Agnes Boltz

A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration

Aim The current accepted standard treatment for neovascular age-related macular degeneration (AMD) consists of antivascular endothelial growth factor agents including ranibizumab and bevacizumab. The aim of the study was to examine whether bevacizumab is inferior to ranibizumab with respect to maintaining/improving visual acuity. Methods In this prospective randomised parallel group multicentre trial patients aged more than 50 years with treatment naive nAMD were included at 10 Austrian centres. Patients were randomised to treatment either with 0.5 mg ranibizumab or 1.25 mg bevacizumab. Both groups received three initial monthly injections and thereafter monthly evaluation of visual acuity and the activity of the lesion. Re-treatment was scheduled as needed. Outcome measures were early treatment of diabetic retinopathy visual acuity, retinal thickness, lesion size and safety evaluation. Results A total of 321 patients were recruited of which four had to be excluded due to different reasons. Of the 317 remaining patients 154 were randomised into the bevacizumab group and 163 into the ranibizumab group. At month 12, there was a mean increase of early treatment of diabetic retinopathy visual acuity of 4.9 letters in the bevacizumab and 4.1 letters in the ranibizumab group (p=0.78). Furthermore, there were no significant differences in the decrease of retinal thickness, change of lesion size and number of adverse events between the groups. Conclusions Bevacizumab was equivalent to ranibizumab for visual acuity at all time points over 1 year. There was no significant difference of decrease of retinal thickness or number of adverse events.

Choroidal blood flow and progression of age-related macular degeneration in the fellow eye in patients with unilateral choroidal neovascularization.

PURPOSE Cardiovascular risk factors such as smoking, hypertension, and atherosclerosis seem to play an important role in the development of choroidal neovascularization (CNV). Recent studies have also provided evidence suggesting that choroidal and retinal blood flow is decreased in patients with AMD. On the basis of these results, the hypothesis for this study was that lower choroidal blood flow is associated with an increased risk of CNV in patients with AMD. METHODS Forty-one patients with unilateral choroidal neovascular AMD were included in this observational longitudinal study. The fellow eyes of the patients served as study eyes. Subfoveal choroidal blood flow (FLOW) and fundus pulsation amplitude (FPA) were assessed with laser Doppler flowmetry and laser interferometry, respectively. A multivariate COX-regression model was used to test the hypothesis that low choroidal perfusion parameters are associated with the development of CNV. RESULTS Of the 37 patients that were followed up until the end of the study, 17 developed CNV and 20 did not. The univariate COX-regression analysis shows that lower FLOW, systolic blood pressure, intraocular pressure, and FPA are risk factors for development of CNV. Moreover, the more advanced the AMD in the study eye, the higher the risk for CNV to develop in the fellow eye. Multivariate COX regression analysis indicated that only FLOW (P = 0.0071), FPA (P = 0.0068), and staging (P = 0.031) had statistically significant influences on the progression to CNV. CONCLUSIONS The present study indicates that lower choroidal perfusion is a risk factor for the development of CNV in the fellow eye of patients with unilateral CNV.

Measurement of absolute blood flow velocity and blood flow in the human retina by dual-beam bidirectional Doppler fourier-domain optical coherence tomography.

PURPOSE The present experiments were undertaken to evaluate the validity of absolute flow velocity measurements with a dual-beam bidirectional Doppler Fourier-domain optical coherence tomography (FD-OCT) system. METHODS The flow velocities of diluted milk through a glass capillary were measured at 30 different preset velocities in the range of 0.9 to 39.3 mm/s by bidirectional Doppler FD-OCT. The flow through the capillary was controlled by two infusion pumps working in different flow ranges and based on different technical principles. In vivo the validity of the method for measuring blood flow in retinal vessels was tested at bifurcations. The continuity equation was verified at 10 retinal venous bifurcations of 10 young healthy subjects (mean age, 29 ± 3 years) by velocity measurements, using dual-beam bidirectional Doppler FD-OCT, and measurements of retinal diameters, using the Dynamic Vessel Analyzer. RESULTS Flow velocities as measured with bidirectional Doppler FD-OCT in the glass capillary were in good agreement with the preset velocities (r = 0.994, P < 0.001 each). No significant difference was found between flow in the trunk vessels before the bifurcation (11.3 ± 5.2 μL/min) and the sum of flows in the daughter vessels (10.7 ± 4.8 μL/min). A significant association was found between retinal vessel diameters and both retinal blood velocities (r = 0.72, P < 0.001) and retinal blood flow (r = 0.95, P < 0.0001). CONCLUSIONS Dual-beam bidirectional Doppler FD-OCT delivered accurate retinal blood velocity values and, thus, offers high potential for examination of retinal blood flow in ocular disease.

