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Purpose To evaluate pneumatic vitreolysis (PVL) in eyes with vitreomacular traction (VMT) with and without full-thickness macular hole (FTMH). Design Two multicenter (28 sites) studies: a randomized clinical trial comparing PVL with observation (sham injection) for VMT without FTMH (Protocol AG) and a single-arm study assessing PVL for FTMH (Protocol AH). Participants Participants were adults with central VMT (vitreomacular adhesion was ≤3000 μm). In Protocol AG, visual acuity (VA) was 20/32 to 20/400. In Protocol AH, eyes had a FTMH (≤250 μm at the narrowest point) and VA of 20/25 to 20/400. Methods Pneumatic vitreolysis using perfluoropropane (C3F8) gas. Main Outcome Measures Central VMT release at 24 weeks (Protocol AG) and FTMH closure at 8 weeks (Protocol AH). Results From October 2018 through February 2020, 46 participants were enrolled in Protocol AG, and 35 were enrolled in Protocol AH. Higher than expected rates of retinal detachment and tear resulted in early termination of both protocols. Combining studies, 7 of 59 eyes (12% [95% CI, 6%–23%]; 2 eyes in Protocol AG, 5 eyes in Protocol AH) that received PVL developed rhegmatogenous retinal detachment (n = 6) or retinal tear (n = 1). At 24 weeks in Protocol AG, 18 of 23 eyes in the PVL group (78%) versus 2 of 22 eyes in the sham group (9%) achieved central VMT release without rescue vitrectomy (adjusted risk difference, 66% [95% CI, 44%–88%]; P Conclusions In most eyes with VMT, PVL induced hyaloid release. In eyes with FTMH, PVL resulted in hole closure in approximately one third of eyes. These studies were terminated early because of safety concerns related to retinal detachments and retinal tears.

BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS: Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 ( P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:327–335.]

Purpose To compare the efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) versus ranibizumab every 4 weeks in treatment-naive patients with neovascular age-related macular degeneration (AMD). Design Two randomized, multicenter, double-masked, parallel-group, active-controlled, phase 3 clinical trials (CEDAR, SEQUOIA) with identical protocols were conducted. Data from both trials were pooled for analysis. Participants Patients with active choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) of 24–73 Early Treatment Diabetic Retinopathy Study letters in the study eye were enrolled. Methods Patients (n = 1888) were randomized in a 1:1:1 ratio to study eye treatment with abicipar 2 mg every 8 weeks after 3 initial doses at baseline and weeks 4 and 8 (Q8), abicipar 2 mg every 12 weeks after 3 initial doses at baseline and weeks 4 and 12 (Q12), or ranibizumab 0.5 mg every 4 weeks (Q4). Main Outcome Measures The primary efficacy end point was proportion of patients with stable vision (defined as Results The proportion of patients with stable vision at week 52 was 93.2%, 91.3%, and 95.8% in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively, with both abicipar Q8 and Q12 noninferior to ranibizumab Q4. Week 52 mean change from baseline in BCVA was 7.5, 6.4, and 8.4 letters and in CRT was −144, −145, and −144 μm in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. Incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3%, respectively. The IOI AEs were typically mild or moderate in severity and treated with topical corticosteroids; 62 of 192 patients (32.3%) received oral and/or injectable corticosteroids. Conclusions Abicipar Q8 and Q12 were both noninferior to ranibizumab Q4 in the primary end point of stable vision at week 52. Intraocular inflammation was more frequent with abicipar. Quarterly and Q8 abicipar reduce nAMD disease and treatment burden compared with monthly treatment.

The positive impact of meditation on human wellbeing is well documented, yet its molecular mechanisms are incompletely understood. We applied a comprehensive systems biology approach starting with whole blood gene expression profiling combined with multi-level bioinformatic analyses to characterize the co-expression, transcriptional, and protein-protein interaction networks to identify meditation-specific core network after an advanced 8-day Inner Engineering retreat program. We found the response to oxidative stress, detoxification, and cell cycle regulation pathways were downregulated after meditation. Strikingly, 220 genes directly associated with immune response, including 68 genes related to interferon (IFN) signaling were upregulated, with no significant expression changes in the inflammatory genes. This robust meditation-specific immune response network is significantly dysregulated in multiple sclerosis and severe COVID-19 patients. The work provides a foundation for understanding the effect of meditation and potential implications to voluntarily and non-pharmacologically improve the immune response before immunotherapy for many conditions, including multiple sclerosis and COVID-19 vaccination.

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

Background and objective To evaluate the safety and efficacy of intravitreal sirolimus for persistent, exudative age-related macular degeneration (AMD). Methods This institutional review board approved, registered (NCT02357342), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative Age-related macular degeneration compared intravitreal sirolimus monotherapy (every 2 months) versus monthly anti-vascular endothelial growth factor (VEGF) over six months. Results 20 subjects were randomized to each arm of the trial. Upon completion of the trial 20 patients were analyzed in the control (anti-vascular endothelial growth factor) group and 17 patients were analyzed in the treatment (sirolimus) group. On average, subjects had 33 previous anti-VEGF injections prior to entry. The primary end-point, mean central subfield thickness (CST), increased by 20 µm in the anti-vascular endothelial growth factor group and decreased by 40 µm in the sirolimus group (p = 0.03). Visual acuity outcomes were similar between groups. Serious ocular adverse events in the sirolimus group included one subject each with anterior uveitis, central retinal artery occlusion and subretinal hemorrhage. Conclusion Monotherapy with intravitreal sirolimus for subjects with persistent, exudative age-related macular degeneration appears to have a limited positive anatomic benefit. The presence of adverse events in the experimental group merits further evaluation, potentially as an adjuvant therapy. Trial registration This trial was registered with the clinicaltrials.gov, NCT02357342, and was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.

