Volume 9, Number 1
January 2013


WELCOME to Review of Ophthalmology's Retina Online e-newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

Clearside Biomedical Plans Clinical Testing of CLS1001 Suprachoroidal Injectable Suspension for Treatment of Eye Diseases
According to Clearside Biomedical Inc., the standard 30-day review period by the FDA relating to the company's Investigational New Drug (IND) Application for CLS1001 (triamcinolone acetonide) Suprachoroidal Injectable Suspension for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unrespsonsive to topical corticosteroids has concluded...

Positive iCo-007 Phase II Clinical Update
In a recent news release, iCo Therapeutics Inc. announced that at the midpoint of its Phase II iDEAL study for the treatment of diabetic macular edema (DME), there have been no drug-related serious adverse events...

And More...

Subretinal Drusenoid Deposits in Non-Neovascular AMD

The authors of this study sought to characterize the morphology, prevalence and topography of subretinal drusenoid deposits, a candidate histological correlate of reticular pseudodrusen, with reference to basal linear deposit (BlinD), a specific lesion of age-related macular degeneration (AMD), and to propose a biogenesis model for both lesions.

They postfixed donor eyes with median death-to-preservation of 2:40 hours in osmium tannic acid paraphenylenediamine and prepared them for macula-wide high-resolution digital sections. They determined annotated thicknesses of 21 chorioretinal layers standard locations in sections through the fovea and the superior perifovea.

According to the authors, in 22 eyes of 20 white donors (83.1 ± 7.7 years), subretinal drusenoid deposits appeared as isolated or confluent drusenoid dollops punctuated by tufts of retinal pigment epithelium apical processes and associated with photoreceptor perturbation. They detected subretinal drusenoid deposits and BlinD in 85% and 90% of non-neovascular AMD donors, respectively, and reported that subretinal drusenoid deposits were thick (median, 9.4 µm) and more abundant in the perifovea than in the fovea (p<0.0001). Furthermore, BlinD was thin (median, 2.1 µm) and more abundant in the fovea than in the perifovea (p<0.0001).

The study authors concluded that subretinal drusenoid deposit and BlinD prevalence in AMD eyes are high. Subretinal drusenoid deposits organized morphology, topography and impact on surrounding photoreceptors imply specific processes of biogenesis. Contrasting topographies of subretinal drusenoid deposits and BlinD suggest relationships with differentiable aspects of rod and cone physiology, respectively. A two-lesion, two-compartment biogenesis model incorporating outer retinal lipid homeostasis is presented.

Source: Curcio CA, Messinger JD, Sloan KR, et al. Subretinal drusenoid deposits in non-neovascular age-related macular degeneration: morphology, prevalence, topography and biogenesis model. Retina. 2012; Dec 21. [Epub ahead of print]. DOI: 10.1097/IAE.0b013e31827b6324.

Predictors for Visual Outcomes with Ranibizumab or Bevacizumab for Neovascular AMD

To determine the baseline predictors of visual acuity (VA) outcomes one year following treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD), a cohort study within the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) was conducted.

A total of 1,105 participants with neovascular AMD, baseline VA 20/25 to 20/320 and VA measured at one year were included. Participants were randomly assigned to ranibizumab or bevacizumab on a monthly or as-needed schedule. Masked readers evaluated fundus morphology and features on optical coherence tomography (OCT). VA was measured using electronic VA testing and independent predictors were identified using regression techniques. Main outcome measures were the VA score, VA score change from baseline and a gain of three lines or more at one year.

At one year, the mean VA score was 68 letters, mean improvement from baseline was seven letters and 28% of participants gained three or more lines. Older age, larger area of choroidal neovascularization (CNV) and elevation of retinal pigment epithelium (RPE) were associated with worse VA (all p<0.005), less gain in VA (all p<0.02) and a lower proportion gaining ≥3 lines (all p<0.04). It was noted that better baseline VA was associated with better VA at one year, less gain in VA, and a lower proportion gaining ≥3 lines (all p<0.0001). Additionally, predominantly or minimally classic lesions were associated with worse VA than occult lesions (66 vs. 69 letters; p=0.0003), retinal angiomatous proliferans (RAP) lesions were associated with more gain in VA (10 vs. seven letters; p=0.03) and a higher proportion gaining ≥3 lines (odds ratio, 1.9; 95% confidence interval, 1.2–3.1), and geographic atrophy (GA) was associated with worse VA (64 vs. 68 letters; p=0.02). Moreover, eyes with total foveal thickness in the second quartile (325–425 µm) had the best VA (p=0.01) and were most likely to gain ≥3 lines (p=0.004). Predictors did not vary by treatment group.

