Perfil epidemiológico das aplicações intravítreas de Ranibizumab / Epidemiological profile of Ranibizumab intravitreal applications

Resumo Objetivo: O objetivo desse trabalho é avaliar o perfil de aplicações intravítreas do Ranibizumab em uma população de adultos atendidos no Instituto Benjamin Constant, no ano de 2015, levando em consideração o efeito sobre a acuidade visual e a espessura macular após tratamento. O objetivo secundário é apresentar as principais indicações desse tipo tratamento no serviço de olhos acima citado. Métodos: Foi realizado um estudo retrospectivo seccional, em indivíduos acima de 20 anos entre os meses de março a agosto de 2015, para analisar a acuidade visual e espessura foveal pré e pós tratamento. A dose do anti-VEGF utilizada foi de 0,05ml por aplicação com intervalo de quatro semanas entre elas. A aferição da acuidade visual assim como o OCT pós tratamento foram realizados em torno de trinta dias após a última aplicação. As análises estatísticas foram feitas com uso do software SPSS versão 21 e o nível de significância estatística foi de 95% com um valor de p <0,05. Resultado: O estudo mostrou que a principal afecção relacionada a esse tratamento foi a retinopatia diabética não proliferativa associada ao edema macular (32,8%). Após o tratamento indicado com Ranibizumab, houve uma melhora da acuidade visual média de 0,70 para 0,59 (logMAR) e uma regressão da espessura macular, visto no OCT, de 408,1µm para 337,2 µm (valor de p <0,05). Conclusão: Pode-se concluir portanto, que o tratamento com Ranibizumab na população estudada contribuiu para uma melhor qualidade de vida dos pacientes, pois a maioria dele apresentou uma melhora estatisticamente significativa na acuidade visual após as aplicações.

Abstract The objective of this work is to evaluate the profile of intravitreal applications of Ranibizumab in a population of adults attended at the Benjamin Constant Institute in the year of 2015, taking into account the effect on visual acuity and macular thickness after the treatment. The secondary objective is to present the main indications of this type of treatment in the eye care mentioned above. A retrospective cross-sectional study was performed in individuals over 20 years of age between March and August of 2015 to analyze visual acuity and foveal thickness before and after treatment. The dose of anti-VEGF used was 0.05 ml per application with an interval of four weeks between them. Visual acuity assessment as well as OCT post treatment were performed around 30 days after the last application. Statistical analyses were performed using SPSS software version 21 and the level of statistical significance was of 95% with a value of p <0.05. The study showed that the main condition related to this treatment was non-proliferative diabetic retinopathy associated with macular edema (32.8%). After treatment indicated with Ranibizumab, there was an improvement in the average visual acuity from 0.70 to 0.59 (logMAR) and a regression of the macular thickness, seen in the OCT, from 408.1μm to 337.2μm (p < 0.05). It can be concluded, therefore, that treatment with Ranibizumab in the studied population contributed to a better quality of life of the patients, since most of them presented a statistically significant improvement in the visual acuity after the applications.

Pathophysiology of Diabetic Retinopathy: The Old and the New

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities—including hyperpermeability, hypoperfusion, and neoangiogenesis—that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.

Relationship between Pericytes and Endothelial Cells in Retinal Neovascularization: A Histological and Immunofluorescent Study of Retinal Angiogenesis

PURPOSE: To evaluate the relationship between pericytes and endothelial cells in retinal neovascularization through histological and immunofluorescent studies. METHODS: C57BL/6J mice were exposed to hyperoxia from postnatal day (P) 7 to P12 and were returned to room air at P12 to induce a model of oxygen-induced retinopathy (OIR). The cross sections of enucleated eyes were processed with hematoxylin and eosin. Immunofluorescent staining of pericytes, endothelial cells, and N-cadherin was performed. Microfluidic devices were fabricated out of polydimethylsiloxane using soft lithography and replica molding. Human retinal microvascular endothelial cells, human brain microvascular endothelial cells, human umbilical vein endothelial cells and human placenta pericyte were mixed and co-cultured. RESULTS: Unlike the three-layered vascular plexus found in retinal angiogenesis of a normal mouse, angiogenesis in the OIR model is identified by the neovascular tuft extending into the vitreous. Neovascular tufts and the three-layered vascular plexus were both covered with pericytes in the OIR model. In this pathologic vascularization, N-cadherin, known to be crucial intercellular adhesion molecule, was also present. Further evaluation using the microfluidic in vitro model, successfully developed a microvascular network of endothelial cells covered with pericytes, mimicking normal retinal angiogenesis within 6 days. CONCLUSIONS: Pericytes covering endothelial cells were observed not only in vasculature of normal retina but also pathologic neovascularization of OIR mouse at P17. Factors involved in the endothelial cell-pericyte interaction can be evaluated as an attractive novel treatment target. These future studies can be performed using microfluidic systems, which can shorten the study time and provide three-dimensional structural evaluation.

