Nepafenac 0.3% after Cataract Surgery in Patients with Diabetic Retinopathy: Results of 2 Randomized Phase 3 Studies.

PURPOSE: To demonstrate the efficacy and safety of once-daily nepafenac 0.3% ophthalmic suspension versus vehicle, based on clinical outcomes, after cataract surgery in patients with diabetes. DESIGN: Two prospective, randomized, multicenter, double-masked, vehicle-controlled phase 3 studies. PARTICIPANTS: Total, 615 patients in study 1 and 605 patients in study 2. METHODS: Patients were randomized (1:1) to topical nepafenac 0.3% or vehicle once-daily starting the day before surgery and continuing for 90 days thereafter. MAIN OUTCOME MEASURES: Key efficacy variables were: patients (%) in whom macular edema (ME) developed (≥30% increase from preoperative baseline central subfield macular thickness) within 90 days after cataract surgery and the patients (%) with a best-corrected visual acuity (BCVA) improvement of ≥15 letters from preoperative baseline through day 14 maintained through day 90. Secondary end points included: patients (%) with a BCVA improvement of ≥15 letters from preoperative baseline through days 90 and 60 and safety over 3 months. RESULTS: A significantly lower percentage of patients demonstrated ME within 90 days after surgery with nepafenac 0.3% versus vehicle (study 1: 2.3% vs. 17.3%; P < 0.001; study 2: 5.9% vs. 14.3%; P = 0.001; pooled: 4.1% vs. 15.9%; P < 0.001). The percentage of patients achieving a ≥15-letter improvement from baseline through day 14 maintained through day 90 with nepafenac 0.3% versus vehicle was 61.7% versus 43.0% (P < 0.001) in study 1, 48.8% versus 50.5% (P = 0.671) in study 2, and 55.4% versus 46.7% (P = 0.003) in the pooled analysis. A greater percentage of patients treated with nepafenac 0.3% versus vehicle in study 1 and similar percentage in study 2 had a BCVA improvement of ≥15 letters from preoperative baseline through day 90 (77.2% vs. 67.7% [P = 0.009] and 65.4% vs. 65.9% [P = 0.888]) and through day 60 (76.2% vs. 64.7% [P = 0.002] and 68.9% vs. 62.1% [P = 0.092]). No unanticipated adverse events were observed. CONCLUSIONS: These studies demonstrated the clinical benefits of nepafenac 0.3% over vehicle in reducing the risk of postoperative ME, with the integrated analysis showing improved BCVA after cataract surgery in patients with diabetic retinopathy, with no unanticipated safety events.

[TREATMENT OPTIONS FOR DIABETIC MACULAR EDEMA].

INTRODUCTION: Diabetic retinopathy (DR) is the leading cause of vision loss in people under 65 years of age. Diabetic macular edema (DME) is the most common cause of moderate visual impairment in individuals with DR. Until recently, focal or grid laser photocoagulation has been the standard of care for DME. Laser photocoagulation has been shown to stabilize vision and prevent moderate vision loss. Recent studies on the effect of anti-vascular endothelial growth factor (VEGF) substances in DME, showed resolution of the edema and visual acuity gain. Thus, anti-VEGF therapy has become the first line of treatment for DME. Intravitreal steroids, also play a role in the management of DME, particularly in refractory cases, due to their antiinflammatory effect. This review focuses on the emerging treatment options in the management of DME.

[PHACOEMULSIFICATION IN EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION (AMD)].

INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. The debate continues over the safety of cataract surgery in the setting of neovascular (wet) AMD. This retrospective review aims to describe our experience in treating patients with wet AMD, who underwent cataract surgery by phacoemulsification. METHODS: We prepared a retrospective chart review of patients treated in our clinic between the years 2006 - 2013. RESULTS: Forty-two eyes of 38 patients were included. Visual acuity (VA) improved significantly 1 month after cataract removal, without a significant change in retinal thickness. Twenty-six patients (62%) needed anti-VEGF injections during follow-up after surgery within an average period of 6 months. In eyes that were dry preoperatively, the re-injection rate was lower than those that were still wet (56 % vs. 80%) and the time from surgery to the first injection was longer in dry eyes (7 months and 3 months, respectively). Eyes that were injected with anti-VEGF up to one week before surgery had greater improvement in VA immediately after surgery but the proportion of those receiving injections (78%) was greater and the time to first injection post-surgery was earlier (3 months) compared to eyes that received the last injection 6 months or more prior to surgery ( 53 % and - 7 months). CONCLUSIONS: Cataract removal improves vision in wet AMD patients. It is of great importance to treat these patients and try to reach dry retina prior to surgery and a close followup is needed after surgery. In eyes that were more stable within 6 months before surgery and their retina was dry, the re-injection rate post surgery was lower and the time to first injection was longer.

