INTRAOCULAR INFLAMMATION INCIDENCE AFTER INTRAVITREAL BROLUCIZUMAB INJECTION FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: We evaluated the clinical outcomes of intraocular inflammation (IOI) of eyes with neovascular age-related macular degeneration (AMD) injected with brolucizumab in our tertiary referral center. METHODS: A retrospective case series for which clinical records of all eyes that received intravitreal brolucizumab at Bascom Palmer Eye Institute between December 1, 2019, and April 1, 2021, were reviewed. RESULTS: There were 345 eyes of 278 patients who received 801 brolucizumab injections. IOI was detected in 16 eyes of 13 patients (4.6%). In those patients, baseline Logarithm of Minimu Angle of Resolution (logMAR) best-corrected visual acuity was 0.32 0.2 (20/42), while it was 0.58 0.3 (20/76) at IOI presentation. The mean number of injections among eyes experiencing IOI was 2.4, and the interval between the last brolucizumab injection and IOI presentation was 20 days. There was no known case of retinal vasculitis. Management of IOI included topical steroids in seven eyes (54%), topical and systemic steroids in five eyes (38%), and observation in one eye (8%). Best-corrected visual acuity returned to baseline and inflammation resolved in all eyes by the last follow-up examination. CONCLUSION: Intraocular inflammation after brolucizumab injection for neovascular AMD was not uncommon. Inflammation resolved in all eyes by the last follow-up visit.

Recovery course of foveal microstructure in the nonsurgical resolution of full-thickness macular hole.

PURPOSE: To analyze the recovery course of foveal microstructures in eyes with nonsurgical healing of full-thickness macular hole (FTMH). METHODS: By serial OCT scans, the temporal healing sequences were analyzed in ocular trauma, vitreomacular traction (VMT), cystoid macular edema (CME), and the remaining group. We evaluated correlations between the final best-corrected spectacle visual acuity and reconstruction time of external limiting membrane (ELM), and inner segment/outer segment (IS/OS). RESULTS: The healing (mean±standard deviation in months) most involved fusion at the level of the outer nuclear layer (ONL) (6.3±10.5) followed by restoration of ELM (9.1±13.8), and lastly, by IS/OS regeneration (13.1±19.5). In severe blunt ocular trauma, healing was fast and involved subretinal zipper glue-like reapposition with resulting outer retinal atrophy. Best spectacle-corrected visual acuity correlated with normalization of the clivus (p=0.012), faster ELM (p=0.006), and IS/OS reconstitution (p=0.024). Recurrence of FTMH occurred when the healing was halted (3 eyes) or was aberrant by lamellar hole epiretinal proliferation (LHEP) (3 eyes) or by the persistence of VMT (1 eye). CONCLUSION: Recovery sequences proceeded from the ONL to the deeper layers with BCVA correlating absolutely and temporally with the restoration of outer retinal layer integrity.

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 < 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.

Tamponade in surgery for retinal detachment associated with proliferative vitreoretinopathy.

