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The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal imaging and liquid biopsy, DRIL in eyes with DME. This was an observational cross-sectional study. Patients affected by center-involved DME were enrolled. All patients underwent spectral domain optical coherence tomography (SD-OCT) and proteomic analysis of aqueous humor (AH). The presence of DRIL at OCT was analyzed by two masked retinal experts. Fifty-seven biochemical biomarkers were analyzed from AH samples. Nineteen eyes of nineteen DME patients were enrolled. DRIL was present in 10 patients (52.63%). No statistically significant difference was found between DME eyes with and without DRIL, considering the AH concentration of all the analyzed biomarkers except for glial fibrillary acidic protein (GFAP), a biomarker of Müller cells dysfunction ( p = 0.02). In conclusion, DRIL, in DME eyes, seems to strictly depend on a major dysfunction of Müller cells, explaining its role not only as imaging biomarker, but also as visual function Müller cells-related parameter.

Diabetic retinopathy is a form of diabetic microangiopathy, and vascular hyperpermeability in the macula leads to retinal thickening and concomitant reduction of visual acuity in diabetic macular edema (DME). In this review, we discuss multimodal fundus imaging, comparing the pathogenesis and interventions. Clinicians diagnose DME using two major criteria, clinically significant macular edema by fundus examination and center-involving diabetic macular edema using optical coherence tomography (OCT), to determine the appropriate treatment. In addition to fundus photography, fluorescein angiography (FA) is a classical modality to evaluate morphological and functional changes in retinal capillaries, e.g., microaneurysms, capillary nonperfusion, and fluorescein leakage. Recently, optical coherence tomography angiography (OCTA) has allowed us to evaluate the three-dimensional structure of the retinal vasculature and newly demonstrated that lamellar capillary nonperfusion in the deep layer is associated with retinal edema. The clinical application of OCT has accelerated our understanding of various neuronal damages in DME. Retinal thickness measured by OCT enables us to quantitatively assess therapeutic effects. Sectional OCT images depict the deformation of neural tissues, e.g., cystoid macular edema, serous retinal detachment, and sponge-like retinal swelling. The disorganization of retinal inner layers (DRIL) and foveal photoreceptor damage, biomarkers of neurodegeneration, are associated with visual impairment. Fundus autofluorescence derives from the retinal pigment epithelium (RPE) and its qualitative and quantitative changes suggest that the RPE damage contributes to the neuronal changes in DME. These clinical findings on multimodal imaging help to elucidate the pathology in the neurovascular units and lead to the next generation of clinical and translational research in DME.

Background and Objectives : The identification of possible biomarkers that can predict treatment response among DME eyes is important for the individualization of treatment plans. We investigated optical coherence tomography (OCT)-based biomarkers that may predict the one-year real-life outcomes among diabetic macular edema (DME) eyes following treatment by intravitreal ranibizumab (IVR) injections. Materials and Methods: A total of 65 eyes from 35 treatment-naïve patients with DME treated with ranibizumab injection were recruited. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), and OCT scans were retrospectively recorded at baseline before treatment and at 3 months, 6 months, and 12 months after treatment. The OCT scans were evaluated for biomarkers of interest, which included central retinal thickness (CRT), amount and locations of hyperreflective foci (HRF), subretinal fluid (SRF), intraretinal cysts (IRC), large outer nuclear layer cyst (LONLC), ellipsoid zone disruption (EZD), disorganization of retinal inner layers (DRIL), hard exudates (HE), epiretinal membrane (ERM), and vitreomacular interface (VMI). Correlations between these OCT biomarkers and outcome measures (visual and structural) were statistically analyzed. Results: A total of 65 eyes from 35 patients with DME were enrolled. The mean age was 64.2 ± 10.9 years old. Significant improvement in terms of mean BCVA ( p < 0.005) and mean CRT was seen at final follow-up compared to baseline. The biomarkers of DRIL, LONLC, and SRF were found to be predictive for at least 50 μm CRT reduction after treatment (with odds ratio of 8.69, 8.5, and 17.58, respectively). The biomarkers of IRC, LONLC, and SRF were predictive for significant improvement in terms of BCVA and CRT after treatment. Finally, the number of HRF was predictive for both BCVA improvement and a CRT reduction of less than 100 μm after treatment. No serious complications were reported during the study. Conclusion: Our study demonstrated the utility of OCT biomarkers as therapeutic predictors of ranibizumab treatment among DME eyes.