Neurovascular dysfunction precedes neural dysfunction in the retina of patients with type 1 diabetes.

PURPOSE A variety of studies have shown that flicker-induced vasodilatation is reduced in patients with diabetes. It is, however, unclear whether reduced neural activity or abnormal neurovascular coupling is the reason for this phenomenon. In the present study, we hypothesized that retinal neurovascular dysfunction precedes neural dysfunction in patients with early type 1 diabetes. METHODS In the present study, 50 patients with type 1 diabetes without retinopathy and 50 healthy age- and sex-matched control subjects were included. The retinal vascular response to flicker stimulation was measured using the dynamic Retinal Vessel Analyzer. In addition, the response in retinal blood velocity to flicker stimulation as assessed with laser Doppler velocimetry was studied in a subgroup of patients. Pattern electroretinography (ERG) was used to measure neural retinal function. RESULTS The flicker responses of both retinal arteries and veins were significantly reduced in patients with diabetes (veins in the diabetic group: 3.5 ± 2.3% versus healthy control group: 4.6 ± 2.0%; P = 0.022 between groups, whereas arteries in the diabetic group: 2.0 ± 2.7% versus healthy control group: 3.8 ± 1.7%; P < 0.001 between groups). Likewise, the response of retinal blood velocity was reduced in patients with diabetes, although adequate readings could only be obtained in a subgroup of subjects (diabetic group [n = 22]: 19 ± 7%; healthy control group [n = 24]: 43 ± 19% P < 0.001 between groups). The parameters of pattern ERG were not different between the two groups. CONCLUSIONS The study confirms that flicker responses are reduced early in patients with type 1 diabetes. This is seen before alterations in pattern ERG indicating abnormal neurovascular coupling.

Comparison of choroidal and optic nerve head blood flow regulation during changes in ocular perfusion pressure.

PURPOSE We compared the response of choroidal and optic nerve head blood flow (ChBF, ONHBF) in response to an increase in ocular perfusion pressure (OPP) during isometric exercise and during a decrease in OPP during an artificial increase in intraocular pressure (IOP). METHODS We included 96 healthy subjects in our study. In 48 subjects OPP was increased by 6 minutes of squatting, and either ONHBF (n = 24) or ChBF (n = 24) was measured continuously. In 48 other healthy subjects either ONHBF (n = 24) or ChBF (n = 24) was measured continuously during a period of artificial increase in IOP using a suction cup. All blood flow measurements were done using laser Doppler flowmetry. RESULTS During all experiments the response in blood flow was less pronounced than the response in OPP, indicating for flow regulation. During isometric exercise ChBF regulated better than ONHBF (P = 0.023). During artificial IOP increase ONHBF regulated better than ChBF (P = 0.001). Inter-individual variability in blood flow responses was high. During squatting ONHBF decreased considerably below baseline ONHBF when OPP fluctuated in 3 subjects, although OPP still was much higher than at baseline. This phenomenon was not observed in the choroid. CONCLUSIONS Our data indicate that regulation of ChBF and ONHBF during changes in OPP is different and complex. In some subjects performing squatting, considerable ONHBF reductions were observed during OPP fluctuations, although OPP still was high. Whether this predisposes to ocular disease remains unclear.

