Koenraad A. Vermeer

Phase-stabilized optical frequency domain imaging at 1-µm for the measurement of blood flow in the human choroid

In optical frequency domain imaging (OFDI) the measurement of interference fringes is not exactly reproducible due to small instabilities in the swept-source laser, the interferometer and the data-acquisition hardware. The resulting variation in wavenumber sampling makes phase-resolved detection and the removal of fixed-pattern noise challenging in OFDI. In this paper this problem is solved by a new post-processing method in which interference fringes are resampled to the exact same wavenumber space using a simultaneously recorded calibration signal. This method is implemented in a high-speed (100 kHz) high-resolution (6.5 µm) OFDI system at 1-µm and is used for the removal of fixed-pattern noise artifacts and for phase-resolved blood flow measurements in the human choroid. The system performed close to the shot-noise limit (<1dB) with a sensitivity of 99.1 dB for a 1.7 mW sample arm power. Suppression of fixed-pattern noise artifacts is shown up to 39.0 dB which effectively removes all artifacts from the OFDI-images. The clinical potential of the system is shown by the detection of choroidal blood flow in a healthy volunteer and the detection of tissue reperfusion in a patient after a retinal pigment epithelium and choroid transplantation.

Depth-resolved model-based reconstruction of attenuation coefficients in optical coherence tomography

We present a method, based on a single scattering model, to calculate the attenuation coefficient of each pixel in optical coherence tomography (OCT) depth profiles. Numerical simulations were used to determine the models response to different depths and attenuation coefficients. Experiments were performed on uniform and layered phantoms with varying attenuation coefficients. They were measured by a 1300 nm OCT system and their attenuation coefficients were evaluated by our proposed method and by fitting the OCT slope as the gold standard. Both methods showed largely consistent results for the uniform phantoms. On the layered phantom, only our proposed method accurately estimated the attenuation coefficients. For all phantoms, the proposed method largely reduced the variability of the estimated attenuation coefficients. The method was illustrated on an in-vivo retinal OCT scan, effectively removing common imaging artifacts such as shadowing. By providing localized, per-pixel attenuation coefficients, this method enables tissue characterization based on attenuation coefficient estimates from OCT data.

Automated segmentation by pixel classification of retinal layers in ophthalmic OCT images

Current OCT devices provide three-dimensional (3D) in-vivo images of the human retina. The resulting very large data sets are difficult to manually assess. Automated segmentation is required to automatically process the data and produce images that are clinically useful and easy to interpret. In this paper, we present a method to segment the retinal layers in these images. Instead of using complex heuristics to define each layer, simple features are defined and machine learning classifiers are trained based on manually labeled examples. When applied to new data, these classifiers produce labels for every pixel. After regularization of the 3D labeled volume to produce a surface, this results in consistent, three-dimensionally segmented layers that match known retinal morphology. Six labels were defined, corresponding to the following layers: Vitreous, retinal nerve fiber layer (RNFL), ganglion cell layer & inner plexiform layer, inner nuclear layer & outer plexiform layer, photoreceptors & retinal pigment epithelium and choroid. For both normal and glaucomatous eyes that were imaged with a Spectralis (Heidelberg Engineering) OCT system, the five resulting interfaces were compared between automatic and manual segmentation. RMS errors for the top and bottom of the retina were between 4 and 6 μm, while the errors for intra-retinal interfaces were between 6 and 15 μm. The resulting total retinal thickness maps corresponded with known retinal morphology. RNFL thickness maps were compared to GDx (Carl Zeiss Meditec) thickness maps. Both maps were mostly consistent but local defects were better visualized in OCT-derived thickness maps.

Real-time eye motion correction in phase-resolved OCT angiography with tracking SLO

In phase-resolved OCT angiography blood flow is detected from phase changes in between A-scans that are obtained from the same location. In ophthalmology, this technique is vulnerable to eye motion. We address this problem by combining inter-B-scan phase-resolved OCT angiography with real-time eye tracking. A tracking scanning laser ophthalmoscope (TSLO) at 840 nm provided eye tracking functionality and was combined with a phase-stabilized optical frequency domain imaging (OFDI) system at 1040 nm. Real-time eye tracking corrected eye drift and prevented discontinuity artifacts from (micro)saccadic eye motion in OCT angiograms. This improved the OCT spot stability on the retina and consequently reduced the phase-noise, thereby enabling the detection of slower blood flows by extending the inter-B-scan time interval. In addition, eye tracking enabled the easy compounding of multiple data sets from the fovea of a healthy volunteer to create high-quality eye motion artifact-free angiograms. High-quality images are presented of two distinct layers of vasculature in the retina and the dense vasculature of the choroid. Additionally we present, for the first time, a phase-resolved OCT angiogram of the mesh-like network of the choriocapillaris containing typical pore openings.

