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Defending Against Oxidative Damage in Macular Degeneration

The eye is particularly susceptible to oxidative stress, or damage to cellular components, caused by dangerous oxygen radicals that are sometimes generated during metabolic processes. Left unchecked, the oxidative stress can be cumulative and lead to age-related macular degeneration (AMD). The authors of this paper comment on a study by Weisman et al [Weismann D, Hartvigsen K, Lauer N, et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature. 2011;478(7367):76–81.] in which the researchers combined in vitro and in vivo data from human patients and animal models to describe how a protein normally associated with an immune pathway also protects against inflammation induced by oxidative stress in AMD as well as provided a plausible explanation for the cause of this devastating chronic disease.

A collection of proteins known as complement factors form part of the innate immune systems, which is the first line of defense against pathogens. Complement proteins have been implicated in certain pathological conditions, and have been found in the accumulated drusen of patients with AMD. Variations in the DNA sequence at particular sites, or polymorphisms, in genes encoding complement factors have been associated with the development of AMD and a polymorphism in complement factor H (CFH) conveys a significant risk of developing AMD, according to the literature.

Weisman et al. had an interest in malondialdehyde (MDA), a common decomposition product of lipid peroxidation by oxygen radicals that reacts with cellular proteins to form adducts that can act as markers of oxidative stress. They showed that CFH peptides constitute the majority of MDA-binding proteins and, through a series of designed experiments, clarified the physical and functional features of the CFH-MDS interaction. This turned out to be highly specific, with CFH binding to MDA whatever its carrier protein, but not to other oxidative products. The researchers mapped the CFH domains that specified MDA binding, including a short segment known as SCR7, which contains the Y402H mutation. They found that the Y402H CFH variant from AMD patients showed a markedly reduced ability to bind MDA compared with normal CFH. They further demonstrated that CFH and MDA co-localize in the eyes irrespective of whether these organs are affected by AMD, which suggests that in the healthy eye, CFH protects the macula, and in dying cells, it recognizes MDA-protein adducts. Weisman and colleagues also found that CFH can prevent MDA-mediated pro-inflammatory effects in at least two cell types associated with AMD: retinal pigment epithelial cells and macrophages.

The authors of this paper believe that the findings of Weisman et al answer the long-standing question about the role of CFH in AMD, while also raising other questions such as whether MDA's connection with CFH is relevant outside the eye. They also found that other members of the CFH family that bind MDA block CFH activity, suggesting that the subtle regulation of complement activity needs to be examined in more detail.

Source: Cruz-Guilloty F, Perez VL. Molecular medicine: Defence against oxidative damage. Nature. 2011;478(7367):42–43.

Choroidal Thickness in AMD Measured by SD-OCT

To understand the relationship between choroidal thickness and various disease factors in patients with age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT), researchers conducted a cross-sectional, retrospective analysis.

They analyzed 57 eyes of 47 patients with wet and dry AMD seen between November 2009 and January 2010 at the New England Eye Center in Boston and choroidal thickness was measured by two independent observers at 11 sites with high-definition horizontal 1-line raster scans through the foveal center. The study researchers performed a retrospective chart review to obtain data concerning duration of disease, number of intravitreal anti-vascular endothelial growth factor injections, visual acuity, lens status and concomitant retinal pathologic features. Additionally, they used the Pearson correlation and Student t test for statistical analysis for assessment of choroidal thickness changes in wet and dry AMD.

They reported that the choroid in eyes with wet and dry AMD demonstrated a wide range of thicknesses above and below the normal mean (range, 77.5 to 399.5 µm; standard deviation [SD], 90.2) and that nearly one-third (33.3%) of the eyes with AMD measured less than 1 SD below the mean. According to the researchers, eyes with wet AMD demonstrated a mean subfoveal choroidal thickness of 194.6 µm (SD, 88.4; n=40) compared with 213.4 µm (SD 92.2; n=17) in the dry AMD group. The choroidal thickness in eyes with dry AMD was correlated inversely with age (r= –0.703; p=.002); however, analysis of the number of intravitreal anti-vascular endothelial growth factor injections, number of years of disease and visual acuity failed to demonstrate any significant correlations with choroidal thickness.