Purpose: To evaluate the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg in the treatment of patients with diabetic macular edema (DME).Design: Two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols were conducted. Data were pooled for analysis.Participants: Patients (n = 1048) with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of ≥300 μm by optical coherence tomography.Methods: Patients were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for patients treated at month 36) at ≤40 scheduled visits. Patients who met retreatment eligibility criteria could be retreated no more often than every 6 months.Main Outcome Measures: The predefined primary efficacy endpoint for the United States Food and Drug Administration was achievement of ≥15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP).Results: Mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (−111.6 μm) and DEX implant 0.35 mg (−107.9 μm) than sham (−41.9 μm; P < 0.001). Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy.Conclusions: The DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA. The safety profile was acceptable and consistent with previous reports.

To report the 2-year efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) compared with monthly ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD).Two multicenter, randomized, phase 3 clinical trials with identical protocols (CEDAR and SEQUOIA). Analyses used pooled trial data.The trials enrolled 1888 patients (1 eye/patient) with active choroidal neovascularization secondary to age-related macular degeneration and best-corrected visual acuity (BCVA) of 24 to 73 Early Treatment Diabetic Retinopathy Study letters.At enrollment, patients were assigned to study eye treatment with abicipar 2 mg every 8 weeks after initial doses at baseline and weeks 4 and 8 (abicipar Q8, n = 630), abicipar 2 mg every 12 weeks after initial doses at baseline and weeks 4 and 12 (abicipar Q12, n = 628), or ranibizumab 0.5 mg every 4 weeks (ranibizumab Q4, n = 630).Efficacy measures included stable vision (15-letter loss in BCVA from baseline) and change from baseline in BCVA and central retinal thickness (CRT). Safety measures included adverse events (AEs).For patients who completed the study, efficacy of abicipar after initial doses was maintained through week 104. At week 104, the proportion of patients with stable vision was 93.0% (396/426), 89.8% (379/422), and 94.4% (470/498); mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters, and mean change in CRT from baseline was -147 μm, -146 μm, and -142 μm in the abicipar Q8 (14 injections), abicipar Q12 (10 injections), and ranibizumab Q4 (25 injections) groups, respectively. The overall incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3% from baseline through week 52 and 16.2%, 17.6%, and 1.3% from baseline through week 104 in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively.Two-year results show efficacy of abicipar Q8 and Q12 in nAMD. First onset of IOI events with abicipar was much reduced in the second year and comparable with ranibizumab (0.8% and 2.3% vs. 1.0%). The extended duration of effect of abicipar allows for quarterly dosing and reduced treatment burden.

Purpose: To evaluate safety and efficacy of the vascular endothelial growth factor binding protein abicipar pegol (abicipar) versus ranibizumab for neovascular age-related macular degeneration. Methods: Phase 2, multicenter, randomized, double-masked comparison (REACH study, stage 3). Patients (n = 64) received intravitreal injections of abicipar 1 mg or 2 mg at baseline, week 4, and week 8 (3 injections) or ranibizumab 0.5 mg at baseline and monthly (5 injections). Results: In the abicipar 1 mg (n = 25), abicipar 2 mg (n = 23), and ranibizumab (n = 16) arms, respectively, least-squares mean best-corrected visual acuity (BCVA) change from baseline was +6.2, +8.3, and +5.6 letters at week 16 (primary endpoint) and +8.2, +10.0, and +5.3 letters at week 20. Least-squares mean central retinal thickness (CRT) reduction from baseline was 134, 113, and 131 μm at week 16 and 116, 103, and 138 μm at week 20. Intraocular inflammation adverse events (AEs), reported in 5/48 (10.4%) abicipar-treated patients, resolved without sustained vision loss or other sequelae. Conclusions: Abicipar demonstrated durability of effect: BCVA and CRT improvements were similar between abicipar and ranibizumab at weeks 16 and 20 (8 and 12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection). No serious AEs were reported.

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

Safety of the intravitreal plasma kallikrein inhibitor (KVD001) was tested in patients with diabetic macular edema. KVD001 was well tolerated. Systemic absorption was low. Improvement of retinal edema and vision occurred in most study eyes.

Purpose To evaluate the safety and preliminary efficacy of THR-687 in patients with center-involved diabetic macular edema (DME). Design Phase 1, open-label, multicenter, 3 + 3 dose-escalation study with 3-month follow-up. Participants Patients 18 years of age or older with visual impairment resulting from DME. Methods Single intravitreal injection of THR-687 (0.4 mg, 1.0 mg, or 2.5 mg). Main Outcome Measures The primary outcome measure was the incidence of dose-limiting toxicities (DLTs). The secondary outcome measure was the incidence of adverse events (AEs), including the occurrence of laboratory abnormalities. Exploratory outcome measures included changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), assessments of ischemia and leakage on fluorescein angiography, and THR-687 levels in plasma. Results Twelve patients were treated: 3 patients received 0.4 mg of THR-687, 3 patients received 1.0 mg of THR-687, and 6 patients received 2.5 mg of THR-687. Most patients were men (9/12 patients). Their mean age was 57.8 years. No DLTs or serious AEs were reported at any of the dose levels tested. Overall, 9 AEs in the study eye were reported for 5 of 12 patients. Of those, 4 AEs in 3 of 12 patients were deemed treatment related by the investigator, all of which were mild, started on the day of the injection, and had resolved within 28 days without treatment. Overall, mean gains from baseline in BCVA were observed at all study visits with a rapid onset (7.2 Early Treatment Diabetic Retinopathy Study [ETDRS] letters at day 7) and a durability up to the end of the study (8.3 ETDRS letters at month 3). A mean decrease in CST was observed up to month 1. Overall, the mean BCVA gains and CST decreases were highest at the highest THR-687 dose level tested. THR-687 was undetectable in plasma at 7 days after the injection. Conclusions At all dose levels tested, a single intravitreal injection of THR-687 was safe and well tolerated. Preliminary efficacy was observed by a rapid gain in BCVA with 3 months’ durability and a decrease in CST up to 1 month after the injection.