Angiography of the retina and the choroid with phase-resolved OCT using interval-optimized backstitched B-scans

In conventional phase-resolved OCT blood flow is detected from phase changes between successive A-scans. Especially in high-speed OCT systems this results in a short evaluation time interval. This method is therefore often unable to visualize complete vascular networks since low flow velocities cause insufficient phase changes. This problem was solved by comparing B-scans instead of successive A-scans to enlarge the time interval. In this paper a detailed phase-noise analysis of our OCT system is presented in order to calculate the optimal time intervals for visualization of the vasculature of the human retina and choroid. High-resolution images of the vasculature of a healthy volunteer taken with various time intervals are presented to confirm this analysis. The imaging was performed with a backstitched B-scan in which pairs of small repeated B-scans are stitched together to independently control the time interval and the imaged lateral field size. A time interval of ≥ 2.5 ms was found effective to image the retinal vasculature down to the capillary level. The higher flow velocities of the choroid allowed a time interval of 0.64 ms to reveal its dense vasculature. Finally we analyzed depth-resolved histograms of volumetric phase-difference data to assess changes in amount of blood flow with depth. This analysis indicated different flow regimes in the retina and the choroid.

The Effect of Glaucoma on the Optical Attenuation Coefficient of the Retinal Nerve Fiber Layer in Spectral Domain Optical Coherence Tomography Images

PURPOSE To demonstrate the effect of glaucoma on the optical attenuation coefficient of the retinal nerve fiber layer (RNFL) in Spectral Domain Optical Coherence Tomography (SD-OCT) images. METHODS We analyzed images of the peripapillary areas in 10 healthy and 30 glaucomatous eyes (mild, moderate, and advanced glaucoma, 10 eyes each), scanned with the Spectralis OCT (Heidelberg Engineering GmbH, Dossenheim, Germany). To calculate the RNFL attenuation coefficient (μ(att)), determined by the scattering properties of the RNFL, we used a model that normalized the reflectivity of the RNFL by the retinal pigment epithelium. The analysis was performed at four preset locations at 1.3 and 1.7 mm from the center of the optic nerve head (ONH) (i.e., temporally, superiorly, nasally, and inferiorly) and on averages per eye. To assess the structure-function relationship, we correlated the μ(att) to the mean deviation (MD) in standard automated perimetry. RESULTS The μ(att) of the RNFL decreased up to 40% with increasing disease severity, on average as well as in each location around the ONH (Jonckheere-Terpstra test, P < 0.019 in all tests). The μ(att) of the RNFL depended significantly on the location around the ONH in all eyes (Kruskal-Wallis test, P < 0.014) and was lowest nasally from the ONH. The μ(att) correlated significantly with the MD in SAP (R(2) = 0.337). CONCLUSIONS The measurements clearly demonstrated that the μ(att) of the RNFL decreased with increasing disease severity. The RNFL attenuation coefficient may serve as a new method to quantify glaucoma in SD-OCT images.

RPE-normalized RNFL attenuation coefficient maps derived from volumetric OCT imaging for glaucoma assessment.

PURPOSE We present spatial retinal nerve fiber layer (RNFL) attenuation coefficient maps for healthy and glaucomatous eyes based on optical coherence tomography (OCT) measurements. Quantitative analyses of differences between healthy and glaucomatous eyes were performed. METHODS Peripapillary volumetric images of 10 healthy and 8 glaucomatous eyes were acquired by a Spectralis OCT system. Per A-line, the attenuation coefficient of the RNFL was determined based on a method that uses the retinal pigment epithelium as a reference layer. The attenuation coefficient describes the attenuation of light in tissue due to scattering and absorption. En-face maps were constructed and visually inspected. Differences between healthy and glaucomatous eyes were analyzed (Mann-Whitney U test), both globally (average values) and spatially (concentric and per segment). RESULTS RNFL attenuation coefficient maps of healthy eyes showed relatively high and uniform values. For glaucomatous eyes, the attenuation coefficients were much lower and showed local defects. Normal and glaucomatous average RNFL attenuation coefficients were highly significantly different (P < 0.0001) and fully separable. The RNFL attenuation coefficient decreased with increasing optic nerve head distance for both groups, with highly significant differences for all distances (P < 0.001). The angular dependency showed high superio- and inferiotemporal and low nasal values, with most significant differences superio- and inferiotemporally. CONCLUSIONS Maps of RNFL attenuation coefficients provide a novel way of assessing the health of the RNFL and are relatively insensitive to imaging artifacts affecting signal intensity. The highly significant difference between normal and glaucomatous eyes suggests using RNFL attenuation coefficient maps as a new clinical tool for diagnosing and monitoring glaucoma.

