The Impact of the COVID-19 Pandemic on the Quality of Care of Treatment-Naïve Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept. / Die Auswirkungen der COVID-19-Pandemie auf die Versorgungsqualität von therapienaiven PatientInnen mit neovaskulärer altersbedingter Makuladegeneration unter intravitrealer Aflibercept-Therapie.

OBJECTIVE: The aim of this study was to compare the quality of care received by treatment-naïve patients with neovascular age-related macular degeneration (nAMD) who received intravitreal aflibercept therapy before the coronavirus disease 2019 (COVID-19) pandemic with patients who received the same therapy during the pandemic. METHODS: Data, including best corrected visual acuity (BCVA) as the logarithm of the minimum angle of resolution (logMAR) and anatomical outcomes at diagnosis and at each follow-up, was collected on 297 treatment-naïve patients who received intravitreal aflibercept. Therapy-naïve patients who started therapy at least 24 months prior to the first pandemic-related lockdown and were thus treated exclusively prior to the pandemic (n = 123) were compared with patients who started therapy within 12 months prior to the first lockdown and were thus treated during the pandemic (n = 174). Both groups were followed over a two-year period. RESULTS: In patients treated before the COVID-19 pandemic, VA remained stable (0.58 ± 0.41 logMAR) compared to baseline (0.54 ± 0.34 logMAR; p = 0.228) until the end of the observation period. In patients treated during the COVID-19 pandemic, BCVA dropped below the baseline (0.56 ± 0.35 logMAR) within 24-month of follow-up (0.79 ± 0.43 logMAR; p = 0.010). Compared to the patients treated prior to the COVID-19 pandemic, the latter group showed a significantly worse VA at the 6-month (p = 0.041), 12-month (p = 0.040), 18-month (p = 0.024), 21-month (p = 0.035), and 24-month (p = 0.004) follow-up. Additionally, the group treated during the COVID-19 pandemic received significantly fewer aflibercept injections (3,94 ± 1,9 vs. 3,30 ± 1,6; p = 0,007) and fewer follow-up examinations (2,71 ± 1,2 vs. 2,16 ± 0,9; p < 0,001) in the second year compared to the group that was treated before the COVID-19 pandemic. CONCLUSION: We confirmed significantly worse VA outcomes in the group of nAMD patients treated during the COVID-19 pandemic. Impeded access to care could be attributed to the restrictions imposed owing to the COVID-19 pandemic.

Long-term persistence with aflibercept therapy among treatment-naïve patients with exudative age-related macular degeneration in a universal health care system: a retrospective study.

BACKGROUND: This study aimed to analyse the persistence rates of treatment-naïve patients with neovascular age-related macular degeneration (nAMD) who received intravitreal aflibercept therapy in a universal health care system. METHODS: In this single-centre retrospective cohort study, we audited data of 918 treatment-naïve patients who received exclusively intravitreal aflibercept therapy for nAMD between September 2015 and May 2021. The primary outcome measures were the rates of treatment nonpersistence (gap in ophthalmological care > 6 months) and long-term nonpersistence (> 12 months). RESULTS: The rates of nonpersistence and long-term nonpersistence were 12.3% and 3.4% after one year; 22.4% and 9.5% after two years; and 38.3% and 19.3% after five years, respectively. Logistic regression analysis revealed that older age (p = 0.045), male sex (p = 0.039), requirement for caretakers or ambulance (p = 0.001), and low visual acuity of the study eye (p = 0.010) or fellow eye (p = 0.029) were independent risk factors for long-term nonpersistence. Patients aged > 80 and > 85 years (p = 0.013 and p = 0.022, respectively) had more than twice the risk for being nonpersistent to therapy within two years of follow-up compared with younger patients. Male patients (p = 0.033), patients requiring a caretaker (p = 0.038), and patients living > 60 km from the clinic (p = 0.029) had a 2 × higher risk of being persistently nonpersistent to therapy. CONCLUSIONS: Patients with nAMD who were treated with aflibercept had lower nonpersistence rates than those reported in current literature. Multiple independent risk factors were correlated with long-term nonpersistence, early nonpersistence, or complete loss to follow-up. Considering the possible consequences of reduced compliance, further strategies are urgently needed for patients at risk of nonpersistence to therapy.

