René M. Werkmeister

Doppler Optical Coherence Tomography

Optical Coherence Tomography (OCT) has revolutionized ophthalmology. Since its introduction in the early 1990s it has continuously improved in terms of speed, resolution and sensitivity. The technique has also seen a variety of extensions aiming to assess functional aspects of the tissue in addition to morphology. One of these approaches is Doppler OCT (DOCT), which aims to visualize and quantify blood flow. Such extensions were already implemented in time domain systems, but have gained importance with the introduction of Fourier domain OCT. Nowadays phase-sensitive detection techniques are most widely used to extract blood velocity and blood flow from tissues. A common problem with the technique is that the Doppler angle is not known and several approaches have been realized to obtain absolute velocity and flow data from the retina. Additional studies are required to elucidate which of these techniques is most promising. In the recent years, however, several groups have shown that data can be obtained with high validity and reproducibility. In addition, several groups have published values for total retinal blood flow. Another promising application relates to non-invasive angiography. As compared to standard techniques such as fluorescein and indocyanine-green angiography the technique offers two major advantages: no dye is required and depth resolution is required is provided. As such Doppler OCT has the potential to improve our abilities to diagnose and monitor ocular vascular diseases.

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.

Bidirectional Doppler Fourier-domain optical coherence tomography for measurement of absolute flow velocities in human retinal vessels

We describe a bidirectional color Doppler Fourier-domain optical coherence tomography system capable of measuring absolute velocities of moving scatterers by illuminating the sample with two linearly and orthogonally polarized beams, incident at a known angle on the sample. The velocity calculation is independent of the exact orientation of the velocity vector in the detection plane. First measurements were performed on a rotating disk driven at well-defined velocities and tilted by various small angles. Our results indicate a high correlation between preset and calculated velocities (correlation coefficient 0.999) and the independency of these velocities from the tilting angle of the disk. We demonstrate that bidirectional color Doppler optical coherence tomography allows for the measurement of absolute blood flow values in vivo in human retinal vessels.

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.).

Retinal Blood Flow in Healthy Young Subjects

PURPOSE To characterize total retinal blood flow in a group of healthy subjects. METHODS Included in this study were 64 healthy volunteers. Retinal venous diameters were measured using a dynamic vessel analyzer. Retinal blood velocities were measured using bidirectional laser Doppler velocimetry. All vessels with a diameter of >60 μm entering the optic nerve head were measured. Total retinal blood flow was measured by summing up all data from the individually measured vessels. In a subgroup of 10 healthy subjects measurements were also taken from the arterioles, and results obtained for total retinal blood flow as measured both from retinal venules and from retinal arterioles were compared. RESULTS Total retinal blood flow was 44.0 ± 13.3 μL/min. Retinal blood flow was highest in the temporal inferior quadrant, followed by the temporal superior quadrant, the nasal inferior quadrant, and the nasal superior quadrant (P < 0.001 each). In all quadrants retinal blood velocities were linearly correlated to vessel diameters. Retinal blood flow as measured in retinal venules (42.1 ± 13.0 μL/min) and in retinal arterioles (43.3 ± 12.1 μL/min) was similar (P = 0.16). CONCLUSIONS The present study provides reference values for total retinal blood flow in 64 healthy subjects. The interindividual variability in retinal blood flow is high, making it unlikely that individual diagnostics can be based on measurements of retinal blood flow. Total retinal blood flow, however, may be important in risk stratification, which needs to be proven in future studies.

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.

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.

Measurement of the total retinal blood flow using dual beam Fourier-domain Doppler optical coherence tomography with orthogonal detection planes

We present a system capable of measuring the total retinal blood flow using a combination of dual beam Fourier-domain Doppler optical coherence tomography with orthogonal detection planes and a fundus camera-based retinal vessel analyzer. Our results show a high degree of conformity of venous and arterial flows, which corroborates the validity of the measurements. In accordance with Murrays law, the log-log regression coefficient between vessel diameter and blood flow was found to be ~3. The bloods velocity scaled linearly with the vessel diameter at higher diameters (> 60 µm), but showed a clear divergence from the linear dependence at lower diameters. Good agreement with literature data and the large range and high measurement sensitivity point to a high potential for further investigations.

In vitro and in vivo three-dimensional velocity vector measurement by three-beam spectral-domain Doppler optical coherence tomography.

Abstract. We developed a three-beam Doppler optical coherence tomography (OCT) system that enables measurement of the velocity vector of moving particles in three-dimensions (3-D). The spatial orientation as well as the magnitude of motion can be determined without prior knowledge of the geometry of motion. The system combines three spectral-domain OCT interferometers whose sample beams are focused at the sample by a common focusing lens at three different angles. This provides three spatially independent velocity components simultaneously from which the velocity vector can be reconstructed. We demonstrate the system in a simple test object (rotating disc), a flow phantom, and for blood flow measurements in the retina of a healthy human subject. Measurements of blood flow at a venous bifurcation achieve a good agreement between in- and outflow and demonstrate the reliability of the method.

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.