The vascularization process after intravitreal ranibizumab injections for aggressive posterior retinopathy of prematurity / Processo de vascularização após injeções intravítreas de ranibizumab para retinopatia da prematuridade posterior agressiva

ABSTRACT Purpose: To evaluate the retinal vascularization process after intravitreal ranibizumab was administered to infants with aggressive posterior retinopathy of prematurity (AP-ROP). Methods: Twenty-six eyes of 13 infants with AP-ROP who received 0.25 mg intravitreal ranibizumab were retrospectively investigated. The patients were evaluated at weekly follow-up visits, and the findings were analyzed after retinal vascularization was complete. Results: The results showed regression in the AP-ROP of all the patients within the first 48-72 h. Average time for complete vascularization of the nasal quadrant (zone II) was postmenstrual week 45 (range 41-56), and vascularization of the temporal quadrant (zone III) was completed in the postmenstrual week 56 (range 50-65). Reactivation was observed in seven patients, on average at postmenstrual week 42; two of these patients underwent additional treatment. Two patients presented with avascular areas in the peripheral retina despite being 1 year old. Conclusion: These results showed that retinal vascularization following intravitreal ranibizumab was completed after a delay in patients with AP-ROP. Further studies are necessary to evaluate when and how vascularization occurs after intravitreal anti-vascular endothelial growth factor treatments.

RESUMO Objetivo: Avaliar o processo de vascularização da retina após injeção intravítrea de ranibizumab aplicada em crianças com retinopatia da prematuridade posterior agressiva (AP-ROP). Métodos: Vinte e seis olhos de 13 crianças com AP-ROP que receberam 0,25 mg de ranibizumab intravítreo foram investigados retrospectivamente. Os resultados foram avaliados após a completa vascularização da retina, observada em acompanhamentos semanais. Resultados: Verificou-se que houve regressão na AP-ROP de todos os pacientes durante as primeiras 48 a 72 horas. Na média, a vascularização do quadrante nasal (zona II) foi concluída na semana 45 pós-menstrual (variação 41-56), enquanto a vascularização do quadrante temporal (zona III) foi concluída na semana 56 pós-menstrual (variação 50-65). Sete pacientes (7/13) apresentaram reativação, que aconteceram em média a 42,14 semanas pós-menstruais, dois pacientes receberam tratamento adicional. Dois pacientes apresentaram áreas avasculares na retina periférica apesar de terem um ano de idade. Conclusões: O presente estudo mostrou que a vascularização da retina após a injeção intravítrea de ranibizumab foi concluída com atraso na AP-ROP. Ensaios clínicos randomizados são necessários para avaliar quando e como a vascularização acontece após tratamentos com injeções intravítreas de anti-VEGF.

Effects of bone marrow mesenchymal stem cell transplantation on retinal neovascularization in neonatal rats with oxygen-induced retinopathy / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To explore the effects of rat bone mesenchymal stem cell (BMSC) transplantation on retinal neovascularization, and to observe the changes of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factors (VEGF) in rats with oxygen-induced retinopathy (OIR).</p><p><b>METHODS</b>Seventy-two seven-day-old Sprague-Dawley rats were randomly divided into three groups: normal control (CON), model (OIR) and BMSC transplantation. In the BMSC transplantation group, BMSCs were transplanted 5 days after oxygen conditioning. The phosphate buffered saline of the same volume was injected in the CON and OIR groups. The OIR model was prerpared according to the classic hyperoxygen method. At seven days after transplantation, retinal neovascularization was examined by retinal flat-mount staining and hematoxylin eosin (HE) staining. The expression of HIF-1α and VEGF proteins was examined by immunohistochemistry staining and Western blot analysis.</p><p><b>RESULTS</b>The retinal flat-mount staining results showed that the vessels were well organized in the CON group, but the vessels were irregularly organized, and lots of nonperfusion areas were observed in the OIR group. The large vessels were a bit circuitous, the retinal vessels were relatively organized, and less nonperfusion areas were noted in the BMSC transplantation group. The HE staining results showed that many neovessels and preretinal neovascular (pre-RNC) cells were observed on the internal limiting membrane in the OIR group. There were less pre-RNC cells in the BMSC transplantation group compared with the OIR group (P<0.01). The immunohistochemistry analysis showed that more HIF-1αand VEGFcells were observed in the OIR group compared with the CON group, and less HIF-1αand VEGFcells were observed in the BMSC transplantation group compared with OIR group (P<0.05). The Western blot analysis showed the expression of HIF-1α and VEGF proteins in the OIR group was significantly higher than that in the CON group. The expression of HIF-1α and VEGF proteins in the BMSC transplantation group was lower than that in the OIR group (P<0.01).</p><p><b>CONCLUSIONS</b>BMSC transplantation therapy could alleviate retinal neovascularization in OIR rats, and its mechanisms might be associated with the inhibition of the expression of HIF-1α and VEGF proteins.</p>

