Manuel Falcão

Progression of Geographic Atrophy in Age-Related Macular Degeneration Imaged with Spectral Domain Optical Coherence Tomography

PURPOSE To determine the area and enlargement rate (ER) of geographic atrophy (GA) in patients with age-related macular degeneration (AMD) using the spectral domain optical coherence tomography (SD-OCT) fundus image. DESIGN Prospective, longitudinal, natural history study. PARTICIPANTS Eighty-six eyes of 64 patients with ≥6 months of follow-up. METHODS Patients with GA secondary to AMD were enrolled in this study. Macular scans were performed using the Cirrus SD-OCT (Carl Zeiss Meditec, Dublin, CA). The areas of GA identified on the SD-OCT fundus images were quantified using a digitizing tablet. Reproducibility of these measurements was assessed and the ER of GA was calculated. The usefulness of performing square root transformations of the lesion area measurements was explored. MAIN OUTCOME MEASURES Enlargement rate of GA. RESULTS At baseline, 27% of eyes had a single area of GA. The mean total area at baseline was 4.59 mm(2) (1.8 disc areas [DA]). The mean follow-up time was 1.24 years. Reproducibility, as assessed with the intraclass correlation coefficient (ICC), was excellent on both the original area scale (ICC = 0.995) and the square root scale (ICC = 0.996). Intergrader differences were not an important source of variability in lesion size measurement (ICC = 0.999, 0.997). On average, the ER of GA per year was 1.2 mm(2) (0.47 DA; range, 0.01-3.62 mm(2)/year). The ER correlated with the initial area of GA (r = 0.45; P<0.001), but there were variable growth rates for any given baseline area. When the square root transformation of the lesion area measurements was used as a measure of lesion size, the ER (0.28 mm/yr) was not correlated with baseline size (r = -0.09; P = 0.40). In this cohort of lesions, no correlation was found between ER and length of follow-up. Square root transformation of the data helped to facilitate sample size estimates for controlled clinical trials involving GA. CONCLUSIONS The SD-OCT fundus image can be used to visualize and quantify GA. Advantages of this approach include the convenience and assurance of using a single imaging technique that permits simultaneous visualization of GA along with the loss of photoreceptors and the retinal pigment epithelium that should correlate with the loss of visual function.

Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab

Purpose: To evaluate the changes of vascular endothelial growth factor (VEGF) plasma levels after intravitreal injections of ranibizumab or bevacizumab in patients with exudative age‐related macular degeneration (AMD).

Arterial Thromboembolic Events in Patients with Exudative Age-Related Macular Degeneration Treated with Intravitreal Bevacizumab or Ranibizumab

Background/Aims: To compare retrospectively the incidence of arterial thromboembolic events (ATEs) in patients treated with bevacizumab or ranibizumab for exudative age-related macular degeneration. Methods: Charts of 378 patients treated with at least 1 intravitreal injection of ranibizumab or bevacizumab were reviewed to calculate the incidence of ATEs. Only patients under monotherapy were analyzed. Results: ATEs occurred in 15 patients: 12 (12/97) with bevacizumab (12.4%) and 3 (3/219) with ranibizumab (1.4%) – odds ratio 10.16; 95% confidence interval 2.80–36.93; p < 0.0001. ATEs in the bevacizumab and ranibizumab cohorts included stroke, myocardial infarction, angina pectoris, peripheral thromboembolic disease, transient ischemic attack, sudden death and lethal stroke. Conclusion: In this series, bevacizumab raised the risk of ATEs when compared to ranibizumab. In an elderly population with multiple cardiovascular risk factors, the new ATEs may not be attributed exclusively to the intravitreal bevacizumab administration. These findings raise an issue that must be confirmed in randomized clinical trials.

Comparative effects of bevacizumab, ranibizumab and pegaptanib at intravitreal dose range on endothelial cells.

Anti-VEGF therapy proved to be useful against several ocular pathological situations, including choroidal neovascularization and proliferative retinopathies. Ranibizumab (Ran), Pegaptanib (Peg) and Bevacizumab (Bev) are the pharmacological agents more frequently used in clinical practice by intravitreal injection. However, their exact effects on the angiogenic process have not been accurately established in a comparative study. The aim of the present study was to elucidate the precise effects of Ran, Peg and Bev on the multiple steps of the angiogenic process. Human umbilical vein endothelial cells (HUVEC) were incubated with each agent within the clinically established concentration range, or identical amounts of the excipients; cell cytotoxicity, proliferation, apoptosis, migration and vessel assembly were assessed. No cytotoxic effects were found for any of the agents studied at any concentration tested. At the clinical dose, cell proliferation was significantly reduced by Bev and Ran, whereas no difference was observed after Peg treatment. In addition, HUVEC apoptosis was effectively increased by Bev and Ran. Cell migration was reduced after incubation with every agent analyzed, though only reaching statistical significance upon Ran intravitreal dose. At clinical doses, capillary assembly was only affected by Bev. In agreement with these data, the active form of VEGF receptor-2 expression was decreased after incubation with Bev (to 66% of control values), Ran (78%) and Peg (86%) relative to controls. These findings indicate that these three agents display distinct effects on endothelial cells.

