Proliferative Vitreoretinopathy: A Review Idrees, Sana; Sridhar, Jayanth; Kuriyan, Ajay E
International ophthalmology clinics,
01/2019, Letnik:
59, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Proliferative vitreoretinopathy (PVR) is the most common cause for failure of rhegmatogenous retinal detachment repair and is characterized by the growth and contraction of cellular membranes within ...the vitreous cavity and on both sides of the retinal surface as well as intraretinal fibrosis. Currently, PVR is thought to be an abnormal wound healing response that is primarily driven by inflammatory, retinal, and RPE cells. At this time, surgery is the only management option for PVR as there is no proven pharmacologic agent for the treatment or prevention of PVR. Laboratory research to better understand PVR pathophysiology and clinical trials of various agents to prevent PVR formation are ongoing.
In three women with age-related macular degeneration and with visual acuity ranging from 20/30 to 20/200 before they received bilateral intravitreal injection of autologous “stem cells,” blinding ...complications developed in each of their eyes.
Age-related macular degeneration (AMD) is the leading cause of vision loss in persons older than 75 years of age in the United States.
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Progressive dysfunction and loss of retinal pigment epithelium cells and photoreceptors lead to poor visual acuity in patients with non-neovascular AMD.
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The potential role of delivering subretinal human retinal pigment epithelium, photoreceptor cells, or both, differentiated from pluripotent stem cells, to replace the damaged cells in patients with non-neovascular AMD is being investigated in several clinical trials registered by the Food and Drug Administration (FDA) and approved by institutional review boards.
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As of November 2, 2016, at . . .
Proliferative vitreoretinopathy (PVR) is characterized by the growth and contraction of cellular membranes within the vitreous cavity and on both surfaces of the retina, resulting in recurrent ...retinal detachments and poor visual outcomes. Proinflammatory cytokines like tumor necrosis factor alpha (TNFα) have been associated with PVR and the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. Cigarette smoke is the only known modifiable risk factor for PVR, but the mechanisms are unclear. The purpose of this study was to examine the impact of cigarette smoke on the proinflammatory TNFα/NF-κB/Snail pathway in RPE cells to better understand the mechanisms through which cigarette smoke increases the risk of PVR. Human ARPE-19 cells were exposed to cigarette smoke extract (CSE), for 4 to 24-hours and TNFα, Snail, IL-6, IL-8, and α-SMA levels were analyzed by qPCR and/or Western blot. The severity of PVR formation was assessed in a murine model of PVR after intravitreal injection of ARPE-19 cells pre-treated with CSE or not. Fundus imaging, OCT imaging, and histologic analysis 4 weeks after injection were used to examine PVR severity. ARPE-19 cells exposed to CSE expressed higher levels of TNFα, SNAIL, IL6 and IL8 mRNA as well as SNAIL, Vimentin and α-SMA protein. Inhibition of TNFα and NF-κB pathways blocked the effect of CSE. In vivo, intravitreal injection of ARPE-19 cells treated with CSE resulted in more severe PVR compared to mice injected with untreated RPE cells. These studies suggest that the TNFα pathway is involved in the mechanism whereby cigarette smoke increases PVR. Further investigation into the role of TNFα/NF-κB/Snail in driving PVR and pharmacological targeting of these pathways in disease are warranted.
Background
Retinitis pigmentosa (RP) comprises a group of hereditary eye diseases characterized by progressive degeneration of retinal photoreceptors. It results in severe visual loss that may lead ...to blindness. Symptoms may become manifest during childhood or adulthood which include poor night vision (nyctalopia) and constriction of peripheral vision (visual field loss). Visual field loss is progressive and affects central vision later in the disease course. The worldwide prevalence of RP is approximately 1 in 4000, with 100,000 individuals affected in the USA. At this time, there is no proven therapy for RP.
