Raul Velez-Montoya

Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention.

Purpose: To address the most dynamic and current issues concerning human genetics, risk factors, pharmacoeconomics, and prevention regarding age-related macular degeneration. Methods: An online review of the database Pubmed and Ovid was performed, searching for the key words: age-related macular degeneration, AMD, pharmacoeconomics, risk factors, VEGF, prevention, genetics and their compound phrases. The search was limited to articles published since 1985 to date. All returned articles were carefully screened and their references were manually reviewed for additional relevant data. The webpage www.clinicaltrials.gov was also accessed in search of relevant research trials. Results: A total of 366 articles were reviewed, including 64 additional articles extracted from the references and 25 webpages and online databases from different institutions. At the end, only 244 references were included in this review. Conclusion: Age-related macular degeneration is a complex multifactorial disease that has an uneven manifestation around the world but with one common denominator, it is increasing and spreading. The economic burden that this disease poses in developed nations will increase in the coming years. Effective preventive therapies need to be developed in the near future.

Current knowledge and trends in age-related macular degeneration: today's and future treatments.

Purpose: To address the most dynamic and current issues concerning today’s treatment options and promising research efforts regarding treatment for age-related macular degeneration. This review is aimed to serve as a practical reference for more in-depth reviews on the subject. Methods: An online review of the database PubMed and Ovid were performed, searching for the key words age-related macular degeneration, AMD, VEGF, treatment, PDT, steroids, bevacizumab, ranibizumab, VEGF-trap, radiation, combined therapy, as well as their compound phrases. The search was limited to articles published since 1985. All returned articles were carefully screened, and their references were manually reviewed for additional relevant data. The web page www.clinicaltrials.gov was also accessed in search of relevant research trials. Results: A total of 363 articles were reviewed, including 64 additional articles extracted from the references. At the end, only 160 references were included in this review. Conclusion: Treatment for age-related macular degeneration is a very dynamic research field. While current treatments are mainly aimed at blocking vascular endothelial growth factor, future treatments seek to prevent vision loss because of scarring. Promising efforts have been made to address the dry form of the disease, which has lacked effective treatment.

The effect of unilateral intravitreal bevacizumab (avastin), in the treatment of diffuse bilateral diabetic macular edema: a pilot study.

Purpose: To investigate whether there are systemic effects of unilateral intravitreal administration of bevacizumab on the untreated eye. Methods: Twenty-three consecutive patients were enrolled in this study. All patients had a clinical diagnosis of bilateral diffuse diabetic macular edema with a central retinal thickness greater than 275 μm by Optical Coherence Tomography. They were treated with 2.5 mg bevacizumab intravitreally in the worst eye based on lines of vision, number of Early Treatment Diabetic Retinopathy Study letters, and central retinal thickness. The patients were observed every 2 weeks for 4 weeks. The Best Corrected Visual Acuity, central retinal thickness (μm), and macular volume (mm3) in the untreated eye measured by Optical Coherence Tomography were recorded at every visit. Results: The Best Corrected Visual Acuity (mean ± SD) in the untreated eye was 34.46 ± 17.29. Early Treatment Diabetic Retinopathy Study letters at baseline, 38.31 ± 14.64 at 2 weeks, and 37.38 ± 14.59 at 4 weeks. The central retinal thickness in the untreated eye was 324.77 ± 76.51 μm at baseline, 319 ± 75.7 μm at 2 weeks, and 315.54 ± 78.2 μm at 4 weeks. The macular volume in the untreated eye was 8.99 ± 1.2 mm3 at baseline, 9.16 ± 1.26 mm3 at 2 weeks, and 8.99 ± 1.09 mm3 at 4 weeks. There were no statistically significant differences between any of the measurements. Conclusion: Due to the lack of significant changes in the measurements of the untreated eye, the systemic effect of intravitreal bevacizumab seems to be unlikely. The small sample and low confidence of this pilot study prevent us to draw concrete conclusions.

Pattern scan laser photocoagulation: safety and complications, experience after 1301 consecutive cases

Background/aims The pattern scan laser photocoagulator (PASCAL) is a novel laser device that uses 10–30 ms pulse duration for retina photocoagulation. The aim of this study was to analyse the safety profile of this approach. Methods This was a retrospective study. We reviewed the clinical records of all laser sessions performed with PASCAL from November 2007 to July 2008. Where there were any complications, we recorded the laser parameters, type, affected retina region, postoperative interval and treatment if required. Results There were 1301 consecutive cases. Complications included 17 cases of retinal bleeding (1.3%), two cases of choroidal detachment (0.15%) and one case of exudative retinal detachment (0.07%). There was no statistical difference between the laser parameters used in patients with or without complications. Conclusion The laser parameters for PASCAL are safe. The complications and adverse effects encountered in this series are similar to those reported in other studies.

Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity

PURPOSE To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular endothelial growth factor in late stages of retinopathy of prematurity. METHODS Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann-Whitney and a Wilcoxon W test was done with a significant P value of 0.05. RESULTS We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 ± 61.89 pg/mL; vitreous, 118.53 ± 65.87 pg/mL; subretinal fluid, 1636.58 ± 356.47 pg/mL; and plasma, 74.64 ± 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001) in the aqueous and vitreous samples. CONCLUSION Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no statistical difference in plasma levels of the molecule between the control and study group.

16-Gy low-voltage x-ray irradiation with ranibizumab therapy for AMD: 6-month safety and functional outcomes.

BACKGROUND AND OBJECTIVE To describe the 6-month safety and preliminary efficacy outcomes of the use of 16-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS A single treatment of a non-invasive, externally delivered low-voltage 16-Gy x-ray irradiation was administered in one session through three locations in the inferior pars plana. Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) examinations were performed at 1 week, 1 month, and monthly thereafter, with quarterly fluorescein angiography (FA). After the two initial ranibizumab injections, subsequent injections were administered according to the following criteria: VA decline of 10 ETDRS letters compared with baseline, increase of 100-μm central foveal thickness on OCT compared with baseline, the development of new submacular hemorrhage, and the development of a new area of classic choroidal neovascularization on FA. RESULTS Twenty-six patients completed a 6-month follow-up. There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean baseline ETDRS score was 46.6 letters (range: 5 to 80; standard deviation [SD]: 21.5). At 6 months, the corresponding ETDRS score was 55.6 letters (range: 25 to 80; SD: 18.9) and the mean change in VA was 9.5 ETDRS letters (SD: 10.3). On responder analysis, 96% lost 15 or fewer ETDRS letters, 81% gained 0 or more ETDRS letters, and 50% gained 15 or more ETDRS letters. Patients received a total of 13 ranibizumab injections following two initial injections. At 6 months, patients received an average of 0.5 additional injections following the initial two mandated injections. CONCLUSION A single treatment of externally applied, non-invasive 16-Gy low-voltage x-ray therapy in conjunction with ranibizumab demonstrated an overall improvement of VA in patients with neovascular AMD at 6 months with no radiation-related adverse effects.

24-Gy Low-Voltage X-Ray Irradiation With Ranibizumab Therapy for Neovascular AMD: 6-Month Safety and Functional Outcomes

BACKGROUND AND OBJECTIVE To describe the 6-month safety and preliminary efficacy outcomes of the use of 24-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS A single treatment of a non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 24 Gy was administered in one session through three locations in the inferior pars plana in a consecutive series of patients with neo-vascular AMD (treatment naïve and previously treated). Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity examinations were performed at 1 week, 1 month, and monthly thereafter with quarterly fluorescein angiography. RESULTS Nineteen patients completed 6 months of follow-up. There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean baseline ETDRS score was 38.3 ± 19.5 letters. At 6 months, the corresponding ETDRS score was 44.7 ± 16.8 letters. At 6 months, the mean change in visual acuity was 6.4 ± 9.8 ETDRS letters. Patients received an average of 0.4 additional ranibizumab injections following the initial two mandated injections. CONCLUSION A single treatment of external 24-Gy low-voltage x-ray therapy in conjunction with ranibizumab demonstrated an overall improvement in visual acuity in patients with neovascular AMD at 6 months, with no radiation-related adverse effects.

Ocular Biocompatibility of Nitinol Intraocular Clips

PURPOSE To evaluate the tolerance and biocompatibility of a preformed nitinol intraocular clip in an animal model after anterior segment surgery. METHODS Yucatan mini-pigs were used. A 30-gauge prototype injector was used to attach a shape memory nitinol clip to the iris of five pigs. Another five eyes received conventional polypropylene suture with a modified Seipser slip knot. The authors compared the surgical time of each technique. All eyes underwent standard full-field electroretinogram at baseline and 8 weeks after surgery. The animals were euthanized and eyes collected for histologic analysis after 70 days (10 weeks) postsurgery. The corneal thickness, corneal endothelial cell counts, specular microscopy parameters, retina cell counts, and electroretinogram parameters were compared between the groups. A two sample t-test for means and a P value of 0.05 were use for assessing statistical differences between measurements. RESULTS The injection of the nitinol clip was 15 times faster than conventional suturing. There were no statistical differences between the groups for corneal thickness, endothelial cell counts, specular microscopy parameters, retina cell counts, and electroretinogram measurements. CONCLUSIONS The nitinol clip prototype is well tolerated and showed no evidence of toxicity in the short-term. The injectable delivery system was faster and technically less challenging than conventional suture techniques.

