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Background/Objective Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD). Subjects/Methods Multicenter, retrospective chart review was conducted on patients treated with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid. Results After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a − 31.3 μM (p p p n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a − 43.4 μM (p p p Conclusions Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD.

Retinopathy of prematurity (ROP) is a neovascular retinal disorder that occurs in infants born prematurely. Nowadays, ROP constitutes a leading cause of childhood blindness worldwide and for decades the standard of care has involved peripheral retinal ablation. However, this type of treatment requires the use of specialized equipment by well-trained physicians, has been associated with poor structural and visual outcomes in some preterm infants, and despite its adequate application, some cases of ROP may continue to progress. Therefore, the need for simpler and more efficient strategies made anti-vascular endothelial growth factor (anti-VEGF) medications an appealing option for treatment. Recently, the use of anti-VEGF agents for ROP has increased worldwide; nevertheless, this practice remains off-label, and there is a lack of information regarding its safety profile and the possibility of unfavorable long-term outcomes causes the utmost concern. This review updates the recent evidence regarding the systemic and ocular safety of anti-VEGF treatment for ROP.

Retinopathy of prematurity (ROP) is a neovascular retinal disorder that occurs in infants born prematurely. Nowadays, ROP constitutes a leading cause of childhood blindness worldwide and for decades the standard of care has involved peripheral retinal ablation. However, this type of treatment requires the use of specialized equipment by well-trained physicians, has been associated with poor structural and visual outcomes in some preterm infants, and despite its adequate application, some cases of ROP may continue to progress. Therefore, the need for simpler and more efficient strategies made anti-vascular endothelial growth factor (anti-VEGF) medications an appealing option for treatment. Recently, the use of anti-VEGF agents for ROP has increased worldwide; nevertheless, this practice remains off-label, and there is a lack of information regarding its safety profile and the possibility of unfavorable long-term outcomes causes the utmost concern. This review updates the recent evidence regarding the systemic and ocular safety of anti-VEGF treatment for ROP.

Purpose To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD). Methods The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results. Results The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant). Conclusions Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD. Translational relevance This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.

After monthly intravitreal injections, the systemic exposures of aflibercept, bevacizumab, and ranibizumab were distinct and correlated with different reductions in plasma free–vascular endothelial growth factor, which could provide biologic plausibility for potential differences in systemic adverse events., Purpose: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). Methods: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. Results: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. Conclusion: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.

Purpose To report the intraoperative methods and anatomic results for subretinal implantation of an investigational human embryonic stem cell–derived retinal pigment epithelium (RPE) monolayer seeded on a synthetic substrate (California Project to Cure Blindness Retinal Pigment Epithelium 1 [CPCB-RPE1]) in geographic atrophy (GA). Design Single-arm, open label, prospective, nonrandomized, Phase 1/2a study. Participants Advanced non-neovascular age-related macular degeneration (NNAMD). Methods The worse-seeing eye (≤20/200) of each subject underwent subretinal implantation of a single 3.5×6.25 mm CPCB-RPE1 implant with a preplanned primary end point of safety and efficacy at 365 days. Commercially available 23-gauge vitrectomy equipment, custom surgical forceps, and operating microscope with or without intraoperative OCT (iOCT) were used. Exact Wilcoxon rank-sum tests and Spearman rank correlation coefficients were used to assess the association of the percentage of the GA area covered by the implant with patient and surgery characteristics. The partial Spearman correlation coefficient was calculated for the correlation between duration of surgery and baseline GA size after adjustment for surgeon experience. Main Outcome Measures Intraoperative exploratory measures are reported, including area of GA covered by implant, subretinal position of implant, duration of surgery, and incidence of adverse events. Operative recordings and reports were used to determine exploratory outcome measures. Results Sixteen subjects were enrolled with a median age of 78 years (range, 69–85 years). Median duration of the surgery for all subjects was 160 minutes (range, 121–466 minutes). Intraoperative OCT was used to guide subretinal placement in 9 cases. Intraoperative OCT was potentially useful in identifying pathology not evident with standard intraoperative visualization. Median GA area at baseline was 13.8 mm2 (range, 6.0–46.4 mm2), and median GA area left uncovered by the implant was 1.7 mm2 (range, 0–20.4 mm2). On average, 86.9% of the baseline GA area was covered by the implant. In 5 subjects, >90% of the GA area was covered. Baseline GA size was inversely correlated with percentage of GA area covered by the implant (rs=−0.72; P = 0.002). No unanticipated serious adverse events related to the implant or surgery were reported. Conclusions Surgical implantation of CPCB-RPE1 targeted to the area of GA in subjects with advanced NNAMD is feasible in an outpatient setting. Intraoperative OCT is not necessary but potentially useful in identifying subretinal pathology and confirming implant location.

Purpose To illustrate that patients with diabetic retinopathy who are treated exclusively with anti–vascular endothelial growth factor (VEGF) therapy and have an interruption in treatment may experience marked progression of disease with potentially devastating visual consequences. Design Retrospective, multicenter, case series. Methods Retrospective review of patients treated exclusively with anti-VEGF therapy for proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy (NPDR), with or without diabetic macular edema (DME), and temporarily lost to follow-up. Baseline disease characteristics, cause and duration of the treatment interruption, and resulting disease progression, complications, and outcomes were assessed. Results Thirteen eyes of 12 patients with type 2 diabetes were identified. The mean age was 57 ± 10 years, and 50% were women. Anti-VEGF therapy was indicated for PDR with DME in 7 (54%) eyes, PDR without DME in 3 (23%) eyes, and moderate to severe NPDR with DME in 3 (23%) eyes. Eight eyes had visual acuity (VA) of 20/80 or better before treatment interruption. The median duration of treatment hiatus was 12 months. Reasons for treatment interruption included intercurrent illness (31%), noncompliance (31%), and financial issues (15%). Complications upon follow-up included vitreous hemorrhage (9 eyes), neovascular glaucoma (5 eyes), and traction retinal detachment (4 eyes). Despite treatment of these complications, 77% of eyes lost ≥3 lines of VA, with 46% of eyes having a final VA of hand motion or worse. Conclusions Diabetic patients are subject to significant lapses in follow-up because of illness, financial hardship, or noncompliance. In patients with diabetic retinopathy, especially PDR, who are managed with anti-VEGF therapy alone, unintentional treatment interruptions can result in irreversible blindness.

Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies may delay disease progression or restore vision. A prospective, interventional, U.S. Food and Drug Administration-cleared, phase 1/2a study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane. We report an interim analysis of the phase 1 cohort consisting of five subjects. Four of five subjects enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation. The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function, at least in the short term, in some patients with severe vision loss from advanced NNAMD.