Two Cases of Acute Macular Neuroretinopathy Associated with the Adenovirus-based COVID-19 Vaccine Vaxzevria (Astrazeneca).

PURPOSE: To report two cases of acute macular neuroretinopathy (AMN) in young female patients following the administration of the adenovirus-based coronavirus disease 2019 (COVID-19) vaccine Vaxzevria (AstraZeneca). METHODS: Spectral-domain optical coherence tomography and infrared imaging were used to confirm the diagnosis of AMN. RESULTS: Both patients showed a parafoveal hyperreflective band in the outer nuclear layer, disruption of the ellipsoid and interdigitation zones of the photoreceptor layers, and correlating hyporeflective areas on the near-infrared images. Both patients presented with flu-like fever and sudden onset of fortifications within 48 hours of vaccination. One patient showed altered flow in the deep capillary plexus and highly elevated thrombotic parameters. CONCLUSION: We report a possible association between immune-mediated AMN and the administration of adenovirus-based COVID-19 vaccine Vaxzevria.

CHANGES IN SYSTEMIC LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AFTER INTRAVITREAL INJECTION OF AFLIBERCEPT OR BROLUCIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To analyze and compare the effects of intravitreal brolucizumab versus aflibercept on systemic vascular endothelial growth factor (VEGF)-A levels in patients with neovascular age-related macular degeneration. METHODS: In this prospective interventional case series study, brolucizumab (6.0 mg/50 µL) or aflibercept (2.0 mg/50 µL) was injected intravitreally in 30 patients each. Blood samples were drawn at baseline and 7 days and 28 days after the first injection. Systemic VEGF-A levels were measured using enzyme-linked immunosorbent assay. Thirty healthy individuals served as controls. RESULTS: The median baseline systemic VEGF-A levels in the brolucizumab, aflibercept, and control groups were 10.8 (8.0-13.2), 12.0 (8.0-18.5), and 10.0 (8.0-15.1) pg/mL, respectively (P = 0.315). In the brolucizumab group, VEGF-A levels significantly decreased to 8.0 (8.0-11.5) pg/mL on Day 7 (P = 0.0254) and to 8.0 (8.0-8.0) pg/mL on Day 28 (P < 0.001). In the aflibercept group, VEGF-A levels significantly decreased to 8.0 (8.0-8.0) pg/mL on Day 7 (P < 0.001) but returned to the baseline level, 12.5 (8.5-14.6) pg/mL, on Day 28 (P = 0.120). Vascular endothelial growth factor-A levels were significantly different between the treatment groups after 28 days (P < 0.001). CONCLUSION: Intravitreal brolucizumab resulted in a sustained reduction of systemic VEGF-A levels until 28 days posttreatment, which raises concerns regarding its safety and long-term effects.

Efficiency benchmarks in the surgical management of primary rhegmatogenous retinal detachment: a monocentric register cohort study of operating room time metrics and influential factors.

OBJECTIVES: To investigate the effect of clinical, methodological and logistic factors on operating room (OR) efficiency in the surgical management of primary rhegmatogenous retinal detachment (RRD). DESIGN: Monocentric retrospective register cohort study. SETTING: Single tertiary centre in the western region of Austria. PARTICIPANTS: We audited patients diagnosed with primary RRD who were treated between January 2014 and August 2019. In total, 783 eyes of 776 consecutive patients were included in this study. Various risk factors affecting OR time efficiency and anatomical success after pars plana vitrectomy (PPV) procedures and scleral buckle (SB) surgery were analysed. PRIMARY AND SECONDARY OUTCOME MEASURES: OR efficiency was the primary outcome measure. Secondary outcome measures were the primary success rate after PPV procedures and SB surgery. RESULTS: PPV was performed in 641 (81.9%) eyes and SB surgery in 142 (18.1%) eyes. Mean surgical times in PPV and SB under retrobulbar anaesthesia (RA) were 74.0 (±32.6) min and 62.1 (±24.6) min (p<0.001), respectively, while under general anaesthesia (GA), these values were 112.0 (±52.0) min and 76.0 (±22.5) min (p<0.001), respectively. A regression analysis revealed the following main risk factors for prolonged OR time for the surgical management of RRD with PPV (all p<0.001): presence of a giant tear (ß=24.01; 32%), proliferative vitreoretinopathy (PVR)-C (ß=16.43; 22%), surgery postponed for 72 hours after diagnosis (ß=21.40; 29%), GA (ß=23.64; 32%) or surgery performed by a trainee (ß=17.35; 23%). PVR (p=0.022) in PPV cases, after-hours settings (p=0.006) and surgeon experience (p=0.030) in SB cases were independent risk factors for reduced success rates. CONCLUSIONS: OR coordinators should consider various independent clinical (giant tear, PVR-C, advanced detachment), methodological (PPV vs SB) and logistic (GA vs RA, after-hours setting and surgeon experience) factors to improve the success rate and surgical management planning of RRD accurately while optimising OR resources and staff efficiency.

