Christopher A. Clark

In vivo adaptive optics microvascular imaging in diabetic patients without clinically severe diabetic retinopathy

We used a confocal adaptive optics scanning laser ophthalmoscope (AOSLO) to image the retina of subjects with non-proliferative diabetic retinopathy (NPDR). To improve visualization of different retinal features, the size and alignment of the confocal aperture were varied. The inner retinal layers contained clearly visualized retinal vessels. In diabetic subjects there was extensive capillary remodeling despite the subjects having only mild or moderate NPDR. Details of the retinal microvasculature were readily imaged with a larger confocal aperture. Hard exudates were observed with the AOSLO in all imaging modes. Photoreceptor layer images showed regions of bright cones and dark areas, corresponding in location to overlying vascular abnormalities and retinal edema. Clinically undetected intraretinal vessel remodeling and varying blood flow patterns were found. Perifoveal capillary diameters were larger in the diabetic subjects (p<0.01), and small arteriolar walls were thickened, based on wall to lumen measurements (p<.05). The results suggest that existing clinical classifications based on lower magnification clinical assessment may not adequately measure key vascular differences among individuals with NPDR.

Peripheral refraction with and without contact lens correction.

Purpose. Peripheral refractive error degrades the quality of retinal images and has been hypothesized to be a stimulus for the development of refractive error. The purpose of this study was to investigate the changes in refractive error across the horizontal visual field produced by contact lenses (CLs) and to quantify the effect of CLs on peripheral image blur. Methods. A commercial Shack-Hartmann aberrometer measured ocular wavefront aberrations in 5° steps across the central 60° of visual field along the horizontal meridian before and after CLs correction. Wavefront refractions for peripheral lines-of-sight were based on the full elliptical pupil encountered in peripheral measurements. Curvature of field is the change in peripheral spherical equivalent relative to the eyes optical axis. Results. Hyperopic curvature of field in the naked eye increases with increasing amounts central myopic refractive error as predicted by Atchison (2006). For an eccentricity of E degrees, field curvature is approximately E percent of foveal refractive error. Rigid gas permeable (RGP) lenses changed field curvature in the myopic direction twice as much as soft CLs (SCLs). Both of these effects varied with CLs power. For all lens powers, SCL cut the degree of hyperopic field curvature in half whereas RGP lenses nearly eliminated field curvature. The benefit of reduced field curvature was partly offset by increased oblique astigmatism. The net reduction of retinal blur because of CLs is approximately constant across the visual field. Conclusions. Both SCL and RGP lenses reduced the degree of hyperopic field curvature present in myopic eyes, with RGP lenses having greater effect. The tradeoff between field curvature and off-axis astigmatism with RGP lenses may limit their effectiveness for control of myopia progression. These results suggest that axial growth mechanisms that depend on retinal image quality will be affected more by RGP than by SCL lenses.

Cone Photoreceptor Packing Density and the Outer Nuclear Layer Thickness in Healthy Subjects

PURPOSE We evaluated the relationship between cone photoreceptor packing density and outer nuclear layer (ONL) thickness within the central 15 degrees. METHODS Individual differences for healthy subjects in cone packing density and ONL thickness were examined in 8 younger and 8 older subjects, mean age 27.2 versus 56.2 years. Cone packing density was obtained using an adaptive optics scanning laser ophthalmoscope (AOSLO). The ONL thickness measurements included the ONL and the Henle fiber layer (ONL + HFL), and were obtained using spectral domain optical coherence tomography (SDOCT) and custom segmentation software. RESULTS There were sizeable individual differences in cone packing density and ONL + HFL thickness. Older subjects had on average lower cone packing densities, but thicker ONL + HFL measurements. Cone packing density and ONL + HFL thickness decreased with increasing retinal eccentricity. The ratio of the cone packing density-to-ONL2 was larger for the younger subjects group, and decreased with retinal eccentricity. CONCLUSIONS The individual differences in cone packing density and ONL + HFL thickness are consistent with aging changes, indicating that normative aging data are necessary for fine comparisons in the early stages of disease or response to treatment. Our finding of ONL + HFL thickness increasing with aging is inconsistent with the hypothesis that ONL measurements with SDOCT depend only on the number of functioning cones, since in our older group cones were fewer, but thickness was greater.

Age-related changes in visual temporal order judgment performance: Relation to sensory and cognitive capacities

Five measures of temporal order judgments were obtained from 261 participants, including 146 elder, 44 middle aged, and 71 young participants. Strong age group differences were observed in all five measures, although the group differences were reduced when letter discriminability was matched for all participants. Significant relations were found between these measures of temporal processing and several cognitive and sensory assays, and structural equation modeling revealed the degree to which temporal order processing can be viewed as a latent factor that depends in part on contributions from sensory and cognitive capacities. The best-fitting model involved two different latent factors representing temporal order processing at same and different locations, and the sensory and cognitive factors were more successful predicting performance in the different location factor than the same-location factor. Processing speed, even measured using high-contrast symbols on a paper-and-pencil test, was a surprisingly strong predictor of variability in both latent factors. However, low-level sensory measures also made significant contributions to the latent factors. The results demonstrate the degree to which temporal order processing relates to other perceptual and cognitive capacities, and address the question of whether age-related declines in these capacities share a common cause.

