Análisis coste-utilidad del modelo de unidad de terapia intravítrea (UTI) frente a la administración tradicional de terapia intravítrea / Cost-utility model of new intravítreous units vs. current patient journey model in Spain

Objetivo Comparar la efectividad y los costes de la implantación del Modelo de Unidad de Terapia Intravítrea (UTI), avalado por la Sociedad Española de Retina y Vítreo (SERV), Sociedad Española de Calidad Asistencial (SECA), Sociedad Española de Oftalmología (SEO) y Sociedad Española de Directivos Sanitarios (SEDISA) vs. el procedimiento habitual. Método Modelo de decisión analítico que compara una organización asistencial tipo UTI con cuatro escenarios de práctica habitual en España, en cuanto al resultado en la calidad de vida por pérdida de agudeza visual y la utilización de recursos. Se estimó la probabilidad, el coste y los años de vida ajustados por calidad (AVAC) para cada escenario planteado. Se realizó un análisis de sensibilidad univariante para cada uno de los parámetros empleados. Resultado Se observó que la implantación del modelo UTI mejora la calidad de vida de los pacientes y presenta un menor coste frente a la práctica habitual. Se produjo ahorro de costes y ganancia de AVAC. El análisis de sensibilidad mostró que el resultado no cambiaría de signo con la modificación de ninguna variable de partida. Conclusiones En las patologías oculares con indicación de tratamiento intravítreo, cualquier reducción en el tiempo que transcurre desde la sospecha diagnóstica hasta la primera inyección intravítrea disminuye la pérdida de agudeza visual. Así, actuar para acortar los tiempos sospecha-aguja es clave para mantener la visión funcional de los pacientes. La mejora de la eficiencia de los servicios de oftalmología que se organizan siguiendo el modelo UTI puede generar ahorros que varían entre los 175 € y 85 € por paciente atendido y año (AU)

Aim To compare the effectiveness and costs of the implementation of the intravitreal therapy unit model, endorsed by the SERV, SECA, SEO and SEDISA, compared to the usual procedure. Method Analytical decision model that compares an UTI-type healthcare organization with four usual practice scenarios in Spain, in terms of quality-of-life results due to loss of visual acuity and the use of resources. The probability, cost, and quality-adjusted life years (QALYs) were estimated for each scenario proposed. A univariate sensitivity analysis was performed for each of the parameters used in the model. Result The model showed that from any of the initial scenarios of the usual practice, transitioning to the UTI-type implementation improves the quality of life of patients and requires lower cost. UTI-type is dominant respect usual practice. The sensitivity analysis showed that the results would not change sign with the variation of any starting variable. Conclusions Shorten suspicion-needle times is key to maintaining functional vision in patients requiring intravitreal treatment. The UTI-type model seeks the efficiency of ophthalmology services and can produce savings that vary between €175 and €85 per patient attended per year (AU)

Eficacia y seguridad del implante intravítreo de dexametasona de liberación prolongada sostenida para el tratamiento de pacientes adultos con edema macular secundario a oclusión venosa retiniana con disminución de la agudeza visual y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab / Efficacy and safety of intravitreal sustained-release dexamethasone implant for the treatment of adult patients with macular edema secondary to retinal vein occlusion with decreased visual acuity and/or increased or maintained macular thickness despite the use of three injections of bevacizumab

