Volume 5, Number 4
April 2009






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.





In This Edition:
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: Positive Interim Results for Othera's Phase 2 trial of OT-551; The AMD-Meat Connection; Iluvien Phase 3 Studies for DME Pass Final Review.





THE LATEST PUBLISHED RESEARCH

Management of Patients with DME and Capillary Loss
Investigators conducted a multicenter, open-label, nonrandomized study in two tertiary ophthlamic referral centers in Brazil to evaluate the effects of intravitreal bevacizumab in patients with diabetic macular edema (DME). Using intravitreal injection(s) of bevacizumab (1.5 mg) as observational procedures, they performed standardized ophthalmic evaluations on 10 consecutive patients with DME and "severe" capillary loss at baseline and at weeks 8, 16, 24 and 54. Main outcome measures were changes in best-corrected visual acuity (BCVA) and in optical coherence tomography variables (central macular thickness [CMT] and total macular volume [TMV]).

The study investigators noted significant changes in BCVA and in CMT/TMV throughout the study (p<.001, p=.009 and p<.001, respectively). The mean logarithm of the minimal angle of resolution Early Treatment Diabetic Retinopathy Study BCVA was 0.786 (approximately 20/125[+1]) at baseline, 0.646 (approximately 20/80 [-2]) at week 8, 0.580 (20/80[+1]) at week 24 and 0.558 (approximately 20/80 [+2]) at week 54. They noted a significant change in BCVA at all follow-up visits compared with baseline (p</=.008). They also reported that the mean CMT/TMV values were, respectively, 472.6/10.9 at baseline, 371.4/9.9 at week 8, 359.5/9.8 at week 16, 323.9/9.4 at week 24 and 54 weeks (p</=.007). At 54 weeks, fluorescein angiography demonstrated no change in the extent of macular capillary loss and reduced dye leakage as compared with baseline in all patients.

Favorable changes in BCVA and in CMT/TMV observed throughout 1 year suggest that intravitreal bevacizumab may be a viable alternative treatment for the management of patients with DME and severe capillary loss, the investigators concluded.

Source: Bonini-Filho M, Costa RA, Calucci D, et al. Intravitreal bevacizumab for diabetic macular edema associated with severe capillary loss: one-year results of a pilot study. Am J Ophthalmol 2009; Mar 25 [Epub ahead of print]. DOI: 10.1016/j.ajo.2009.01.009.


Sleep-Disordered Breathing and Diabetic Retinopathy
The authors of this cross-sectional, case-control study sought to clarify the relationships of sleep-disordered breathing (SDB) to nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).

They included 48 consecutive NPDR and 118 PDR cases that had undergone surgery in their hospital and conducted pulse oximetry during the night as well as calculated the sleeping 4% oxygen desaturation index (ODI, number of oxygen desaturation events/hour exceeding 4%) and mean SpO2%. They diagnosed SDB if 4% ODI>5 times/hour. Furthermore, the study authors evaluated the results and compared them between the two groups. They also analyzed these results and preop patient background factors using multiple regression analysis to identify correlations with the diagnosis of PDR.

Of the NPDR patients, 29% were diagnosed with SDB (compared with 48% of the PDR patients). The incidence of SDB and the 4% ODI/hour value were significantly higher in the PDR than in the NPDR group (p=.003 and .03, respectively). Based on multiple regression analysis, younger age and a higher 4% ODI value were determined to be factors independently contributing to a diagnosis of PDR (age, standard regression coefficient = -0.34; t value = -4.44; p<.001; 4% ODI, standard regression coefficient = 0.20; t value = 2.15; p = .03, correlation coefficient [R] = 0.43).

Based on their study results, the authors believe that, in diabetic retinopathy patients with nocturnal desaturation, reoxygenation caused by SDB may relate to the development of PDR.

Source:Shiba T, Sato Y, Takahashi M. Relationship between diabetic retinopathy and sleep-disordered breathing. Am J Ophthalmol 2009; Mar 9 [Epub ahead of print].


Blood Pressure and Diabetic Retinopathy
To identify whether the variability of blood pressure (BP) is associated with diabetic retinopathy (DR) in normotensive type 2 diabetes mellitus (DM) patients, 65 normotensive type 2 DM patients who had 24-hour ambulatory BP monitoring (ABPM) were grouped according to any degree of DR.