Objectives
The objective of this review was to synthesize the best available evidence regarding the effectiveness and safety of vitamin A and fish oils (docosahexaenoic acid (DHA)) in preventing the progression of RP.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (2020, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP); and OpenGrey. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 7 February 2020.
Selection criteria
We included randomized controlled trials that enrolled participants of any age diagnosed with any degree of severity or type of RP, and evaluated the effectiveness of vitamin A, fish oils (DHA), or both compared to placebo, vitamins (other than vitamin A), or no therapy, as a treatment for RP. We excluded cluster‐randomized trials and cross‐over trials.
Data collection and analysis
We prespecified the following outcomes: mean change from baseline visual field, mean change from baseline electroretinogram (ERG) amplitudes, and anatomic changes as measured by optical coherence tomography (OCT), at one‐year follow‐up, and mean change in visual acuity, at five‐year follow‐up. Two review authors independently extracted data and evaluated risk of bias for all included trials. We also contacted study investigators for further information when necessary.
Main results
In addition to three trials from the previous version of this review, we included a total of four trials with 944 participants aged 4 to 55 years. Two trials included only participants with X‐linked RP and the other two included participants with RP of all forms of genetic predisposition. Two trials evaluated the effect of DHA alone; one trial evaluated vitamin A alone; and one trial evaluated DHA and vitamin A versus vitamin A alone. Two trials recruited participants from the USA, and the other two recruited from the USA and Canada. All trials were at low risk of bias for most domains. We did not perform meta‐analysis due to clinical heterogeneity.
Four trials assessed visual field sensitivity. Investigators found no evidence of a difference in mean values between the groups. However, one trial found that the annual rate of change of visual field sensitivity over four years favored the DHA group in foveal (−0.02 ± 0.55 (standard error (SE)) dB versus −0.47 ± 0.03 dB, P = 0.039), macular (−0.42 ± 0.05 dB versus −0.85 ± 0.03 dB, P = 0.031), peripheral (−0.39 ± 0.02 versus −0.86 ± 0.02 dB, P < 0.001), and total visual field sensitivity (−0.39 ± 0.02 versus −0.86 ± 0.02 dB, P < 0.001). The certainty of the evidence was very low.
The four trials evaluated visual acuity (LogMAR scale) at a follow‐up of four to six years. In one trial (208 participants), investigators found no evidence of a difference between the two groups, as both groups lost 0.7 letters of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity per year. In another trial (41 participants), DHA showed no evidence of effect on visual acuity (mean difference −0.01 logMAR units (95% confidence interval −0.14 to 0.12; one letter difference between the two groups; very low‐certainty evidence). In the third trial (60 participants), annual change in mean number of letters correct was −0.8 (DHA) and 1.4 letters (placebo), with no evidence of between‐group difference. In the fourth trial (572 participants), which evaluated (vitamin A + vitamin E trace) compared with (vitamin A trace + vitamin E trace), decline in ETDRS visual acuity was 1.1 versus 0.9 letters per year, respectively.
All four trials reported electroretinography (ERG). Investigators of two trials found no evidence of a difference between the DHA and placebo group in yearly rates of change in 31 Hz cone ERG amplitude (mean ± SE) (−0.028 ± 0.001 log μV versus −0.022 ± 0.002 log μV; P = 0.30); rod ERG amplitude (mean ± SE) (−0.010 ± 0.001 log μV versus −0.023 ± 0.001 log μV; P = 0.27); and maximal ERG amplitude (mean ± SE) (−0.042 ± 0.001 log μV versus −0.036 ± 0.001 log μV; P = 0.65). In another trial, a slight difference (6.1% versus 7.1%) in decline of ERG per year favored vitamin A (P = 0.01). The certainty of the evidence was very low.
One trial (51 participants) that assessed optical coherence tomography found no evidence of a difference in ellipsoid zone constriction (P = 0.87) over two years, with very low‐certainty evidence. The other three trials did not report this outcome.