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N' 111-IETSI-ESSALUD-2021 se ha elaborado el presente dictamen. el cual expone la evaluación de la eficacia y seguridad del implante intravítreo de dexametasona de liberación prolongada sostenida para el tratamiento de pacientes adultos con edema macular secundario a oclusión venosa retiniana con disminución de la agudeza visual y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab. Así. la médica Fiorella Norabuena Mautino. especialista en oftalmología del Servicio de Retina, a través del Comité Farmacoterapéutico del Hospital Nacional Edgardo Rebagliati Martins y siguiendo la Directiva N' 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de autorización de uso del producto farmacéutico dexametasona (implante intravítreo) no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: La oclusión venosa retiniana (OVR), una obstrucción parcial o completa del sistema venoso retinal, es considerada la segunda causa más común de trastorno vascular de la retina (Cugati et al., 2006; PAAO, 2019), y es una causa importante de pérdida de la visión en adultos a nivel mundial (Rogers et al., 2010: Song et al., 2019). En el 2015, se estimó que la prevalencia global de la OVR en personas de entre 30 y 89 años fue de 0.77 % (Song et al., 2019). Los dos tipos más comunes de OVR, son la oclusión de la rama venosa de la retina (ORVR), que ocurre en la vena retinal distal y ocasiona hemorragia en un vaso pequeño de la retina; y la oclusión de la vena central de la retina (OVCR), que ocurre en la vena retinal proximal y ocasiona hemorragia en toda la retina (Han & Ahmad, 2021). En un estudio realizado con datos de Europa, Asia, Australia y Estados Unidos se reporta que la prevalencia ajustada por edad y sexo de la ORVR es de 3.77 por 1000 personas, y de la OVCR es de 0.65 por 1000 personas. METODOLOGÍA: Se realizó una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad del uso de IIDLPS en el tratamiento de pacientes adultos con EM secundario a ORVR u OVCR con disminución de la AV y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library, LILACS y The Web of Science. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas. evaluaciones de tecnologías sanitarias y guías de práctica clínica. tales como The National Institute for Health and Care Excellence (NICE). RESULTADOS: De la búsqueda bibliográfica, se incluyó una GPC elaborada por The Royal College of Ophthalmologists (RCO) (The Royal College of Ophthalmologists. 2022). y tres estudios retrospectivos que evaluaron el cambio de bevacizumab a IIDLPS (Chiquet et al.. 2016: Lee et al.. 2017: Sharareh et al., 2013). Además se incluyeron dos GPC que fueron sugeridas por los especialistas de EsSalud, elaboradas por The European Society of Retina Specialists (EURETINA) (Schmidt-Erfurth et al., 2019) y la Sociedad Española de Retina y Vítreo (SERV) (SERV, 2015). No se identificaron RS con MA ni ETS que respondan a la pregunta PICO del presente dictamen. CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de implante intravitreo de dexametasona de liberación prolongada sostenida (IIDLPS) para el tratamiento de pacientes adultos con edema macular (EM) secundario a oclusión de la vena central de la retina (OVCR) u oclusión de la rama venosa de la retina (ORVR) con disminución de la AV y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab. como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud. según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de 1 año a partir de la fecha de publicación. La continuación de dicha aprobación está sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Influencia del tratamiento intravítreo en la presión intraocular en pacientes con glaucoma y degeneración macular / Influence of Intravitreal Treatment on Intraocular Pressure in Patients with Glaucoma and Macular Degeneration

En los últimos años, la aparición de los fármacos antiangiogénicos ha revolucionado el tratamiento de numerosas enfermedades de la retina, su asociación con la hipertensión ocular tras las inyecciones ha sido objeto de estudio en numerosas ocasiones. Se presenta un caso clínico de una paciente con glaucoma y degeneración macular asociada a la edad con la que se estudió la relación entre la administración de antiangiogénicos intravítreos y la elevación de la presión intraocular, a corto y largo plazo. La administración de fármacos antiangiogénicos es en la actualidad el procedimiento oftalmológico más empleado en las consultas de todo el mundo. La administración de intravítreas se ha asociado a la producción de un pico hipertensivo transitorio en el momento agudo y a la elevación de la presión intraocular a largo plazo. Un estrecho intervalo entre inyecciones ( 7 al año), pacientes con cámara estrecha, fáquicos y con diagnóstico previo de glaucoma son los principales factores de riesgo para el desarrollo de una elevación sostenida de presión intraocular tras el tratamiento intravítreo con antiangiogénicos. Identificar a los pacientes con alto riesgo de desarrollar hipertensión ocular tras el uso de inyecciones intravítreas y adoptar medidas que reduzcan dicho riesgo, como la administración de hipotensores tópicos antes de la inyección, es fundamental para mejorar su salud visual. Se presenta el caso de una paciente de 78 años de edad con diagnóstico de glaucoma primario de ángulo abierto de cinco años de evolución en ambos ojos(AU)