Of the 65 patients, 14 (21%) had DR. Office BP and 24-hour parameters did not differ between groups and at late afternoon period, patients with DR had higher increment in both systolic (11.3 ± 12.7 mmHg vs. 1.0 ± 11.4 mmHg, p=0.006) and diastolic (6.7 ± 8.6 mmHg vs. -0.73 ± 10.0 mmHg, p=0.017) BP levels than those without. Multivariate logistic analyses were performed with DR as a dependent variable. Additionally, each 1 mmHg increment in systolic BP at the late afternoon period was associated with a 10.2% increase in DR prevalence [OR 1.102 (CI 95% 1.011-1.202, p=0.027)], after adjustments for A1C test, DM duration, age, albuminuria and current smoking.

It was determined that BP increase at late afternoon in normotensive type 2 DM patients is associated to DR independently from cofounder factors or other ABPM parameters.

Source: Kramer CK, Leitão CB, Canani LH, et al. Late afternoon blood pressure increase is associated with diabetic retinopathy in normotensive type 2 diabetes mellitus patients. Diabetes Res Clin Pract 2009; 84(1):e12-e14.


Retinal Neovascular Tissue and Vitreous Humor in Diabetic Patients
In this Finnish study, the histopathology of neovascular tufts and vitreous samples collected from diabetic patients were evaluated. Vitreous samples and neovascular tufts were collected from type 1 (n=13) and type 2 (n=17) diabetics with proliferative retinopathy and controls with macular hole (n=5). In addition, neovessels were analyzed using immunohistochemistry and vitreous samples with enzyme-linked immunosorbent assay (ELISA). Main outcome measure was to find differences in growth factors in proliferative retinopathy between type 1 and type 2 diabetics.

Vascular endothelial growth factor (VEGF)-A was most strongly present in the samples in type 1 diabetics and VEGF-D was more abundantly present in type 2 diabetics than in type 1 diabetics. Angiopoietin (ANG)-2 was also abundantly present. Additionally, macrophages and nuclear factor kappa B (NFB) were found, which indicates the presence of an inflammatory process in the neovascular tissues.

At the conclusion of this study, it was determined that VEGF-A and ANG-2 are equally important in neovascular process in both type 1 and type 2 diabetics. To achieve better control of diabetic retinopathy, it might be beneficial to target against the actions of ANG-2 and VEGF-D.

Source: Kinnunen K, Puustjärvi T, Teräsvirta, et al. Differences between type 1 and type 2 diabetics in retinal neovascular tissue and vitreous humour. Br J Ophthalmol 2009; Mar 19 [Epub ahead of print]. DOI: 10.1136/bjo.2008.148841.


Efficacy of Triple Therapy for Neovascular AMD
To evaluate the efficacy and safety of triple therapy consisting of single-session photodynamic therapy (PDT), intravitreal bevacizumab (IVB) and intravitreal triamcinolone (IVTA) for the treatment of neovascular AMD, researchers treated consecutive patients with subfoveal choroidal neovascularization (CNV) secondary to AMD with PDT, IVB and IVTA.

They gave IVB at 3 months for residual leakage and performed best-corrected Snellen visual acuity (BCVA) and fluorescein angiography (FA) prior to treatment. Additionally, BCVA, IOP and presence of vitritis were documented at 1 and 6 weeks, 3 and 6 months and FA was repeated at 3 and 6 months. Outcome measures were visual improvement measured by logMAR equivalent, angiographic evident of leakage and safety profile.

The study researchers analyzed 36 eyes of 33 patients, aged 76.4±10.5 years with mean follow up of 14.7 (6.9-19.2) months. Baseline logMAR acuity was 1.22±0.71 and mean logMAR acuity was 1.14±0.62 and 1.18±0.63 at 3 and 6 months, respectively. They noted that at 6 months, 61.1% got stable or gaining vision and 27.8% gained 3 or more lines. Also, 28 eyes (77.8%) achieved CNV resolution by single session of triple therapy. One eye lost more than 6 lines, 3 eyes had significant cataract requiring surgery and 2 had persistent raised IOP at 6 months. There were no cases of endophthalmitis or reported thrombo-embolic event.

Short-term results of single-session triple therapy suggested that it might be a useful treatment option for neovascular AMD; however, risk and benefits of using IVTA in addition to combined PDT and IVB warrant further evaluation.

Source: Yip PP, Woo CF, Tang HY, Ho CK. Triple therapy for neovascular age-related macular degeneration using single session photodynamic therapy combined with intravitreal bevacizumab and triamcinolone. Br J Opthalmol 2009; Mar 8 [Epub ahead of print]. DOI: 10.1136/bjo.2008.150987.


