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Background and Objective: To report the 3-year outcomes for endolaserless vitrectomy with intravitreal aflibercept injection (IAI) monotherapy for proliferative diabetic retinopathy (PDR)-related vitreous hemorrhage (VH). Materials and Method: Eyes underwent endolaserless vitrectomy and received one preoperative and intraoperative IAI followed by randomization to a q8week or q16week IAI group. Additional IAI was administered as needed. Results: 31/40 eyes were randomized (14 q8week eyes, 17 q16week eyes). Through 152 weeks, q8week and q16week eyes received 18.6 and 12.1 IAI, respectively. Q8week eyes observed a 34 letter visual acuity (VA) increase ( P = 0.003) compared to a 27 letter increase in the q16week group ( P = 0.013). Conclusions: Endolaserless vitrectomy with aflibercept monotherapy for PDR-related VH provides significant long-term visual gains. Frequent IAI is required for fewer proliferative consequences. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:89–96.]

To determine if obstructive sleep apnea syndrome (OSAS) predisposes patients to glaucoma and macular disease due to vascular compromise by evaluating retinal and optic nerve vasculature and function using optical coherence tomography angiography and Humphrey visual field testing, respectively.In this prospective, observational, cross-sectional study 45 patients undergoing polysomnography ordered per standard of care were selected and stratified based on apnea-hypopnea index (AHI). Medical history, visual acuity testing, 24-2 Humphrey visual field, intraocular pressure measurement, and optical coherence tomography angiography studies of the macular and peripapillary retina were obtained. Correlations between polysomnography parameters and imaging data were analyzed.The radial peripapillary capillary vascular density demonstrated no relationship to AHI (95% confidence interval [CI] [-0.026,0.038]) or severity of OSAS (95% CI: [-0.772, 3.648]) for moderate OSAS compared to mild/normal and (-1.295, 3.1421) for severe compared to mild/normal. Optical coherence tomography angiography superficial parafoveal vascular density (95% CI: [-0.068,0.011], deep parafoveal vascular density (95% CI: [-0.080,0.009]), and foveal avascular zone (95% CI: [-0.001, 0.001]) showed no statistically significant relationship to AHI or OSAS severity after controlling for confounders. Optical coherence tomography retinal nerve fiber layer thickness increased with AHI (The severity of OSAS did not show a statistically significant effect on parameters associated with glaucoma or macular vascular disease. Larger cohorts may be required to determine the physiologic consequences of OSAS on the macular and optic nerve vasculature, structure, and function.Davanian A, Williamson L, Taylor C, et al. Optical coherence tomography angiography and Humphrey visual field in patients with obstructive sleep apnea.

In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear.At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed.A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group.In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).

PURPOSE: To describe the Port Delivery System with ranibizumab refill-exchange procedure. METHODS: Procedure based on the clinical trial program in patients with retinal diseases. RESULTS: The refill-exchange procedure is performed under topical anesthesia and strict aseptic conditions. Supplemental task lighting and magnification are recommended throughout the procedure. Ranibizumab is aseptically transferred from the vial with the filter needle and air is removed from the syringe. The filter needle is then replaced with the refill needle; any remaining air is removed from the syringe and the plunger is advanced to the 0.1-mL mark. Targeting the implant septum center, the refill needle is inserted perpendicularly to the globe until the soft stop contacts the conjunctiva (perpendicular orientation and conjunctival contact are maintained throughout the procedure); a cotton-tipped applicator is recommended for globe stabilization. The entire syringe contents are slowly injected over 5–10 seconds while existing solution fills the fluid collection reservoir. Once completed, the needle is carefully withdrawn while maintaining perpendicularity. The procedure can be successfully performed in rare, specific cases, including subconjunctival thickening or fibrous capsule formation, fluid-filled bleb formation, and corneal patch grafts. CONCLUSION: The procedure is straightforward but distinct from intravitreal injections and requires adherence to standardized techniques. With appropriate preparation, the procedure can be performed in specific cases. [ Ophthalmic Surg Lasers Imaging Retina. 2022;53:257–265.]

Purpose To determine if treatment with a photobiomodulation (PBM) device results in greater improvement in central subfield thickness as compared with placebo in eyes with center-involved diabetic macular edema (CI-DME) and good vision Design Phase 2 randomized clinical trial Participants Participants had CI-DME and visual acuity (VA) 20/25 or better in the study eye and were recruited from 23 clinical sites in the US. Methods One eye of each participant was randomly assigned 1:1 to a 670-nm light-emitting PBM eye patch or an identical device emitting broad-spectrum white light at low power. Treatment was applied for 90 seconds twice daily for 4 months. Main Outcome Measure Change in central subfield thickness (CST) on spectral-domain optical coherence tomography (OCT) at 4 months. Results From April 2019 to February 2020, 135 adults were randomly assigned to either PBM (N = 69) or placebo (N = 66); median age was 62, 37% were female and 82% were white. Median device compliance was 92% with PBM and 95% with placebo. OCT CST increased from baseline to 4 months by a mean (SD) of 13 (53) μm in PBM eyes and 15 (57) μm in placebo eyes (mean difference (95% CI) = -2 (-20 to 16) μm; p = .84). CI-DME, based on DRCR Retina Network sex and machine-based thresholds, was present in 61 (90%) of PBM eyes and 57 (86%) of placebo eyes at 4 months (adjusted odds ratio (95% CI) = 1.30 (0.44 to 3.83); p = .63). Visual acuity decreased by a mean (SD) of -0.2 (5.5) letters and -0.6 (4.6) letters in the PBM and placebo groups, respectively (difference (95% CI) = 0.4 (-1.3 to 2.0) letters; p = .64). There were eight adverse events possibly related to the PBM device, and two adverse events possibly related to the placebo device. None were serious. Conclusions PBM as given in this study, while safe and well tolerated, was not found to be effective for the treatment of CI-DME in eyes with good vision.

Purpose This study evaluated the potential safety, efficacy, and durability advantages of CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept compared to aflibercept monotherapy for the treatment of Diabetic Macular Edema (DME). Design TYBEE was a prospective, randomized, controlled, double-masked study. Subjects were randomized 1:1 to CLS-TA in conjunction with aflibercept (‘Active’) or aflibercept monotherapy (‘Control’) and tracked over 24 weeks. Participants Treatment-naive DME subjects with Best Corrected Visual Acuity (BCVA) 20-70 letters and central subfield retinal thickness (CST) > 300 μm. Methods Subjects in the Active group (n=36) received CLS-TA in conjunction with aflibercept at baseline and week 12. Subjects in the Control group (n=35) received aflibercept at baseline, week 4, week 8, and week 12. All subjects were eligible to receive aflibercept as needed (PRN) at weeks 4, 8, 16 and 20 per additional therapy criteria: presence of macular edema CST ≥ 340 μm; increase in CST of > 50 μm associated with a decrease in BCVA (≥6 letters from the previous visit or 10 letters from the best measurement) Main Outcome Measure Mean change in BCVA from baseline; treatment differences were assessed with a 2-sided significance level of 0.10. Results Mean changes from baseline in BCVA at week 24 were not statistically different in the Active and Control groups (+11.4 and +13.8 letters, p=0.288, intention to treat (ITT); +12.3 and +13.5 letters, p=0.664, per protocol (PP) populations, respectively). Greater improvement in CST was seen in the Active group versus Control (-212.1 μm and -178.6 μm, p=0.089, ITT; -226.5 μm and -176.1 μm, p=0.035, PP, respectively). Eyes in the Active group received an average of 2.6 treatments, while eyes in the Control group received an average of 4.6 treatments. No treatment-related serious AEs were observed. Elevated IOP and cataract events trended higher in the Active group versus the Control group. Conclusion CLS-TA administered suprachoroidally in conjunction with IVT aflibercept in the treatment of DME provides no visual benefit at 24 weeks follow up compared to IVT aflibercept monotherapy, but a modest anatomical benefit and the potential to reduce treatment burden. Ocular adverse events were low for both arms.