PURPOSE To report initial experience with intravitreal ocriplasmin (IVO) and to describe outer retina reflectivity changes observed on spectral domain optical coherence tomography (SD-OCT) after IVO injection in patients with vitreomacular traction (VMT) with or without macular holes (MHs). METHODS A consecutive retrospective review of patients with VMT and MH who were treated with IVO was performed. Patients underwent complete ophthalmic evaluation, including nonstandardized Snellen visual acuity testing, and SD-OCT at baseline and follow-up visits. RESULTS A total of 23 patients who received IVO for VMT and/or MH were included for analysis. Patient age ranged from 53 years to 93 years with a mean of 74 years. The mean follow-up was 174 days (range: 20-291 days). Vitreomacular traction release at Day 30 after IVO was achieved in 11 of 23 patients (47.82%), at an average of 14.54 days (range: 1-30 days) after treatment. The mean visual acuity improved from 0.50 to 0.38. At presentation, eight patients had MH associated with VMT. Closure of the MH with ocriplasmin was achieved in two patients, and six patients underwent pars plana vitrectomy for MH repair. Ten of 23 patients (43.47%) presented with changes in the outer retina reflectivity on SD-OCT after IVO, 4 patients of this group experienced a decrease in visual acuity. In 7 of these 10 patients (70%), VMT release was documented on OCT by Day 30 postinjection compared with 4 of 13 patients (30.76%) without outer retina changes post-IVO. Normalization of the outer retina reflectivity was achieved in all cases. CONCLUSION In this case series of VMT/MH patients treated with ocriplasmin, changes in the SD-OCT outer retina reflectivity were relatively common. Within weeks, the outer retinal reflectivity on SD-OCT improved, as did the visual acuity. Further studies to investigate the association between outer retina reflectivity changes with the use of IVO and long-term visual acuity outcomes are warranted.

To present the long-term follow-up of a patient injected with intravitreal ocriplasmin who experienced severe acute post-intravitreal ocriplasmin complications.Case report.A 68-year-old man with vitreomacular traction was treated with intravitreal ocriplasmin. He experienced dyschromatopsia, severe acute visual acuity, and field loss 4 hours after the injection. This was accompanied by decreased reflectivity on spectral domain optical coherence tomography in the ellipsoid zone of the outer retina. These changes were transient, and 3 years after the injection, the patient is asymptomatic and no outer reflectivity changes are noted on his spectral domain optical coherence tomography images.Acute visual changes and spectral domain optical coherence tomography hyporeflectivity in the ellipsoid zone after intravitreal ocriplasmin can occur in some individuals, but in this case, these changes were reversible, and there have been no long-term implications.

Despite its off-label status, intravitreal bevacizumab is the most commonly used intraocular anti-vascular endothelial growth factor agent. Regulation of compounding pharmacies has recently increased to make compounded pharmaceuticals safer. Despite these changes, a marked increase in symptomatic, large silicone oil droplets following intravitreal bevacizumab injections was noticed.Retrospective chart review was performed. Within a single private practice, patients who were noted to have large or symptomatic silicone oil bubbles after an intravitreal injection were reviewed.A recent, dramatic increase in the incidence of large or symptomatic silicone oil droplets was noted, with 23 cases noted in the past 5 months, compared with 1 in the previous decade. Patients frequently noted a circular floater consisting of a dark ring surrounding a bright central area immediately following an injection of intravitreal bevacizumab. All bevacizumab injections were from single-piece insulin syringes. B-scan ultrasonography produced a very characteristic reverberation pattern. No inflammation or visual acuity loss was noted because of the droplets; however, some patients were annoyed enough to consider vitrectomy.Patients should be carefully evaluated for this possibility, and the characteristic symptom of a round floater consisting of a dark ring surrounding a bright center, and the prominent reverberation pattern on B-scan ultrasonography may help increase detection. Changes in consent forms and discussion of this possibility are indicated while investigation into the cause of this increased incidence continues, especially if one is administering bevacizumab via the one-piece insulin syringes commonly used by compound pharmacies.

Background Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. Methods Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. Results Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL. Conclusions There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. Trial registration number NCT02118831.

The prevalence of diabetes is growing at epidemic rates in the USA. Diabetic retinopathy develops in a large proportion of patients and is a leading cause of blindness worldwide. Systemic management of diabetic retinopathy has included glycemic, hypertension, and lipid control. Local ophthalmic treatment in the form of focal/grid or panretinal laser photocoagulation has been shown to prevent vision loss in diabetic edema and proliferative diabetic retinopathy, respectively. The introduction of anti-vascular endothelial growth factor for diabetic macular edema and retinopathy has provided clinicians with improved clinical outcomes with potentially less damaging effects than laser.

Importance Incidence of conversion to neovascular age-related macular degeneration (nAMD) in untreated fellow eyes of patients who are treated for nAMD in 1 eye with anti–vascular endothelial growth factor agents provides important prognostic information to clinically manage patients. Objective To investigate the association of treatment assignment (intravitreal aflibercept vs ranibizumab) and baseline characteristics with fellow eye conversion to nAMD in the VEGF (Vascular Endothelial Growth Factor) Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies. Design, Setting, and Participants This post hoc analysis of the VIEW 1 and VIEW 2 studies (randomized, double-masked, active-controlled, multicenter, 96-week, phase 3 trials comparing the efficacy and safety of intravitreal aflibercept in 2457 patients with treatment-naive eyes with nAMD) analyzed a subgroup of participants treated for nAMD in 1 eye who had untreated fellow eyes without neovascularization at baseline. All participants in the VIEW studies were included in 1 of 4 groups: ranibizumab, 0.5 mg, every 4 weeks; aflibercept, 2 mg, every 4 weeks; aflibercept, 0.5 mg, every 4 weeks; or aflibercept, 2 mg, every 8 weeks after 3 injections at 4-week intervals. Data collection in the VIEW studies occurred from July 2007 to August 2011; the data analysis presented in this report took place from April 2016 to November 2018. Interventions Patients received no treatment in the fellow eyes unless after conversion to nAMD, when any treatment approved by heath authorities was given per the investigators’ discretion. Main Outcomes and Measures Incidence of conversion to nAMD in patients with untreated fellow eyes that had not had clinical signs of neovascularization at baseline. Results A total of 1561 participants were included in this analysis. At 96 weeks, 375 patients (24.0%) experienced cases of conversion to neovascular disease in the fellow eye, including 107 of the 399 individuals who received ranibizumab, 0.5 mg, every 4 weeks; 93 of the 387 individuals who received aflibercept, 2 mg, every 4 weeks; 84 of the 387 individuals who received aflibercept, 0.5 mg, every 4 weeks; and 91 of the 388 individuals who received aflibercept, 2 mg, every 8 weeks after 3 doses at 4-week intervals. The rates were 18.1, 16.2, 14.7, and 16.0 per 100 patient-years at risk at week 96, respectively. On multivariate analysis, fellow eye conversion was associated with increasing patient age (per 10 years) at baseline (hazard ratio [HR], 1.20 [95% CI, 1.05-1.36]), female sex (HR, 1.32 [95% CI, 1.06-1.63]), intraretinal fluid in the study eye at baseline (HR, 1.28 [95% CI, 1.02-1.61]), and increasing choroidal neovascularization lesion size (per 10 mm2) in the study eye at baseline (HR, 1.29 [95% CI, 1.06-1.57]). Rates of fellow eye conversion were similar with either of the treatments. Conclusions and Relevance In this secondary analysis of randomized clinical trial data, patients with active nAMD in 1 eye appeared to have a high risk for fellow eye conversion. Such patients should be monitored closely.

