Effect of intravitreal injections due to neovascular age-related macular degeneration on retinal nerve fiber layer thickness and minimum rim width: a cross sectional study.

PURPOSE: The present study tested the hypothesis that repeated anti-VEGF injections are associated with reduced retinal nerve fiber layer (RNFL) and minimum rim width (MRW) of the optic nerve head. PATIENTS AND METHODS: Sixty-six patients with a history of intravitreal injections due to neovascular age-related macular degeneration were included. RNFL and MRW were measured using optical coherence tomography (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany). RESULTS: Mean global RNFL was 90.62 µm and both RNFL as well as MRW significantly decreased with advanced age (p = 0.005 and p = 0.019, respectively). Correlating for the number of injections, no significant impact on RNFL was found globally (p = 0.642) or in any of the sectors. In contrast, however, global MRW was significantly reduced with increasing numbers of intravitreal injections (p = 0.012). The same holds true when adjusted for the confounding factor age (RNFL p = 0.566 and MRW p = 0.023). CONCLUSION: Our study shows that repeated intravitreal injections due to choroidal neovascularization seem to have a deleterious effect on MRW but not on RNFL. This suggests that MRW is a more sensitive marker than RNFL for evaluating the effect of frequent intravitreal injections on the optic nerve head since it seems to be the first structure affected.

Ocular manifestation of hand, foot, and mouth disease : A case series.

Virus-related illnesses are a common phenomenon, especially in the colder months of the year. They usually manifest with cough, cold, and other flu-associated symptoms. They affect people of all ages and genders. In recent years, also virus-associated ocular symptoms have been documented repeatedly. One of the viruses known to cause these is the Coxsackievirus A, which causes hand, foot, and mouth disease. Three cases of these virus-associated macular changes are described below. In all three cases, the symptoms occurred unilaterally and with little time delay to the virus-typical general changes. Complete functional remission occurred in all cases, whereby permanent changes in the pigment epithelium were observed.

Brolucizumab for pre-treated patients with choroidal neovascularization and signs of tachyphylaxis to aflibercept and bevacizumab.

PURPOSE: Treatment of choroidal neovascularization due to age-related macular degeneration is a challenging topic since an increasing number of patients show reduced morphological response to conventional treatment with intravitreal injections. The present study tested the hypothesis that the newly introduced anti-VEGF antibody brolucizumab does not only show promising results in pre-treated patients but is also a viable option in cases of tachyphylaxis to aflibercept or bevacizumab. METHODS: Thirty-six eyes of 34 patients with a history of at least 10 anti-VEGF injections as well as persistent retinal fluid following the past 5 monthly injections with aflibercept and bevacizumab prior to first treatment with brolucizumab were included in the study. Morphological and functional treatment response was compared before and after switching to brolucizumab. RESULTS: Mean best-corrected visual acuity did not significantly change after treatment with brolucizumab. In contrast, central retinal thickness significantly decreased 4 weeks after treatment with brolucizumab from 340.36 to 282.22 µm (p < 0.001) as well as pigment epithelial detachment from 346.73 to 280.47 µm (p < 0.001). In 24 eyes (66.67%), complete resolution of intra-and subretinal fluid was observed after a single dose of brolucizumab. No serious adverse events, such as intraocular inflammation and retinal vasculitis, were reported after a single injection of brolucizumab. CONCLUSION: Brolucizumab is not only effective in treatment-naïve patients as shown in the pivotal HAWK and Harrier trials, but also in pre-treated patients as seen in the present study. Our data also suggest that brolucizumab is potent in patients with signs of tachyphylaxis to other anti-VEGF agents and thus a viable treatment option.

Quality of life in patients with glaucoma assessed by 39-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-39).

