THE LATEST PUBLISHED RESEARCH

TLR3 Gene Variant Linked to Cell Death in Geographic Atrophy
To identify specific genetic variants that predispose individuals with age-related macular degeneration to geographic atrophy, a group of researchers tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and AMD in Americans of European descent. They genotyped 441 patients with choroidal neovascularization (CNV), 232 with geographic atrophy, 152 with soft confluent drusen and 359 unaffected controls. They also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial (RPE) cells in vitro and on apoptosis of RPE cells from wild-type mice and TLR3-knockout mice.

They found that the Phe variant (encoded by the T allele at rs3775291) was protective against geographic atrophy (p=0.005). They replicated this association in two independent case-control series of geographic atrophy (p=5.43x10–4, p=0.002). They found no association between TLR3 variants and CNV, but that a prototypic TLR3 ligand induced apoptosis in a greater fraction of human RPE cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than TLR3-knockout mice.

The researchers noted that the TLR3 412 Phe variant likely protects against geographic atrophy by suppressing the death of RPE cells. They also noted that because double-stranded RNA can activate TLR3-mediated apoptosis, AMD therapies based on short-interfering-RNA could potentially have toxic effects in the eye.

Source: Yang Z, Stratton C, Francis PJ, et al. Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 2008 Aug 27 [Epub ahead of print].

Traditional and Novel Cardiovascular Risk Factors for Retinal Vein Occlusion
A population-based, cross-sectional study involving 6,147 participants in the Multi-Ethnic Study of Atherosclerosis confirmed some previously known cardiovascular risk factors for retinal vein occlusion (RVO) and revealed some novel risk factors. In the study, RVO was defined from retinal photographs of both eyes of the participants (whites, blacks, Hispanics, Chinese), who were from six U.S. communities. Risk factors were assessed from interviews, examinations and laboratory and radiological testing.

The prevalence of RVO was found to be similar among different racial/ethnic groups. Also, in the general population, RVO was associated with hypertension, dyslipidemia and renal dysfunction, but not with atherosclerotic disease, systemic inflammation and hematological abnormalities.

Independent risk factors associated with RVO were hypertension (odds ratio [OR] 2.06; 95 percent confidence interval [CI]: 1.18, 3.59), older age (OR 1.34; 95 percent CI: 1.00, 1.81, per decade increase), less education (OR 4.08; 95 percent CI: 2.20, 7.54), hypertriglyceridemia (OR 1.98; 95 percent CI: 1.10, 3.56), renal dysfunction (OR 1.85; 95 percent CI: 1.01, 3.39) and the presence of retinal arteriovenous nicking (OR 4.01; 95 percent CI: 2.06, 7.81) and focal arteriolar narrowing (OR 4.38; 95 percent CI: 1.44, 13.34).

RVO was not significantly associated with direct measures of subclinical atherosclerosis, such as carotid intima media thickness and coronary artery calcium scores, or markers of inflammation, such as C reactive protein and interleukin-6, or endothelial dysfunction or coagulation.

Source: Cheung N, Klein R, Wang JJ, et al. Traditional and novel cardiovascular risk factors for retinal vein occlusion: the Multi-Ethnic Study of Atherosclerosis. Invest Ophthalmol Vis Sci 2008 Jun 6 [E-pub ahead of print].

Ranibizumab for Macular Edema Due to Perfused CRVO
In a prospective, open-label, single-center, uncontrolled study, treatment with intravitreal ranibizumab improved visual acuity, central retinal thickness (CRT) and other disease parameters in patients with macular edema due to perfused central retinal vein occlusion (CRVO). However, early gains achieved with monthly dosing were diminished during subsequent prn quarterly dosing.

In the study, 10 patients were randomized to receive three monthly injections of either 0.3 mg or 0.5 mg ranibizumab. Additional injections were administered quarterly over the next 21 months at the physician's discretion for recurrent or persistent macular edema.

After three months of follow-up, compared with baseline, 40 percent of patients gained 15 or more letters in best-corrected visual acuity (BCVA), mean BCVA improved 12 ± 20 letters and mean CRT decreased by 272 ± 244 µm. After six months of follow-up, 10 percent of patients gained 15 or more letters in BCVA, mean BCVA improved 3 ± 21 letters and mean CRT decreased by 88 ± 178 µm. After nine months of follow-up, 30 percent of patients gained 15 or more letters in BCVA, mean BCVA improved 1 ± 24 letters, and mean CRT decreased by 119 ± 153 µm. In addition, most patients experienced decreases in the extent of retinal hemorrhage, retinal vein diameter and optic nerve head swelling at months three and six compared with baseline. No significant differences in results were observed between the 0.3- and 0.5-mg doses.

No eyes progressed to ischemic CRVO and no drug-related adverse events occurred. The study is ongoing, and alternative dosing regimens are being evaluated.

Source: Pieramici PJ, Rabena M, Castellarin AA, et al. Ranibizumab for the treatment of macular edema associated with perfused central retinal vein occlusions. Ophthalmology in press;DOI:10.1016/j.ophtha.2008.06.021.