Anti-vascular endothelial growth factor (VEGF) therapy has revolutionised the treatment of retinal disease, and appears to be very safe. Nevertheless, there are several lines of evidence that imply that small doses of these agents could potentially have a systemic effect. The clinical significance of these systemic effects remains unclear, but further study is indicated.

BACKGROUND AND OBJECTIVE: To determine whether a novel guarded 33-gauge injection device can make the intravitreal injection procedure faster and more comfortable for patients. PATIENTS AND METHODS: Single-center, prospective, randomized interventional study. Seventy participants receiving bilateral injections on the same day had one eye injected with the 33-gauge injection device without a speculum and the other eye injected with a standard 30-gauge needle using a speculum. Length of time needed for the injection procedure was assessed, and subjects were asked to complete a questionnaire regarding their comfort level with each device during the injection procedure as well as immediately after, later that evening, and the next day. RESULTS: Intravitreal injections using the 33-gauge injection device were significantly faster, but there was no significant difference in the incidence or levels of pain between the two needle types. CONCLUSION: The 33-gauge injection device may offer advantages over a standard 30-gauge needle when performing an intravitreal injection. [ Ophthalmic Surg Lasers Imaging Retina. 2013;44:561–568.]

To assess the posterior vitreous release rates following a single, office-based intravitreal injection of expansile gas in treating vitreomacular traction.Thirty eyes of 29 consecutive patients with symptomatic vitreomacular traction received a single, office-based intravitreal injection of up to 0.3 mL of 100% perfluoropropane (C3F8).Overall, vitreomacular traction release occurred in 25 of 30 eyes by the final follow-up visit (83% final release rate); furthermore, 90% (9 of 10 eyes) with diabetes mellitus released, 83% (5 of 6 eyes) with concurrent epiretinal membrane released, and 83% (5 of 6 eyes) previously treated with ocriplasmin released. Vitreomacular traction release occurred overnight in some patients and was documented on spectral domain optical coherence tomography at an average of 13 days (range, 1-62 days). The phakic release rate was 89% (16 of 18 eyes) versus a 75% pseudophakic release rate (9 of 12 eyes) (P = 0.3173). Ellipsoid zone changes on spectral domain optical coherence tomography occurred in 1 of 30 gas-treated eyes. One patient developed pupillary block.Office-based intravitreal injection of C3F8 offers an inexpensive and effective treatment for vitreomacular traction, including for patients who underwent previous ocriplasmin administration and in patients with diabetes mellitus or epiretinal membrane.

Patrick D Williams,1 David Callanan,1 Wayne Solley,1 Robert L Avery,2 Dante J Pieramici,2 Tom Aaberg31Texas Retina Associates, Dallas, TX, 2California Retina Consultants and Research Foundation, Santa Barbara, CA, 3Retinal Associates, Grand Rapids, MI, USAPurpose: This prospective multi-center pilot study compares the use of half-fluence photodynamic therapy combined with ranibizumab with ranibizumab monotherapy for the treatment of neovascular age-related macular degeneration.Methods: All patients presenting with untreated subfoveal neovascular age-related macular degeneration were considered for inclusion. Patients were randomized to receive either ranibizumab with half-fluence photodynamic therapy or ranibizumab alone. Patients in the ranibizumab alone group were given three consecutive monthly ranibizumab injections and were followed monthly. They were treated with ranibizumab as needed, based on clinical discretion, using vision and optical coherence tomography. Patients in the combined group were given one same-day combined ranibizumab and half-fluence (25 j/cm2) photodynamic therapy treatment and were treated monthly as needed. Outcomes included changes in standardized visual acuity, optical coherence tomography foveal thickness, and percentage of as-needed injections to maintenance examinations.Results: Fifty-six out of 60 enrolled patients completed the twelve month primary outcome visit; this consisted of 27 patients receiving ranibizumab alone and 29 receiving combined treatment. The average age was 79.1 for the ranibizumab alone group and 79.3 for the combined group. The mean visual acuity in the ranibizumab alone group improved from 52.9 Early Treatment of Diabetic Retinopathy letters initially to 62.8 letters at twelve months. The mean visual acuity in the combined group improved from 49.2 letters to 51.8 letters at twelve months. The differences in visual acuity improvements were not statistically significant based on a two-tailed t-test (P = 0.2). Due to the presence of outliers in each group, a Mann–Whitney U test was performed to confirm the results (U = 325; P = 0.28). The mean optical coherence tomography foveal thickness improved 92.5 microns and 106.7 microns in the ranibizumab alone and the combined group, respectively. The difference was not significant based on a two-tailed t-test (P = 0.6). The ranibizumab alone group received an average of 6.8 injections, while the combined group received an average of three injections. This difference was not significant based on a chi-square test (P = 0.11).Conclusion: The groups appeared similar based on statistical analysis, but larger studies are needed to determine possible small differences between combination therapy and monotherapy.Keywords: ranibizumab, macular degeneration, photodynamic therapy, verteporfin, choroidal neovascularization, anti-vegf

The Diabetic Retinopathy Clinical Research Network (DRCR Network), sponsored by the National Eye Institute, reported the results of a comparative effectiveness randomized clinical trial (RCT) evaluating the 3 anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept (2.0 mg), bevacizumab (1.25 mg), and ranibizumab (0.3 mg) for treatment of diabetic macular edema (DME) involving the center of the retina and associated with visual acuity loss. The many important findings of the RCT prompted the American Society of Retina Specialists to convene a group of experts to provide their perspective regarding clinically relevant findings of the study.To describe specific outcomes of the RCT judged worthy of highlighting, to discuss how these and other clinically relevant results should be considered by specialists treating DME, and to identify unanswered questions that merit consideration before treatment.The DRCR Network-authored publication on primary outcomes of the comparative effectiveness RCT at 89 sites in the United States. The study period of the RCT was August 22, 2012, to August 28, 2013.On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and with visual acuity impairment, including mean (SD) improvements by +13.3 (11.1) letters with aflibercept vs +9.7 (10.1) letters with bevacizumab (P.001) and +11.2 (9.4) letters with ranibizumab (P = .03). Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept (+18.9 [11.5]) over bevacizumab (+11.8 [12.0]) or ranibizumab (14.2 [10.6]) 1 year later (P.001 for interaction with visual acuity as a continuous variable, and P = .002 for interaction with visual acuity as a categorical variable). It is unknown whether different visual acuity outcomes associated with the use of the 3 anti-VEGF agents would be noted with other treatment regimens or with adequately repackaged bevacizumab, as well as in patients with criteria that excluded them from the RCT, such as persistent DME despite recent anti-VEGF treatment.On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and visual acuity impairment. Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept over bevacizumab or ranibizumab 1 year later. Care needs to be taken when attempting to extrapolate outcomes of this RCT to differing treatment regimens. With access to adequately repackaged bevacizumab, many specialists might initiate therapy with bevacizumab when visual acuity is good (ie, 20/32 to 20/40 as measured in the DRCR Network), recognizing that the cost-effectiveness of bevacizumab outweighs that of aflibercept or ranibizumab.