PURPOSE: The purpose of the study was to evaluate glaucoma patients' quality of life (QoL) as measured by National Eye Institute Visual Functioning Questionnaire (NEI VFQ-39) and to examine the influence of patient characteristics and disease stage measured by visual field loss on QoL. METHODS: A prospective survey of patients with an established diagnosis of glaucoma without concomitant eye disease was conducted. Patients completed a validated German translation of the NEI VFQ-39 questionnaire. Visual field defects were graded using simplified Hodapp's classification. VFQ-39 scores were compared between groups. RESULTS: We included 60 patients, 28 of whom were classified as early, 16 as moderate, and 16 as advanced stage glaucoma. No differences were found in sex, visual acuity of the better eye, near visual acuity, treatment type, and VFQ rating for "General health" between groups. In the advanced group, VFQ-39 (p = 0.01) and VFQ-25 (p = 0.01) composite scores were significantly lower than in the early group. In addition, distance visual acuity (worse eye) was significantly worse in the advanced than in early stage patients (p = 0.04, Table 4). Patients with advanced glaucoma had significantly lower VFQ-39 subscale scores for "General vision" (p = 0.023), "Near activities" (p = 0.02), "Distance activities" (p = 0.003), "Mental health" (p = 0.008), "Driving" (p = 0.011), and "Peripheral vision" (p = 0.017) than early glaucoma patients. Patients with moderate glaucoma had significantly lower scores for "Distance activities" (p = 0.028) than early stage glaucoma patients. VFI (better eye: r = 0.65, worse eye: r = 0.5) and MD (better eye: r = 0.6, worse eye: r = 0.49) were significantly (p < 0.001) correlated with VFQ-39. Correlations of VFQ-39 with age, VFI intereye difference, distance, or near visual acuity were not significant. CONCLUSION: Compared to patients with early glaucoma, patients with moderate stage glaucoma reported higher difficulty with distance activities (e.g. navigating an urban environment, watching television). Patients with advanced stage glaucoma reported lower VFQ-39 composite and subscale scores relevant to topics of general vision complaints, difficulties with near work and finding things, navigating urban outdoor environments, and watching television; worries and frustrations with vision difficulties; and difficulty driving and noticing objects off to the side of footpaths. Visual field indices MD and VFI were strongly correlated with QoL as assessed by VFQ-39. VA was not correlated with QoL. In patients with moderate or advanced glaucoma, QoL may be significantly impacted by glaucomatous visual field defects even when visual acuity is preserved.

Method comparison of two non-invasive dual-wavelength spectrophotometric retinal oximeters in healthy young subjects during normoxia.

PURPOSE: Spectrophotometric retinal oximetry is a non-invasive technology for measuring oxygen saturation in arterioles and venules (SaO2 , SvO2 ). We compared two commercially available systems: the Oxymap T1 (Oxymap ehf., Reykjavik, Iceland) and the Dynamic Vessel Analyzer (DVA, Imedos, Jena, Germany). METHODS: Twenty healthy adults were included after giving informed consent. Two measurement cycles 30 min apart, including Oxymap T1, DVA, arterialized capillary blood draw of the earlobe (ScO2 ) and peripheral oxygen saturation using finger pulse oximetry (SpO2 ) were scheduled. RESULTS: SaO2 (p > 0.0004) but not SvO2 (p < 0.05) was statistically significantly different between the retinal oximeters used. Agreement between devices using repeated SO2 measurements resulted in a standard deviation (SD) of differences of 3.5% in retinal arterioles and 4.8% in venules. Bland-Altman plot using the mean of a participant's two measurements from each device showed an average mean difference of 4.4% (95% confidence limits of agreement: -8.6 to 17.4) and -3.3% (95% confidence limits of agreement: -28.8 to 22.2) for SaO2 and SvO2 , respectively. Comparison of mean SaO2 and SvO2 with mean ScO2 and SpO2 indicated that SO2 measurements were generally higher in ScO2 and SpO2 . CONCLUSION: This study shows very good repeatability for both devices, which is consistent with the literature. However, it does not show sufficient concordance between SaO2 measurements from both devices, indicating that patients should be followed by one device only. Differences in absorbance wavelengths used and image post-processing may explain the differences.

Psychophysical Vision Simulation of Diffractive Bifocal and Trifocal Intraocular Lenses.

