Samantha Fraser-Bell

A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT Study): 12-Month Data: Report 2

PURPOSE To report the findings at 1 year of a study comparing repeated intravitreal bevacizumab (ivB) and modified Early Treatment of Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant diabetic macular edema (CSME). DESIGN Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial. PARTICIPANTS A total of 80 eyes of 80 patients with center-involving CSME and at least 1 prior MLT. METHODS Subjects were randomized to either ivB (6 weekly; minimum of 3 injections and maximum of 9 injections in the first 12 months) or MLT (4 monthly; minimum of 1 treatment and maximum of 4 treatments in the first 12 months). MAIN OUTCOME MEASURES The primary end point was the difference in ETDRS best-corrected visual acuity (BCVA) at 12 months between the bevacizumab and laser arms. RESULTS The baseline mean ETDRS BCVA was 55.7+/-9.7 (range 34-69) in the bevacizumab group and 54.6+/-8.6 (range 36-68) in the laser arm. The mean ETDRS BCVA at 12 months was 61.3+/-10.4 (range 34-79) in the bevacizumab group and 50.0+/-16.6 (range 8-76) in the laser arm (P = 0.0006). Furthermore, the bevacizumab group gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (P = 0.0002). The odds of gaining > or =10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95% confidence interval, 1.3-19.7; P = 0.019). At 12 months, central macular thickness decreased from 507+/-145 microm (range 281-900 microm) at baseline to 378+/-134 microm (range 167-699 microm) (P<0.001) in the ivB group, whereas it decreased to a lesser extent in the laser group, from 481+/-121 microm (range 279-844 microm) to 413+/-135 microm (range 170-708 microm) (P = 0.02). The median number of injections was 9 (interquartile range [IQR] 8-9) in the ivB group, and the median number of laser treatments was 3 (IQR 2-4) in the MLT group. CONCLUSIONS The study provides evidence to support the use of bevacizumab in patients with center-involving CSME without advanced macular ischemia.

Five-year cumulative incidence and progression of epiretinal membranes: The Blue Mountains Eye Study

PURPOSE To describe the 5-year cumulative incidence and change in epiretinal membranes in a defined older Australian population. DESIGN Population-based cohort study. PARTICIPANTS Three thousand six hundred fifty-four persons 49 years of age or older, living in the Blue Mountains area, west of Sydney, Australia, participated in the baseline survey during 1992 to 1994. The cohort was reexamined after 5 years in 1997 to 1999. Excluding persons (543) who died since the baseline, 75% of survivors (n = 2335) attended the follow-up examination. METHODS All participants underwent a detailed eye examination, including stereo retinal photography. Epiretinal membranes were diagnosed from grading of baseline and 5-year retinal photographs. MAIN OUTCOME MEASURES Epiretinal membranes were classified as either preretinal macular fibrosis (PMF), with retinal folds, or as a less severe form, termed cellophane macular reflex (CMR), without retinal folds. The incidence of epiretinal membranes was determined if either lesion was found in eyes with no preexisting epiretinal membrane at baseline. Progression was defined if the area of involvement increased by more than 25%, regression if it decreased by more than 25%, and stable if it changed by less than 25%. RESULTS Epiretinal membranes developed in the first eye of 108 of 2030 participants who had no sign of this condition in either eye at baseline, 5.3%, 95% confidence interval (CI) 4.4 to 6.4. Five-year cumulative incidence rates for PMF and CMR were 1.5% and 3.8%, respectively. Of those participants with epiretinal membranes in one eye at baseline, 18 of 133 (13.5%) developed this sign in their second eye after 5 years. New epiretinal membranes (mostly CMR) occurred in 15 of 165 subjects (9.1%; CI, 5.2-14.6) who had undergone cataract surgery since the Blue Mountains Eye Study I. This rate was significantly higher than in the nonsurgical group, 92 of 1861 (4.9%; CI, 4.0-6.0) of whom developed epiretinal membranes. Progression from CMR to PMF was observed in 17 of 183 eyes (9.3%). Existing epiretinal membranes progressed, regressed, or remained stable in 28.6%, 25.7%, and 38.8% of eyes, respectively. CONCLUSIONS This study has documented the 5-year cumulative incidence and the natural history of epiretinal membranes in an older population.

Central serous chorioretinopathy: a review of epidemiology and pathophysiology.

