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Purpose: To compare the efficacy of intravitreal aflibercept and laser photocoagulation in the treatment of retinopathy of prematurity (ROP)., Methods: The files of patients who were diagnosed as having type 1 ROP or aggressive posterior ROP (APROP) and treated with laser photocoagulation and 1 mg/0.025 mL of intravitreal aflibercept were retrospectively analyzed. The patients' birth weight, gestational age, detection week of the disease, zone, stage, presence of plus disease and rubeosis, regression of ROP, re-treatments administered during the follow-up, and spherical equivalent values obtained at the corrected sixth month were recorded., Results: The study included 27 eyes of 15 patients who underwent laser photocoagulation and 24 eyes of 12 patients who received intravitreal aflibercept. Retinal vascularization was in zone II in all eyes in the laser photocoagulation group and zone 1 in 22 eyes (91.7%) in the intravitreal aflibercept group (P < .05). In the laser photocoagulation group, 25 eyes (92.6%) had stage 3 ROP and 2 eyes (7.4%) had stage 2 ROP. In the intravitreal aflibercept group, 14 eyes (58.3%) had stage 3 ROP and 10 eyes (41.7%) had APROP (P < .05). Treatment was established at a postmenstrual age of 37.6 ± 2.5 weeks in the laser photocoagulation group and 34.2 ± 2.4 weeks in the intravitreal aflibercept group (P < .05). The regression rates after treatment were 92.6% and 100%, respectively (P > .05). In the intravitreal aflibercept group, laser photocoagulation was performed on 10 eyes (41.6%) during follow-up visits. Spherical equivalents were measured as +1.10 ± 2.30 and +1.50 ± 2.41 diopters, respectively (P < .05) at the corrected sixth month., Conclusions: Intravitreal aflibercept is an effective treatment for ROP. However, it requires more additional treatments than laser photocoagulation during the follow-up visits. [J Pediatr Ophthalmol Strabismus. 2020;57(1):54-60.]., (Copyright 2020, SLACK Incorporated.) more...

Purpose: To study the role of combined vitrectomy and intravitreal anti-vascular endothelial growth factor (VEGF) injection for stage 4 retinopathy of prematurity (ROP) with extensive neovascular proliferation., Methods: In a retrospective interventional study at a tertiary eye care center, 15 eyes (9 infants) with advanced stage 4 ROP underwent 25-gauge vitrectomy combined with intravitreal 0.625 mg of bevacizumab (n = 12) or 0.25 mg of ranibizumab (n = 3) injection and were followed up until 65 weeks' postconceptional age (PCA). The perinatal history, tractional retinal detachment (TRD) characteristics (zone, stage, and presence of "plus" disease), treatment details, and anatomical outcomes were reviewed. The main outcome measures were fibrovascular tissue and TRD regression and final macular status., Results: Mean gestational age and birth weight were 28.5 ± 1.2 weeks and 1,167 ± 185 g, respectively. Thirteen eyes had zone I disease and 2 eyes had zone II disease. Thirteen eyes were stage 4A and 2 eyes were stage 4B ROP. The morphology was aggressive posterior ROP in 10 eyes. The mean PCA at surgery was 37.8 ± 2.3 weeks. Lensectomy was also performed in 2 eyes. Rapid fibrovascular tissue regression was seen in 14 eyes within 2 weeks, followed by TRD regression and macular vascularization, although 2 eyes had macular pucker formation. Persistent vitreous bleeding was present in 1 eye, which needed lavage, and eventually the TRD regressed. Disease reactivation was noted in 1 eye at 5 weeks and was managed with repeat intravitreal anti-VEGF injection., Conclusions: Anti-VEGF treatment combined with vitrectomy leads to rapid disease regression in advanced stage 4 ROP with extensive neovascular proliferation. [J Pediatr Ophthalmol Strabismus. 2020;57(1):61-66.]., (Copyright 2020, SLACK Incorporated.) more...

Importance: The DRCR Retina Network Protocol S randomized clinical trial suggested that the mean visual acuity of eyes with proliferative diabetic retinopathy (PDR) treated with ranibizumab is not worse at 5 years than that of eyes treated with panretinal photocoagulation (PRP). Moreover, the ranibizumab group had fewer new cases of diabetic macular edema (DME) with vision loss or vitrectomy but had 4 times the number of injections and 3 times the number of visits. Although 2-year cost-effectiveness results of Protocol S were previously identified, incorporating 5-year data from Protocol S could alter the longer-term cost-effectiveness of the treatment strategies from the perspective of the health care system., Objective: To evaluate 5- and 10-year cost-effectiveness of therapy with ranibizumab, 0.5 mg, compared with PRP for treating PDR., Design, Setting, and Participants: A preplanned secondary analysis of the Protocol S randomized clinical trial using efficacy, safety, and resource utilization data through 5 years of follow-up for 213 adults diagnosed with PDR and simulating results through 10 years., Interventions: Intravitreous ranibizumab, 0.5 mg, at baseline and as frequently as every 4 weeks based on a structured retreatment protocol vs PRP at baseline for PDR; eyes in both groups could receive ranibizumab for concomitant DME with vision loss., Main Outcomes and Measures: Incremental cost-effectiveness ratios (ICERs) of ranibizumab therapy compared with PRP were evaluated for those with and without center-involved DME (CI-DME) and vision loss (Snellen equivalent, 20/32 or worse) at baseline., Results: The study included 213 adults with a mean (SD) age of 53 (12) years, of whom 92 (43%) were women and 155 (73%) were white. The ICER of the ranibizumab group compared with PRP for patients without CI-DME at baseline was $582 268 per quality-adjusted life-year (QALY) at 5 years and $742 202/QALY at 10 years. For patients with baseline CI-DME, ICERs were $65 576/QALY at 5 years and $63 930/QALY at 10 years., Conclusions and Relevance: This study suggests that during 5 to 10 years of treatment, ranibizumab, 0.5 mg, as given in the studied trial compared with PRP may be within the frequently cited range considered cost-effective in the United States for eyes presenting with PDR and vision-impairing CI-DME, but not for those with PDR but without vision-impairing CI-DME. Substantial reductions in anti-vascular endothelial growth factor cost may make the ranibizumab therapy cost-effective within this range even for patients without baseline CI-DME., Trial Registration: ClinicalTrials.gov identifier: NCT01489189. more...