PURPOSE: The visual performance of monofocal, bifocal, and trifocal intraocular lenses was evaluated by human individuals using a vision simulator device. This allowed investigation of the visual impression after cataract surgery, without the need actually to implant the lenses. METHODS: The randomized, double-masked, three-way cross-over study was conducted on 60 healthy male and female subjects aged between 18 and 35 years. Visual acuity (Early Treatment Diabetic Retinopathy Study; ETDRS) and contrast sensitivity tests (Pelli-Robson) under different lighting conditions (luminosities from 0.14-55 cd/m2, mesopic to photopic) were performed at different distances. RESULTS: Visual acuity tests showed no difference for corrected distance visual acuity data of bi- and trifocal lens prototypes (P = 0.851), but better results for the trifocal than for the bifocal lenses at distance corrected intermediate (P = 0.021) and distance corrected near visual acuity (P = 0.044). Contrast sensitivity showed no differences between bifocal and trifocal lenses at the distant (P = 0.984) and at the near position (P = 0.925), but better results for the trifocal lens at the intermediate position (P = 0.043). Visual acuity and contrast sensitivity showed a strong dependence on luminosity (P < 0.001). CONCLUSIONS: At all investigated distances and all lighting conditions, the trifocal lens prototype often performed better, but never worse than the bifocal lens prototype. TRANSLATIONAL RELEVANCE: The vision simulator can fill the gap between preclinical lens development and implantation studies by providing information of the perceived vision quality after cataract surgery without implantation. This can reduce implantation risks and promotes the development of new lens concepts due to the cost effective test procedure.

Antioxidative capacity of a dietary supplement on retinal hemodynamic function in a human lipopolysaccharide (LPS) model.

PURPOSE: Beneficial effects of dietary supplements in age-related macular degeneration (AMD) are related to antioxidative properties. In the Age-Related Eye Disease Study 1 (AREDS 1), a reduced progression to late stage AMD was found using vitamin C, E, zinc, and ß-carotene. We showed previously that the AREDS 1 formulation restores the O2-induced retinal vasoconstrictor response of retinal vessels in a human endotoxin (lipopolysaccharide [LPS]) model. METHODS: We hypothesized that the abnormal O2-induced retinal red blood cell (RBC) flow response can be modulated by a different formulation (vitamin C, E, and zinc, lutein/zeaxanthin, selenium, taurine, Aronia extract, and omega-3 free fatty acids). A total of 43 healthy subjects was included in this randomized, double masked, placebo-controlled parallel group study. The reactivity of retinal arterial and venous diameter, RBC velocity, and flow to 100% O2 breathing was investigated in the absence and presence of 2 ng/kg LPS. Between the two study days was a 14-day period of daily dietary supplement intake. RESULTS: The decrease in retinal arterial diameter, RBC velocity, and flow during 100% O2 breathing was diminished significantly after LPS infusion. Dietary supplement intake for 14 days almost restored the response of retinal hemodynamic parameters to 100% O2 after LPS administration. This effect was significant for retinal arterial diameter (P = 0.03 between groups), and RBC velocity and flow (each P < 0.01 between groups). CONCLUSIONS: The present data indicate restoring of the RBC flow response to 100% O2 after LPS administration. This is likely due to an amelioration of endothelial dysfunction resulting from oxidative stress, a factor involved in AMD pathophysiology. (ClinicalTrials.gov number, NCT00914576.).

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.

Effect of increased oxygen tension on flicker-induced vasodilatation in the human retina.