Purpose Assessment of biological effect, visual acuity changes, and safety of intravitreal (IVT) ranibizumab in patients with macular edema associated with perfused central retinal vein occlusion (CRVO). Design Ongoing, prospective, open-label, single-center, uncontrolled study. Participants Ten adult patients with macular edema associated with perfused CRVO. Methods Patients were randomly assigned to receive 3 monthly IVT injections of either 0.3 or 0.5 mg ranibizumab (n = 5 at each dose). Additional injections were administered quarterly as needed over the ensuing 21 months at the physician's discretion for recurrent or persistent macular edema. Main Outcome Measures The predetermined primary endpoint was the percentage of patients gaining ≥15 letters of best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity (BCVA). The secondary endpoints include the mean change in BCVA and central retinal thickness (CRT) measured by optical coherence tomography, the rate of progression to ischemic CRVO, extent of intraocular hemorrhage, retinal vein diameter, optic nerve head swelling, and the incidence and severity of ocular and nonocular adverse events. Results After 3, 6, and 9 months of follow-up, 40%, 10%, and 30% of patients, respectively, gained ≥15 letters in BCVA; mean BCVA improved by 12±20 letters, 3±21 letters, and 1±24 letters, respectively, compared with baseline; CRT showed a mean decrease of 272±244 μm, 88±178 μm, and 119±153 μm, compared with baseline. No significant differences were observed between the 0.3- and 0.5-mg doses. Most patients experienced decreases in the extent of retinal hemorrhage, retinal vein diameter, and optic nerve head swelling at months 3 and 6 compared with baseline. No patients progressed to ischemic CRVO or experienced a severe adverse event that was attributed to ranibizumab. Conclusions Ranibizumab is generally well-tolerated and may improve BCVA and decrease CRT. The improvements in BCVA and CRT observed during the initial monthly injection period (0 to 3 months) were possibly lost to the recurrence of macular edema in between ranibizumab injection during the quarterly treatments (3 to 9 months). The extent of retinal hemorrhage, retinal vein diameter, and nerve swelling continued to normalize for most of the patients from baseline to 6 months. Follow-up is ongoing, and alternative dosing regimens are being evaluated. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

PURPOSE To report the authors' experience after intravitreal bevacizumab (Avastin, Genentech) injection in patients with macular edema (ME) secondary to branch retinal vein occlusive disease (BRVO). METHODS A consecutive retrospective review of patients with ME secondary to BRVO who were treated with intravitreal bevacizumab (1.25 mg/0.05 mL). Patients underwent complete ophthalmic evaluation, which included nonstandardized Snellen visual acuity testing, optical coherence tomography (OCT), and/or angiographic testing at baseline and follow-up visits. RESULTS There were 27 consecutive patients who received intravitreal bevacizumab injections. The mean length of follow-up was 5.3 months (median 6 months, range 3-8 months). The mean visual acuity improved from 20/200(-) at baseline to 20/100(-) at 1 month and 20/100(+) at 3 months and last follow-up (P < 0.001). The mean central 1 mm macular thickness was 478 microm at baseline and decreased to 310, 336, and 332 microm at 1 month, 3 months, and last follow-up (P < 0.001). Patients received an average of two injections (range one to three). No adverse side effects were observed following injections. CONCLUSION The observed anatomic (by ophthalmic examination, OCT, and/or fluorescence angiography) and visual acuity improvements and lack of serious adverse side effects after intravitreal bevacizumab injection demonstrates, in principle, the potential of bevacizumab for the treatment of ME in this setting.

Excessive retinal vascular permeability contributes to the pathogenesis of proliferative diabetic retinopathy and diabetic macular edema, leading causes of vision loss in working-age adults. Using mass spectroscopy–based proteomics, we detected 117 proteins in human vitreous and elevated levels of extracellular carbonic anhydrase-I (CA-I) in vitreous from individuals with diabetic retinopathy, suggesting that retinal hemorrhage and erythrocyte lysis contribute to the diabetic vitreous proteome. Intravitreous injection of CA-I in rats increased retinal vessel leakage and caused intraretinal edema. CA-I–induced alkalinization of vitreous increased kallikrein activity and its generation of factor XIIa, revealing a new pathway for contact system activation. CA-I–induced retinal edema was decreased by complement 1 inhibitor, neutralizing antibody to prekallikrein and bradykinin receptor antagonism. Subdural infusion of CA-I in rats induced cerebral vascular permeability, suggesting that extracellular CA-I could have broad relevance to neurovascular edema. Inhibition of extracellular CA-I and kallikrein-mediated innate inflammation could provide new therapeutic opportunities for the treatment of hemorrhage-induced retinal and cerebral edema. The effects of diabetes in the eye are characterized by microvascular abnormalities, proliferation of retinal vessels and increased retinal vascular permeability (RVP), which contributes to nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), respectively. Among working-age adults in developed countries, PDR and DME are the leading causes of severe and moderate vision loss 1,2 . Although the incidence and progression of diabetic retinopathy can be reduced by intensive glycemic and blood pressure control 3–5 , nearly

To evaluate the association of subretinal hyperreflective material (SHRM) with visual acuity (VA), geographic atrophy (GA), and scar in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Prospective cohort study within a randomized clinical trial.The 1185 CATT participants.Masked readers graded scar and GA on fundus photography and fluorescein angiography and graded SHRM on time-domain and spectral-domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1 mm(2), or outside the center 1mm(2) were obtained on SD OCT images at 56 (n = 76) and 104 (n = 66) weeks.Presence of SHRM, as well as location and size, and associations with VA, scar, and GA.Among CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and to 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than in eyes with SHRM that resolved (64% vs. 31%; P0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n = 76) and 104 (n = 66), mean VA letter score was 73.5 (standard error [SE], 2.8), 73.1 (SE, 3.4), 65.3 (SE, 3.5), and 63.9 (SE, 3.7) when SHRM was absent, present outside the central 1 mm(2), present within the central 1 mm(2) but not the foveal center, or present at the foveal center (P = 0.02), respectively. When SHRM was present, the median maximum height under the fovea, within the central 1 mm(2) including the fovea and anywhere within the scan, was 86 μm, 120 μm, and 122 μm, respectively. Visual acuity was decreased with greater SHRM height and width (P0.05).In eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM dimensions were associated with worse VA. In eyes with neovascular AMD, SHRM is an important morphologic biomarker.