For all treatment groups, older age, better baseline VA, larger CNV area, predominantly or minimally classic lesion, absence of RAP lesion, presence of GA, greater total fovea thickness and RPE elevation on OCT were independently associated with less improvement in VA at one year.

Source: Ying GS, Huang J, Maguire MG, et al; Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration. Ophthalmology. 2013; 120(1):122–129.

Long-Term Safety of Ranibizumab 0.5 mg in the Treatment of Neovascular AMD

In this 24-month, open-label, multicenter, phase IV extension study, investigators evaluated long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (AMD).

They included 234 patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. Ranibizumab 0.5 mg administered at the investigator's discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigator's opinion). Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time and the number of injections were the main outcome measures.

The study investigators reported that of 234 enrolled patients, 210 (89.7%) completed the study. They observed that patients received 6.1 (mean) ranibizumab injections over 24 months and that approximately 42% of patients had seven or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than five letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; one event related to study drug), cataract (11.5%; one event related to treatment procedure) and increased IOP (6.4%; one event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients, but none was suspected to be related to study drug or procedure, the investigators noted. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, but none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline.

In conclusion, the SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigator's discretion was well-tolerated over two years. No new safety signals were identified in patients who received ranibizumab for a total of three years, and on average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment.

Source: Silva R, Axer-Siegel R, Eldem B, et al; SECURE Study Group. The SECURE Study: Long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration. Ophthalmology. 2013;120(1):130–139.

Intravitreal Ranibizumab Used to Treat PED with Subfoveal Occult CNV

The investigators in the following prospective, interventional case series sought to assess the effects of intravitreal ranibizumab injection in patients affected by pigment epithelial detachment (PED) associated with occult subfoveal choroidal neovascularization (CNV).

The considered 40 eyes of 40 patients for the purpose of the study and recruited consecutive patients for a 24-month study. All patients underwent a complete ophthalmic examination, including best-corrected visual acuity (BCVA) on Early Treatment Diabetic Retinopathy Study (ETDRS) charts. After a three-month loading phase, the investigators administered further intravitreal ranibizumab injections on the basis of detection of any type of fluid on optical coherence tomography (OCT). Primary outcome measures included any changes in mean BCVA at 12 and 24 months and the proportion of eyes losing fewer than 15 letters (corresponding to three ETDRS lines) from baseline visual acuity. Secondary outcome measures included changes in central macular thickness on OCT and variation in mean area of the entire lesion.

The investigators reported that 40 patients were included in their study. They also noted that mean BCVA decreased from 20/66 (58 ETDRS letters) to 20/83 (53 letters) at 12 months and 20/112 (489 ETDRS letters) at 24 months (p=.003). They observed that 80% and 67.5% of eyes lost fewer than three lines at 12 and 24 months, respectively. Furthermore, mean central macular thickness passed from 545 µm to 428 µm at 12 months and 426 µm at 24 months. Mean lesion area changed from 6,826 µm² to 6,312 µm² at 12 months and 6,010 µm² at 24 months.

The treatment of PED associated with occult subfoveal CNV with intravitreal ranibizumab injection after a three-month loading phase and pro re nata strategy can lead to partial results over a 24-month follow-up, the study investigators determined. Further investigations are warranted to establish the best therapeutic approach to this disease.

Source: Parodi MB, Iacono P, Papayannis A, et al. Intravitreal ranibizuamb for pigment epithelium detachment with subfoveal occult choroidal neovascularization: a prospective 24-month case series. Am J Ophthalmol. 2013;155(1):103–108.

Treatment Results of Ranibizumab for Neovascular AMD and Causes for Discontinuation

Danish researchers conducted a retrospective, single-center chart review to evaluate four-year treatment results of neovascular age-related macular degeneration (AMD) with ranibizumab using a variable dosing regimen.

The study included 855 patients with neovascular AMD receiving treatment with ranibizumab during a four-year period. Included in the study were patients with a minimum follow-up of 15 months and all patients who terminated treatment regardless of follow-up.