In the retina, blood flow and neural activity are tightly coupled. Stimulation of the retina with flickering light is accompanied by an increase in blood flow. The current study seeks to investigate whether an increase in oxygen tension modulates flicker (FL)-induced vasodilatation in the human retina. A total of 52 healthy volunteers were included. Via a breathing mask, 100% oxygen (O(2)) was administered in one, a mixture of 8% carbon dioxide and 92% oxygen (C/O) in a second cohort. Retinal vessel diameters were measured with a Vessel Analyzer and FL responses were assessed before and during the breathing periods. At baseline, FL stimulation increased retinal vessel diameters by +3.7±2.3% in arteries and by +5.1±3.7% in veins. Breathing of C/O led to a decrease in arterial (-9.0±6.9%) and venous (-11.3±5.9%) vessel calibers. Flicker response was increased to 5.7±2.5% in arteries and to 8.6±4.1% in veins. Breathing of pure O2 induced a vasoconstriction of vessel diameters by -14.0±5.3% in arteries and -18.4±7.0% in veins and increased FL responses in arteries (+6.2±2.8%) and veins (+7.2±3.1%). Systemic hyperoxia increases FL-induced retinal vasodilatation in the retina. The mechanism by which oxygen modulates the hyperemic response to FL stimulation remains to be elucidated.

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.).

Flicker-induced retinal vasodilatation is not dependent on complement factor H polymorphism in healthy young subjects.

PURPOSE: The complement factor H (CFH) tyrosine 402 histidine (Y402H, rs1061170) variant is known to be significantly associated with age-related macular degeneration (AMD). Whether this genetic variant may impact retinal blood flow regulation is largely unknown. This study investigated whether flicker-induced vasodilation, an indicator for the coupling between neural activity and blood flow, is altered in subjects carrying the rs1061170 risk allele. METHODS: One hundred healthy subjects (aged between 18 and 45 years) were included in this study. Retinal blood flow regulation was tested by assessing retinal vessel calibres in response to stimulation with diffuse flicker light. Retinal vascular flicker responses were determined with a Dynamic Vessel Analyzer (DVA). In addition, genotyping for rs1061170 was performed. RESULTS: Eighteen subjects were homozygous for the risk allele C, 50 were homozygous for the ancestral allele T, and 31 subjects were heterozygous (CT). One subject had to be excluded from data evaluation, as no genetic analysis could be performed due to technical difficulties. Baseline diameters of retinal arteries (p = 0.39) and veins (p = 0.64) were comparable between the three groups. Flicker-induced vasodilation in both retinal arteries (p = 0.38) and retinal veins (p = 0.62) was also comparable between the three studied groups. CONCLUSIONS: Our data indicate that homozygous healthy young carriers of the C risk allele at rs1061170 do not show abnormal flicker-induced vasodilation in the retina. This suggests that the high-risk genetic variant of CFH polymorphism does not impact neuro-vascular coupling in healthy subjects.

Retinal hemodynamic effects of antioxidant supplementation in an endotoxin-induced model of oxidative stress in humans.

PURPOSE: The Age-Related Eye Disease Study 1 (AREDS 1) has shown that nutritional supplementation with antioxidants and zinc modifies the natural course of AMD. It is presumed that the supplements exert their beneficial effects by ameliorating oxidative stress due to the scavenging of reactive oxygen species (ROS). We have shown in a human model that under oxidative stress induced by administration of lipopolysaccharide (LPS) the vasoconstrictor response of retinal vessels to oxygen breathing is diminished. This reduced vascular response to hyperoxia was previously shown to be normalized by the AREDS 1 supplements. In the present study, we tested the hypothesis that the response can also be restored by a different antioxidant formulation. METHODS: This randomized, double-masked, placebo-controlled parallel group study included 40 healthy volunteers. On each study day, retinal red blood cell (RBC) flow and the reactivity of retinal RBC flow to hyperoxia were investigated in the absence and presence of 2 ng/kg LPS. Between the two study days, subjects received either the supplement or placebo for 14 days. RESULTS: Before supplementation LPS reduced retinal arterial vasoconstriction (P < 0.001) and reactivity of retinal RBC flow (P = 0.03) in response to 100% oxygen breathing. Two weeks of supplementation did not affect baseline retinal RBC flow, but normalized the LPS-induced change in the response to hyperoxia. The arterial vasoconstrictor response during LPS and 100% oxygen breathing was 4.1 ± 1.0% after administration of placebo and 10.6 ± 0.9% after supplementation (P = 0.005). The response of RBC flow to 100% oxygen breathing during LPS was 52.2 ± 2.1% after administration of placebo and 59.5 ± 2.0% after supplementation (P = 0.033). CONCLUSIONS: Our data show that the supplement used in the present study can normalize the response of retinal RBC flow to hyperoxia under LPS administration. This indicates that supplementation can prevent endothelial dysfunction induced by oxidative stress, which is assumed to play a role in the pathophysiology of AMD. (ClinicalTrials.gov number, NCT00914576.).