Purpose To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment. Design Phase 2, multicenter, randomized, active treatment–controlled clinical trial. Participants Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti–vascular endothelial growth factor intravitreal injections and were responsive to treatment. Methods Patients were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/ml, 40 mg/ml, 100 mg/ml, or monthly intravitreal ranibizumab 0.5-mg injections. Main Outcome Measures Time to first implant refill assessed when the last enrolled patient completed the month 9 visit (primary efficacy end point), improvement in best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. Results The primary analysis population was 220 patients, with 58, 62, 59, and 41 patients in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. Median time to first implant refill was 8.7, 13.0, and 15.0 months in the PDS 10-mg/ml, PDS 40-mg/ml, and PDS 100-mg/ml arms, respectively. At month 9, the adjusted mean BCVA change from baseline was ‒3.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒0.5 ETDRS letters, +5.0 ETDRS letters, and +3.9 ETDRS letters in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. At month 9, the adjusted mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms. The optimized PDS implant insertion and refill procedures were generally well tolerated. After surgical procedure optimization, postoperative vitreous hemorrhage rate was 4.5% (7/157; 1 event classified as serious). There was no evidence of implant clogging. Conclusions In the phase 2 Ladder trial, the PDS was generally well tolerated and demonstrated a dose response across multiple end points in patients with nAMD. The PDS 100-mg/ml arm showed visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5-mg injections but with a reduced total number of ranibizumab treatments. The PDS has the potential to reduce treatment burden in nAMD while maintaining vision.

IMPORTANCE: The role of anti–vascular endothelial growth factor injections for the management of nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) has not been clearly established. OBJECTIVE: To determine the efficacy of intravitreous aflibercept injections compared with sham treatment in preventing potentially vision-threatening complications in eyes with moderate to severe NPDR. DESIGN, SETTING, AND PARTICIPANTS: Data for this study were collected between January 15, 2016, and May 28, 2020, from the ongoing DRCR Retina Network Protocol W randomized clinical trial, conducted at 64 US and Canadian sites among 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study severity level, 43-53), without CI-DME. Analyses followed the intent-to-treat principle. INTERVENTIONS: Eyes were randomly assigned to 2.0 mg of aflibercept injections (n = 200) or sham (n = 199) given at baseline; 1, 2, and 4 months; and every 4 months through 2 years. Between 2 and 4 years, treatment was deferred if the eye had mild NPDR or better. Aflibercept was administered in both groups if CI-DME with vision loss (≥10 letters at 1 visit or 5-9 letters at 2 consecutive visits) or high-risk proliferative diabetic retinopathy (PDR) developed. MAIN OUTCOMES AND MEASURES: Development of CI-DME with vision loss or PDR through May 2020, when the last 2-year visit was completed. RESULTS: Among the 328 participants (57.6% men [230 of 399 eyes]; mean [SD] age, 56 [11] years), the 2-year cumulative probability of developing CI-DME with vision loss or PDR was 16.3% with aflibercept vs 43.5% with sham. The overall hazard ratio for either outcome was 0.32 (97.5% CI, 0.21-0.50; P

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

Purpose: For proliferative diabetic retinopathy (PDR) eyes not requiring vitrectomy, Diabetic Retinopathy Clinical Research Protocol S and the CLARITY trial demonstrated better visual function and anatomical outcomes with less proliferative and diabetic macular edema consequences in the antivascular endothelial growth factor groups compared to the panretinal photocoagulation groups. Intravitreal aflibercept injection (IAI) may represent a useful therapy with vitrectomy for PDR-related vitreous hemorrhage (VH) as a viable alternative to intraoperative endolaser during vitrectomy. We will determine the safety and efficacy when aflibercept is used for PDR-related VH with endolaserless vitrectomy. Methods: Evaluation of endolaserless vitrectomy and 2 mg IAI for PDR-related VH. Eyes receive 1 preoperative and intraoperative IAI followed by randomization to a q8week group receiving 4 postoperative q4week IAI followed by q8week IAI or q16week group receiving 2 postoperative q4week IAI followed by q16week IAI. Main Outcome Measures: Herein, we present pooled safety and efficacy outcomes through 4 months. Results: Twenty-one of 24 eyes were randomized. Preoperative average visual acuity (VA) was 36 letters (20/200). At 4-month follow-up, 18 of 21 randomized eyes showed an average VA of 72 letters (20/40) with an average visual gain of 38 (range, 0-84 gain) letters. Average optical coherence tomography (OCT) central subfield thickness (CST) at 1-month postoperative follow-up was 311 µm. Average OCT CST at 4-month follow-up was 272 µm (average thinning of 38 µm). No significant short-term ocular or systemic adverse events were observed through 4 months. Conclusions: Endolaserless vitrectomy with IAI for PDR-related VH demonstrates short-term safety with significant VA improvement.

PURPOSE To evaluate intravitreal aflibercept injection (IAI) in patients with presumed ocular histoplasmosis syndrome and choroidal neovascularization. METHODS Open-label randomized Phase I/II study of IAI in patients with presumed ocular histoplasmosis syndrome-related choroidal neovascularization. Thirty-nine eyes from 39 patients were randomized in a 1:1 ratio to 2 groups. The Sustained Group eyes (n = 19) underwent monthly IAI for 3 months, then mandatory IAI every 2 months for 12 months (with an option for monthly PRN dosing, if needed). The PRN Group eyes (n = 20) received 1 IAI at randomization, then monthly PRN IAI for 12 months. RESULTS Thirty-nine eyes (19 eyes Sustained Group and 20 eyes PRN Group) were randomized. Average age of participants was 50 years (19-75), with 16 men and 23 women. Ten, 12, and 17 eyes demonstrated extrafoveal, juxtafoveal, and subfoveal choroidal neovascularization, respectively. All eyes in both groups received IAI at baseline, with the Sustained and PRN groups receiving on an average 7.5 (5-11) and 4.6 (1-10) injections, respectively, over the 12 months. At baseline, overall average visual acuity was 68 letters (13-87 letters) with Snellen equivalent of 20/42 (20/20-20/160). At 12-month follow-up, Sustained Group's average visual acuity was 84.9 letters (74-94) and Snellen equivalent was 20/21 (20/13-20/32), indicating an average improvement of 12 letters (6 letters loss to 36 letters gain) (P < 0.01). The PRN Group's 12-month average visual acuity was 80.9 letters (60-94) and Snellen equivalent was 20/26 (20/13-20/63), indicating an average gain of 19 letters (4-75) (P < 0.01). Mean baseline central subfield thickness (CST) was 374 μm and mean 1-year CST was 260 μm (P < 0.01) among all study participants. The Sustained Group's mean baseline CST was 383 μm and mean 12-month CST was 268 μm (P < 0.01). Mean baseline CST of the PRN Group was 360.8 μm, with the final mean CST of 260.5 μm (P < 0.01). No reported endophthalmitis, retinal tears, detachments, vitreous hemorrhage, nor adverse thrombotic events were reported. CONCLUSION Intravitreal aflibercept resulted in improved visual and anatomical outcomes with a favorable safety profile. PRN IAI dosing required less injections with similar visual and anatomical outcomes compared with sustained dosing.