BACKGROUND: Retinal detachment (RD) with proliferative vitreoretinopathy (PVR) often requires surgery to restore normal anatomy and to stabilize or improve vision. PVR usually occurs in association with recurrent RD (that is, after initial retinal re-attachment surgery), but occasionally may be associated with primary RD. Either way, for both circumstances a tamponade agent (gas or silicone oil) is needed during surgery to reduce the rate of postoperative recurrent RD. OBJECTIVES: The objective of this review was to assess the relative safety and effectiveness of various tamponade agents used with surgery for RD complicated by PVR. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (the Cochrane Library 2019, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2019), Embase (January 1980 to January 2019), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2019), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 January 2019. SELECTION CRITERIA: We included randomized controlled trials (RCTs) on participants undergoing surgery for RD associated with PVR that compared various tamponade agents. DATA COLLECTION AND ANALYSIS: Two review authors screened the search results independently. We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified four RCTs (601 participants) that provided data for the primary and secondary outcomes. Three RCTs provided data on visual acuity, two reported on macular attachment, one on retinal reattachment and another two on adverse events such as RD, worsening visual acuity and intraocular pressure. Study Characteristics Participants' characteristics varied across studies and across intervention groups, with an age range between 21 to 89 years, and were predominantly men. The Silicone Study was conducted in the USA and consisted of two RCTs: (silicone oil versus sulfur hexafluoride (SF6) gas tamponades; 151 participants) and (silicone oil versus perfluropropane (C3F8) gas tamponades; 271 participants). The third RCT compared heavy silicone oil (a mixture of perfluorohexyloctane (F6H8) and silicone oil) with standard silicone oil (either 1000 centistokes or 5000 centistokes; 94 participants). The fourth RCT compared 1000 centistokes with 5000 centistokes silicone oil in 85 participants. We assessed most RCTs at low or unclear risk of bias for most 'Risk of bias' domains. Findings Although SF6 gas was reported to be associated with worse anatomic and visual outcomes than was silicone oil at one year (quantitative data not reported), at two years, silicone oil compared to SF6 gas showed no evidence of a difference in visual acuity (33% versus 51%; risk ratio (RR) 1.57; 95% confidence interval (CI) 0.93 to 2.66; 1 RCT, 87 participants; low-certainty evidence). At one year, another RCT comparing silicone oil and C3F8 gas found no evidence of a difference in visual acuity between the two groups (41% versus 39%; RR 0.97; 95% CI 0.73 to 1.31; 1 RCT, 264 participants; low-certainty evidence). In a third RCT, participants treated with standard silicone oil compared to those receiving heavy silicone oil also showed no evidence of a difference in the change in visual acuity at one year, measured on logMAR scale ( mean difference -0.03 logMAR; 95% CI -0.35 to 0.29; 1 RCT; 93 participants; low-certainty evidence). The fourth RCT with 5000-centistoke and 1000-centistoke comparisons did not report data on visual acuity. For macular attachment, participants treated with silicone oil may probably experience more favorable outcomes than did participants who received SF6 at both one year (quantitative data not reported) and two years (58% versus 79%; RR 1.37; 95% CI 1.01 to 1.86; 1 RCT; 87 participants; low-certainty evidence). In another RCT, silicone oil compared to C3F8 at one year found no evidence of difference in macular attachment (RR 1.00; 95% CI 0.86 to 1.15; 1 RCT, 264 participants; low-certainty evidence). One RCT that compared 5000 centistokes to 1000 centistoke reported that retinal reattachment was successful in 67 participants (78.8%) with first surgery and 79 participants (92.9%) with the second surgery, and no evidence of between-group difference (1 RCT; 85 participants; low-certainty evidence). The fourth RCT that compared standard silicone oil with heavy silicone oil did not report on macular attachment. Adverse events In one RCT (86 participants), those receiving standard 1000 centistoke silicone oil compared with those of the 5000 centistoke silicone oil showed no evidence of a difference in intraocular pressure elevation at 18 months (24% versus 22%; RR 0.90; 95% CI 0.41 to 1.94; low-certainty evidence), visually significant cataract (49% versus 64%; RR 1.30; 95% CI 0.89 to 1.89; low-certainty evidence), and incidence of retina detachment after the removal of silicone oil (RR 0.36 95% CI 0.08 to 1.67; low-certainty evidence). Another RCT that compared standard silicone oil with heavy silicone oil suggests no difference in retinal detachment at one year (25% versus 22%; RR 0.89; 95% CI 0.54 to 1.48; 1 RCT; 186 participants; low-certainty evidence). Retinal detachment was not reported in the RCTs that compared silicone oil versus SF6 and silicone oil versus to C3F8. AUTHORS' CONCLUSIONS: There do not appear to be any major differences in outcomes between C3F8 and silicone oil. Silicone oil may be better than SF6 for macular attachment and other short-term outcomes. The choice of a tamponade agent should be individualized for each patient. The use of either C3F8 or standard silicone oil appears reasonable for most patients with RD associated with PVR. Heavy silicone oil, which is not available for routine clinical use in the USA, may not demonstrate evidence of superiority over standard silicone oil.

