Gerhard Garhöfer

Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes

Background/aim: Stimulation of the retina with flickering light increases retinal arterial and venous diameters in animals and humans, indicating a tight coupling between neural activity and blood flow. The aim of the present study was to investigate whether this response is altered in patients with insulin dependent diabetes mellitus. Methods: 26 patients with diabetes mellitus with no or mild non-proliferative retinopathy and 26 age and sex matched healthy volunteers were included in the study. Retinal vessel diameters were measured continuously with the Zeiss retinal vessel analyser. During these measurements three episodes of square wave flicker stimulation periods (16, 32, and 64 seconds; 8 Hz) were applied through the illumination pathway of the vessel analyser. Results: In retinal arteries, the response to stimulation with diffuse luminance flicker was significantly diminished in diabetic patients compared to healthy volunteers (ANOVA, p<0.0031). In non-diabetic controls flicker stimulation increased retinal arterial diameters by +1.6% (1.8%) (mean, p<0.001 v baseline), +2.8% (SD 2.2%) (p<0.001) and +2.8% (1.6%) (p<0.001) during 16, 32, and 64 seconds of flicker stimulation, respectively. In diabetic patients flicker had no effect on arterial vessel diameters: +0.1% (3.1%) (16 seconds, p = 0.9), +1.1% (2.7%) (32 seconds, p = 0.07), +1.0% (2.8%) (64 seconds, p = 0.1). In retinal veins, the response to flicker light was not significantly different in both groups. Retinal venous vessel diameters increased by +0.7% (1.6%) (16 seconds, p<0.05), +1.9% (2.3%) (32 seconds, p<0.001) and 1.7% (1.8%) (64 seconds, p<0.001) in controls during flicker stimulation. Again, no increase was observed in the patients group: +0.6% (2.4%), +0.5% (1.5%), and +1.2% (3.1%) (16, 32, and 64 seconds, respectively). Conclusion: Flicker responses of retinal arteries and veins are abnormally reduced in patients with IDDM with no or mild non-proliferative retinopathy. Whether this diminished response can be attributed to altered retinal vascular reactivity or to decreased neural activity has yet to be clarified.

Use of the retinal vessel analyzer in ocular blood flow research

Acta Ophthalmol. 2010: 88: 717–722

The complex interaction between ocular perfusion pressure and ocular blood flow – Relevance for glaucoma

Glaucoma is an optic neuropathy of unknown origin. The most important risk factor for the disease is an increased intraocular pressure (IOP). Reducing IOP is associated with reduced progression in glaucoma. Several recent large scale trials have indicated that low ocular perfusion pressure (OPP) is a risk factor for the incidence, prevalence and progression of the disease. This is a strong indicator that vascular factors are involved in the pathogenesis of the disease, a hypothesis that was formulated 150 years ago. The relation between OPP and blood flow to the posterior pole of the eye is, however, complex, because of a phenomenon called autoregulation. Autoregulatory processes attempt to keep blood flow constant despite changes in OPP. Although autoregulation has been observed in many experiments in the ocular vasculature the mechanisms underlying the vasodilator and vasoconstrictor responses in face of changes in OPP remain largely unknown. There is, however, recent evidence that the human choroid regulates its blood flow better during changes in blood pressure induced by isometric exercise than during changes in IOP induced by a suction cup. This may have consequences for our understanding of glaucoma, because it indicates that blood flow regulation is strongly dependent not only on OPP, but also on the level of IOP itself. Indeed there is data indicating that reduction of IOP by pharmacological intervention improves optic nerve head blood flow regulation independently of an ocular vasodilator effect.

Endothelial dysfunction in glaucoma

Glaucoma is a group of ocular diseases characterized by optic neuropathy associated with loss of the retinal nerve fibre layer and re‐modelling of the optic nerve head, and a subsequent particular pattern of visual field loss. Increased intraocular pressure is the most important risk factor for the disease, but the pathogenesis of glaucoma is not monofactorial. Among other factors, ischaemia and vascular dysregulation have been implicated in the mechanisms underlying glaucoma. The vascular endothelium plays an important role in the regulation of ocular blood flow and pathological alterations of vascular endothelial cells may induce ischaemia and dysregulation. The present review summarizes our current evidence of endothelial dysfunction in glaucoma. This is of interest because endothelial dysfunction is a good prognostic factor for progression in several diseases. Although such data are lacking for glaucoma, endothelial dysfunction may provide an attractive target for therapeutic intervention in open‐angle glaucoma and other vascular disorders of the eye.

Ocular perfusion pressure and ocular blood flow in glaucoma.

Graphical abstract Highlights ► Reduced ocular perfusion pressure is a risk factor for the prevalence, incidence and progression of glaucoma. ► The death of retinal ganglion cells appears to involve primary and secondary insults. ► Reduced OPP may enhance both primary and secondary insults. ► Abnormal autoregulation and neurovascular coupling may lead to ganglion cell death.