Glaucoma is a leading cause of irreversible blindness, presently affecting approximately 70 million people worldwide.1,2 The most common form is primary open-angle glaucoma (POAG), which accounts for approximately 90% of all cases. Ocular hypertension (OH) is the major risk factor for POAG and lowering IOP is the only effective treatment.3 However, many patients remain refractory to existing IOP-lowering interventions and eventually may become blind, underscoring the unmet medical need for novel approaches to control IOP. Intraocular pressure is a product of the rate of aqueous humor production, resistance to outflow, and episcleral venous pressure.3,4 The aqueous outflow pathways in the angle of the eye are composed of a spongy tissue called the trabecular meshwork (TBM), which leads into Schlemm's canal. Much of the resistance to outflow resides within the TBM, putatively within 7 to 14 μm of the inner wall of Schlemm's canal in a region known as the juxtacanalicular or cribriform region.5–,8 Primary open-angle glaucoma is caused by an increase in outflow resistance9,10 due to poorly understood defects in this region.11–,14 Ocular hypertension in POAG has been associated with dysregulated intracellular signaling pathways controlled by IL-1/NF-κB,15 TGF-β superfamily,16 and Wnt.17,18 The pathophysiology of OH leading to POAG shares many features with a secondary form of OH caused by treatment with glucocorticoids (GCs).19–,25 Glucocorticoids are a class of steroid hormones released in response to stress. As part of the natural feedback mechanism that turns down the inflammatory response, they are useful for treating a wide variety of diseases.26 Complicating this, however, is the considerable interindividual variability and tissue-specific GC sensitivity among individuals, which can cause a variety of systemic side effects.27–,31 Treatment with steroids, such as dexamethasone or triamcinolone acetonide (TA), in the eye causes elevated IOP in predisposed individuals. It has been documented that approximately 40% of the normal population develops an IOP increase > 6 mm Hg above baseline following topical administration of GCs, 4 times a day for 4 to 6 weeks.32 When GCs are administered intravitreally, IOP may increase by 30% or more in up to half of patients.33 These individuals are considered to be “steroid responders.” Interestingly, almost all POAG patients are steroid responders25,32,34–,40; conversely, steroid-responders who do not have POAG are at much higher risk of developing POAG compared to nonresponders.37–,41 A better understanding of genetic and molecular mechanisms underlying individual variation in the response to steroids could shed light on our understanding of steroid-induced OH and OH leading to POAG. That being said, mechanisms of steroid-induced OH and OH leading to POAG also show distinct differences; therefore, studying the genetics of steroid-induced OH specifically could lead to discovery of genes involved in IOP regulation that could not have been revealed any other way. The genome-wide association study (GWAS) represents an agnostic approach for prioritization of genes that are associated with a disease process, and makes it possible to discover novel genes that could not otherwise be identified. In the current study, we performed a pharmaco-GWAS for this purpose, using a cohort enrolled from patients treated with off-label intravitreal TA (IVTA) for various retinal indications, and followed up with an independent candidate gene study. We identified two independent quantitative trait loci (QTLs) at chromosomal locus 6p21.33 associated with the novel mucin gene HCG22.

Vascular endothelial growth factor (VEGF)-A is a major regulator of angiogenesis and vascular permeability implicated in the development of diseases involving pathological angiogenesis and increased vascular permeability, such as neovascular age-related macular degeneration (AMD). LUCENTIS (ranibizumab), a humanized antigen-binding fragment (Fab) that neutralizes all VEGF-A isoforms and their biologically active degradation products, was recently approved by the FDA. Ranibizumab is the first FDA-approved treatment for neovascular AMD that maintains or improves vision inor = 90% patients and provides aor = 15-letter improvement in visual acuity for a quarter to a third of patients with all choroidal neovascularisation subtypes. Ranibizumab was associated with aor = 1.7% rate of key serious ocular adverse events, such as endophthalmitis and uveitis, in two pivotal Phase III trials.

Purpose To review evidence and provide updated guidelines on intravitreal (IVT) injection technique and monitoring. Methods A review of the published literature on IVT injection from 2004 to 2014 formed the basis for round table deliberations by an expert panel of ophthalmologists. Results The dramatic increase in the number of IVT injections has been accompanied by a comparable increase in evidence surrounding IVT practice patterns and techniques. The expert panel identified a number of areas that have evolved since publication of the original IVT injection guidelines in 2004, the most notable of which were a lack of evidence to support the routine use of pre-, peri-, and postinjection antibiotics to reduce the risk of endophthalmitis, and the role of aerosolized droplets containing oral contaminants from the patient and/or providers as a potential source of infection. The panel emphasized the continued importance of applying povidone-iodine to and avoiding eyelid contact with the intended injection site and needle. Conclusion Updated guidelines on IVT injection technique and monitoring are proposed based on a review of published literature and expert panel deliberations.

Purpose To evaluate the ability of delayed hyperoxia to slow or prevent degenerative and gliotic changes initiated by retinal detachment. Design An experimental study. Methods Rhegmatogenous detachments were produced in the right eyes of eight cats. After 1 day in room air (21% O 2 ), four cats were placed in chambers with the O 2 concentration regulated at 70%; the other four were left in room air. At 7 days the retinas were harvested and examined by light and confocal microscopy. Cell specific antibodies, TUNEL and proliferation assays, outer segment length, and photoreceptor counts, were used to assess the condition of the retina. The contralateral unoperated eyes were used as controls. Results Animals maintained in elevated O 2 showed a dramatic preservation of rod and cone outer segments as well as in the organization of the outer plexiform layer. The number of surviving photoreceptors was increased in the hyperoxia-treated animals. Neurite sprouting, a characteristic of detached retina, was rarely observed in the experimental eyes. Proliferation of non-neuronal cells was reduced, but not halted, by hyperoxia. GFAP and vimentin expression was not effected by hyperoxia; these intermediate filament proteins increased in Muller cells similar to that observed in control detachments. Conclusions Exposure to hyperoxia, delayed by 1 day after the onset of retinal detachment, was highly effective in preserving photoreceptor cells and in reducing proliferation within the retina. It did not, however, reduce the hypertrophy of Muller glia. There were no apparent detrimental effects of exposure to 70% O 2 for 6 days. These results suggest that human patients may benefit from breathing elevated oxygen levels while awaiting reattachment surgery, even if the hyperoxia is delayed relative to the time of detachment.

