Doreen Schmidl

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.

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.

Measurement of tear film thickness using ultrahigh-resolution optical coherence tomography.

PURPOSE To visualize the precorneal tear film with ultrahigh-resolution spectral domain optical coherence tomography, enabling quantification of tear film thickness in healthy subjects. METHODS A custom-built spectral domain optical coherence tomography system comprising a broadband titanium:sapphire laser operating at 800 nm and a high-speed charge coupled device (CCD) camera with a read-out rate of 47 kHz was used for measurement of precorneal tear film thickness. The system provides a theoretical axial resolution of 1.2 μm in tissue. The signal-to-noise ratio close to the zero delay was measured with 94 dB. A total of 26 healthy subjects were included in this study. Measurement was started immediately after blinking and averaged over a period of 1 second. In a subset of eight healthy subjects, the reproducibility of the approach was studied by measuring the tear film thickness every 10 minutes over 1 hour. RESULTS The average central tear film thickness of the measured population was 4.79 ± 0.88 μm. Reproducibility was very high, with an intraclass correlation coefficient of 0.97. A breakup of the tear film was observed in one subject after 14 seconds. CONCLUSIONS Our data indicate that the human precorneal tear film can be measured with excellent reproducibility using ultrahigh-resolution optical coherence tomography. This technique may be a valuable tool in the management of dry eye syndrome.

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.).

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.).

Effect of regular smoking on flicker induced retinal vasodilatation in healthy subjects.

BACKGROUND Habitual smoking is a risk factor for a variety of vascular diseases, including ocular pathologies. In the current study, we set out to investigate whether the regulation of retinal vascular tone is impaired in habitual smokers. For this purpose, vascular reactivity was tested during flicker light induced vasodilatation in smokers and in a non-smoking control group. METHODS In this prospective, balanced, parallel group study 24 chronic smokers (28.1 ± 3.3 years) and 24 age-matched never-smoking volunteers (28.2 ± 4.0 years) were included. Flicker induced vasodilatation was measured in major retinal arteries and veins using a retinal vessel analyzer and flicker induced changes in retinal blood velocities were assessed in retinal veins by laser Doppler velocimetry. Three flicker periods of 60s were scheduled. Blood cotinine concentration was determined and a Fagerstrom questionnaire was performed to evaluate nicotine dependency. RESULTS In non-smoking subjects, stimulation with flicker light increased retinal venous diameter by +7.7 ± 3.1%, +6.9 ± 2.9% and +7.1 ± 2.8% during the three flicker periods, respectively. Flicker induced vasodilatation in veins was significantly diminished in chronic smokers (+4.9 ± 2.4%, +6.3 ± 3.1% and +5.7 ± 3.4%, ANOVA between groups, p=0.032) as compared to the non-smoking control group. Calculated retinal blood flow in the measured veins increased by a maximum of +54 ± 21%, +43 ± 18% and +46 ± 19% during the three stimulation periods in the non-smoking subjects, respectively. The flicker induced increase in retinal blood flow as assessed in the veins was significantly reduced in chronic smokers as compared to the non-smoking control group (+19 ± 16%, +26 ± 14%, +24 ± 13%, ANOVA between groups, p=0.013). In retinal arteries, flicker stimulation increased retinal arterial diameters by 5.2 ± 3.8%, 5.8 ± 4.8% and 5.5 ± 5.6% during the three flicker periods in the non-smoking group. In smokers, the flicker induced arterial vasodilatation was not significantly different compared to non-smokers (4.6 ± 4.1%, 3.8 ± 3.7% and 4.8 ± 3.4%, ANOVA between groups, p=0.4). CONCLUSION Our data indicate that the flicker induced hemodynamic response of retinal veins is reduced in chronic smokers as compared to age matched healthy volunteers. This supports the hypothesis that chronic smoking leads to vascular dysfunction in the eye.

Effect of hyaluronic acid on tear film thickness as assessed with ultra‐high resolution optical coherence tomography

The aim of this study was to assess the effect of a single drop of hyaluronic acid on tear film thickness (TFT) in healthy subjects.

In vivo tear film thickness measurement and tear film dynamics visualization using spectral domain optical coherence tomography.

Dry eye syndrome is a highly prevalent disease of the ocular surface characterized by an instability of the tear film. Traditional methods used for the evaluation of tear film stability are invasive or show limited repeatability. Here we propose a new non-invasive fully automated approach to measure tear film thickness based on spectral domain optical coherence tomography and on an efficient delay estimator. Silicon wafer phantom were used to validate the thickness measurement. The technique was applied in vivo in healthy subjects. Series of tear film thickness maps were generated, allowing for the visualization of tear film dynamics. Our results show that the in vivo central tear film thickness measurements are precise and repeatable with a coefficient of variation of about 0.65% and that repeatable tear film dynamics can be observed. The presented approach could be used in clinical setting to study patients with dry eye disease and monitor their treatments.