Whole exome sequencing of extreme age-related macular degeneration phenotypes.

PURPOSE: Demographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes. METHODS: A genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex. RESULTS: No variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: an intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls. CONCLUSIONS: Identified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.

Rates of Reoperation and Retinal Detachment after Macular Hole Surgery.

PURPOSE: To evaluate rates of reoperation and retinal detachment (RD) after macular hole surgery. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Patients in the insurance claim-based MarketScan databases from 2007 through 2013 with a record of macular hole surgery. METHODS: Patients with macular hole surgery were identified. Cases of definite (the same eye was coded both times) and presumed (the eye laterality was not coded) macular hole reoperations within 2, 3, and 12 months were queried. In addition, cases of postoperative RD within 2, 3, and 12 months were captured. MAIN OUTCOME MEASURES: Rates of macular hole reoperation and postoperative RD, including subgroup analysis based on presence or absence of internal limiting membrane (ILM) peeling. RESULTS: Records of 23465 macular hole surgeries among 20 764 patients were analyzed. Among presumed reoperations, the rates of reoperation were 4.3% (4.1% after ILM peeling and 5.0% after no ILM peeling; P = 0.01) within 2 months of surgery, 5.5% (5.3% after ILM peeling and 6.2% after no ILM peeling; P = 0.03) within 3 months of surgery, and 9.5% (9.0% after ILM peeling and 11.0% after no ILM peeling; P = 0.01) within 12 months of surgery. The rates for definite reoperations were 1.3% (1.2% after ILM peeling and 1.8% after no ILM peeling; P = 0.04) at 2 months, 1.7% (1.6% after ILM peeling and 2.5% after no ILM peeling; P = 0.004) at 3 months, and 4.1% (3.3% after ILM peeling and 7.5% after no ILM peeling; P < 0.001) at 12 months. The cumulative rate of postoperative RD was 1.81±0.09% to 2.18±0.5% after 2 months, 2.27±0.10% to 3.18±0.67% after 3 months, and 3.92±0.16% to 5.70±1.1% after 12 months. Internal limiting membrane peeling was associated negatively with postoperative RD at 2 months (2.3% vs. 1.7%; P = 0.007), 3 months (2.8% vs. 2.1%; P = 0.004), and 12 months (4.7% vs. 3.3%; P < 0.001). CONCLUSIONS: In this sample, reoperations for macular hole were performed at low rates. Internal limiting membrane peeling was associated with lower rates of reoperation and RD.

Estimating cumulative pathway effects on risk for age-related macular degeneration using mixed linear models.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the elderly in developed countries and typically affects more than 10% of individuals over age 80. AMD has a large genetic component, with heritability estimated to be between 45% and 70%. Numerous variants have been identified and implicate various molecular mechanisms and pathways for AMD pathogenesis but those variants only explain a portion of AMD's heritability. The goal of our study was to estimate the cumulative genetic contribution of common variants on AMD risk for multiple pathways related to the etiology of AMD, including angiogenesis, antioxidant activity, apoptotic signaling, complement activation, inflammatory response, response to nicotine, oxidative phosphorylation, and the tricarboxylic acid cycle. While these mechanisms have been associated with AMD in literature, the overall extent of the contribution to AMD risk for each is unknown. METHODS: In a case-control dataset with 1,813 individuals genotyped for over 600,000 SNPs we used Genome-wide Complex Trait Analysis (GCTA) to estimate the proportion of AMD risk explained by SNPs in genes associated with each pathway. SNPs within a 50 kb region flanking each gene were also assessed, as well as more distant, putatively regulatory SNPs, based on DNaseI hypersensitivity data from ocular tissue in the ENCODE project. RESULTS: We found that 19 previously associated AMD risk SNPs contributed to 13.3% of the risk for AMD in our dataset, while the remaining genotyped SNPs contributed to 36.7% of AMD risk. Adjusting for the 19 risk SNPs, the complement activation and inflammatory response pathways still explained a statistically significant proportion of additional risk for AMD (9.8% and 17.9%, respectively), with other pathways showing no significant effects (0.3% - 4.4%). DISCUSSION: Our results show that SNPs associated with complement activation and inflammation significantly contribute to AMD risk, separately from the risk explained by the 19 known risk SNPs. We found that SNPs within 50 kb regions flanking genes explained additional risk beyond genic SNPs, suggesting a potential regulatory role, but that more distant SNPs explained less than 0.5% additional risk for each pathway. CONCLUSIONS: From these analyses we find that the impact of complement SNPs on risk for AMD extends beyond the established genome-wide significant SNPs.