The researchers noted that 1,321 patients were treated over the four-year period, and 855 patients were eligible for inclusion. Of those, 456 patients were still receiving active treatment, whereas 399 patients had discontinued treatment. Overall treatment results showed a significant decrease in vision from 53.2 Early Treatment Diabetic Retinopathy Study letters (range, 1 to 85 letters) to 50.5 letters (range, 1 to 87 letters; p<.001). According to the study researchers, mean follow-up was 23.3 months (range, four to 48 months). The reason for discontinuing treatment in 181 patients was no signs of activity, whereas 113 patients were judged to be non-treatable. A total of 36 patients declined further treatment for various reasons.

This report shows that when follow-up extends beyond two to three years, visual acuity does seem to decrease. Our data show that different responder groups can be identified: bad or nonresponders (approximately 15% of all patients) and good responders (approximately 21% of all patients). These two groups in general can be identified within the first two years of treatment, whereas the third group of regular responders (approximately 64% of all patients) require continuous monitoring and treatment for years.

Source: Falk MK, Kemp H, So/rensen TL. Four-year treatment results of neovascular age-related macular degeneration with ranibizumab and causes for discontinuation of treatment. Am J Ophthalmol. 2013;155(1):89–95.

Changes in VA of Wet AMD Patients Treated with Intravitreal Ranibizumab

A retrospective, descriptive, observational study in patients with subfoveal wet age-related macular degeneration (AMD) treated with ranibizumab was conducted to survey compliance with recommended intravitreal ranibizumab treatment protocols in daily clinical practice in France, with reference to outcomes.

All historical data for the study period, including demographic, treatment and disease details and visual acuity measurements (baseline, month three, and month 12), were recorded retrospectively at least 12 months after the beginning of treatment.

It was observed that in 551 patients followed by 16 ophthalmologists, 12 months of intravitreal ranibizumab treatment induced a mean visual acuity gain of 3.2 ± 14.8 Early Treatment Diabetic Retinopathy Study-equivalent letters. It was also noted that less than 40% of patients received the recommended treatment of initial three monthly injections. More than 50% had to wait more than eight days between diagnosis and treatment. At month three, visual acuity gain was greater in patients who had received recommended induction and in whom treatment was initiated quickly. At month 12, the induction-related effect had largely disappeared, but the time-to-treatment effect persisted. Patients had an average of 5.1 injections (2.6 during induction period). No patients were monitored monthly as stipulated in the guidelines.

To conclude, although poor compliance with recommendations has been reflected in mediocre outcomes, there is evidence that practice is improving.

Source: Cohen SY, Mimoun G, Oubraham H, et al; for the LUMIERE Study Group. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE Study. Retina. 2013; Dec 21. [Epub ahead of print]. DOI: 10.1097/IAE.0b013e31827b6324.

Variants in the VEGFA Gene and Outcome of Treatment Following Anti-VEGF Treatment for Neovascular AMD

The authors of the following Australian prospective cohort study sought to determine the association of genetic variants of the VEGFA gene with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD).

They included 201 consecutive patients receiving anti-VEGF injection for neovascular AMD, whom they followed over 12 months. Patients were treated with three initial monthly ranibizumab or bevacizumab injections. Thereafter, the decision to retreat was made by clinicians at each follow-up visit on the basis of retreatment criteria. Seven tagged single nucleotide polymorphisms (tSNPs) in the VEGFA gene were selected and examined and multivariate data analysis was used to determine the role of each tSNP in treatment outcome. The influence of selected VEGFA tSNPs on visual acuity (VA) outcome at six months was the main outcome measure.

Mean baseline VA was 51 ± 17 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores, the authors reported. Overall, they found that the mean change in VA from baseline was +6.5 ± 12, +4.4 ± 13.4, and +2.3 ± 14.6 letters at three, six and 12 months, respectively. The tSNP rs3025000 was the only SNP significantly associated (p<1 × 10–4) with visual outcome at six months with multiple correction. The presence of the T allele (TC or TT genotypes) at this tSNP predicted a better outcome of +7 letters at six months compared with the CC genotype. In a subgroup analysis, presence of the T allele predicted a significantly higher chance of the patients belonging to the responder group (gain of ≥5 letters from baseline) after three, six and 12 months treatment (odds ratio, 2.7, 3.5 and 2.4; 95% confidence interval, 1.46 to 5.07, 1.82 to 6.71 and 1.27 to 4.57, respectively) than any other outcome group.

