Tahreem A. Mir

Scatter Photocoagulation Does Not Reduce Macular Edema or Treatment Burden in Patients with Retinal Vein Occlusion The RELATE Trial

PURPOSE To determine whether scatter and grid laser photocoagulation (laser) adds benefit to ranibizumab injections in patients with macular edema from retinal vein occlusion (RVO) and to compare 0.5-mg with 2.0-mg ranibizumab. DESIGN Randomized, double-masked, controlled clinical trial. PARTICIPANTS Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS Subjects were randomized to 0.5 mg or 2.0 mg ranibizumab every 4 weeks for 24 weeks and re-randomized to pro re nata ranibizumab plus laser or ranibizumab alone. MAIN OUTCOME MEASURES Mean change from baseline best-corrected visual acuity (BCVA) at week 24 for BCVA at weeks 48, 96, and 144 for second randomization. RESULTS Mean improvement from baseline BCVA at week 24 was 15.5 and 15.8 letters in the 0.5-mg and 2.0-mg CRVO groups, and 12.1 and 14.6 letters in the 0.5-mg and 2.0-mg BRVO groups. For CRVO, but not BRVO, there was significantly greater reduction from baseline mean central subfield thickness (CST) in the 2.0-mg versus 0.5-mg group (396.1 vs. 253.5 μm; P = 0.03). For the second randomization in CRVO patients, there was no significant difference from week 24 BCVA in the ranibizumab plus laser versus the ranibizumab only groups at week 48 (-3.3 vs. 0.0 letters), week 96 (+0.69 vs. -1.6 letters), or week 144 (+0.4 vs. -6.7 letters), and a significant increase from week 24 mean CST at week 48 (+94.7 vs. +15.2 μm; P = 0.05) but not weeks 96 or 144. For BRVO, there was a significant reduction from week 24 mean BCVA in ranibizumab plus laser versus ranibizumab at week 48 (-7.5 vs. +2.8; P < 0.01) and week 96 (-2.0 vs. +4.8; P < 0.03), but not week 144, and there were no differences in mean CST change from week 24 at weeks 48, 96, or 144. Laser failed to increase edema resolution or to reduce the ranibizumab injections between weeks 24 and 144. CONCLUSIONS In patients with macular edema resulting from RVO, there was no short-term clinically significant benefit from monthly injections of 2.0-mg versus 0.5-mg ranibizumab injections and no long-term benefit in BCVA, resolution of edema, or number of ranibizumab injections obtained by addition of laser treatment to ranibizumab.

Is There Excess Oxidative Stress and Damage in Eyes of Patients with Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of diseases in which a mutation in one of the large variety of genes causes death of rod photoreceptors. After rods die, cone photoreceptors gradually die resulting in constriction of visual fields and eventual blindness in many patients. Studies in animal models of RP have demonstrated that oxidative damage is a major contributor to cone cell death. In this study, we extended those findings to patients with RP, because compared to control patients, those with RP showed significant reduction in the reduced to oxidized glutathione (GSH/GSSG) ratio in aqueous humor and a significant increase in aqueous protein carbonyl content. In contrast, there was no significant decrease in the serum GSH/GSSG ratio or increase in carbonyl content of serum proteins. These data indicate that patients with RP have ocular oxidative stress and damage in the absence of manifestations of systemic oxidative stress and/or damage indicating that demonstrations of oxidative damage-induced cone cell death in animal models of RP may translate to human RP. These observations lead to the hypothesis that potent antioxidants will promote cone survival and function in patients with RP and that the aqueous GSH/GSSG ratio and carbonyl content on proteins may provide useful biomarkers. Antioxid. Redox Signal. 23, 643-648.

Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study

Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat®). Patients with advanced NVAMD were enrolled at three centers in the United States, and the study eye received a subretinal injection of 2.4 × 104 (n = 3), 2.4 × 105 (n = 3), or 8.0 × 105 transduction units (TU; n = 15). Each of the doses was well-tolerated with no dose-limiting toxicities. There was little or no ocular inflammation. There was one procedure-related serious adverse event (AE), a macular hole, which was managed without difficulty and resolved. There was a vector dose-related increase in aqueous humor levels of endostatin and angiostatin with high reproducibility among subjects within cohorts. Mean levels of endostatin and angiostatin peaked between 12 and 24 weeks after injection of 2.4 × 105 TU or 8.0 × 105 TU at 57-81 ng/mL for endostatin and 15-27 ng/mL for angiostatin, and remained stable through the last measurement at week 48. Long-term follow-up demonstrated expression was maintained at last measurement (2.5 years in eight subjects and >4 years in two subjects). Despite an apparent reduction in fluorescein angiographic leakage that broadly correlated with the expression levels in the majority of patients, only one subject showed convincing evidence of anti-permeability activity in these late-stage patients. There was no significant change in mean lesion size in subjects injected with 8.0 × 105 TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy.

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion

PURPOSE To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab. DESIGN Secondary outcome measure in randomized double-masked controlled clinical trial. PARTICIPANTS Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS Subjects were randomized to 0.5 or 2.0 mg ranibizumab every month for 6 months and then were re-randomized to pro re nata (PRN) groups receiving either ranibizumab plus scatter laser photocoagulation or ranibizumab alone for an additional 30 months. MAIN OUTCOME MEASURES Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5 versus 2.0 mg ranibizumab, during monthly injections versus ranibizumab PRN, and in patients treated with ranibizumab PRN versus ranibizumab PRN plus laser. RESULTS In RVO patients given monthly injections of 0.5 or 2.0 mg ranibizumab for 6 months, there was no significant difference in the percentage who showed reduction or increase in the area of RNP. However, regardless of dose, during the 6-month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared with subsequent periods of ranibizumab PRN treatment. After the 6-month period of monthly injections, BRVO patients, but not CRVO patients, randomized to ranibizumab PRN plus laser showed significantly less progression of RNP compared with patients treated with ranibizumab PRN. CONCLUSIONS Regardless of dose (0.5 or 2.0 mg), monthly ranibizumab injections promote improvement and reduce progression of RNP compared with PRN injections. The addition of scatter photocoagulation to ranibizumab PRN may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO.