Central serous chorioretinopathy (CSCR) is a common retinal cause of vision loss. This review surveys the epidemiology, risk factors, clinical presentation, natural history and pathophysiology of CSCR. Studies suggest an annual incidence rate of 10 per 100 000 in men, with CSCR occurring six times more commonly in men compared with women. Most acute CSCR cases resolve spontaneously within 2–3 months. Prognosis is highly dependent on presenting visual acuity; patients with initial visual acuities of 6/6 remain at that level, while patients with initial visual acuities of less than 6/9 recover on average two to three Snellen lines over the next few years. The main risk factors for CSCR are systemic corticosteroid use, type A personality, pregnancy and endogenous Cushings syndrome. The pathophysiology of CSCR remains obscure, although disorders in both the choroidal circulation and retinal pigment epithelium are implicated.Central serous chorioretinopathy (CSCR) is a common retinal cause of vision loss. This review surveys the epidemiology, risk factors, clinical presentation, natural history and pathophysiology of CSCR. Studies suggest an annual incidence rate of 10 per 100 000 in men, with CSCR occurring six times more commonly in men compared with women. Most acute CSCR cases resolve spontaneously within 2–3 months. Prognosis is highly dependent on presenting visual acuity; patients with initial visual acuities of 6/6 remain at that level, while patients with initial visual acuities of less than 6/9 recover on average two to three Snellen lines over the next few years. The main risk factors for CSCR are systemic corticosteroid use, type A personality, pregnancy and endogenous Cushings syndrome. The pathophysiology of CSCR remains obscure, although disorders in both the choroidal circulation and retinal pigment epithelium are implicated.

A Randomized Clinical Trial of Intravitreal Bevacizumab versus Intravitreal Dexamethasone for Diabetic Macular Edema: The BEVORDEX Study

OBJECTIVE To report the 12-month results of the first head-to-head comparison of a dexamethasone implant (Ozurdex; Allergan, Inc., Irvine, CA) versus bevacizumab (Avastin; Genentech, South San Francisco, CA) for center-involving diabetic macular edema (DME). DESIGN Phase 2, prospective, multicenter, randomized, single-masked clinical trial (clinicaltrials.gov identifier NCT01298076). PARTICIPANTS We enrolled 88 eyes of 61 patients with center-involving DME. METHODS Forty-two eyes were randomized to receive bevacizumab every 4 weeks and 46 eyes were randomized to receive a dexamethasone implant every 16 weeks, both pro re nata. Results were analyzed using linear regression with generalized estimation equation methods to account for between-eye correlation. MAIN OUTCOME MEASURES The primary outcome was the proportion of eyes that improved vision by 10 logarithm of minimum angle of resolution letters. Secondary outcomes included mean change in best-corrected visual acuity (BCVA), change in central macular thickness (CMT), injection frequency, and adverse events. Patient-reported outcomes were measured using the Impact of Vision Impairment (IVI) questionnaire. RESULTS Improvement in BCVA of 10 or more letters was found in 17 of 42 eyes (40%) treated with bevacizumab compared with 19 of 46 dexamethasone implant-treated eyes (41%; P = 0.83). None of the 42 bevacizumab eyes lost 10 letters or more, whereas 5 of 46 (11%) dexamethasone implant eyes did, mostly because of cataract. Mean CMT decreased by 122 μm for bevacizumab eyes and by 187 μm for dexamethasone implant eyes (P = 0.015). Bevacizumab-treated eyes received a mean of 8.6 injections compared with 2.7 injections for dexamethasone implant eyes. Significant improvement in IVI scores occurred for both treatment groups. CONCLUSIONS Dexamethasone implant achieved similar rates of visual acuity improvement compared with bevacizumab for DME, with superior anatomic outcomes and fewer injections. Both treatments were associated with improvement in visual quality-of-life scores. However, more dexamethasone implant-treated eyes lost vision, mainly because of cataract.

Cardiovascular risk factors and age-related macular degeneration: the Los Angeles Latino Eye Study.

