Surgery for idiopathic epiretinal membrane

BACKGROUND: Epiretinal membrane is an abnormal sheet of avascular fibrocellular tissue that develops on the inner surface of the retina. Epiretinal membrane can cause impairment of sight as a consequence of progressive distortion of retinal architecture. OBJECTIVES: To determine the effects of surgery compared to no intervention for epiretinal membrane. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, ISRCTN registry, US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). There were no restrictions to language or year of publication. The databases were last searched on 20 May 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing surgical removal of idiopathic epiretinal membrane compared to placebo, no treatment or sham treatment. Paired or within-person studies were included, as well as those where both eyes of a single participant were treated. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane, and assessed certainty using the GRADE system. We considered the following five outcome measures: mean change in best corrected visual acuity (BCVA) in the study eye between baseline (before randomisation), 6 months and 12 months later; proportion of people with a gain of 0.3 logMAR or more of visual acuity in the study eye as measured by a logMAR chart at a starting distance of 4 m at 6 months and 12 months after randomisation; proportion of people with a loss of 0.3 logMAR or more of visual acuity in the study eye as measured by a logMAR chart at a starting distance of 4 m at 6 months and 12 months after randomisation; mean quality of life score at 6 months and 12 months following surgery, measured using a validated questionnaire; and any harm identified during follow-up. MAIN RESULTS: We included one study in the review. This was a RCT including 53 eyes of 53 participants with mild symptomatic epiretinal membrane and BCVA of 65 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Participants were randomly allocated to immediate surgery or to watchful waiting with deferred surgery if indicated by evidence of disease progression. The study was limited by imprecision owing to the small number of participants and was at some risk of bias owing to inconsistencies in the time points for outcome assessment and in the management of lens opacity. At 12 months, the visual acuity in the immediate surgery group was higher by a mean of 2.1 (95% confidence interval (CI) -2.0 to 6.2 ETDRS letters; 53 participants; low-certainty evidence) than the watchful waiting/deferred surgery group. The evidence of the effect of immediate surgery on gains of 0.3 logMAR or more of visual acuity is very uncertain (risk ratio (RR) 0.55, 95% CI 0.06 to 4.93; 53 participants; very low-certainty evidence). At 12 months, no participant in either group sustained a loss of 0.3 logMAR or more of visual acuity (53 participants; low-certainty evidence). The included study did not measure quality of life. At 12 months, no serious adverse event was identified in any participant. One participant developed chronic minimal cystoid macular oedema following immediate surgery (53 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: We found no RCT that directly investigated the effect of surgery compared to no intervention. For severe disabling epiretinal membrane, the lack of a RCT comparing surgery to no intervention may reflect evidence from non-randomised studies in favour of surgery; a RCT may be considered unnecessary and ethically unacceptable because a superior effect of surgery is widely accepted. For mild symptomatic epiretinal membrane, however, the value of surgery is uncertain. Low-certainty evidence from this review suggests that watchful waiting or deferred surgery may offer outcomes as favourable as immediate surgery. However, this finding needs to be confirmed in further RCTs with appropriate statistical power, masking of treatment allocation, consistent management of cataract, and measurement of outcomes including patient-reported quality of life over a more extended time frame

Early vitrectomy for exogenous endophthalmitis following surgery

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the potential role of combined pars plana vitrectomy and intravitreal antibiotics in the acute management of exogenous endophthalmitis, versus the standard of care, defined as vitreous tap and intravitreal antibiotics

Nystagmus and optical coherence tomography findings in CNGB3-associated achromatopsia

PURPOSE: To describe the nystagmus characteristics of subjects with molecularly confirmed CNGB3-associated achromatopsia and report the spectral domain optical coherence tomography (SD-OCT) findings in these individuals. METHODS: Adults and children with CNGB3-achromatopsia underwent visual acuity testing, ocular motility assessments, video nystagmography, and SD-OCT imaging. Qualitative assessment of foveal structure was performed by grading SD-OCT images into one of five categories. RESULTS: A total of 18 subjects (11 adults) were included. The majority demonstrated a phoria, with manifest strabismus present in only 3 subjects. The predominant nystagmus waveform within the cohort was pure pendular. Nine individuals demonstrated a mixture of waveforms. Nystagmus frequencies were 4-8 cycles/second, with no notable differences in eye movements between adults and children. SD-OCT imaging revealed a continuous ellipsoid zone (EZ) at the fovea in 2 subjects (grade 1) and EZ disruption (grade 2) in the remaining 16. Retinal structure characteristics were symmetrical in both eyes in each subject. CONCLUSIONS: In our study cohort, nystagmus in CNGB3-associated achromatopsia had distinctive features, and the majority of subjects had retinal abnormalities at the fovea on SD-OCT. Early use of SD-OCT in the clinical work-up may eliminate the need for more invasive investigations, such as neuro-imaging

Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179

The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice

Assessment and in vivo scoring of murine experimental autoimmune uveoretinitis using optical coherence tomography

Despite advances in clinical imaging and grading our understanding of retinal immune responses and their morphological correlates in experimental autoimmune uveoretinitis (EAU), has been hindered by the requirement for post-mortem histology. To date, monitoring changes occurring during EAU disease progression and evaluating the effect of therapeutic intervention in real time has not been possible. We wanted to establish whether optical coherence tomography (OCT) could detect intraretinal changes during inflammation and to determine its utility as a tool for accurate scoring of EAU. EAU was induced in C57BL/6J mice and animals evaluated after 15, 26, 36 and 60 days. At each time-point, contemporaneous Spectralis-OCT scanning, topical endoscopic fundal imaging (TEFI), fundus fluorescein angiography (FFA) and CD45-immunolabelled histology were performed. OCT features were further characterised on retinal flat-mounts using immunohistochemistry and 3D reconstruction. Optic disc swelling and vitreous opacities detected by OCT corresponded to CD45+ cell infiltration on histology. Vasculitis identified by FFA and OCT matched perivascular myeloid and T-cell infiltrates and could be differentiated from unaffected vessels. Evolution of these changes could be followed over time in the same eye. Retinal folds were visible and found to encapsulate mixed populations of activated myeloid cells, T-cells and microglia. Using these features, an OCT-based EAU scoring system was developed, with significant correlation to validated histological (Pearson r(2) = 0.6392, P<0.0001, n = 31 eyes) and TEFI based scoring systems (r(2) = 0.6784, P<0.0001). OCT distinguishes the fundamental features of murine EAU in vivo, permits dynamic assessment of intraretinal changes and can be used to score disease severity. As a result, it allows tissue synchronisation with subsequent cellular and functional assessment and greater efficiency of animal usage. By relating OCT signals with immunohistochemistry in EAU, our findings offer the opportunity to inform the interpretation of OCT changes in human uveitis

Flow cytometric analysis of inflammatory and resident myeloid populations in mouse ocular inflammatory models

Myeloid cells make a pivotal contribution to tissue homeostasis during inflammation. Both tissue-specific resident populations and infiltrating myeloid cells can cause tissue injury through aberrant activation and/or dysregulated activity. Reliable identification and quantification of myeloid cells within diseased tissues is important to understand pathological inflammatory processes. Flow cytometry is a valuable technique for leukocyte analysis, but a standardized flow cytometric method for myeloid cell populations in the eye is lacking. Here, we validate a reproducible flow cytometry gating approach to characterize myeloid cells in several commonly used models of ocular inflammation. We profile and quantify myeloid subsets across these models, and highlight the value of this strategy in identifying phenotypic differences using Ccr2-deficient mice. This method will aid standardization in the field and facilitate future investigations into the roles of myeloid cells during ocular inflammation

Early-Onset Progressive Degeneration of the Area Centralis in RPE65-Deficient Dogs.

PURPOSE: Retinal epithelium-specific protein 65 kDa (RPE65)-deficient dogs are a valuable large animal model species that have been used to refine gene augmentation therapy for Leber congenital amaurosis type-2 (LCA2). Previous studies have suggested that retinal degeneration in the dog model is slower than that observed in humans. However, the area centralis of the dog retina is a cone and rod photoreceptor rich region comparable to the human macula, and the effect of RPE65 deficiency specifically on this retinal region, important for high acuity vision, has not previously been reported. METHODS: Spectral-domain optical coherence tomography, fundus photography, and immunohistochemistry of retinal wholemounts and sagittal frozen sections were used to define the time-course and cell-types affected in degeneration of the area centralis in affected dogs. RESULTS: Area centralis photoreceptor degeneration was evident from 6 weeks of age, and progressed to involve the inner retina. Immunohistochemistry showed that RPE65-deficient dogs developed early loss of S-cone outer segments, with slower loss of L/M-cone outer segments and rods. CONCLUSIONS: Early-onset severe photoreceptor degeneration in the area centralis of dogs with RPE65-deficiency offers a model of the early foveal/perifoveal degeneration in some patients with LCA2. This model could be used to refine interventions aiming to improve function and halt the progression of foveal/perifoveal photoreceptor degeneration