Background: To compare the surgical status in idiopathic epiretinal membrane (IERM) patients with or without disorganization of retinal inner layers (DRIL) and to correlate with optical coherence tomography angiography (OCTA) and clinical data., Methods: In 74 eyes from 74 patients with IERM treated by surgery with 12-month follow-up. According to the superficial hemorrhage, the patients were divided into group A (no macular bleeding), group B (macular parafoveal bleeding) and group C (macular foveal bleeding). Optical coherence tomography (OCT) were evaluated for presence of DRIL,central retina thickness and integrity of the inner/outer segment layer recorded at baseline and at 1, 3, 6, and 12 months postoperatively and best-corrected visual acuity (BCVA) was recorded simultaneously. OCTA was conducted at 12 months postoperatively. Main outcome measures is correlation between DRIL and superficial hemorrhage in membrane peeling,and BCVA and OCTA outcomes postoperatively., Results: The rate of DRIL and BCVA had statistically significant differences between the three groups at the time points(baseline and 1, 3, 6, and 12 months after surgery), respectively (P < 0.001 for all). FD-300 value (P = 0.001)and DCP in all parafoveal regions (superior: P = 0.001; inferior: P = 0.002;Nasal: P = 0.014;Tempo: P = 0.004) in eyes with DRIL were lower than those without DRIL.There was a linear regression relationship between FD-300 and postoperative BCVA (P = 0.011)., Conclusion: IERM Patients with DRIL have more intraoperative adverse events and limited benefits from surgery which should be considered in the decision whether to perform mebrane peeling.OCT-A provides more detailed vascular information that extends our understanding of persistent DRIL., (© 2023. The Author(s).)

Purpose: To identify optical coherence tomography (OCT) biomarkers that may predict functional and anatomical outcomes in diabetic macular edema (DME) patients treated with intravitreal dexamethasone (DEX) implant., Materials and Methods: Sixty-four eyes from 50 patients with DME were enrolled. Best-corrected visual acuity (BCVA) and OCT biomarkers including central retinal thickness (CRT), subretinal fluid (SRF), intraretinal cysts (IRC), ellipsoid zone disruption (EZD), disorganization of retinal inner layers (DRIL), hard exudate (HE), hyperreflective foci (HRF), epiretinal membrane (ERM), and vitreomacular interface (VMI) changes were evaluated at baseline and at 3, 6, and 12 months after treatment. Multiple logistic analysis was performed to evaluate each OCT biomarker as a predictive factor for functional and anatomical improvement at the end of treatment., Results: The presence of SRF at baseline was associated with a favorable outcome, with CRT improving by more than 100 μm after treatment from multivariate logistic regression analysis [odds ratio 6.16 (1.75-21.6)]. In addition, baseline SRF predicted a greater CRT improvement from multiple regression analysis (model R-square 0.11, p = 0.006). The reduction of DRIL, SRF, LONLC, IRC, and EZD were correlated with better CRT improvement (more than 100 μm) ( P < 0.05). SRF and EZD recovery can also predict better visual prognosis ( P < 0.05)., Conclusion: OCT biomarkers can be used to predict who may benefit the most after DEX treatment. We suggest that the DEX implant should be considered as a first line treatment in DME patients with SRF., Competing Interests: H-SC was employed by NephroCare Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Chang, Meng, Lin, Lai, Hsia, Chen, Tien, Bair, Lin, Chen and Tsai.)

Background: This study aimed to investigate retinal imaging biomarkers, such as disorganization of the retinal inner layers (DRIL) and/or ellipsoid zone (EZ) disruption by spectral domain optical coherence tomography (SD-OCT), and functional outcomes in eyes treated with 0.2 µg/day of a fluocinolone acetonide intravitreal implant (FAc) after an insufficient response to previous treatments., Methods: This was a retrospective comparative study of 18 eyes (15 patients) with persistent and/or recurrent diabetic macular edema (DME) treated with FAc. Eyes were divided according to the number of prior intravitreal treatments: group 1 (n = 8) with ≤ 6 injections (early switch) and group 2 (n = 10) with > 6 injections (late switch). Outcomes included percentage of eyes with DRIL and/or EZ disruption at baseline and analysis of the best corrected visual acuity (BCVA) using ETDRS letters, central macular thickness (CMT), DRIL, and EZ disruption at the last observation., Results: Group 2 revealed a significantly higher percentage of DRIL and/or EZ disruption than group 1 ( P < 0.05). At the last observation, group 1 revealed a higher percentage of eyes achieving vision stability/ improvement, gaining ≥ 15 letters, and achieving ≥70 letters ( P > 0.05 for all comparisons). The mean BCVA gain was 8.8 and 0.7 letters for groups 1 and 2 ( P = 0.397). Both groups revealed a significant mean CMT reduction (> 20% reduction from the baseline value), without a significant statistical difference between them ( P = 0.749). After treatment, most eyes from both groups showed resolution of DRIL and EZ disruption., Conclusions: Patients with DME presenting with a lower percentage of DRIL and/or EZ disruption at baseline had better functional outcomes, supporting the possible benefit of an early switch to FAc after insufficient response to previous treatments. Future randomized studies with a larger patient cohort are warranted to confirm our conclusions., Competing Interests: None., (© Author(s).)