To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment.Phase 2, multicenter, randomized, active treatment-controlled clinical trial.Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti-vascular endothelial growth factor intravitreal injections and were responsive to treatment.Patients were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/ml, 40 mg/ml, 100 mg/ml, or monthly intravitreal ranibizumab 0.5-mg injections.Time to first implant refill assessed when the last enrolled patient completed the month 9 visit (primary efficacy end point), improvement in best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety.The primary analysis population was 220 patients, with 58, 62, 59, and 41 patients in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. Median time to first implant refill was 8.7, 13.0, and 15.0 months in the PDS 10-mg/ml, PDS 40-mg/ml, and PDS 100-mg/ml arms, respectively. At month 9, the adjusted mean BCVA change from baseline was ‒3.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒0.5 ETDRS letters, +5.0 ETDRS letters, and +3.9 ETDRS letters in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. At month 9, the adjusted mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms. The optimized PDS implant insertion and refill procedures were generally well tolerated. After surgical procedure optimization, postoperative vitreous hemorrhage rate was 4.5% (7/157; 1 event classified as serious). There was no evidence of implant clogging.In the phase 2 Ladder trial, the PDS was generally well tolerated and demonstrated a dose response across multiple end points in patients with nAMD. The PDS 100-mg/ml arm showed visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5-mg injections but with a reduced total number of ranibizumab treatments. The PDS has the potential to reduce treatment burden in nAMD while maintaining vision.

BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of 0.3 mg ranibizumab (Lucentis; Genentech, South San Francisco, CA) in eyes with persistent diabetic macular edema (DME) after recent, chronic, and frequent bevacizumab (Avastin; Genentech, South San Francisco, CA). PATIENTS AND METHODS: Open-label, prospective study of 0.3 mg ranibizumab for eyes with persistent DME after bevacizumab. Thirty eyes randomized to a sustained group or a pro re nata (PRN) dosing group. RESULTS: The mean change in ETDRS best-corrected visual acuity from baseline to 1 year was +6.7 letters in the sustained group, +6.4 letters in the PRN group, and +6.5 letters overall. There was an overall mean reduction of 116 µm from baseline central subfield thickness at 1 year, with −92 µm and −127 µm decreases in the sustained and PRN groups, respectively. Adverse events included two deaths; one patient with multiple cardiopulmonary comorbidities, myocardial infarction, stroke, osteomyelitis; and mild posterior subcapsular cataracts in two eyes. CONCLUSION: Ranibizumab 0.3 mg demonstrated improved visual and anatomic outcomes in patients with persistent DME following bevacizumab. [ Ophthalmic Surg Lasers Imaging Retina . 2016;47:1030–1037.]

Purpose To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). Design Two similarly designed, randomized, phase 3 trials, VISTA DME and VIVID DME . Participants Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. Methods Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. Main Outcome Measures The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. Results Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters ( P P P P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% ( P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% ( P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). Conclusions In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.

Importance Information on the effect of anti–vascular endothelial growth factor therapy in eyes with diabetic macular edema (DME) with vision loss after macular laser photocoagulation is clinically valuable. Objective To evaluate visual and anatomic outcomes in a subgroup of macular laser photocoagulation treatment control (hereafter laser control) eyes with substantial vision loss receiving treatment with intravitreal aflibercept injection. Design, Setting, and Participants This investigation was a post hoc analysis of a subgroup of laser control eyes in 2 phase 3 trials—VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME)—in a multicenter setting. One hundred nine laser control eyes with center-involving DME were included. Interventions Treatment with intravitreal aflibercept injection (2 mg) every 8 weeks after 5 monthly doses with sham injections on nontreatment visits starting at week 24 was initiated on meeting prespecified criteria of at least a 10-letter visual acuity loss at 2 consecutive visits or at least a 15-letter visual acuity loss from the best previous measurement at 1 visit and vision not better than at baseline. Main Outcomes and Measures Visual and anatomic outcomes in a subgroup of laser control eyes receiving treatment with intravitreal aflibercept injection. Results Through week 100, a total of 63 of 154 eyes (40.9%) in VISTA and 46 of 133 eyes (34.6%) in VIVID initially randomized to laser control received treatment with intravitreal aflibercept injection. The median time from week 24 to the first intravitreal aflibercept injection treatment was 34.0 (VISTA) and 83.5 (VIVID) days. In this subgroup, the mean (SD) visual gain from baseline to week 100 was 2.2 (12.5) (VISTA) and 3.8 (10.1) (VIVID) letters. At the time of intravitreal aflibercept injection initiation, these eyes had a mean (SD) loss of 11.0 (10.1) (VISTA) and 10.0 (6.5) (VIVID) letters from baseline, and they subsequently gained a mean (SD) of 17.4 (9.7) (VISTA) and 13.6 (8.6) (VIVID) letters from the initiation of treatment with intravitreal aflibercept injection through week 100. There was a minimal mean change in central subfield thickness from baseline in these eyes at the time of intravitreal aflibercept injection initiation (an increase of 3.9 μm in VISTA and a decrease of 3.0 μm in VIVID), after which further mean (SD) reductions of 285.6 (202.6) μm (VISTA) and 313.4 (181.9) μm (VIVID) occurred through week 100. Conclusions and Relevance Intravitreal aflibercept injection improves visual and anatomic outcomes in eyes experiencing substantial vision loss after macular laser photocoagulation treatment for DME. Trial Registration clinicaltrials.gov Identifiers:NCT01363440andNCT01331681

Objective To determine long-term outcomes of patients with ranibizumab-treated retinal vein occlusion (RVO). Design Prospective follow-up of a subset of patients from 2 phase 3 trials. Participants Thirty-four patients with branch RVO (BRVO) and 32 with central RVO (CRVO) who completed the Genentech-sponsored ranibizumab study RVO trials. Methods Patients seen every month in year 1 and at least every 3 months in year 2 were treated with ranibizumab for intraretinal fluid. Patients requiring injections on consecutive visits were treated with ranibizumab plus scatter photocoagulation. Main Outcome Measures Mean improvement in best-corrected visual acuity (BCVA) and percentage of patients with edema resolution. Results With a mean follow-up of 49.0 months, 17 of 34 BRVO patients (50%) had edema resolution defined as no intraretinal fluid for 6 months or more after the last injection. The last injection was given within 2 years of treatment initiation in 76%. The mean number of injections required in unresolved patients in year 4 was 3.2. In patients with resolved edema mean improvement in BCVA was 25.9 letters versus 17.1 letters ( P = 0.09) in unresolved patients, and in both groups, approximately 80% had a final BCVA of 20/40 or better. With a mean follow-up of 49.7 months, 14 of 32 CRVO patients (44%) had edema resolution, with 71% receiving their last injection within 2 years of treatment initiation. The mean number of injections in unresolved patients in year 4 was 5.9. Compared with patients with unresolved CRVO, patients with resolved disease had greater improvement in BCVA (25.2 vs. 4.3 letters; P = 0.002), and a greater percentage had a final BCVA of 20/40 or better (64.3% vs. 27.8%; P = 0.04). Nine patients with BRVO and 9 with CRVO received scatter photocoagulation, and with mean follow-up of 9 months (BRVO) and 11 months (CRVO) after last laser, only 1 in each group had resolution of edema. Conclusions Long-term outcomes in BRVO patients treated with ranibizumab were excellent, and although half still required occasional injections after 4 years, they maintained good visual potential. A substantial minority (44%) of patients with ranibizumab-treated CRVO had edema resolution and a good outcome within 4 years, but most (56%) still required frequent injections, had reduced visual potential, and have a guarded prognosis.