In recent years, the emergence of antiangiogenic drugs has revolutionized the treatment of numerous retinal diseases, their association with ocular hypertension after injections has been the subject of study on numerous occasions. We present a clinical case of a patient with glaucoma and age-related macular degeneration in which the relationship between the administration of intravitreal antiangiogenic drugs and the elevation of intraocular pressure, in the short and long term, was studied. The prescribing of antiangiogenic drugs is currently the most widely used ophthalmologic procedure in practices worldwide. Intravitreal administration has been associated with the production of a transitory hypertensive peak in the acute setting and long-term elevation of intraocular pressure. A narrow interval between injections ( 7 per year), patients with narrow chamber, phakic and with a previous diagnosis of glaucoma are the main risk factors for the development of sustained intraocular pressure elevation after intravitreal treatment with antiangiogenics. Identifying patients at high risk of developing ocular hypertension after intravitreal injections and adopting measures to reduce this risk, such as the administration of topical hypotensives before the injection, is essential to improve their eyesight health. The case of a 78-year-old female patient with a diagnosis of primary open-angle glaucoma of five years of evolution in both eyes is presented(AU)

Protocolo assistencial de injeções intravítreas do HCPA: edema macular diabético / HCPA's patient care protocol for intravitreal injections: diabetic macular edema

RESUMO: O edema macular diabético é uma das principais causas de baixa visual no mundo e a indicação mais frequente de injeções intravítreas no Hospital de Clínicas de Porto Alegre. O tratamento com injeção intra-vítrea de medicamentos anti-vascular endothelial growth factor, incluindo o bevacizumaberevolucionou o desfecho visual destes pacientes às custas de múltiplas aplicações mensais. Assim como em outros centros, discrepâncias entre condutas da equipe assistencial e dificuldades logísticas acabam comprometendo a efetividade do tratamento. Portanto, desenvolvemos um protocolo de tratamento para a doença embasado na literatura, estabelecendo critérios de inclusão, exclusão, regime de tratamento e seguimento do paciente. Com isto, esperamos otimizar a efetividade e assistência do paciente com edema macular diabético.

ABSTRACT: Diabetic macular edema is one of the leading causes of visual impairment worldwide and the most common indication for intravitreal injections at the Hospital de Clínicas de Porto Alegre. Treatment with intravitreal injection of anti-vascular endothelial growth factor drugs, including bevacizumab, has revolutionized patient outcome at the expense of multiple monthly injections. As in other hospitals, discrepancies in health team conduct and logistical difficulties compromise treatment effectiveness. Therefore, we developed a literature-based treatment protocol for diabetic macular edema, in which we established criteria for patient inclusion and exclusion, treatment regimen, and patient follow-up. We expect the treatment protocol to optimize patient care effectiveness in diabetic macular edema.

Pathologic Correlation with Renal Dysfunction after Intravitreal Injections of Vascular Endothelial Growth Factor Antagonists.

OBJECTIVE: Vascular endothelial growth factor (VEGF) antagonists have been used for treating metastatic neoplasms. It has also been known that one of its side effects is to cause proteinuria and renal failure in the setting of thrombotic microangiopathy (TMA). The underlying mechanism is likely due to the inhibition of VEGF production in podocytes, resulting in diffuse fusion of foot processes and impaired glomerular endothelial fenestrations, and leading to massive proteinuria and subsequent glomerular endothelium injury. Intravitreal injection of VEGF antagonists (IIVA) has been also used to treat macular degeneration and diabetic retinal neo-vascular proliferation. The majority of patients tolerate the treatment well. However, IIVA can lead to renal dysfunction including proteinuria and gradual renal failure as a rare side effect. The goal of this study was to report two cases related to the nephrotoxicity of IIVA and review the literature associated with this topic. CASE REPORT: The first diabetic patient had elevated serum creatinine at 3.25 mg/dl and proteinuria/creatinine ratio at 6.1 after 48-month treatment of IIVA. The first renal biopsy revealed thrombotic microangiopathy that was correlated with his increased serum creatinine and nephrotic range of proteinuria. The second diabetic patient had increased serum creatinine up to 1.89 mg/dl but low proteinuria. The second biopsy showed acute tubular necrosis that was correlated with his elevated serum creatinine. CONCLUSION: Intravitreal injection of VEGF antagonist can be associated with thrombotic microangiopathy and acute tubular necrosis, leading to renal dysfunction.

Ocular Trauma Caused by Confetti Cannons.