Tear oxygen under hydrogel and silicone hydrogel contact lenses in humans.

Purpose. To determine the tear oxygen tension under a variety of conventional and silicone hydrogel contact lenses in human subjects. Methods. Three hydrogel and five silicone hydrogel lenses (Dk/t = 17 to 329) were coated on the back surface with an oxygen sensitive, bovine serum albumin-Pd meso-tetra (4-carboxyphenyl) porphine complex (BSA-porphine). Each lens type was placed on the right eye of 15 non-contact lens wearers to obtain a steady-state open eye tear oxygen tension using oxygen sensitive phosphorescence decay of BSA-porphine. A closed-eye oxygen tension estimate was obtained by measuring the change in tear oxygen tension after 5 min of eye closure. In separate experiments, a goggle was placed over the lens wearing eye and a gas mixture (PO2 = 51 torr) flowed over the lens to simulate anterior lens oxygen tension during eye closure. Results. Mean open eye oxygen tension ranged from 58 to 133 torr. Closed eye estimates ranged from 11 to 42 torr. Oxygen tension under the goggle ranged from 8 to 48 torr and was higher than the closed eye estimate for six out of the eight lenses, suggesting that the average closed eye anterior lens surface oxygen tension is <51 torr. For Dk/t >30, the measured tear oxygen tension is significantly lower than that predicted from previous studies. Conclusions. The phosphorescence decay methodology is capable of directly measuring the in vivo post lens PO2 of high Dk/t lenses without disturbing the contact lens or cornea. Our data indicate that increasing Dk/t up to and beyond 140 continues to yield increased flux into the central cornea.

Foveal localization in non-exudative AMD using scanning laser polarimetry.

Purpose. To determine whether custom scanning laser polarimetry (SLP) images, differing in polarization content, can be used to accurately localize the fovea in the presence of non-exudative age-related macular degeneration (AMD). To determine whether alterations to the foveal structure in non-exudative AMD significantly disrupts the birefringent Henle fiber layer, responsible for the macular cross pattern in some SLP images. To determine whether phase retardation information, specifically color-coded information representing its magnitude and axis, allow better foveal localization than images including retardation amplitude only. Methods. SLP images were acquired in 25 AMD subjects and 25 age-matched controls. Raw data were used to generate five custom image types differing in polarization content. The foveal location was marked by three graders in each image type for each subject. The difference in variability was compared between the AMD subjects and matched controls. We further determined whether the orientation of Henle fiber layer phase retardation improved localization in 10 subjects with the highest variability in images including only phase retardation amplitude. Results. Images that differed in polarization content led to strikingly different visualizations of AMD pathology. The Henle fiber layer remained sufficiently intact to assist in fovea localization in all subjects but with more variability in the AMD group. For both the AMD and matched control group, images containing birefringence amplitude and orientation information reduced the amount of intragrader, intergrader, and interimage variability for estimating foveal location. Conclusions. The disruption in Henle fiber birefringence was evident in the eyes with AMD but nevertheless was sufficient to help in foveal localization despite macular pathology. Phase retardation amplitude and axis of orientation can be a useful tool in foveal localization in patients with AMD.

Comparison of Cysts in Red and Green Images for Diabetic Macular Edema

ABSTRACT Purpose To investigate whether cysts in diabetic macular edema are better visualized in the red channel of color fundus camera images, as compared with the green channel, because color fundus camera screening methods that emphasize short-wavelength light may miss cysts in patients with dark fundi or changes to outer blood retinal barrier. Methods Fundus images for diabetic retinopathy photoscreening were acquired for a study with Aeon Imaging, EyePACS, University of California Berkeley, and Indiana University. There were 2047 underserved, adult diabetic patients, of whom over 90% self-identified as a racial/ethnic identify other than non-Hispanic white. Color fundus images at nominally 45 degrees were acquired with a Canon Cr-DGi non-mydriatic camera (Tokyo, Japan) then graded by an EyePACS certified grader. From the 148 patients graded to have clinically significant macular edema by the presence of hard exudates in the central 1500 μm of the fovea, we evaluated macular cysts in 13 patients with cystoid macular edema. Age ranged from 33 to 68 years. Color fundus images were split into red, green, and blue channels with custom Matlab software (Mathworks, Natick, MA). The diameter of a cyst or confluent cysts was quantified in the red-channel and green-channel images separately. Results Cyst identification gave complete agreement between red-channel images and the standard full-color images. This was not the case for green-channel images, which did not expose cysts visible with standard full-color images in five cases, who had dark fundi. Cysts appeared more numerous and covered a larger area in the red channel (733 ± 604 μm) than in the green channel (349 ± 433 μm, P < .006). Conclusions Cysts may be underdetected with the present fundus camera methods, particularly when short-wavelength light is emphasized or in patients with dark fundi. Longer wavelength techniques may improve the detection of cysts and provide more information concerning the early stages of diabetic macular edema or the outer blood retinal barrier.