TAK1 is involved in the autophagy process in retinal pigment epithelial cells.

Autophagy is an evolutionarily conserved mechanism for degrading long-lived or malfunctioning proteins and organelles, such as those resulting from oxidative stress. Several publications have demonstrated the importance of the autophagy process in the pathophysiology of dry age-related macular degeneration (AMD). Still, the mechanism underlying this process and its involvement in dry AMD are not fully characterized. Investigating the autophagy process in retinal pigment epithelial (RPE) cells, we identified transforming growth factor ß activated kinase 1 (TAK1) as a key player in the process. We found increased TAK1 phosphorylation in ARPE-19 and D407 cells treated with different inducers of autophagy, such as oxidative stress and rapamycin. Moreover, utilizing TAK1 specific inhibitor prior to oxidative stress or rapamycin treatment, we found significant reduction in LC3A/B-II expression. These results point at the involvement of TAK1 in the regulation of autophagy in RPE cells. This study suggests that aberrant activity of this kinase impairs autophagy and subsequently leads to alterations in the vitality of RPE cells. Proper activity of TAK1 may be essential for efficient autophagy, and crucial for the ability of RPE cells to respond to stress and dispose of damaged organelles, thus preventing or delaying retinal pathologies.

INTRAOCULAR PRESSURE IN PATIENTS WITH DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE INTRAVITREAL IMPLANT IN THE 3-YEAR MEAD STUDY.

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) with diabetic macular edema were randomized to DEX implant 0.7-mg, DEX implant 0.35-mg, or sham procedure with retreatment allowed at ≥6-month intervals (seven injections maximum). RESULTS: In the DEX implant 0.7-mg, DEX implant 0.35-mg, and sham groups, respectively, ≥10-mmHg IOP increases from baseline occurred in 27.7%, 24.8%, and 3.7% of patients, and their frequency did not increase with repeat injections. IOP-lowering medication was used by 41.5%, 37.6%, and 9.1% of patients. Only one patient (0.3%) in each DEX implant group had filtering surgery to manage a steroid-induced IOP increase. Among DEX implant 0.7-mg-treated patients with and without a ≥10-mmHg IOP increase, 21.9% (21 of 96) and 22.4% (57 of 255), respectively, achieved ≥15-letter best-corrected visual acuity gain at the end of the study, and mean average change in central retinal thickness from baseline was -127 µm and -106 µm, respectively. CONCLUSION: DEX implant demonstrated clear benefit of treatment despite increases in IOP. Sequential implants had no cumulative effect on IOP.

Dexamethasone Intravitreal Implant as Adjunctive Therapy to Ranibizumab in Neovascular Age-Related Macular Degeneration: A Multicenter Randomized Controlled Trial.

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.

Toward earlier detection of choroidal neovascularization secondary to age-related macular degeneration: multicenter evaluation of a preferential hyperacuity perimeter designed as a home device.

PURPOSE: The primary purpose of this study was to evaluate the ability of a home device preferential hyperacuity perimeter to discriminate between patients with choroidal neovascularization (CNV) and intermediate age-related macular degeneration (AMD), and the secondary purpose was to investigate the dependence of sensitivity on lesion characteristics. METHODS: All participants were tested with the home device in an unsupervised mode. The first part of this work was retrospective using tests performed by patients with intermediate AMD and newly diagnosed CNV. In the second part, the classifier was prospectively challenged with tests performed by patients with intermediate AMD and newly diagnosed CNV. The dependence of sensitivity on lesion characteristics was estimated with tests performed by patients with CNV of both parts. RESULTS: In 66 eyes with CNV and 65 eyes with intermediate AMD, both sensitivity and specificity were 0.85. In the retrospective part (34 CNV and 43 intermediate AMD), sensitivity and specificity were 0.85 +/- 0.12 (95% confidence interval) and 0.84 +/- 0.11 (95% confidence interval), respectively. In the prospective part (32 CNV and 22 intermediate AMD), sensitivity and specificity were 0.84 +/- 0.13 (95% confidence interval) and 0.86 +/- 0.14 (95% confidence interval), respectively. Chi-square analysis showed no dependence of sensitivity on type (P = 0.44), location (P = 0.243), or size (P = 0.73) of the CNV lesions. CONCLUSION: A home device preferential hyperacuity perimeter has good sensitivity and specificity in discriminating between patients with newly diagnosed CNV and intermediate AMD. Sensitivity is not dependent on lesion characteristics.

Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis.

The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-gamma (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-alpha production, and overcame blockage of IGF-I production caused by IFN-gamma. In rodents with acute or chronic EAE, injection of IL-4-activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool.

Early OCT changes of neuroretinal foveal thickness after first versus repeated PDT in AMD.

PURPOSE: To compare early optical coherence tomography (OCT) changes in neuroretinal foveal thickness (NFT) after first versus repeated photodynamic treatment (PDT) in eyes with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). METHODS: This is a prospective comparative case series study. Consecutive AMD patients, treated with PDT due to subfoveal CNV, were enrolled. The eyes were divided into two groups: group A included eyes that had received the first initial treatment, and group B included eyes that had received repeated treatment. All eyes underwent serial examinations with OCT: prior to PDT, 1 h, and 3 months after the PDT. The primary outcome measure was early OCT change in NFT after PDT. RESULTS: Thirty-three eyes of 33 patients were included in this study; 16 in group A and 17 in group B. Optical coherence tomography showed a significant increase in NFT 1 h after PDT, as compared to pre-treatment status, in group A eyes (P = 0.008) but not in group B eyes (P = 0.731). Subretinal fluid was increased in both groups (93.8% and 88.2%, respectively), whereas intraretinal fluid was remarkably more increased in group A eyes (88%) than in group B eyes (59%). CONCLUSION: Early change in NFT, demonstrated on OCT, indicates that PDT causes different retinal response in primary versus repeated treatment of PDT for CNV due to AMD.

Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel (DERBI study).

PURPOSE:: To evaluate the outcome of second-line intravitreal ranibizumab treatment in eyes with diabetic macular edema having persistent edema following initial therapy with intravitreal bevacizumab. METHODS:: Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel was a retrospective, multi-center study. Consecutive eyes with persistent diabetic macular edema following at least three previous intravitreal bevacizumab injections prior to intravitreal ranibizumab, at least three-monthly intravitreal ranibizumab injections and at least 12 months of follow-up were included. Data collected included demographics, ocular findings, diabetes control, details of intravitreal bevacizumab and ranibizumab injections, and visual and anatomical measurements before and after intravitreal ranibizumab treatment. RESULTS:: In total, 202 eyes of 162 patients treated at 11 medical centers across Israel were included. Patients received a mean (±standard deviation) of 8.8 ± 4.9 intravitreal bevacizumab injections prior to the switch to intravitreal ranibizumab. A mean of 7.0 ± 2.7 intravitreal ranibizumab injections were given during the 12 months following the switch to intravitreal ranibizumab. The median central subfield retinal thickness (±interquartile range) by spectral-domain optical coherence tomography decreased from 436 ± 162 µm at baseline to 319 ± 113 µm at month 12 (p < 0.001). Median logMAR visual acuity (±interquartile range) improved from 0.40 ± 0.48 at baseline to 0.38 ± 0.40 at month 12 (p = 0.001). Linear regression suggested that higher number of intravitreal ranibizumab injections and higher pre-switch central subfield retinal thickness were associated with favorable visual outcome. Higher number of intravitreal bevacizumab injections and the presence of intraretinal fluid before the switch lessened the odds of favorable outcome. CONCLUSION:: Switching from bevacizumab to ranibizumab in persistent diabetic macular edema was associated with anatomical improvement in the majority of eyes and ⩾2 lines of vision improvement in 22% of eyes.

Association of complement factor H Y402H polymorphism with phenotype of neovascular age related macular degeneration in Israel.