Pharmacogenetic association with anti-VEGF treatments may influence the visual outcomes in neovascular AMD, the authors concluded. In patients with the T allele in tSNP rs3025000, there was a significantly better visual outcome at six months and a greater chance of the patients belonging to the responder group with anti-VEGF treatment at three, six and 12 months. The VA outcomes of patients harboring the T allele at SNP rs3025000 were comparable with those of the pivotal clinical trials but with fewer injections, making the treatment perhaps more cost effective in certain subgroups of patients.

Source: Abedi F, Wickremasinghe S, Richardson AJ, et al. Variants in the VEGFA gene and treatment outcome after anti-VEGF treatment for neovascular age-related macular degeneration. Ophthalmology. 2012;120(1):115–121.

An Association of Transferrin Gene Polymorphism and Serum Transferrin Levels with AMD

Oxidative stress has been proven to play a key role in age-related macular degeneration (AMD) pathogenesis, and because iron accumulation has been found in AMD maculae, it may accelerate the oxidative processes in this tissue. In the present work, scientists in Poland investigated the association between four polymorphisms of the transferrin gene (rs8177178; rs8177179; rs4481157; rs1130459) and AMD in dependence on the transferrin protein and iron serum levels.

They employed polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) for genotype determination, ELISA assay for serum transferrin evaluation and colorimetric assay for measurement of iron concentration in the serum and found that advanced age and AMD family history may be independent risk factors for AMD (1.02, p<0.05 and 8.88, p<0.001, respectively).

At the rs4481157 site, the GG genotype of the rs4481157 polymorphism decreased the risk of dry AMD (OR 0.50; p<0.05), while the GA increased this risk (OR 1.07; p<0.05). Moreover, the GA genotype of this polymorphism decreased the risk of progression to the wet form (OR 0.63; p<0.05). The scientists' analysis of the gene-environment interactions showed that the rs4481157 polymorphism modulates the AMD risk among obese (BMI above 30) individuals.

In the former smokers group, they observed a moderate association between rs4481157 polymorphism and AMD risk, while this association in current smokers was stronger. They found also that the serum level of transferrin was higher in the AMD group (p<0.001) than in the control, but the total serum iron levels did not differ between both groups. Furthermore, they found that the serum transferrin was associated with the rs8177178 (p<0.001) and rs4481157 (p<0.01) polymorphisms, and the common variant (GG) of both sites was related to a lower level of transferrin. Presented data may contribute to the involvement of iron homeostasis in AMD risk.

Source: Wysokinski D, Danisz K, Blasiak J, et al. An association of transferrin gene polymorphism and serum transferring levels with age-related macular degeneration. Exp Eye Res. 2013;106:14–23.

Letter Reanalyzes AREDS Data

In the Age-Related Eye Disease Study (AREDS), the growth of geographic atrophy (GA) over four years was shown to be dependent on the baseline area of GA; however, three articles have demonstrated that the square root transformation of lesion area measurements eliminates the dependence on baseline lesion size for both the test-retest variability and the growth rates.

Area measurements of GA collected from 181 eyes of 181 AREDS study patients and followed up longitudinally for up to four years were analyzed using the square root transformation strategy. The correlations between growth of the lesion area over four years and baseline lesion size were performed on the original area scale and on the square root area scale with both Pearson and Spearman correlation analyses. A second analysis divided lesions into the published categories of baseline lesion size expressed as disc areas (<0.75, 0.75 to <4 and ≥4 disc areas), and lesion growth was calculated and compared using the standard area of measurements (millimeters squared) and the square root of these same measurements (millimeters). The influences of the assigned treatments (zinc and antioxidants) were also analyzed using the square root transformation strategy and these analyses were performed using generalized estimating equations with correlation structure modeled as first-order autoregressive.

According to the authors of this letter, application of the square root transformation to the area measurements eliminated the statistical significance of the correlations between growth and baseline area. Four-year growth rates were significantly correlated with baseline lesion size using the original area measurements (Pearson r=0.53, p<.001; Spearman r=0.49, p<.001), but there was not statistically significant correlation once the area measurements underwent the square root transformation strategy (Pearson r=0.10, p=.30; Spearman r=0.17, p=.08). When the baseline lesions were divided into different size categories, there was a statistically significant difference in the growth of GA using the original area measurements (p<.001), but no statistically significant difference after applying the square root transformation strategy (p=.34). Zinc and antioxidant treatment and their interaction were not associated with decreased lesion growth using either the original area or square root area measurements (all p>.28).