16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for age-related macular degeneration: 12 month outcomes of a ‘radiation-first’ strategy

Background and objective To describe ‘radiation-first’ combination treatment with a non-invasive, low-voltage x-ray irradiation system followed by as needed ranibizumab for neovascular age-related macular degeneration (AMD). Study design and methods Phase I study of non-invasive, low-voltage 16 Gy x-ray irradiation delivered in three beams via the inferior pars plana in patients with active neovascular AMD. Ranibizumab was administered as needed per protocol. Patients were followed monthly for safety and efficacy over 12 months. Results 13 patients were enrolled and completed 12 months follow-up. Safety was good with no serious ocular/non-ocular adverse events or radiation-related ocular complications. 11 patients lost <15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, seven gained ≥0 ETDRS letters and 0 gained ≥15 ETDRS letters. Patients received a total of 31 subsequent ranibizumab injections (of possible 156) over the 12 months following x-ray irradiation. Mean time to first injection was 3.9 months. One patient received no ranibizumab injections, three patients received one injection, four patients received two injections, and five patients received three or more injections. Conclusions After 12 months, non-invasive, low-voltage x-ray irradiation with as needed ranibizumab rescue therapy demonstrated good safety with a visual acuity stabilising effect and reduction in retinal thickness in patients with neovascular AMD.

Bevacizumab Local Complications

Dear Editor: Bevacizumab (Avastin, Genetech, San Francisco, CA) is a recombinant monoclonal antibody (IgG1) that selectively binds and neutralizes the biological activity of vascular endothelial growth factor. Its intravenous administration was approved by the Food and Drug Administration (FDA) in February 2004 as a first-line therapy for metastatic colorectal cancer. In the past few years, “off-label” uses in the ophthalmology field have become popular due to its encouraging results in the treatment of vasoproliferative diseases. While no one disputes its apparent effectiveness, the relative effectiveness compared with ranibizumab, and the safety of its intravitreal administration, has recently been debated. This is due to lack of comparative data from large prospective randomized trials, and in part, because of doubts cast by the warnings issued by the FDA and the manufacturer about possible local and systemic adverse effects (AE). One cause of confusion lies in the multiple AEs reported after intravenous administration (dose of 5 mg/kg). Even though the intravitreal doses are almost 400 times smaller than the intravenous, there is some systemic absorption of the drug (3.3 mg/ml, 8 days after intravitreal injection). The fact that this amount of bevacizumab may produce systemic AEs is a major concern for the retinal specialists. Due to the lack of information in the literature regarding the incidence of local complications after its intravitreal administration; we decided to review our experience in the use of this antibody. Our study was approved by the hospital ethics board. We reviewed the clinical records of 3517 consecutive injections in 2863 patients, in a period of time involving 27 months (September 2005 to December 2007). We included all bevacizumab injections, regardless the pretreatment diagnosis or the intravitreal dose. For every case, we recorded the age, gender, diagnosis, type of AE, drug dose, number of injections, best corrected visual acuity (BCVA) before the AE, BCVA in the last follow up, the time between the intravitreal injection and the diagnosis of the AE, the need for surgery, the time until the AE was resolved, and time of follow-up (follow-up time). We also recorded the blood pressure before and after the injection. Descriptive analyses were performed using SPSS software, version 10.1.0 (SPSS Inc., Chicago, IL). We identified 16 AEs that appeared to be directly related to the administration of intravitreal bevacizumab. The general demographic data is summarized in Table 1 (available at http://aaojournal.org). The dose used in all patients was 2.5 mg. Most of the patients had previous injections but not always in the same eye. Only 2 patients had 1 or more injections in the same eye (2 females, 1 developed endophthalmitis and the second developed a tractional retinal detachment). Two male patients (0.05%) presented with anterior chamber inflammation (anterior chamber cells 2 ), without other clinical sign of infection. Neither of these 2 cases required surgery or additional treatment beside topical nonsteroidal anti-inflammatories. Four female and 2 male patients presented endophthalmitis (0.17%). The mean time between the intravitreal injection and the development of the en-