Pathologic posterior neovascularization of eye is a major cause of irreversible vision loss and limitations of therapeutics to be successfully delivered to back of the eye has been a main obstacle for its effective treatment. Current pharmacological treatment using anti-VEGF agents being delivered intravitreally are effective but complicated due to anatomical and physiological barriers, as well as administration of high and frequent doses. With expanding horizons of nanotechnology, it can be possible to formulate promising nanoscale delivery system to improve penetration and sustained the release of therapeutic in posterior segment of the eye. Taking into consideration advances in the field of nanoscale delivery systems, this special report focuses on emerging strategies and their applications for treatment of posterior ocular neovascularization. more...

Purpose: Submacular haemorrhage (SMH) is a cause of severe visual loss in neovascular age-related macular degeneration (nAMD). The incidence is uncertain and furthermore there is no widely used classification system nor agreed best practice. The aim of this national surveillance study was to identify the incidence, presenting features and clinical course of new fovea-involving submacular haemorrhage associated with nAMD., Methods: A questionnaire was sent monthly to every ophthalmic specialist in Scotland over a 12-month period asking them to report all newly presenting patients with acute SMH secondary to nAMD of at least two disc diameters (DDs) in greatest linear diameter. A follow-up questionnaire was sent 6 months after initial presentation. Cases related to other causes were excluded., Results: Twenty-nine cases were reported giving an incidence of 5.4 per million per annum (range 2-15). The mean age was 83 years (range 66-96) and females accounted for 17/29 (59%). Fifteen of the 29 cases (52%) had a past history of AMD, of which 7 had nAMD. Nineteen of the 29 cases (66%) presented within 7 days of onset and the majority had SMH of < 11 DD (20/29, 69%). Treatment options comprised the following: observation (n = 6, 21%), anti-VEGF alone (n = 6, 21%) or vitrectomy with co-application of tissue plasminogen activator (TPA), anti-VEGF and gas (n = 17, 58%). The vitrectomy group experienced the greatest change in vision from logMAR 1.89-1.50 (p = 0.374). Four of 20 (20%) cases with 6 months follow-up suffered a re-bleed at a mean time of 96 days., Conclusions: The incidence, clinical features and course of a consecutive national cohort of patients with SMH secondary to nAMD are presented. more...

Purpose: To compare anatomic and functional outcomes in eyes with proliferative diabetic retinopathy (PDR) that were lost to follow-up (LTFU) for more than 6 months after treatment with either intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) agents or panretinal photocoagulation (PRP)., Design: Retrospective cohort study., Participants: Fifty-nine patients who were LTFU immediately after treatment for more than 6 months between September 2013 and September 2016., Methods: Patients with eyes receiving either intravitreal anti-VEGF treatment or PRP with the next follow-up visit occurring more than 6 months after treatment were identified. Visual acuity (VA) and anatomic outcomes at the visit before being LTFU, the return visit, the 6-month visit after return, the 12-month visit after return, and the final visit were gathered and compared between the 2 treatment groups., Main Outcomes Measures: Visual acuity and anatomic outcomes., Results: Seventy-six eyes of 59 patients were included in the study, of which 30 received IVI with anti-VEGF and 46 received PRP. In the anti-VEGF group, mean VA worsened significantly when comparing the visit before being LTFU (0.43±0.38 logarithm of the minimum angle of resolution [logMAR]) with the return visit (0.97±0.80 logMAR; P = 0.001) as well as with the final visit (0.92±0.94 logMAR; P = 0.01). In the PRP group, mean VA worsened significantly when comparing the visit before being LTFU (0.42±0.34 logMAR) with the return visit (0.62±0.64 logMAR; P = 0.03). However, no significant difference was observed at the final visit (0.46±0.47 logMAR; P = 0.38). There was a significantly greater number of eyes with tractional retinal detachment in the IVI group compared with the PRP group at the final visit (10 vs. 1, respectively; P = 0.005). There was a significantly greater incidence of neovascularization of the iris in the IVI arm compared with the PRP arm at the final visit (4 vs. 0, respectively; P = 0.02)., Conclusions: Eyes with PDR that received only intravitreal anti-VEGF demonstrated worse anatomic and functional outcomes after being LTFU compared with eyes that received PRP. Given the potential sequelae of being LTFU, the choice of treatment for PDR must be considered carefully., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.) more...