Bevacizumab and ranibizumab on microvascular endothelial cells: A comparative study

Given its broad effects in endothelium, vascular endothelial growth factor (VEGF) represents the primary rate‐limiting step of angiogenesis. Therefore, VEGF targeting therapies were soon developed. Bevacizumab and ranibizumab are two of these therapeutic agents already in clinical use. Bevacizumab was first used for cancer treatment, whereas ranibizumab was designed to target choroidal neovascularization, the main cause of blindness in age‐related macular degeneration. The present study aims to compare the multiple effects of bevacizumab and ranibizumab in human microvascular endothelial cells (HMECs). HMEC cultures were established and treated during 24 h with the anti‐VEGF agents within the intravitreal‐established concentration range or excipients. Analyses of VEGF content in cell media and VEGF receptor‐2 (VEGFR‐2) expression in cell lysates were performed. No cell cytotoxicity (MTS assay) was found in anti‐VEGF‐treated cultures at any concentration. Apoptosis (TUNEL assay) was significantly increased and cell proliferation (BrdU assay), migration (transwell assay) and assembly into vascular structures were significantly reduced by incubation with both agents at the two doses used. These findings were accompanied by a strong decrease in VEGF release, and in phosphorylated VEGFR‐2 and Akt expression for both agents at the clinical concentration. Interestingly, phosphorylated Erk was only significantly reduced upon bevacizumab treatment. In addition, proliferation was more affected by ranibizumab, whereas migration, capillary formation, and phosphorylated VEGFR2 expression were significantly reduced by bevacizumab as compared to ranibizumab. Therefore, although both agents presented anti‐angiogenic actions, distinct effects were exerted by the two molecules in HMEC. These findings suggest that a careful confirmation of these effects in clinical settings is mandatory. J. Cell. Biochem. 108: 1410–1417, 2009.

Quantitative imaging of retinal pigment epithelial detachments using spectral-domain optical coherence tomography.

PURPOSE To evaluate the reproducibility of area and volume measurements of retinal pigment epithelium detachments (PEDs) in eyes of patients with age-related macular degeneration using spectral-domain optical coherence tomography imaging and a novel automated, quantitative algorithm. DESIGN Prospective study to evaluate a diagnostic technology. METHODS Patients with PEDs associated with age-related macular degeneration underwent spectral-domain optical coherence tomography imaging. Each eye was imaged 5 times, and each scan consisted of a raster pattern comprising 40 000 uniformly spaced A-scans organized as a 200 × 200 A-scan array. Each raster scan covered a retinal area of 6 × 6 mm encompassing the entire PED. A novel algorithm was used to create PED maps that permitted both qualitative and quantitative assessment of PED area and volume. Test-retest standard deviations of PED area and volume measurements were calculated for each eye. RESULTS Sixty-three eyes of 58 patients were enrolled in this study. The qualitative appearance and the quantitative measurements of PED area and volume were highly reproducible over the 5 different datasets obtained from each eye. The intraclass correlation coefficient was more than 0.99 for both area and volume measurements obtained using the entire dataset. CONCLUSIONS A novel algorithm for the qualitative and quantitative assessment of PEDs imaged using spectral-domain optical coherence tomography was shown to be highly reproducible. The ability to measure PED area and volume reliably represents a novel strategy for following disease progression, especially when assessing the response of vascularized PEDs to antiangiogenic therapy.

Switch to Aflibercept in the Treatment of Neovascular AMD: One-Year Results in Clinical Practice

Purpose: To report the clinical outcomes of intravitreal aflibercept therapy in eyes with refractory and recurrent neovascular age-related macular degeneration (AMD) switched from intravitreal bevacizumab or ranibizumab. Methods: This is a retrospective review of eyes with neovascular AMD switched to intravitreal aflibercept with at least 1 year of follow-up after the switch. All patients had had a minimum of 3 injections of bevacizumab or ranibizumab before the switch. Aflibercept was used in patients considered refractory to bevacizumab (group 1) and in recurrent patients on therapy with ranibizumab due to an institutional policy decision (group 2). Changes in best-corrected visual acuity, fluid on optical coherence tomography (OCT), central retinal thickness (CRT) and the frequency of injections were compared. Results: Eighty-five eyes of 69 patients were analyzed, 39 eyes in group 1 and 46 in group 2. The mean follow-up time was 31.6 months prior to the switch and 14.7 months on treatment with aflibercept. One year after the switch, there was a nonsignificant mean decrease of 2 letters in visual acuity in both groups (group 1: from 58.2 to 55.8 letters, p = 0.086; group 2: from 56.4 to 54.5 letters, p = 0.168), but the mean number of injections per month was significantly lower (from 0.76 to 0.57, p < 0.001). With the switch, 90.6% of the patients showed anatomic improvement with a reduction of fluid on OCT, and both groups presented significant improvement in CRT (group 1: 65.3 µm, p = 0.051; group 2: 91.0 µm, p < 0.001). Conclusion: Aflibercept appears to be a valuable tool for the management of patients with poor responses to other anti-vascular endothelial growth factor drugs. These patients could have anatomic improvement, and the injection intervals could be extended.

Spectral-domain optical coherence tomography of the choroid during valsalva maneuver.

PURPOSE To evaluate the influence of Valsalva maneuver on the morphology and thickness of the choroid at the macular area. DESIGN Prospective interventional case series. METHODS Institutional setting. Nine healthy volunteers performed macular spectral-domain optical coherence tomography using enhanced-depth imaging at rest and during a Valsalva maneuver. Horizontal and vertical B-scans centered on the fovea were acquired. Subfoveal and average choroidal thickness in the central 3 mm were compared in the resting position and during the Valsalva maneuver using manual and semiautomatic measuring tools. Changes in choroidal thickness were evaluated. RESULTS There was no statistically significant difference in choroidal thickness at rest or during Valsalva maneuver in any of the compared groups. The subfoveal thickness difference was -4.1 μm on horizontal scans (P = .28) and 1.4 μm on vertical scans (P = .75). The mean choroidal thickness difference in the central 3000 μm was 8.5 μm on horizontal scans (P = .73) and -5.3 μm on vertical scans (P = .41). CONCLUSIONS Valsalva maneuver does not change choroidal thickness at the posterior pole. The increase in ocular pressure caused by this maneuver cannot be explained by an increase in choroidal thickness in this portion of the uveal tract.

Choroidal and macular thickness changes induced by cataract surgery

Background The aim of this study was to evaluate the effect of uneventful phacoemulsification on the morphology and thickness of the macula, the submacular choroid, and the peripapillary choroid. Methods In 14 eyes from 14 patients, retinal macular thickness, choroidal submacular thickness, and choroidal peripapillary thickness were measured preoperatively and at one week and one month after phacoemulsification using enhanced depth imaging spectral domain optical coherence tomography. Changes in thickness of the different ocular tissues were evaluated. Results There was a statistically significant increase in mean retinal macular thickness at one month. In horizontal scans, the mean increase was +8.67±6.75 μm (P<0.001), and in vertical scans, the mean increase was +8.80±7.07 μm (P=0.001). However, there were no significant changes in choroidal morphology in the submacular and peripapillary areas one month after surgery. In vertical scans, there was a nonsignificant increase in choroidal thickness (+4.21±20.2 μm; P=0.47) whilst in horizontal scans a nonsignificant decrease was recorded (−9.11±39.59 μm; P=0.41). In peripapillary scans, a nonsignificant increase in mean choroidal thickness was registered (+3.25±11.80 μm; P=0.36). Conclusion Uncomplicated phacoemulsification induces nonpathologic increases in retinal macular thickness probably due to the inflammatory insult of the surgery; however these changes are not accompanied by significant changes in choroidal thickness. In the posterior segment, the morphologic response to the inflammatory insult of phacoemulsification is mainly observed at the retinal level, and seems to be independent of choroidal thickness changes.

Ranibizumab Treatment for Choroidal Neovascularization from Causes Other than Age-Related Macular Degeneration and Pathological Myopia

Aim: Evaluation of safety and efficacy of intravitreal ranibizumab in the treatment of choroidal neovascularization (CNV) secondary to causes other than age-related macular degeneration (AMD) or pathological myopia (PM). Methods: Retrospective and multicentric analysis of 21 eyes with CNV. Nine eyes had angioid streaks, 5 inflammatory chorioretinal diseases, 3 central serous chorioretinopathy and 4 idiopathic CNV. Follow-ups lasted ≧3 months. Best-corrected visual acuity (BCVA), ocular coherence tomography (OCT) and fundus examination were assessed monthly. Results: Sixteen eyes (76%) completed 180 days of follow-up. Overall BCVA increased by +9.8 letters with treatment (p = 0.015). Visual acuity improvements ≧15 letters occurred in 43%. A significant reduction in OCT central thickness was observed. No cases of severe visual acuity loss, systemic or ocular side effects were registered. Conclusion: Short-term results of intravitreal ranibizumab for CNV unrelated to AMD or PM are encouraging. This treatment may constitute the only option for some of these patients.