The square root transformation strategy reduced the association between growth rates and baseline area measurements in AREDS, which confirmed the recent reports. Additionally, the square root strategy simplifies the design and enrollment of clinical trials by eliminating the need to either specify a range of lesion sizes or adjust for lesion size in the analysis. While this reanalysis of the AREDS data did not alter the conclusion about the lack of efficacy when using zinc and antioxidants for the treatment of GA, the square root strategy did eliminate the artifactual dependence of growth on baseline size within the range of lesion sizes enrolled in AREDS. However, very small lesions when GA first appears and very large lesions nearing the end of their growth cycle are expected to grow more slowly based on the natural history of GA in AMD.

Source: Feuer WJ, Yehoshua Z, Gregori G, et al. Square root transformation of geographic atrophy area measurements to eliminate dependence of growth rates on baseline lesion measurements: a reanalysis of Age-Related Eye Disease Study Report No. 26. JAMA Ophthalmol. 2013; 131(1):110–111.

Retinal Sensitivity Following Intravitreal Triamcinolone Acetonide Injection for ME Secondary to BRVO

To evaluate the effect of intravitreal triamcinolone acetonide (IVTA) on retinal sensitivity in cases of macular edema (ME) secondary to branch retinal vein occlusion (BRVO), Turkish investigators conducted this prospective study, which included 14 eyes of 14 cases of BRVO.

In each eye, at baseline and one, three and six months after IVTA injection, they assessed logMAR visual acuity, central 4° retinal sensitivity by MP-1 microperimetry and optical coherence tomography (OCT) foveal thickness.

The investigators reported that ages ranged from 60 to 79 years (mean 68 ± 8 years). At one, three and six months, the logMAR visual acuity had increased from 0.71 ± 0.21 to 0.42 ± 0.21, 0.46 ± 0.30 and 0.46 ± 0.27; the mean foveal thickness had decreased from 540 ± 88 µm to 254 ± 51 µm, 288 ± 84 µm and 280 ± 91 µm; and the mean retinal sensitivity had increased from 4.7 ± 2.5 dB to 7.9 ± 2.7 dB, 8.2 ± 3.6 dB and 8.3 ± 4.6 dB, respectively.

In eyes with ME secondary to BRVO, IVTA injections result in a significant increase in not only the visual acuity, but also the central 4° retinal sensitivity in six months follow-up.

Source: Senturk F, Ozdemir H, Karacorlu M, et al. Retinal sensitivity improvement after intravitreal triamcinolone acetonide injection for macular edema secondary to branch retinal vein occlusion. Indian J Ophthalmol. 2013;61(1):3–7.

Link Between Morphologic and Functional Changes in Retinal Vessels and BRVO

The authors of the following Japanese prospective, observational, cross-sectional study examined the morphologic and functional changes in retinal veins of eyes affected with branch retinal vein occlusion (BRVO) by thin sectioning with optical coherence tomography (OCT).

They included 25 consecutive patients (25 eyes) with acute BRVO and examined major retinal veins, arteries and arteriovenous (A/V) crossing by sequential thin sectioning by Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg). The retinal blood flow was mimicked in vitro and scanned with Spectralis HRA+OCT. Morphologic characteristics of normal and BRVO-affected retinal vessels seen in OCT sections were the main outcome measures.

Cross-sectional OCT images revealed physiologic retinal vessels as oval configurations with four distinctive hyperreflectivities in a line, the authors noted. They also reported that the vessel walls showed the innermost and outermost hyperreflectivity, and the blood flow showed internal paired hyperreflectivities with an hourglass shape. According to the authors, no eye with disturbed blood flow due to BRVO showed this internal hyperreflectivity pattern. They found that, in vitro, OCT sections of the blood within the glass tube without flow showed homogeneous reflectivities. Increased blood flow velocity resulted in the development of heterogeneous internal reflectivity and hourglass-shaped hyperreflectivities. In all eyes with acute BRVO, sequential sectioning with OCT visualized three-dimensional vascular architecture and the intravascular conditions at the A/V crossing. At the affected A/V crossing, arterial overcrossing was seen in 17 eyes and venous overcrossing was seen in eight eyes. In eyes with arterial overcrossing, the study authors noted that the retinal vein seemed to run deep under the artery at the A/V crossing, and the venous lumen often appeared to be preserved even at the A/V crossing. In all eyes with venous overcrossing, the retinal vein appeared to be compressed and choked between the internal limiting membrane and the arterial wall at the A/V crossing. Optical coherence tomography sectioning showed intravenous thrombi in 21 eyes, and the thrombi were detected downstream of the A/V crossing in all the cases. The detection of thrombus was significantly associated with ischemic pattern in BRVO (p=0.036).