Purpose: To evaluate the presence of macular edema secondary to retinal vein occlusion (RVO)-both central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO)-3 years after diagnosis in patients who underwent intravitreal therapy and to identify potential prognostic factors and biomarkers of persistent macular edema., Methods: National multicenter, observational, exploratory, retrospective cohort study of 104 consecutive patients with macular edema secondary to RVO diagnosed from January 2014 to December 2015 with minimum 3-year follow-up time. Data analyzed included best-corrected visual acuity (BCVA), clinical and demographic data, and spectral domain optical coherence tomography parameters., Results: At final observation, median baseline central retinal thickness significantly improved from baseline 538 to 290 μm (p < 0.001) and complete macular edema resolution was achieved in 51.0% of patients (56.3% and 42.5% in BRVO and CRVO patients, respectively). BCVA also improved (p < 0.01). Logistic regression analysis revealed a relationship between recurrence of macular edema and disorganization of retinal inner layers (DRIL) at baseline (odds ratio = 2.88; p = 0.013)., Conclusion: Good long-term anatomical and functional outcomes are achieved with intravitreal treatments in RVO patients. Anatomical success and visual gains seen in the first year were maintained throughout the entire follow-up, though DRIL is a major risk factor for recurrence.

Purpose: To investigate the prognostic value of peripheral retinal nonperfusion in patients with diabetic retinopathy using ultra-widefield fluorescein angiography (UWFA)., Methods: A cross-sectional study included 78 treatment-naïve eyes with nonproliferative and proliferative diabetic retinopathy (NPDR and PDR). Eyes were divided into three groups: mild/moderate NPDR (n = 31), severe NPDR (n = 31), and PDR (n = 16). Three nonperfusion variables were calculated reflecting the proportion of nonperfused to visible retina based on initial UWFA: central nonperfusion (CNP) index, peripheral nonperfusion (PNP) index, and PNP ratio. The relationships between these indices and central subfield thickness (CST) and spectacle-corrected visual acuity (SCVA) were evaluated., Results: CNP and PNP indices were significantly higher in the PDR group vs. mild/moderate NPDR group (p = 0.007 and 0.008, respectively) but not in the PDR group vs. severe NPDR group (p = 0.149 and p = 0.535, respectively). A significant linear correlation was found between the CNP and PNP indices in both severe NPDR and PDR groups (R 2  = 0.141, p = 0.041, and R 2  = 0.311, p = 0.025, respectively). Nonperfusion predominance was not statistically correlated with the presence of macular edema (p = 0.058) or disorganization of retinal inner layers (p = 1). In the severe NPDR group, there was a moderately positive correlation between CNP index and CST (r s  = 0.496, p = 0.019) and no correlation between CNP index and SCVA when controlling for CST (p = 0.160). In the PDR group, a strong negative correlation between PNP ratio and CST was found (r s  = -0.659, p = 0.014), but no correlation was observed between CNP index, CST, and SCVA. In the PDR group, a positive correlation was found between PNP index, PNP ratio, and SCVA (r s  = 0.549, p = 0.027, and r s  = 0.626, p = 0.010, respectively), even after controlling for CST (r s  = 0.599, p = 0.040)., Conclusions: Higher amounts of retinal nonperfusion are seen in patients with more severe retinopathy. Increased CNP is associated with macular thickening and subsequent vision loss. Having predominantly PNP was independently associated with worse VA, regardless of macular thickness. Further studies are needed to investigate the role of PNP in vision loss in diabetic retinopathy.