PURPOSE: The Tyr402His variant of complement factor H (CFH) is associated with age-related macular degeneration (AMD) in several populations. Our aim was to evaluate if this single nucleotide polymorphism (SNP) is associated with AMD in the Israeli population and see if it underlies heterogeneity in clinical manifestation and responses to photodynamic therapy (PDT), which characterize neovascular AMD (NVAMD). METHODS: Genotyping for the Tyr402His variant was performed in 240 NVAMD patients (78.1+/-7 age range) and 118 controls (70.8+/-8.2 age range). Genotyping was correlated with clinical characteristics and treatment parameters in sequential 131 NVAMD patients who underwent PDT. RESULTS: TheTyr402His coding allele was associated with NVAMD in the Israeli population: odds ratio (OR)=1.9; 95% confidence interval (CI)=1.3-2.6; p=0.0002. Homozygosity for this variant was associated with an OR of 3.4 (95% CI: 1.7-6.8) for having AMD. There was no association among this SNP and age of onset of NVAMD, gender, neovascular lesion size, initial or final visual acuity, and number of PDT sessions required. CONCLUSIONS: In accordance with findings from the majority of previous study populations, the Tyr402His variant of CFH is associated with NVAMD in Israel. However, heterogeneity in clinical manifestations of NVAMD and in its response to PDT is not underlined by this CFH variant and may be accounted for by other genetic and environmental factors.

Sequence variants in HTRA1 and LOC387715/ARMS2 and phenotype and response to photodynamic therapy in neovascular age-related macular degeneration in populations from Israel.

PURPOSE: Single nucleotide polymorphisms (SNPs) in the tightly linked LOC387715/ARMS2 and HTRA1 genes have been associated with age-related macular degeneration (AMD). We tested whether these SNPs are associated with AMD in Israeli populations, if they underlie variable phenotype and response to therapy in neovascular AMD (NVAMD), and if HTRA1 expression in vivo is associated with its promoter variant. METHODS: Genotyping for the rs10490924 SNP in LOC387715/ARMS2 and the rs11200638 SNP in HTRA1 was performed on 255 NVAMD patients and 119 unaffected controls from Ashkenazi and Sephardic Jewish, and from Arab origins which are the main ethnic groups composing the Israeli population. Genotyping was correlated with phenotype and response to therapy among 143 patients who underwent photodynamic therapy (PDT). HTRA1 mRNA levels in white blood cells (WBCs), measured by quantitative PCR, were correlated with genotype in 27 participants. RESULTS: Both SNPs were in almost complete linkage disequilibrium (D'=0.96-1). Homozygotes for the T allele of rs10490924 had an odds ratio (OR) of 8.6, with a 95% confidence interval (CI) of 3.5-20.8, and homozygotes for the A allele of rs11200638 had an OR of 10.7, with a 95% CI of 3.2-35.7, for having AMD (p<0.00001). There was no association among these SNPs and phenotype or response to PDT. HTRA1 mRNA levels in WBCs were not associated with rs11200638 genotypes. CONCLUSIONS: The rs10490924 SNP in LOC387715/ARMS2 and the rs11200638 SNP in HTRA1 are strongly associated with NVAMD in this Israeli population. These variants do not have a major contribution to the variable phenotype and response to PDT which characterize NVAMD.

Behavioral disorders in children with idiopathic intracranial hypertension.

The purpose of this research was to evaluate the association between idiopathic intracranial hypertension and behavior, attention, and learning abilities in children. Parents of school-age children with idiopathic intracranial hypertension were asked to fill out a questionnaire and to rank the child's behavioral patterns before and after the diagnosis and treatment of the disease. The questionnaire was based on Conners' test. Ten children were included in the study. Mean age at diagnosis was 11.5 years. Mean follow-up time was 25 months. Six patients (60%) met the definition of attention- and concentration-deficit disorders before diagnosis of idiopathic intracranial hypertension; 1 patient was treated with methylphenidate (Ritalin) before referral to eye examination. After the diagnosis was made and treatment was established, 5 patients (83%) reported an improvement in their attention and behavior. Of these 6 patients, 2 (33%) reported marked improvement. We conclude that attention- and concentration-deficit disorder might be an early sign for pediatric idiopathic intracranial hypertension. Diagnosis and treatment of idiopathic intracranial hypertension in these children may improve the child's behavior, attention, and achievements in school, without the need to resort to other modes of therapy.

Visual loss after transscleral diode laser cyclophotocoagulation for primary open-angle and neovascular glaucoma.