Purpose: To compare retinal function changes in eyes with proliferative diabetic retinopathy (PDR) after intravitreal ranibizumab (IVR), combined or not with conventional (ETDRS) or multispot laser panretinal (PASCAL) photocoagulation (PRP)., Methods: This study included laser-naive PDR patients that required PRP. Eyes were randomly and prospectively assigned to receive IVR or IVR combined with PASCAL or EDTRS. PRP was performed at baseline in 1 (PASCAL) or 2 (ETDRS) sessions. In eyes with macular edema, macular short pulse grid laser was associated with IVR at baseline and IVR was repeated monthly or quarterly if neovascularization was detected on angiography. Comprehensive ophthalmological evaluations, including SD-OCT, were performed at baseline and every 4 weeks after treatment. Full-field electroretinography (ERG: extended ISCEV standard) was performed at baseline and at 12, 24 and 48 weeks., Results: IVR = 13, PASCAL = 15 and ETDRS = 15 eyes finished 48-week follow-up. There was a statistically significant BCVA improvement of 0.1-0.3 logMAR in all groups, and fluorescein angiography leakage area (FLA) reduced in 56%, 73%, and 73% from baseline for ETDRS, IVR and PASCAL, respectively, up to 48 weeks without significant differences between groups (p > 0.05). A significant a- and b-wave amplitudes reduction was observed for dark- and light-adapted ERG for ETDRS and PASCAL, but only minor dark-adapted b-wave reduction was found for IVR, up to 48 weeks. As an example, at week 48, combined response b-wave amplitude reduced in 181.5 ± 31.4 µV, 128.0 ± 27.9 µV and 82.4 ± 15.2 µV for ETDRS, PASCAL and IVR (p < 0.05 each group), respectively. No significant difference was observed between ETDRS and PASCAL for any ERG parameter., Conclusions: IVR combined with single or multiple spot PRP causes similar retinal function impairment during 48 weeks of observation, while IVR alone seems to be similarly effective controlling FLA without changing retinal function. more...

Purpose: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period., Design: Prospective, randomized, multicenter, open-label, phase II/III study., Participants: Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female)., Methods: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion., Main Outcome Measures: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments., Results: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported., Conclusions: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.) more...

Generation of lentivirus (LV)-based vectors holding multiple gene cassettes for coexpression of several therapeutic factors provides potent tools in both gene delivery studies as well as in gene therapy. Here we describe the development of such multigenic LV gene delivery vectors enabling cell-specific coexpression of antiangiogenic microRNA (miRNA) and protein factors and, if preferred, a fluorescent reporter, from RNApol(II)-driven expression cassettes orientated in a back-to-back fashion. This configuration may contribute to the development of new combination therapies for amelioration of diseases involving intraocular neovascularization including exudative age-related macular degeneration (AMD). more...

Neoangiogenesis is the main pathogenic event involved in a variety of retinal diseases. It has been recently demonstrated that inhibiting the urokinase-type plasminogen activator receptor (uPAR) results in reduced angiogenesis in a mouse model of oxygen-induced retinopathy (OIR), establishing uPAR as a therapeutic target in proliferative retinopathies. Here, we evaluated in cultured human retinal endothelial cells (HRECs) and in OIR mice the potential of a specific antisense oligodeoxyribonucleotide (ASO) in blocking the synthesis of uPAR and in providing antiangiogenic effects. uPAR expression in HRECs was inhibited by lipofection with the phosphorotioated 5'-CGGCGGGTGACCCATGTG-3' ASO-uPAR, complementary to the initial translation site of uPAR mRNA. Inhibition of uPAR expression via ASO-uPAR was evaluated in HRECs by analyzing VEGF-induced tube formation and migration. In addition, the well-established and reproducible murine OIR model was used to induce retinal neovascularization in vivo. OIR mice were injected intraperitoneally with ASO-uPAR and retinopathy was evaluated considering the extent of the avascular area in the central retina and neovascular tuft formation. The ASO-uPAR specifically decreased uPAR mRNA and protein levels in HRECs and mitigated VEGF-induced tube formation and cell migration. Noteworthy, in OIR mice ASO-uPAR administration reduced both the avascular area and the formation of neovascular tufts. In conclusion, although the extrapolation of these experimental findings to the clinic is not straightforward, ASO-uPAR may be considered a potential therapeutic tool for treatment of proliferative retinal diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.) more...

Purpose: To compare patient-centered outcomes in patients with proliferative diabetic retinopathy (PDR) treated with ranibizumab vs panretinal photocoagulation (PRP)., Design: Randomized clinical trial., Methods: Setting: Multicenter (55 U.S. sites)., Patient Population: Total of 216 adults with 1 study eye out of 305 adults (excluding participants with 2 study eyes, because each eye received a different treatment) with PDR, visual acuity 20/320 or better, no history of PRP., Intervention: Ranibizumab (0.5 mg/0.05 mL) vs PRP., Main Outcome Measures: Change from baseline to 2 years in composite and prespecified subscale scores from the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), University of Alabama Low Luminance Questionnaire (UAB-LLQ), and Work Productivity and Activity Impairment Questionnaire (WPAIQ)., Results: For the NEI VFQ-25 and UAB-LLQ composite scores, ranibizumab-PRP treatment group differences (95% CI) were +4.0 (-0.2, +8.3, P = .06) and +1.8 (-3.5, +7.1, P = 0.51) at 1 year, and +2.9 (-1.5, +7.2, P = .20) and +2.3 (-2.9, +7.5, P = .37) at 2 years, respectively. Work productivity loss measured with the WPAIQ was 15.6% less with ranibizumab (-26.3%, -4.8%, P = .005) at 1 year and 2.9% (-12.2%, +6.4%, P = .54) at 2 years. Eighty-three ranibizumab participants (97%) were 20/40 or better in at least 1 eye (visual acuity requirement to qualify for an unrestricted driver's license in many states) at 2 years compared with 82 PRP participants (87%, adjusted risk ratio = 1.1, 95% CI: 1.0, 1.2, P = .005)., Conclusions: Though differences in some work productivity and driving-related outcomes favored ranibizumab over PRP, no differences between treatment regimens for PDR were identified for most of the other patient-centered outcomes considered., (Copyright © 2016 Elsevier Inc. All rights reserved.) more...

