Uniformity of visual acuity measures in published studies

PURPOSE. To investigate the methods used in contemporary ophthalmic literature to designate visual acuity (VA). METHODS. Papers in all 2005 editions of five ophthalmic journals were considered. Papers were included if (1) VA, vision, or visual function was mentioned in the abstract and (2) if the study involved age-related macular degeneration, cataract, or refractive surgery. If a paper was selected on the basis of its abstract, the full text of the paper was examined for information on the method of refractive correction during VA testing, type of chart used to measure VA, specifics concerning chart features, testing protocols, and data analysis and means of expressing VA in results. RESULTS. One hundred twenty-eight papers were included. The most common type of charts used were described as logMAR-based. Although most (89.8%) of the studies reported on the method of refractive correction during VA testing, only 58.6% gave the chart design, and less than 12% gave any information whatsoever on chart features or measurement procedures used. CONCLUSIONS. The methods used and the approach to analysis were rarely described in sufficient detail to allow others to replicate the study being reported. Sufficient detail should be given on VA measurement to enable others to duplicate the research. The authors suggest that charts adhering to Bailey-Lovie design principles always be used to measure vision in prospective studies and their use encouraged in clinical settings. The distinction between the terms logMAR, an acuity notation, and Bailey-Lovie or ETDRS as chart types should be adhered to more strictly. Copyright © Association for Research in Vision and Ophthalmology.

Traumatic Graft Dehiscence after Penetrating Keratoplasty

Objective: To determine the incidence and to explore the risk factors for traumatic graft dehiscence after penetrating keratoplasty. Design: Retrospective case note review. Participants: Five hundred seventy-two consecutive cases were included. Intervention: All subjects who underwent penetrating keratoplasty in 1 regional center between 1992 and 2004 inclusive. Main Outcome Measures: Cases that experienced postoperative traumatic graft dehiscence were identified. Results from 12 other similar studies were pooled for comparison. Results: Fifteen eyes (2.6%) were treated for traumatic wound dehiscence after penetrating keratoplasty. The most striking feature of this series was the bimodal relationship of age and cause of graft dehiscence, with older patients involved in falls and younger patients in accidental or deliberate trauma. Factors that may influence the risk of traumatic graft dehiscence are discussed, in the light of the present findings and pooled data from previous series. Conclusions: This case series indicates that there is long-term risk of traumatic wound dehiscence after penetrating keratoplasty. Younger patients, especially males, should be made aware that their eye, after keratoplasty, will always be vulnerable to injury. High-risk situations should be avoided if possible. Older patients at particular risk should have adequate risk reduction strategies, social support, and supervision, in particular to minimize the risk of falls. © 2008 American Academy of Ophthalmology.

Change of visual acuity recording methods in clinical studies across the years

Purpose: To report any differences in the visual acuity (VA) recording method used in peer-reviewed ophthalmology clinical studies over the past decade. Methods: We reviewed the method of assessing and reporting VA in 160 clinical studies from 2 UK and 2 US peer-reviewed journals, published in 1994 and 2004. Results: The method used to assess VA was specified in 62.5% of UK-published and 60% of US-published papers. In the results sections of the UK publications the VA measurements presented were Snellen acuity (n = 58), logMAR acuity (n = 20) and symbol acuity (n = 1). Similarly in the US publications the VA was recorded in the results section using Snellen acuity (n = 60) and logMAR acuity (n = 14). Overall 10% of the authors appeared to convert Snellen acuity measurements to logMAR format. Five studies (3%) chose to express Snellen-type acuities in decimal form, a method which can easily lead to confusion given the increased use of logMAR scoring systems. Conclusion: The authors recommend that to ensure comparable visual results between studies and different study populations it would be useful if clinical scientists worked to standardized VA testing protocols and reported results in a manner consistent with the way in which they are measured. Copyright © 2008 S. Karger AG.

Will VEGF Trap-Eye reduce the treatment burden in neovascular age-related macular degeneration?