Systemic counterregulatory response of angiopoietin-2 after aflibercept therapy for nAMD: a potential escape mechanism.

PURPOSE: To analyse the effect of intravitreal aflibercept injections on systemic angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF)-A levels in patients with neovascular age-related macular degeneration (nAMD). METHODS: In a prospective, randomized study, aflibercept (2.0 mg/50 µl) or ranibizumab (0.5 mg/50 µl) was administered intravitreally to 38 treatment-naive patients. Blood samples were taken before, 7 days after, and 28 days after the first intravitreal therapy. Cytokine levels were measured by enzyme-linked immunosorbent assay. Twenty-two age- and sex-matched individuals served as controls. RESULTS: At baseline, there were no significant differences of systemic Ang2 and VEGF-A levels among the treatment and control groups. After intravitreal aflibercept administration, median (interquartile range: IQR) systemic Ang2 was significantly upregulated from 1819 pg/ml (1262-3099) to 2123 pg/ml (1441-3769; p = 0.011) 7 days after the drug injection and remained non-significantly elevated at 1944 pg/ml (1431-2546 pg/ml; p = 0.653) 28 days after the drug injection. Median (IQR) systemic VEGF-A levels were significantly reduced from 43 pg/ml (30-57) to 8 pg/ml (8-8; p < 0.0001) 7 days and 16 pg/ml (8-26; p = 0.001) 28 days after the injection in the aflibercept group. There were no significant effects on systemic VEGF-A and Ang2 levels in the ranibizumab group at any time point following the first injection. CONCLUSION: In this study, we report significant systemic upregulation of Ang2 after intravitreal aflibercept administration. This counterregulatory response may represent a potential escape mechanism from antiangiogenic therapy.

[Patient Mobility and Journey Distance as Risk Factors for Severe Visual Impairment: Real-Life Data Analysis of Treatment-naïve Patients with nAMD under Intravitreal Aflibercept Therapy]. / PatientInnen-Mobilität und Anreisedistanz als Risiko für höhergradige Sehbehinderung: Real-Life-Daten therapienaiver AMD-PatientInnen unter intravitrealer Aflibercept-Therapie.

OBJECTIVE: The aim of this study is to describe the effectiveness of aflibercept in treatment-naive patients with neovascular age related macular degeneration (nAMD) and the impact of patients' residential distance to the clinic and patients' mobility on therapy in a pro re nata regime. METHODS: A retrospective dataset analysis of 483 treatment-naive patients with nAMD was performed. The main outcomes were best corrected visual acuity (BCVA), central foveal thickness (CFT), bilateral visual impairment, distance and type of transport to the clinic. Secondary outcomes were injection rate, numbers and reasons of loss to follow-up. RESULTS: Patients received 4.91 ± 1.9 injections in their first year and 7.06 ± 3.6 after the period of 25 months (m). Initially the BCVA improved significantly after a loading dose from 0.72 logMAR (± 0.44) to 0.63 logMAR (± 0.45; p = 0.03). However, the BCVA significantly decreased after 2 years to 0.82 (± 0.48; p < 0.001). The proportion of patients with higher visual impairment and patients needing assistance with transport increased with the distance of their residence to the clinic (both p < 0.001). The LTFU rate was 3% and showed a correlation with greater age (p = 0.019). CONCLUSION: The presented data show that aflibercept is effective for the treatment of nAMD. Although a good increase in visual acuity is initially achieved in the majority of patients, the initial success of treatment is not maintained throughout the course of the disease. Compared to controlled clinical studies, the presented data show reduced therapeutic success and lower injection frequencies. The rising demand for patient transport aid and increased visual impairment with increased distance indicate potential problems within the healthcare system.