Background. Anxiety and depression are common in the modern world, and there is growing demand for alternative therapies such as meditation. Meditation can decrease perceived stress and increase general well-being, although the physiological mechanism is not well-characterized. Endocannabinoids (eCBs), lipid mediators associated with enhanced mood and reduced anxiety/depression, have not been previously studied as biomarkers of meditation effects. Our aim was to assess biomarkers (eCBs and brain-derived neurotrophic factor [BDNF]) and psychological parameters after a meditation retreat. Methods. This was an observational pilot study of adults before and after the 4-day Isha Yoga Bhava Spandana Program retreat. Participants completed online surveys (before and after retreat, and 1 month later) to assess anxiety, depression, focus, well-being, and happiness through validated psychological scales. Voluntary blood sampling for biomarker studies was done before and within a day after the retreat. The biomarkers anandamide, 2-arachidonoylglycerol (2-AG), 1-arachidonoylglycerol (1-AG), docosatetraenoylethanolamide (DEA), oleoylethanolamide (OLA), and BDNF were evaluated. Primary outcomes were changes in psychological scales, as well as changes in eCBs and BDNF. Results. Depression and anxiety scores decreased while focus, happiness, and positive well-being scores increased immediately after retreat from their baseline values (P<0.001). All improvements were sustained 1 month after BSP. All major eCBs including anandamide, 2-AG, 1-AG, DEA, and BDNF increased after meditation by > 70% (P<0.001). Increases of ≥20% in anandamide, 2-AG, 1-AG, and total AG levels after meditation from the baseline had weak correlations with changes in happiness and well-being. Conclusions. A short meditation experience improved focus, happiness, and positive well-being and reduced depression and anxiety in participants for at least 1 month. Participants had increased blood eCBs and BDNF, suggesting a role for these biomarkers in the underlying mechanism of meditation. Meditation is a simple, organic, and effective way to improve well-being and reduce depression and anxiety.

Purpose:To evaluate the occurrence, management, and clinical significance of increases in intraocular pressure (IOP) in patients with diabetic macular edema treated with dexamethasone intravitreal implant (DEX implant).Methods:Randomized, multicenter, 3-year, Phase III study. Patients (N = 1,048) wi

BACKGROUND AND OBJECTIVE: To evaluate comparability of abicipar pegol (abicipar) effects in patients with treatment-naïve neovascular age-related macular degeneration (nAMD) in Japan and the United States. PATIENTS AND METHODS: Phase 2, multicenter, randomized, double-masked, 20-week studies (BAMBOO, Japan; CYPRESS, United States). Patients (n = 25 each study) received three monthly intravitreal injections of abicipar 1 mg or 2 mg or five monthly intravitreal injections of ranibizumab 0.5 mg. RESULTS: Mean best-corrected visual acuity change from baseline at week 16 (primary endpoint) for abicipar 1 mg, abicipar 2 mg, and ranibizumab was +7.8 letters, +8.9 letters, and +17.4 letters (BAMBOO); +4.4 letters, +10.1 letters, and +15.2 letters (CYPRESS). Mean central retinal thickness change from baseline was −187.3 μm, −196.5 μm, and −230.4 μm (BAMBOO); −106.5 μm, −112.8 μm, and −124.4 μm (CYPRESS). Uveitis or vitritis was reported in three abicipar-treated patients. CONCLUSION: Abicipar demonstrated extended duration of effect and safety that were comparable between Japanese and non-Japanese patients with nAMD. Abicipar effectively treated Japanese patients with polypoidal choroidal vasculopathy. [ Ophthalmic Surg Lasers Imaging Retina. 2019;50:e10–e22.]

Purpose: To evaluate the efficacy and safety of dexamethasone intravitreal implant 0.7 mg (DEX) as adjunctive therapy to ranibizumab in neovascular age-related macular degeneration (nvAMD). Procedures: This was a 6-month, single-masked, multicenter study. Patients were randomized to DEX implant (n = 123) or sham procedure (n = 120) and received 2 protocol-mandated intravitreal ranibizumab injections. The main outcome measure was injection-free interval to first as-needed ranibizumab injection. Results: DEX increased the injection-free interval versus sham (50th percentile, 34 vs. 29 days; 75th percentile, 85 vs. 56 days; p = 0.016). 8.3% of DEX versus 2.5% of sham-treated patients did not require rescue ranibizumab (p = 0.048). Visual acuity and retinal thickness outcomes were similar in DEX and sham-treated patients. Only reports of conjunctival hemorrhage (18.2 vs. 8.5%) and intraocular pressure elevation (13.2 vs. 4.2%) were significantly different in the DEX versus the sham treatment groups. Conclusion: DEX reduced the need for adjunctive ranibizumab treatment and showed acceptable tolerability in nvAMD patients.

Stress-induced disorders such as anxiety represent the leading causes of adult disability worldwide. Previous studies indicate that yoga and other contemplative practices such as pranayama, or controlled yogic breathing techniques, may be effective in the treatment of mood disorders and stress. In this study, 142 individuals (mean age = 43 years; SD = 13.90) participated in a 3-day retreat program during which they learned Shambhavi Mahamudra kriya, which is a yogic practice that includes both deep breathing and meditation techniques. Participants were instructed to practice the kriya each day for 21 minutes. After 6 weeks of daily practice, participants reported subjectively lower levels of perceived stress (Perceived Stress Scale) and higher levels of general well-being (General Well-Being Scale) compared to baseline. These results support the notion that Shambhavi Mahamudra kriya may represent a natural treatment for stress reduction.