The Relationship Between Retinal Vessel Oxygenation and Spatial Distribution of Retinal Nonperfusion in Retinal Vascular Diseases

Purpose: We study the relationship between retinal vessel oxygenation and the spatial distribution of retinal nonperfusion using ultrawide field angiography in eyes with retinal vascular diseases. Methods: This prospective single center study recruited 57 eligible eyes from 44 patients with retinal vascular diseases. Retinal oximetry measurements were obtained using the Oxymap T1 device to determine the arteriovenous (AV) difference. Retinal nonperfusion was measured from ultrawide field angiography images taken with the Optos 200TX system and superimposing the images with the concentric rings template to determine the area and distribution of retinal nonperfusion. Results: Seven (12.3%) eyes had a diagnosis of a branch or hemiretinal vein occlusion, 24 (42.1%) with central retinal vein occlusion and 26 (45.6%) with diabetic retinopathy (11 [19.3%] nonproliferative and 15 [26.3%] proliferative diabetic retinopathy). The correlation between the total area of retinal nonperfusion with the AV difference controlling for age was not statistically significant (R = -0.103, P = 0.449). However, when analyzing the correlation of AV difference with the area of retinal nonperfusion in the posterior pole controlling for age and peripheral nonperfusion, this was significant (R = -0.295, P = 0.029). This was not significant for the area of retinal nonperfusion in the periphery while controlling for posterior pole nonperfusion and age (R = 0.124, P = 0.368). Conclusions: Retinal nonperfusion has a negative correlation with AV difference measured on retinal oximetry. This correlation is significant in the posterior pole, but not in the peripheral retina

Transplantation of Photoreceptor Precursors Isolated via a Cell Surface Biomarker Panel From Embryonic Stem Cell-Derived Self-Forming Retina.

Loss of photoreceptors due to retinal degeneration is a major cause of untreatable blindness. Cell replacement therapy, using pluripotent stem cell-derived photoreceptor cells, may be a feasible future treatment. Achieving safe and effective cell replacement is critically dependent on the stringent selection and purification of optimal cells for transplantation. Previously, we demonstrated effective transplantation of post-mitotic photoreceptor precursor cells labelled by fluorescent reporter genes. As genetically labelled cells are not desirable for therapy, here we developed a surface biomarker cell selection strategy for application to complex pluripotent stem cell differentiation cultures. We show that a five cell surface biomarker panel CD73(+)CD24(+)CD133(+)CD47(+)CD15(-) facilitates the isolation of photoreceptor precursors from three-dimensional self-forming retina differentiated from mouse embryonic stem cells. Importantly, stem cell-derived cells isolated using the biomarker panel successfully integrate and mature into new rod photoreceptors in the adult mouse retinae after subretinal transplantation. Conversely, unsorted or negatively selected cells do not give rise to newly integrated rods after transplantation. The biomarker panel also removes detrimental proliferating cells prior to transplantation. Notably, we demonstrate how expression of the biomarker panel is conserved in the human retina and propose that a similar selection strategy will facilitate isolation of human transplantation-competent cells for therapeutic application. Stem Cells 2015;33:2469-2482

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.

Objective: VEGFA (Vascular endothelial growth factor A) and its receptor VEGFR2 (vascular endothelial growth factor receptor 2) drive angiogenesis in several pathologies, including diabetic retinopathy, wet age-related macular degeneration, and cancer. Studies suggest roles for HSPGs (heparan sulfate proteoglycans) in this process, although the nature of this involvement remains elusive. Here, we set to establish the role of the HSPG SDC4 (syndecan-4) in pathological angiogenesis. / Approach and Results: We report that angiogenesis is impaired in mice null for SDC4 in models of neovascular eye disease and tumor development. Our work demonstrates that SDC4 is the only SDC whose gene expression is upregulated during pathological angiogenesis and is selectively enriched on immature vessels in retinas from diabetic retinopathy patients. Combining in vivo and tissue culture models, we identified SDC4 as a downstream mediator of functional angiogenic responses to VEGFA. We found that SDC4 resides at endothelial cell junctions, interacts with vascular endothelial cadherin, and is required for its internalization in response to VEGFA. Finally, we show that pathological angiogenic responses are inhibited in a model of wet age-related macular degeneration by targeting SDC4. / Conclusions: We show that SDC4 is a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization during pathological angiogenesis and a potential target for antiangiogenic therapies