Co-Expression of Podoplanin and CD44 in Proliferative Vitreoretinopathy Epiretinal Membranes.

Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs' extracellular matrix components to better understand molecular dysfunctions that trigger and fuel the onset and development of this disease. The bioinformatics approach we applied delineated a comprehensive overview on this fibrocellular tissue and on critical proteins that could really impact ERM physiopathology. Our interactomic analysis proposed the hyaluronic-acid-receptor cluster of differentiation 44 (CD44) as a central regulator of ERM aberrant dynamics and progression. Interestingly, the interaction between CD44 and podoplanin (PDPN) was shown to promote directional migration in epithelial cells. PDPN is a glycoprotein overexpressed in various cancers and a growing body of evidence indicates its relevant function in several fibrotic and inflammatory pathologies. The binding of PDPN to partner proteins and/or its ligand results in the modulation of signaling pathways regulating proliferation, contractility, migration, epithelial-mesenchymal transition, and extracellular matrix remodeling, all processes that are vital in ERM formation. In this context, the understanding of the PDPN role can help to modulate signaling during fibrosis, hence opening a new line of therapy.

Macular sequelae in vasoproliferative tumors: results of surgical approach.

PURPOSE: The purpose of this study is to report the clinical manifestations and treatment outcomes in three patients diagnosed with vasoproliferative tumors (VPTs). METHODS: A retrospective, single-center case series was conducted, and retinal findings from three cases were documented by clinical examination and multimodal imaging. RESULTS: Three patients presented with an elevated, yellow-white retinal lesion located at the peripheral retina and extensive retinal exudation. All three patients were closely monitored, and tumor-associated features included lipid exudates, cystoid macular edema (CMO), pre-retinal fibrosis and epi-retinal membrane (ERM). Clinical management relied on observation, cryotherapy, laser photocoagulation, intravitreal steroids and anti-vascular endothelial growth factor (anti-VEGF) treatment. Despite different clinical courses, two patients underwent vitreo-retinal surgery to address VPT-related complications of macular hole and vitreo-macular traction, whereas a patient underwent phacoemulsification to treat steroid-induced cataract. CONCLUSION: VPTs are uncommon benign vascular tumors and usually located at the infero-temporal peripheral retina. Close observation and early diagnosis of VPTs are of great importance in preventing vision-threatening complications and ensuring the best final visual outcome. The optimal treatment has yet to be defined due to lack of multi-center clinical studies. Despite the availability of less invasive therapeutic interventions, however, our case series show that pars plana vitrectomy is sometimes the most appropriate choice to restore visual acuity.

Evaluation of pre- and post-surgery reading ability in patients with epiretinal membrane: a prospective observational study.

BACKGROUND: This study aimed to investigate the pre- and post-surgery reading ability in patients with idiopathic epiretinal membrane (ERM) to evaluate whether measurement of reading performance is a helpful test in addition to visual acuity (VA) as an assessment measure. METHODS: This prospective observational study involved 42 eyes of 40 patients with idiopathic ERM. Best-corrected visual acuity (BCVA), reading ability, and metamorphopsia score were evaluated at baseline and at 3, 6, and 12 months post-surgery. As the outcome measure, the reading ability of each patient (i.e., overall performance) was examined with MNREAD-J, the Japanese version of the MNREAD reading acuity (RA) charts, to determine RA, critical print size (CPS), and maximum reading speed (MRS). Generally, a difference of 0.2 logMAR or more is considered a significant change in BCVA. Thus, as a subgroup analysis, we additionally evaluated the BCVA and reading ability of the patients with a BCVA difference of 0.1 logMAR or less between at baseline and at 12 months post-surgery. RESULTS: Relative to their values at baseline, the subjects exhibited significantly improved BCVA, RA, and CPS throughout the post-surgery examination period (P < 0.001) and significantly improved MRS at 12 months post-surgery (P = 0.04). No significant change in the vertical metamorphopsia score was observed throughout the post-surgery follow-up period. However, and compared to the value at baseline, significant improvements in the horizontal metamorphopsia score were observed at 3, 6 (P < 0.05), and 12 months (P < 0.001) post-surgery. In the subgroup analysis of the 23 eyes that exhibited a BCVA improvement of 0.1 logMAR or less, the median BCVA did not change, but the median RA and CPS improved by 0.2 logMAR. CONCLUSIONS: Our findings showed that the surgical removal of ERM improves reading ability, even when the BCVA score does not improve. The measurement of reading performance appears to be a helpful test in addition to VA as a measure for assessing the surgical removal of ERM.

Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations.

Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis-a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM.

Description and surgical management of epiretinal membrane due to combined hamartoma of the retina and retinal pigment epithelium.

Purpose: To outline the characteristics of Combined Hamartoma of the Retina and Retinal Pigmentation Epithelium (CHRRPE) and provide a comprehensive overview of surgical management of epiretinal membrane (ERM) caused by CHRRPE. Main text: CHRRPE is a rare ocular tumor. It clinically mimics other diseases such as retinoblastoma and choroidal melanoma. The present study reviewed the multimodal imaging of CHRRPE, highlighted the multimodal imaging modalities which are useful for revealing the unique features of CHRRPE and hence allowing physicians to confirm the diagnosis.Although most of CHRRPEs are benign harmatoma, progressive visual loss may occur because of the traction of the tumor and other complications. It is treated through surgical removal of the ERM caused by CHRRPE to free retina from the traction. Currently, there is no consensus on the surgical management of CHRRPE. Therefore, the current review was designed to explore the surgical management of ERM caused by CHRRPE and hence provide updated data on this subject. Conclusions: Multimodal imaging technologies, especially optical coherence tomography (OCT), significantly contributes to the diagnosis of CHRRPE and visual prognosis. Surgical management of CHRRPE through removal of ERM is beneficial in patients with worsening VA which is secondary to ERM which is associated with CHRRPE. However, the strategy is limited to patients with long-standing poor vision. However, earlier surgical therapy and subsequent postoperative amblyopia therapy can be explored for children of amblyogenic age.

Evaluating the effect of vitreomacular interface abnormalities on anti-vascular endothelial growth factor treatment outcomes in diabetic macular edema by optical coherence tomography: A systematic review and meta-analysis.

PURPOSE: To evaluate the effect of vitreomacular interface (VMI) configuration on treatment outcomes after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) using optical coherence tomography (OCT). METHODS: A systematic literature search was performed on PubMed, Embase, web of science and clinicaltrials.gov. The primary outcome parameters were central macular thickness (CMT), best-corrected visual acuity (BCVA) and mean injection numbers. We performed this meta-analysis by Review Manager (RevMan) 5.4.1. RESULTS: The impact of epiretinal membrane (ERM), vitreomacular traction (VMT) and vitreomacular adhesion (VMA) on the treatment outcomes were analyzed separately. 9 clinical studies involving 699 eyes were eligible for the meta-analysis for evaluating the effect of ERM/VMT on efficacy. And 7 studies with 610 eyes were included to access whether VMA affected the response to anti-VEGF therapy in patients with DME. The ERM/VMT group had poorer CMT reductions than the control group at 1 month ([MD] 52.91 mm, P<0.00001), while no significant difference at 3 months ([MD] 43.95 mm, P = 0.22) and over 12 months ([MD] 30.51 mm, P = 0.45). No statistically significant difference in the mean BCVA change at 1 month ([MD] -0.03 Log MAR, P = 0.79), whereas ERM/VMT group had poor visual acuity gains at 3 months ([MD] 0.08 Log MAR, P = 0.003), and a tendency of poor vision improvement over 12 months follow-up ([MD] 0.07 Log MAR, P = 0.11). There was no significant difference in the visual and anatomical results over 3 months in DME patients with or without VMA ([MD] -21.92 mm, P = 0.09; [MD] 1.79 letters, P = 0.22). Besides, VMI configuration was not found to affect mean injection numbers. CONCLUSION: The limited evidence suggested that ERM/VMT was associated with worse CMT reduction at 1 month, poor BCVA gain at 3 months and a tendency of limited vision improvement over 12 months follow-up in DME patients treated with anti-VEGF agents. And VMA may not adversely affect the anatomic and functional outcomes. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity among study designs.