Effects Of Lutein Supplementation On Macular Pigment Optical Density And Visual Acuity In Patients With Age-related Macular Degeneration

PURPOSE There is evidence from several large-scale clinical trials that reduced intake of lutein, a major component of the macular pigment, is a risk factor for the development of AMD. In the present study (LISA; Lutein Intervention Study Austria) it was hypothesized that lutein supplementation increases macular pigment optical density (MPOD). In addition, an investigation was conducted into whether lutein supplementation improves visual acuity (VA) and macular function (mean differential light threshold; MDLT), as assessed with microperimetry. METHODS One hundred twenty-six patients with AMD (AREDS [Age-related Eye Disease Study] stages 2, 3, and 4) were included in this randomized (2:1), placebo-controlled, double-masked parallel group study. Lutein or placebo was administered for 6 months. MPOD was measured with a custom-built reflectometer. VA was assessed with ETDRS (Early Treatment Diabetic Retinopathy Study) charts, and MDLT was assessed with a microperimeter. RESULTS Lutein significantly increased MPOD by 27.9% ± 2.9% (P < 0.001 versus placebo). No significant effect of lutein supplementation on MDLT or VA was seen, although a tendency toward an increase was seen for both parameters (MDLT, P = 0.096 versus placebo; VA, P = 0.070 versus placebo). A significant correlation was found, however, between the increase in MPOD after 6 months and the increase in MDLT after 6 months (r = 0.25, P = 0.027), as well as between the increase in MPOD after 6 months and the increase in VA after 6 months (r = 0.27, P = 0.013). CONCLUSIONS The present study demonstrates that lutein supplementation increases MPOD, as assessed with an objective METHOD The correlation between the change in MPOD and the change in VA and MDLT indicates that patients who show a pronounced increase in MPOD also benefit in terms of visual function. (ClinicalTrials.gov number, NCT00879671.).

Effect of inhalation of different mixtures of O2 and CO2 on retinal blood flow

Aim: To determine the effects of various mixtures of O2 and CO2 on retinal blood flow in healthy subjects. Methods: A randomised, double masked, four way crossover trial was carried out in 12 healthy male non-smoking subjects. Gas mixtures (100% O2, 97.5% O2 + 2.5% CO2, 95% O2 + 5% CO2, and 92% O2 + 8% CO2) were administered for 10 minutes each. Two non-invasive methods were used: laser Doppler velocimetry (LDV) for measurement of retinal blood velocity and fundus imaging with the Zeiss retinal vessel analyser (RVA) for the assessment of retinal vessel diameters. Arterial pH, pCO2, and pO2 were determined with an automatic blood gas analysis system. Retinal blood flow through a major temporal vein was calculated. Results: Retinal blood velocity, retinal vessel diameter, and retinal blood flow decreased during all breathing periods (p <0.001 each). Administration of 92% O2 + 8% CO2 significantly increased SBP, MAP, and PR (p <0.001 each, versus baseline), whereas the other gas mixtures had little effect on systemic haemodynamics. Addition of 2.5%, 5%, and 8% CO2 to oxygen caused a marked decrease in pH and an increase in pCO2 (p <0.001 versus pure oxygen). Conclusions: Breathing of pure oxygen and oxygen in combination with carbon dioxide significantly decreases retinal blood flow. Based on these data the authors speculate that hyperoxia induced vasoconstriction is not due to changes in intravascular pH and cannot be counteracted by an intravascular increase in pCO2.

Use of colour Doppler imaging in ocular blood flow research.

The main objective of this report is to encourage consistent quality of testing and reporting within and between centres that use colour Doppler imaging (CDI) for assessment of retrobulbar blood flow. The intention of this review is to standardize methods in CDI assessment that are used widely, but not to exclude other approaches or additional tests that individual laboratories may choose or continue to use.

Estimation of Ocular Rigidity Based on Measurement of Pulse Amplitude Using Pneumotonometry and Fundus Pulse Using Laser Interferometry in Glaucoma

PURPOSE There is evidence from theoretical models and animal studies that the biomechanical properties of the optic nerve head and the sclera play a role in the pathophysiology of glaucoma. There are, however, only a few data available that demonstrate such biomechanical alterations in vivo. In this study, the hypothesis was that patients with primary open-angle glaucoma (POAG) have an abnormal ocular structural stiffness based on measurements of intraocular pressure amplitude and ocular fundus pulsation amplitude (FPA). METHODS Seventy patients with POAG and 70 healthy control subjects matched for age, sex, intraocular pressure and systemic blood pressure were included. The ocular PA and pulsatile ocular blood flow were assessed with pneumotonometry. The FPA was measured by using laser interferometry. Based on the Friedenwald equation, a coefficient of ocular rigidity (E1) was calculated relating PA to FPA. RESULTS There was no difference in systemic blood pressure, intraocular pressure, and ocular perfusion pressure (OPP) between the patients with glaucoma and the healthy control subjects. Both, FPA and PA were lower in the patients with glaucoma than in the control subjects. The calculated factor E1 was significantly higher in the patients with POAG (0.0454 +/- 0.0085 AU) than in the control subjects (0.0427 +/- 0.0058 AU, P = 0.03). Multiple regression analysis revealed that E1 was independent of age and sex, and correlated only slightly with OPP. CONCLUSIONS The present study indicates increased ocular rigidity in patients with POAG. This is compatible with a number of previous animal experiments and supports the concepts that the biomechanical properties of ocular tissues play a role in the diseases process.

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.