In conclusion, in eyes with BRVO, sequential thin sections with OCT visualized three-dimensional retinal vasculature. The present OCT findings suggest that BRVO may occur by two different mechanisms, depending on the relative anatomic positions of the crossing vessels.

Source: Muraoka Y, Tsujikawa A, Murakami T, et al. Morphologic and functional changes in retinal vessels associated with branch retinal vein occlusion. Ophthalmology. 2013;120(1):91–99.

Impact of Subconjunctival Bevacizumab on Corneal NV

London researchers evaluated the off-label use of subconjunctival bevacizumab for corneal neovascularization (NV) and found that three subconjunctival injections of 2.5 mg bevacizumab are more effective than placebo at inducing the regression of recent-onset corneal NV.

They randomly assigned 30 patients with recent-onset corneal NV from various causes into a double-masked, placebo-controlled trial. Each received three 0.1 ml injections containing either 2.5 mg bevacizumab or 0.9% saline at monthly intervals. The researchers used dexamethasone 0.1% drops four times a day for the first month, at which time the dose was modified, if clinically indicated. The primary outcome was change in area of corneal involvement by corneal NV from baseline to three months measured using specialized imaging technology.

The mean area of corneal NV reduced by –36% (range –92% to +40%) in the 15 eyes that received bevacizumab compared with an increase of 90% (range –58% to +1,394%) in eyes that received saline placebo (analysis of covariance (ANCOVA); p=0.007), the researchers noted. One outlier in the placebo arm developed corneal graft rejection with aggressive neovascularization (+1,384%), but even when this patient was excluded, the mean reduction in corneal NV in the placebo group (–3%, range –58% to +40%) was still significantly different from the treatment arm (ANCOVA; p=0.016). Moreover, changes in best-corrected visual acuity, central corneal thickness, intraocular pressure and endothelial cell counts were similar between groups. The intervention was well tolerated with no major safety concerns.

Further studies are needed to confirm this effect and our data suggest that a sample size of 40 patients per treatment group is required.

Source: Petsoglou C, Balaggan KS, Dart JK, et al. Subconjunctival bevacizumab induces regression of corneal neovascularization: a pilot randomized placebo-controlled double-masked trial. Br J Ophthlamol. 2013;97(1):28–32.

Sustained Chronic Inflammatory Reaction in RP

This Japanese retrospective, observational study investigated the nature of inflammatory reaction in eyes of patients with retinitis pigmentosa (RP) and its possible role in the pathogenesis of the disease.

A total of 371 consecutive patients diagnosed with typical RP were included in this study and an additional 165 patients without active inflammatory diseases, including 20 patients diagnosed with cataract, and 36 patients diagnosed with idiopathic epiretinal membrane, were included as controls.

Density of the inflammatory cells in the anterior vitreous cavity was measured and graded by slit lamp biomicroscopy. A multiplex enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the concentration of cytokines and chemokines in aqueous humor and vitreous fluid of patients with RP and controls. In addition, the relationship between visual function and anterior vitreous cells in these patients was investigated. Main outcome measures were slit lamp biomicroscopic analysis, best-corrected visual acuity, visual field analysis and multiplex ELISA.

In 190 of 509 eyes with RP (37.3%), “1+” (five to nine cells per field) or more cells were observed in the anterior vitreous cavity. Strong inflammatory reaction with “2+” cells (10–30 cells per field) was associated with younger age. It was noted that in the elderly patients with RP, significantly decreased visual function was seen in a group with “1+” or more cells (p<0.05). Moreover, the levels of a variety of proinflammatory cytokines and chemokines, including monocyte chemotactic protein-1, were increased both in the aqueous humor and vitreous fluid of RP patients compared with the levels in control patients.

It was determined that sustained chronic inflammatory reaction may underlie the pathogenesis of RP, suggesting interventions for ocular inflammatory reaction as a potential treatment for patients with RP.

Source: Yoshida N, Ikeda Y, Notomi S, et al. Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology. 2013;120(1):100–105.