Optic nerve head blood flow autoregulation during changes in arterial blood pressure in healthy young subjects.

AIM: In the present study the response of optic nerve head blood flow to an increase in ocular perfusion pressure during isometric exercise was studied. Based on our previous studies we hypothesized that subjects with an abnormal blood flow response, defined as a decrease in blood flow of more than 10% during or after isometric exercise, could be identified. METHODS: A total of 40 healthy subjects were included in this study. Three periods of isometric exercise were scheduled, each consisting of 2 minutes of handgripping. Optic nerve head blood flow was measured continuously before, during and after handgripping using laser Doppler flowmetry. Blood pressure was measured non-invasively in one-minute intervals. Intraocular pressure was measured at the beginning and the end of the measurements and ocular perfusion pressure was calculated as 2/3*mean arterial pressure -intraocular pressure. RESULTS: Isometric exercise was associated with an increase in ocular perfusion pressure during all handgripping periods (p < 0.001). By contrast no change in optic nerve head blood flow was seen. However, in a subgroup of three subjects blood flow showed a consistent decrease of more than 10% during isometric exercise although their blood pressure values increased. In addition, three other subjects showed a consistent decline of blood flow of more than 10% during the recovery periods. CONCLUSION: Our data confirm previous results indicating that optic nerve head blood flow is autoregulated during an increase in perfusion pressure. In addition, we observed a subgroup of 6 subjects (15%) that showed an abnormal response, which is in keeping with our previous data. The mechanisms underlying this abnormal response remain to be shown.

Role of nitric oxide in optic nerve head blood flow regulation during an experimental increase in intraocular pressure in healthy humans.

The present study set out to investigate whether nitric oxide, a potent vasodilator, is involved in the regulatory processes in optic nerve head blood flow during an experimental increase in intraocular pressure (IOP). The study was conducted in a randomized, double-masked, placebo-controlled, three way cross-over design. 12 healthy subjects were scheduled to receive either L-NMMA (an unspecific nitric oxide synthase inhibitor), phenylephrine (an α-adrenoceptor agonist) or placebo on three different study days. Optic nerve head blood flow was measured using laser Doppler flowmetry and IOP was increased stepwise with a suction cup. Mean arterial pressure (MAP) and IOP were measured non-invasively and ocular perfusion pressure (OPP) was calculated as OPP = 2/3 MAP-IOP. Administration of L-NMMA and phenylephrine significantly increased MAP and therefore OPP at rest (p < 0.01). L-NMMA significantly reduced baseline blood flow in the optic nerve head (p < 0.01). Application of the suction cup induced a significant increase in IOP and a decrease in OPP (p < 0.01). During the stepwise increase in IOP, some autoregulatory potential was observed until OPP decreased approximately -30% below baseline. None of the administered substances had an effect on this autoregulatory behavior (p = 0.49). The results of the present study confirm that the human optic nerve head shows some regulatory capacity during a decrease in OPP. Nitric oxide is involved in the regulation of basal vascular tone in the optic nerve head but does not seem to be involved in the regulatory mechanisms during an acute increase in IOP in young healthy subjects.

Regulation of optic nerve head blood flow during combined changes in intraocular pressure and arterial blood pressure.