Some eyes have persistent diabetic macular edema (DME) following anti-vascular endothelial growth factor (anti-VEGF) therapy for DME. Subsequently adding intravitreous corticosteroids to the treatment regimen might result in better outcomes than continued anti-VEGF therapy alone.To compare continued intravitreous ranibizumab alone with ranibizumab plus intravitreous dexamethasone implant in eyes with persistent DME.Phase 2 multicenter randomized clinical trial conducted at 40 US sites in 129 eyes from 116 adults with diabetes between February 2014 and December 2016. Eyes had persistent DME, with visual acuity of 20/32 to 20/320 after at least 3 anti-VEGF injections before a run-in phase, which included an additional 3 monthly 0.3-mg ranibizumab injections. Data analysis was according to intent to treat.Following the run-in phase, study eyes that had persistent DME and were otherwise eligible were randomly assigned to receive 700 μg of dexamethasone (combination group, 65 eyes) or sham treatment (ranibizumab group, 64 eyes) in addition to continued 0.3-mg ranibizumab in both treatment arms as often as every 4 weeks based on a structured re-treatment protocol.The primary outcome was change in mean visual acuity letter score at 24 weeks as measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS). The principal secondary outcome was change in mean central subfield thickness as measured with the use of optical coherence tomography.Of the 116 randomized patients, median age was 65 years (interquartile range [IQR], 58-71 years); 50.9% were female and 60.3% were white. Mean (SD) improvement in visual acuity from randomization was 2.7 (9.8) letters in the combination group and 3.0 (7.1) letters in the ranibizumab group, with the adjusted treatment group difference (combination minus ranibizumab) of -0.5 letters (95% CI, -3.6 to 2.5; 2-sided P = .73). Mean (SD) change in central subfield thickness in the combination group was -110 (86) μm compared with -62 (97) μm for the ranibizumab group (adjusted difference, -52; 95% CI, -82 to -22; 2-sided P .001). Nineteen eyes (29%) in the combination group experienced increased intraocular pressure or initiated treatment with antihypertensive eyedrops compared with 0 in the ranibizumab group (2-sided P .001).Although its use is more likely to reduce retinal thickness and increase intraocular pressure, the addition of intravitreous dexamethasone to continued ranibizumab therapy does not improve visual acuity at 24 weeks more than continued ranibizumab therapy alone among eyes with persistent DME following anti-VEGF therapy.clinicaltrials.gov Identifier: NCT01945866.

Diabetic macular oedema (DMO) results from alterations of several biochemical pathways in diabetic eyes. Centre-involving DMO is an important cause of visual loss in diabetes. Anti-vascular endothelial growth factor agents are now the mainstay of centre-involving DMO treatment. Oedema that does not achieve optimal response to these agents occurs in a sizeable proportion of eyes and is called refractory or persistent DMO. Management of refractory DMO is challenging. In this paper, the pathophysiology of DMO, and the definitions used in various studies are summarised. Therapeutic options for refractory DMO management including corticosteroids, laser, combination therapies, and surgery are explored. Novel agents on the horizon for DMO control that are being investigated at present are discussed as well. A literature review was performed and a summary of the research studies for each of the agents is provided in order to guide the reader regarding the existing evidence for their application in DMO. Importance of early recognition of disease and prompt treatment to achieve best visual outcome is discussed. Utility of optical coherence tomography to guide disease diagnosis and monitoring is highlighted. An algorithmic approach for DMO management is described. Finally, the impact that personalized medicine and genetics might have on DMO management is assessed.

� PURPOSE: To evaluate the outcome of pars plana vitrectomy, subretinal tissue plasminogen activator (t-PA) infusion and intraocular gas tamponade with and without postsurgical antivascular endothelial growth factor (VEGF) injection for thick submacular hemorrhage due to exudative age-related macular degeneration (AMD). � DESIGN: Retrospective, comparative, interventional case series. � METHODS: SETTING: 2 retina referral centers. The patient population included 101 eyes of 101 patients with neovascular AMD and thick submacular hemorrhage who underwent surgical displacement of the hemorrhage with or without postoperative anti-VEGF injections. Main outcome measures included degree of blood displacement, best and final postoperative visual acuity (VA), and adverse events. Snellen acuity was converted to logMAR for statistical analysis. � RESULTS: All patients were followed for a minimum of 3 months (mean, 15.3 months, range, 3-70 months). In 83 (82%) of 101 eyes, the procedure resulted in complete hemorrhage displacement from the fovea. Mean preoperative VA was 20/2255 (2.05 logMAR). The acuity significantly improved to 20/893 (1.65 logMAR) at month 1 (P < 0.001) at month 1; 20/678 (1.53 logMAR) at month 3 (P < 0.001), and 20/1150 (1.76 logMAR) at month 12 (P [ 0.002). Best postoperative visual acuity improved by at least 1 line in 83 (82%) of 101 eyes, and 19.6% of eyes gained 3 lines or more at month 3. The visual acuity of the group of eyes that received postoperative anti-VEGF injection (n [ 39) showed greater visual acuity improvement 6 months postoperatively compared to the group of eyes that did not receive postoperative anti-VEGF. Postoperative complications included vitreous hemorrhage in 2 eyes, rhegmatogenous retinal detachment in 4 eyes, and recurrent thick subretinal hemorrhage in 6 eyes. � CONCLUSIONS: Vitrectomy with subretinal t-PA injection and gas tamponade was found to be relatively effective for displacement of thick submacular hemorrhage with a significant improvement in visual acuity. There is a loss of acuity over time; the addition of postoperative anti-VEGF therapy may help maintain the visual