[Diagnosis, treatment and monitoring of diabetic eye disease (Update 2019)]. / Diagnose, Therapie und Verlaufskontrolle der diabetischen Augenerkrankung (Update 2019).

Diabetes mellitus can cause diabetic retinopathy, diabetic macular edema, optic neuropathy, cataract or dysfunction of the eye muscles. The incidence of these defects correlates with disease duration and quality of metabolic control. Recommendations of the Austrian Diabetes Association for diagnosis, therapeutic procedures and requirements for adequate follow-up depending on stage of diabetic eye disease are summarized.

Effects of Intravitreal Aflibercept on Galectin-1 and Vascular Endothelial Growth Factor-A Plasma Levels in Patients with Diabetic Retinopathy.

PURPOSE: To analyze the interaction between aflibercept and galectin-1 and evaluate the plasma levels of galectin-1 and vascular endothelial growth factor (VEGF)-A after intravitreal injection of aflibercept in patients with diabetic retinopathy (DR). METHODS: Interaction of galectin-1 with aflibercept was determined via immunoprecipitation. Seventeen patients with type 2 diabetes and diabetic macular edema (DME) were each treated with a single intravitreal injection of aflibercept (2.0 mg, 50 µL) monthly for three consecutive months. Plasma galectin-1 and VEGF-A levels were measured just before an injection was administered, 1 week after the first injection, and 2 months after the last injection. Nineteen age- and sex-matched healthy participants served as controls. RESULTS: Irrespective of the tested galectin-1 concentration, 24% of added galectin-1 was precipitated by aflibercept. Baseline plasma concentrations of galectin-1 were 22.0 and 23.0 ng/mL in the control and aflibercept-treated groups, respectively. Systemic galectin-1 levels increased to 27.0 and 24.0 ng/mL at 7 days and 4 weeks, respectively, after treatment. At week 8, plasma galectin-1 levels significantly increased to 36.0 ng/mL. This level persisted for 20 weeks. Systemic VEGF-A levels significantly reduced to below the minimum detectable dose in 16 DME patients at 7 days after treatment. This level persisted for 4 weeks. Plasma VEGF-A levels were reduced at weeks 8 (p = 0.099) and 20 (p = 0.023). Decreased plasma VEGF-A levels were observed in all patients after treatment. CONCLUSION: We confirmed that physiological aflibercept levels precipitate galectin-1 in in vitro assays. Additionally, systemic upregulation of galectin-1 might be induced by intravitreal aflibercept, which may be relevant in the clinical outcomes of DR treatment.

[Diagnosis, treatment and monitoring of diabetic eye control]. / Diagnose, Therapie und Verlaufskontrolle der diabetischen Augenerkrankung.

Diabetes mellitus can cause diabetic retinopathy, diabetic macular edema, optic neuropathy, cataract or dysfunction of the eye muscles. The incidence of these defects correlates with disease duration and quality of metabolic control. Recommendations of the Austrian Diabetes Association for diagnosis, therapeutic procedures and requirements for adequate follow up depending on stage of diabetic eye disease are summarized.

Systemic counterregulatory response of placental growth factor levels to intravitreal aflibercept therapy.

PURPOSE: Placental growth factor (PlGF) has been implicated as a contributor to resistance against anti-VEGF therapy. The purpose of the present study was to analyze the systemic levels of PlGF, VEGF-A, and VEGF-B in patients with neovascular age-related macular degeneration (AMD) after treatment with aflibercept, ranibizumab, or bevacizumab. METHODS: Totals of 19 patients were treated with intravitreal aflibercept, 19 with ranibizumab, and 18 with bevacizumab. The cytokine levels were measured by ELISA just before the injection, and 7 days and 1 month thereafter. Age- and sex-matched participants (n = 22) served as controls. RESULTS: The median PlGF plasma concentration at baseline was <12.0 pg/mL in the control group as well as in all three anti-VEGF treatment cohorts. After intravitreal aflibercept injection, a significant upregulation of systemic PlGF could be observed in all treated patients (38.0 [31.0-44.0] pg/mL after 1 week [P < 0.001] and 16.0 [0.0-19.0] pg/mL [P = 0.005] after 4 weeks). No significant effects on plasma PlGF concentrations could be detected in those treated with ranibizumab and bevacizumab. The systemic VEGF-A levels were significantly reduced 1 and 4 weeks after intravitreal aflibercept (P < 0.001, P < 0.001) and bevacizumab (P < 0.001, P < 0.01) injections. No significant effects on plasma cytokine concentrations could be observed in the ranibizumab cohort. No significant effects on systemic VEGF-B could be observed in any of the treatment groups. CONCLUSIONS: In this study, we report a significant systemic upregulation of the proangiogenic cytokine PlGF after intravitreal administration of aflibercept. This might represent a counter-regulatory response to antiangiogenic therapy.

