Best-corrected Early Treatment Diabetic Retinopathy Research Articles

Technique of retinal gene therapy: delivery of viral vector into the subretinal space

PurposeSafe and reproducible delivery of gene therapy vector into the subretinal space is essential for successful targeting of the retinal pigment epithelium (RPE) and photoreceptors. The success of surgery is critical for the clinical efficacy of retinal gene therapy. Iatrogenic detachment of the degenerate (often adherent) retina in patients with hereditary retinal degenerations and small volume (eg, 0.1 ml) subretinal injections pose new surgical challenges.MethodsOur subretinal gene therapy technique involved pre-operative planning with optical coherence tomography (OCT) and autofluorescence (AF) imaging, 23 G pars plana vitrectomy, internal limiting membrane staining with Membrane Blue Dual (DORC BV, Zuidland, Netherlands), a two-step subretinal injection using a 41 G Teflon tipped cannula (DORC) first with normal saline to create a parafoveal bleb followed by slow infusion of viral vector via the same self-sealing retinotomy. Surgical precision was further enhanced by intraoperative OCT (Zeiss Rescan 7000, Carl Zeiss Meditec AG, Jena, Germany). Foveal functional and structural recovery was evaluated using best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, microperimetry and OCT.ResultsTwo patients with choroideremia aged 29 (P1) and 27 (P2) years, who had normal and symmetrical levels of best-corrected visual acuity (BCVA) in both eyes, underwent unilateral gene therapy with the fellow eye acting as internal control. The surgeries were uncomplicated in both cases with successful detachment of the macula by subretinal vector injection. Both treated eyes showed recovery of BCVA (P1: 76–77 letters; P2: 84–88 letters) and mean threshold sensitivity of the central macula (P1: 10.7–10.7 dB; P2: 14.2–14.1 dB) to baseline within a month. This was accompanied by normalisation of central retinal thickness on OCT.ConclusionsHerein we describe a reliable technique for subretinal gene therapy, which is currently used in clinical trials to treat choroideremia using an adeno-associated viral (AAV) vector encoding the CHM gene. Strategies to minimise potential complications, such as avoidance of excessive retinal stretch, air bubbles within the injection system, reflux of viral vector and post-operative vitritis are discussed.

Visual Acuity, Contrast Sensitivity and Color Vision Three Years After Iodine-125 Brachytherapy for Choroidal and Ciliary Body Melanoma.

Purpose : To report visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after iodine-125 brachytherapy for choroidal and ciliary body melanoma (CCM).Design : Prospective interventional case series.Participants : Thirty-seven patients (37 eyes) with CCM.Methods : Patients had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, Pelli-Robson contrast sensitivity and Hardy-Rand-Rittler color vision measurement; comprehensive ophthalmology examination; optical coherence tomography; and ultrasonography at baseline prior to, 1 year after, 2 years after and 3 years after I-125 brachytherapy.Main Outcome Measures : Visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after brachytherapy.Results :Nineteen (19) men and 18 women with mean age of 58 years (SD 13, range 30-78) prior to, 1 year after, 2 years after and 3 years after brachytherapy had mean best-corrected visual acuity of 77 letters (20/32), 65 letters (20/50), 56 letters (20/80) and 47 letters (20/125); contrast sensitivity of 30, 26, 22 and 19 letters; color vision of 26, 20, 17 and 14 test figures, respectively. Decrease in visual acuity, contrast sensitivity and color vision was statistically significant from baseline at 1 year, 2 years, and 3 years after brachytherapy. Decreased acuity at 3 years was associated with mid-choroid and macula melanoma location, ≥ 4.1 mm melanoma height, radiation maculopathy and radiation optic neuropathy.Conclusion : 1, 2 and 3 years after brachytherapy, eyes with CCM had significantly decreased visual acuity, contrast sensitivity and color vision.

The Effect of the Oral PKC β Inhibitor Ruboxistaurin on Vision Loss in Two Phase 3 Studies