PURPOSE To assess the association of cardiovascular risk factors and ocular perfusion pressure with early and advanced age-related macular degeneration (AMD) in Latinos. DESIGN Population-based, cross-sectional study. METHODS Data were collected from a population-based sample of self-identified adult Latinos using standardized protocols for assessing blood pressure and intraocular pressure (IOP) measurement and stereoscopic macular photography. Hypertension was defined as either a history of hypertension or systolic blood pressure (SBP) > 140 mm Hg +/- diastolic blood pressure (DBP) > or = 85 mm Hg. Ocular perfusion pressure (OPP) was defined as the difference between mean arterial blood pressure and IOP. AMD was diagnosed from photographic grading by masked trained graders. Logistic regression was used to assess associations. RESULTS Gradable retinal photographs were available in 5,875 participants. After adjusting for age, gender, and cigarette smoking, higher DBP and uncontrolled diastolic hypertension were associated with exudative AMD (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1 to 2.8; and OR, 3.3; CI, 1.2 to 9.3, respectively). Higher OPP was associated with a decreased risk of geographic atrophy (GA) (OR, 0.4 per 10 mm Hg; CI, 0.3 to 0.5). Low pulse pressure was associated with a lower risk of exudative AMD (OR, 0.2; CI, 0.1 to 0.6). Obesity was associated with increased retinal pigment (OR, 1.6; CI, 1.0 to 2.3). CONCLUSIONS These data suggest that in Latinos cardiovascular risk factors may play a role in advanced AMD. Given that Latinos have a high prevalence of cardiovascular risk factors, an intervention aimed at reducing these risk factors may also have a beneficial impact on the risk of having early and advanced AMD.

Update on treatments for diabetic macular edema.

Purpose of review Due to modest outcomes with macular laser, other treatment modalities for diabetic macular edema have been evaluated. Intravitreal triamcinolone acetonide, pars plana vitrectomy, oral protein kinase C inhibitors and, from more recently, anti-vascular endothelial growth factor therapy are reviewed. Recent findings Intravitreal triamcinolone acetonide may be more effective than laser. Intravitreal triamcinolone acetonide followed by laser may be more effective than intravitreal triamcinolone acetonide alone. Ruboxistaurin, a selective protein kinase C βinhibitor, reduced retinal vascular leakage in patients with diabetic macular edema and reduced the rate of sustained moderate visual loss in those with moderately severe to very severe non proliferative diabetic retinopathy. Several anti-vascular endothelial growth factor agents are under evaluation. Intravitreal pegaptanib sodium (0.3 mg) improved vision and reduced central retinal thickness compared to sham. Data on the other anti-vascular endothelial growth factor agents is limited, but there are promising results, with ranibizumab (0.5 mg) and bevacizumab reducing foveal thickness and improving visual acuity in some patients with diabetic macular edema. Summary There remains no proven intervention that consistently prevents or reverses visual loss from diabetic macular edema in all patients. A variety of promising new medical and surgical therapies are under investigation, but further research is required to determine their role alone or in combination.

Diagnosis and interventions for central serous chorioretinopathy: review and update

Most acute cases of central serous chorioretinopathy resolve spontaneously with minimal visual impairment. The small percentage of eyes developing chronic or recurrent disease that do warrant treatment is often difficult to control. Emergent investigations and treatments have added to the established options available to manage these cases. Optical coherence tomography has proved valuable for both imaging subtle fundoscopic findings and monitoring disease progression. Fluorescein angiography aids identification of pigment epithelial leaks and targets the use of argon laser treatment if outside the fovea. Fluorescein angiography also assists differentiation from other choroidal pathologies such as choroidal neovascularization and polypoidal choroidal vasculopathy. Where the diagnosis is uncertain, indocyanine green angiography can demonstrate classic midphase hyperpermeability. This is also useful to guide the application of photodynamic therapy. Newer treatments such as intravitreal anti‐vascular endothelial growth factor are as yet unproven.Most acute cases of central serous chorioretinopathy resolve spontaneously with minimal visual impairment. The small percentage of eyes developing chronic or recurrent disease that do warrant treatment is often difficult to control. Emergent investigations and treatments have added to the established options available to manage these cases. Optical coherence tomography has proved valuable for both imaging subtle fundoscopic findings and monitoring disease progression. Fluorescein angiography aids identification of pigment epithelial leaks and targets the use of argon laser treatment if outside the fovea. Fluorescein angiography also assists differentiation from other choroidal pathologies such as choroidal neovascularization and polypoidal choroidal vasculopathy. Where the diagnosis is uncertain, indocyanine green angiography can demonstrate classic midphase hyperpermeability. This is also useful to guide the application of photodynamic therapy. Newer treatments such as intravitreal anti-vascular endothelial growth factor are as yet unproven.