Retinal Vessel Caliber and Glaucoma Incidence

To examine associations between quantitatively measured retinal vessel caliber and the 10-year incidence of primary open-angle glaucoma (OAG), the authors of this population-based cohort study (The Blue Mountains Eye Study) examined 3,654 persons at baseline and 2,461 persons at either five years, 10 years or both times.

After excluding 44 subjects with OAG at baseline, 2,417 participants at risk of OAG at the five- or 10-year examinations were included. The authors measured retinal vessel calibers of baseline retinal photographs using a computer-based program and summarized these as central retinal artery and vein equivalents (CRAE, CRVE). They defined incident OAG as the development of typical glaucomatous visual field loss combined with matching optic disc rim thinning and an enlarged cup-to-disc (C:D) ratio of >0.7 or C:D asymmetry between the two eyes (≥0.3) at either the five- or 10-year examination. The study authors used generalized estimating equation models to account for correlation between eyes while adjusting for glaucoma risk characteristics including intraocular pressure (IOP) or ocular perfusion pressure (OPP). For the main outcome measures, they assessed the 10-year incidence of OAG.

According to the authors, 82 persons (104 eyes) developed incident OAG over the 10-year follow-up. After adjusting for age, sex, family history of glaucoma, smoking, diabetes, hypertension, hypercholesterolemia, body mass index, spherical equivalent refraction and C:D ratio, they found an associated between narrower CRAE and higher risk of incident OAG (adjusted odds ratio [OR], 1.77; 95% confidence interval [CI], 1.12 to 2.79, per standard deviation decrease in CRAE). This association persisted after further adjustment for IOP (adjusted OR, 1.87; 95% CI, 1.14 to 3.05) or OPP (adjusted OR, 1.76; 95% CI, 1.11 to 2.78), and remained significant when analyses were confined to eyes with IOP <20 mmHg and C:D ratio <0.6 at baseline. There were no independent associations between CRVE and incident OAG.

Retinal arteriolar narrowing, quantitatively measured from retinal photographs, was associated with long-term risk of OAG. These data support the concept that early vascular changes are involved in the pathogenesis of OAG and suggest that computer-based measurements of retinal vessel caliber may be useful to identify people with an increased risk of developing the clinical stage of glaucoma.

Source: Kawasaki R, Wang JJ, Rochtchina E, et al. Retinal vessel caliber is associated with the 10-year incidence of glaucoma: the Blue Mountains Eye Study. Ophthalmology. 2013;120(1):84–90.

Clearside Biomedical Plans Clinical Testing of CLS1001 Suprachoroidal Injectable Suspension for Treatment of Eye Diseases

According to Clearside Biomedical Inc., the standard 30-day review period by the FDA relating to the company's Investigational New Drug (IND) Application for CLS1001 (triamcinolone acetonide) Suprachoroidal Injectable Suspension for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unrespsonsive to topical corticosteroids has concluded and clinical testing can proceed. Clearside Biomedical treats the pathological changes to the blood retinal barrier that lead to retinal blindness by delivering therapeutics through the suprachoroidal space using a proprietary microinjection dosage form that allows compartmentalization within the distinct areas of the eye. It is currently targeting the initiation of a Phase I–II clinical trial in the United States in the first quarter 2013 to evaluate the safety and tolerability of the product candidate in subjects with non-infectious uveitis.

Source: Clearside Biomedical Inc., January 2013.

Positive iCo-007 Phase II Clinical Update

In a recent news release, iCo Therapeutics Inc. announced that at the midpoint of its Phase II iDEAL study for the treatment of diabetic macular edema (DME), there have been no drug-related serious adverse events among patients receiving repeat doses of iCo-007. The trial explores whether varying combinations of iCo-007 are effective in improving visual acuity in DME patients. The Phase II trial is studying patients at 26 clinical sites across the United States and iCo also reported that it has exceeded its recruitment threshold of patients for statistical analysis of the study and expects to announce final data for the primary endpoint in the fourth quarter of 2013. Additional information on the Phase II iDEAL study can be found here as well as here.

Source: iCo Therapeutics Inc., January 2013.

U.S. Launch of JETREA

ThromboGenics NV recently launched its JETREA (ocriplasmin) Intravitreal Injection, which is indicated for the treatment of symptomatic vitreomacular adhesion, in the United States. The company states that the price for a single-use glass vial of JETREA is set at $3,950. For further information, visit www.jetrea.com.

Source: ThromboGenics NV, January 2013.


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