Análisis de costo-efectividad de ranibizumab comparado con aflibercept y bevacizumab para el tratamiento de pacientes con degeneración macular relacionada con la edad (DMRE ) de tipo neovascular en Colombia / Cost-effectiveness analysis of ranibizumab compared to aflibercept and bevacizumab for the treatment of patients with age-related macular degeneration (AMD) of the neovascular type in Colombia

Problema de investigación: Realizar el análisis de costo-efectividad del uso de ranibizumab comparado con \r\naflibercept y bevacizumab para pacientes con degeneración macular relacionada con la edad en Colombia. Tipo de evaluación económica: Evaluación económica descriptiva de tipo costo-efectividad. Población objetivo: \r\nPoblación con la condición de degeneración macular relacionada a la edad mayor de 50 años en Colombia. Intervención y comparadores: Intervención: ranibizumab.Comparadores: aflibercept y bevacizumab. Horizonte\r\ntemporal: 24 años. Perspectiva: La del Sistema General de Seguridad Social en Salud (SGSSS). Tasa de descuento: Es de 5% tanto para los costos como para los desenlaces de efectividad. Estructura del modelo: \r\nModelo de Markov de 6 estados con ciclos de 6 meses. Fuentes de datos de efectividad y seguridad: Ensayos clínicos. Desenlaces y valoración: Años de vida ajustados por calidad (AVAC). Costos incluidos: Costos de medicamentos, Costos de procedimientos e insumos. Fuentes de datos de costos: Consulta a proveedores, SISMED, Manual tarifario ISS 2001. Resultados del caso base: La razón de costo-efectividad de una cohorte con pacientes de 50 años de edad sometidos a un tratamiento durante 24 años para cada uno de los medicamentos es: bevacizumab Pro Re Nata $46.8millones/AVAC, bevacizumab mensual $46.1 Millones/AVAC, ranibizumab Pro Re Nata $64.7 millones/AVAC, ranibizumab mensual $64.4 Millones/AVAC, aflibercept Pro Re nata $64.3 Millones/AVAC y aflibercept mensual $63.3Millones/AVAC. Análisis de sensibilidad: Los análisis de sensibilidad llevados a cabo sobre la tasa de descuento evidencian que ninguno de estos parámetros modifica los resultados encontrados. dominancia del bevacizumab en un esquema de \r\ntratamiento mensual es dominante en todos los escenarios planteados demostrando ser un resultado robusto. Conclusiones y discusión: Los resultados de la evaluación indican que el ranibizumab no es costo-\r\nefectivo comparado con bevacizumab y con aflibercept mensual. El ranibizumab es costo-efectivo comparado \r\ncon aflibercept con tratamiento Pro Re nata.(AU)

