Vitamin A and fish oils for preventing the progression of retinitis pigmentosa.

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 \u3c 0.001), and total visual field sensitivity (-0.39 ± 0.02 versus -0.86 ± 0.02 dB, P \u3c 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\u27 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

Myo/Nog Cells Give Rise to Myofibroblasts During Epiretinal Membrane Formation in a Mouse Model of Proliferative Vitreoretinopathy.

PURPOSE: Myo/Nog cells are the source of myofibroblasts in the lens and synthesize muscle proteins in human epiretinal membranes (ERMs). In the current study, we examined the response of Myo/Nog cells during ERM formation in a mouse model of proliferative vitreoretinopathy (PVR). METHODS: PVR was induced by intravitreal injections of gas and ARPE-19 cells. PVR grade was scored by fundus imaging, optical coherence tomography, and histology. Double label immunofluorescence localization was performed to quantify Myo/Nog cells, myofibroblasts, and leukocytes. RESULTS: Myo/Nog cells, identified by co-labeling with antibodies to brain-specific angiogenesis inhibitor 1 (BAI1) and Noggin, increased throughout the eye with induction of PVR and disease progression. They were present on the inner surface of the retina in grades 1/2 PVR and were the largest subpopulation of cells in grades 3 to 6 ERMs. All α-SMA-positive (+) cells and all but one striated myosin+ cell expressed BAI1 in grades 1 to 6 PVR. Folds and areas of retinal detachment were overlain by Myo/Nog cells containing muscle proteins. Low numbers of CD18, CD68, and CD45+ leukocytes were detected throughout the eye. Small subpopulations of BAI1+ cells expressed leukocyte markers. ARPE-19 cells were found in the vitreous but were rare in ERMs. Pigmented cells lacking Myo/Nog and muscle cell markers were present in ERMs and abundant within the retina by grade 5/6. CONCLUSIONS: Myo/Nog cells differentiate into myofibroblasts that appear to contract and produce retinal folds and detachment. Targeting BAI1 for Myo/Nog cell depletion may be a pharmacological approach to preventing and treating PVR

TNF-α and NF-κB Signaling Play a Critical Role in Cigarette Smoke-induced Epithelial-mesenchymal Transition of Retinal Pigment Epithelial Cells in Proliferative Vitreoretinopathy

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

Google Search Trends to Assess Public Interest in and Concern About Vuity for Treating Presbyopia

PURPOSE: To assess public awareness, interest, and concerns regarding Vuity (1.25% pilocarpine hydrochloride ophthalmic solution), an eye drop for the treatment of presbyopia, based on Google Trends. METHODS: We used Google Trends that provides a relative search volume for queried terms, to evaluate searches for Vuity from June 30, 2021, to June 30, 2022, in the United States. The data for this study were downloaded on June 30, 2022. Main outcome measures were changes in relative search volumes for the terms Vuity, Eye drops for reading, Eye drops for near vision, Presbyopia, Pilocarpine, and related popular search terms, such as Vuity side effects, and Vuity retinal detachment . RESULTS: Since the approval of Vuity on October 29, 2021, notable increases in the relative search volumes occurred for Vuity in October 2021, December 2021, and from March to April 2022, which coincided with its approval, availability, and subsequent direct-to-consumer advertising based on positive results of clinical trials. The direct-to-consumer advertising had the greatest impact on the search volume for Vuity. Specific interests included Vuity cost, where to buy it, and its side effects. Retinal detachment was the most highly searched Vuity side effect. Geographic variation was evident, with the relative search volumes highest for Vuity in Wyoming, followed by North Dakota. CONCLUSION: Google Trends is a useful tool for monitoring increases in public interest in Vuity for presbyopia. Public concerns regarding side effects warrant further real-world investigations of the causal relationship between Vuity and retinal detachment

A Comparative Study of Responses to Retina Questions from Either Experts, Expert-Edited Large Language Models, or Expert-Edited Large Language Models Alone

OBJECTIVE: To assess the quality, empathy, and safety of expert edited large language model (LLM), human expert created, and LLM responses to common retina patient questions. DESIGN: Randomized, masked multicenter study. PARTICIPANTS: Twenty-one common retina patient questions were randomly assigned among 13 retina specialists. METHODS: Each expert created a response (Expert) and then edited a LLM (ChatGPT-4)-generated response to that question (Expert + artificial intelligence [AI]), timing themselves for both tasks. Five LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, and Bard) also generated responses to each question. The original question along with anonymized and randomized Expert + AI, Expert, and LLM responses were evaluated by the other experts who did not write an expert response to the question. Evaluators judged quality and empathy (very poor, poor, acceptable, good, or very good) along with safety metrics (incorrect information, likelihood to cause harm, extent of harm, and missing content). MAIN OUTCOME: Mean quality and empathy score, proportion of responses with incorrect information, likelihood to cause harm, extent of harm, and missing content for each response type. RESULTS: There were 4008 total grades collected (2608 for quality and empathy; 1400 for safety metrics), with significant differences in both quality and empathy ( CONCLUSIONS: In this randomized, masked, multicenter study, LLM responses were comparable with experts in terms of quality, empathy, and safety metrics, warranting further exploration of their potential benefits in clinical settings. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of the article

Non-arteritic anterior ischemic optic neuropathy secondary to acute primary-angle closure

PURPOSE: To describe a case of non-arteritic ischemic optic neuropathy (NAION) secondary to acute primary-angle closure (APAC). METHODS: Case report. RESULTS: A 50-year-old woman with painful visual loss in the right eye was found to be in APAC with a right afferent pupillary defect. Laser peripheral iridotomy relieved pain but did not improve vision. Diffuse optic disc edema in the right eye and a small cup-to-disc ratio in the left eye were evident. Magnetic resonance imaging was normal. The patient was diagnosed with non-arteritic ischemic optic neuropathy (NAION) secondary to APAC, a rare clinical entity which can result in markedly decreased visual acuity. CONCLUSION: NAION secondary to APAC is a rare clinical entity that can result in severe vision loss

Cell-based therapies for retinal diseases: a review of clinical trials and direct to consumer cell therapy clinics

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\u27s 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\u27s 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