Importance Identifying the factors that are associated with the magnitude of treatment benefits from anti–vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) may help refine treatment expectations. Objective To identify the baseline factors that are associated with vision and anatomic outcomes when managing DME with anti-VEGF and determine if there are interactions between factors and the agent administered. Design, Setting, and Participants This post hoc analysis of data from the Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial , Protocol T, was conducted between December 2016 and December 2017. Between August 22, 2012, and August 28, 2013, 660 participants were enrolled with central-involved DME and vision impairment (approximate Snellen equivalent, 20/32-20/320). Interventions Repeated 0.05-mL intravitreous injections of 2.0-mg aflibercept (201 eyes), 1.25-mg bevacizumab (185 eyes), or 0.3-mg ranibizumab (192 eyes) per protocol. Main Outcomes and Measures Change in visual acuity (VA) and optical coherence tomography (OCT) central subfield thickness at 2 years and change in VA over 2 years (area under the curve [AUC]). Results Among 578 participants, the median age (interquartile range) was 61 (54-67) years. Across anti-VEGF treatment groups, each baseline factor was associated with mean improvement in VA and a reduction in central DME compared with the baseline. For every decade of participant age, the mean VA improvement was reduced by 2.1 letters (95% CI, −3.0 to −1.2;P Conclusions and Relevance Lower hemoglobin A1clevels were associated with the magnitude of vision improvement following anti-VEGF therapy, providing further evidence to encourage glycemic control among persons with diabetes. Younger patients and those without prior PRP might expect greater improvement in VA than older patients or those with prior PRP.

Purpose To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME). Design Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection–controlled for 2 years. Participants Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥275 μm on optical coherence tomography. Methods Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary. Main Outcome Measures The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24. Results Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group. Conclusions The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

PURPOSE: To determine safety, tolerability, and efficacy of intravitreal ranibizumab in the treatment of polypoidal choroidal vasculopathy in a non-Asian population. METHODS: Phase I/II, prospective, open-label, single-center, nonrandomized, uncontrolled, consecutive, interventional case series of 20 eyes in 19 patients with exudative active polypoidal choroidal vasculopathy. Eyes received 3 monthly intravitreal ranibizumab injections (0.3 or 0.5 mg), with additional ranibizumab injections, observation, or alternative treatments at investigators' discretion, through 24 months. Main outcome measures were ocular and systemic safety and mean change from baseline in best-corrected visual acuity and center point thickness. RESULTS: Visually significant ocular adverse events included cataract progression (n = 3), mild vitreous hemorrhage (n = 2), and macular hole (n = 1). No systemic drug-related adverse events were observed. Mean baseline best-corrected visual acuity was 20/127 (range, 20/16-20/500) and center point thickness was 298 μm. Mean best-corrected visual acuity increased from baseline by 1.2 Snellen lines at 12 months and 24 months. Mean center point thickness decreased by 53 μm and 67 μm from baseline at 12 months and 24 months, respectively. CONCLUSION: Intravitreal ranibizumab was well tolerated in non-Asian patients with polypoidal choroidal vasculopathy; the majority of eyes experienced improvements in best-corrected visual acuity and center point thickness after ranibizumab treatment.

BACKGROUND AND OBJECTIVE: To evaluate safety and efficacy of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) injection (IAI) for the treatment of neovascular polypoidal choroidal vasculopathy (PCV) in a predominantly non-Asian population. PATIENTS AND METHODS: This was an open-label, prospective, unmasked, nonrandomized clinical trial. Twenty eyes with neovascular PCV received monthly 2.0 mg IAI for 3 months followed by mandatory IAI every 2 months for 12 months. RESULTS: The mean change in ETDRS best-corrected visual acuity from baseline to 1 year was +11 letters in the treatment-naïve group, +5 letters in the treatment non-naïve group, and +9 letters overall. There was an overall mean reduction of 70 µm from baseline central subfield thickness (CST) at 1 year. Patients received a mean of 6.2 mandatory and 0.7 additional IAI injections overall during the course of 1 year. No serious ocular adverse events were reported. CONCLUSION: At 1 year, neovascular PCV in a predominantly non-Asian population treated with IAI demonstrated favorable visual, anatomic, and safety outcomes. [ Ophthalmic Surg Lasers Imaging Retina . 2017;48:34–44.]

Amyloid β peptides (Aβ) have been implicated in the pathogenesis of age-related macular degeneration (ARMD) and glaucoma. In this study, retinas of mice overexpressing Aβ (Tg) were compared to those of wild-type mice (Wt) and analyzed for oxidative stress parameters. We observed a progressive decrease in all retinal cell layers, which was significantly greater in Tg mice at 14 months and culminated in loss of the outer retina at 18 months of age. We also observed higher levels of reactive oxygen species, glial fibrillary acidic protein, and hydroperoxide in Tg versus Wt mice (14 months). These effects were associated with phosphorylation/activation of the apoptosis signal kinase 1 and the p38 mitogen-activated kinase. Western blotting analysis revealed progressive increases in the levels of thioredoxin 1 and thioredoxin inhibitory protein in Tg compared to Wt mice. No changes were observed in the levels of thioredoxin reductase 1 (TrxR1); however, measurements of TrxR1 activity showed a 42.7±8% reduction in Tg mice versus Wt at 14 months of age. Our data suggest that Aβ-mediated retinal neurotoxicity involves impairment of the thioredoxin system and enhanced oxidative stress, potentially implicating this mechanism in the pathogenesis of ARMD and glaucoma.

Purpose To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients. Design Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies. Participants Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT). Intervention Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria. Main outcome measures Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months. Results In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P Conclusions Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.

To investigate the vitreal penetration of moxifloxacin after oral administration.Prospective, nonrandomized clinical series.Twenty-four patients (mean age = 62.8 years) undergoing elective pars plana vitrectomy were assigned to a dosing group: control (n = 3), which received no medication; single-dose (n = 11), which received one 400 mg oral dose of moxifloxacin 3 hours before surgery; and five-dose (n = 10), which received one 400 mg dose on each of the 4 days preceding surgery and a fifth dose 3 hours before surgery. Vitreous samples were obtained and analyzed.Control, below quantifiable levels; single-dose, 0.572 +/- 0.239 microg/mL; and five-dose, 1.200 +/- 0.645 microg/mL.Five doses of oral moxifloxacin lead to higher intravitreal drug concentrations than single-dose administration. Both regimens, however, achieve levels that exceed the MIC90 of many bacteria implicated in postoperative endophthalmitis.

Objective To evaluate currently available data in the published literature to answer the question of whether laser scanning imaging is a sensitive and specific tool for detecting macular disease when compared with the current standard technique of slit-lamp biomicroscopy or stereoscopic fundus photography. Methods Literature searches conducted in December 2004 and in August 2006 retrieved 370 citations. The Retina Panel members selected 65 articles for the panel methodologist to review and rate according to the strength of the evidence. Of the 65 articles reviewed, 6 provided level I evidence, 9 provided level II evidence, and 50 provided level III evidence. A level I rating was assigned to studies that reported an independent masked comparison of an appropriate spectrum of consecutive patients, all of whom had undergone both the diagnostic test and the reference standard. A level II rating was assigned to an independent masked or objective comparison; a study performed in a set of nonconsecutive patients or confined to a narrow spectrum of study individuals (or both), all of whom had undergone both the diagnostic test and the reference standard; or an independent masked comparison of an appropriate spectrum, but the reference standard had not been applied to all study patients. A level III rating was assigned when the reference standard was unobjective, unmasked, or not independent; positive and negative tests were verified using separate reference standards; or the study was performed in an inappropriate spectrum of patients. Results There are high-level studies of the use of laser scanning imaging to quantify macular thickness and, thereby, macular edema in patients with diabetic retinopathy and to examine patients with a macular hole. There is lower-quality evidence on the use of laser scanning imaging for other diseases of the macula. There is insufficient evidence to compare the different instruments. Conclusions There is level I evidence that laser scanning imaging can accurately and reliably quantify macular thickness in patients with diabetic retinopathy. There is level I evidence that optical coherence tomography provides additional information to clinical examination when used in patients with a macular hole. Laser scanning imaging provides important information that is helpful in patient management by allowing objective serial quantitative measurements. Although further studies are needed to develop an optimal testing strategy using these imaging modalities, laser scanning imaging is a sensitive, specific, reproducible tool for diagnosing macular edema and, therefore, is likely to be useful for managing diseases that result in macular edema.