Impact of Retreatment Frequency on Neurosensory Retinal Volume in Neovascular AMD
To determine the characteristics of patients with neovascular AMD who show initial anatomic improvements on optical coherence tomography in response to treatment with ranibizumab, but who subsequently regress toward their anatomic baseline, researchers collected data from 50 consecutive patients receiving ranibizumab therapy for neovascular AMD.

They analyzed raw Stratus OCT images using custom software and calculated changes in volume of neurosensory retina at months 1, 3 and 6. They also compared baseline demographic and morphologic characteristics and found that 42 patients (84%) showed a reduction in total retinal volume 1 month after initial treatment with ranibizumab. Of the patients who initially showed a reduction, 16 (38%) maintained this reduction through month 6, whereas 26 patients (62%) demonstrated a subsequent increase in retinal volume. According to the researchers, patients who maintained a reduction in edema received 3.75 ± 1.18 injections of ranibizumab versus 2.96 ± 1.34 injections for patients who did not (p=0.049). Regression of initial anatomic improvements was associated with worsening of visual acuity (r=0.599, p=0.002).

Patients receiving fewer injections of ranibizumab appeared less likely to maintain anatomic improvements achieved following commencement of ranibizumab therapy, the researchers concluded. Furthermore, regression of these improvements was associated with deterioration in visual acuity.

Source: Keane PA, Chang KT, Liakopoulos S, et al. Effect of ranibizumab retreatment frequency on neurosensory retinal volume in neovascular AMD. Retina 2009; Mar 13 [Epub ahead of print]. DOI: 10.1097/IAE.0b013e31819b17a5.


PDT and Intravitreal Bevacizumab Injection for Retinal Pigment Epithelial Detachment
According to Japanese scientists, combined photodynamic therapy (PDT) and intravitreal bevacizumab may decrease the pigment epithelial detachment (PED) height and stabilize visual acuity at 1 year.

To evaluate the efficacy of combined PDT and intravitreal bevacizumab injection in eyes with a serous PED association with AMD, they administered combined PDT and intravitreal bevacizumab to 22 eyes with a serous PED exceeding two disc areas associated with AMD with choroidal vascular abnormalities (choroidal neovascularizaton [n=10], polypoidal choroidal vasculopathy [n=9] and retinal angiomatous proliferation [n=3]). They followed the subjects about every 6 weeks for more than a year and administered additional treatments for residual or recurrent lesions. Mean outcome measures were changes in the PED height measured by optical coherence tomography and the best-corrected visual acuity.

The PED resolved in 12 eyes (55%) and decreased in 10 eyes (45%) after one treatment. The scientists observed no recurrence in eight (36%) eyes; however, they noted that PED did recur in 14 eyes. At 1 year, the average PED height decreased to 413 µm from the baseline 751 µm (p<0.001). Moreover, 20 eyes (91%) had improved or stabilized vision and two eyes had decreased vision due to a retinal pigment epithelial tear and subretinal hemorrhage.

Source: Shima C, Gomi F, Sawa M, et al. One-year results of combined photodynamic therapy and intravitreal bevacizumab injection for retinal pigment epithelial detachment secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2009; Mar 24 [Epub ahead of print]. DOI: 10.1007/s00417-009-1067-9.


Morphologic Characteristics of Highly Myopic Eyes
Taking into account the fact that morphologic changes of the retina and choroid are closely related with high myopia-related pathologies, this Japanese study evaluated the morphologic characteristics of 31 phakic, highly myopic eyes with no posterior abnormalities in 18 patients (mean ±SD age 51.7±11.4years). It was determined that posterior staphyloma formation was a key factor for choroidal thinning in highly myopic eyes.

Retinal/choroidal thickness at the fovea 1.5 mm superiorly, inferiorly, nasally and temporally, as well as the choroidal curvature, were measured in the 512x128 3D scan mode with spectral domain optical coherence tomography. Furthermore, degree of posterior staphyloma was determined as the sum of the vertical distance from the retinal pigment epithelial line beneath the fovea to the nasal, temporal, superior, inferior edge of the image, including the fovea and the association of clinical data with these parameters was evaluated.

Mean ± SD central retinal thickness was 200.9±39.3µm and mean choroidal thickness at the fovea (100.5±56.9µm) was significantly different from the temporal (125.4±59.7µm), nasal (81.9±35.0µm) and superior (129.4±57.5µm) thicknesses (p's<0.01). While central retinal thickness was not correlated with age, sex, refractive error, axial length or central choroidal thickness, central choroidal thickness was significantly associated with refractive error (p<0.05) and posterior staphyloma height (p<0.01).