Objective To report the 3-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred (for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 mg ranibizumab for diabetic macular edema (DME). Design Multicenter, randomized clinical trial. Participants Three hundred sixty-one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. Methods Ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and random assignment to prompt or deferred (≥24 weeks) focal/grid laser treatment. Main Outcome Measures Best-corrected visual acuity and safety at the 156-week (3-year) visit. Results The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4–5.4 letters; P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a ≥10-letter gain/loss was 42% and 56% ( P = 0.02), whereas the respective percentage of eyes with a ≥10-letter gain/loss was 10% and 5% ( P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively ( P = 0.007), including 1 and 2 injections, respectively, from the 2-year up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness of 250 μm or more on time-domain optical coherence tomography were 36% in both groups ( P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events seemed to be similar in the 2 groups. Conclusions These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through 5 years continues. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Objective To describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti–vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network ( DRCR.net ) randomized clinical trial. Design Discussion of treatment protocol for DME. Participants Subjects with vision loss resulting from DME involving the center of the macula. Methods The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser treatment in eyes with vision loss resulting from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. To share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale. Main Outcome Measures Clinical guidelines based on a DRCR.net protocol. Results The treatment protocol required real-time feedback from a web-based data entry system for intravitreal injections, focal/grid laser treatment, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed. Conclusions Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Retinal hemangioblastomas are the most common manifestation of Von Hippel-Lindau (VHL) disease [1-3]. While peripheral retinal hemangioblastomas may be treated by thermal laser treatment or cryotherapy, optic nerve and macular lesions are more difficult to treat [4, 5]. Based on the theoretical benefit of administering anti-VEGF treatment, intra-vitreally administered bevacizumab (Avastin, a general pan-VEGF inhibitor) is attractive [6, 7]. Several short-term case series using ranibizumab (Lucentis, mAb fragment of bevacizumab with stronger affinity for VEGF-A) have shown it has promising but minimal success on most VHL-related hemangioblastomas [8, 9]. A comprehensive study by Wong et al. examined 5 patients over a period up to 61 weeks (47 ± 14 weeks) while Michels et al. examined one patient over a period of 4 months. Due to the short-term nature of these studies, we attempted long-term bevacizumab treatment over 60 months in a monocular subject with progressive visual loss due to a VHL associated macular and optic nerve hemangioblastoma. Over the treatment regimen of 15 injections, visual acuity improved 25 letters, OCT thickness improved from 646 um to 424 um, and structural lesions stabilized while exudates and edema resolved.

To determine whether a dexamethasone intravitreal implant 0.7 mg (dexamethasone delivery system [DDS], Ozurdex) combined with bevacizumab 1.25 mg (Avastin) provides greater benefit than bevacizumab monotherapy in eyes with diabetic macular edema with incomplete response to multiple antivascular endothelial growth factor injections.Eyes with diabetic macular edema were randomly assigned to receive combination therapy (bevacizumab plus DDS) or bevacizumab monotherapy. Combination therapy eyes received intravitreal bevacizumab at baseline, DDS at Month 1, and subsequent DDS (at Months 5 and 9), whereas monotherapy eyes received bevacizumab (monthly) if indicated. Eyes were eligible for retreatment if the central subfield thickness measured250 μm, and Early Treatment of Diabetic Retinopathy Study visual acuity was80 letters (20/25).Forty eyes of 30 patients were enrolled. The mean visual acuity changes from baseline to 12 months were similar in the 2 groups (combined: +5.4 letters; bevacizumab: +4.9 letters; difference = 0.2 letters, 95% confidence interval = -5.9 to 6.3; P = 0.75). The mean reduction in central subfield thickness was greater in the combination group (-45 μm vs. -30 μm, difference = 69 μm, 95% confidence interval = 9-129; P = 0.03) and more patients in the combination group had central subfield thickness250 μm. The combined treatment group received three fewer supplemental injections of bevacizumab, but this was counterbalanced by the need for an average of 2.1 DDS injections.The dexamethasone implant combined with bevacizumab significantly improves visual acuity and significantly improves macular morphology in eyes with refractory diabetic macular edema, although visual acuity changes are not superior to continued bevacizumab monotherapy.

To evaluate the short-term electrophysiologic effects of intravitreal bevacizumab in the treatment of exudative age-related macular degeneration (AMD).Nine subjects with AMD who received treatment with intravitreal bevacizumab for exudative AMD underwent pretreatment testing with multifocal electroretinography (mf-ERG) or Ganzfeld electroretinography (G-ERG). All five G-ERG subjects underwent repeated testing at 1 week after intravitreal bevacizumab. All four mf-ERG subjects and four of the five G-ERG subjects underwent repeated testing with the same pretreatment protocol at 1 month after treatment. One G-ERG subject also received a second intravitreal injection of bevacizumab at 6 weeks after initial treatment and underwent repeated testing at 1 month after the second dose (3 months after initial treatment).All four subjects undergoing mf-ERG had improvement of the macular response at 1 month of after treatment. The average improvement in response density of the central 15 degrees of macular response was 35% (range, 11-65%). Subjects undergoing G-ERG testing had no significant changes in electrophysiologic response, although some variation in amplitude and implicit time was noted at different testing times. Optical coherence tomography central subfield thickness decreased from 298 microm at baseline to 274 microm at 1 month after treatment. Visual acuity improved in a majority of subjects.In this study, the intravitreal use of bevacizumab resulted in improvement of mf-ERG macular function responses and relatively stable G-ERG responses. The macular electrophysiologic response suggests that macular function improves with treatment. G-ERG suggests that there is no significant measurable photoreceptor toxicity with the use of intravitreal bevacizumab over the short term.