Emerging drugs for diabetic macular edema.

INTRODUCTION: Diabetic macular edema (DME) is the most common cause of visual impairment due to diabetic retinopathy. The treatment of DME has recently undergone a paradigm shift. Traditionally, photocoagulation was standard treatment, but pharmacologic therapies are becoming increasingly used for this purpose. All currently available drug therapies for DME are either anti-VEGF agents or corticosteroids. AREAS COVERED: The pathogenesis of DME involves angiogenesis, inflammation and oxidative stress. The scientific rationale to treat DME through the pharmacologic blockade of VEGF and other pro-angiogenic factors is discussed. The fluocinolone insert is approved for the treatment of DME in several European countries, but not in the US at this time. Some medications that are already approved for other retinal diseases, most prominently aflibercept and the dexamethasone delivery system, have recently obtained approval for DME in the US. Other compounds are being studied in earlier-phase clinical trials. EXPERT OPINION: Pharmacologic treatment of DME will likely become increasingly used, especially for patients with edema involving the fovea. At this time, the two main classes of medication for treatment of DME are anti-VEGF agents and corticosteroids. As we continue to collect clinical trials data, the precise role of individual agents, and the continuing role for photocoagulation, will become more clear.

Tamponade in surgery for retinal detachment associated with proliferative vitreoretinopathy.