Cytokine polymorphism in noninfectious uveitis.

PURPOSE Noninfectious uveitis is a sight-threatening immune-mediated intraocular inflammatory disorder. The inheritance of uveitis in multiplex families and its association with known monogenic and polygenic immunologic disorders suggests that common genetic variants underlie susceptibility to uveitis as well as to other immunologic disorders. TNFA and IL10 are strong candidate genes, given the influence of these cytokines on inflammation, immune tolerance, and apoptosis. METHODS The role of 12 polymorphisms spanning the TNFA and IL10 genomic regions was investigated in 192 uveitis patients and 92 population control subjects from four regional centers in the United Kingdom and Republic of Ireland. RESULTS The results demonstrate that uveitis is associated with three haplotype-tagging SNPs (htSNPs) in the IL10 gene: htSNP2 (rs6703630), htSNP5 (rs2222202), and htSNP6 (rs3024490). IL10htSNP2AG/htSNP5TC was the most significantly associated haplotype (P = 0.00085), whereas the LTA+252AA/TNFhtSNP2GG haplotype was protective (P = 0.00031). Furthermore, subgroup analysis showed that the frequency of the TNFd4 allele was higher in patients with nonremitting ocular disease and/or those requiring higher levels of maintenance immunosuppression. Although these associations lost significance after Bonferroni correction, they infer a relationship that may be validated by a larger study. CONCLUSIONS Since these variants are implicated in the susceptibility and severity of several immunologic disorders, the results support the hypothesis that common genetic determinants influence shared mechanisms of autoimmunity.

Asymmetric refraction in an older population: The Blue Mountains eye study

PURPOSE To describe prevalence and associations of asymmetric refraction in an older population. METHODS All participants in the Blue Mountains Eye Study had comprehensive eye examinations, including refraction. Spherical equivalent (SEq = sum sphere +.5 cylinder), in diopters, defined refractive error. Refractive asymmetry was assessed in phakic participants; anisometropia was defined as > or =1.0 diopters SEq difference between eyes. RESULTS Anisometropia was present in 14.7% of participants. Mean refractive asymmetry (in diopters) in persons aged <60 years was 0.43; 60 to 69 years, 0.51; 70 to 79 years, 0.72; and 80+ years, 0.88. Prevalence and severity of anisometropia increased with age (P <.001), increasing ametropia or astigmatism. Associations included older age, cataract, and increasing ametropia. Myopic participants >-3.0 diopters had the highest anisometropia prevalence. CONCLUSIONS Refractive asymmetry was associated with age, increasing ametropia, and cataract.

Interventions for the treatment of uveitic macular edema: a systematic review and meta-analysis

Background Uveitic macular edema is the major cause of reduced vision in eyes with uveitis. Objectives To assess the effectiveness of interventions in the treatment of uveitic macular edema. Search strategy Cochrane Central Register of Controlled Trials, Medline, and Embase. There were no language or data restrictions in the search for trials. The databases were last searched on December 1, 2011. Reference lists of included trials were searched. Archives of Ophthalmology, Ophthalmology, Retina, the British Journal of Ophthalmology, and the New England Journal of Medicine were searched for clinical trials and reviews. Selection criteria Participants of any age and sex with any type of uveitic macular edema were included. Early, chronic, refractory, or secondary uveitic macular edema were included. We included trials that compared any interventions of any dose and duration, including comparison with another treatment, sham treatment, or no treatment. Data collection and analysis Best-corrected visual acuity and central macular thickness were the primary outcome measures. Secondary outcome data including adverse effects were collected. Conclusion More results from randomized controlled trials with long follow-up periods are needed for interventions for uveitic macular edema to assist in determining the overall long-term benefit of different treatments. The only intervention with sufficiently robust randomized controlled trials for a meta-analysis was acetazolamide, which was shown to be ineffective in improving vision in eyes with uveitic macular edema, and is clinically now rarely used. Interventions showing promise in this disease include dexamethasone implants, immunomodulatory drugs and anti-vascular endothelial growth-factor agents. When macular edema has become refractory after multiple interventions, pars plana vitrectomy could be considered. The disease pathophysiology is uncertain and the course of disease unpredictable. As there are no clear guidelines from the literature, interventions should be tailored to the individual patient.