Corrigendum: Customized Color Settings of Digitally Assisted Vitreoretinal Surgery to Enable Use of Lower Dye Concentrations During Macular Surgery.

[This corrects the article DOI: 10.3389/fmed.2021.810070.].

Spectral domain oct for screening of macular diseases prior to multifocal intraocular lens implantation.

BACKGROUND: Cataract surgery with multifocal IOLs could give patients good vision and great satisfaction, at the same time generating high expectations; therefore, its precise indication is essential if we are to reach our goal. The use of optical coherence tomography may be a valuable tool in the screening of macular diseases, which often cannot be detected in routine clinical examinations. This study evaluates the benefit of including spectral domain optical coherence tomography (SD-OCT) in routine preoperative cataract surgery protocols for better case selection in multifocal IOLs. METHODS: Observational and retrospective clinical study that includes patients with an indication for multifocal IOL implantation who underwent retinal fundus exam and SD-OCT examination between 2018 and 2019. The clinical examination with ophthalmoscopy and SD-OCT imaging results were evaluated to observe their influence on the final choice of the lens implanted lens in cataract surgery. RESULTS: 405 eyes from 207 patients with multifocal IOL indication were included. It was found that 220 (54.2%) of all indicated multifocal or trifocal IOLs were in fact implanted. The most important reason for not implanting the indicated IOL was financial, in 116 (59.46%) eyes. The second cause were retinal abnormalities detected by SD-OCT, 63 eyes (15.6%). Those abnormalities included dry age-related macular degeneration (AMD) (50.7%), neovascular AMD (3.1%), vitreomacular adhesion (11.1%), diabetic macular edema (3.1%), epiretinal membrane (ERM) (25.3%) and other macular abnormalities (6.3%). Of the 63 eyes with an abnormal SD-OCT result, 44 (69.8%) were also identified by fundus examination. Nineteen (30.2%) eyes had abnormalities detected only by SD-OCT imaging with a normal clinical exam. CONCLUSIONS: Routine use of SD-OCT imaging may help diagnose pre-existing macular pathologies not identified by clinical exam, helping both physicians and patients choose the ideal IOL individually and has the potential to prevent unsatisfactory functional results.

Epiretinal Membrane Vitrectomy With and Without Intraoperative Intravitreal Dexamethasone Implant: A Systematic Review With Meta-Analysis.