Only one trial reported adverse events, which found that 27/60 participants experienced 42 treatment‐related emergent adverse events (22 in DHA group, 20 in placebo group). The certainty of evidence was very low. The rest of the trials reported no adverse events, and no study reported any evidence of benefit of vitamin supplementation on the progression of visual acuity loss.
Authors' conclusions
Based on the results of four studies, it is uncertain if there is a benefit of treatment with vitamin A or DHA, or both for people with RP. Future trials should also take into account the changes observed in ERG amplitudes and other outcome measures from trials included in this review.
We propose a deep-learning based annotation-efficient framework for vessel detection in ultra-widefield (UWF) fundus photography (FP) that does not require de novo labeled UWF FP vessel maps. Our ...approach utilizes concurrently captured UWF fluorescein angiography (FA) images, for which effective deep learning approaches have recently become available, and iterates between a multi-modal registration step and a weakly-supervised learning step. In the registration step, the UWF FA vessel maps detected with a pre-trained deep neural network (DNN) are registered with the UWF FP via parametric chamfer alignment. The warped vessel maps can be used as the tentative training data but inevitably contain incorrect (noisy) labels due to the differences between FA and FP modalities and the errors in the registration. In the learning step, a robust learning method is proposed to train DNNs with noisy labels. The detected FP vessel maps are used for the registration in the following iteration. The registration and the vessel detection benefit from each other and are progressively improved. Once trained, the UWF FP vessel detection DNN from the proposed approach allows FP vessel detection without requiring concurrently captured UWF FA images. We validate the proposed framework on a new UWF FP dataset, PRIME-FP20, and on existing narrow-field FP datasets. Experimental evaluation, using both pixel-wise metrics and the CAL metrics designed to provide better agreement with human assessment, shows that the proposed approach provides accurate vessel detection, without requiring manually labeled UWF FP training data.
Proliferative vitreoretinopathy (PVR) is a progressive disease that develops in a subset of patients who undergo surgery for retinal detachment repair, and results in significant vision loss. PVR is ...characterized by the migration of retinal pigment epithelial (RPE) cells into the vitreous cavity, where they undergo epithelial-to-mesenchymal transition and form contractile membranes within the vitreous and along the retina, resulting in recurrent retinal detachments. Currently, surgical intervention is the only treatment for PVR and there are no pharmacological agents that effectively inhibit or prevent PVR formation. Here, we show that a single intravitreal injection of the polyether ionophore salinomycin (SNC) effectively inhibits the formation of PVR in a mouse model with no evidence of retinal toxicity. After 4 weeks, fundus photography and optical coherence tomography (OCT) demonstrated development of mean PVR grade of 3.5 (SD: 1.3) in mouse eyes injected with RPE cells/DMSO (vehicle), compared to mean PVR grade of 1.6 (SD: 1.3) in eyes injected with RPE cells/SNC (p = 0.001). Additionally, immunohistochemistry analysis showed RPE cells/SNC treatment reduced both fibrotic (αSMA, FN1, Vim) and inflammatory (GFAP, CD3, CD20) markers compared to control RPE cells/DMSO treatment. Finally, qPCR analysis confirmed that Tgfβ, Tnfα, Mcp1 (inflammatory/cytokine markers), and Fn1, Col1a1 and Acta2 (fibrotic markers) were significantly attenuated in the RPE cells/SNC group compared to RPE/DMSO control. These results suggest that SNC is a potential pharmacologic agent for the prevention of PVR in humans and warrants further investigation.