Retinal oxygen metabolism during normoxia and hyperoxia in healthy subjects.

PURPOSE To characterize retinal metabolism during normoxia and hyperoxia in healthy subjects. METHODS Forty-six healthy subjects were included in the present study, and data of 41 subjects could be evaluated. Retinal vessel diameters, as well as oxygen saturation in arteries and veins, were measured using the Dynamic Vessel Analyzer. In addition, retinal venous blood velocity was measured using bidirectional laser Doppler velocimetry, retinal blood flow was calculated, and oxygen and carbon dioxide partial pressures were measured from arterialized capillary blood from the earlobe. Measurements were done during normoxia and during 100% oxygen breathing. RESULTS Systemic hyperoxia caused a significant decrease in retinal venous diameter (-13.0% ± 4.5%) and arterial diameter (-12.1% ± 4.0%), in retinal blood velocity (-43.4% ± 7.7%), and in retinal blood flow (-57.0% ± 5.7%) (P < 0.001 for all). Oxygen saturation increased in retinal arteries (+4.4% ± 2.3%) and in retinal veins (+19.6% ± 6.2%), but the arteriovenous oxygen content difference significantly decreased (-29.4% ± 19.5%) (P < 0.001 for all). Blood oxygen tension in arterialized blood showed a pronounced increase from 90.2 ± 7.7 to 371.3 ± 92.7 mm Hg (P < 0.001). Calculated oxygen extraction in the eye decreased by as much as 62.5% ± 9.5% (P < 0.001). CONCLUSIONS Our data are compatible with the hypothesis that during 100% oxygen breathing a large amount of oxygen, consumed by the inner retina, comes from the choroid, which is supported by previous animal data. Interpretation of oxygen saturation data in retinal arteries and veins without quantifying blood flow is difficult. (ClinicalTrials.gov number, NCT01692821.).

Role of vascular endothelial growth factor polymorphisms in the treatment success in patients with wet age-related macular degeneration.

PURPOSE Along with environmental risk factors such as smoking, hypertension, and atherosclerosis, genetic susceptibility is a primary contributor to the development and progression of exudative age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a central angiogenic regulator and there has been general agreement now that it is an important trigger for the progression of exudative AMD. In the present study, we tested the hypothesis that VEGF gene polymorphisms play a role in the treatment success with VEGF inhibitors in patients with exudative AMD. DESIGN Prospective cohort study. PARTICIPANTS We included 185 eyes of 141 patients with exudative AMD who were scheduled for their first treatment with intravitreally administered bevacizumab in this trial. METHODS All patients were aged >50 years and had angiographically verified exudative AMD. Blood from the finger pad was collected on blood cards for genotyping for the VEGF polymorphisms rs1413711, rs3025039, rs2010963, rs833061, rs699947, rs3024997, and rs1005230. At each follow-up visit, visual acuity was reassessed and an ophthalmic examination was carried out. Visual acuity outcome, number of retreatments, and overall time of treatment were analyzed in dependence of the VEGF polymorphisms. MAIN OUTCOME MEASURES Mean change in visual acuity at the end of the treatment period. RESULTS The included patients were reinjected with bevacizumab 1 to 15 times, resulting in a total treatment period of 42 to 1182 days. In univariate analysis only the G/G genotypes of rs3024997 and rs2010963 compared with all other 5 single nucleotide polymorphisms (SNPs) showed a significantly lower visual acuity at the end of treatment. In multivariate analysis including parameters such as time, baseline visual acuity, and number of reinjections, none of the SNPs showed a significant correlation. CONCLUSIONS The current study indicates that VEGF polymorphisms are not major predictors of anti-VEGF treatment success in patients with exudative AMD.