Evaluation of: Brown DM, Heier JS, Ciulla T et al. Primary end point results of a Phase II study of vascular endothelial growth factor trap-eye in wet age-related macular degeneration. Ophthalmology 118(6), 1089-1097 (2011); Heier JS, Boyer D, Nguyen QD et al. The 1-year results of CLEAR-IT 2, a Phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology 118(6), 1098-1106 (2011). Age-related macular degeneration is the most common cause of blindness in older adults in western countries, and is likely to become the largest cause of irreversible sight loss in the developing world. Treatments such as ranibizumab and bevacizumab that inhibit VEGF have improved visual outcomes markedly. Controlled trials and clinical experience have shown that the best outcomes are achieved when monthly treatment has been administered over 2 years. This poses a significant burden on health providers and patients. A novel inhibitor of VEGF, VEGF Trap-Eye, which allows less frequent dosing without loss of efficacy, has emerged as a potential treatment. CLEAR-IT 2 was a prospective randomized Phase II trial designed to assess the safety, tolerability and the anatomic and visual effects of repeated treatments with a range of doses of VEGF Trap-Eye. Impressive anatomic and visual improvements were noted with no safety concerns. © 2011 Expert Reviews Ltd.

FLT1 Genetic Variation Predisposes to Neovascular AMD in Ethnically Diverse Populations and Alters Systemic FLT1 Expression

Purpose: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway.
Methods: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis.
Results: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway.
Conclusions: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.

Clinical Characteristics of Reticular Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration

Purpose: To describe associations between reticular pseudodrusen, individual characteristics, and retinal function.

Design: Cohort study.

Participants: We recruited 105 patients (age range, 52–93 years) who had advanced neovascular age-related macular degeneration (AMD) in only 1 eye from 3 clinical centers in Europe.

Methods: Minimum follow-up was 12 months. The eye selected for study was the fellow eye without advanced disease. Clinical measures of vision were distance visual acuity, near visual acuity, and results of the Smith-Kettlewell low-luminance acuity test (SKILL). Fundus imaging included color photography, red-free imaging, blue autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and optical coherence tomography using standardized protocols. These were used to detect progression to neovascular AMD in the study eye during follow-up. All imaging outputs were graded for the presence or absence of reticular pseudodrusen (RPD) using a multimodal approach. Choroidal thickness was measured at the foveal center and at 2 other equidistant locations from the fovea (1500 μm) nasally and temporally. Metrics on retinal thickness and volume were obtained from the manufacturer-supplied automated segmentation readouts.

Main Outcome Measures: Presence of RPD, distance visual acuity, near visual acuity, SKILL score, choroidal thickness, retinal thickness, and retinal volume.

Results: Reticular pseudodrusen was found in 43 participants (41%) on 1 or more imaging method. The SKILL score was significantly worse in those with reticular drusen (mean score ± standard deviation [SD, 38±12) versus those without (mean score ± SD, 33±9) (P = 0.034). Parafoveal retinal thickness, parafoveal retinal volume, and all of the choroidal thickness parameters measured were significantly lower in those with reticular drusen than in those without. The presence of RPD was associated with development of neovascular AMD when corrected for age and sex (odds ratio, 5.5; 95% confidence interval, 1.1–28.8; P = 0.042). All participants in whom geographic atrophy developed during follow-up had visible RPD at baseline.

Conclusions: Significant differences in retinal and choroidal anatomic features, visual function, and risk factor profile exist in unilateral neovascular AMD patients with RPD compared with those without; therefore, such patients should be monitored carefully because of the risk of developing bilateral disease.

Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina

Clinical epidemiological studies have revealed relatively weak, yet statistically significant, associations between dyslipidemia/dyslipoproteinemia and diabetic retinopathy (DR). Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids. To unify the apparent discrepancies, we hypothesize that plasma lipoproteins play an indirect but important role in DR, contingent on the integrity of the blood-retina-barrier (BRB). In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells. In this hypothesis, BRB leakage is the key, plasma lipoprotein concentrations mainly modulate its consequences, and fenofibrate has intra-retinal actions. This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

Experimental Autoimmune Uveoretinitis (EAU)-Related Tissue Damage and Angiogenesis Is Reduced in CCL2−/−CX3CR1gfp/gfp Mice

Purpose: To investigate the roles of the CCL2-CCR2 and CX3CL1-CX3CR1 pathways in experimental autoimmune uveoretinitis (EAU)-mediated retinal tissue damage and angiogenesis.

Methods: The C57BL/6J wild-type (WT) and CCL2−/−CX3CR1gfp/gfp (double knockout [DKO]) mice were immunized with IRBP1-20. Retinal inflammation and tissue damage were evaluated clinically and histologically at different days postimmunization (p.i.). Retinal neovascular membranes were evaluated by confocal microscopy of retinal flat mounts, and immune cell infiltration by flow cytometry.

Results: At day 25 p.i., DKO mice had lower clinical and histological scores and fewer CD45highCD11b+ infiltrating cells compared with WT mice. The F4/80+macrophages constitute 40% and 21% and CD11b+Gr-1+Ly6G+ neutrophils constitute 10% and 22% of retinal infiltrating cells in WT and DKO mice, respectively. At the late stages of EAU (day 60–90 p.i.), DKO and WT mice had similar levels of inflammatory score. However, less structural damage and reduced angiogenesis were detected in DKO mice. Neutrophils were rarely detected in the inflamed retina in both WT and DKO mice. Macrophages and myeloid-derived suppressor cells (MDSCs) accounted for 8% and 3% in DKO EAU retina, and 19% and 10% in WT EAU retina; 71% of infiltrating cells were T/B-lymphocytes in DKO EAU retina and 50% in WT EAU retina.

Conclusions: Experimental autoimmune uveoretinitis–mediated retinal tissue damage and angiogenesis is reduced in CCL2−/−CX3CR1gfp/gfp mice. Retinal inflammation is dominated by neutrophils at the acute stage and lymphocytes at the chronic stage in these mice. Our results suggest that CCR2+ and CX3CR1+monocytes are both involved in tissue damage and angiogenesis in EAU.

The reduction of serum soluble Flt-1 in patients with neovascular age-related macular degeneration

PURPOSE: To evaluate serum soluble Flt-1 (sFlt-1) in age-related degeneration (AMD) patients.

DESIGN: Case control study.

METHODS: Fifty-six non-AMD participants, fifty-three early AMD patients and ninety-seven neovascular AMD patients from Belfast in Northern Ireland. Serum samples were collected from each patient. Serum sFlt-1 was measured by human sVEGFR1/sFlt-1 ELISA kit. The results were analyzed by Excel and SPSS.

RESULTS: Serum sFlt-1 concentration of non-AMD, early AMD, and neovascular AMD were 90.8±2.9 pg/mL (±SEM), 88.2±2.6 pg/mL and 79.9±2.2 pg/mL. sFlt-1 from neovascular AMD patients was significantly decreased compared to non-AMD and early AMD patients (ANOVA, p<0.01). For each 10 point increase in sFlt-1, the odds for having neovascular AMD compared with non-AMD and neovascular AMD decreases by 27.8% OR=0.722 (95% CI: 0.588-0.888, p=0.002) and 27.0% OR=0.730 (95% CI: 0.594-0.898, p=0.003), respectively. In patients over 73 years of age, serum sFlt-1 <80 pg/mL was associated with a >6-fold higher risk of neovascular AMD.

CONCLUSIONS: Reduced serum sFlt-1 differentiates those patients with neovascular AMD from both early AMD and non-AMD participants. In those aged over 73, serum sFlt <80 pg/mL seems to indicate a particularly high risk of neovascular AMD. Our results indicate serum sFlt-1 could be a biomarker for development of neovascular AMD.