BACKGROUND: Retinal detachment (RD) with proliferative vitreoretinopathy (PVR) often requires surgery to restore normal anatomy and to stabilize or improve vision. PVR usually occurs in association with recurrent RD (that is, after initial retinal re-attachment surgery) but occasionally may be associated with primary RD. Either way, a tamponade agent (gas or silicone oil) is needed during surgery to reduce the rate of postoperative recurrent RD. OBJECTIVES: The objective of this review was to assess the relative safety and effectiveness of various tamponade agents used with surgery for retinal detachment (RD) complicated by proliferative vitreoretinopathy (PVR). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2013), EMBASE (January 1980 to June 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to June 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 26 June 2013. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of participants undergoing surgery for RD associated with PVR that compared various tamponade agents. DATA COLLECTION AND ANALYSIS: Two review authors screened the search results independently. We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: The review included 516 participants from three RCTs. One study was conducted in the USA and consisted of two trials: the first trial randomized 151 adults to receive either silicone oil or sulfur hexafluoride (SF6) gas tamponades; and the second trial randomized 271 adults to receive either silicone oil or perfluropropane (C3F8) gas tamponades. The third trial was a multi-center international trial and randomized 94 participants (age range not specified) to receive heavy silicone oil (a mixture of perfluorohexyloctane (F6H8) and silicone oil) versus standard silicone oil (either 1000 centistokes or 5000 centistokes, per the surgeon's preference).In participants with RD associated with PVR, outcomes after pars plana vitrectomy and infusion of either silicone oil, perfluropropane gas, or sulfur hexafluoride gas appeared comparable for a broad variety of cases. There were no significant differences between silicone oil and perfluoropropane gas in terms of the proportion of participants achieving at least 5/200 visual acuity (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.73 to 1.31) or achieving macular attachment (RR 1.00; 95% CI 0.86 to 1.15) at a minimum of one year. Although sulfur hexafluoride gas was reported to be associated with significantly worse anatomic and visual outcomes than was silicone oil at one year (quantitative data not reported), there were no significant differences between silicone oil and sulfur hexafluoride gas in terms of achieving at least 5/200 visual acuity at two years (RR 1.57; 95% CI 0.93 to 2.66). For macular attachment, participants treated with silicone oil received significantly more favourable outcomes than did participants who received sulfur hexafluoride at both one year (quantitative data not reported) and two years (RR 1.37; 95% CI 1.01 to 1.86). The first two trials did not perform any sample size calculation or power detection. In the third trial, which had a power of 80% to detect differences, heavy silicone oil was not shown to be superior to standard silicone oil. There were no significant differences between standard silicone oil and heavy silicone oil in the change in visual acuity at one year using adjusted mean logMAR visual acuity (mean difference -0.03 logMAR; 95% CI -0.35 to 0.29). Adverse events were not reported for the first two trials. For the third trial, only the total number of adverse events was reported, and adverse events for each group were not specified. Of the 94 participants, four died, 26 had recurrent retinal detachment, 22 developed glaucoma, four developed a cataract, and two had capsular fibrosis.All three trials employed adequate methods for random sequence generation and allocation concealment. None of the trials employed masking of participants and surgeons, and only the third trial masked outcome assessors. The first trial had a large portion of participants excluded from the final analyses, while the other two trials were at low risk of attrition bias. All trials appear to be free of reporting bias. The first two trials were funded by the National Eye Institute, and the third trial was funded by the German Research Foundation. AUTHORS' CONCLUSIONS: The use of either perfluropropane or standard silicone oil appears reasonable for most patients with RD associated with PVR. Because there do not appear to be any major differences in outcomes between the two agents, the choice of a tamponade agent should be individualized for each patient. Heavy silicone oil, which is not available for routine clinical use in the USA, has not demonstrated evidence of superiority over standard silicone oil.

Genetics and Age-Related Macular Degeneration: A Practical Review for Clinicians.

Age-related macular degeneration (AMD) is a multifactorial genetic disease, with at least 52 identifiable associated gene variants at 34 loci, including variants in complement factor H (CFH) and age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase-1 (ARMS2/HTRA1). Genetic factors account for up to 70% of disease variability. However, population-based genetic risk scores are generally more helpful for clinical trial design and stratification of risk groups than for individual patient counseling. There is some evidence of pharmacogenetic influences on various treatment modalities used in AMD patients, including Age-Related Eye Disease Study (AREDS) supplements, photodynamic therapy (PDT), and anti-vascular endothelial growth factor (anti-VEGF) agents. However, there is currently no convincing evidence that genetic information plays a role in routine clinical care.

Occlusive Retinal Vasculitis After a Single Injection of Pegcetacoplan.

Purpose: To describe a patient with retinal vasculitis after a single intravitreal injection (IVI) of pegcetacoplan. Methods: A case and its findings were analyzed. Results: An 80-year-old woman was treated with pegcetacoplan for subfoveal geographic atrophy. Ten days later, the patient noted "purple iridescent waves" but did not immediately report it. On day 18, she presented with pain and decreased visual acuity from 20/80 (pinhole) preinjection to 20/150 postinjection. No signs of inflammation were observed, and she was treated for high intraocular pressure (30 mm Hg). On day 23, iritis was noted. The fluorescein angiogram showed severe occlusive vasculitis involving all quadrants and the macula. The vasculitis/neuroretinitis laboratory panels were negative, and no contributing systemic features were identified other than well-controlled diabetes. Conclusions: In this patient, occlusive retinal vasculitis occurred shortly after a single IVI of pegcetacoplan.