BACKGROUND: Eye trauma is an unfortunate and often preventable cause of vision loss. Confetti cannons are common causes of injury. Awareness of ocular hazards of confetti cannons remains low because of limited reports describing ophthalmic injuries following their use. OBJECTIVES: To describe outcomes of ocular trauma caused by confetti cannons and to increase recognition of their ocular risks. METHODS: A retrospective analysis was conducted of eye injuries caused by confetti cannons presenting to a single medical center between 2016 and 2020. Data collected included age, gender, eye injured, ocular damage, visual outcome, and details of surgeries performed. RESULTS: Overall, six consecutive patients (2 males, mean age 19.5 ± 9.74 years) were identified and studied. In all patients only one eye was injured (3 right eyes) during a private celebration, most commonly (n=5) to a bystander while in the vicinity of a cannon operated by someone else. Most common eye injuries included corneal erosion (n=4), traumatic hyphema (n=4), and retinal edema (n=3). Mean initial logMAR visual acuity in the injured eye was 0.73 ± 0.18, improving to 0.25 ± 0.16 at the final visit (P = 0.125). Two patients underwent eye surgery due to their trauma: one to repair globe penetration and another to undergo intravitreal injection of tissue plasminogen activator and C3F8 for submacular hemorrhage, followed 8 months later by intravitreal bevacizumab injection for choroidal neovascularization. CONCLUSIONS: Confetti cannons pose hazards that can cause severe ocular trauma resulting in permanent vision loss. Increasing awareness of device hazards is necessary to prevent eye injuries.

Modifications of intravitreal injections in response to the COVID-19 pandemic.

The Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented disruption to the normal operation of the healthcare system. On a worldwide scale, hospitals suspended nonurgent surgeries and outpatient visits to downsize clinical loadings to redistribute manpower to counteract the pandemic's impact. So far, there is no evidence-based guideline defining a clear line between urgent and nonurgent indications of intravitreal injections (IVI). Herein, we aimed to summarize IVI algorithm modifications and discuss the patient prioritization according to medical needs in the hostile environment in the COVID crisis. Assessing current literature, we found that neovascular age-related macular degeneration is considered the utmost priority among conditions that require IVI. Other conditions assigned with a high priority include monocular or quasi-monocular patients (only one eye > 20/40), neovascular glaucoma, and new patients with significant vision loss. Although patients with central retinal vein occlusion and proliferative diabetic retinopathy are not advised to delay treatments, we found no consistent evidence that correlated with a worse outcome. Diabetic macular edema and branch retinal vein occlusion patients undertaking treatment delay should be regularly followed up every 2 to 3 months. Serving as the principle of management behind the algorithm modifications, the reduction of both patient visit and IVI therapy counts should be reckoned together with the risk of permanent visual loss and COVID infection.

Intraocular pressure and injection forces during intravitreal injection into enucleated porcine eyes.

Injection of biological molecules into the intravitreous humor is of increasing interest for the treatment of posterior segment eye diseases such as age-related degenerative macular degeneration. The injection volume is limited by an increase in intraocular pressure (IOP) and 50-100 µL are typically used for most intravitreally (IVT) applied commercial products. Direct measurement of IOP is difficult and has not been studied dependent on solution properties and injection rates. We used an instrumental set-up to study IOP ex vivo using healthy enucleated porcine eyes. IOP was determined as a function of injection volume for viscosities between 1 and 100 mPas, injection rates of 0.1, 1, and 1.5 mL/min, and needle length and diameter (27/30G and 0.5/0.75″) using Dextran solutions. IOP increased exponentially for injection volumes larger than 100 µL. We did not observe differences in IOP dependent on viscosity, injection rate, and needle diameter. However, variability increased significantly for injection volumes larger than 100 µL and, unexpectedly, declined with higher viscosities. We demonstrate that the exponential increase in IOP is not reflected by injection force measurements for typical configurations that are used for IVT application. The present findings may guide injection volumes for intravitreal injection and inform injection force considerations during technical drug product development.

Intravitreal injection of anti-miRs against miR-142-3p reduces angiogenesis and microglia activation in a mouse model of laser-induced choroidal neovascularization.