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age-related macular degeneration: a randomised, prospective trial.

PURPOSE: To evaluate the changes of vascular endothelial growth factor (VEGF) plasma levels after intravitreal injections of aflibercept or ranibizumab in patients with exudative age-related macular degeneration (AMD). METHODS: Thirty-eight patients with exudative AMD were included in this randomised, prospective study. Nineteen patients were randomised to treatment with intravitreal aflibercept (2.0 mg) and 19 to intravitreal ranibizumab (0.5 mg). The concentration of VEGF was measured by ELISA just before the injection, after 7 days and 1 month. Twenty-two age- and sex-matched healthy patients without chorioretinal diseases served as control. RESULTS: The median baseline plasma VEGF concentration was 61.0 pg/ml in the control group, 43.0 pg/ml in the aflibercept group and 59.0 pg/ml in the ranibizumab group (p=0.127). Seven days after intravitreal injection of aflibercept plasma levels were significantly reduced to values below the minimum detectable dose (MDD) in 17 of 19 patients (89.5%) resulting in a median VEGF concentration of <9 pg/ml (p<0.001). The reduction persisted throughout 1 month with values below the MDD in 5 of 19 patients (26.3%) and a median measurement of 17.0 pg/ml (p<0.001). In patients treated with ranibizumab no significant effects could be observed with a baseline VEGF of 59.0 pg/ml, 54.0 pg/ml at 7 days (p=0.776) and 58.5 pg/ml at 4 weeks of follow-up (p=0.670). CONCLUSION: After intravitreal aflibercept injection, the systemic VEGF levels were significantly reduced throughout the observational period of 4 weeks. No significant systemic effects of intravitreal ranibizumab on plasma VEGF were observed.

Systemic upregulation of PDGF-B in patients with neovascular AMD.

PURPOSE: To determine the plasma levels of platelet-derived growth factor-B (PDGF-B), VEGF, and TNF-α in patients with neovascular AMD and in patients with diabetic macular edema (DME). METHODS: Thirty patients with neovascular AMD, 30 patients with DME, and 12 healthy controls were included in this prospective study. The concentrations of PDGF-B, VEGF, and TNF-α were measured by ELISA. RESULTS: The PDGF-B concentration in the plasma of controls was (median [25th-75th percentile]) 263.5 (162.0-513.3) pg/mL and in patients with DME 219.0 (122.8-604.8) pg/mL. In patients with neovascular AMD, PDGF-B levels were significantly higher with a median plasma concentration of 783.5 (289.3-1183.5) pg/mL (P = 0.003). The VEGF concentrations in patients with DME 33.0 (21.8-73.0) pg/mL and in patients with neovascular AMD 55.0 (37.0-116.3) pg/mL showed no significant differences (P = 0.159). A positive correlation of PDGF-B and VEGF plasma levels was found in patients with neovascular AMD and in patients with DME (r = 0.683, P < 0.001, and r = 0.612, P < 0.001, respectively). No significant differences of systemic TNF-α levels could be found between the three study groups. CONCLUSIONS: Patients with neovascular AMD have significantly higher plasma PDGF-B levels compared with patients with DME and healthy controls. Our study data indicate that PDGF-B may be involved in the pathogenesis of neovascular AMD. (https://eudract.ema.europa.eu number, EudraCT 2010-024654-11)

Correlation of vascular endothelial growth factor plasma levels and glycemic control in patients with diabetic retinopathy.