Purpose: To evaluate the efficacy of vitrectomy combined with intravitreal dexamethasone implant vs. vitrectomy without the implant in patients with epiretinal membrane (ERM) by conducting a systematic review and meta-analysis. Methods: Studies that compared ERM vitrectomy with and without intraoperative dexamethasone implant with a follow-up ≥3 months were included. The primary outcome was mean best corrected visual acuity (BCVA) change between eyes undergoing ERM vitrectomy combined with dexamethasone implant (DEX group) and eyes undergoing ERM vitrectomy alone (control group) at 3 months. Secondary outcomes included mean BCVA change at 6 months and mean optical coherence tomography central macular thickness (CMT) change at both 3-months and 6-months follow-up. Mean differences (MDs) with their 95% confidence interval (95%CI) were calculated. Meta-analyses were based either on random effect model or fixed effect model according to heterogeneity. Results: Four studies were included. At 3 months, ERM vitrectomy combined with dexamethasone implant yielded a greater visual gain compared to vitrectomy alone (MD = 9.7; 95%CI = 2.6-16.8; p = 0.01). However, significant heterogeneity was found. A sensitivity analysis excluding the only retrospective non-randomized study confirmed a greater visual gain in the DEX group (MD = 7.1; 95%CI = 2.7-11.6; p < 0.01), with no heterogeneity. At 6 months, a non-significant but borderline difference in visual gain was shown between in the two groups (MD = 5.1; 95%CI = -0.3-10.5; p = 0.06), with no heterogeneity. Three-month analysis of CMT revealed a greater reduction in the DEX group (MD = -80.2; 95%CI =-149.1-11.2; p = 0.02), but with significant heterogeneity. A sensitivity analysis excluding the only retrospective non-randomized study allowed to reduce heterogeneity, but no difference in 3-months CMT change was found between the two groups (MD = -50.0; 95%CI = -106.2-6.2; p = 0.08). At 6 months, no difference in CMT change was shown between the two groups (MD = -48.5; 95%CI = -120.5-23.5; p = 0.19), with significant heterogeneity. Conclusions: Intraoperative dexamethasone implant in eyes undergoing vitrectomy for ERM provided a better visual outcome at 3 months compared to ERM vitrectomy without the implant, with limited evidence of better anatomic outcome as well. Further studies are needed to ascertain whether dexamethasone implant would ensure a significant long-term visual benefit as a result of a faster reduction of macular thickening.

Customized Color Settings of Digitally Assisted Vitreoretinal Surgery to Enable Use of Lower Dye Concentrations During Macular Surgery.

PURPOSE: This study evaluated the color contrast ratio (CCR) of the internal limiting membrane (ILM) using different color settings of digitally assisted vitreoretinal surgery (DAVS) with different indocyanine green (ICG) concentrations.s. METHODS: This is a prospective comparative observational study. Consecutive patients that underwent 25G vitrectomy and ILM peeling using a standard operating microscope (SOM) (25 eyes), DAVS Ver. 1.1 (12 eyes), or DAVS Ver. 1.3 (13 eyes) were enrolled. The SOM and DAVS Ver. 1.1 groups used 0.075% ICG, and the DAVS Ver. 1.3 group used 0.025% ICG. In DAVS Ver. 1.1, macular CCR was compared between four different presets in the red, green, and blue channels: Default (Red (R) 100%, Green (G) 100%, and Blue (B) 100%); Preset 1 (R 20%, G 100%, B 100%); Preset 2 (R 80%, G 80%, B 100%), and Preset 3 (R 85%, G 100%, B 90%). In DAVS Ver. 1.3, macular CCR was evaluated using two different customized settings that modified the hue and saturation: Customized Setting 1 (R 86, G 100, B 100%, Hue +2°, Saturation 90%, Gamma 1.2) and Customized Setting 2 (R 90, G 100, B 100%, Hue +20°, Saturation 100%, Gamma 0.9). All patients underwent ophthalmologic examinations including BCVA at baseline and at 12 months. RESULTS: In DAVS Ver. 1.1, macular CCR was highest in Preset 3 (P < 0.01). The CCR of Customized Setting 2 of DAVS Ver. 1.3 using 0.025% ICG did not differ from that of Preset 3 in DAVS Ver. 1.1 using 0.075% ICG. Furthermore, there was no significant difference in BCVA between the Customized Setting 2 of DAVS Ver. 1.3 with 0.025% ICG and the Preset 3 of DAVS Ver. 1.1 with 0.075% ICG groups at baseline and at 12 months (P > 0.05, respectively). CONCLUSION: Customized DAVS settings enabled surgeons to use a 3-fold lower ICG concentration in ILM peeling.

Impact of Epiretinal Membrane on Optical Coherence Tomography Tools Used for Monitoring Glaucoma.