Purpose: To compare choroidal thickness (CT) and retinal thickness (RT) between eyes with proliferative diabetic retinopathy treated with panretinal photocoagulation (PRP) or PRP with intravitreal bevacizumab (PRP + IVB)., Methods: Thirty-three patients with proliferative diabetic retinopathy were randomized to have one eye treated with PRP and the other with PRP + IVB. Change in CT was compared with baseline using enhanced depth imaging-optical coherence tomography at baseline and Months 1, 3, 6, and 10 after treatment. Change in RT was similarly assessed using spectral domain optical coherence tomography. Changes in both CT and RT were assessed in all nine macular areas as defined by Early Treatment Diabetic Retinopathy Study subfields., Results: The PRP + IVB group had a significant decrease in subfoveal CT at 3 and 10 months (323.9 ± 62 μm at baseline vs. 320.7 ± 64.8 μm at Month 3 [P = 0.024] and 304.7 ± 65.6 μm at Month 10 [P = 0.003]). Subfoveal CT significantly decreased at 10 months compared with baseline in the PRP group (320.8 ± 57.7 at baseline to 297 ± 66.3 μm at 10 months, P = 0.01). Subfoveal CT was not significantly different between the 2 groups at 10 months. The best-corrected visual acuity did not change after treatment in the two groups, and there was no correlation between BCVA and CT changes (r = 0.222, P = 0.37 in the PRP group and r = 0.387, P = 0.12 in the PRP + IVB group). Significant increases in RT were seen in the PRP + IVB group at 6 months and in the PRP group at Months 1, 3, 6, and 10. A correlation between changes in CT and RT was only seen in the PRP group at 10 months after treatment., Conclusion: Eyes with proliferative diabetic retinopathy treated with PRP + IVB and PRP both had significant reduction in CT at 10 months; however, the eyes that were also treated with IVB also underwent an earlier but transient reduction at 3 months. Patients treated with IVB underwent less increase in RT. more...

Purpose: To evaluate the role, safety, and effectiveness of intravitreal conbercept (KH902) injections as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy., Methods: A randomized controlled trial was performed on 36 eyes of 36 patients affected by vitreous hemorrhage and tractional retinal detachment, which occurred as a consequence of active proliferative diabetic retinopathy. The patients were randomly assigned to two groups. The patients in one of the groups received an intravitreal injection of conbercept in the inferior temporal sector 4 mm from the sclerocorneal limbus with a sterile technique 1 week before vitrectomy., Results: In the group without conbercept, intraoperative bleeding occurred in 14 patients (77.8%), and in five of these cases, bleeding was significant. The use of endodiathermy was necessary in 8 patients (44.4%). In 3 patients (16.6%), iatrogenic retinal breaks occurred, and in 1 patient (5.5%), a relaxing retinotomy was performed. Endotamponade with silicone oil was performed in 12 patients (66.6%). In the group treated with conbercept, intraoperative bleeding occurred in 2 cases (11.1%). The use of endodiathermy was necessary in 1 patient (5.5%). No patients experienced iatrogenic breaks or relaxing retinotomy during the surgery. Endotamponade with silicone oil was performed in 2 patients (11.1%)., Conclusion: Preoperative intravitreal injection of conbercept could reduce the chances of intraoperative bleeding, which are beneficial in the management of proliferative diabetic retinopathy. more...

Background: Previous studies have proven that long-lasting success in the therapy of neovascular age-related macular degeneration (AMD) and other neovascular retinal diseases depends on monthly follow-up examinations to assess visual acuity and retinal morphology., Materials and Methods: The interactive database Bonn ophthalmology online network (BOON) offers a platform for patient monitoring, increasing control reliability and providing a tool for permanent communication between treating centers and referring ophthalmologists. The BOON data-based project started in 2009 at the department of ophthalmology at Bonn University and ten referring ophthalmology practices. It was programmed to communicate diagnostic findings, images and patient appointments online. In order to react promptly the system gave immediate notice if patients had missed a follow-up appointment or the condition had worsened. Patients were recruited in 2009 and 2010 and were followed for 1 year. Each patient had an electronic master file with several registers in which, besides personal data, precise diagnostic findings, imaging and reports were quickly and easily entered by means of detailed check box and drop-down menus. Each follow-up was registered and an alert email was sent to the referring physician in cases of missed appointments or disease progression., Results and Conclusions: The BOON database supports the requirements for a fast and detailed communication between treating and referring physicians in the treatment of patients with AMD as well as other retinal diseases. It was programmed to support data exchange and monthly control visits and thus a better patient management. Results will show whether this helps to enhance long-term treatment success in neovascular diseases. more...