To compare the efficacy of ranibizumab 0.5-mg and 2.0-mg intravitreal injections for persistent diabetic macular edema (DME) previously treated with bevacizumab.In all, 43 patients with residual center-involved DME following intravitreal bevacizumab were included in this 12-month prospective, nonrandomized, multicenter study. Enrolled patients received three monthly ranibizumab 0.5-mg injections. At month 3, patients with residual macular edema switched to three monthly injections of ranibizumab 2.0-mg. Assessments included monthly visual acuity and spectral-domain optical coherence tomography.Mean visual acuity improved by +6.4 letters at month 3 and +8.8 letters at month 6. Mean central subfield thickness (CST) decreased by -113 μm at month 3 and -165 μm at month 6. Before enrollment, 29/43 (67.4%) patients showed10% CST reduction following monthly bevacizumab treatment. After three monthly ranibizumab 0.5-mg injections, 22/29 (75.9%) patients showed10% reduction in CST, whereas 6 showed10% reduction. Of these six, three (50%) showed10% reduction in CST after switching to three monthly ranibizumab 2.0-mg doses. No serious adverse events were observed to month 6.Ranibizumab 0.5-mg or 2.0-mg may improve visual and anatomic outcomes in patients with DME who demonstrated minimal or no response to bevacizumab therapy. Moreover, increased dosage of ranibizumab (2.0-mg) may provide additional benefit over ranibizumab 0.5-mg in some patients. However, 2.0-mg ranibizumab is not currently commercially licensed or available.

T he use of anti-vascular endothelial growth factor (VEGF) agents has dramatically changed the way we treat many retinal diseases. This paradigm shift in treatment is due to the ability of these drugs to inhibit VEGF, a molecule that has a pivotal role in a large variety of retinal conditions, including age-related macular degeneration (AMD), proliferative diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity (ROP), and many forms of retinal edema. Intravitreal ranibizumab (Lucentis; Genentech, San Francisco, CA) is currently FDA approved for the treatment of neovascular AMD. Prior to ranibizumab’s approval, bevacizumab (Avastin; Genentech), a larger antibody approved for the treatment of colon cancer, achieved widespread off-label intravitreal use in ophthalmology. The phenomenal speed with which bevacizumab use was adopted was due to a variety of reasons: there was an unmet need in the treatment of AMD and bevacizumab worked much better than approved drugs; it was inexpensive and available; and from a molecular standpoint, it was very similar to ranibizumab, which had just completed several large randomized clinical trials with outstanding results—but was not yet approved. After ranibizumab received FDA approval for neovascular AMD, bevacizumab maintained a significant share of the market for AMD due to its much lower cost than ranibizumab, and for non-AMD indications, it is used much more frequently than ranibizumab. Despite the similarities between these 2 drugs, there are significant differences. Bevacizumab is a full-length antibody, and ranibizumab is a modified Fab fragment that is ⁄3 the size of bevacizumab. Once the drug reaches the bloodstream, bevacizumab has a dramatically longer half-life than ranibizumab. Despite ranibizumab’s shorter systemic half-life, concern of systemic risk was raised during an interim analysis of almost 2400 AMD patients in the SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) trial.

Purpose The purpose of the study was to report the clinicopathologic features of four patients with uveal lymphoid infiltration who were diagnosed by a conjunctival biopsy. Design A case series. Participants Four patients at four institutions participated. Measures The histopathologic findings of the conjunctival and episcleral biopsy specimens from four patients with the diagnosis of uveal lymphoid infiltration were recorded. The conjunctival specimens were placed in 10% neutral buffered formaldehyde solution or B5 solution and processed routinely for light microscopic examination and immunohistochemical analysis for B cells and T cells and kappa and lambda light chains. The clinical and histopathologic findings were compared with 47 previously reported cases of uveal lymphoid infiltration. Results Two men and two women (average age = 57 years) presented with diffuse punctate to coalescent yellow uveal infiltrates and epibulbar pink fleshy lesions. Ultrasonography of the lesions showed diffuse choroidal thickening and a lack of choroidal or scleral excavation. The conjunctival biopsy specimens showed diffuse infiltration of the substantia propria with B lymphocytes with variable kappa and lambda restriction. Scattered T lymphocytes also were present. Plasmacytoid cells and a prominent Grenz zone were present. Conclusions Patients with solitary or multiple yellow uveal infiltrates should have careful conjunctival evaluation for the presence of pink conjunctival lesions. Biopsy specimens of the conjunctival lesion may establish the diagnosis of uveal lymphoid infiltration.

BACKGROUND AND OBJECTIVE: Determine whether the new dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA) injector needle design can reduce the force needed for insertion when compared to the original needle design. MATERIALS AND METHODS: In vitro testing assessed the force required for insertion from five new-design and five old-design Ozurdex needles on a synthetic test medium and explanted porcine eyes. Maximum penetration force was measured in grams-force, while the total work of the needle was measured in joules. RESULTS: The new design required 29% and 68% less overall work to perform an injection in the synthetic medium ( P = .0002) and porcine eyes ( P = .009), respectively. The maximum force required to insert the new needle was 25% and 61% that of the old needle in the synthetic medium ( P = .001) and porcine eyes ( P = .007), respectively. CONCLUSION: The new needle design significantly reduces the force and work needed for insertion, which should improve physician control as well as patient safety and comfort. [ Ophthalmic Surg Lasers Imaging Retina . 2014;45:232–238.]

Objective To assess the influence of drug; dosing regimen; and traditional, nontraditional, and genetic risk factors on the incidence of choroidal neovascularization (CNV) in the fellow eye of patients treated for CNV with ranibizumab or bevacizumab. Design Cohort study of patients enrolled in a multicenter, randomized clinical trial. Participants Patients with no CNV in the fellow eye at the time of enrollment in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Methods Eligibility criteria for the clinical trial required that study eyes have evidence on fluorescein angiography and optical coherence tomography of CNV secondary to age-related macular degeneration (AMD) and visual acuity between 20/25 and 20/320. Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different regimens for dosing over a 2-year period. The genotypes for 4 single nucleotide polymorphisms (SNPs) associated with risk of AMD were determined. Only patients without CNV in the fellow eye at baseline were considered at risk. The CATT ophthalmologists examined patients every 4 weeks through 2 years and recorded treatment for CNV in the fellow eye. Main Outcome Measures Development of CNV in the fellow eye. Results Among 1185 CATT participants, 727 (61%) had no CNV in the fellow eye at enrollment. At 2 years, CNV had developed in 75 (20.6%) of 365 patients treated with ranibizumab and in 60 (16.6%) of 362 patients treated with bevacizumab (absolute difference, 4.0%; 95% confidence interval [CI], –1.7% to 9.6%; P = 0.17). The risk ratio for pro re nata dosing relative to monthly dosing was 1.1 (95% CI, 0.8–1.6). Greater elevation of the retinal pigment epithelium and fluid in the foveal center of the study eye were associated with increased incidence of CNV in the fellow eye. Incidence was not associated with genotype on rs1061170 ( CFH ), rs10490924 ( ARMS2 ), rs11200638 ( HTRA1 ), and rs2230199 ( C3 ; P >0.35). Conclusions Through 2 years, there was no statistically significant difference between ranibizumab and bevacizumab in incidence of CNV in the fellow eye. Genotype on 4 SNPs previously found to be associated with AMD did not affect the risk of CNV in the fellow eye among CATT patients. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