Age-related macular degeneration (AMD) is a worldwide leading cause of blindness affecting individuals over 50 years old. The most aggressive form, wet AMD, is characterized by choroidal neovascularization (CNV) and inflammation involving microglia recruitment. By using a laser-induced CNV mouse model, we provide evidence for a key role played by miR-142-3p during CNV formation. MiR-142-3p was overexpressed in murine CNV lesions and its pharmacological inhibition decreased vascular and microglia densities by 46% and 30%, respectively. Consistently, miR-142-3p overexpression with mimics resulted in an increase of 136% and 126% of blood vessels and microglia recruitment. Interestingly, miR-142-3p expression was linked to the activation state of mouse microglia cells as determined by morphological analysis (cell solidity) through a computational method. In vitro, miR-142-3p overexpression in human microglia cells (HMC3) modulated microglia activation, as shown by CD68 levels. Interestingly, miR142-3p modulation also regulated the production of VEGF-A, the main pro-angiogenic factor. Together, these data strongly support the unprecedented importance of miR-142-3p-dependent vascular-inflammation axis during CNV progression, through microglia activation.

Exosome-mediated delivery of an anti-angiogenic peptide inhibits pathological retinal angiogenesis.

Background: Pathological angiogenesis is the hallmark of many vision-threatening diseases. Anti-VEGF is a primary treatment with substantial beneficial effects. However, such agents require frequent intravitreal injections. Our previous work established a method for effectively modifying exosomes (EXOs) for loading therapeutic peptides. Here, we used this system to load the anti-angiogenic peptide KV11, aiming to establish an EXO-based therapy strategy to suppress neovascularization in the retina. Methods: Using an anchoring peptide, CP05, we linked KV11 to endothelial cell (EC) derived EXOs, yielding EXOKV11. We tested the delivery efficiency of EXOKV11 via two commonly used ocular injection methods: retro-orbital injection and intravitreal injection. Deploying an oxygen-induced retinopathy (OIR) model and a VEGF injection model, we tested the effects of EXOKV11 on neovascular formation, EC proliferation, and vascular permeability. In vitro experiments were used to test the mechanism and to analyze the effects of EXOKV11 on EC proliferation, migration, and sprouting. Results: By using the EXO loading system, KV11 was more efficiently delivered to the blood vessels of the mouse retina via retro-orbital injection. In both OIR model and VEGF injection model, EXOKV11 was more effective than KV11 alone in inhibiting neovascularization and vessel leakage. The therapeutic effect of retro-orbital injection of EXOKV11 was comparable to the intravitreal injection of VEGF-trap. Mechanistically, KV11 alone inhibited VEGF-downstream signaling, while EXOKV11 showed a stronger effect. Conclusions: We used EXOs as a carrier for intraocular delivery of KV11. We showed that KV11 itself has an anti-angiogenic effect through retro-orbital injection, but that this effect was greatly enhanced when delivered with EXOs. Thus, this system has the potential to treat proliferative retinopathy via retro-orbital injection which is a less invasive manner compared with intravitreal injection.

Baseline characteristics of myopic choroidal neovascularization in patients above 50 years old and prognostic factors after intravitreal conbercept treatment.

To investigate the influence of age on the function and morphology of patients with myopic choroidal neovascularization (mCNV) and to evaluate the effect and prognostic factors of recurrence of Conbercept treatment on mCNV patients over 50 years. A total of 64 patients (64 eyes) with mCNV were enrolled in this retrospective study. The differences in baseline best-corrected visual acuity (BCVA) and morphological features on imaging between the younger group (˂ 50 years) and the older group (≥ 50 years) were analyzed. Of all, 21 eyes of 21 mCNV patients aged over 50 years who received Conbercept injection were further analyzed. Between the younger and the older group, significant differences were shown in mean BCVA (0.58 ± 0.28 vs 0.77 ± 0.31), subfoveal choroidal thickness (SFCT) (108.17 ± 78.32 µm vs 54.68 ± 39.03 µm) and frequency of vitreoretinal interface abnormalities (VIA) (2 vs 13), respectively (P < 0.05). After treated with Conbercept, the mean BCVA of 21 older mCNV patients increased from 0.83 ± 0.30 at baseline to 0.49 ± 0.24 at one year. Baseline BCVA, external limiting membrane damage, CNV area and CNV location correlated with the visual acuity at the 1-year follow-up. There were 7 (33.3%) recurrent cases during the follow-up and the risk of recurrence in patients with baseline central macular thickness (CMT) ≥ 262.86 µm was 14 times greater than that of patients with CMT < 262.86 µm. The risk of recurrence increased 1.84 times for every 100-µm increment in the CMT. Patients over 50 years with mCNV had a worse BCVA, thinner choroid, and higher risk of VIA than young mCNV patients. The standard Conbercept treatment strategy was safe and effective in mCNV patients over 50 years. As patients over 50 years with a greater CMT have a high risk of recurrence, more attention should be paid on these patients by following them up closely.