PURPOSE: To determine whether glycemic control of patients with diabetic retinopathy (DR) due to type 2 diabetes was related to VEGF plasma levels. METHODS: The prospective study included 30 patients with DR due to type 2 diabetes. Retinopathy was classified according to the international clinical DR disease severity scale. The concentrations of VEGF in the blood plasma were measured by ELISA. Glycosylated hemoglobin (HbA1c) was assessed all patients. Results were reported as DCCT/NGSP-HbA1c (%) values. RESULTS: The median plasma level of VEGF was 34.5 (range 15-217) pg/ml. Median HbA1c was 7.5 (range 5.3-10.6). The highest individual plasma VEGF measurements were found in patients with severe non-proliferative DR. HbA1c levels revealed a significant correlation with plasma VEGF concentrations (r = 0.573, p = 0.001). Age (r = 0.097, p = 0.611), gender (r = -0.315, p = 0.09) and severity of DR (r = 0.256, p = 0.172) were with no significant relationship to the VEGF measurements. CONCLUSION: Poor glycemic control is positively correlated with increased levels of plasma VEGF in patients with type 2 diabetes. As normalization of HbA1c is one of the most effective ways to prevent progression of DR and VEGF has been to shown to be clearly implicated in the development of DR, it affirms the importance of glycemic control in patients with DR.

Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema.

AIMS: To determine the level of vascular endothelial growth factor (VEGF) in the plasma of patients with diabetic macular edema (DME) and of patients with exudative age-related macular degeneration (ARMD) before and after intravitreal injection of bevacizumab, ranibizumab or pegaptanib. METHODS: 30 patients with DME and 30 patients with ARMD were included in this randomized controlled study. Patients were randomized to treatment with ranibizumab (0.5 mg), bevacizumab (1.25 mg) or pegaptanib (0.3 mg). 10 patients with DME received bevacizumab, 10 ranibizumab and 10 pegaptanib. The same randomized treatment allocation applied to the 30 patients with ARMD. The concentrations of VEGF were measured by ELISA just before the injection, after 7 days and 1 month. RESULTS: Plasma VEGF in patients with exudative ARMD before the injection of bevacizumab was 89.7 pg/ml. It was significantly reduced to 25.1 pg/ml after 7 days (p=0.01), and to 22.8 pg/ml after 1 month (p=0.008). In patients with DME the same systemic reduction by bevacizumab was observed with a significant decrease of baseline VEGF level from 72.2 pg/ml to 13.7 pg/ml after 7 days (p=0.008) and 17.1 pg/ml at 4 weeks with (p=0.012). No significant reductions of plasma VEGF levels were observed in patients receiving ranibizumab or pegaptanib during follow-up. CONCLUSIONS: Bevacizumab significantly reduces the level of VEGF in the blood plasma for up to one month in patients with DME as well as in those with ARMD. No significant systemic effects of intravitreal ranibizumab or pegaptanib on plasma VEGF could be observed.

VIP, PACAP-38, BDNF and ADNP in NMDA-induced excitotoxicity in the rat retina.

PURPOSE: To evaluate the effect of intravitreal injection of N-methyl-D-aspartate (NMDA) on brain-derived neurotrophic factor (BDNF), pituitary adenylate cyclase-activating peptide-38 (PACAP-38), vasoactive intestinal peptide (VIP) and the VIP-associated glial protein activity-dependent neuroprotective protein (ADNP) in the rat retina. These elements have well-documented neuroprotective properties and may thus be integrated in endogenous neuroprotective mechanisms in the retina which break down in NMDA excitotoxicity. METHODS: A volume of 2 µl of 100 nmol NMDA was intravitreally injected into one eye of rats, the untreated eye served as a control. Time-dependent effects of NMDA on VIP, PACAP-38 and BDNF were detected by radioimmunoassay and ELISA, and the effect on the expression of VIP, PACAP-38 and ADNP was evaluated by quantitative RT-PCR 20 days after NMDA injection. Topical flunarizine served to find out whether the effect of NMDA is counteracted. RESULTS: Compared to PACAP-38, VIP levels significantly decreased on days 1, 7, 14, 28 and 56 after NMDA injection indicating that VIPergic cells are more vulnerable than PACAP-38-expressing cells. The expression of VIP and ADNP but not of PACAP-38 was found to be reduced, and application of topical flunarizine counteracted the decrease of VIP. BDNF levels significantly increased after days 1 and 3. CONCLUSION: The early upregulation of BDNF seems to act neuroprotectively and leads to a delay of ganglion cell loss. Although there is no direct evidence, the decrease of VIP and ADNP - the consequence of the presence of NMDA receptors on these peptide-expressing cells - might contribute to the breakdown of endogenous neuroprotective mechanisms given that the decrease of the VIP-related ADNP runs in parallel with the decrease of VIP. Activating and maintaining these mechanisms must be the primary aim in the therapy of diseases with retinal neuronal degeneration.

