Alina Popa-Cherecheanu

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.

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.).

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.

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.

Gender differences in ocular blood flow.

Abstract Gender medicine has been a major focus of research in recent years. The present review focuses on gender differences in the epidemiology of the most frequent ocular diseases that have been found to be associated with impaired ocular blood flow, such as age-related macular degeneration, glaucoma and diabetic retinopathy. Data have accumulated indicating that hormones have an important role in these diseases, since there are major differences in the prevalence and incidence between men and pre- and post-menopausal women. Whether this is related to vascular factors is, however, not entirely clear. Interestingly, the current knowledge about differences in ocular vascular parameters between men and women is sparse. Although little data is available, estrogen, progesterone and testosterone are most likely important regulators of blood flow in the retina and choroid, because they are key regulators of vascular tone in other organs. Estrogen seems to play a protective role since it decreases vascular resistance in large ocular vessels. Some studies indicate that hormone therapy is beneficial for ocular vascular disease in post-menopausal women. This evidence is, however, not sufficient to give any recommendation. Generally, remarkably few data are available on the role of sex hormones on ocular blood flow regulation, a topic that requires more attention in the future.

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.

A double-masked randomized crossover study comparing the effect of latanoprost/timolol and brimonidine/timolol fixed combination on intraocular pressure and ocular blood flow in patients with primary open-angle glaucoma or ocular hypertension.

PURPOSE Ocular blood flow dysregulation has been implicated in the pathogenesis of glaucoma. Whereas the effect of single antiglaucoma substances on ocular blood flow has been addressed in various experiments, evidence for fixed combinations is sparse. In the present study, we set out to compare the effects of latanoprost 0.005%/timolol 0.5% (LT) fixed combination and brimonidine 0.2%/timolol 0.5% (BT) fixed combination on intraocular pressure (IOP) and ocular blood flow. METHODS In the present study, which followed a randomized, double-masked 2-way crossover design, 16 patients with primary open-angle glaucoma and 2 patients with ocular hypertension were included. The patients underwent a 6-week treatment with LT and a 6-week treatment with BT after a washout for previous antiglaucoma medication. Optic nerve head blood flow (ONHBF) was measured using laser Doppler flowmetry; retrobulbar flow velocities were measured using color Doppler imaging in the ophthalmic artery, the central retinal artery, and the posterior ciliary arteries. IOP was measured at 8 AM, 12 PM, and 4 PM. RESULTS The mean baseline IOP was 25.3±2.8 mmHg. Both drugs were equally effective in reducing IOP (LT: -35.0%±10.0%; BT: -33.6%±8.8%, P=0.463 between groups). In addition, no difference in ocular perfusion pressure was observed between the 2 treatment groups (P=0.1, between groups). Neither LT nor BT altered ONHBF (P=0.4, baseline vs. treatment) and no effect on flow velocities in the retrobulbar vessels was seen with either of the 2 treatments. CONCLUSIONS In the present study, a 6-week treatment with LT or BT was equally effective in reducing IOP. In addition, none of the administered drugs induced a significant effect on ocular blood flow parameters.

Optic nerve head and retinal blood flow regulation during isometric exercise as assessed with laser speckle flowgraphy

The aim of the present study was to investigate regulation of blood flow (BF) in the optic nerve head (ONH) and a peripapillary region (PPR) during an isometric exercise-induced increase in ocular perfusion pressure (OPP) using laser speckle flowgraphy (LSFG) in healthy subjects. For this purpose, a total of 27 subjects was included in this study. Mean blur rate in tissue (MT) was measured in the ONH and in a PPR as well as relative flow volume (RFV) in retinal arteries (ART) and veins (VEIN) using LSFG. All participants performed isometric exercise for 6 minutes during which MT and mean arterial pressure were measured every minute. From these data OPP and pressure/flow curves were calculated. Isometric exercise increased OPP, MTONH and MTPRR. The relative increase in OPP (78.5 ± 19.8%) was more pronounced than the increase in BF parameters (MTONH: 18.1 ± 7.7%, MTPRR: 21.1 ± 8.3%, RFVART: 16.5 ±12.0%, RFVVEIN: 17.7 ± 12.4%) indicating for an autoregulatory response of the vasculature. The pressure/flow curves show that MTONH, MTPRR, RFVART, RFVVEIN started to increase at OPP levels of 51.2 ± 2.0%, 58.1 ± 2.4%, 45.6 ± 1.9% and 45.6 ± 1.9% above baseline. These data indicate that ONHBF starts to increase at levels of approx. 50% increase in OPP: This is slightly lower than the values we previously reported from LDF data. Signals from the PPR may have input from both, the retina and the choroid, but the relative contribution is unknown. In addition, retinal BF appears to increase at slightly lower OPP values of approximately 45%. LSFG may be used to study ONH autoregulation in diseases such as glaucoma. Trial Registration: ClinicalTrials.gov NCT02102880

Effect of different lubricant eye gels on tear film thickness as measured with ultrahigh-resolution optical coherence tomography

To compare the effect of a single drop of different lubricant eye gels on tear film thickness (TFT) as measured with ultrahigh‐resolution optical coherence tomography (UHR‐OCT) in patients with mild‐to‐moderate dry eye disease (DED).