Effect of Macular Ischemia on Anti-VEGF Treatment for DME
In a retrospective review of data on 59 eyes of 53 consecutive patients treated with intravitreal bevacizumab (Avastin) for diabetic macular edema (DME), macular ischemia had a negative impact on short-term visual outcomes. Macular ischemia was defined as a foveal avascular zone (FAZ) 1,000 µm or larger or a broken perifoveal capillary ring at the border of the FAZ with a distinct area of capillary nonperfusion within one disk diameter of the foveal center in the transit phase of fluorescein angiography.

At three months after treatment, in ischemic eyes (n=18), mean visual acuity decreased to 0.57 ± 0.21 (20/80 Snellen) from 0.52 ± 0.27 (20/63) at baseline. In nonischemic eyes (n=41), visual acuity improved from 0.66 ± 0.34 (20/100) to 0.59 ± 0.33 (20/80). Fifty percent of eyes in the ischemic group lost one or more lines of visual acuity compared with 21 percent of the nonischemic eyes (p=0.031). Four eyes (22 percent) in the ischemic group lost three or more lines of visual acuity compared with two eyes (5 percent) in the nonischemic group (p=0.042).

Source: Chung EJ, Roh MI, Kwon OW, Koh HJ. Effects of macular ischemia on the outcome of intravitreal bevacizumab therapy for diabetic macular edema. Retina 2008;28(7):957–963.

Vascular Endothelial Cadherin Implicated in Angiogenesis
A study in mice suggested that vascular endothelial cadherin (VE-cadherin) may play a key role in the process of angiogenesis and inhibiting it may be an effective strategy for treating proliferative retinopathies. Researchers induced retinal neovascularization in newborn mice and then administered daily intraperitoneal injections of either a VE-cadherin antagonist or a control peptide from postnatal days 12 to 17.

The VE-cadherin antagonist significantly reduced retinal angiogenesis, suppressed tubule formation in endothelial cells and decreased cell migration and proliferation. The antagonist treatment did not affect the integrity of existing cell junctions, and immunostaining for VE-cadherin and rates of monolayer permeability were comparable to those in untreated controls.

Source: Navaratna D, Maestas J, McGuire PG, Das A. Suppression of retinal neovascularization with an antagonist to vascular endothelial cadherin. Arch Ophthalmol 2008;126(8):1082-1088.

SDOCT Imaging in Eyes with Advanced Dry AMD
To describe morphologic variations in outer retinal layers in eyes with atrophic AMD, a group of researchers used combined spectral domain optical coherence tomography (SDOCT)/confocal scanning laser ophthalmoscopy to obtain simultaneous tomographic and topographic in vivo images of 81 eyes of 56 patients with geographic atrophy. The images revealed a wide spectrum of morphologic alterations in atropic areas as well as surrounding retinal tissue.

Distinct morphologic changes in the perilesional zone included elevations of the outer retinal layers, thickening, spikes of the outer hyperreflective band and clumps at different neurosensory retinal levels. Highly variable transitions of the outer retinal layers were observed at the junctions of atropic and nonatropic tissue with different degrees of loss of the normal hyperreflective bands. Within the actual atropic areas, hyperreflective clumps at different retinal levels, segmented plaques of the outer band and elevations with variable reflectivity were seen.

The researchers reported that the findings may reflect different disease stages or perhaps heterogeneity on a cellular and molecular level. They noted that longitudinal studies utilizing in vivo SD-OCT may shed light on the relevance of these phenotypic changes as potential predictive markers for the progression of disease and may be used for monitoring future therapeutic interventions.

Source: Fleckenstein M, Issa PC, Helb HM, et al. High-resolution spectral domain-OCT imaging in geographic atrophy associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49(9):4137–4144.

Use of Electronic Health Records Among Ophthalmologists
In a population-based, cross-sectional study conducted by the American Academy of Ophthalmology (AAO) Medical Information Technology Committee, the adoption rate of electronic health records (EHRs) by ophthalmology practices is low but comparable to that seen in other specialties. A total of 3,796 AAO members were randomly selected on the basis of geography and solicited to participate in a survey regarding EHR adoption. Among those solicited, 392 members completed an Internet-based version of the survey and 200 members completed a telephone-based version.

Overall, 12 percent of the practices surveyed had already implemented EHRs, 7 percent were in the process of doing so, and 10 percent were planning to within 12 months. Among practices using EHRs, 69 percent reported they were satisfied or extremely satisfied with their system, 64 percent reported increased or stable overall productivity, 51 percent reported decreased or stable overall costs, and 76 percent would recommend an EHR system to a fellow ophthalmologist.

The committee plans to update the results of this survey on a regular basis.

Source: Chiang MF, Boland MV, Margolis JW, et al. Adoption and perceptions of electronic health record systems by ophthalmologists: an American Academy of Ophthalmology survey. Ophthalmology 2008;115(9):1591–1597.