Safety and feasibility of a novel intravitreal tamponade using a silicone oil/acetyl-salicylic acid suspension for proliferative vitreoretinopathy: first results of the Austrian Clinical Multicenter Study.

BACKGROUND: The safety and efficacy of a new surgical method of intravitreal tamponade using silicone oil suspended with aspirin (acetylsalicylic acid) was investigated for the treatment of proliferative vitreoretinopathy. METHODS: The study was designed as a prospective, randomized, controlled, double-blind multicenter study. A total of 29 patients were included; 15 patients were treated with the silicone oil suspended with aspirin, and 14 patients represented the control group receiving only silicone oil. A standard three-port pars plana vitrectomy was performed in 29 eyes of 29 patients. In cases in which the natural lens was present, simultaneous phacoemulsification was required. The control group received as standard therapy a vitreous tamponade with pure 5000 mPas silicone oil and the treatment group received silicone oil containing 0.2 mg/ml aspirin (AS SiO). At 6 months after surgery, the tamponade was removed from all eyes. The main outcome measure was the incidence of retinal redetachment requiring reoperation. Secondary outcome measures were visual acuity and ophthalmic examination results. RESULTS: The rate of redetachment, defined as the primary outcome parameter, was the same for both groups. The AS SiO was well tolerated and remained clear during the 6-month study period. Clinical examination revealed no signs of local or systemic adverse effects. The visual acuities were well matched before inclusion in the study and there were no significant differences during the follow-up period and in the final visual outcome between the two groups. CONCLUSIONS: Aspirin delivery by intravitreal silicone oil in the human eye is safe and also may provide a delivery vehicle for other antiproliferative agents to the posterior pole.

Peptidergic nerves in the eye, their source and potential pathophysiological relevance.

Over the last five decades, several neuropeptides have been discovered which subsequently have been found to be highly conserved during evolution, to be widely distributed both in the central and peripheral nervous system and which act as neurotransmitters and/or neuromodulators. In the eye, the first peptide to be explored was substance P which was reported to be present in the retina but also in peripherally innervated tissues of the eye. Substance P is certainly the best characterized peptide which has been found in sensory neurons innervating the eye. Functionally, it has been shown to act trophically on corneal wound healing and to participate in the irritative response in lower mammals, a model for neurogenic inflammation, where it mediates the noncholinergic nonadrenergic contraction of the sphincter muscle. Over the last three decades, the interest has extended to investigate the presence and distribution of other neuropeptides including calcitonin gene-related peptide, vasoactive intestinal polypeptide, neuropeptide Y, pituitary adenylate cyclase-activating polypeptides, cholecystokinin, somatostatin, neuronal nitric oxide, galanin, neurokinin A or secretoneurin and important functional results have been obtained for these peptides. This review focuses on summarizing the current knowledge about neuropeptides in the eye excluding the retina and retinal pigment epithelium and to elucidate their potential functional significance.

Iontophoretic delivery of carboplatin in a murine model of retinoblastoma.

PURPOSE: To evaluate the efficacy and dose-response of transcorneoscleral Coulomb controlled iontophoresis (CCI) of carboplatin in the treatment of retinal tumors of a murine model of retinoblastoma. METHODS: Thirty 6-week-old LHBETATAG mice underwent a total of six, serial iontophoretic treatments administered two times per week using a current density of 2.57 mA/cm2 for 5 minutes. Fourteen animals received carboplatin treatments at concentrations of 1.4, 7.0, 10.0, or 14.0 mg/mL without current. Ten control mice underwent treatment with balanced saline solution. RESULTS: A dose-dependent inhibition of intraocular tumor was observed after repetitive iontophoretic treatment. At carboplatin concentrations of 7 mg/mL, 50% of the treated eyes (4/8) exhibited tumor control. No corneal toxicity was observed in eyes treated at carboplatin concentrations under 10 mg/mL. CONCLUSIONS: CCI delivery of carboplatin safely and effectively controls intraocular tumors in a dose-dependent manner in this murine model of retinoblastoma. CCI is a noninvasive, painless option for the focal delivery of carboplatin. However, further clinical and laboratory research is needed before this method of drug delivery is available for children with retinoblastoma.