Purpose: To report the short-term efficacy and safety of intravitreal bevacizumab (Avastin) injection with panretinal laser photocoagulation (PRP) in patients with high-risk proliferative diabetic retinopathy (PDR) according to the Early Treatment Diabetic Retinopathy Study criteria., Methods: A prospective, interventional case series study was conducted in 17 patients (20 eyes) with high-risk PDR, who were treated with intravitreal bevacizumab (2.5 mg) followed by PRP when the peripheral vitreous became clear or 2 weeks after injection. Patients underwent complete ophthalmic evaluation, including Snellen visual acuity and fluorescein angiography at baseline, 1, 3, and 6 months after bevacizumab injection. Main outcome measures included the serial changes in visual acuity, vitreous clear-up time, and neovascularization on the disc (NVD) regression time., Results: All patients had obvious reduction in angiographic leakage and involution of retinal neovascularization (NV) at the 1- and 3-month follow-up. The mean follow-up time was 7.5 months. The vitreous hemorrhage (VH) showed a partial resolution as early as 1 week, and complete regression at 3 months. The mean vitreous clear-up time after intravitreal Avastin was 8.5±2.2 weeks. The mean time interval from intravitreal Avastin to NVD regression was 10.8±3.4 weeks. Mean logarithm of the minimum angle resolution visual acuity improved from 1.03 at baseline to 0.36 at 1-month, 0.38 at 3-month, and 0.48 at the 6-month follow-up (P<0.01). Three eyes (18%) required vitrectomy surgery during follow-up. The indication for vitrectomy was dense, persistent VH in 2 eyes, and focal tractional retinal detachment (TRD) in 1 eye. Recurrent retinal NV with minor preretinal hemorrhage was observed in 6 eyes (30%) 3 months after the first injection, and resolved after repeated bevacizumab injections. Patients received an average of 1.4 injections (range: 1-2). Seven eyes (35%) underwent 2 injections. One eye (5%) had ocular complication of PDR progression to TRD. No systemic adverse events were observed following injections., Conclusions: Short-term results suggest combined intravitreal bevacizumab and PRP achieved rapid clearance of VH, regression of retinal NV, and visual improvement in the treatment of high-risk PDR. Long-term study is warranted to assess the long-term efficacy and safety. more...

Purpose: To discuss treatment modalities for aggressive posterior retinopathy of prematurity (AP-ROP)., Methods: The medical charts of all infants with AP-ROP at Uppsala University Hospital, Sweden, during a 2-year period (2009 and 2010) were reviewed. Eight infants (16 eyes) with a mean gestational age of 23.8 weeks and a mean birth weight of 592 g were treated with laser and/or intravitreal injections of bevacizumab (0.4 and 0.625 mg). RetCam photography was used to document the retinal appearance before and after treatment., Results: All infants (16 eyes) had AP-ROP in zone I. Mean time at initial treatment was 34 weeks postmenstrual age. Two eyes (one infant) were only treated with laser, and six eyes (three infants) were treated with laser therapy or cryopexy and, because of lack of regression, with bevacizumab as salvage therapy. Eight eyes (four infants) were treated with a first-line bevacizumab injection and four of these eyes (two infants) with additional laser ablation for continued disease progression in zone II. Macular dragging occurred in one eye of one infant primarily treated with laser., Conclusions: Given the high complication rate of the extensive laser treatment for zone I ROP, it is worth considering anti-vascular endothelial growth factor treatment as an alternative therapy. Further knowledge concerning side effects and long-term ocular and systemic outcome is warranted before this drug becomes general clinical practice., (© 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.) more...

Background: Patients with diabetes often develop ocular complications. The most common and most blinding of these complications, however, is diabetic retinopathy. The objective of this study was to compare the retinal neovessels regression in Proliferative Diabetic Retinopathy (PDR) treated with Pan Retinal Photocoagulation (PRP) versus panretinal photocoagulation plus Intra Vitreal Bevacizumab (IVB)., Methods: A comparative study was conducted at Khyber Institute of Ophthalmic Medical Sciences, Hayatabad Medical Complex, Peshawar from 1st October 2010 to 31st August 2011. A total of 54 eyes were randomised into two groups. Neovessels status was assessed before and at every follow up visit. Neo Vessels on the Disc (NVDs) were assessed as per percentage of NVD occupying the disc surface whereas Neo Vessels Elsewhere (NVE) were also assessed as per reference to disc surface diameter., Results: Neovascularization on the disc was 40 +/- 5% at presentation which increased to 50 +/- 7% on 30th day and stabilised to 40 +/- 6% on day 90 in PRP group. In PRP-plus group, 40 +/- 7% NVD regressed to 10 +/- 5% on 30th day and 11 +/- 3% on day 90. The NVE in PRP group was 2 +/- 0.75% at baseline, 2.25 +/- 0.75% on 30th day, and 2.00 +/- 0.50% on day 90. In PRP-plus group it was 2 +/- 0.50% at baseline, 1 +/- 0.5% on day 30, and 0.75 +/- 0.25% on day 90. On day 90 both the groups had highly significant different NVD (p = 0.00008) and NVE (p = 0.0001)., Conclusion: Intra Vitreal Bevacizumab in short term is effective as adjunctive treatment to PRP with early and higher rate of retinal neovessels regression than PRP alone in PDR patients. more...