Fiber-based polarization-sensitive OCT of the human retina with correction of system polarization distortions

In polarization-sensitive optical coherence tomography (PS-OCT) the use of single-mode fibers causes unpredictable polarization distortions which can result in increased noise levels and erroneous changes in calculated polarization parameters. In the current paper this problem is addressed by a new Jones matrix analysis method that measures and corrects system polarization distortions as a function of wavenumber by spectral analysis of the sample surface polarization state and deeper located birefringent tissue structures. This method was implemented on a passive-component depth-multiplexed swept-source PS-OCT system at 1040 nm which was theoretically modeled using Jones matrix calculus. High-resolution B-scan images are presented of the double-pass phase retardation, diattenuation, and relative optic axis orientation to show the benefits of the new analysis method for in vivo imaging of the human retina. The correction of system polarization distortions yielded reduced phase retardation noise, and better estimates of the diattenuation and the relative optic axis orientation in weakly birefringent tissues. The clinical potential of the system is shown by en face visualization of the phase retardation and optic axis orientation of the retinal nerve fiber layer in a healthy volunteer and a glaucoma patient with nerve fiber loss.

Robust and censored modeling and prediction of progression in glaucomatous visual fields

PURPOSE Classic regression is based on certain assumptions that conflict with visual field (VF) data. We investigate and evaluate different regression models and their assumptions in order to determine point-wise VF progression in glaucoma and to better predict future field loss for personalised clinical glaucoma management. METHODS Standard automated visual fields of 130 patients with primary glaucoma with a minimum of 6 years of follow-up were included. Sensitivity estimates at each VF location were regressed on time with classical linear and exponential regression models, as well as different variants of these models that take into account censoring and allow for robust fits. These models were compared for the best fit and for their predictive ability. The prediction was evaluated at six measurements (approximately 3 years) ahead using varying numbers of measurements. RESULTS For fitting the data, the classical uncensored linear regression model had the lowest root mean square error and 95th percentile of the absolute errors. These errors were reduced in all models when increasing the number of measurements used for the prediction of future measurements, with the classical uncensored linear regression model having the lowest values for these errors irrespective of how many measurements were included. CONCLUSIONS All models performed similarly. Despite violation of its assumptions, the classical uncensored linear regression model appeared to provide the best fit for our data. In addition, this model appeared to perform the best when predicting future VFs. However, more advanced regression models exploring any temporal-spatial relationships of glaucomatous progression are needed to reduce prediction errors to clinically meaningful levels.

INTRAVITREAL VERSUS SUBRETINAL ADMINISTRATION OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR COMBINED WITH GAS FOR ACUTE SUBMACULAR HEMORRHAGES DUE TO AGE-RELATED MACULAR DEGENERATION: An Exploratory Prospective Study.

Purpose: Current management of submacular hemorrhage (SMH) favors vitrectomy and gas with subretinal administration of recombinant tissue plasminogen activator (rtPA) over mere intravitreal rtPA injections and gas. In this study, we aimed to compare the effectiveness of both treatment modalities to displace submacular blood. Methods: Twenty-four patients with SMH secondary to age-related macular degeneration were included. The SMH had to exist ⩽14 days at time of surgery and SMH thickness had to be between 250 &mgr;m and 1,250 &mgr;m. Patients were randomized to either intravitreal injections of rtPA, perfluoropropane (C3F8) gas, and bevacizumab (n = 12) or vitrectomy with subretinal rtPA administration, intravitreal C3F8 gas, and bevacizumab (n = 12). The SMH volume change was measured on spectral domain optical coherence tomography postoperatively within a 2.5-mm cylinder centered at the fovea. Results: Median relative volume reduction of subretinal blood at 6 weeks postoperatively was 97% (95% confidence interval: 91–99%) in the intravitreal rtPA group and 100% (95–100%) in the subretinal rtPA group and did not differ significantly between groups (P = 0.56). Conclusion: Both treatment modalities effectively displaced SMH in this exploratory clinical trial. To more definitely study the noninferiority of intravitreal rtPA with gas to subretinal rtPA, vitrectomy with gas, a larger clinical trial would be necessary.