To assess the effect of ruboxistaurin (RBX) on vision loss through a prospectively defined combined analysis of two phase 3 trials (MBDL and MBCU). Patients in both of these 3-year randomized, placebo-controlled, double-masked trials had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) ≥ 75 letters (∼20/32 Snellen), ETDRS retinopathy level 20 to 47D (MBDL) or 35B to 53E (MBCU), and no prior panretinal or focal photocoagulation in at least one eye at baseline. Patients received oral placebo (N = 508 total from both studies) or RBX 32 mg/d (N = 520 total). Best-corrected ETDRS VA was measured at 6-month intervals for 3 years (MBDL) or for 18 to 48 months (MBCU). Sustained moderate visual loss (SMVL) was defined as a 15-letter or more reduction from baseline in VA sustained for a patient's last 6 months of study participation. In the combined studies (N = 1028 total), SMVL occurred in 4.4% of placebo- versus 2.3% of RBX-treated patients (P = 0.069). In patients with a minimum of 2 years of follow-up (N = 825 total), there was less SMVL in the RBX group (4.4% placebo versus 2.1% RBX, P = 0.045). Other VA-related measures (mean VA, contrast sensitivity, Visual Functioning Questionnaire 25 [VFQ-25]) either trended toward a benefit for RBX or were also statistically significant in favor of RBX. In contrast, diabetic macular edema (DME) morphology-related measures (occurrence of significant center of macula involvement, optical coherence tomography [OCT]-determined center of macula thickness, application of focal photocoagulation) did not show a consistent trend in favor of or against RBX. SMVL data in a prospectively defined combined analysis from these two phase 3 trials suggest a magnitude of effect of RBX on vision loss similar to that seen in two prior studies (approximately 50% reduction above standard care). However, event rates were low and statistical significance was not achieved. (ClinicalTrials.gov numbers, NCT00133952, NCT00090519.).

Longitudinal Relationships among Visual Acuity and Tasks of Everyday Life: The Salisbury Eye Evaluation Study

To study the relationships among visual and physical function trajectories of aging adults. The community-based random sample consists of 2520 adults who were aged 65 to 84 years in 1993 to 1995 and reassessed 2, 6, and 8 years later. Presenting and best-corrected Early Treatment Diabetic Retinopathy Study visual acuity were obtained. Activities of daily living (ADLs) and instrumental ADLs (IADLs) were evaluated through survey instruments. Growth curve models were used to simultaneously estimate health trajectories and obtain associations among the trajectories while controlling for relevant covariates. Best-corrected acuity (logMAR) worsened by an average of 0.013 (∼1 letter) annually. ADL difficulties increased by 0.22 standard deviations (SD) and IADL difficulties increased by 0.28 SD annually. Controlling for demographic and health covariates, visual acuity rates of decline correlated with rates of increase in ADL difficulties (r = 0.15, P = 0.05) and IADL difficulties (r = 0.41, P < 0.001). Acuity loss was significantly related to increases in ADLs for men (b = 0.039, P < 0.01), but not for women (b = 0.001, P > 0.9). The direct effects of acuity loss were strongest for IADLs where a 1-unit decline in acuity (logMAR) was associated with a 0.067 SD increase in IADL difficulties (P < 0.001) at baseline, and a 1-unit acuity decline (logMAR) per year resulted in a 0.10 SD unit increase in the rate of change in IADL difficulties (P < 0.001) per year. Over time, increases in visual acuity loss were related to increased IADL difficulties in men and women and increases in ADL difficulties for men only. The findings support the importance of maintaining vision in older adults.

INTRAVITREAL INJECTION OF RANIBIZUMAB DURING CATARACT SURGERY IN PATIENTS WITH DIABETIC MACULAR EDEMA

To investigate macular thickness and visual acuity changes after 1 intravitreal injection of 0.5-mg ranibizumab during phacoemulsification cataract surgery in eyes with diabetic macular edema refractory to laser treatment. Eleven eyes of 11 patients with diabetic macular edema refractory to modified Early Treatment Diabetic Retinopathy Study laser therapy received intravitreal during phacoemulsification cataract surgery. Comprehensive ophthalmic evaluation was performed preoperatively and at 1, 4, 8 ± 1, and 12 ± 2 weeks postoperatively. Main outcome measures included central subfield thickness and best-corrected Early Treatment Diabetic Retinopathy Study visual acuity. Eleven patients completed the 12-week study visit. Mean central subfield thickness (± SEM) was 399.82 ± 29.50 μm at baseline and did not change significantly at any postoperative study visit (P > 0.05). Mean (± SEM) best-corrected Early Treatment Diabetic Retinopathy Study visual acuity was 0.95 ± 0.13 logarithm of the minimum angle of resolution (20/200) at baseline and was significantly improved at Weeks 1 (0.38 ± 0.13), 4 (0.38 ± 0.11), 8 (0.35 ± 0.08), and 12 (0.46 ± 0.12) after treatment (P < 0.05). In this case series of patients with diabetic macular edema refractory to laser therapy, intravitreal ranibizumab administered during cataract surgery was associated with no significant change in central subfield thickness postoperatively. Significant improvement in best-corrected Early Treatment Diabetic Retinopathy Study visual acuity was observed after treatment, likely because of cataract removal.