Purpose: To evaluate the effects of panretinal photocoagulation (PRP) compared with PRP plus intravitreal injection of 0.5 mg of ranibizumab (IVR) in patients with high-risk proliferative diabetic retinopathy (PDR)., Methods: Prospective study included patients with high-risk PDR and no prior laser treatment randomly assigned to receive PRP (PRP group) or PRP plus IVR (PRPplus group). PRP was administered in two sessions (weeks 0 and 2), and IVR was administered at the end of the first laser session in the PRPplus group. Standardized ophthalmic evaluations including best-corrected visual acuity (BCVA) measured according to the methods used in the Early Treatment Diabetic Retinopathy Study (BCVA), fluorescein angiography to measure area of fluorescein leakage (FLA) and optical coherence tomography (OCT) for the assessment of central subfield macular thickness (CSMT), were performed at baseline and at weeks 16 (± 2), 32 (± 2) and 48 (± 2)., Results: Twenty-nine of 40 patients (n = 29 eyes) completed the 48-week study follow-up period. At baseline, mean ± SE FLA (mm(2)) was 9.0 ± 1.3 and 11.7 ± 1.3 (p = 0.1502); BCVA (logMAR) was 0.31 ± 0.05 and 0.27 ± 0.06 (p = 0.6645); and CSMT (μm) was 216.3 ± 10.7 and 249.4 ± 36.1 (p = 0.3925), in the PRP and PRPplus groups, respectively. There was a significant (p < 0.05) FLA reduction at all study visits in both groups, with the reduction observed in the PRPplus group significantly larger than that in the PRP group at week 48 (PRP = 2.9 ± 1.3 mm(2) ; PRPplus = 5.8 ± 1.3 mm(2) ; p = 0.0291). Best-corrected visual acuity worsening was observed at 16, 32 and 48 weeks after treatment in the PRP group (p < 0.05), while no significant BCVA changes were observed in the PRPplus group. A significant CSMT increase was observed in the PRP group at all study visits, while a significant decrease in CSMT was observed in the PRPplus group at week 16, and no significant difference in CSMT from baseline was observed at weeks 32 and 48., Conclusions: Intravitreal ranibizumab after PRP was associated with a larger reduction in FLA at week 48 compared with PRP alone in eyes with high-risk PDR, and the adjunctive use of IVR appears to protect against the modest visual acuity loss and macular swelling observed in eyes treated with PRP alone., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.) more...

The aim of this report is to describe a case of age-related macular degeneration with juxtafoveal subretinal neovascular membrane, initially treated with intravitreal bevacizumab (Avastin(®)) and afterwards with focal photocoagulation laser therapy. The efficacy of the initial and complementary treatment was evaluated through the visual acuity measurement and complementary exams (fluorescein angiography and optical coherence tomography). After three bevacizumab intravitreal injections , it has occurred the eccentric reduction of the neovascular subretinal membrane, changing its classification to extrafoveal, what allowed the subsequent treatment with focal photocoagulation laser therapy. more...

Purpose: To evaluate the effects of intervals between preoperative intravitreal injection of bevacizumab (IVB) and surgery on the components of removed diabetic fibrovascular proliferative membranes., Design: Interventional, consecutive, prospective, comparative case series., Participants: A total of 52 eyes of 49 patients with active diabetic fibrovascular proliferation with complications necessitating vitrectomy., Methods: Participant eyes that had IVB were divided into 8 groups in which vitreoretinal surgery was performed at days 1, 3, 5, 7, 10, 15, 20, and 30 postinjection. A group of eyes with the same diagnosis and surgical intervention without IVB injection was used for comparison. In all eyes, proliferative membrane specimens obtained during vitrectomy were sent for histopathologic examination using hematoxylin-eosin stain, immunohistochemistry (CD34 and smooth muscle actin), and Masson's trichrome stain., Main Outcome Measures: Comparative analysis of different components of the fibrovascular proliferation (CD34, smooth muscle actin, and collagen) among the study groups., Results: Pan-endothelial marker CD34 expression levels starting from day 5 postinjection were significantly less than in the control group (P < 0.001), with minimum expression (1+) in all specimens removed at or after day 30 postinjection. Positive staining for smooth muscle actin was barely detected in the control eyes at day 1, and consistently intense at day 15 and beyond (P < 0.001). The expression level of trichrome staining was significantly high at day 10, compared with control eyes (P < 0.001), and continued to increase at subsequent surgical time points., Conclusions: A profibrotic switch was observed in diabetic fibrovascular proliferation after IVB, and our results suggest that at approximately 10 days post-IVB the vascular component of proliferation is markedly reduced, whereas the contractile components (smooth muscle actin and collagen) are not yet abundant., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.) more...