To compare 2.0 mg ranibizumab (RBZ) injections with 0.5 mg RBZ for eyes with center-involved diabetic macular edema (DME) and a central subfield thickness (CFT) of ≥250 μm on time-domain optical coherence tomography.DesignRandomized, controlled, multicenter clinical trial.Eligible eyes were randomized in a 1:1 ratio to 0.5 mg (n=77) or 2.0 mg (n=75) RBZ. Study eyes received 6-monthly injections.Main outcome measuresThe primary outcome measure was the mean change in best corrected visual acuity (BCVA) at month 6. Secondary outcomes included the incidence and severity of systemic and ocular adverse events and the mean change in CFT from baseline.In all, 152 eyes (152 patients) were randomized in the study. At month 6, the mean improvement from baseline BCVA was +9.43 letters in the 0.5 mg RBZ group and +7.01 letters in the 2.0 mg RBZ group (P=0.161). At month 6, one death occurred in the 0.5 mg RBZ group and three deaths in the 2.0 mg RBZ group, all due to myocardial infarction in subjects with a prior history of heart disease. Mean CFT was reduced by 168.58 μm in the 0.5 mg RBZ group and by 159.70 μm in the 2.0 mg RBZ group (P=0.708).There was no statistically significant difference in the mean number of letters gained between the 0.5 and 2.0 mg RBZ groups through month 6. In this DME study population, high-dose RBZ does not appear to provide additional benefit over 0.5 mg RBZ.

To determine safety and efficacy of intravitreal high-dose ranibizumab in the treatment of active neovascular polypoidal choroidal vasculopathy (PCV). In this Phase I/II, single-center, randomized, controlled, double-masked study, predominantly non-Asian, previously treated or treatment-naive, male and female adult patients were randomized to receive high-dose (1.0/0.1 ml or 2.0 mg/0.05 ml; n=15) or standard-dose (0.5 mg/0.05 ml; n=5) ranibizumab in 3 monthly loading doses, followed by 9 months of criteria-based, as-needed retreatment. Safety was evaluated by a descriptive analysis of all non-serious and serious adverse events, angiographic assessments, physical examinations, vital signs, ocular examinations, and visual acuity measurements. Visual acuity and anatomic outcomes are described for the high-dose group. Twenty patients (aged 35–76 years; 8 Black, 11 White, 1 Asian) were enrolled. At baseline, in the high-dose group, mean best-corrected visual acuity (BCVA) was 63.5 letters (Snellen equivalent ~20/50), and mean baseline central foveal thickness (CFT) was 253.7 μm. High-dose ranibizumab was generally well tolerated without evidence of ocular or systemic severe adverse events, including arterial thromboembolic events. At month 12, in the high-dose group, the mean overall change from baseline in BCVA was +6.7 letters and in CFT was −49.7 μm. High-dose ranibizumab monotherapy is safe and efficacious for treating patients with PCV.

PURPOSE To evaluate retinal sensitivity in patients with diabetic macular edema who received intravitreal aflibercept injection (IAI) or laser. METHODS A substudy included 46 patients from DA VINCI (a randomized, double-masked Phase 2 study) receiving either laser, 0.5 mg IAI every 4 weeks, 2 mg IAI every 4 weeks, 2 mg IAI every 8 weeks after 3 monthly doses (2q8), or 2 mg IAI as-needed after 3 monthly doses for 52 weeks. Retinal sensitivity was measured in one (central), five (one central and four inner), and eight (four inner and four outer) optical coherence tomography subfields. RESULTS Mean best-corrected visual acuity improvement in the subgroup at Week 52 was 3.3 letters with laser and ranged from 5.4 to 16.3 letters in the IAI groups. Retinal sensitivity of laser patients at Week 52 was comparable with baseline in the central optical coherence tomography subfield but decreased in the five and eight optical coherence tomography subfields. Compared with laser, retinal sensitivity significantly increased with IAI in the 2q8 and pooled IAI groups in the 5 and 8 optical coherence tomography subfields at Week 52 (P < 0.05). CONCLUSION Intravitreal aflibercept injection improved best-corrected visual acuity and retinal sensitivity in this subgroup of patients. Laser may cause a deterioration of macular function that is not detectable with best-corrected visual acuity testing.

To assess the short-term safety and efficacy of treating subfoveal choroidal neovascularization (CNV) with external beam radiation delivered in 5 x 4 Gy fractions among patients having age-related macular degeneration (AMD).A multicenter prospective randomized controlled pilot study.Eighty-eight patients were enrolled through 10 sites and were randomized to radiotherapy (20 Gy delivered in 5 daily fractions of 4 Gy each; 6 MV [N = 41]) or no radiotherapy (sham radiotherapy [N = 22] or observation [N = 25]). Eligibility criteria included visual acuity of at least 20/320 and subfoveal CNV not amenable to treatment. Randomization was stratified by lesion type (new or recurrent CNV) and blood (50% or/=50% of the lesion [N = 13]). The primary outcome measure was loss of/=3 lines of visual acuity. Secondary outcome measures were angiographic response and side effects.At baseline, patient and ocular characteristics were similar between treatment groups. At six months, 9 radiated eyes (26%) and 17 eyes not radiated (49%) lost/=3 lines of visual acuity (P = .04; stratified chi(2) test). At 12 months, 13 radiated eyes (42%) and 9 observed eyes (49%) lost/=3 visual acuity lines (P = .60). The radiated group demonstrated smaller lesions and less fibrosis than the nonradiated group (P = .05 and .004, respectively) at 12 months. Radiation-induced complications were not observed except for one radiated eye with numerous cotton wool spots and possible radiation retinopathy.External beam radiation at 5 x 4 Gy may have a modest and short-lived (six month) benefit in preserving visual acuity.

Purpose To report the visual outcomes and complications of surgical removal of extensive peripapillary choroidal neovascularization (PPCNV) in elderly patients. Design Retrospective review. Participants Seventeen consecutive eyes of 17 patients older than age 55 undergoing PPCNV resection. Methods Retrospective review of eyes undergoing surgical removal of extensive PPCNV via pars plana vitrectomy. Main outcome measures Preoperative and postoperative Snellen visual acuity. Results The mean age of patients was 76.9 years, and the mean duration of follow-up was 29.8 months. In 6 of 17 eyes, the PPCNV was extrafoveal; in two eyes, it was juxtafoveal; and in nine eyes, it was subfoveal. The cause of CNV was idiopathic (nine eyes), age-related macular degeneration (six eyes), presumed ocular histoplasmosis syndrome (one eye), and inflammation (one eye). All eyes were ineligible for laser treatment by MPS criteria. In eyes with extrafoveal CNV, the preoperative Snellen visual acuity ranged from 20/25 to 20/300, and the final visual acuity ranged from 20/40 to 20/800. The two eyes with juxtafoveal CNV had preoperative visual acuities of 20/125 and 20/300, and both had a postoperative acuity of 20/200. Eyes with subfoveal CNV had a range of preoperative visual acuity from 20/125 to 20/800, whereas the final visual acuity ranged from 20/30 to hand motions. Four of the nine eyes with subfoveal lesions had improved visual acuity. Overall, the final visual acuity was stable or improved in six eyes and worsened in 11 eyes. CNV recurrence was noted in four eyes and required reexcision, laser photocoagulation, or both. Surgical complications included retinal detachment (two eyes), retinal hole and epiretinal membrane (one eye), cystoid macular edema (two eyes), and subsequent cataract extraction (four eyes). Conclusions Surgical removal of extensive PPCNV in the elderly does not often yield improvement or stabilization of visual acuity. However, 6 of 17 patients had stable or improved visual acuity.