ORAL PROTEIN KINASE C β INHIBITION USING RUBOXISTAURIN

To evaluate efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with moderately severe to very severe nonproliferative diabetic retinopathy from the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2 ruboxistaurin (RBX) protein kinase C β inhibitor trials. Patients in these 3-year, randomized, placebo-controlled, double-masked, Phase 3 trials had best-corrected Early Treatment Diabetic Retinopathy Study visual acuity ≥45 letters (∼20/125 Snellen), Early Treatment Diabetic Retinopathy Study retinopathy level 47A/B-53E, and no previous panretinal photocoagulation in ≥1 eye. Patients received placebo (N = 401) or RBX 32 mg/day (N = 412). Data from the 2 studies were combined and masked evaluation of retinal photographs was performed for cause of visual decline in all patients experiencing sustained moderate visual loss (≥15-letter loss sustained for the last 6 months of study). In the studies combined, sustained moderate visual loss occurred in 10.2% of placebo-treated patients versus 6.1% of RBX-treated patients (P = 0.011). A ≥15-letter gain occurred in 2.4% of placebo versus 4.7% of RBX eyes (P = 0.021) and a ≥15-letter loss occurred in 11.4% versus 7.4%, respectively (P = 0.012). Diabetic macular edema was the probable primary cause of vision loss. Among eyes without focal/grid photocoagulation at baseline, fewer RBX group eyes (26.7%) required initial focal/grid photocoagulation versus placebo (35.6%; P = 0.008). No safety concerns were identified. Analysis of data combined from two similar studies adds further statistical significance to RBX's beneficial effects on visual loss, need for focal laser, and vision gain, most likely through effects on macular edema.

Intravitreal Anti-VEGF Bevacizumab (Avastin) for External Beam-Related Radiation Retinopathy

To report on intravitreal bevacizumab treatment for external beam radiation therapy (EBRT)-related radiation maculopathy. Three patients (4 eyes) with EBRT-related maculopathy were treated with periodic (4- to 8-week) intravitreal injections of bevacizumab (1.25 mg in 0.05 cc). Outcome measures included best-corrected Early Treatment Diabetic Retinopathy Study visual acuity, retinal examination, fundus photography, fluorescein angiography, and optical coherence tomography. Patients were diagnosed with Stage 3 radiation maculopathy occurring 12, 19, and 48 months after irradiation. One received 50 Gy of 6-MV photon EBRT for a maxillary carcinoma, the second 30.6 Gy of 6-MV photon EBRT for intraocular lymphoma, and the third 72 Gy proton beam irradiation for adenoid cystic carcinoma of the lacrimal gland. With up to 33 months follow-up, visual acuities improved (8 and 11 letters) in 2 eyes, gained 5 letters in 1 eye and 1 decreased 5 letters from 20/16 to 20/20. All cases demonstrated clinical findings of decreased intraretinal hemorrhages, cotton-wool spots, and retinal edema. There were no significant ocular or systemic side effects. Intravitreal anti-VEGF therapy was associated with reductions of EBRT-related retinopathy. No ocular or systemic side effects were noted. Anti-VEGF therapy may be considered radiation maculopathy secondary to EBRT.

Selective retina therapy for acute central serous chorioretinopathy

AimsTo evaluate selective retina therapy (SRT) as a treatment of acute central serous chorioretinopathy.Methods30 eyes of 30 patients with central serous chorioretinopathy of at least a 3 months' duration were...

EFFECT OF ORAL PENTOXIFYLLINE ON CYSTOID MACULAR EDEMA ASSOCIATED WITH CENTRAL RETINAL VEIN OCCLUSION

To determine whether oral pentoxifylline, a xanthine-derived hemorheologic agent, decreases cystoid macular edema (CME) and improves visual acuity in eyes with a perfused central retinal vein occlusion (CRVO). Retrospective chart review of consecutive patients on pentoxifylline (400 mg po TID) for CRVO was performed. Inclusion criteria included CME, pentoxifylline use for at least 1 month, and a follow-up period of at least 4 months. Exclusion criteria included nonperfused or indeterminate CRVO, the presence of neovascularization, and previous or concurrent laser therapy or any other treatment for CRVO. Statistical analysis of collected data was performed. Eleven patients were identified. All patients had a perfused CRVO. The mean best-corrected Early Treatment Diabetic Retinopathy Study visual acuity was 60 letters (Snellen equivalent 20/128) before the initiation of oral pentoxifylline. The mean time from onset of CRVO to start of pentoxifylline therapy was 5 months (range, 1-12 months). The mean duration of pentoxifylline use was 5.3 months (range, 2.5-10.2 months). The mean follow-up period was 8 months (range, 2.7-16.5 months). Cystoid macular edema had improved in 64% (7/11) of eyes at last follow-up as measured by biomicroscopy and optical coherence tomography. The visual acuity was not significantly changed at 62 letters (20/128 +2) (Student t-test, P = 0.7) at last follow-up. There were no significant side effects from pentoxifylline. One patient had mild gastrointestinal disturbance. Pentoxifylline has a favorable adverse effect profile, and can reduce CME in eyes with CRVO. Visual acuity does not appear to change significantly. A larger, randomized, multiarmed clinical trial evaluating the effects of pentoxifylline as an adjunctive treatment modality may be of benefit since even a small positive effect in altering the natural history of CME related to CRVO may be of value for these patients.