Container Closure and Delivery Considerations for Intravitreal Drug Administration.

Intravitreal (IVT) administration of therapeutics is the standard of care for treatment of back-of-eye disorders. Although a common procedure performed by retinal specialists, IVT administration is associated with unique challenges related to drug product, device and the procedure, which may result in adverse events. Container closure configuration plays a crucial role in maintaining product stability, safety, and efficacy for the intended shelf-life. Careful design of primary container configuration is also important to accurately deliver small volumes (10-100 µL). Over- or under-dosing may lead to undesired adverse events or lack of efficacy resulting in unpredictable and variable clinical responses. IVT drug products have been traditionally presented in glass vials. However, pre-filled syringes offer a more convenient administration option by reducing the number of steps required for dose preparation there by potentially reducing the time demand on the healthcare providers. In addition to primary container selection, product development studies should focus on, among other things, primary container component characterization, material compatibility with the formulation, formulation stability, fill volume determination, extractables/leachables, and terminal sterilization. Ancillary components such as disposable syringes and needles must be carefully selected, and a detailed administration procedure that includes dosing instructions is required to ensure successful administration of the product. Despite significant efforts in improving the drug product and administration procedures, ocular safety concerns such as endophthalmitis, increased intraocular pressure, and presence of silicone floaters have been reported. A systematic review of available literature on container closure and devices for IVT administration can help guide successful product development.

A prospective multicentre study of intravitreal injections and ocular surface in 219 patients: IVIS study.

PURPOSE: To assess the impact of intravitreal injections (IVTI) on ocular surface of patients treated with multiple injections. METHODS: Prospective, tricentric study conducted in patients treated with unilateral IVTI. An asepsis protocol with povidone-iodine was used for all patients during IVTI. The primary endpoint was the difference between the pre-IVTI Ocular Surface Disease Index (OSDI 1) score and that measured on day one (D1) post-IVTI (OSDI 2). Secondary endpoints were the evaluation of predictive factors for OSDI scores, pain assessment on D1, and the Lacrydiag® analysis of tears from the injected eye versus contralateral eye before IVTI. RESULTS: Two hundred and nineteen patients with a mean age of 75.9 ± 10 years were included. The mean OSDI2-OSDI1 difference was 19.2 ± 20.6 (p < 0.001). The mean noninvasive tear break-up time was 6.41 ± 4.59 seconds in the injected eye versus 7.36 ± 4.36 seconds in the contralateral eye (p < 0.001). In the multivariate analysis, the factors significantly associated with the OSDI 2 score were the OSDI 1 score (p < 0.001), the pain score on D1 (p < 0.001) the number of instilled glaucoma eye drop (p = 0.01) and a centre effect (centres 2 and 3 versus centre 1, p < 0.001). CONCLUSION: Our results confirm the impairment of the ocular surface and quality of life immediately after an IVTI. These results suggest 3 levels of action to improve the immediate tolerance: improving the basal status of the ocular surface, reducing the contact time with povidone-iodine that might be toxic to the surface, and improving immediate post-IVTI treatment.

Relationship between metamorphopsia and inner retinal microstructure following intravitreal ranibizumab injection for branch retinal vein occlusion.

To evaluate the effects of intravitreal ranibizumab injection (IVR) on metamorphopsia in patients with branch retinal vein occlusion (BRVO), and to assess the relationship between metamorphopsia and inner retinal microstructure and other factors. Thirty-three treatment-naïve eyes of 33 patients with macular edema caused by BRVO with at least 12 months of follow-up were included. The degree of metamorphopsia was quantified using the M-CHARTS. Retinal microstructure was assessed with spectral-domain optical coherence tomography. Disorganization of the retinal inner layers (DRIL) at the first month after resolution of the macular edema (early DRIL) and at 12 months after treatment (after DRIL) was studied. Central retinal thickness (CRT), and status of the external limiting membrane as well as ellipsoid zone were also evaluated. IVR treatment significantly improved best-corrected visual acuity (BCVA) and CRT, but the mean metamorphopsia score did not improve even after 12 months. Post-treatment metamorphopsia scores showed a significant correlation with pre-treatment metamorphopsia scores (P < 0.005), the extent of early DRIL (P < 0.05) and after DRIL (P < 0.05), and the number of injections (P < 0.05). Multivariate analysis revealed that the post-treatment mean metamorphopsia score was significantly correlated with the pre-treatment mean metamorphopsia score (P < 0.05). IVR treatment significantly improved BCVA and CRT, but not metamorphopsia. Post-treatment metamorphopsia scores were significantly associated with pre-treatment metamorphopsia scores, the extent of DRIL, and the number of injections. Prognostic factor of metamorphopsia was the degree of pre-treatment metamorphopsia.

Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-ß and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-ß and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition.

SELF-DESIGNATION OF THE TREATED EYE BEFORE INTRAVITREAL INJECTIONS: Prevalence and Predictors of Incorrect Calling.

PURPOSE: To identify risk factors for incorrect self-identification of the treatment eye before intravitreal injections. METHODS: This prospective study included consecutive patients who were asked to designate the eye for which the intravitreal injection was intended and were subsequently divided into two groups according to whether or not they identified the correct eye. RESULTS: Overall, 349 eyes (n = 349) were included, and 8.6% (n = 30) designated the incorrect eye or did not know which eye was intended for treatment. Incorrect designation was associated with diabetic macular edema (odds ratio [OR] = 0.33 [0.15-0.75]), first injection in the intended eye or ≥1 year since previous injection (OR = 0.34 [0.14-0.87]), Arabic native tongue (OR = 0.48 [0.22-1.01]), previous injection to the fellow eye (OR = 0.26 [0.10-0.64]), and concurrent treatment of both eyes (OR = 0.35 [0.16-0.74]). Multivariate analysis showed the first injection or ≥1 year since last injection in the treatment eye (R2 = 2.24%, P = 0.004, OR = 0.20 [0.07-0.57]) and previous injection in the fellow eye (R2 = 6.55%, P < 0.001, OR = 0.20 [0.07-0.52]) as significant independent predictors of incorrect identification. CONCLUSION: Several factors are associated with a greater probability for incorrect patient's self-identification of the eye laterality intended for intravitreal injections. These findings may help identify patients with a higher risk of such potential errors.

Critical analysis of techniques and materials used in devices, syringes, and needles used for intravitreal injections.

Intravitreal injections have become the most commonly performed intraocular treatments worldwide. Because intravitreal injections may induce severe adverse events, such as infectious and noninfectious endophthalmitis, cataract, ocular hypertension, vitreous hemorrhage, or retinal detachment, appropriate awareness of the materials and techniques used are essential to reduce these sight-threatening complications. This review provides insights into the needles, syringes, silicone oil coating, sterilization methods, devices to assist intravitreal injections, scleral piercing techniques using needles, syringe handling, anesthesia, and safety issues related to materials and techniques. It is paramount that physicians be aware of every step involved in intravitreal injections and consider the roles and implications of all materials and techniques used. The ability to understand the theoretical and practical circumstances may definitely lead to state-of-the-art treatments delivered to patients. The most important practical recommendations are: choosing syringes with as little silicone oil as possible, or, preferably, none; avoiding agitation of syringes; awareness that most biologics (e.g., antiangiogenic proteins) are susceptible to changes in molecular properties under some conditions, such as agitation and temperature variation; understanding that improper materials and techniques may lead to complications after intravitreal injections, e.g., inflammation; and recognizing that some devices may contribute to an enhanced, safer, and faster intravitreal injection technique.

Injectable in-situ gel depot system for targeted delivery of biologics to the retina.

In current clinical settings, frequent intravitreal (IVT) injections of anti-vascular endothelial growth factors are used due to their short in-vivo half-life and rapid clearance from the back of the eye. The IVT injections are associated with pain, risk of infection, retinal detachment, and financial burden. Biologics molecules can undergo physical, chemical, and enzymatic degradation during formulation development and in the biological environment. Moreover, the complex ocular structures also act as a rate-limiting barrier for these biologics. Thus, delivering stable and clinically relevant biologics concentration to the back of the eye is still a challenge. Compare to other drug delivery platforms, injectable in-situ gelling depot systems (IISGDs) have emerged as an effective system for biologics delivery. In this review, we have discussed various biologics used in ocular therapeutics and their associated challenges. Different routes of delivery and associated tissue barriers are also discussed. Different types of IISGDs developed to date for biologics delivery to the back of the eye were also covered. To conclude, various critical parameters related to the formulation development process and injectable depot systems that need careful consideration and further investigations were highlighted.