This study demonstrated that choroidal thickness can be measured by SD-OCT and that variable choroidal thickness exists among patients with the clinical diagnosis of wet and dry AMD. However, it is unclear at this time why in some eyes, choroidal thickness either increases or decreases with the disease. Further studies to understand the significance of choroidal thickness with respect to visual function and disease progression over time are warranted.

Source: Manjunath V, Goren J, Fujimoto JG, Duker JS. Analysis of choroidal thickness in age-related macular degeneration using spectral-domain optical coherence tomography. Am J Ophthalmol. 2011;152(4):663–668.

SD-OCT to Evaluate Vitreoretinal Adhesions in Exudative AMD

The role of changes at the vitreoretinal interface and vitreomacular traction forces in pathogenesis, and the course of exudative age-related macular degeneration (AMD) need further exploration. Researchers in Austria conducted this study to examine the localization of adhesion and the direction of traction lines in eyes with exudative AMD.

They reviewed the cubes 512 x 128 of Cirrus optical coherence tomography (OCT) and volume scans of Spectralis OCT in a consecutive series of patients presenting between December 2008 and March 2009 with vitreomacular adhesion in exudative AMD.

The researchers studied 30 eyes of 25 patients with exudative AMD and vitreomacular adhesion. They found that 50% had type III lesions, 46.7% occult and 3.3% predominantly classic lesions. Additionally, the localization of the adhesion corresponded in 100% with the area of the neovascularization (CNV), in 73.3% traction directed toward the CNV and in 83.3% toward the optic disc could be noted. Spectral domain OCT and 3D visualization enabled clearer localization of vitreomacular adhesion and definition of resulting traction lines.

There is a high prevalence of type III lesions within eyes with vitreomacular adhesions, and complete correspondence between the location of the adhesion and the CNV, the researchers concluded. There is also a high incidence of vitreopapillary adhesion in these cases, suggesting a possible role in pathogenesis.

Source: Krebs I, Glittenberg C, Zeiler F, Binder S. Spectral domain optical coherence tomography for higher precision in the evaluation of vitreoretinal adhesions in exudative age-related macular degeneration. Br J Ophthlamol. 2011;95(10):1415–1418.

Use of 3D Computer-Automated Threshold Amsler Grid Testing for Differentiating Wet from Dry AMD

With increased efficacy of current therapy for wet age-related macular degeneration (AMD), better ways to detect wet AMD are needed. U.S. investigators sought to test the ability of three-dimensional contrast threshold Amsler grid (3D-CTAG) testing to distinguish wet AMD from dry AMD.

They performed conventional paper Amsler grid and 3D-CTAG tests in 90 eyes: 63 with AMD (34 dry, 29 wet) and 27 controls. They also based qualitative comparisons on the three-dimensional shapes of central visual field (VF) defects. Quantitative analyses considered the number and volume of the three-dimensional defects.

A total of 25/34 (74%) of the dry AMD eyes and 6/29 (21%) of the wet AMD eyes had no distortions on paper Amsler grid and of these, 5/25 (20%) dry and 6/6 (100%) wet (p=0.03) AMD eyes exhibited central VF defects with 3D-CTAG, the investigators reported. They found that wet AMD displayed stepped defects in 16/28 (57%) eyes, compared with only 2/34 (6%) of dry AMD eyes (p=0.002). They also noted that all three volumetric indices of VF defects were two- to four-fold greater in wet than dry AMD (p<0.006). Moreover, 3D-CTAG had 83.9% positive and 90.6% negative predictive values for wet AMD.

The study investigators concluded that 3D-CTAG has a higher likelihood of detecting central VF defects than conventional Amsler grid, especially in wet AMD. Wet AMD can be distinguished from dry AMD by qualitative and quantitative 3D-CTAG criteria. Thus, 3D-CTAG may be useful in screening for wet AMD, quantitating disease severity, and providing a quantitative outcome measure of therapy.