New Approaches to Overcoming Antimicrobial Resistance in Endophthalmitis.

Endophthalmitis is a rare but vision-threatening infection characterized by marked inflammation of intraocular fluids and tissues, uncommonly seen following surgery and intravitreal injection. Antimicrobials are used worldwide in the prophylaxis and treatment of bacterial and fungal infections of the eye and are standard treatment in the preoperative and postoperative care of surgical patients. However, antimicrobials are reported to be overprescribed in many parts of the world, which contributes to antimicrobial resistance (AMR). AMR complicates the prophylaxis and treatment of endophthalmitis. This article examines the prevalence and mechanisms of AMR in ocular microorganisms, emphasizing the importance of understanding AMR patterns for tailored treatments. It also explores prophylaxis and management strategies for endophthalmitis, with a discussion on the use of intracameral antibiotic administration. The use of prophylactic intracameral antibiotics during cataract surgery is common in many parts of the world but is still controversial in some locations, especially in the US. Finally, it highlights the role of stewardship in ophthalmology and its benefits in the treatment of endophthalmitis.

Faricimab in Previously Treated Eyes With Neovascular Age-Related Macular Degeneration: An Assessment of Durability and Treatment Outcomes.

BACKGROUND AND OBJECTIVE: This study evaluated the efficacy and durability of faricimab in patients with neovascular age-related macular degeneration (nAMD) who were previously treated with anti-vascular endothelial growth factor (anti-VEGF) agents. PATIENTS AND METHODS: This retrospective case series was conducted at a single tertiary center in the United States. It focused on nAMD patients who transitioned to faricimab after initial anti-VEGF therapy, with a follow-up period of at least 9 months. "Complete dryness" was defined as the absence of intra- and/or subretinal fluid on optical coherence tomography. Durability was gauged by the extension of treatment intervals relative to the injection frequency of the previous agent. RESULTS: Sixty-two eyes from 62 patients were included. Treatment interval ranged from 5 to 10 weeks; 10 (16%) patients were able to be extended by 2 or more weeks compared to their previous regimen. Median (interquartile range [IQR]) central field thickness was 310 µm (254, 376) on initiating faricimab and declined by the ninth month (P values at 3, 6, and 9 months were 0.01, 0.02, and 0.07, respectively). Median (IQR) visual acuity at initiation of faricimab was 0.4 (0.20, 0.50) and did not change by the ninth month. Complete anatomical dryness was present in 10 (16%) eyes before switching; 90% remained dry at 9 months. Of 52 (84%) incompletely dry eyes before switching, 15% achieved complete dryness by 9 months on faricimab. CONCLUSIONS: Faricimab modestly improved the treatment intervals for a small proportion of previously treated patients on anti-VEGF therapy. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Genetic factors in nonsmokers with age-related macular degeneration revealed through genome-wide gene-environment interaction analysis.

Relatively little is known about the interaction between genes and environment in the complex etiology of age-related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene-smoking interactions in a genome-wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants' history of smoking at least 100 cigarettes lifetime was determined by a self-administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome-wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10(-30) ), ARMS2 (P = 1.94×10(-23) ), and RDBP/CFB/C2 (P = 4.37×10(-10) ), while joint effects analysis revealed three genomic regions with P < 10(-5) . Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10(-5) ), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.

Variants at chromosome 10q26 locus and the expression of HTRA1 in the retina.

Variations in a locus at chromosome 10q26 are strongly associated with the risk of age-related macular degeneration (AMD). The most significantly associated haplotype includes a nonsynonymous SNP rs10490924 in the exon 1 of ARMS2 and rs11200638 in the promoter region of HTRA1. It is under debate which gene(s), ARMS2, HTRA1 or some other genes are functionally responsible for the genetic association. To verify whether the associated variants correlate with a higher HTRA1 expression level as previously reported, HTRA1 mRNA and protein were measured in a larger human retina-RPE-choroid samples (n = 82). Results show there is no significant change of HTRA1 mRNA level among genotypes at rs11200638, rs10490924 or an indel variant of ARMS2. Furthermore, two AMD-associated synonymous SNPs rs1049331 and rs2293870 in HTRA1 exon 1 do not change its protein level either. These results suggest that the AMD-associated variants in the chromosome 10q26 locus do not significantly affect the expression of HTRA1.