In the choroid, there is evidence that blood flow does not only depend on ocular perfusion pressure (OPP), but also on absolute mean arterial pressure (MAP) and intraocular pressure (IOP). The present study included 40 healthy subjects to investigate whether such behavior is also found in the optic nerve head (ONH). The ONH blood flow (ONHBF) was studied using laser Doppler flowmetry during a separate increase in IOP and MAP as well as during a combined elevation. Mean arterial pressure was increased by isometric exercise and IOP by the suction method. During both, the change in ONHBF was less pronounced than the change in OPP indicating autoregulation. Correlation analysis was performed for the combined experiments after pooling all data according to IOP and MAP values. A correlation between ONHBF and MAP was found at IOPs 25 mm Hg (P<0.001), but not at IOPs>25 mm Hg (P=0.79). Optic nerve head blood flow and IOP were significantly correlated (P<0.001), and ONHBF was only slightly dependent on MAP. The data of the present study indicate a complex regulation of ONHBF during combined changes in MAP and IOP. Our results may be compatible with myogenic mechanisms underlying autoregulation, and indicate better ONHBF regulation during an increase in MAP than during an increase in IOP.

Alterations of choroidal blood flow regulation in young healthy subjects with complement factor H polymorphism.

A common polymorphism in the complement factor H gene (rs1061170, Y402H) is associated with a high risk of age-related macular degeneration (AMD). In the present study we hypothesized that healthy young subjects homozygous for the high-risk haplotype (CC) show abnormal choroidal blood flow (ChBF) regulation decades before potentially developing the disease. A total of 100 healthy young subjects were included in the present study, of which 4 subjects were excluded due to problems with genotyping or blood flow measurements. ChBF was measured continuously using laser Doppler flowmetry while the subjects performed isometric exercise (squatting) for 6 minutes. The increase in ChBF was less pronounced than the response in ocular perfusion pressure (OPP), indicating for some degree of choroidal blood flow regulation. Eighteen subjects were homozygous for C, 47 subjects were homozygous for T and 31 subjects were heterozygous (CT). The increase in OPP during isometric exercise was not different between groups. By contrast the increase in ChBF was more pronounced in subjects homozygous for the high risk C allele (p = 0.041). This was also evident from the pressure/flow relationship, where the increase in ChBF in homozygous C carriers started at lower OPPs as compared to the other groups. Our data indicate that the regulation of ChBF is abnormal in rs1061170 CC carriers. So far this polymorphism has been linked to age related macular degeneration (AMD) mainly via inflammatory pathways associated with the complement system dysfunction. Our results indicate that it could also be related to vascular factors that have been implicated in AMD pathogenesis.

Role of nitric oxide in optic nerve head blood flow regulation during isometric exercise in healthy humans.

PURPOSE: We determined whether administration of a nitric oxide synthase (NOS) inhibitor alters optic nerve head blood flow (ONHBF) regulation during isometric exercise in healthy subjects. METHODS: Our study was done in a randomized, placebo-controlled, double-masked, three-way crossover design. A total of 18 healthy subjects was randomized to receive either placebo, phenylephrine, or an inhibitor of NOS (L-NMMA) on three different study days. ONHBF was measured with laser Doppler flowmetry while the study participants performed isometric exercise (squatting). This was done before drug administration and during infusion of the study drugs. Mean arterial pressure (MAP) and IOP were measured noninvasively, and ocular perfusion pressure (OPP) was calculated as 2/3 MAP - IOP. RESULTS: The response in ONHBF to isometric exercise was less pronounced than the response in OPP, indicating for some autoregulatory capacity in the ONH. Administration of L-NMMA significantly decreased ONHBF at rest (P < 0.01). In contrast, inhibition of NOS did not alter the pressure-flow relationship in the ONH during an experimental increase in OPP compared to phenylephrine and placebo (P = 0.37 between groups). CONCLUSIONS: The data of our study support previous findings that ONHBF is autoregulated during an experimental increase in OPP. Nitric oxide has an important role in basal ONHBF regulation, but seems not to be involved in the autoregulatory response during an increase in OPP induced by isometric exercise. (ClinicalTrials.gov number, NCT00806741.).

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.

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 Pearson's 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 Pearson's 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.).

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.