanoma either to treat/prevent radiation complications, such as so-called toxic tumour syndrome, or to primarily treat the tumour with or without adjunctive radiotherapy. These include endoresection and transscleral resection for melanomas of the choroid/ciliary body or irido-trabeculo-cyclectomy for melanomas of the iris-ciliary body. Furthermore, tumour biopsy is playing a progressively more important role in the diagnosis, treatment and follow-up planning of melanoma cases. This paper focuses on the background, the surgical technique as well as the results and complications of tumour excisional and biopsy surgery.

Detection of infectious SARS-CoV-2 in ocular samples is linked to viral load in the nasopharynx.

Introduction: SARS-CoV-2 is known to infect respiratory tissue cells. However, less is known about infection of ocular tissue and potential infectivity of lacrimal fluid. With this study, we want to compare viral loads in eye and nasopharyngeal swabs and analyze these for infectious virus. Methods: Between May 2020 and April 2021 ocular and nasopharyngeal swabs were collected from 28 SARS-CoV-2 infected patients treated on the corona virus disease 2019 (COVID-19)-ward of the University Hospital of Innsbruck, Austria. Samples with PCR detectable SARS-CoV-2 were analyzed via whole genome sequencing and an attempt was made to isolate infectious virus. Results: At the time point of sample collection, 22 individuals were still PCR positive in nasopharyngeal samples and in 6 of these patients one or both ocular samples were additionally positive. CT-values in eyes were generally higher compared to corresponding nasopharyngeal samples and we observed a tendency for lower CT-values, i.e. increased viral load, in nasopharyngeal swabs of individuals with at least one infected eye, compared to those where ocular samples were PCR negative. Ocular and nasopharyngeal sequences from the same patient were assigned to the same variant, either the D614G or the Alpha variant. Infectious virus was successfully isolated from 9 nasopharyngeal swabs, however only from one of the seven PCR positive ocular samples. Conclusion: We could detect SARS-CoV-2 in eyes of some of the infected patients albeit at lower levels compared to nasopharyngeal swabs. However, our results also indicate that lacrimal fluid might be infectious in patients with high viral load.

Reduced-fluence photodynamic therapy combined with ranibizumab for nonproliferative macular telangiectasia type 2.

PURPOSE: To report the efficacy of reduced-fluence photodynamic therapy (PDT) combined with intravitreal ranibizumab for the treatment of nonproliferative macular telangiectasia (MacTel) type 2. METHODS: Noncomparative, interventional, retrospective case series; 5 eyes of 4 patients were studied. Patients were treated with reduced-fluence PDT and intravitreal ranibizumab within 24 h. After initial treatment, follow-up was at least 12 months in all patients. RESULTS: At baseline median logMAR (logarithm of the minimal angle of resolution) best-corrected visual acuity (BCVA) was 1.0 (range, 1.0-0.3). At 3 months of follow-up vision increased in 3 out of 5 eyes and median BCVA was 0.4 (range, 1.0-0.2). The gain of BCVA ranged from 6 lines to 1 line. Visual acuity remained stable in the other 2 study eyes. No eyes lost vision at 3 months of follow-up. At 12 months of follow-up median logMAR BCVA was 0.7 (range, 1.3-0.3). Two eyes had maintained their gain in BCVA compared to baseline. Two eyes lost vision compared to baseline and 1 eye showed unchanged visual acuity at 12 months of follow-up. CONCLUSION: A combination therapy with reduced-fluence PDT and intravitreal ranibizumab might be a valuable treatment option for eyes with progressive vision loss due to nonproliferative MacTel type 2.

Optical Coherence Tomography Angiography Characteristics of Polypoidal Lesions in Caucasians.

Purpose: The aim of the study is to analyze the swept source-optical coherence tomography angiography (SS-OCTA) characteristics of polypoidal lesions in Caucasian patients. Methods: In this retrospective observational case series, 43 polypoidal lesions in 32 eyes of 32 patients were diagnosed using indocyanine green angiography (ICGA) and compared to SS-OCTA at a tertiary medical retina center (Clinic Landstraße, Vienna Healthcare Group, Austria) between June 2017 and March 2020. Vascularity was identified by color-coded B-scan SS-OCTA while morphology was described as revealed by en face SS-OCTA after alignment with ICGA-confirmed findings. Results: In total, SS-OCTA detected all polypoidal lesions, as identified by ICGA. On B-scan SS-OCTA, circumscribed flow was detected in 33 (76.7%) polypoidal lesions and diffuse flow in 10 (23.3%) lesions. On en face SS-OCTA, polypoidal lesions appeared morphologically as 19 tangled vessel balls (44.2%), 6 tangled vessel balls next to dilated vessels (13.9%), 8 vascular dilatations (18.6%), and 8 ill-defined vascular networks (18.6%), leaving 2 lesions (4.6%) undetected. Circumscribed flow was significantly associated with tangled vessel balls (p = 0.005). Conclusion: This study highlights the importance of a multimodal imaging approach, including SS-OCTA, for the evaluation of polypoidal lesions. Our findings suggest a morphological heterogeneity of vascular patterns in Caucasian patients with polypoidal lesions, as pictured by SS-OCTA.