Update on retinal detachment surgery.

PURPOSE OF REVIEW: Update on controversies in the surgical management of rhegmatogenous retinal detachment. RECENT FINDINGS: There are multiple new reports regarding the development and management of retinal detachment. Current use of oral fluoroquinolones may be associated with onset of retinal detachment, although the clinical relevance of this correlation is uncertain at this time and the finding has not been replicated in subsequent studies. Pars plana vitrectomy (PPV) continues to demonstrate efficacy as a primary treatment for retinal detachment, especially in pseudophakic patients. In many patients with macula-on retinal detachment, scheduling surgery after a short time delay is not necessarily deleterious and may actually be beneficial. Novel surgical tools, including bioerodible scleral buckling materials and artificial vitreous substitutes, are being investigated. SUMMARY: Retinal detachment remains an important cause of visual loss. Although current surgical techniques demonstrate high rates of anatomic and visual success, further advances will probably benefit patients with retinal detachment.

Vitamin A and fish oils for 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 legal blindness. Symptoms may become manifest during childhood or adulthood, and include poor night vision (nyctalopia) and constriction of peripheral vision (visual field loss). This field loss is progressive and usually does not reduce central vision until late in the disease course.The worldwide prevalence of RP is one in 4000, with 100,000 patients 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 CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2013, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2013), EMBASE (January 1980 to August 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 20 August 2013. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating the effectiveness of vitamin A, fish oils (DHA) or both, as a treatment for RP. We excluded cluster-randomized trials and cross-over trials. DATA COLLECTION AND ANALYSIS: We pre-specified 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; as well as mean change in visual acuity at five-year follow-up. Two authors independently evaluated risk of bias for all included trials and extracted data from the publications. We also contacted study investigators for further information on trials with publications that did not report outcomes on all randomized patients. MAIN RESULTS: We reviewed 394 titles and abstracts and nine ClinicalTrials.gov records and included three RCTs that met our eligibility criteria. The three trials included a total of 866 participants aged four to 55 years with RP of all forms of genetic predisposition. One trial evaluated the effect of vitamin A alone, one trial evaluated DHA alone, and a third trial evaluated DHA and vitamin A versus vitamin A alone. None of the RCTs had protocols available, so selective reporting bias was unclear for all. In addition, one trial did not specify the method for random sequence generation, so there was an unclear risk of bias. All three trials were graded as low risk of bias for all other domains. We did not perform meta-analysis due to clinical heterogeneity of participants and interventions across the included trials.The primary outcome, mean change of visual field from baseline at one year, was not reported in any of the studies. No toxicity or adverse events were reported in these three trials. No trial reported a statistically significant benefit of vitamin supplementation on the progression of visual field loss or visual acuity loss. Two of the three trials reported statistically significant differences in ERG amplitudes among some subgroups of participants, but these results have not been replicated or substantiated by findings in any of the other trials. AUTHORS' CONCLUSIONS: Based on the results of three RCTs, there is no clear evidence for benefit of treatment with vitamin A and/or DHA for people with RP, in terms of the mean change in visual field and ERG amplitudes at one year and the mean change in visual acuity at five years follow-up. In future RCTs, since some of the studies in this review included unplanned subgroup analysis that suggested differential effects based on previous vitamin A exposure, investigators should consider examining this issue. Future trials should take into account the changes observed in ERG amplitudes and other outcome measures from trials included in this review, in addition to previous cohort studies, when calculating sample sizes to assure adequate power to detect clinically and statistically meaningful difference between treatment arms.

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.