Intravitreal conbercept improves outcome of proliferative diabetic retinopathy through inhibiting inflammation and oxidative stress.

Conbercept is a newly-developed anti-vascular endothelial growth factor (VEGF) drug. This study aimed to evaluate the effects of conbercept on inflammation and oxidative response in proliferative diabetic retinopathy (PDR). Morphology changes in retinal microvasculature of PDR patients were determined by optical coherence tomographic angiography (OCTA). The mice were injected with streptozocin (STZ) for 20 weeks to induced PDR, then the changes in inflammatory factors, oxidative response and histological analysis were examined with Elisa assay, real time-PCR and commercial kits analysis. Conbercept treatment significantly alleviated the retinal pathological changes and significantly reduced intercellular cell adhesion molecule-1 (ICAM-1), macrophage inflammatory protein-1 (MIP-1), IL-1ß, IL-6 and TNF-α protein levels but not prostaglandin E1 (PGE1), prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) levels, all of which were remarkably elevated in aqueous fluid of PDR patients compared with non-PDR subjects. Meanwhile the inhibitory effects of conbercept on these inflammatory factors were proved by RT-PCR assays in mice experiments. And the inflammatory signal such as p-IKBα and p-p65 was correspondingly inhibited by conbercept in STZ-treated mice. Conbercept treatment significantly elevated the aqueous glutathione level of PDR patients and inhibited NOX-1, NOX-4 and ph22phox mRNA expressions and ROS production of PDR mice. Ki67 immunofluorescence staining showed that conbercept inhibited endothelial cell proliferation in retina of PDR mice. In conclusion, conbercept significantly inhibited the angiogenesis, inflammation and oxidative response in PDR mice, and these findings further reveals the molecular mechanisms of conbercept in treating PDR.

Manejo da coroidite interna punctata complicada por membrana neovascular sub-retiniana / Management of punctate inner choroidopathy complicated by subretinal neovascular membrane

RESUMO Este trabalho visou evidenciar a importância da detecção precoce da coroidite interna punctata e destacar sua fisiopatologia inflamatória e possíveis diagnósticos diferenciais dentro das white dot syndromes. O destaque foi dado principalmente à coroidite multifocal e à panuveíte, ao se demonstrar sua epidemiologia peculiar em mulheres jovens, caracterizar sua apresentação clínica típica na fundoscopia e explorar as vantagens e as desvantagens de realizar os exames complementares que fazem parte da análise multimodal útil para o diagnóstico (especialmente a angiografia fluoresceínica, a tomografia de coerência óptica e a indocianina verde). Descreve-se o caso de uma mulher de 28 anos diagnosticada com coroidite interna punctata com membrana neovascular coroidal em olho direito. O tratamento foi realizado com injeção intravítrea de aflibercepte e corticoterapia sistêmica 1mg/kg ao dia. Este relato é importante por permitir debater o manejo da coroidite interna punctata durante a gestação e a decisão de realizar o tratamento mediante uma diversidade de opções terapêuticas.

ABSTRACT This work aimed to demonstrate the importance of early detection of punctate inner choroidopathy, highlighting the pathophysiology of inflammation and the differential diagnoses among white dot syndromes. Special attention was given to multifocal choroiditis and panuveitis, by demonstrating the peculiar epidemiology in young women, characterizing the typical clinical presentation in ophthalmoscopy, and exploring the advantages and disadvantages of performing the complementary examinations, which are part of the multimodal analysis useful for diagnosis (particularly fluorescein angiography, optical coherence tomography, and indocyanine green). We report the case of a 28-year-old female, diagnosed as punctate inner choroidopathy with choroidal [N.T. no título aparece subretinal = subrretiniana] neovascular membrane in the right eye. She was treated with intravitreal injection of aflibercept and systemic corticosteroid 1 mg/kg/day. This case report is important for addressing the management of punctate inner choroidopathy during pregnancy, and the decision to carry out treatment considering diverse therapeutic options.