Two Cases of Acute Macular Neuroretinopathy Associated with the Adenovirus-based COVID-19 Vaccine Vaxzevria (Astrazeneca).

PURPOSE: To report two cases of acute macular neuroretinopathy (AMN) in young female patients following the administration of the adenovirus-based coronavirus disease 2019 (COVID-19) vaccine Vaxzevria (AstraZeneca). METHODS: Spectral-domain optical coherence tomography and infrared imaging were used to confirm the diagnosis of AMN. RESULTS: Both patients showed a parafoveal hyperreflective band in the outer nuclear layer, disruption of the ellipsoid and interdigitation zones of the photoreceptor layers, and correlating hyporeflective areas on the near-infrared images. Both patients presented with flu-like fever and sudden onset of fortifications within 48 hours of vaccination. One patient showed altered flow in the deep capillary plexus and highly elevated thrombotic parameters. CONCLUSION: We report a possible association between immune-mediated AMN and the administration of adenovirus-based COVID-19 vaccine Vaxzevria.

Intravitreal Aflibercept Therapy and Treatment Outcomes of Eyes with Neovascular Age-Related Macular Degeneration in a Real-Life Setting: A Five-Year Follow-Up Investigation.

INTRODUCTION: We aimed to evaluate visual and anatomical outcomes among eyes with neovascular age-related macular degeneration (nAMD) that were persistent to intravitreal aflibercept therapy compared to those that were nonpersistent to therapy. METHODS: We audited 648 treatment-naïve eyes of 559 patients regarding visual acuity (VA) given as the logarithm of the minimum angle of resolution (logMAR) and anatomic outcomes at baseline and at each subsequent follow-up visit for up to 5 years. Nonpersistence was defined as a visit-free interval of > 6 months. RESULTS: Among the enrolled eyes, 405 were persistent to the therapy and 243 (37%) were nonpersistent, of which 161 (66%) eyes returned for further therapy after a gap of clinical care. In the nonpersistent group, we observed a decline from 0.58 ± 0.35 to 0.92 ± 0.57 logMAR (p = 0.01) after 60 months. Compared with the persistent group, the nonpersistent group had worse visual outcomes at their 33-month (p = 0.03), 42-month (p = 0.01), 51-month (p = 0.001) and 60-month (p = 0.01) visits. Additionally, 5/405 (1.2%) eyes in the persistent group and 8/161 (5.0%) eyes in the nonpersistent group developed an end-stage disease with a subfoveal fibrosis during the observational period (p = 0.013). CONCLUSION: We found that eyes with nAMD that were nonpersistent to intravitreal aflibercept therapy experienced statistically significantly worse VA compared to eyes persistent to therapy within 3 years. Moreover, eyes in the nonpersistent group had a four-fold higher risk of developing a fovea-involving fibrosis. Considering the potential irreversible deterioration with respect to best-corrected VA within nAMD, strategies need to be developed for patients at risk of nonpersistence to therapy.

The impact of compliance among patients with diabetic macular oedema treated with intravitreal aflibercept: a 48-month follow-up study.

PURPOSE: This study aimed to compare anatomical and functional outcomes between patients with non-proliferative diabetic retinopathy (NPDR) with diabetic macular oedema (DME) who adhered to intravitreal aflibercept therapy and patients lost to follow-up (LTFU). METHODS: We enrolled 200 patients and recorded the interval between each procedure and the subsequent follow-up visit. Moreover, visual acuity (VA) and anatomical outcomes were measured at each follow-up examination. RESULTS: Among the patients, 103 (51%) patients adhered to intravitreal aflibercept therapy and follow-up examination while 97 (49%) patients were LTFU. Forty-six (47%) patients LTFU who returned for further treatment showed a significant decrease in VA from 0.51 (±0.46) to 0.89 (±0.38) logarithm of the minimum angle of resolution (logMAR) after 48 months (p = 0.004). Compared with the adherent group, the return group showed a worse VA at 48 months (p = 0.036). Further, 1 (1%) patient in the adherent group and 8 (17%) patients in the return group developed a proliferative DR. Patients who were LTFU had a 13.0 times greater chance to develop a proliferative DR (p = 0.022). CONCLUSIONS: Patients who did not adhere to intravitreal aflibercept therapy for DME showed significantly worse visual outcomes compared to patients with good therapy adherence. Moreover, patients with LTFU had a 13 times higher risk of developing a proliferative DR. Considering the potential disease progress, better strategies should be applied to optimize the functional outcome of patients at risk of reduced adherence.