Purpose: To assess grading reproducibility of disorganization of the retinal inner layers (DRIL) and other morphologic features of diabetic macular edema (DME) across spectral domain optical coherence tomography (SDOCT) instruments and scan types., Methods: A cross-sectional study enrolled participants with current or recent center-involved DME. In group A (27 eyes), we obtained two Cirrus scans (512 × 128 macular cube [Cube] and high-definition five-line raster [HD 5-Line]) and two Spectralis scans (high-resolution [HR] and high-speed [HS]). In group B, 26 eyes underwent HR scans and Optovue AngioVue (OP) 3 × 3-mm scans. All scans were graded for type and extent of DRIL, intraretinal cysts, cone outer segment tip visibility, and subretinal fluid (SRF)., Results: In the total cohort, mean central subfield thickness was 342.9 ± 83.4 µm. Intraclass correlations were high for DRIL extent across the four different imaging settings (HR vs. HS, r = 0.93; HR vs. Cube, r = 0.84, HR vs. HD 5-Line, r = 0.76, HR vs. OP, r = 0.87) and ranged from good to excellent for intraretinal cyst and SRF area. There were significantly smaller mean normalized differences between HR/HS scans versus HR and all other scan modalities (HR/HS vs. HR/Cube, P = 0.02; HR/HD 5-Line, P = 0.0005; HR/OP, P < 0.0001)., Conclusions: Our data suggest that the reproducibility for SDOCT parameters of DRIL and intraretinal cysts was high across all five SDOCT scan types; thus, evaluation of DRIL is feasible using multiple SDOCT models in eyes with DME., Translational Relevance: DME morphological changes can be evaluated on multiple SDOCT devices with good reproducibility, allowing clinicians and researchers flexibility in DME assessment for clinical care and research., Competing Interests: Disclosure: K. Sampani, None; M. Abdulaal, None; T. Peiris, none; M.M. Lin, None; C. Pitoc, None; M. Ledesma, None; J. Lammer, None; P.S. Silva, None; L.P. Aiello, Heidelberg Engineering (F), Carl Zeiss Meditec (F); J.K. Sun, Optovue (F), (Copyright 2020 The Authors.)

Purpose: To evaluate the predictive and associated factors in determining the visual outcome in patients having central retinal vein occlusion (CRVO)-related macular edema (ME)., Methods: The charts of the patients who were treated due to CRVO-related visual disturbance were reviewed. The optical coherence tomography (OCT) images of eyes were analyzed, and disorganization of retinal inner layers (DRILs), ellipsoid zone (EZ) and external limiting membrane (ELM) disruption length, hyper-reflectivity of retinal inner layer (HRIL) existence, baseline and final visual acuity (VA), subfoveal thickness (SFT), subretinal fluid (SRF), and injection numbers were noted. The regression and correlation analyses were applied., Results: Thirty eyes of thirty patients were included in the study. The mean follow-up time was 17.5 ± 11 (8-47) months. The mean baseline VA was 1.4 ± 0.7 (0.2-3.1) logMAR. A total of 87 intravitreal injections were applied for the treatment of ME during the follow-up. The initial mean central subfield thickness was 795 ± 264 (1470-398) μm. HRIL and SRF were observed in 16 and 23 eyes at the initial visit, respectively. The final mean VA was 1.2 ± 0.9 (0.1-3.1) logMAR. At the final visit, additional OCT parameters were evaluated. The mean DRIL length was 463 ± 324 μm. The mean disruption length of EZ and ELM was 367 ± 247 μm and 414 ± 327 μm, respectively. The final mean SFT was 290 ± 91 μm. SRF presence at the initial visit was found to be associated with elongated EZ and ELM disruption length at the final visit ( P = 0.03 and P = 0.04, respectively). On linear regression analyses, none of the baseline features (SRF, SFT, and HRIL) except baseline poor best corrected visual acuity were found to be predictive in anticipating the final visual outcome ( P = 0.04). On linear bivariate analysis, the final poor visual outcome was found to be affected by EZ disruption length of ≥500 μm at the last visit ( P = 0.02)., Conclusion: Baseline VA was the only predictive factor in anticipating the final visual outcome. At the final visit, extensive disruption length of EZ in the subfoveal area was associated with a poor visual outcome., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Current Ophthalmology.)