BACKGROUND AND OBJECTIVE: Varying incidences of visual loss after transscleral diode laser cyclophotocoagulation for uncontrolled intraocular pressure (IOP) have been reported. This study compared the treatment response in primary open-angle (POAG) and neovascular (NVG) glaucoma, particularly regarding vision loss. PATIENTS AND METHODS: Case notes of consecutive patients who underwent transscleral diode laser cyclophotocoagulation between March 2001 and September 2005 were retrospectively reviewed. A diagnosis of POAG or NVG and at least 6 months of follow-up were required for inclusion. Conservative laser parameters were used. The treatment response of the POAG and NVG groups was compared. RESULTS: Twenty-five eyes of23 patients with POAG and 14 eyes of 14 patients with NVG were studied. Mean follow-up was 22.4 and 12.9 months in the POAG and NVG groups, respectively. Post-treatment, both groups had significant reduction in mean IOP of 7.3 (29.2%) and 13.2 (36.6%) mm Hg, respectively (between group P = .18). One eye in each group had mild hypotony of 4 mm Hg, and no eyes became phthisical. Oral acetazolamide treatment was significantly reduced in both groups. Visual acuity post-treatment decreased in both groups; the POAG eyes had better initial visual acuity and lost more visual acuity. Nine of 25 (36%) POAG and 4 of 8 (50%) NVG eyes lost 2 or more LogMAR lines. CONCLUSIONS: Transscleral diode laser cyclophotocoagulation reduced IOP and medication requirements in POAG and NVG. Patients should be warned that visual loss may occur, especially in endstage glaucoma.

OM-101 Decreases the Fibrotic Response Associated with Proliferative Vitreoretinopathy.

PURPOSE: This study aimed to investigate the effect of OM-101 on the fibrotic response occurring in proliferative vitreoretinopathy (PVR) in an animal model. METHODS: Antifibrotic effect of OM-101 was investigated in vivo. As control, eight weeks old c57black mice underwent intravitreal injection with Hepes (group A) or dispase (0.3 units), to induce retinal detachment (RD) and PVR. The dispase-injected mice were randomly divided into two groups B and C (N = 25 mice); in group C, the eyes were treated with intravitreal injection of OM-101 (3 µl), and group B with PBS, as a control. After additional five days, mice were injected with the same initial treatment. Three days later, mice were euthanized, and the eyes were enucleated and processed for histological analysis. RESULTS: Intravitreal injection of dispase caused RD in 64% of the mice in group B, and 93% of those mice had PVR. Only 32% of mice treated with OM-101 and dispase (group C) developed RD, and only 25% of those developed PVR. CONCLUSIONS: OM-101 was found effective in reducing the incidence of RD and PVR maintaining the normal architecture of the retina. This study suggests that OM-101 is a potentially effective and safe drug for the treatment of PVR patients.

Prospective randomised clinical trial to evaluate the safety and efficacy of nepafenac 0.1% treatment for the prevention of macular oedema associated with cataract surgery in patients with diabetic retinopathy.

BACKGROUND/AIMS: This study evaluated nepafenac ophthalmic suspension 0.1% for prevention of macular oedema (MO) when used 90 days following cataract surgery in patients with diabetic retinopathy (DR). METHODS: Randomised, double-masked, vehicle-controlled, parallel group study conducted at 32 centres across the world. Participants were patients with diabetes with non-proliferative diabetic retinopathy scheduled for cataract surgery with (posterior chamber) intraocular lens implantation. Patients were randomised to nepafenac ophthalmic suspension 0.1% or vehicle three times daily, beginning on the day before surgery and continuing through the last study visit (day 90 or early exit). All patients were instilled one drop of tobramycin 0.3% and dexamethasone 0.1% four times daily for 2 weeks after surgery. Primary efficacy end point was the percentage of patients who developed MO (defined as ≥30% increase in central subfield macular thickness from baseline) within 90 days following surgery. The secondary end point was mean change in best-corrected visual acuity (BCVA) from baseline to day 90. RESULTS: A total of 175 patients were randomised, with 87 and 88 patients in the nepafenac and vehicle groups, respectively. A significantly greater percentage of eyes in the vehicle group (17.5%; 95% CI 9.9% to 27.6%) developed MO within 90 days following surgery compared with the nepafenac group (5.0%; 95% CI 1.4% to 12.3%, p=0.01). Mean change in BCVA from baseline to day 90 following surgery was greater in the nepafenac group (17.7±14.6 letters) relative to the vehicle group (14.3±13.9 letters), though the difference was not statistically significant (p=0.14). No new safety issues or trends were identified. CONCLUSIONS: A 90-day nepafenac treatment regimen prevented MO after cataract surgery in patients with DR and demonstrated no safety issues within this study group. TRIAL REGISTRATION NUMBER: NTC00782717 and NCT00939276.