Fernando Falcão-Reis

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.

Combination of Intravitreal Ranibizumab and Laser Photocoagulation for Aggressive Posterior Retinopathy of Prematurity

Purpose: To report on 2 cases of aggressive posterior retinopathy of prematurity (ROP) treated with intravitreal ranibizumab (Lucentis®) and laser photocoagulation. Methods: Two premature females, born at 25 and 26 weeks’ gestation with a birth weight of 530 and 550 g, respectively, with aggressive posterior ROP received combined treatment with laser photocoagulation and intravitreal ranibizumab (0.3 mg [30 µl]) to each eye. Structural outcomes were evaluated by indirect ophthalmoscopy and documented by retinography. Results: An intravitreal injection was made at 34 weeks of postmenstrual age in the first case, followed by laser photocoagulation 1 week later. There was a partial regression of ROP with treatment. Five weeks later, neovascularization regrowth with bleeding in both eyes (intraretinal and subhyaloid) occurred and retreatment with combined therapy was performed. In the second case, single therapy with laser photocoagulation was made at 34 weeks of postmenstrual age. In spite of the confluent photocoagulation in the avascular area, progression to 4A ROP stage occurred 1 week later. Both eyes were retreated 1 week later with intravitreal ranibizumab and laser photocoagulation. Treatment resulted in ROP regression in both cases. There were no signs of systemic or ocular adverse side effects. Conclusion: The cases presented show that combination therapy of indirect laser photocoagulation and intravitreal ranibizumab can be effective in the management of aggressive posterior ROP. Further investigation on anti-VEGF safety in premature infants is necessary . Additional studies are needed to define the role of anti-VEGF in ROP treatment.

Modern sports eye injuries

Aims: To determine the severity and long term sequelae of eye injuries caused by modern sports that could be responsible for significant ocular trauma in the future. Methods: Prospective observational study of 24 (25 eyes) athletes with sports related ocular injuries from health clubs, war games, adventure, radical and new types of soccer, presenting to an eye emergency department between 1992 and 2002 (10 years). Results: Modern sports were responsible for 8.3% of the 288 total sports eye injuries reported. Squash (29.2%) was the most common cause, followed by paintball (20.8%) and motocross (16.6%). The most common diagnosis during the follow up period was retinal breaks (20%). 18 (75%) patients sustained a severe injury. The final visual acuity remained <20/100 in two paintball players. Conclusions: Ocular injuries resulting from modern sports are often severe. Adequate instruction of the participants in the games, proper use of eye protectors, and a routine complete ophthalmological examination after an eye trauma should be mandatory.

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.

Characterization of neovascular age-related macular degeneration patients with outer retinal tubulations.

Purpose: To characterize the neovascular lesions of patients with age-related macular degeneration (AMD) and outer retinal tubulations (ORTs). Methods: A retrospective study of 377 eyes with exudative AMD, submitted to intravitreal anti-angiogenic treatment. Patients were divided into 2 groups according to the presence or absence of ORTs on spectral-domain optical coherence tomography (SD-OCT; group 1 - with ORTs; group 2 - without ORTs). Age, best corrected visual acuity (BCVA), fluorescein angiography characteristics, presence of subretinal fibrosis and subfoveal photoreceptor integrity on SD-OCT were analyzed. Results: Although both groups had a BCVA gain during the follow-up period, initial and final BCVA were lower in group 1 (p = 0.020 and p = 0.042, respectively). There was no statistically significant difference in the BCVA variation between the 2 groups (p = 0.907). Regarding the initial angiographic lesion type, there was a statistically significant difference between the 2 groups (p = 0.008): group 1 had more lesions with a classic component and group 2 had more occult lesions with no classic component. There was a statistically significant difference concerning the loss of subfoveal photoreceptor integrity (p = 0.0007). Conclusions: Even though AMD patients with ORTs were associated with poor visual outcomes, we reported BCVA improvement. AMD patients with a classical component in their lesions are prone to develop ORTs.