Source: Robison CD, Jivrajka RV, Bababeygy SR, et al. Distinguishing wet from dry age-related macular degeneration using three-dimensional computer-automated threshold Amsler grid testing. Br J Ophthalmol. 2011;95(10):1419–1423.

Early Visual Impacts of OCT Parameters in AMD Patients After the First vs Repeated Ranibizumab Injections

To evaluate the early visual impacts of various optical coherence tomographic (OCT) parameters after the first versus repeated intravitreal ranibizumab injection in patients with exudative age-related macular degeneration (AMD), this retrospective comparative case series study was conducted on 20 eyes of 18 consecutive patients who received intravitreal ranibizumab injection for exudative AMD either for the first time (group 1; n=8) with no prior anti-vascular endothelial growth factor (anti-VEGF) injection in the same or fellow eyes, or for repeated times during the course of monthly injected ranibizumab (group 2; n=12 eyes).

The following baseline and 1 month post-injection data was collected for both groups and compared: best-corrected visual acuity (BCVA), qualitative and quantitative OCT parameters including: foveal thickness, foveal volume (central 1-mm circle), retinal volume at 3- and 5-mm central circles, retinal pigment epithelium (RPE) elevation, type of fluid collections and type of AMD lesion. The size of the fluid and fibrovascular lesion (FVL) areas were measured using manual delineation and automatic calculation of the device. Additionally, correlations were made between the post-injection visual acuity (VA) and each of post-injection OCT parameters in both groups and these were the main outcome measures.

It was reported that in group 1, there was a strong correlation between post-injection logarithm of minimum angle of resolution (logMAR) BCVA and each of the following: FVL size, foveal thickness, retinal volume at 3- and 5-mm central circles, RPE elevation, the size of the fluid area and age of the patient (r>0.70, p<0.05), whereas in group 2; logMAR BCVA was strongly correlated only with foveal volume (r=0.74, p=0.01). Multivariate analysis showed that post-injection FVL size (r²=0.69) and foveal volume (r²=0.55) were the most important factors for VA 1 month following the initial and repeated ranibizumab injection, respectively.

In conclusion, the size of FVL and foveal volume showed a significant correlation with VA in AMD patients shortly after the first and repeated ranibizumab injection, respectively. Further studies with larger sample sizes are needed to support these results.

Source: Sayed KM, Naito T, Nagasawa T, et al. Early visual impacts of optical coherence tomographic parameters in patients with age-related macular degeneration following the first versus repeated ranibizumab injections. Graefes Arch Clin Exp Ophthalmol. 2011;249(10):1449–1458.

Comparison of Intravitreal Bevacizumab and Intravitreal Bevacizumab Plus Triamcinolone for Neovascular AMD

The authors of the following prospective, randomized clinical trial sought to determine whether combined intravitreal bevacizumab (IVB) and triamcinolone (IVT) is more effective than IVB alone in neovascular age-related macular degeneration (AMD).

They randomly assigned eligible eyes to one of the two study arms. In the IVB group, they gave 3 consecutive injections of 1.25 mg of bevacizumab 6 weeks apart, while in the IVB/IVT group, they combined the first of the triple IVB injections with 2 mg of IVB. They injected a fourth IVB in eyes demonstrating active choroidal neovascularization at Week 24.

The authors noted that 60 and 55 eyes were in the IVB and IVB/IVT groups, respectively. They observed that best-corrected visual acuity (BCVA) improved, and that central macular thickness was reduced significantly in both groups at all time points. They also found that visual improvement was more pronounced in the IVB/IVT group compared with the IVB group 6 weeks (8.5 ± 14.4 vs 3.8 ± 8.9 letters, p=0.04) and 12 weeks (11.8 ± 16.6 vs. 6.2 ± 10.8 letters, p=0.03) after initiation of therapy. However, the study authors detected no significant difference in visual improvement at Week 24 (11.3 ± 17.2 letters in the IVT/IVT group vs. 8.7 ± 15.6 letters in the IVG group, p=0.40). Furthermore, the IVB/IVT group showed significantly less need for a fourth injection at Week 24 (34.5% vs 53.3% in the IVB/IVT and IVB groups, respectively, p=0.04).