Additionally, posterior staphyloma height was significantly correlated with refractive error and axial length (p's<0.01). Stepwise analysis indicated that choroidal thickness was significantly correlated with age and posterior staphyloma height (p's<0.01).

High myopia had a greater effect on choroidal thickness than on retinal thickness.

Source: Ikuno Y, Tano Y. Retinal and choroidal biometry in highly myopic eyes using spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 2009; Mar 11 [Epub ahead of print].


360-Degree Retinectomy for Complicated Retinal Detachments
The authors of this Iranian study report the functional and anatomical results and complications of 360-degrees peripheral retinectomy for the management of complicated retinal detachment.

A total of 20 eyes of 19 patients with a mean age of 32.4 years (8 to 75 years) underwent pars plana vitrectomy and 360-degrees peripheral retinectomy for complicated retinal detachment due to anterior proliferative vitreoretinopathy (PVR), unstable edge of retinal break, anterior hyaloidal fibrovascular proliferation, retinal incarceration in scleral wound and 300-degrees giant retinal tear. Intraoperative reattachment was achieved in 18 eyes and mean postop follow-up time was 24.2 months (2 to 70 months). In the last visit, retina was attached in 14 eyes (70%) and eight eyes (40%) had 5/200 or greater visual acuity. The study authors reported that neither preop nor postop visual acuities had significant correlation (Spearman correlation coefficient = 0.291). Moreover, there was no relation between diagnosis and anatomical outcome (p>0.2).

They conclude that relaxing peripheral 360-degree retinectomy is an effective procedure for flattening the retina in complicated retinal detachments when no other option is available.

Source: Banaee T, Hosseini SM, Eslampoor A, et al.Peripheral 360-degrees retinectomy in complex retinal detachment. Retina 2009; Mar 13 [Epub ahead of print]. DOI: 10.1097/IAE.0b013e31819bab1d.


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NOTEWORTHY

Positive Interim Results for Othera's Phase 2 trial of OT-551
Othera Pharmaceuticals, Inc. announced interim data results for the 12-month findings of its 2-year, Phase 2 OT-551 Multi-center Evaluation of Geographic Atrophy trial, which suggest an emerging trend for reducing moderate vision loss (i.e., 15 letters or more on the ETDRS chart) in patients with geographic atrophy (GA) who were treated with OT-551 compared with placebo. The OMEGA study is a randomized, double-masked, dose-ranging, multi-center, Phase 2 study of OT-551, a topically dosed, patented small molecule that acts on oxidative stress and disease-induced inflammation, in patients with GA associated with AMD. A total of 137 patients were enrolled at 20 leading retinal disease treatment centers across the United States. The analysis of drug safety and effectiveness for the entire study population and in subgroups is still in progress, but according to Othera, a summary of the top-line results will be discussed at the annual Association for Research in Vision and Ophthalmology meeting in Fort Lauderdale next month.

Source: Othera Pharmaceuticals, Inc., April 2009.


The AMD-Meat Connection
In a cohort study of 6,734 persons aged 58 to 69 years of age between 1990 and 1994, Chong and colleagues found that higher red meat intake was positively associated with early AMD (the odds ratio for consumption of red meat 10 times/week versus <5 times/week was 1.47 (95% confidence interval: 1.21, 1.79; p-trend<0.001) and noted similar trends toward increasing prevalence of early AMD with higher intakes of fresh and processed red meat. Conversely, consumption of chicken 3.5 times/week versus <1.5 times/week was inversely associated with late AMD (odds ratio = 0.43, 95% confidence interval: 0.20, 0.91;p-trend=0.007).

Source: Chong EWT, Simpson JA, Robman LD, et al. Red meat and chicken consumption and its association with age-related macular degeneration. Amer J Epidemiol 2009;169(7):867-876. DOI: 10.1093/aje/kwn393.


Iluvien Phase 3 Studies for DME Pass Final Review
In a recent press release, Alimera Sciences, Inc. stated that, an independent Data Safety Monitoring Board (DSMB) has recommended the continuation of two pivotal Phase 3 clinical trials for the use of the intravitreal insert Iluvien in the treatment of diabetic macular edema under the current protocol without change. The DSMB completed its final review of the currently available safety and efficacy data prior to the readout in October 2009.

Source: Alimera Sciences, Inc., April 2009.



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