Purpose: To evaluate the role of preoperative intravitreal bevacizumab as an adjunct to vitrectomy in diabetic eye disease., Methods: Twenty eyes of 18 patients were recruited and underwent a single intravitreal injection of bevacizumab 1.25 mg 1 week prior to vitrectomy. Fundus fluorescein angiography (FFA) was done before and 1 week after injections. Best corrected visual acuity (BCVA) and ophthalmic evaluation were done before, 1 week after injections, 1 day, 1 week and monthly for 3 months after vitrectomy., Results: The mean age was 47.7 ± 10.39 years. The male:female ratio was 2:3. Mean preinjection BCVA (logMAR) was 1.460 ± 0.439. FFA showed a dramatic reduction in dye leakage 1 week after injection. Intraoperative bleedings were minimal in most cases (85%, n = 17). Postoperatively, 16 patients had no bleeding (80%), 4 had minimal bleeding (20%), and 1 had recurrent fibrovascular proliferation (5%). The mean BCVA on day 1, week 1, months 2 and 3 after surgery were 1.645 ± 0.422, 1.300 ± 0.413, 1.065 ± 0.538 and 1.065 ± 0.538 logMAR, respectively (p = 0.078, 0.123, 0.002 and 0.002, respectively)., Conclusion: Bevacizumab administered prior to vitrectomy was well tolerated and was particularly useful during surgery., (Copyright © 2010 S. Karger AG, Basel.) more...

Vascular endothelial growth factor (VEGF) is produced either as a pro-angiogenic or anti-angiogenic protein depending upon splice site choice in the terminal, eighth exon. Proximal splice site selection (PSS) in exon 8 generates pro-angiogenic isoforms such as VEGF(165), and distal splice site selection (DSS) results in anti-angiogenic isoforms such as VEGF(165)b. Cellular decisions on splice site selection depend upon the activity of RNA-binding splice factors, such as ASF/SF2, which have previously been shown to regulate VEGF splice site choice. To determine the mechanism by which the pro-angiogenic splice site choice is mediated, we investigated the effect of inhibition of ASF/SF2 phosphorylation by SR protein kinases (SRPK1/2) on splice site choice in epithelial cells and in in vivo angiogenesis models. Epithelial cells treated with insulin-like growth factor-1 (IGF-1) increased PSS and produced more VEGF(165) and less VEGF(165)b. This down-regulation of DSS and increased PSS was blocked by protein kinase C inhibition and SRPK1/2 inhibition. IGF-1 treatment resulted in nuclear localization of ASF/SF2, which was blocked by SPRK1/2 inhibition. Pull-down assay and RNA immunoprecipitation using VEGF mRNA sequences identified an 11-nucleotide sequence required for ASF/SF2 binding. Injection of an SRPK1/2 inhibitor reduced angiogenesis in a mouse model of retinal neovascularization, suggesting that regulation of alternative splicing could be a potential therapeutic strategy in angiogenic pathologies. more...

Purpose: To evaluate the role of intravitreal bevacizumab in the treatment of Eales' disease. Study design Retrospective, interventional case series., Methods: Two patients with proliferative Eales' disease were managed with an intravitreal injection of bevacizumab (1.25 mg). The presence of persistent retinal neovascularization despite adequate laser photocoagulation caused recurrent episodes of vitreous hemorrhage in the first patient. The second patient had florid retinal and disc neovascularization with a dispersed vitreous bleed, which prevented laser therapy. Both patients were followed up for 6 months., Results: Rapid regression of the retinal neovascularization and clearing of the vitreous hemorrhage were observed in both cases following intravitreal bevacizumab therapy, allowing laser photocoagulation. In both patients, the visual acuity improved, and no signs of recurrence were observed 6 months post-treatment., Conclusion: Intravitreal bevacizumab injections may be effective as an adjunctive or alternative treatment of retinal neovascularization in Eales' disease, where inadequate visualization precludes laser photocoagulation. This approach may also be useful in avoiding vitreoretinal surgical intervention in certain cases. Intravitreal bevacizumab was well tolerated by our patients, and no adverse effects were observed. more...

Purpose: To evaluate the additional therapeutic effect of single intravitreal bevacizumab injection on standard laser treatment in the management of proliferative diabetic retinopathy., Methods: A prospective, fellow-eye sham controlled clinical trial was conducted on 80 eyes of 40 high-risk characteristic proliferative diabetic retinopathy type II diabetics. All cases received standard laser treatment according to Early Treatment Diabetic Retinopathy Study protocol. Avastin-assigned eyes received 1.25 mg intravitreal bevacizumab (Genentech Inc., San Francisco, CA) on the first session of their laser treatments. Fluorescein angiography was performed at baseline and at weeks 6 and 16, and proliferative diabetic retinopathy regression was evaluated in a masked fashion., Results: The median age was 52 years (range: 39-68) and 30% of the participants were male. All patients were followed for 16 weeks. A total of 87.5% of Avastin-injected eyes and 25% of sham group showed complete regression at week 6 of follow-up (p<0.005). However, at week 16, PDR recurred in a sizable number of the Avastin-treated eyes, and the complete regression rate in the two groups became identical (25%; p=1.000); partial regression rates were 70% vs 65%. In the subgroup of Avastin-treated eyes, multivariate analysis identified hemoglobin A1c as the strongest predictor of proliferative diabetic retinopathy recurrence (p=0.033)., Conclusions: Intravitreal bevacizumab remarkably augmented the short-term response to scatter panretinal laser photocoagulation in high-risk characteristic proliferative diabetic retinopathy but the effect was short-lived, as many of the eyes showed rapid recurrence. Alternative dosing (multiple and/or periodic intravitreal Avastin injections) is recommended for further evaluation. more...