Pro-Permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; the Ozurdex for Retinal Vein Occlusion (ORVO) Study

PURPOSE To correlate aqueous vasoactive protein changes with macular edema after dexamethasone implant in retinal vein occlusion (RVO). DESIGN Prospective, interventional case series. METHODS Twenty-three central RVO (CRVO) and 17 branch RVO (BRVO) subjects with edema despite prior anti-vascular endothelial growth factor (VEGF) treatment had aqueous taps at baseline and 4 and 16 weeks after dexamethasone implant. Best-corrected visual acuity (BCVA) and center subfield thickness were measured every 4 weeks. Aqueous vasoactive protein levels were measured by protein array or enzyme-linked immunosorbent assay. RESULTS Thirty-two vasoactive proteins were detected in aqueous in untreated eyes with macular edema due to RVO. Reduction in excess foveal thickness after dexamethasone implant correlated with reduction in persephin and pentraxin 3 (Pearson correlation coefficients = 0.682 and 0.638, P = .014 and P = .003). Other protein changes differed among RVO patients as edema decreased, but ≥50% of patients showed reductions in hepatocyte growth factor, endocrine gland VEGF, insulin-like growth factor binding proteins, or endostatin by ≥30%. Enzyme-linked immunosorbent assay in 18 eyes (12 CRVO, 6 BRVO) showed baseline levels of hepatocyte growth factor and VEGF of 168.2 ± 20.1 pg/mL and 78.7 ± 10.0 pg/mL, and each was reduced in 12 eyes after dexamethasone implant. CONCLUSIONS Dexamethasone implants reduce several pro-permeability proteins providing a multitargeted approach in RVO. No single protein in addition to VEGF can be implicated as a contributor in all patients. Candidates for contribution to chronic edema in subgroups of patients that deserve further study include persephin, hepatocyte growth factor, and endocrine gland VEGF.

The mechanism of cone cell death in Retinitis Pigmentosa

Retinitis Pigmentosa (RP) is a group of diseases in which one of a large number of mutations causes death of rod photoreceptors. After rods die, cone photoreceptors slowly degenerate in a characteristic pattern. The mechanism of rod cell death varies depending upon the gene that is mutated and the rate that rods degenerate is an important prognostic feature, because cones do not begin to degenerate until almost all rods have been eliminated. Rod cell death causes night blindness, but visual disability and blindness result from cone degeneration and therefore it is critical to determine the mechanisms by which it occurs. The death of rods reduces oxygen consumption resulting in high tissue levels of oxygen in the outer retina. The excess oxygen stimulates superoxide radical production by mismatches in the electron transport chain in mitochondria and by stimulation of NADPH oxidase activity in cytoplasm. The high levels of superoxide radicals overwhelm the antioxidant defense system and generate more reactive species including peroxynitrite which is extremely damaging and difficult to detoxify. This results in progressive oxidative damage in cones which contributes to cone cell death and loss of function because drugs or gene transfer that reduce oxidative stress promote cone survival and maintenance of function. Compared with aqueous humor samples from control patients, those from patients with RP show significant elevation of carbonyl content on proteins indicating oxidative damage and a reduction in the ratio of reduced to oxidized glutathione indicating depletion of a major component of the antioxidant defense system from ongoing oxidative stress. The first step in clinical trials will be to identify doses of therapeutic agents that reverse these biomarkers of disease to assist in design of much longer trials with functional and anatomic endpoints.

Optimising drug therapy for non-infectious uveitis

IntroductionUveitis encompasses a wide variety of sight-threatening diseases characterized by intraocular inflammation. It is often classified as infectious and non-infectious uveitis. Unlike infectious uveitis, a distinct infectious agent cannot be identified in non-infectious uveitis and disease origin is usually autoimmune, drug related, or idiopathic.The Issue at HandNon-infectious uveitis can often have a relapsing-remitting course, making it difficult to treat, and poses a significant challenge to ophthalmologists. The autoimmune nature of non-infectious uveitis warrants the use of anti-inflammatory and immunomodulatory agents for disease control. However, a subset of patients has persistent or recurrent ocular inflammation despite appropriate treatment, stressing the need for newer therapies aimed at more specific inflammatory targets such as tumour necrosis factor (TNF) alpha agents, anti-interleukin agents, and anti-interleukin receptor agents.ObjectivesThis article discusses the various medical options available for the treatment of non-infectious uveitis in the light of the most recent evidence.ConclusionSuccessful management of non-infectious uveitis requires the clinician carefully balance advantages and disadvantages of each new and old therapy while considering individual circumstances. Counselling regarding the benefits and complications of each therapy can help patients make an informed choice.

The role of the posterior corneal surface in surgical planning

Historically, the role of posterior cornea has been largely ignored. As technology has improved our ability to image the posterior cornea, its increasingly important role is becoming evident. This review article will summarize the complex role of the posterior cornea in surgical planning and outcomes as relevant to refractive surgery, cataract surgery and corneal transplantation.