Mandated therapy with IVB improved BCVA and decreased central macular thickness in neovascular AMD, the authors determined. The addition of low-dose IVT temporarily increased the therapeutic efficacy in the early postinjection period and resulted in fewer requirements for repeat IVB injections at 6 months; however, the authors found that final levels of visual improvement were comparable in the two study groups.

Source: Ahmadieh H, Taei R, Riazi-Esfahani M, et al. Intravitreal bevacizumab versus combined intravitreal bevacizumab and triamcinolone for neovascular age-related macular degeneration: six-month results of a randomized clinical trial. Retina. 2011;31(9):1819–1826.

Monthly Ranibizumab for the Treatment of CNV Secondary to Angioid Streaks in PXE

This 12-month prospective, open-label, uncontrolled, nonrandomized interventional clinical trial evaluated the efficacy and safety of monthly intravitreal ranibizumab for the treatment of choroidal neovascularizations (CNV) secondary to angioid streaks (AS) in pseudoxanthoma elasticum (PXE).

In 7 patients, 1 eye with an active CNV was injected with 0.5 mg ranibizumab monthly over 1 year. Distance and reading visual acuity, ready speed, angiographic findings and central retinal thickness (CRT) on optical coherence tomography were assessed at each visit. Central retinal light increment sensitivity (LIS) was also assessed by microperimetry at baseline, at 6 months, and 3 to 4 months after the last injection.

It was found that best-corrected visual acuity (BCVA) increased significantly from baseline to month 12 (20/63 or 61 ETDRS letters to 20/32 or 73 ETDRS letters; p=.012). The effect was maintained 3 months later (61 ETDRS letters to 72 ETDRS letters; p=.055). Reading acuity and speed could be maintained throughout the study and central LIS improved (6.6 dB, SD ± 5.9 at baseline to 7.4 dB, SD ± 6.2 at last follow up; p<.001). It was also reported that leakage from active CNVs subsided and that mean change in CRT from baseline to month 12 and 15 was –86 µm (p=.074) and –65 µm (p=.182), respectively. No serious adverse events occurred.

It was determined that efficacy outcomes indicate a beneficial therapeutic effect of intravitreal ranibizumab on central visual function including retinal LIS. Both the functional and morphologic response based on angiographic and OCT findings to ranibizumab treatment implicate an important pathophysiological role of vascular endothelial growth factor in CNVs secondary to AS in PXE. Overall, intravitreal ranibizumab appears to be a safe and efficacious treatment in these patients.

Source: Finger RP, Issa PC, Hendig D, et al. Monthly ranibizumab for choroidal neovascularizations secondary to angioid streaks in pseudoxanthoma elasticum: a one-year prospective study. Am J Ophthalmol. 2011;152(4):695–703.

Efficacy of Polypoidal Choroidal Vasculopathy Treatments: Combined PDT and Intravitreal Bevacizumab vs PDT Alone

The medical records of 39 patients with symptomatic polypoidal choroidal vasculopathy who received combination therapy with photodynamic therapy (PDT) and intravitreal bevacizumab injections or PDT monotherapy were retrospectively reviewed to compare the efficacy of these treatment options.

Best-corrected visual acuity (BCVA), number of treatments and optical coherence tomography (OCT) and angiographic findings were compared between the two patient groups and it was determined that combined PDT and bevacizumab therapy effectively treated polypoidal choroidal vasculopathy with fewer PDTs compared with PDT alone during the 1 year of follow up.

In the PDT monotherapy group (n=19), the mean number of PDTs was 1.89, whereas in the combined therapy group (n=20), mean 1.30 times of PDT and 2.90 times of intravitreal bevacizumab injection were performed during the 12 months of follow up. It was observed that the number of PDTs was significantly different between the two groups (p=0.032) and that at 12 months, the mean improvement in BCVA was 3.0 lines in the combined group and 1.6 lines in the PDT monotherapy group. Moreover, at 12 months, improved vision by ≥3 lines was achieved in 55.0% in the combined therapy group and 36.8% in the PDT monotherapy group.