microRNA-218 Inhibits Oxygen-induced Retinal Neovascularization via Reducing the Expression of Roundabout 1 / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The mechanisms of pathological retinal neovascularization (RNV) remain unknown. Several microRNAs were reported to be involved in the process of RNV. Oxygen-induced retinopathy (OIR) is a useful model to investigate RNV. Our present work explored the expression and the role of microRNA-128 (miR-218) in oxygen-induced RNV.</p><p><b>METHODS</b>OIR was used to establish RNV model. The expression level of miR-218 in the retina from OIR mice was assessed by quantitative real-time reverse transcriptase polymerase chain reaction. Fluorescein angiography was performed in retinae of OIR mice, and RNV was quantified by hematoxylin and eosin staining to evaluate the effect of pCDH-CMV-miR-218 intravitreal injection on RNV in OIR mice. Roundabout 1 (Robo1) expression was detected by Western blotting in mouse retinal vascular endothelial cells expressing a high or low level of miR-218 and retinal tissues from OIR mice. Cell migration was evaluated by scratch wound assay.</p><p><b>RESULTS</b>In OIR mice, the expression level of miR-218 was significantly down-regulated (P = 0.006). Retinal Robo1 expression was significantly increased at both mRNA and protein levels (P = 0.001, 0.008; respectively). miR-218 intravitreal injection inhibited retinal angiogenesis in OIR mice, and the restoration of miR-218 in retina led to down-regulation of Robo1.</p><p><b>CONCLUSIONS</b>Our experiments showed that restoration of miR-218 inhibited retinal angiogenesis via targeting Robo1. MiR-218 contributed to the inhibition of retinal angiogenesis and miR-218 might be a new therapeutic target for preventing RNV.</p>

Effects of propranolol on oxygen-induced retinal neovascularization in mouse / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate whether propranolol application as collyrium or intraperitoneal (IP) injection can promote the recovery of oxygen-induced retinopathy (OIR).</p><p><b>METHOD</b>Thirty-six 7-day-old mice were divided into the following 6 groups: normal control, propranolol eye drops, propranolol IP injection, eye drops negative control, IP injection negative control, and pathological model with 6 mice in each. In a typical model of OIR, litters of mice pups with their nursing mothers were exposed to an infant incubator to high oxygen concentration (75 ± 5)% between postnatal day (PD) 7 and PD12, prior to returning to room air. Two routes of propranolol treatment were assessed from PD12 to PD17: IP injection and eye drop, with doses 2 mg/(kg·time), three times a day. Another three groups were given citric acid buffer eye drops, IP injection of citric acid buffer, and negative control were not treated with any drug. Neonatal mice fed in normal conditions served as normal control. Mice were sacrificed at PD17 to evaluate the morphological changes of retinal vessels by fluorescein isothiocyanate-dextran perfusion and retinal whole mount. The retinal neovascularization was evaluated by counting the number of nuclei of the endothelial cell breaking through the internal limiting membrane (ILM).</p><p><b>RESULT</b>Compared with the oxygen-exposed group, the branches of retinal vessels went normal with a less un-perfused area in the propranolol eye drops and propranolol IP injection groups [(38.9 ± 9.9)% and (5.6 ± 2.3)% vs. (16.2 ± 10.0)% and (2.2 ± 0.8)%, (25.9 ± 5.0)% and (2.1 ± 2.7)%, F=36.12 and 14.55, P both<0.001]. The number of nuclei of endothelial cells breaking through the ILM on the retinal cross-section in the propranolol eye drops group decreased (14.2 ± 5.1) per slide, which was less than that in the oxygen-exposed group (49.1 ± 8.9) per slide and the propranolol IP injection group (18.0 ± 5.9) per slide; it was also less than that in the eye drops negative control group (47.4 ± 8.1) per slide (F=187.60, P<0.05). Moreover, the number of nuclei of endothelial cells breaking through the ILM on the retinal cross-section in the propranolol IP injection group was less than that in the IP injection negative control group (49.9 ± 7.1) per slide (P<0.05).</p><p><b>CONCLUSION</b>Propranolol could effectively inhibit the formation of retinal neovascularization in mice; the eye drops was more effective than the IP injection.</p>

Regulation of retinal neovascularization in mice treated by recombinant PGC-1α protein / 中南大学学报(医学版)

OBJECTIVE@#To evaluate the regulatory effect of recombinant peroxisome-proliferatoractivatedreceptor- γ coactivator-1α (PGC-1α) on retinal neovascularization in mice.@*METHODS@#Forty 7-day-old C57BL/6J mice were randomly divided into 2 groups including a normal injection group and a normal control group. Additional 40 7-day-old C57BL/6J mice were randomly divided into 2 groups including a model injection group and a model control group, in which the mice were induced retinal neovascularization by hypoxia. Liposome with recombinant PGC-1α protein was injected into the vitreous of mice in the normal injection group and the model injection group at postnatal day 12 (P12). No injection was performed in the control group. Fluorescein angiography was used to assess the vascular pattern. The proliferative neovascular response was quantified by counting the nuclei of new vessels extending from the retina into the vitreous in cross-sections. PGC-1α levels in retina were measured by Western blot, and the vascular endothelial growth factor (VEGF) level in retina was measured by quantitative Real-time polymerase chain reaction and Western blot.@*RESULTS@#Neovascular tuft was found in the normal injection group, but there was almost no neovascular tuft in the normal control group. Neovascular tuft and fluorescein leakage were increased in the model injection group compared with the model control group. The neovascular nuclei were increased both in the normal injection group and the model injection group compared with the control group (P<0.01). The expression of PGC-1α protein in retina was increased significantly both in the normal injection group and the model injection group as compared with the normal control group and the model control group, respectively (P<0.01). The expression of VEGF mRNA and protein in retina was increased significantly both in the normal injection group and the model injection group as compared with the normal control group and the model control group, respectively (P<0.01).@*CONCLUSION@#PGC-1α can induce the formation of retinal neovascularization in the mice.

Aflibercept Treatment for Neovascular Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy Refractory to Anti-vascular Endothelial Growth Factor

PURPOSE: To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti-VEGF (ranibizumab and bevacizumab). METHODS: This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated. RESULTS: BCVA and CMT improved from 0.58 to 0.55 (p = 0.005) and from 404 to 321 microm (p < 0.001), respectively, after switching to aflibercept. The 14 eyes that received 6 or more aflibercept injections remained stable at 0.81 to 0.81 and 321 to 327 microm (p = 1.0, 0.29), respectively, after 3 aflibercept injections. The 10 eyes that received 3 or more bevacizumab injections after 3 or more aflibercept injections worsened, from 0.44 to 0.47 and from 332 to 346 microm (p = 0.06, 0.05), respectively. The results showed similar improvement of BCVA and CMT in neovascular AMD and PCV. CONCLUSIONS: Aflibercept seems to be effective for improvement and maintenance of BCVA and CMT for neovascular AMD and PCV refractory to anti-VEGF. Switching from aflibercept back to bevacizumab treatment may not be a proper strategy.

Aumento da imunorreatividade da molécula de adesão intercelular-1 na esclera e coroide em modelo experimental de hipercolesterolemia / Increased intercellular adhesion molecule-1 immunoreactivity in the sclera-choroid complex in hypercholesterolemia experimental model

Objetivo: O objetivo deste trabalho é avaliar a expressão da molécula de adesão intercelular-1 (ICAM-1) na esclera e coroide de coelhos hipercolesterolêmicos. Métodos: Coelhos New Zealand foram organizados em dois grupos: GN (grupo dieta normal), composto por 8 coelhos (8 olhos), recebeu ração padrão para coelhos, durante 4 semanas; GH (grupo hipercolesterolêmico), composto por 13 coelhos (13 olhos), recebeu dieta rica em colesterol a 1% por 8 semanas. Foi realizada a dosagem sérica de colesterol total, triglicerídeos, HDL colesterol, glicemia de jejum no início do experimento e no momento da eutanásia. Ao final da 4ª semana para o GN e 8ª semana para o GH foi realizada a eutanásia dos animais. Os olhos foram corados com hematoxilina-eosina e submetidos à análise histológica, histomorfométrica e imunohistoquímica com o anticorpo ICAM-1. Resultados: Observou-se significativo aumento do colesterol total e triglicerídeos do GH em relação ao GN (p<0,001). A avaliação histológica com hematoxilina eosina revelou grande quantidade de macrófagos no complexo esclero-coroidal do GH. No GH constatou-se significativo aumento da espessura da esclera e coroide em relação ao GN (p<0,001). Houve significativo aumento da expressão da ICAM-1 na esclera e coroide dos animais do GH em relação ao GN (p<0,001). Conclusão: Este estudo demonstra que a dieta hipercolesterolêmica induz ao aumento da expressão da ICAM-1 na esclera e coroide de coelhos. .

Objective: The aim of this study is to investigate the expression of the intercellular adhesion molecule 1 (ICAM-1) in the sclera and choroid of hypercholesterolemic rabbits Methods: New Zealand rabbits were divided into two groups: the normal diet group (NG), with 8 rabbits (8 eyes), was fed a standard rabbit diet for 4 weeks; the hypercholesterolemic group (HG), with 13 rabbits (13 eyes), was fed a 1% cholesterol- enriched diet for 8 weeks. Total serum cholesterol, triglyceride, HDL cholesterol and fasting blood glucose exams were performed at the start of the experiment and at the euthanasia time. HG and NG animals were euthanized after 8th week and 4th week, respectively. Their eyes were stained with hematoxylin-eosin and underwent histological, histomorphometric and immunohistochemical analyses with ICAM-1 antibody. Results: The diet has induced a significant increase in total cholesterol and triglyceride levels in HG when compared with NG (p<0.001). The histological analysis with hematoxylin-eosin revealed a large number of macrophages in the HG sclera-choroid complex. Moreover, a significant increase in the HG sclera and choroid thickness was observed in relation to NG (p<0.001). There was a significant increase in the ICAM-1 expression in HG sclera and choroid in relation to NG Conclusion: This study has revealed that the hypercholesterolemic diet induces an increase in the ICAM-1 expression in the rabbits’ sclera and choroid. .

Fotocoagulación panretinal y bevacizumab intravítreo en el tratamiento de la retinopatía diabética proliferativa activa / Panretinal photocoagulation and intravitreal bevacizumab in the treatment of active proliferative diabetic retinopathy

OBJETIVO: evaluar el efecto de la fotocoagulación panretinal e inyección intravítrea de bevacizumab sobre las áreas de neovascularización en pacientes con retinopatía diabética proliferativa activa. MÉTODOs: estudio experimental en 80 ojos de 62 pacientes con retinopatía diabética proliferativa con características de alto riesgo, a quienes se les asignó aleatoriamente fotocoagulación panretinal (Grupo L) o fotocoagulación panretinal con bevacizumab intravítreo (Grupo L + B). Variables: edad, sexo, color de la piel, tipo de diabetes mellitus, tiempo de evolución, tipo de tratamiento, área de difusión de fluoresceína y regresión de neovascularización retinal y/o del disco óptico. Se realizó un seguimiento de 9 meses. RESULTADOS: en la evaluación inicial el área media de difusión fue de 8,95 mm2 en el grupo L y de 10,08 mm2 en el grupo L + B (p = 0,347), que se modificó a 6,40 mm2 y 3,91 mm2 (p = 0,012) al mes; 3,15 mm2 y 1,02 mm2(p = 0,002) a los tres meses; 2,45 mm2 y 0,58 mm2 (p = 0,001) a los seis meses; 2,18 mm2 y 0,46 mm2 (p = 0,001) a los nueve meses, respectivamente. El análisis de las diferencias absolutas de los promedios mostró una reducción significativa de las áreas de difusión a favor del tratamiento combinado en comparación con el momento inicial. CONCLUSIONES: en pacientes con retinopatía diabética proliferativa activa el bevacizumab intravítreo combinado con fotocoagulación panretinal produjo regresión dramática de la neovascularización, permaneciendo estable desde el tercer mes al noveno.

OBJECTIVE: to evaluate the effect of panretinal photocoagulation and intravitreal injection of bevacizumab on neovascularization areas of patients with active proliferative diabetic retinopathy. METHODS: experimental study conducted in 80 eyes from 62 patients with proliferative diabetic retinopathy with high risk characteristics. These patients were randomly assigned to panretinal photocoagulation group (group L) or to the panretinal photocoagulation plus intravitreal bevacizumab group (group L + B). The studied variables were age, sex, race, type of diabetes mellitus, illness duration, type of treatment, fluorescein distribution area and retinal/optical disc neovascularization regression area. They were followed-up for 9 months. RESULTS: in the initial evaluation, the average diffusion area was 8,95 mm2 in group L and 10,08 mm2 in group L + B (p = 0,347), which changed to 6,40 mm2 and 3,91 mm2 (p = 0,012) respectively, after one month; 3,15 mm2 and 1,02 mm2 (p = 0,002) three months later, 2,45 mm2 and 0,58 mm2 (p = 0,001) after six months and 2,18 mm2 and 0,46 mm2 (p = 0,001) after nine months, respectively. The analysis of absolute differences of averages showed a significant reduction in the distribution areas of fluorescein that favored the combined therapy. CONCLUSIONS: in patients with active proliferative diabetic retinopathy, intravitreal bevacizumab combined with panretinal photocoagulation bring about dramatic regression of neovascularization, which remained stable from the third to the ninth month.

Retinal vasoproliferative tumor / Tumor vasoproliferativo da retina

Retinal vasoproliferative tumor is a rare disease that has capillary hemangioma as the most frequent diferential diagnosis. The tumor is considered to be of reactive nature. It can be idiophatic or secondary to other ocular diseases such as: uveitis, retinitis pigmentosa, sickle cell disease, previous surgery and retinopathy of prematurity. Lesions with no exsudation or visual decrease can be observed. Lesions that need treatment can be managed by on or more modalities such as cryotherapy, a variety of lasers, surgical excision, radiation, and antiangiogenic intravitreal injections.

O tumor vasoproliferativo da retina é uma lesão rara, cujo principal diagnóstico diferencial é o hemangioma capilar da retina. O tumor tem natureza reacional. Pode ser idiopático ou secundário a outras doenças como: uveítes, retinose pigmentar, retinopatia da anemia falciforme, cirurgia prévia e retinopatia da prematuridade. Lesões sem exsudação ou baixa visual podem ser observadas. Quando há indicação de tratamento este pode ser feito pela crioterapia, vários tipos de lasers, excisão cirúrgica, radioterapia e injeções intravítrea de antiangiogênicos, isoladamente ou em associação.

Characteristic Findings of Optical Coherence Tomography in Retinal Angiomatous Proliferation

PURPOSE: To identify the unique pathologic findings of retinal angiomatous proliferation (RAP) in optical coherence tomography (OCT). METHODS: Retrospectively, 29 eyes of 25 patients with age-related macular degeneration and complicated RAP were analyzed. All 29 eyes had choroidal neovascularization (CNV) in the area of pigment epithelial detachment (PED) or adjacent to it, which was visible with fluorescein angiography or indocyanine green angiography. Cross-sectional images were obtained by OCT scanning through the CNV lesions. RESULTS: Six distinctive findings of OCT included drusen (100%), inner retinal cyst (80%), outer retinal cyst (68%), fibrovascular PED (84%), serous retinal detachment (40%), and PED (68%). CONCLUSIONS: Through analysis of OCT findings, we revealed six different types of lesions distinctive of RAP which may provide helpful diagnostic information for subsequent treatment and predicting the prognosis of RAP.

Small interference RNA targeting vascular endothelial growth factor gene effectively attenuates retinal neovascularization in mice model / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The mechanism of retinal neovascularization is not understood completely. Many growth factors are involved in the process of retinal neovascularization, such as vascular endothelial growth factor (VEGF) and pigment epithelium-deprived factor (PEDF), which are the representatives of angiogenic and antiangiogenic molecules respectively. Oxygen induced retinopathy (OIR) is a useful model to investigate retinal neovascularization. The present study was conducted to investigate the feasibility of small interference RNA (siRNA) targeting VEGF gene in attenuating oxygen induced retinopathy (OIR) by regulating VEGF to PEDF ratio (VEGF/PEDF).</p><p><b>METHODS</b>In vitro, cultured EOMA cells were transfected with VEGF-siRNA (psi-HI(TM)/EGFP/VEGF siRNA) and Lipofectamine(TM) 2000 for 24, 48, and 72 hours, respectively. Expression of VEGF mRNA was evaluated by real time polymerase chain reaction (PCR) and the level of VEGF protein was analyzed by Western blotting. In vivo, OIR model mice were established, the mice (C57BL/6J) received an intra-vitreal injection of 1 µl of mixture of psi-HI(TM)/EGFP/VEGF siRNA and Lipofectamine 2000. Expressions of retinal VEGF and PEDF protein were measured by Western blotting, retinal neovascularization was observed by fluorescein angiography, and quantified.</p><p><b>RESULTS</b>In vitro psi-HI(TM)/EGFP/VEGF siRNA treatment significantly reduced VEGF mRNA and protein expression. In vivo, with decreased VEGF and VEGF-PEDF ratio, significant attenuation of neovascular tufts, avascular regions, tortuous, and dilated blood vessels were observed in the interfered animals.</p><p><b>CONCLUSIONS</b>VEGF plays an important role in OIR, and the transfection of VEGF-siRNA can effectively downregulate VEGF expression in vivo, accompanied by the downregulation of VEGF-PEDF ratio, and simultaneous attenuation of retinal neovascularization was also observed. These findings suggest that VEGF/PEDF may serve as a potential target in the treatment of retinal neovascularization and RNA interference targeting VEGF expression, which represents a possible therapeutic strategy.</p>

Effect of Curcumin in a Mouse Model of Oxygen-Induced Retinopathy

PURPOSE: To investigate the effect of curcumin, known to inhibit hypoxia-inducible factor-1, on retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). METHODS: OIR was induced by exposing C57BL/6 mice on postnatal day 7 (P7) to 75% hyperoxia for 5 days, followed by 5 days in a room with normal oxygen level. Curcumin was administered intraperitoneally once a day for 5 days from P12 or intravitreally once on P13. Mice retinas on P17 were analyzed for retinal neovascularization, which was compared between curcumin-treated and control mice. RESULTS: After intraperitoneal and intravitreal administration of curcumin, qualitative assessment of retinal neovascularization of flat-mounted retina showed no significant difference compared to control retinas. Quantitative assessment of retinal neovascularization also showed no significant difference between curcumin-treated and control mice. CONCLUSIONS: Both intraperitoneal and intravitreal administration of curcumin did not reduce retinal neovascularization in an OIR mouse model. Further investigation including development of new formulations is required for the use of curcumin as an anti-angiogenic agent for retinal neovascularization.

Inhibition of neovascularization and expression shift of pro-/anti-angiogenic vascular endothelial growth factor isoforms after intravitreal bevacizumab injection in oxygen-induced-retinopathy mouse model / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Retinopathy of prematurity (ROP) has become one of the leading causes of visual loss in children. Vascular endothelial growth factor A (VEGF-A) is the principal stimulator of angiogenesis. VEGF was differentially spliced from exon 8 to exons 8a and 8b to form two families: the pro-angiogenic VEGFxxx family and the anti-angiogenic VEGFxxxb family. Previous research has shown variable effeteness of bevacizumab in inhibiting retinal neovascularization in ROP. This study aimed to investigate whether the effectiveness of this inhibition depends on the relative ratio of the two VEGF isoforms.</p><p><b>METHODS</b>Intravitreal bevacizumab injection (IVB) was performed in the oxygen-induced-retinopathy (OIR) mice on postnatal day 12 (P12) (intravitreal phosphate buffered saline (PBS) injection as control). The Evans blue perfused retina were used to test the retinal neovascularization-leakage (NVL) area and non-perfusion (NP) area.</p><p><b>RESULTS</b>The retinal NVL and NP area in the IVB group were significantly smaller than the intravitreal PBS injection group (IVP group). On P17, the protein level of total VEGF isoforms was significantly inhibited compared to IVP group (P < 0.05) while VEGF(165)b isoform was slight reduced (P > 0.05). The switch from pro-angiogenic isoforms to anti-angiogenic isoforms after IVB could be found. The relative protein expression of VEGF(165)b isoform was significantly higher in IVB group than in IVP group (P < 0.05) on P17 which was correlated with the reduced ischemia-induced angiogenesis in OIR mice after IVB.</p><p><b>CONCLUSIONS</b>The anti-angiogenic effectiveness might depend on the relative high expression of VEGF(165)b after intravitreal bevacizumab injection. Anti-angiogenic therapy is a more effective therapy for ROP.</p>

Terapia antiangiogênica associada à fotocoagulação a laser no tratamento de membrana neovascular sub-retiniana: relato de caso / Anti-angiogenic therapy associated with laser photocoagulation in the treatment of subretinal neovascular membrane: case report

O objetivo deste relato é descrever um caso de degeneração macular relacionada à idade com presença de membrana neovascular sub-retiniana (MNVSR) justafoveal, tratada inicialmente com bevacizumab (Avastin®) intravítrea e posteriormente com terapia de fotocoagulação focal (TFC) com laser. A eficácia do tratamento inicial e complementar foi avaliada pela medida da acuidade visual e por exames complementares (angiografia fluoresceínica e tomografia de coerência óptica). Após três injeções intravítreas de bevacizumab ocorreu a redução excêntrica da MNVSR, alterando sua classificação para extrafoveal, o que permitiu o tratamento subsequente com TFC.

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.

The management of complicated glaucoma.

Complicated glaucomas present considerable diagnostic and management challenges. Response to treatment can be unpredictable or reduced compared with other glaucomas. However, target intraocular pressure and preservation of vision may be achieved with selected medical, laser and surgical treatment. The evidence for such treatment is expanding and consequently affords clinicians a better understanding of established and novel techniques. Herein we review the mechanisms involved in the development of complicated glaucoma and the current evidence supporting its management.