While recent advances in deep learning have significantly advanced the state of the art for vessel detection in color fundus (CF) images, the success for detecting vessels in fluorescein angiography ...(FA) has been stymied due to the lack of labeled ground truth datasets. We propose a novel pipeline to detect retinal vessels in FA images using deep neural networks (DNNs) that reduces the effort required for generating labeled ground truth data by combining two key components: cross-modality transfer and human-in-the-loop learning. The cross-modality transfer exploits concurrently captured CF and fundus FA images. Binary vessels maps are first detected from CF images with a pre-trained neural network and then are geometrically registered with and transferred to FA images via robust parametric chamfer alignment to a preliminary FA vessel detection obtained with an unsupervised technique. Using the transferred vessels as initial ground truth labels for deep learning, the human-in-the-loop approach progressively improves the quality of the ground truth labeling by iterating between deep-learning and labeling. The approach significantly reduces manual labeling effort while increasing engagement. We highlight several important considerations for the proposed methodology and validate the performance on three datasets. Experimental results demonstrate that the proposed pipeline significantly reduces the annotation effort and the resulting deep learning methods outperform prior existing FA vessel detection methods by a significant margin. A new public dataset, RECOVERY-FA19, is introduced that includes high-resolution ultra-widefield images and accurately labeled ground truth binary vessel maps.
Cell therapy for retinal disease Yalla, Goutham R; Kuriyan, Ajay E
Current opinion in ophthalmology,
2024-May-01, 2024-05-00, 20240501, Letnik:
35, Številka:
3
Journal Article
This review presents an update on completed stem cell therapy trials aimed at retinal diseases.
In recent years, several clinical trials have been conducted examining the safety and role of cell ...therapy in diseases, including age-related macular degeneration, Stargardt's macular dystrophy, and retinitis pigmentosa. Studies have utilized a variety of cell lines, modes of delivery, and immunosuppressive regimens. The prevalence of fraudulent cell therapy clinics poses threats to patients.
Clinical trials have begun to characterize the safety of cell therapy in retinal disease. While studies have described the potential benefits of cell therapy, larger studies powered to evaluate this efficacy are required to continue progressing toward preventing retinal disease. Nonapproved cell therapy clinics require regulation and patient education to avoid patient complications.
Background The retinal pigment epithelium (RPE) is implicated in the pathophysiology of many retinal degenerative diseases. This cell layer is also an ideal target for cell-based therapies. Several ...early phase clinical trials evaluating cell therapy approaches for diseases involving the RPE, such as age-related macular degeneration and Stargardt's macular dystrophy have been published. However, there have also been numerous reports of complications from unproven "cell therapy" treatments marketed by "cell therapy" clinics. This review aims to outline the particular approaches in the different published clinical trials for cell-based therapies for retinal diseases. Additionally, the controversies surrounding experimental treatments offered outside of legitimate studies are presented. Main body Cell-based therapies can be applied to disorders that involve the RPE via a variety of techniques. A defining characteristic of any cell therapy treatment is the cell source used: human embryonic stem cells, induced pluripotent stem cells, and human umbilical tissue-derived cells have all been studied in published trials. In addition to the cell source, various trials have evaluated particular immunosuppression regiments, surgical approaches, and outcome measures. Data from early phase studies investigating cell-based therapies in non-neovascular age-related macular degeneration (70 patients, five trials), neovascular age-related macular degeneration (12 patients, four trials), and Stargardt's macular dystrophy (23 patients, three trials) have demonstrated safety related to the cell therapies, though evidence of significant efficacy has not been reported. This is in contrast to the multiple reports of serious complications and permanent vision loss in patients treated at "cell therapy" clinics. These interventions are marketed directly to patients, funded by the patient, lack Food and Drug Administration approval, and lack significant oversight. Conclusion Currently, there are no proven effective cell-based treatments for retinal diseases, although several trials have investigated potential therapies. These studies reported favorable safety profiles with multiple surgical approaches, with cells derived from multiple sources, and with utilized different immunosuppressive regiments. However, data demonstrating the efficacy and long-term safety are still pending. Nevertheless, "cell therapy" clinics continue to conduct direct-to consumer marketing for non-FDA-approved treatments with potentially blinding complications. Keywords: Age-related macular degeneration, Cell therapy clinics, Human embryonic stem cells, Human umbilical tissue-derived cells, Induced pluripotent stem cells, Retinal pigment epithelium, Stargardt's macular dystrophy
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