In conclusion, combined treatment appeared to result in better visual acuity, but a larger scale study is required to draw a definite conclusion.

Source: Kim SJ, Yu HG. Efficacy of combined photodynamic therapy and intravitreal bevacizumab injection versus photodynamic therapy alone in polypoidal choroidal vasculopathy. Retina. 2011;31(9):1827–1834.

Inflammatory Factors and Soluble VEGF Receptor-2 in Macular Edema with BRVO

Scientists in Japan investigated relationships among vitreous fluid levels of soluble vascular endothelial growth factor receptor-2 (sVEGFR-2), vascular endothelial growth factor (VEGF) and soluble intercellular adhesion molecule 1 (sICAM-1) in patients with branch retinal vein occlusion (BRVO) and macular edema or patients with idiopathic macular hole.

Their retrospective, case-control study took place at Tokyo Women's Medical University and Eguchi Eye Hospital and involved 49 Japanese patients who underwent unilateral vitrectomy (27 with BRVO and 22 with macular hole). They obtained vitreous fluid samples during vitreoretinal surgery to measure the levels of sVEGFR-2, VEGF and sICAM-1 and evaluated retinal ischemia from capillary nonperfusion on fluorescein angiography. They also examined macular edema by optical coherence tomography. Main outcome measures were vitreous fluid levels of the 3 molecules and severity of macular edema.

The scientists reported that BRVO patients had a significantly higher vitreous fluid level of sVEGFR-2 (median, 1670 pg/mL; interquartile range [IQL], 1205 to 2225 pg/mL) than macular hole patients (median, 1265 pg/mL; IQR, 731 to 1800 pg/mL; p=.017), as was the case for VEGF (median, 237 pg/mL; IQR, 42.2 to 1305 pg/mL; vs median, 15.6 pg/mL; IQR, 15.6 to 15.6 pg/mL; p<.001) and sICAM-1 (median, 10.1 ng/mL; IQR, 6.3 to 22.5 ng/mL; vs median, 4.1 ng/mL; IQR, 3.3 to 6.0 ng/mL; p<.001). In BRVO patients, they noted a significant positive correlation between vitreous fluid levels of sVEGFR-2 or VEGF and sICAM-1, but not between sVEGFR-2 and VEGF. Furthermore, they found that vitreous fluid levels of all 3 molecules were correlated significantly with the severity of macular edema in BRVO patients.

sVEGFR-2 may induce an increase of vascular permeability together with or via sICAM-1, or both with and via sICAM-1, in BRVO patients with macular edema.

Source: Noma H, Funatsu H, Mimura T, et al. Soluble vascular endothelial growth factor receptor-2 and inflammatory factors in macular edema with branch retinal vein occlusion. Am J Ophthalmol. 2011;152(4):669–677.

Treatment of Macular Edema Secondary to BRVO with Intravitreal Bevacizumab

To evaluate the effect of intravitreal bevacizumab on the visual and anatomical outcome in eyes with macular edema secondary to branch retinal vein occlusion (BRVO), investigators looked at a retrospective, consecutive case series that identified 53 consecutive patients with a BRVO treated with intravitreal bevacizumab. They analyzed clinical variables, including best-corrected visual acuity (BCVA), angiographic characteristics, central foveal thickness and complications.

A total of 53 eyes were identified with a mean initial BCVA of 20/137 and final BCVA of 20/96 (p=0.05) and the investigators noted that the mean final line change was +1.6 lines (95% confidence interval, +0.7 to +2.3; +8 letters [95% confidence interval, +3.5 to 11.5]. At final follow up, they reported that 28% gained ≥3 lines, whereas a loss of >3 lines was seen in 6% of eyes. The mean initial central foveal thickness of 425 µm decreased to 289 µm (p<0.001). Additionally, mean number of injections was 2.5, and mean follow up was 9 months. According to the study investigators, eyes treated for ≤6 months after the onset of BRVO showed improved functional outcomes (e.g., final BCVA, mean line change) as compared with those treated with >6 months of symptoms (p<0.01).