BACKGROUND: Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) measurements can be influenced by many factors including the presence of concomitant retinal diseases. The aim of this study it to assess the impact of epiretinal membrane (ERM) on RNFL and GCL assessment using optical coherence tomography (OCT). METHODS: GCL, peripapillary RNFL (pRNFL), and Bruch's Membrane Opening Minimum Rim Width (BMO-MRW) thicknesses were analysed using an SD-OCT (Spectralis OCT) in eyes with idiopathic ERM and compared with a control group. RESULTS: 161 eyes were included, 73 eyes in the control group and 88 eyes with idiopathic ERM. The pRNFL analysis revealed a statistically significant difference between the two groups in overall and temporal sector thicknesses. For GCL thickness report, the percentage of scans in which the GCL was erroneously segmented by automatic segmentation was assessed for each eye. A statistically significant difference was found in all sectors (p < 0.001), with the exception of external nasal sector. A statistically significant difference (p < 0.001) in the GCL total volume report was found in ERM group compared to the control group. For MRW at BMO analysis, there was no statistically significant difference in MRW thickness in any sector. CONCLUSION: In eyes with ERM, the GCL and pRNFL analysis seemed affected by the morphological retinal layers' modification. MRW-BMO did not appear to be directly affected by the presence of ERM.

Surgical outcomes in patients with lamellar macular holes selected based on the optical coherence tomography consensus definition.

PURPOSE: The surgical indication for lamellar macular holes (LMH) is controversial due to a misclassification of different macular diseases. A consensus based on an optical coherence tomography (OCT) definition has recently been suggested. The aim of this study was to investigate the surgical outcomes of patients with LMH selected based on this OCT-based consensus definition. METHODS: Retrospective review of patients who underwent surgery for LMH with a follow-up of at least 3 months. Anatomical OCT criteria for the diagnosis of LMH were the presence of an irregular foveal contour with foveal cavitation and a loss of retinal tissue. Cases of macular pseudoholes and epiretinal membrane foveoschisis were excluded. Surgery consisted in pars plana vitrectomy with centripetal peri-hole peeling of epiretinal proliferation and internal limiting membrane. Pre- and postoperative visual acuities (VA) were compared, and changes in OCT anatomical features, including the restoration of the foveal profile and outer retinal layers, were assessed. RESULTS: Eleven eyes of 11 patients were included, of which 9 eyes (81.8%) showed proliferation on preoperative OCT. The mean VA improved from 0.44 ± 0.19 LogMAR (20/55 Snellen equivalent) to 0.16 ± 0.08 LogMAR (20/28 Snellen equivalent), after a mean follow-up of 7.2 ± 2.9 months (P = 0.02). Postoperatively, all eyes showed a restored foveal profile. The mean central foveal thickness increased from 127.6 ± 29.9 µm to 209.0 ± 44.0 µm (P = 0.001). At baseline, ellipsoid zone disruption and external limiting membrane disruption were found in 9 and 7 eyes, respectively. Postoperatively, the ellipsoid zone and external limiting membrane were restored in respectively 6/9 eyes (66.7%) and 5/7 eyes (71.4%). No cases of postoperative full-thickness macular hole were found. CONCLUSION: In patients with LMH carefully selected based on the recent OCT-based criteria and showing a loss of retinal tissue, the foveal architecture was restored and the VA was improved after vitrectomy with peri-hole peeling for epiretinal proliferation.

Comparative study of pars plana vitrectomy with or without intravitreal dexamethasone implant for idiopathic epiretinal membrane.