Purpose: To investigate disorganization of retinal inner layers (DRIL) as a biomarker in eyes with diabetic macular oedema (DME) treated by intravitreal dexamethasone (DEX) implant., Methods: Multicentre, retrospective study including eyes with DME treated with DEX implant and follow-up of 12 months after the first injection. OCT scans were evaluated for the presence of DRIL and other structural features. Best corrected visual acuity (BCVA) and central subfield thickness (CST) were recorded at baseline and at 2, 4, 6 and 12 months after treatment. Correlation between DRIL at baseline and outcomes after DEX treatment and the change in DRIL were analysed., Results: A total of 177 eyes (177 patients; naïve, n = 131; refractory, n = 46) were included. Patients without DRIL at baseline gained significantly more vision and enjoyed greater reduction in CST over 12 months (both p = 0.03). DRIL at the boundary between the ganglion cell-inner plexiform complex and inner nuclear layer improved in 48/64 eyes (75%, p < 0.001), while DRIL between the inner nuclear layer and outer plexiform layer improved in 27/77 eyes (35%, p = 0.004)., Conclusions: This is the first study to show that DEX implant has the potential to ameliorate DRIL. Patients without DRIL at baseline have a favourable outcome. DRIL may serve a robust biomarker in DME treated by DEX implant., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: The purpose of this retrospective study was to evaluate the disorganization of the retinal inner layers (DRIL) as a potential predictive factor of postoperative visual outcome in patients with idiopathic epiretinal membrane (iERM), treated with pars plana vitrectomy (PPV)., Methods: Participants in the study were 46 consecutive patients diagnosed with iERM, who underwent PPV. Best corrected visual acuity (BCVA) measurement and spectral-domain optical coherence tomography (SD-OCT) were performed at baseline (preoperatively), and at months 3 and 6 postoperatively. DRIL and additional OCT parameters were assessed at 1-mm-wide foveal centered area., Results: DRIL was observed in 47.8% of patients at baseline. There was statistically significant improvement in BCVA and central retinal thickness (CRT) between baseline and months 6 and 12 in all patients. There was a statistically significant difference in BCVA and CRT change between patients with and without DRIL at months 6 and 12 compared to baseline, showing that there was a correlation between change in BCVA or CRT and baseline DRIL. Ellipsoid zone and external limiting membrane were intact in 91.3 and 95.7%, respectively, not affecting our results., Conclusions: Baseline DRIL has been shown to be predictive of postoperative visual outcome in patients with iERM, treated with PPV., (© 2019 S. Karger AG, Basel.)

Purpose: To investigate the association of retinal fluid volume with the visual and anatomic outcomes of patients with diabetic macular edema (DME) after treatment with bevacizumab., Study Design: Retrospective observational study., Methods: We retrospectively analyzed 65 eyes of 58 DME patients treated with bevacizumab. The volumes of the inner intraretinal fluid (IRF) in the inner nuclear layer (INL), outer IRF in the outer plexiform layer (OPL)/outer nuclear layer (ONL), and subretinal fluid (SRF) were calculated. The correlations between the baseline fluid volumes and best-corrected visual acuity (BCVA), area of disorganization of the retinal inner layers (DRIL), disrupted external limiting membrane (ELM), and disrupted ellipsoid zone (EZ) at 12 months after treatment were assessed., Results: The baseline volume of the inner IRF correlated with poor BCVA at the final visit (r = 0.52, P < .001) whereas the baseline volume of the outer IRF and SRF volume did not show a significant correlation with BCVA at the final visit (P = .07 and P = .61, respectively). The improvement in BCVA correlated with the reduction in the baseline volume of the inner IRF and outer IRF (r = 0.25, P = .04 and r = 0.36, P = .003), but not with the SRF volume (P = .59). The baseline volume of the inner IRF correlated positively with the area of DRIL and the disrupted ELM at the final visit (r = 0.56, P < .001 and r = 0.25, P = .04, respectively). Such relationship remained in each quadrant of the macula (P < .005 for all quadrants)., Conclusion: The baseline volume of the inner IRF correlated with a poor visual outcome, an increased DRIL area, and a more disrupted ELM area in patients with DME after treatment with bevacizumab.

Purpose: To determine the predictive values of baseline optical coherence tomography (OCT) abnormalities on 12-month visual acuity changes in eyes with macular edema (ME) caused by branch retinal vein occlusions (BRVO)., Methods: We performed a post hoc analysis of data from 75 participants in the 12-month MARVEL trial. OCT abnormalities at baseline, including ganglion cell layer cystoid spaces (GCL), intraretinal hyper-reflective dots, and central subfield thickness (CST), were correlated with improvements in visual acuity and the number of anti-vascular endothelial growth factor injections required using a multivariate regression model., Results: Eyes with baseline CST > 500 μm had greater visual gains compared to those with CST <500 μm (+21.09 vs +16.08 letters, P = 0.04). Eyes with hyper-reflective dots (+13.97 vs +19.93 letters, P = 0.02), and GCL cysts (+9.8 vs +18.9, P = 0.003) had inferior gains in visual acuity. Neurosensory macular detachments at the baseline did not affect gains in visual acuity. Ninety percent of the gain in visual acuity was recorded after two injections and was maintained until month 12., Conclusion: Baseline OCT of <500 μm, hyper-reflective dots, and GCL cystoid spaces are associated with poorer gains in visual acuity. Most of the visual gain occurs after two injections., Competing Interests: There are no conflicts of interest