Importance Studies have established the efficacy and safety of aflibercept for the treatment of macular edema due to central retinal vein occlusion. Bevacizumab is used off-label to treat this condition despite the absence of supporting data. Objective To investigate whether bevacizumab is noninferior to aflibercept for the treatment of macular edema secondary to central retinal or hemiretinal vein occlusion. Design, Setting, and Participants The SCORE2 randomized noninferiority clinical trial was conducted at 66 private practice or academic centers in the United States, and included 362 patients with macular edema due to central retinal or hemiretinal vein occlusion who were randomized 1:1 to receive aflibercept or bevacizumab. The first participant was randomized on September 17, 2014, and the last month 6 visit occurred on May 6, 2016. Analyses included data available as of December 30, 2016. Interventions Eyes were randomized to receive intravitreal injection of bevacizumab (1.25 mg; n = 182) or aflibercept (2.0 mg; n = 180) every 4 weeks through month 6. Main Outcomes and Measures The primary outcome was mean change in visual acuity (VA) letter score (VALS) from the randomization visit to the 6-month follow-up visit, based on the best-corrected electronic Early Treatment Diabetic Retinopathy Study VALS (scores range from 0-100; higher scores indicate better VA). The noninferiority margin was 5 letters, and statistical testing for noninferiority was based on a 1-sided 97.5% confidence interval. Results Among 362 randomized participants (mean [SD] age, 69 [12] years; 157 [43.4%] women; mean [SD] VALS at baseline, 50.3 [15.2] [approximate Snellen VA 20/100]), 348 (96.1%) completed the month 6 follow-up visit. At month 6, the mean VALS was 69.3 (a mean increase from baseline of 18.6) in the bevacizumab group and 69.3 (a mean increase from baseline of 18.9) in the aflibercept group (model-based estimate of between-group difference, −0.14; 97.5% CI, −3.07 to ∞; P = .001 for noninferiority), meeting criteria for noninferiority. Ocular adverse events in the aflibercept group included 4 participants with intraocular pressure (IOP) more than 10 mm Hg greater than baseline; ocular adverse events in the bevacizumab group included 1 participant with endophthalmitis (culture negative), 9 with IOP more than 10 mm Hg greater than baseline, 2 with IOP higher than 35 mm Hg, and 1 with angle-closure glaucoma not attributed to the study drug or procedure. Conclusions and Relevance Among patients with macular edema due to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to visual acuity after 6 months of treatment.

A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME).Two similarly designed, double-masked, randomized, phase 3 trials, VISTA(DME) and VIVID(DME).We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement.Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation.The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography.Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P0.0001) in VIVID. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (P0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 μm (P0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 μm (P0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups.At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated.

Purpose To investigate the vitreal penetration of moxifloxacin after oral and topical administration. Design Prospective, nonrandomized clinical trial. Methods Twenty-four patients were assigned to one of four dosing groups: control (n = 3), which received no medication; oral (n = 8), which received two 400 mg oral doses of moxifloxacin before surgery; topical (n = 8), which received one drop of topical moxifloxacin 0.5% every 15 minutes for the hour preceding surgery; and combined (n = 5), which received two 400 mg oral doses and one drop of topical moxifloxacin 0.5% hourly for 18 hours prior to surgery. Vitreous samples were obtained and analyzed. Results Control, below quantifiable levels; oral, 1.553 ± 0.33 μg/ml; topical, 0.027 μg/ml; and combined, 2.219 ± 0.71 μg/ml. One topical patient developed postoperative endophthalmitis. Conclusions In contrast to topical moxifloxacin, oral moxifloxacin achieves significant levels in the noninflamed human vitreous.

Objective To report a pilot study of telemedical direct ophthalmoscopy in the diagnosis of acquired immune deficiency syndrome (AIDS)-related retinopathy in a human immunodeficiency virus (HIV)-positive population and in the diagnosis of glaucoma, cataract, and retinopathy in a diabetic population. Design Prospective comparative case series. Participants Seventeen HIV-positive and 20 diabetic patients. Methods A direct ophthalmoscope custom-fitted with a digital microcamera capable of transmitting images from any of 61 sites within the Georgia Statewide Telemedicine Program was used by a nonophthalmologist to examine 34 eyes of 17 HIV-positive patients and 39 eyes of 20 patients with diabetes. Fundus images were transmitted in real-time to a reviewing ophthalmologist. An in-person, comprehensive examination including indirect ophthalmoscopy, was performed by a second ophthalmologist. Telemedical examination was compared to the in-person comprehensive examination. Results For the HIV study, 21 eyes did not show HIV retinopathy (noninfectious retinopathy with cotton-wool spots) by in-person examination. Telemedical examination correctly identified 20 of these eyes as disease-free (specificity = 95%). HIV retinopathy was present in 12 of the 34 eyes by in-person evaluation with telemedical examination correctly diagnosing 10 of these eyes (sensitivity = 83%). One eye with dense cataract and retinal detachment was unable to be evaluated ophthalmoscopically by either in-person or telemedical examination. Telemedical and in-person assessments for HIV retinopathy were identical in 100% of eyes without cataract. Disagreement in diagnosis between telemedical and in-person examination was associated with cataract ( P For the diabetes study, because of an inadequate image, telemedical examination was unable to classify 46% and 36% of eyes for glaucoma and diabetic retinopathy, respectively. Inability to make a telemedical determination for glaucoma ( P P P Conclusion Telemedical direct ophthalmoscopic, real-time fundus imaging may provide a valuable means for providing ophthalmic consultation to the primary care physician in younger patients without lens or media opacity, but is inadequate for eyes with any degree of lens or media opacity.

Trilateral retinoblastoma (TRb) is a syndrome involving midline intracranial malignancies in children with the heritable form of retinoblastoma. All cases of TRb reported from 1971 to 1997 were reviewed. The histopathologic findings, clinical features, treatment modalities, and survival rates from 80 cases were evaluated. Histopathologic findings from intracranial malignancies demonstrated primitive neuroectodermal tumors in 61.5% of cases. Various degrees of neuronal or photoreceptor differentiation were seen in the other 38.5% of cases. Autopsy, histopathologic, and radiologic examinations did not show a more definitive site of origin of these intracranial tumors, although "pinealoblastoma" was often the diagnosis reported. These findings, together with analysis of the histopathologic similarities among human primitive neuroectodermal tumors, pinealoblastoma, retinoblastoma, and ependymoblastoma, suggest that TRb more likely arises from a germinal layer of predisposed primitive subependymal neuroblasts that are not necessarily destined for pineal or photoreceptor differentiation. Trilateral tumors have also been found in transgenic mice expressing the simian virus 40 T-antigen. Transgenic murine intracranial tumors are primitive neuroectodermal tumors arising from the subependymal layer. Transgenic mice with the murine interphotoreceptor cell binding protein promoter and simian virus 40 T-antigen also develop pineal tumors. Trilateral retinoblastoma is usually fatal, with an average survival time of 11.2 months. Therapies include radiation, systemic chemotherapy, intrathecal chemotherapy, and surgical resection/craniotomy in combination with radiation and/or chemotherapy. Survival may be prolonged with combination chemotherapy (24.6 months) and if neuroradiologic screening identifies TRb before symptoms are present (23.5 months). Recent success with platinum-based chemoreduction of intraocular retinoblastoma may indicate a similar role for platinum-based chemotherapy in the treatment of TRb. Routine central nervous system imaging should be considered in the management of TRb.