The authors describe the natural history of subfoveal subretinal hemorrhage (for which laser treatment was not indicated) in age-related macular degeneration.A retrospective review of data was performed at a tertiary retinal referral center for 41 eyes from 40 patients with age-related macular degeneration examined during an 18-month period. All patients had at least 3 months of follow-up, as well as subfoveal subretinal hemorrhage that made up more than 50% of a neovascular lesion-as documented by fluorescein angiography-and therefore, did not meet criteria for laser treatment. The number of lines of visual acuity lost or gained in each eye during follow-up was calculated; presenting characteristics were evaluated as predictors of visual outcome.A progressive loss of visual acuity from baseline was observed throughout the 3-year follow-up period in most eyes. At 36 months, a mean of 3.5 lines of visual acuity had been lost in the 16 eyes examined; 44% of eyes had lost 6 or more lines of visual acuity. The percentage of patients who sustained a spontaneous improvement of 3 or more lines of visual acuity decreased from 31% at 12 months to 21% at 36 months of follow-up. Univariate linear regression analysis demonstrated significant relationships of initial size of the hemorrhage, elevation of the retina by the hemorrhage, and size of the entire lesion with visual outcome at the 12-month and 36-month examinations (P0.05).Although this study confirms that some eyes with subfoveal subretinal hemorrhage associated with age-related macular degeneration have poor prognoses, the visual acuity of other eyes did not deteriorate. These findings underscore the importance of evaluating the role of therapeutic interventions such as surgery to remove subretinal hemorrhage in randomized clinical trials.

Purpose To evaluate the effectiveness of pars plana implants in the treatment of neovascular glaucoma. Patients and methods Twenty-two consecutive pars plana implant procedures performed for neovascular glaucoma were retrospectively reviewed. Results Preoperative intraocular pressures ranged from 22 to 80 mmHg (mean 46 mmHg) on a mean of three glaucoma medications. With a mean follow-up interval of 16 months, final postoperative intraocular pressures ranged 9-21 mmHg (mean 16) on a mean 0.7 medications. One patient required a second implant to achieve final intraocular pressure control. Visual acuity was stabilized or improved in 19 of 22 cases (86%). Complications included retinal detachment in two cases (9%). Macular pucker, vitreous hemorrhage, hyphema, choroidal hemorrhage, diplopia, and loss of light perception occurred in one case (5%) each. None developed phthisis bulbi. Conclusion Pars plana drainage tube implants are effective in the treatment of neovascular glaucoma.

Importance Anti–vascular endothelial growth factor (VEGF) therapy is commonly used to treat numerous retinal conditions and appears safe, yet controversy remains regarding systemic safety. Objective To evaluate the systemic safety of intravitreous anti-VEGF injections in high-risk patients with diabetic macular edema (DME) and to investigate separately the subgroup of these patients with the highest level of exposure to anti-VEGF monthly treatment for 2 years. Data Sources A search of MEDLINE, Cochrane Central Register of Controlled Trials, clincaltrials.gov, and ophthalmology congress abstracts January 1, 1947, to May 19, 2015. Study Selection Randomized clinical trials were selected that evaluated monthly anti-VEGF injections for DME for 2 years and reported the outcome measures of cerebrovascular accidents, myocardial infarctions, arteriothrombotic events, and mortality. Data Extraction and Synthesis Two reviewers collected data independently from each study for the meta-analysis. Data were pooled using a fixed-effects model and analyzed from November 6, 2014, to June 28, 2015. Peto odds ratios with 95% CIs were calculated. Main Outcomes and Measures Primary end points included cerebrovascular accidents and all-cause mortality in the highest-dose arms. Secondary outcomes included myocardial infarctions, arteriothrombotic events, and vascular-related death. Results Of 1126 articles reviewed, 598 were removed as duplicate studies and 524, for lack of monthly treatment data for 2 years, leaving 4 studies for the meta-analysis that met the search criteria: 2 trials using monthly aflibercept and 2 using monthly ranibizumab, representing 1328 patients. The primary evaluation (1078 patients) combined the monthly aflibercept and the 0.5-mg ranibizumab arms and yielded an increased risk for death compared with sham and laser treatments (odds ratio [OR], 2.98; 95% CI, 1.44-6.14; P = .003). Analysis including monthly aflibercept and 0.5-mg ranibizumab yielded an increased risk for cerebrovascular accidents (OR, 2.33; 95% CI, 1.04-5.22; P = .04) and vascular death (OR, 2.51; 95% CI, 1.08-5.82; P = .03). No definitive increased risk for myocardial infarctions and arteriothrombotic events was seen with all dose combinations. Conclusions and Relevance In this meta-analysis of anti-VEGF agents for patients with DME, assessment of the highest-level exposure group (those high-risk patients with DME who received 2 years of monthly treatment) revealed a possible increased risk for death and potentially for cerebrovascular accidents. Consideration of total exposure to anti-VEGF agents when treating those at high risk for vascular disease may be important.

Retinal ischemia induces intraocular neovascularization, which often leads to glaucoma, vitreous hemorrhage, and retinal detachment, presumably by stimulating the release of angiogenic molecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor whose production is increased by hypoxia.We measured the concentration of VEGF in 210 specimens of ocular fluid obtained from 164 patients undergoing intraocular surgery, using both radioimmuno-assays and radioreceptor assays. Vitreous proliferative potential was measured with in vitro assays of the growth of retinal endothelial cells and with VEGF-neutralizing antibody.VEGF was detected in 69 of 136 ocular-fluid samples from patients with diabetic retinopathy, 29 of 38 samples from patients with neovascularization of the iris, and 3 of 4 samples from patients with ischemic occlusion of the central retinal vein, as compared with 2 of 31 samples from patients with no neovascular disorders (P0.001, P0.001, and P = 0.006, respectively). The mean (+/- SD) VEGF concentration in 70 samples of ocular fluid from patients with active proliferative diabetic retinopathy (3.6 +/- 6.3 ng per milliliter) was higher than that in 25 samples from patients with nonproliferative diabetic retinopathy (0.1 +/- 0.1 ng per milliliter, P = 0.008), 41 samples from patients with quiescent proliferative diabetic retinopathy (0.2 +/- 0.6 ng per milliliter, P0.001), or 31 samples from nondiabetic patients (0.1 +/- 0.2 ng per milliliter, P = 0.003). Concentrations of VEGF in vitreous fluid (8.8 +/- 9.9 ng per milliliter) were higher than those in aqueous fluid (5.6 +/- 8.6 ng per milliliter, P = 0.033) in all 10 pairs of samples obtained simultaneously from the same patient; VEGF concentrations in vitreous fluid declined after successful laser photocoagulation. VEGF stimulated the growth of retinal endothelial cells in vitro, as did vitreous fluid containing measurable VEGF. Stimulation was inhibited by VEGF-neutralizing antibodies.Our data suggest that VEGF plays a major part in mediating active intraocular neovascularization in patients with ischemic retinal diseases, such as diabetic retinopathy and retinal-vein occlusion.