Ocular neovascularization is a major cause of blindness and visual disability in developed countries. There has been considerable recent progress identifying molecular signals that participate in ocular neovascularization and it appears that imbalances between stimulatory and inhibitory proteins contribute. Re-establishing balance by ocular gene transfer to block stimulators or increase expression of endogenous inhibitors is an appealing therapeutic approach, because it provides a potential means to achieve sustained intraocular effects with little impact on the rest of the body. Proof-of-concept has been provided in animal models using several vector systems and several transgenes and completion of a phase I study testing intraocular injection of an adenoviral vector expressing pigment epithelium-derived factor is an important milestone that will help to accelerate future progress. It is likely that additional vectors and transgenes will enter clinical trials in the near future. This report discusses the rationale and experimental evidence regarding several candidate transgenes. more...

Objective: To evaluate the effect of liposome mediated plasmids encoding endostatin (ES) injected into the vitreous to inhibit experimental retinal neovascularization., Methods: Cationic liposome mediated ES expression plasmid PCDNA(3)-ES was constructed. One-week-old C57Bl/6N mice were exposed to (75 +/- 2)% oxygen for 5 days, then returned to the room air to induce retinal neovascularization. Cationic liposome mediated ES complex (2 microl) was injected into the vitreous in the treatment group. PBS 2 microl or liposome with carrier DNA complex were injected in the control group. The ES protein expression in the retina was tested with immunohistological methods at 1, 3, 7 and 14 days after injection. Retinal neovascularization was evaluated by angiography with injection of fluorescein dextran and quantification of neovascular proliferative retinopathy after 5 days in room air. To examine the toxicity of the liposome and plasmid PCDNA(3)-ES complex, the histological changes in the retina were examined by light and electron microscopy., Results: ES protein was expressed in the retina 24 hours after injection. Most of them presented in the retinal ganglion layer. This could last for 2 weeks at least. Retina of the PBS-injected eyes of retinal neovascular animal model showed prominent neovascular tuft and fluorescein leakage. Fewer neovascular tufts could be seen after ES injection. Retinal neovascularization in the eyes injected with ES plasmids complex was reduced as compared with the control group. No side effect on the retina was observed by light and electron microscopy., Conclusions: Liposome mediated plasmids encoding ES can be transferred to retinal cells by vitreous injection and can suppress retinal neovascularization, no side or toxic effects are presented in the retina. Further studies should be done to improve the treatment results. more...

Purpose: As vasoproliferative diseases account for a substantial fraction of worldwide blindness and share the activation of the angiogenic pathway as a common etiology, the expression of antiangiogenic proteins offers a promising means of treatment. This study was designed to develop viral vectors, harboring angiostatic genes, for the study and treatment of experimental proliferative ocular disease. A variety of methods (in vitro, ex vivo tissue, and in vivo) were employed to model the process of proliferation and test the effectiveness of these reagents., Methods: Antiangiogenic genes included single genes as well as hybrid genes that fused the active elements of different genes. Genes studied included the soluble vascular endothelial growth factor receptor (sKDR), soluble neuropilin (sNRP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), plasminogen gene fragments (Kringle 1-3, 1-4, and 1-5), and soluble receptors for advanced glycosylation end products (sRAGE) genes, as well as the Endo:Ang, MIG:IP10, and Endo:Kringle5 fusion genes. All genes were cloned into a lentiviral vector system and were used to produce replication deficient lentiviral particles. These viral particles were used to transduce a variety of ocular cells and tissues to test viral transfer efficiency and transgene expression. In vivo systems were employed to explore the potential of these genes as antiangiogenic agents in models of corneal and retinal neovascular disease., Results: Recombinant lentiviral particles, capable of transducing cell lines germane to eye disease (ocular endothelial, epithelial, and fibroblast cells), were successfully produced. These vectors were demonstrated to be effective in long-term transformation of cells and tissues. In vivo experiments confirmed that at least three different potentially angiostatic genes were successful in aborting the angiogenic process in the ocular models tested., Conclusions: Lentiviral vectors are a viable means to deliver angiostatic genes to tissues of the eye. Some angiostatic genes appear to have a stronger and longer-lasting effect than others in modulating the angiogenic pathway. more...

Diabetic retinopathy and retinopathy of prematurity are among the leading causes of vision impairment throughout the world. Both diseases are characterized by pathological angiogenesis, which severely impairs vision. Extracellular proteinases play important roles in endothelial cell migration during angiogenesis. Amino-terminal fragment (ATF) is an angiostatic molecule that targets the uPA/uPAR system and inhibits endothelial cell migration. The angiostatic effect of ATF has been demonstrated in models of cancer, but has never been assessed in pathological retinal neovascularization. Endostatin also has angiostatic effects on tumor growth and retinal neovascularization. We used an adenoviral vector carrying the murine ATF (AdATFHSA) or endostatin gene coupled to human serum albumin (HSA) (AdEndoHSA) to increase the half-life of the therapeutic protein in the circulation. We induced retinopathy by exposing 7-day-old mice to high levels of oxygen. They were intravitreally injected with the vectors. Local injection of AdATFHSA or AdEndoHSA reduced retinal neovascularization by 78.1 and 79.2%, respectively. Thus, the adenovirus-mediated delivery of ATFHSA or EndoHSA reduces retinal neovascularization in a mouse model of hypoxia-induced neovascularization. more...