To investigate the influence of pH and glucose concentration, both of which represent significant biochemical variables in tissue ischemia, on the production of VEGF protein by retinal Müller cells and C6 glioma cells, under normoxic and hypoxic conditions.Rat retinal Müller cells and C6 glioma cells grown in tissue culture monolayers were studied. The effect of pH (range 7.0-8.0) and glucose concentration (0.6-25 mmol/L) on VEGF protein production, under both normoxic and hypoxic conditions, were evaluated by ELISA analysis of the conditioned media. Establishment of significant cell hypoxia was verified by measurement of lactate release into the conditioned media.Hypoxia caused a 7.9-fold increase in VEGF production in C6 cells at 24 h, and a 3.4-fold increase in Müller cells after 48 h. Under hypoxic conditions, VEGF protein production was increased further by increasing pH and increasing glucose, and decreased by low pH and low glucose. Varying the glucose concentration or pH of the medium did not result in significant induction of VEGF protein production by either cell type under normoxic conditions.Both glucose and pH significantly affected VEGF production induced by low oxygen. However, neither exerted a measurable stimulatory effect on VEGF production in normoxic conditions. Coexisting hypoxia and acidosis or hypoglycemia, as might occur in severe tissue ischemia, may render glial cells incapable of effectively upregulating VEGF synthesis, while alkalosis or hyperglycemia may augment hypoxia-induced VEGF production.

Purpose: To compare the sensitivity and specificity of detection, and accuracy of localization, of small steel intraocular and episcleral foreign bodies, using conventional axial and helical computed tomographic scanning in an experimental model. Methods: Small steel foreign bodies ranging in size from 0.048 to 0.179 mm 3 were placed in intraocular and episcleral locations in eye bank eyes mounted in the orbits of a human skull and scanned using helical and conventional axial techniques. Helical scanning was performed using 1-mm and 3-mm thick sections. Conventional axial scanning was performed using 3-mm thick sections. Images were reviewed by masked observers to determine sensitivity, specificity, and accuracy of localization for each imaging method. Results: Steel foreign bodies as small as 0.048 mm 3 were detectable with each scanning protocol. Although the helical scans appeared to provide higher levels of sensitivity compared to conventional axial scanning, the difference in outcome between the scan types was not statistically significant. Sensitivity was dependent on the size of the foreign body and ranged from 45% to 65% for the smaller ones ( 3 ) to 100% for the larger ones (> 0.06 mm 3 ). Multiplanar reformatting of images was helpful in achieving optimal accuracy. Conclusion: In an experimental model of steel intraocular foreign body, helical computed tomographic scanning provided images of high quality similar to that of conventional axial scanning.

To determine long-term outcomes of patients with ranibizumab-treated retinal vein occlusion (RVO).Prospective follow-up of a subset of patients from 2 phase 3 trials.Thirty-four patients with branch RVO (BRVO) and 32 with central RVO (CRVO) who completed the Genentech-sponsored ranibizumab study RVO trials.Patients seen every month in year 1 and at least every 3 months in year 2 were treated with ranibizumab for intraretinal fluid. Patients requiring injections on consecutive visits were treated with ranibizumab plus scatter photocoagulation.Mean improvement in best-corrected visual acuity (BCVA) and percentage of patients with edema resolution.With a mean follow-up of 49.0 months, 17 of 34 BRVO patients (50%) had edema resolution defined as no intraretinal fluid for 6 months or more after the last injection. The last injection was given within 2 years of treatment initiation in 76%. The mean number of injections required in unresolved patients in year 4 was 3.2. In patients with resolved edema mean improvement in BCVA was 25.9 letters versus 17.1 letters (P = 0.09) in unresolved patients, and in both groups, approximately 80% had a final BCVA of 20/40 or better. With a mean follow-up of 49.7 months, 14 of 32 CRVO patients (44%) had edema resolution, with 71% receiving their last injection within 2 years of treatment initiation. The mean number of injections in unresolved patients in year 4 was 5.9. Compared with patients with unresolved CRVO, patients with resolved disease had greater improvement in BCVA (25.2 vs. 4.3 letters; P = 0.002), and a greater percentage had a final BCVA of 20/40 or better (64.3% vs. 27.8%; P = 0.04). Nine patients with BRVO and 9 with CRVO received scatter photocoagulation, and with mean follow-up of 9 months (BRVO) and 11 months (CRVO) after last laser, only 1 in each group had resolution of edema.Long-term outcomes in BRVO patients treated with ranibizumab were excellent, and although half still required occasional injections after 4 years, they maintained good visual potential. A substantial minority (44%) of patients with ranibizumab-treated CRVO had edema resolution and a good outcome within 4 years, but most (56%) still required frequent injections, had reduced visual potential, and have a guarded prognosis.

We report a congenital neurosensory retinal detachment associated with an optic nerve coloboma with subsequent spontaneous reattachment. This represents the earliest reported case of such a clinical situation. An observation period is recommended for infants with this clinical course to allow for the opportunity of spontaneous reattachment. J Pediatr Ophthalmol Strabismus 2004; 41:358–360.

The most common cause of branch retinal vein occlusion is hypertension. Since retinal arteries and veins share a common adventitial sheath, the thickened artery compresses a retinal vein causing an occlusion, resulting in a retinal hemorrhage. Most patients present in their 60s with unilateral involvement. The patient may be asymptomatic if the macula is not involved. Visual complications of branch retinal vein occlusion include macular edema, retinal ischemia, and retinal and iris neovascularization. Argon laser photocoagulation is beneficial in patients with macu‐Photographed by Michael S. Stanley, Ophthalmic Photographer lar edema. If neovascularization develops, laser treatment reduces secondary vitreous hemorrhage and/or neovascular glaucoma.

To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME).Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years.Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography.Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary.The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24.Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group.The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24.Proprietary or commercial disclosure may be found after the references.