They determined that intravitreal bevacizuamb appears to be an effective treatment for macular edema secondary to BRVO in many subjects. Eyes treated with intravitreal bevacizumab showed a significant reduction in central foveal thickness and improvement in visual acuity. Early treatment with intravitreal bevacizumab resulted in a greater improvement in visual acuity compared with delayed treatment.

Source: Ehlers JP, Decroos FC, Fekrat S. Intravitreal bevacizumab for macular edema secondary to branch retinal vein occlusion. Retina. 2011;31(9):1856–1862.

Structure and Function of Macula in Advanced RP Patients

The authors of the following study aimed to assess the structure and function of the macula in advanced retinitis pigmentosa (RP).

The compared 29 eyes of 22 patients with RP against 17 control eyes. They processed time-domain optical coherence tomography (OCT) data using OCTRIMA as a means of quantifying Stratus OCT images. They also measured the thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer and inner plexiform layer complex (GCL+IPL), inner nuclear layer and outer plexiform layer complex (INL+OPL) and the outer nuclear layer (ONL). The study authors performed multifocal electroretinography (mfERG); they formed two groups based on the mfERG findings. A total of 14 eyes had no detectable central retinal function (NCRF) on mfERG; detectable but abnormal retinal function (DRF) was present in the mfERG of the other 15 eyes.

According to the authors, the thickness of the ONL in the central macular region was significantly less in the NCRF eyes compared to both DRF eyes and controls. They observed that the ONL was significantly thinner in the pericentral region in both patient groups compared to controls, while the thickness of the GCL+IPL and INL+OPL was significantly decreased only in the NCRF eyes. The authors also found that the RNFL in the peripheral region was significantly thicker while the thickness of the GCL+IPL and ONL was significantly thinner in both patient groups compared to controls.

The results are consistent with degeneration of the outer retina preceding inner retinal changes in RP. OCT image segmentation enables objective evaluation of retinal structural changes in RP with potential use in the planning of therapeutic interventions and conceivably as an outcome measure.

Source: Vámos R, Tátrai E, Németh J, et al. The structure and function of the macula in patients with advanced retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2011;Sept 22 [Epub ahead of print]. DOI : 10.1167/iovs.11-7780.

Determination of FAF and Retinal Structure with SD-OCT and Retinal Function in RP

In Japan, investigators examined the association between fundus autofluorescence (FAF) and retinal structure and function in retinitis pigmentosa (RP).

For image acquisition, they used HRA2 (Heidelberg Engineering) and 3D-OCT1000 (Topcon Corp.) and based on FAF examination, they categorized 88 eyes of 44 RP patients into three types. The investigators calculated the area within the hyperautofluorescent ring and the area of preserved retinal autofluorescence with FAF. They also assessed the association between the pattern of FAF and the residual area of the junction between the inner and outer segments of the photoreceptors (IS/OS line) and the relationship between the area within hyperautofluorescent ring, the area of preserved retinal autofluorescence and the mean deviation (MD) of static perimetry.

A total of 24 eyes were with preserved retinal autofluorescence without hyperautofluorescent ring, 54 eyes were with hyperautofluorescent ring and 10 eyes were with abnormal foveal autofluorescence both in the fovea and the periphery of the 30° scan, the investigators noted. They clearly detected the IS/OS line in the first type, and in the second type, they reported that the residual area of the partially distinct IS/OS line corresponded with the area within hyperautofluorescent ring with significant correlation between the area within hyperautofluorescent ring and the MD (R²=0.705, p<0.001); however, there was no correlation between the area of preserved retinal autofluorescence and the MD, or between the area of preserved retinal autofluorescence and the area within hyperautofluorescent ring. In the third type, the IS/OS was completely absent.

To conclude, the residual IS/OS line can be found in the area inside the hyperautofluorescent ring and correlates with residual visual function.

Source: Iriyama A, Yanagi Y. Fundus autofluorescence and retinal structure as determined by spectral domain optical coherence tomography, and retinal function in retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol. 2011; Sept 24 [Epub ahead of print]. DOI: 10.1007/s00417-011-1823-5.