BACKGROUND AND OBJECTIVE: To report acute postoperative, presumed sterile endophthalmitis following intravitreal injection of triamcinolone acetonide (IVTA).PATIENTS AND METHODS: Retrospective, interventional, multicenter study of patients with acute sterile endophthalmitis following IVTA injection.RESULTS:A total of 922 IVTA injections were performed. Eight eyes of 8 patients with presumed sterile endophthalmitis were identified. The incidence of endophthalmitis was 0.87% (95% confidence interval, 0.38% to 1.70%). Median time to presentation was 1.5 days (range, 1 to 7 days). Median presenting visual acuity was 20/563 (range, 20/80 to light perception). Initial treatment included vitreous tap and injection of antibiotics (n = 4), pars plana vitrectomy and injection of intravitreal antibiotics (n = 2), or systemic treatment alone with oral levofloxacin (n = 2). Six of 6 intraocular cultures were sterile. Median follow-up was 5.9 months (range, 4 to 9 months) with a median visual acuity at last follow-up of 20/75 (range, 20/40 to counting fingers).CONCLUSIONS:Acute presumed sterile endophthalmitis following IVTA injection presents early in the postoperative period. Visual outcomes are generally good.[Ophthalmic Surg Lasers Imaging 2005;36:24–29.]

PURPOSE To study and compare the findings on multifocal electroretinography (MERG) between multifocal choroiditis (MFC) and the multiple evanescent white dot syndrome (MEWDS). SUBJECT AND METHODS Patients were recruited prospectively from the Department of Ophthalmology & Visual Sciences at the University of Iowa Hospitals & Clinics. They were evaluated using Goldmann visual fields (GVF) and MERG. Patients were diagnosed as having either MFC or MEWDS based on their clinical findings before MERG testing. RESULTS Nineteen patients (23 eyes) were included in the study. Eleven patients were diagnosed with MFC and eight patients with MEWDS. Fourteen eyes with MFC and seven eyes with MEWDS were tested with MERG during the acute phase of their respective conditions. Fourteen patients (8 MFC and 6 MEWDS) were followed serially with MERG. Patients with MEWDS demonstrated focal depression corresponding to GVF defects with subsequent near total recovery of the MERG to baseline. Patients with MFC typically demonstrated diffuse loss of function over the entire test field. Focal scotomata, in addition to the diffuse depression, could be identified in 7 of 14 patients. Patients with MFC demonstrated only partial or no recovery of MERG following acute episodes, which was significantly different from the course followed by patients with MEWDS (P < 0.001, Fisher's exact test). CONCLUSION Multifocal electroretinography differentiates MFC from MEWDS. Patients with MFC have permanent damage to the retina with diffuse depression of MERG. Patients with MEWDS, however, typically demonstrate greater focal loss initially on MERG followed by nearly full recovery of first order retinal function.

Purpose:To investigate patients with visual field defects following macular hole surgery to determine the cause of such defects, specifically with reference to ischemic damage versus mechanical trauma.Methods:Five patients with known visual field defects following macular hole surgery were studied w

* PURPOSE: To report our experience with perfluoro-N-octane (PFO) in the surgical management of complicated retinal detachments due to proliferative diabetic retinopathy. * METHODS: Retrospective review of 18 consecutive eyes of 18 patients with tractional or combined tractional and rhegmatogenous retinal detachments due to severe proliferative diabetic retinopathy managed by pars plana vitrectomy and the intraoperative use of PFO. Preoperative characteristics, intraoperative findings and procedures and postoperative results were recorded. * RESULTS: The mean preoperative acuity was 2/200 (range, 20/25 to light perception). The mean final visual acuity was 4/200 (range, 20/20 to no light perception). With a mean follow-up of 6 months, there was an 89% anatomic reattachment rate at the last visit and visual acuity was stable or improved in 72% of eyes. * CONCLUSIONS: In our experience, PFO is a helpful surgical adjunct in the anatomic reattachment of tractional or combined tractional and rhegmatogenous diabetic retinal detachments. Visual acuity was stabilized or improved in the majority of eyes. [Ophthalmic Surg Lasers 1999;30:715-720.]

Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Early stage DR involves inflammation, vascular leakage, apoptosis of vascular cells and neurodegeneration. In this study, we hypothesized that cells derived from the stromal fraction of adipose tissue (ASC) could therapeutically rescue early stage DR features. Streptozotocin (STZ) induced diabetic athymic nude rats received single intravitreal injection of human ASC into one eye and saline into the other eye. Two months post onset of diabetes, administration of ASC significantly improved "b" wave amplitude (as measured by electroretinogram) within 1-3 weeks of injection compared to saline treated diabetic eyes. Subsequently, retinal histopathological evaluation revealed a significant decrease in vascular leakage and apoptotic cells around the retinal vessels in the diabetic eyes that received ASC compared to the eyes that received saline injection. In addition, molecular analyses have shown down-regulation in inflammatory gene expression in diabetic retina that received ASC compared to eyes that received saline. Interestingly, ASC were found to be localized near retinal vessels at higher densities than seen in age matched non-diabetic retina that received ASC. In vitro, ASC displayed sustained proliferation and decreased apoptosis under hyperglycemic stress. In addition, ASC in co-culture with retinal endothelial cells enhance endothelial survival and collaborate to form vascular networks. Taken together, our findings suggest that ASC are able to rescue the neural retina from hyperglycemia-induced degeneration, resulting in importantly improved visual function. Our pre-clinical studies support the translational development of adipose stem cell-based therapy for DR to address both retinal capillary and neurodegeneration.

Diabetic macular edema results from progressive retinopathy related to chronic hyperglycemic and inflammatory vascular damage. Loss of vision secondary to diabetic macular edema is the most common cause of vision loss in patients with diabetes. Blood glucose control remains the main means of preventing progression of retinopathy and macular edema. Recent advancements allowing more efficient mechanisms for screening patients and emerging treatments for macular edema have led to improved visual outcomes in this group of patients.