Ischemic retinopathy is the leading cause of blindness in persons younger than 60 in the United States. It is a complication of diabetes, retinal vein occlusion, and retinopathy of prematurity, with loss of vision occurring as a result of retinal hypoxia, increased vascular permeability, and pathologic neovascularization (NV). Considerable scientific and clinical investigation have focused on identifying the molecular mediators involved in initiating pathologic angiogenesis in the retina and developing effective inhibitors. Anti-VEGF agents are now in widespread use in the treatment of patients with subretinal neovascularization associated with age-related macular degeneration and are being investigated in clinical trials in diabetic retinopathy.1 Several antiangiogenic agents are in clinical use to manage a wide variety of conditions involving pathologic angiogenesis and vascular permeability in the eye.1 Several issues, however, detract from the potential clinical value of these agents. Whereas angiogenic inhibitors are effective in reversing vascular permeability and eliminating NV, this therapy does not address the issue of retinal ischemia or promote the normal vascular repair that is essential to ending tissue hypoxia and maintaining normal function. In fact, an inhibitor's lack of antiangiogenic selectivity might adversely impact the process of physiological vascular repair.2,3 Similarly, suppression of VEGF-mediated cell survival pathways in hypoxic neurons might inhibit neuronal survival and function.4 In addition, antiangiogenic therapy is not indicated at the pre-proliferative stage of ischemic retinopathy, a time when metabolic support of the retina and repair of the damaged capillary beds are most critical. Delivery of antiangiogenic agents by intravitreal injection also carries a risk for vision-threatening endophthalmitis and uveitis.5,6 The therapeutic use of oxygen has been extensively studied in wound healing,7,8 especially in clinical situations in which tissue perfusion is compromised by arterial insufficiency,9 diabetes,10,11 or previous radiation treatment for neoplasia.12 Numerous studies support the use of hyperbaric oxygen as adjunctive treatment for nonhealing lower extremity wounds in patients with diabetes,10,11 compromised tissue flaps and grafts,13 and radiation-induced ischemic osteonecrosis.14 Experiments in various animal models of ischemia have suggested that supplemental oxygen can improve the rate of wound healing and reduce apoptosis in the affected tissue.8,15 In addition to supporting oxidative phosphorylation, oxygen plays a critical role in redox signaling for cytokines, including VEGF and PDGF, and in cell motility, integrin function, and leukocyte recruitment.7,8,16 The therapeutic effects of oxygen supplementation in ischemic retinopathy have not been well characterized. However, it has been shown that hyperbaric oxygen treatment reduces breakdown of the blood-retinal barrier in streptozotocin-induced diabetic rats.17 In humans, small case series have suggested that normobaric supplemental oxygen can reduce vascular permeability and retinal thickness in diabetic macular edema18 and central retinal vein occlusion.19,20 Oxygen supplementation immediately after vaso-obliteration but before the onset of retinal hypoxia was also shown to reduce the severity of vitreous NV and to attenuate the degeneration of astrocytes in oxygen-induced retinopathy (OIR) models.21–23 These clinical and scientific studies support the potential value of oxygen therapy as a primary or adjunctive treatment for vision-threatening ischemic retinopathies.24 In the present study, we investigated the therapeutic benefit of oxygen supplement during the ischemic pre-proliferative phase of ischemic retinopathy in an OIR mouse model. Unlike other studies that start treatment of ischemic retinopathy before the onset of hypoxia, we initiated hyperoxia treatment (HT) after a period of retinal ischemia, when the multiple signs of ischemic retinopathy—such as no perfusion in the central retina, tortuous and dilated vessels,25 and upregulation of many angiogenic and inflammatory genes in the retina—are evident. This delay was chosen to determine the potential clinical use of HT in the pre-proliferative stage of ischemic retinopathy because most patients with ischemic retinopathy seek evaluation before NV has developed. We show that normobaric HT after a period of retinal ischemia selectively blocks the development of pathologic NV while it simultaneously accelerates the process of physiologic revascularization. Mechanistically, we further demonstrate the beneficial effect of HT may be attributed to its pleiotropic effect by correcting a broad range of biochemical and cellular abnormalities. Our data strongly support the potential of hyperoxia as an effective primary or adjunctive therapy for pre-proliferative ischemic retinopathy.

To evaluate 14-week effects of intravitreal ranibizumab or triamcinolone in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation.Three hundred and forty-five eyes with a visual acuity of 20/320 or better, center-involved diabetic macular edema receiving focal/grid laser, and diabetic retinopathy receiving prompt panretinal photocoagulation were randomly assigned to sham (n = 123), 0.5-mg ranibizumab (n = 113) at baseline and 4 weeks, and 4-mg triamcinolone at baseline and sham at 4 weeks (n = 109). Treatment was at investigator discretion from 14 weeks to 56 weeks.Mean changes (±SD) in visual acuity letter score from baseline were significantly better in the ranibizumab (+1 ± 11; P0.001) and triamcinolone (+2 ± 11; P0.001) groups compared with those in the sham group (-4 ± 14) at the 14-week visit, mirroring retinal thickening results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. One eye (0.9%; 95% confidence interval, 0.02%-4.7%) developed endophthalmitis after receiving ranibizumab. Cerebrovascular/cardiovascular events occurred in 4%, 7%, and 3% of the sham, ranibizumab, and triamcinolone groups, respectively.The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study.

We assessed the usefulness of silver staining of nucleolar organizer regions in the diagnosis of pigmented conjunctival tumors. Fifty-one biopsy specimens were silver stained to identify the nucleolar organizer regions. Nineteen nevi without atypia, three nevi with atypia, eight primary acquired melanosis lesions, and 14 melanomas were studied. In each specimen, silver staining of the nucleolar organizer regions was counted in 100 cells to yield an average of the silver staining of the nucleolar organizer region count. The mean silver staining of the nucleolar organizer region counts per cell was correlated with the degree of malignancy of pigmented conjunctival lesions as follows: nevi, 3.0; primary acquired melanosis, 3.2; nevi with atypia, 3.9; primary acquired melanosis with atypia, 5.0; and melanoma, 5.7 (Spearman correlation [rS] = .83, P = .0001; analysis of variance [ANOVA] F test = 20.9, P = .0001). A cutoff value of 4.0 (mean silver staining of nucleolar organizer regions per cell) will differentiate melanoma and primary acquired melanosis with atypia from other lesions (sensitivity, 100%; specificity, 96%). The silver staining of nucleolar organizer regions is a useful adjunct in determining the malignancy of pigmented conjunctival tumors.

To evaluate anatomic outcomes and vision, injection frequency, and safety during the as-needed (PRN) treatment phase of a study evaluating a 12-week fixed dosing period followed by PRN dosing to week 52 with vascular endothelial growth factor (VEGF) Trap-Eye for neovascular (wet) age-related macular degeneration (AMD).Multicenter, randomized, double-masked trial.We included 159 patients with subfoveal choroidal neovascularization (CNV) secondary to wet AMD.Patients were randomly assigned to 1 of 5 intravitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1-12). From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg).Change in central retinal/lesion thickness (CR/LT), change in total lesion and CNV size, mean change in best-corrected visual acuity (BCVA), proportion of patients with 15-letter loss or gain, time to first PRN injection, reinjection frequency, and safety at week 52.The decrease in CR/LT at week 12 versus baseline remained significant at weeks 12 to 52 (-130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm(2) at 48 weeks. After achieving a significant improvement in BCVA during the 12-week, fixed-dosing phase for all groups combined, PRN dosing for 40 weeks maintained improvements in BCVA to 52 weeks (5.3-letter gain; P0.0001). The most robust improvements and consistent maintenance of visual acuity generally occurred in patients initially dosed with 2 mg every 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first reinjection was 129 days; 19% of patients received no injections and 45% received 1 or 2 injections. Treatment with VEGF Trap-Eye was generally safe and well tolerated, with few ocular or systemic adverse events.PRN dosing with VEGF Trap-Eye at weeks 16-52 maintained the significant anatomic and vision improvements established during the 12-week fixed-dosing phase with a low frequency of reinjections. Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of treatment.Proprietary or commercial disclosure may be found after the references.

Fat infiltration and inflammation cause liver injury and fibrosis and may progress to nonalcoholic steatohepatitis (NASH) and end-stage liver disease. Currently, there are no effective treatments for NASH. Zeaxanthin is a carotenoid which has been shown to be preferentially accumulated in the adipose tissue and liver. We hypothesized that treatment with zeaxanthin may decrease oxidative stress in the liver and, possibly, halt the inflammation and fibrosis associated with NASH. Here we tested zeaxanthin effects in preventing progression of liver injury in a model of NASH. Mongolian gerbils, fed a methionine-choline-deficient diet, were treated with different doses of zeaxanthin. We assessed histopathological changes by hematoxylin-eosin and Masson trichrome staining and determined oxidative stress by measuring lipid peroxidation. The obtained results show that zeaxanthin significantly prevented NASH progression by decreasing oxidative stress and liver fibrosis, thus suggesting a potential therapeutic application for this carotenoid in the management of NASH.