Measurement of Retinal Oxygen Saturation in Patients with Chronic Obstructive Pulmonary Disease

PURPOSE There is growing evidence that disturbances in retinal oxygenation may trigger ocular diseases. New instruments allow for the noninvasive measurement of retinal oxygen saturation in humans. The present study was designed to investigate the retinal oxygen saturation in patients with chronic obstructive pulmonary disease (COPD). This was also done in an effort to test the validity of retinal oxygenation measurements with a retinal vessel analyzer. METHODS In all, 16 patients with severe COPD grade 4 who were on long-term oxygen treatment were included in the study. For each patient two identical study days were scheduled. Measurements of retinal arterial and venous oxygen saturation were done using a commercially available instrument for retinal oxygen analysis. Peripheral arterial oxygen saturation values were analyzed with pulse oximetry and via a capillary blood sample drawn from the earlobe. Measurements were performed during oxygen treatment and during a period without oxygen supplementation. Analysis of all images for retinal oxygen saturation quantification was done by a masked investigator. Analysis was done using Pearsons correlation and a multivariate regression model. RESULTS Arterial and venous retinal oxygen saturation decreased significantly after the cessation of the oxygen therapy. The arteriovenous oxygen difference was unchanged while breathing ambient air or pure oxygen-enriched air. With both Pearsons correlation and the multivariate model, we found significant positive correlation coefficients between retinal arterial and peripheral arterial oxygen saturation as assessed with pulse oximetry as well as between retinal arterial and peripheral arterial oxygen saturation measured in blood samples. The change of oxygen saturation after discontinuation of oxygen supplementation showed a good correlation between retinal arterial oxygen saturation and peripheral arterial oxygen saturation (r = 0.53, P < 0.05). Reproducibility on the two study days was high. DISCUSSION The present study shows a good correlation between retinal arterial and peripheral arterial oxygen saturation indicating good validity of the technique. (ClinicalTrials.gov number, NCT00999024.).

Regulation of retinal oxygen metabolism in humans during graded hypoxia.

Animal experiments indicate that the inner retina keeps its oxygen extraction constant despite systemic hypoxia. For the human retina no such data exist. In the present study we hypothesized that systemic hypoxia does not alter inner retinal oxygen extraction. To test this hypothesis we included 30 healthy male and female subjects aged between 18 and 35 years. All subjects were studied at baseline and during breathing 12% O₂ in 88% N₂ as well as breathing 15% O₂ in 85% N₂. Oxygen saturation in a retinal artery (SO₂art) and an adjacent retinal vein (SO₂vein) were measured using spectroscopic fundus reflectometry. Measurements of retinal venous blood velocity using bidirectional laser Doppler velocimetry and retinal venous diameters using a Retinal Vessel Analyzer (RVA) were combined to calculate retinal blood flow. Oxygen and carbon dioxide partial pressure were measured from earlobe arterialized capillary blood. Retinal blood flow was increased by 43.0 ± 23.2% (P < 0.001) and 30.0 ± 20.9% (P < 0.001) during 12% and 15% O₂ breathing, respectively. SO₂art as well as SO₂vein decreased during both 12% O₂ breathing (SO₂art: -11.2 ± 4.3%, P < 0.001; SO₂vein: -3.9 ± 8.5%, P = 0.012) and 15% O₂ breathing (SO₂art: -7.9 ± 3.6%, P < 0.001; SO₂vein: -4.0 ± 7.0%, P = 0.010). The arteriovenous oxygen difference decreased during both breathing periods (12% O2: -28.9 ± 18.7%; 15% O₂: -19.1 ± 16.7%, P < 0.001 each). Calculated oxygen extraction did, however, not change during our experiments (12% O₂: -2.8 ± 18.9%, P = 0.65; 15% O₂: 2.4 ± 15.8%, P = 0.26). Our results indicate that in healthy humans, oxygen extraction of the inner retina remains constant during systemic hypoxia.

Reproducibility of retinal vessel oxygen saturation measurements in healthy young subjects

Purpose:  An adequate oxygenation and perfusion is essential for the function of the inner retina. Recently, several techniques for the measurement of retinal oxygen saturation became available. We set out to evaluate reproducibility of the measurements using a modified Retinal Vessel Analyzer.