PURPOSE The purpose of this study was to assess the efficacy of intravitreal bevacizumab for choroidal neovascularization resulting from presumed ocular histoplasmosis syndrome. METHODS This is a chart review of retrospective consecutive case series in which intravitreal bevacizumab (1.25 mg) was injected into 24 eyes with choroidal neovascularization resulting from presumed ocular histoplasmosis syndrome. Visual acuity was measured in all patients. Optical coherence tomography and/or fluorescein angiography was performed before and after treatment. The minimum follow-up time was 3 months. Retreatment criteria included failure to improve visual acuity and/or persistent leakage as determined by optical coherence tomography or fluorescein angiography. RESULTS Patients' mean age was 43.08 years (standard deviation, 13.58 years) and mean follow-up was 31.8 weeks (standard deviation, 20.79 weeks). The average number of bevacizumab injections was 6.8 injections/year. After 3 months, visual acuity improved from mean logMAR 0.76 +/- 0.48 (Snellen equivalent of 20/114) to mean logMAR 0.45 +/- 0.47 (Snellen equivalent of 20/55) (P < 0.001, paired t test; n = 24). After 12 months, visual acuity improved from mean logMAR 0.86 +/- 0.35 (Snellen equivalent of 20/150) to mean logMAR 0.34 +/- 0.33 (Snellen equivalent of 20/45) (P = 0.006, paired t test; n = 9). Fourteen (58.3%) eyes had final visual acuity of 20/40 or better compared with 5 (20.8%) eyes at baseline (P = 0.003, McNemar test). Ten patients (41.6%) had visual acuity of 20/200 or worse at baseline compared with 5 (20.8%) eyes at the final visit (P = 0.059, McNemar test). CONCLUSION Intravitreal injection of bevacizumab seems to be an effective treatment for choroidal neovascularization resulting from presumed ocular histoplasmosis syndrome.

Purpose To report the clinical features, causative organisms, management, and visual acuity outcomes of eight eyes of eight patients who developed acute postoperative endophthalmitis following intravitreal injection of triamcinolone acetonide (IVTA). Design Retrospective, multicenter, interventional, case series. Methods A retrospective, interventional, case series of all patients with acute postoperative endophthalmitis following IVTA at seven academic clinical centers between March 2001 and July 2002. Results A total of 922 IVTAs were performed. Eight eyes of eight patients with acute postoperative endophthalmitis were identified in the 6 weeks following IVTA for an incidence of 0.87% (95% confidence interval of 0.38% to 1.70%). The median time to presentation was 7.5 days (range, 1–15 days) after IVTA. The most common clinical findings were iritis (n = 8), vitritis (n = 8), hypopyon (n = 8), pain (n = 7), red eye (n = 6), and decreased vision (n = 5). The median presenting visual acuity was 20/1127 (range, 20/60 to light perception). Initial treatment consisted of vitreous tap and injection of antibiotics (n = 6) or pars plana vitrectomy and injection of intravitreal antibiotics (n = 2). Intraocular cultures yielded identification in seven patients. One demonstrated intracellular gram-positive cocci in chains with numerous polymorphonuclear cells on gram stain. The median postinfection vision was 20/400 (range, 20/40 to no light perception). Three patients ended up with no light perception visual acuity, including enucleation (n = 1) and phthisis (n = 1). Conclusions Acute postoperative endophthalmitis following IVTA occurs rapidly and can result in severe loss of vision.

Raj K Maturi,1,2 Vincent Chen,3 Dan Raghinaru,3 Laurie Bleau,1 Michael W Stewart4 1Midwest Eye Institute, Indianapolis, IN, USA; 2Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA; 3Jaeb Center for Health Research, Tampa, FL, USA; 4Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA Aims: To determine if intravitreal bevacizumab combined with the dexamethasone intravitreal implant0.7mg improves visual acuity and macular thickness more than bevacizumab monotherapy in eyes with macular edema due to branch and central retinal vein occlusions. Methods: Thirty eyes were randomly assigned to receive either combination therapy or bevacizumab monotherapy. All patients received intravitreal bevacizumab at baseline, followed by dexamethasone implants or sham injections1week later. Monthly bevacizumab injections were given if the central subfield thickness (CST) was >250µm, and the combined group received a second implant at month4or5if CST was >250µm. Results: At6months, several secondary endpoints were met. Patients receiving combined therapy required fewer bevacizumab reinjections compared to those receiving monotherapy (two versus three; P=0.02), experienced greater mean reductions in CST from randomization (–56µm versus +45µm; P=0.01), and were more likely to have resolved all edema (CST