Purpose: To investigate if use of adjunctive intravitreal dexamethasone implant during pars plana vitrectomy (PPV) leads to faster visual recovery and reduction of retinal thickness in idiopathic epiretinal membrane (ERM). Methods: In this non-randomized, comparative, interventional study 30 eyes (from 30 patients with idiopathic ERM) were enrolled. In the control group (n = 15), patients underwent 25-G pars plana vitrectomy (PPV) and ERM peeling. In the study group (n = 15), each patient underwent the same procedure as those in the control group, and also received an additional dexamethasone implant. Primary outcome after treatment was mean gain in best corrected visual acuity (BCVA), and secondary outcome was reduction in central retinal thickness (CRT). Data were analyzed using Fisher's exact test, Wilcoxon rank sum test, and two-sample t-test. Results: The mean gain in BCVA (logMAR) from baseline at 1-month follow-up was significantly higher in the study group (median = -0.3, IQR = -0.4, -0.1) than in the control group (median = 0, IQR = -0.1, 0.3; P < 0.008). However, no significant difference in mean gain in BCVA between the two groups was detectable at the 6-month follow-up (P < 0.55). At 1-month follow-up, one and seven patients in the control and study groups gained ≥15 letters of BCVA (P < 0.05), respectively. The mean reductions in CRT at the 1-month follow-up were significantly higher in the study group than in the control group (Mean = -60 µm, SD = 92.1; P < 0.014; 95% CI = 19.75-156.54). The difference in mean reduction of CRT at 6 months was not significant (P < 0.24). Conclusion: Adjunctive dexamethasone implant can aid faster visual recovery after PPV in idiopathic ERM, although the implants do not affect long-term gains in visual acuity.

Scanning laser 'en face' retinal imaging of epiretinal membranes.

PURPOSE: Comparison of scanning laser ophthalmoscopy (SLO) based 'en face' imaging techniques of patients with epiretinal membranes (ERM) and evaluation of the accuracy of preoperative diagnostic imaging. METHODS: A consecutive, prospective series of 53 study eyes of 46 patients with clinically diagnosed and in optical coherence tomography (OCT) confirmed symptomatic ERMs were included in this study. Spectral domain (SD-) OCT volume scans (20° × 20° with 49 horizontal sections, ART 15) including SLO en face and fundus autofluorescence (FAF) images of the macula were obtained with HRA2 (Heidelberg Retina Angiograph-Optical Coherence Tomography, Heidelberg Engineering, Heidelberg, Germany). In addition, wide-field SLO color and FAF images (Optomap 200Tx, Optos PLC, Dunfermline, UK) were performed also covering the macular area. En face images of both devices were graded for each included study eye based on SD-OCT cross sectional scans. RESULTS: Grading of SD-OCT (HRA2) based SLO en face green-blue enhanced multi-color, green reflectance, blue reflectance and standard multi-color visualization revealed a better detectability of ERM than SD-OCT-based en face infrared or FAF images or wide-field SLO (Optomap) based pseudo-color, red laser separation, green laser separation, or FAF images. Both FAF visualizations, HRA2 and Optomap based, achieved low mean scores. SD-OCT based en face thickness map visualization revealed good visualization but poor demarcation of epiretinal membranes. CONCLUSIONS: In summary, en face regular or enhanced multicolor SLO images acquired with HRA2 allow a better visualization of epiretinal membranes for preoperative evaluation compared to SD-OCT based en face thickness map or pseudo-color images acquired with Optomap while infrared or FAF images are least suitable to depict epiretinal membranes.

Factors Associated with Recurrence after Surgery for Epiretinal Membrane

PURPOSE: To evaluate the factors associated with the recurrence of epiretinal membrane (ERM) after surgery for ERM METHODS: We reviewed patients' medical records who received vitrectomy for ERM. The preoperative findings, best postoperative and final visual acuity, and intraoperative findings of eyes with recurred ERM were compared with those of eyes without recurrence after removal of ERM. RESULTS: Recurrence of ERM was high in eyes with ERM associated with chronic uveitis, compared with the eyes with idiopathic ERM (p=0.030, Cox regression analysis). Neither the type of membrane nor incomplete membrane removal during pars plana vitrectomy was correlated with the recurrence of ERM. CONCLUSIONS: Considering the recurrence of ERM after surgical removal being high in eyes with chronic uveitis, close follow up is recommended in these patients.