Sd-oct and Adaptive Optics Imaging of Outer Retinal Tubulation.

ABSTRACT Purpose To investigate outer retinal tubulation (ORT) using spectral domain optical coherence tomography (SD-OCT) and an adaptive optics scanning laser ophthalmoscope (AOSLO). To document the frequency of ORT in atrophic retinal conditions and quantify ORT dimensions versus adjacent retinal layers. Methods SD-OCT images were reviewed for the presence of retinal atrophy, scarring, and/or exudation. The greatest width of each ORT was quantified. Inner and outer retinal thicknesses adjacent to and within the area of ORT were measured for 18 patients. AOSLO imaged ORTs in five subjects with direct and scattered light imaging. Results ORT was identified in 47 of 76 subjects (61.8%) and in 65 eyes via SD-OCT in a wide range of conditions and ages, and in peripapillary atrophy. ORTs appeared as finger-like projections in atrophy, seen in the en face images. AOSLO showed some ORTs with bright cones that guide light within atrophic areas. Multiply scattered light mode AOSLO visualized variegated lines (18–35 μm) radiating from ORTs. The ORTs’ width on OCT b-scan images varied from 70 to 509 μm. The inner retina at the ORT was significantly thinner than the adjacent retina, 135 vs.170 μm (P = .004), whereas the outer retina was significantly thicker, 115 vs. 80 μm (P = .03). Conclusions ORTs are quite common in eyes with retinal atrophy in various disorders. ORTs demonstrate surviving photoreceptors in tubular structures found within otherwise nonsupportive atrophic areas that lack retinal pigment epithelium and choriocapillaris.

Henle Fiber Layer Phase Retardation Changes Associated With Age-Related Macular Degeneration

PURPOSE To quantify and compare phase retardation amplitude and regularity associated with the Henle fiber layer (HFL) between nonexudative AMD patients and age-matched controls using scanning laser polarimetry (SLP) imaging. METHODS A scanning laser polarimeter was used to collect 15 × 15° macular-centered images in 25 patients with nonexudative AMD and 25 age-matched controls. Raw image data were used to compute macular phase retardation maps associated with the HFL. Consecutive, annular regions of interest from 0.5 to 3.0° eccentricity, centered on the fovea, were used to generate intensity profiles from phase retardation data and analyzed with two complementary techniques: a normalized second harmonic frequency (2f) of the fast Fourier Transform (FFT) analysis and a curve fitting analysis using a 2f sine function. Paired t-tests were used to compare the normalized 2f FFT magnitude at each eccentricity between the two groups, the eccentricity that yielded the maximum normalized 2f FFT between paired individuals across the two groups, and curve fitting RMS error at each eccentricity between the two groups. RESULTS Normalized 2f FFT components were lower in the AMD group at each eccentricity, with no difference between the two groups in the maximum normalized 2f FFT component eccentricity. The root-mean-square (RMS) error from curve fitting was significantly higher in the AMD group. CONCLUSIONS Phase retardation changes in the central macula indicate loss and/or structural alterations to central cone photoreceptors in nonexudative AMD patients. Scanning laser polarimetry imaging is a noninvasive method for quantifying cone photoreceptor changes associated with central macular disease.

Eye shape using partial coherence interferometry, autorefraction, and SD-OCT.

Purpose Peripheral refraction and retinal shape may influence refractive development. Peripheral refraction has been shown to have a high degree of variability and can take considerable time to perform. Spectral domain optical coherence tomography (SD-OCT) and peripheral axial length measures may be more reliable, assuming that the retinal position is more important than the peripheral optics of the lens/cornea. Methods Seventy-nine subjects’ right eyes were imaged for this study (age range, 22 to 34 years; refractive error, −10 to +5.00). Thirty-degree SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) images were collected in a radial pattern along with peripheral refraction with an autorefractor (Shin-Nippon Autorefractor) and peripheral axial length measurements with partial coherence interferometry (IOLMaster, Zeiss). Statistics were performed using repeated-measures analysis of variance in SPSS (IBM, Armonk, NY), Bland-Altman analyses, and regression. All measures were converted to diopters to allow direct comparison. Results Spectral domain OCT showed a retinal shape with an increased curvature for myopes compared with emmetropes/hyperopes. This retinal shape change became significant around 5 degrees. The SD-OCT analysis for retinal shape provides a resolution of 0.026 diopters, which is about 10 times more accurate than using autorefraction (AR) or clinical refractive techniques. Bland-Altman analyses suggest that retinal shape measured by SD-OCT and the partial coherence interferometry method were more consistent with one another than either was with AR. Conclusions With more accurate measures of retinal shape using SD-OCT, consistent differences between emmetropes/hyperopes and myopes were found nearer to the fovea than previously reported. Retinal shape may be influenced by central refractive error, and not merely peripheral optics. Partial coherence interferometry and SD-OCT appear to be more accurate than AR, which may be influenced by other factors such as fixation and accommodation. Autorefraction does measure the optics directly, which may be a strength of that method.