INTRAVITREAL BEVACIZUMAB (AVASTIN) FOR PERSISTENT NEW VESSELS IN DIABETIC RETINOPATHY (IBEPE STUDY)

To evaluate the short-term fluorescein angiographic and visual acuity effects of a single intravitreal injection of bevacizumab (Avastin) for the management of persistent new vessels (NV) associated with diabetic retinopathy. A prospective, nonrandomized open-label study of diabetic patients with actively leaking NV refractory to laser treatment and best-corrected Early Treatment Diabetic Retinopathy Study visual acuity (BCVA) worse than 20/40. Standardized ophthalmic evaluation was performed at baseline and at weeks 1, 6, and 12 (+/-1) following intravitreal injection of 1.5 mg of bevacizumab. Main outcome measures include changes in total area of fluorescein leakage from active NV and BCVA. Fifteen consecutive patients (men, 9 [60%]; women, 6 [40%]) were included and all completed the 12-week follow-up period of the study. The mean +/- SD age of participants was 60.08 +/- 7.75 years (median, 59.5; range, 49-73 years). At baseline, mean +/- standard error of the mean (SEM) NV leakage area was 27.79 +/- 6.29 mm2. The mean +/- SEM area of active leaking NV decreased significantly to 5.43 +/- 2.18 mm2 and 5.50 +/- 1.24 mm2 (P < 0.05, Tukey multiple comparisons post-test) at 1 and 12 weeks postinjection, respectively; at week 6 no leakage was observed. The mean +/- SEM logMAR (Snellen equivalent) BCVA improved significantly from 0.90 (20/160) +/- 0.11 at baseline to 0.76 (20/125(+2)) +/- 0.12, 0.77 (20/125(+2)) +/- 0.11, and 0.77 (20/125(+2)) +/- 0.12 at weeks 1, 6, and 12, respectively (P < 0.05, Tukey multiple comparisons post-test). No major adverse events were observed. Intravitreal injection of bevacizumab achieved short-term reduction of fluorescein leakage from persistent active NV without loss of vision in patients with diabetic retinopathy. Further studies to investigate the role of anti-VEGF therapy with bevacizumab for the management of diabetic retinopathy refractory to laser treatment are warranted.

Macular translocation surgery with 360-degree peripheral retinectomy following ocular photodynamic therapy of choroidal neovascularization

Purpose To determine the visual outcomes of eyes that underwent macular translocation surgery with 360 degrees peripheral retinectomy and silicone oil tamponade (MTS360) following ocular photodynamic therapy (OPT) with verteporfin for subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration (ARMD). Design Observational case series. Methods A retrospective review of patients who underwent MTS360 with silicone oil tamponade from August 5, 1998 through December 1, 2002. Patients who had at least one episode of OPT with verteporfin before surgery were identified. The number of OPT session, best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, complications (including postoperative CNV, retinal detachment [RD]), the presence or absence of cystoid macular edema (CME) by optical coherence tomography (OCT) were recorded. Results Eight eyes of eight patients were identified that fulfilled the inclusion criteria. All eyes had at least one episode of OPT (mean, 1.5 treatments). All of these patients at the time of MTS360 demonstrated continued visual loss following the most recent OPT session. The mean preoperative visual acuity was 56 letters. Four of the eight eyes demonstrated CME by OCT on preoperative examination. There were no significant postoperative complications other than one eye that had a successful repair of an RD. At 3 months, the mean visual acuity was 54 letters. At last follow-up (mean, 10 months), the mean visual acuity was 61 letters ( P = .5). The final mean visual acuity change for the patients who had only one prior OPT (five eyes) was +10 letters. The mean final visual acuity change for the patients who had multiple OPT sessions (three eyes) was −1 letter. Three of the four eyes that had preoperative CME continued to demonstrate CME at last follow-up. Two eyes that had concurrent cataract extraction surgery with MTS360 did not develop CME. No eyes developed a recurrent CNV during the postoperative period. Conclusions MTS360 with silicone oil tamponade for CNV associated with ARMD appears to be a viable option for patients who are continuing to lose vision in their better seeing eye following OPT with verteporfin. MTS360 appears to be effective in stabilizing vision, especially in patients who had previously undergone only one OPT session. Further studies are indicated to evaluate the efficacy of MTS360 in this current era of OPT.