I nterest in and controversy over the use of bevacizumab (Avastin; Genentech/Roche, South San Francisco, CA) for the treatment of retinopathy of prematurity (ROP) have increased dramatically after the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study. Off-label bevacizumab has been used extensively for age-related macular degeneration (AMD) for more than 6 years, and recently the Comparison of AMD Treatments Trials showed it to have similar safety and efficacy to ranibizumab (Lucentis; Genentech/Roche, South San Francisco, CA) in this population. There was, however, an increased incidence of systemic adverse events scattered across many organ systems in the bevacizumab arm of this study, the significance of which remains unclear. There are pharmacokinetic differences between these two vascular endothelial growth factor (VEGF) inhibitors that may be important in at-risk populations such as infants with ROP undergoing organogenesis. In adults the intrinsic serum elimination half-life of ranibizumab is approximately 2 hours, whereas that of bevacizumab is approximately 20 days because it is a full-length antibody with an Fc domain that binds Fc receptors on endothelial cells and reduces systemic clearance. The systemic pharmacokinetics of both ranibizumab and bevacizumab in children is unknown but could be longer. Early in the use of bevacizumab for proliferative diabetic retinopathy (DR), we noted a reduction in leakage of neovascularization in the contralateral, uninjected fellow eye, a finding that raised concern about systemic levels capable of therapeutic effects. This observation prompted us to evaluate lower doses of intravitreal bevacizumab, and we showed reduction in neovascularization even when injecting a dose 200-fold below the typical dose (6.25 mg instead of 1.25 mg). There was initial skepticism as to the causality of fellow eye effects, but these effects have now been observed after bevacizumab injection in DR, vein occlusion, and uveitic cystoid macular edema (CME). One recent report even demonstrated the resolution of CME and retinal neovascularization in the

PURPOSE To assess whether performing an air or gas exchange at the conclusion of a microincision vitrectomy procedure is beneficial regarding the rate of endophthalmitis. METHODS This was a collaborative, multicenter, retrospective chart review of 2,336 eyes that underwent microincision sutureless vitrectomy (23 or 25 gauge) with either SF6 or C3F8 gas endotamponade for macular hole between January 2008 and December 2009. For all eyes, the search methodology was structured to identify the main outcome measure, which was the occurrence of acute postoperative endophthalmitis (

Purpose: To evaluate the safety and efficacy of intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion. Methods: Patients with macular edema secondary to perfused central retinal vein occlusion were enrolled in this ongoing, prospective, open-label study. Treatment was initiated with monthly intravitreal ranibizumab for 3 months. In the first year, additional injections were administered for edema in quarterly intervals as needed (PRN) for Cohort 1 (n = 10) and monthly PRN for Cohort 2 (n = 10). In the second year of treatments, all patients received monthly PRN treatment. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central retinal thickness, fundus photographs, and fluorescein angiograms were evaluated, and the incidence and severity of adverse events were documented. Results: Mean change in best-corrected visual acuity and central retinal thickness improved during the induction phase in both groups. During the remainder of the first year for Cohort 1, initial gains were lost during quarterly treatment but returned with monthly PRN treatment in the second year. For Cohort 2, improvement in best-corrected visual acuity and central retinal thickness from the induction phase was maintained through Month 24. Nineteen of 20 patients experienced a reduction in intraretinal hemorrhage, optic nerve swelling, and/or venous diameter after treatment. One myocardial infarction, one cerebrovascular accident, and no serious ocular adverse events were reported. Iris neovascularization was developed in none of the eyes. Conclusion: Ranibizumab was well tolerated and associated with a greater reduction in macular edema and improvement in visual acuity in the monthly PRN regimen compared with quarterly treatment. Vision lost during the quarterly PRN injection intervals in the first year of Cohort 1 could be regained by switching to monthly PRN dosing.

Macular edema as a result of diabetic retinopathy can lead to central vision loss. It is one of the major causes of visual loss in the United States,1 with ∼4.1 million Americans (age ≥40 years) estimated to have diabetic retinopathy.2 Vision-threatening diabetic retinopathy, which includes both proliferative diabetic retinopathy and diabetic macular edema (DME), is estimated to occur in ∼899,000 persons with the majority having type 2 diabetes.2 The estimated proportions of persons with diabetes affected by macular edema are type 1 diabetes, 20%; type 2 diabetes, using insulin, 25%; and type 2 diabetes, not using insulin, 14%.3 The prevalence of diabetes is expected to substantially increase by 2020 with the increasing prevalence of diabetes mellitus in the aging U.S. population. When macular edema is established, focal laser photocoagulation reduces the risk of moderate visual loss (loss of ≥15 letters from baseline on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity charts) by 50%.4 However, treatment is often not associated with improvement in visual acuity. Furthermore, the focal laser burns may result in an increase in atrophy of the retinal pigment epithelium and progressive enlargement of the initial focal scars of laser photocoagulation and eventually visual loss with central scotomas and decreased color vision.5 Reduction of tissue destruction from laser burns while maintaining the beneficial treatment effect would potentially reduce this long-term risk of laser treatment. These adverse side effects of the continuous wavelength laser used in the ETDRS technique may theoretically be diminished by using a micropulse diode laser grid, which would result in subthreshold burns with the accompanying reduction of damage from photocoagulation to the retinal pigment epithelium.6,7 This technique has been evaluated in case series without concurrent controls.8–10 This study was designed to compare the micropulse diode grid laser with the standard ETDRS focal laser technique using the continuous wavelength laser. Animal models of diabetic retinopathy demonstrate that inflammation plays an important role in diabetic retinopathy.11 In early onset of diabetic retinopathy, up-regulation of cyclo-oxygenase-2 (COX-2) occurs in retinal cells. This results in elevated prostaglandin production, leading to an increased expression of vascular endothelial growth factor and an increased risk of vascular leakage and retinal neovascularization.12 High doses of aspirin and intermediate doses of COX-2 inhibitors (celecoxib) were apparently beneficial in early experimental diabetic retinopathy.13 Other investigations have shown that periocular celecoxib-poly (lactide-co-glycolide) microparticles inhibited elevations of retinal vascular endothelial growth factor and other factors for as long as 60 days in a diabetic animal model.14 Cyclo-oxygenase-2 inhibitors have been demonstrated to have antiangiogenic effects in a rat model of ischemic proliferative retinopathy,15 and COX-2 expression is evident in human retina of individuals with diabetes.8 These data suggest that treatment with a COX-2 inhibitor may be beneficial in the treatment of DME. The purpose of this study was to gather pilot data to evaluate the feasibility of mounting a larger multicenter study to evaluate the efficacy of celecoxib (a COX-2 inhibitor and a nonsteroid anti-inflammatory drug) and of a modified laser photocoagulation technique for the treatment of DME.

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case–control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 × 10 −3 ; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10 −8 ; and Boston: P = 2.1 × 10 −2 ]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications.