Bevacizumab intravítreo en el tratamiento de las oclusiones venosas de la retina / Bevacizumab in the treatment of macular edema complicating retinal vein occlusions

INTRODUCCIÓN: Dentro de las vasculopatías retinianas, las oclusiones venosas de la retina (OVR) representan la segunda causa más frecuente de pérdida de visión luego de la retinopatía diabética. Se han descripto dos tipos diferentes de OVR: la oclusión de vena central de la retina (OVCR), y la oclusión de rama venosa retinal (ORVR). De acuerdo al compromiso oclusivo del lecho capilar de la retina, se las clasifica en isquémicas (o no perfundidas), y no isquémicas (perfundidas), presentando una patogénesis, diagnóstico, pronóstico y tratamiento diferente. Se ha demostrado que los niveles de factor de crecimiento vascular endotelial (VEGF) aumentan significativamente en las oclusiones venosas retinianas, lo que tiene como consecuencia una disfunción de la barrera hematorretinal y el aumento de la permeabilidad vascular, con el consecuente edema macular. La inyección intravítrea de bevacizumab, un anticuerpo monoclonal recombinante que actúa en forma directa contra cualquier forma activa de VEGF, ha demostrado ser efectiva para reducir el espesor macular y mejorar la agudeza visual en el tratamiento de OVR. OBJETIVO: Evaluar los cambios en la agudeza visual y en los espesores maculares de pacientes con oclusiones venosas retinianas tratados con inyecciones intravítreas de bevacizumab. Pacientes y métodos: Se evaluaron retrospectivamente 39 pacientes con diagnóstico de oclusión venosa retiniana (OVR) complicada de edema macular y tratados mediante inyección intravítrea de 1,25 mg/0,05 ml bevacizumab (Avastin®, Roche Diagnostic GmbH, Manheim, Alemania), con un seguimiento mínimo de 18 meses. La agudeza visual se evaluó mediante tabla de Snellen y se convirtió en unidades LogMAR. El espesor macular se evaluó mediante tomografía de coherencia óptica (OCT). Según la presentación clínica se las clasificó en: 1. Oclusión de rama (ORVR), incluyendo las oclusiones hemisféricas y 2. Oclusión de vena central (OVCR), incluyendo oclusión venosa hemicentral. A su vez, mediante angiografía fluoresceínica se las clasificó en oclusiones predominántemente isquémicas, y predominántemente no isquémicas. Las variables cuantitativas se analizaron mediante medidas de tendencia central, dispersión y forma. Los cambios en la agudeza visual se calcularon utilizando la prueba de Wilcoxon. Las diferencias entre variables continuas fueron calculadas mediante la prueba T de Student para variables paramétricas, y Mann Whitney para variables no paramétricas. RESULTADOS: La edad promedio fue de 66,8 años (DE: 13,65; rango= 31-92 años). El 55% de los casos estudiados fueron OVCR y el 37,5% ORVR. La media del total de inyecciones durante los 18 meses de seguimiento fue de 4,11±1,61 (rango= 1 a 6). La terapia con láser de rescate se realizó en 10 (25%) pacientes. Todos los pacientes que debieron ser tratados con láser tuvieron una AV inferior a 1 décima al final del seguimiento. La agudeza visual promedio al inicio del tratamiento fue de 1,092 con una desviación estándar (DE) de 0,36, con un rango de 0,10 y 1,60. Tras el inicio del tratamiento, todos los grupos de pacientes logran un incremento significativo en la AV (P= <0,0001). A los 18 meses de tratamiento la agudeza visual promedio fue de 0,739 con una DE de 0,45 con un rango de entre 0,00 y 1,50. La agudeza visual media de los pacientes con OVCR antes del tratamiento fue de 1,09 (DE: 0,35; rango= máxima 0,50 y mínima 1,60), y a los 18 meses de tratamiento de 0,87 (DE: 0,73; rango= 0,20 a 1,50). En cambio, los pacientes con ORVR antes del tratamiento presentaron una media de 1,10 (DE: 0,31; rango= máxima de 0,40 y mínima de 1,6), y luego del tratamiento una media de 0,53 (DE: 0,38; rango= máxima 0,1 y mínima 1,2). El 54,5% de los casos fue de predominio isquémico o mixtos, y el 43,5% fue a predominio edematosos al inicio del tratamiento. La agudeza visual media de los pacientes con tipo edematoso fue de 0,93 (DE: 0,34; rango= máxima 0,10 y mínima 1,40), mientras que los pacientes con patología isquémica presentaron una media de 1,25 (DE: 0,32; rango= máxima de 0,40 y mínima de 1,6). Ambos grupos respondieron en forma significativa al tratamiento (p< 0.05). Sin embargo, los pacientes con predominio edematoso lograron una mejoría mayor que aquellos con predominio isquémico. (P=0.0054) La agudeza visual media de los pacientes con predominio edematoso a los 18 meses del tratamiento fue de 0,50 (DE: 0,44; rango= máxima 0,0 y mínima 1,40), mientras que los pacientes con predominio isquémico presentaron una media de 0,97 (DE: 0,35; rango= máxima 0,20 y mínima 1,4). La media de los espesores maculares previo al inicio del tratamiento fue de 654.19 ± 272.05 micras (rango= 215 a 1497 micras), mientras que la media luego del tratamiento fue de 449 ± 247,62 micras (rango= 140 a 1005 micras) (p=0,0009). No hubo efectos colaterales ni complicaciones locales ni sistémicas atribuibles a la inyección de bevacizumab durante el seguimiento. CONCLUSIÓN: El bevacizumab fue eficaz en el tratamiento del edema macular secundario a OVR. La respuesta terapéutica fue mayor en las ORVR. En nuestra serie no hubo complicaciones oculares ni sistémicas vinculadas al tratamiento. (AU)

INTRODUCTION: Within the retinal vascular disease,retinal venous occlusion (RVO) represents the second most common cause of vision loss after diabetic retinopathy. In turn, it is estimated that the RVO affects approximately 1.6% of people worldwide. It has been described two different types of RVO: the central retinal vein occlusion (CRVO), which includes the hemicentral retinal vein occlusion (HCRVO), and the branch retinal vein occlusion (BRVO), which includes Major BRVO (occlusion of a retinal vein that drains one of the quadrants or more), Minor BRVO (occlusion of a retinal vein that drains less than a quadrant) and Hemispheric retinal vein occlusions (half or more of the retina). According to the occlusive pattern of the retinal capillary bed, this disease is classified as ischemic (or non perfused); when the areas of noncapillary perfusion, seen under fluorescein angiography, have an extension of more than 10 disc diameters; and non-ischemic (o perfused), presenting a pathogenesis, diagnosis, prognosis and different treatment. Non-ischemic form is generally more benign, with a less dramatic visual impairment, a greater chance of spontaneous recovery, a better treatment response, and generally has no risk of neovascularization. Instead; ischemic form is much more severe, causing a more dramatic visual acuity decline, with little chance of clinical improvement, an increased risk of blindness and an increased risk of neovascularization. Although the physiopathogenesis of OVR is not accurately known, it is suggested that the thickening and stiffness of arteries and arterioles caused by arteriosclerosis leads to compression of the retinal veins at the sites where adventitia is shared with arteries (in its intraneural route to the optic nerve and the arteriovenous crossings), leading eventually to a turbulent blood flow, damage to endothelial cells, thrombus formation and eventual vein occlusion. This theory is supported by studies showing pathological structural changes in veins and arteries of patients with VO. Moreover, other factors related to venous deregulation, such as inadequate vasoconstriction and increased vascular permeability, could also play an important role in the retinal venous occlusive phenomena. In some patients, especially young people and adults under 50 years old, inflammatory disorders and hypercoagulable states may contribute to the hysiopathogenesis of the RVO. It has been shown that the presence of vascular endothelial growth factor (VEGF) increased significantly the chances to develop retinal vein occlusions. The result is a blood­retinal barrier dysfunction and an increased vascular permeability, with consequent macular edema. It has also been reported that VEGF plays an important role in the pathogenesis of macular edema in both ORV and CRVO.10 While there is insufficient level 1 evidence to support OVR treatment, multiple therapeutic possibilities have been described, such as anticoagulation, intravitreal fibrinolysis, hemodilution, laser photocoagulation, laser-induced anastomosis, radial optical neurotomy, adventiciotomía, intravitreal injection of triamcinolone acetonide, intravitreal injection of dexamethasone, and injection intravitreal antiangiogenic monoclonal antibodies, such as ranibizumab, bevacizumab, and aflibercept, alone or associated with photocoagulation, have shown efficacy and variables complications rates. Intravitreal injection of bevacizumab, a recombinant monoclonal antibody that acts directly against any active form of VEGF, has been shown to be effective in reducing macular thickness and improving visual acuity in the treatment of OVR. However, the need for multiple injections has been reported since the effects of intravitreal bevacizumab (as well as the other antiangiogenics) are short-lived. On one hand, Bevacizumab has the disadvantage that it is administered off-label; in addition each dose must be extracted from a vial for oncological use, which represents a risk of contamination if strictly rules of asepsis are not taken. On the other hand, the cost of each dose is lower than that of other products (ranibizumab, aflibercept) already approved for intraocular use. This allows that more patients have access to a prolonged treatment in underdeveloped or developing countries, such as Argentina. PURPOSE: To evaluate changes in visual acuity and macular thickness after intravitreal bevacizumab for the treatment of macular edema in patients with retinal vein occlusions (RVO). PATIENS AND METHODS: 39 consecutive patients with macular edema complicating RVO and treated with intravitreal injections of bevacizumab 1.25 mg/0.05 ml alone or associated with scattered peripheral laser photocoagulation, with a minimun follow-up of 18 months, were evaluated. Snellen visual acuity in LogMar units and macular thinckness measured by optical coherence tomography (OCT) were the end points. According to clinical and fluorescein angiographic presentation RVO were classified in branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO), and in non ischemic and ischemic. Wilcoxon test for paired variables, Mann Whitney for independant variables, and Student test for continuous variables, were used for statistical analysis. RESULTS: With a mean age of 66.8 years (SD: 13.65; range= 31-92 years), 62.5% of cases were CRVO and 37.5% BRVO. Mean number of injections was 4.11±161 (range= 1-6). Laser was performed in 25% of patients that did not respond to bevacizumab. At 18 months of follow-up, improvement of visual acuity and macular thickness was statistically significant (p=0.0001 and p=0.0009 respectively). BRVO showed better response to treatment than CRVO. Best visual results were obtained at first month (median= 1.00 P25= 0.5 P75= 1.30) and at 9 month (median= 0.8 P25= 0.5 P75= 1.20) after first injection, but no further improvement was observed beyond 9 months of treatment (p=0.84). No significant visual and macular thickness differences were obtained between patients treated with bevacizumab alone (p=0.116) and bevacizumab and laser (p=0.846). No ocular or systemic attributable-to-treatment side effects were observed. CONCLUSIONS: Bevacizumab was effective in improving visual acuity and reducing macular thinckness in patients with macular edema complicating RVO, especially in BRVO. No ocular or systemic complications were observed during follow-up. (AU)

Efectos producidos por diferentes tipos de láser en córnea de cobayos: identificación de un láser capaz de provocar lesiones superficiales sin dejar cicatrices / Effects produced by different types of laser in córnea of Guinea pigs: identification of a laser capable of producing superficial lesions without leaving scars

OBJETIVO: La queratopatía climática esferoidea (QCE) está íntimamente asociada a erosiones corneales superficiales y a carencia de mecanismos protectores contra los efectos nocivos de la radiación ultravioleta (RUV) durante muchos años. Debido a que una de las dificultades en el estudio de los mecanismos patogénicos de esta enfermedad humana es la ausencia de un modelo experimental, en este trabajo quisimos identificar cuál es el mejor método para estudiar una de las variables involucradas en su génesis (erosiones superficiales de la córnea). A tal fin investigamos los efectos producidos por 4 tipos de láser con diferentes condiciones de potencia y tiempo en la córnea de cobayos normales con el fin de seleccionar un láser y condición que lesione solamente el epitelio y estroma superficial, de manera reversible, sin dejar cicatrices. MÉTODOS: Se indujeron daños en la córnea de cobayos utilizando distintas potencias y tiempos con 4 tipos de láser: argón, CO2, diodo y Nd-Yag en distintos grupos de animales y se evaluaron dichas lesiones por biomicroscopia (BM) y microscopia óptica. Córneas de otros animales normales fueron expuestas a láser de argón (350 mW, 0,3 s, 50μm de diámetro) y las alteraciones inducidas se estudiaron en diferentes tiempos utilizando BM, tomografía de coherencia óptica (TCO) y microscopia electrónica (ME). RESULTADOS: Solo el láser argón a una potencia de 350 mW, 0,3 s, 50μm de diámetro produjo lesiones de epitelio y estroma superficial, manteniéndose indemne el endotelio. Por BM se observaron algunos leucomas que desaparecieron hacia el día 15. Mediante TCO se observó un adelgazamiento del espesor corneal en los ojos tratados con esas condiciones de láser argón durante la primera semana. Mediante ME, se observaron diferentes alteraciones ultraestructurales en epitelio y estroma corneal durante los primeros días, las cuales desaparecieron hacia el día 15. CONCLUSIONES: Fue posible desarrollar lesiones corneales en epitelio y estroma anterior de cobayos de manera reproducible mediante el uso de láser argón. Los estudios in vivo e in vitro demostraron que las córneas lesionadas con este láser y en esas condiciones no dejaron alteraciones microscópicas ni ultraestructurales irreversibles. Este modo de erosión corneal combinado con exposición a RUV y déficit parcial de ascorbato en la dieta de los animales durante un período prolongado de tiempo está siendo utilizado con el fin de intentar desarrollar un modelo experimental de QCE

PURPOSE: Climatic droplets keratopathy (CDK) is closely associated with superficial corneal erosions and lack of protective mechanisms against the harmful effects of ultraviolet radiation (UVR) during a prolonged period of time. One of the difficulties in studying the pathogenic mechanisms involved in this human disease is the lack of an experimental animal model. In this paper, a study is conducted on the effects of 4 types of lasers at various powers and time conditions on the normal guinea pig corneas in order to select only one laser condition that reversibly injures the epithelium and superficial stroma, without leaving scarring. METHODS: Damage was induced in the cornea of Guinea pigs using different powers and exposure times of 4 types of laser: argon, CO2, diode and Nd-Yag, and any injuries were evaluated by biomicroscopy (BM) and optical microscopy. Corneas from other normal animals were exposed to argon laser (350 mW, 0.3s, 50μm of diameter), and the induced alterations were studied at different times using BM, optical coherence tomography (OCT) and transmission electron microscopy (TEM). RESULTS: Only argon laser at 350 mW, 0.3s, 50μm of diameter produced epithelium and superficial stroma lesions. Some leukomas were observed by BM, and they disappeared by day 15. Corneal thickness measured by OCT decreased in the eyes treated with argon laser during the first week. Using TEM, different ultra structural alterations in corneal epithelium and stroma were observed during the early days, which disappeared by day 15. CONCLUSIONS: It was possible to develop reproducible corneal epithelium and anterior stroma injuries using Argon laser at 350 mW, 0.3s, 50μm of diameter. In vivo and in vitro studies showed that injured corneas with these laser conditions did not leave irreversible microscopic or ultra structural alterations. This protocol of corneal erosion combined with exposure to UVR and partial deficiency of ascorbate in the diets of the animals for an extended period of time has been used in order to try to develop an experimental model of CDK

Effects produced by different types of laser in cornea of Guinea pigs: Identification of a laser capable of producing superficial lesions without leaving scars.

PURPOSE: Climatic droplets keratopathy (CDK) is closely associated with superficial corneal erosions and lack of protective mechanisms against the harmful effects of ultraviolet radiation (UVR) during a prolonged period of time. One of the difficulties in studying the pathogenic mechanisms involved in this human disease is the lack of an experimental animal model. In this paper, a study is conducted on the effects of 4 types of lasers at various powers and time conditions on the normal guinea pig corneas in order to select only one laser condition that reversibly injures the epithelium and superficial stroma, without leaving scarring. METHODS: Damage was induced in the cornea of Guinea pigs using different powers and exposure times of 4 types of laser: argon, CO2, diode and Nd-Yag, and any injuries were evaluated by biomicroscopy (BM) and optical microscopy. Corneas from other normal animals were exposed to argon laser (350 mW, 0.3s, 50 µm of diameter), and the induced alterations were studied at different times using BM, optical coherence tomography (OCT) and transmission electron microscopy (TEM). RESULTS: Only argon laser at 350 mW, 0.3s, 50 µm of diameter produced epithelium and superficial stroma lesions. Some leukomas were observed by BM, and they disappeared by day 15. Corneal thickness measured by OCT decreased in the eyes treated with argon laser during the first week. Using TEM, different ultra structural alterations in corneal epithelium and stroma were observed during the early days, which disappeared by day 15. CONCLUSIONS: It was possible to develop reproducible corneal epithelium and anterior stroma injuries using Argon laser at 350 mW, 0.3s, 50 µm of diameter. In vivo and in vitro studies showed that injured corneas with these laser conditions did not leave irreversible microscopic or ultra structural alterations. This protocol of corneal erosion combined with exposure to UVR and partial deficiency of ascorbate in the diets of the animals for an extended period of time has been used in order to try to develop an experimental model of CDK.