Vascular endothelial growth factor plays a role in proliferative diabetic retinopathy (PDR). Intravitreal injection of saline has been shown potentially to lead to improved visual acuity compared with observation alone in eyes with vitreous hemorrhage. Therefore, it is important to determine if intravitreal anti-vascular endothelial growth factor can reduce vitrectomy rates (and risks associated with vitrectomy) compared with saline for vitreous hemorrhage from PDR that precludes placement or confirmation of complete panretinal photocoagulation.To evaluate intravitreal ranibizumab compared with intravitreal saline injections on vitrectomy rates for vitreous hemorrhage from PDR.Phase 3, double-masked, randomized, multicenter clinical trial. Data reported were collected from June 2010 to March 2012 and include 16 weeks of follow-up.Community-based and academic-based ophthalmology practices specializing in retinal diseases.Two hundred sixty-one eyes of 261 study participants, who were at least 18 years of age with type 1 or type 2 diabetes mellitus. Study eyes had vitreous hemorrhage from PDR precluding panretinal photocoagulation completion.Eyes were randomly assigned to 0.5-mg intravitreal ranibizumab (n = 125) or intravitreal saline (n = 136) at baseline and 4 and 8 weeks.Cumulative probability of vitrectomy within 16 weeks.Cumulative probability of vitrectomy by 16 weeks was 12% with ranibizumab vs 17% with saline (difference, 4%; 95% CI, -4% to 13%) and of complete panretinal photocoagulation without vitrectomy by 16 weeks was 44% and 31%, respectively (P = .05). The mean (SD) visual acuity improvement from baseline to 12 weeks was 22 (23) letters and 16 (31) letters, respectively (P = .04). Recurrent vitreous hemorrhage occurred within 16 weeks in 6% and 17%, respectively (P = .01). One eye developed endophthalmitis after saline injection.Overall, the 16-week vitrectomy rates were lower than expected in both groups. This study suggests little likelihood of a clinically important difference between ranibizumab and saline on the rate of vitrectomy by 16 weeks in eyes with vitreous hemorrhage from PDR. Short-term secondary outcomes including visual acuity improvement, increased panretinal photocoagulation completion rates, and reduced recurrent vitreous hemorrhage rates suggest biologic activity of ranibizumab. Long-term benefits remain unknown. Whether vitrectomy rates after saline or ranibizumab injection are different than observation alone cannot be determined from this study.The study is listed on www.clinicaltrials.gov, under identifier NCT00996437 (website registration date October 14, 2009).

Objective To assess changes in electroretinography (ERG) and other retinal function parameters during 6 months of daily use of tadalafil, sildenafil citrate, or placebo. Methods Subjects were randomized to use of a placebo (n = 82), 5 mg of tadalafil (n = 85), or 50 mg of sildenafil (n = 77) daily for 6 months. Electroretinographs were recorded using the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol and standardized ERG equipment at all 15 study sites. Other tests of ocular anatomy and visual function were performed at each assessment. Main Outcome Measures The primary outcome was the average mean change for both eyes from baseline to endpoint in ERG b-wave amplitude using dark-adapted combined standard response to a bright ISCEV standard flash. Secondary endpoints were other ERG parameter changes, visual acuity, number of errors in color discrimination testing, mean deviation in automated visual field testing, and intraocular pressure (IOP). Results No significant differences were found between treatment/placebo groups for the primary outcome, most other ERG variables, visual function, IOP, or anatomic assessments. The medications were well tolerated. Conclusions No abnormalities in ERG or visual function and no treatment-related findings suggestive of drug toxicity are associated with daily administration of tadalafil or sildenafil for 6 months. Application to Clinical Practice Assessed visual safety of tadalafil/sildenafil administered daily over a prolonged period. Trial Registration clinicaltrials.gov Identifier:NCT00333281

Objective To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME). Design Randomized phase II clinical trial. Participants One hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320. Interventions Random assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22). Main outcome measures Central subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks. Results At baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3). Conclusion These results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose.

Objectives To observe the long-term effects of hydroxychloroquine sulfate on retinalelectrical activity by multifocal electroretinography (mfERG) and to evaluatethe regional variation of retinal dysfunction in subjects with hydroxychloroquineretinopathy. Methods Multifocal ERG with 103-hexagon stimulation was performed on 19 patients(36 eyes) treated with hydroxychloroquine for systemic lupus erythematosus,rheumatoid arthritis, or localized atypical scleroderma. Visual acuity testing,Amsler grid testing, and Ishihara color vision testing were also performed.In 2 of the patients, hydroxychloroquine was discontinued due to concernsabout toxicity. Both of these patients had additional mfERG performed afterdiscontinuation of medication. Results Twelve patients (19 eyes) had a normal response density in one or botheyes, including 6 patients (12 eyes) with a low lifetime dose (≤438 g)of hydroxychloroquine who had normal response densities in both eyes. Elevenpatients (17 eyes) had abnormal response densities in one or both eyes, and2 of these patients (4 eyes) had significant attenuation of response densitiesin almost the whole tested field; 4 patients had a normal mfERG result forone eye but had a slight decrease of response densities for the other eye.There were 4 patterns of abnormal mfERG amplitude change observed: (1) paracentralloss, (2) foveal loss, (3) peripheral loss, and (4) generalized loss. Implicittimes were abnormal for pericentral responses in 3 patients. The results ofcolor vision and Amsler grid testing were normal, except for one patient witha generalized loss pattern. In 2 subjects in whom hydroxychloroquine toxicitywas suspected, response densities improved after termination of hydroxychloroquine. Conclusions Long-term hydroxychloroquine use may be associated with mfERG abnormalities.The mfERG appears to detect retinal physiological change earlier than visualacuity testing, color vision testing, or Amsler grid testing can. The greatestvalue of the mfERG is in differentiating a retinal cause and, hence, providingimportant evidence for hydroxychloroquine toxicity, for whatever visual fieldloss is apparent on perimetry.

We report a rare case of orbital metastasis from hepatocellular carcinoma and review previously documented cases of this condition. The clinical, histopathological, and immunohistochemical characteristics of hepatocellular carcinoma metastatic to the orbit are described. Results from histopathological examination and histochemical findings of the orbital mass established the diagnosis. A review of 10 cases of metastatic hepatocellular carcinoma to the eye and orbit disclosed painful proptosis as the most common clinical sign of hepatocellular carcinoma metastatic to the orbit. In 5 (56 %) of the 9 cases that had orbital metastasis (including the present case), the diagnosis was made after the patient first was examined with symptoms from the orbital mass. Metastatic hepatocellular carcinoma should be considered as a rare cause of painful proptosis. While patients usually are seen with signs and symptoms of widespread metastatic carcinoma, patients with hepatocellular carcinoma with orbital involvement may be first examined by the ophthalmologist because of the clinical manifestations of the disease, proptosis and pain. Other orbital lesions associated with painful proptosis are discussed briefly.