Henle fiber layer thickening and deficits in objective retinal function in participants with a history of multiple traumatic brain injuries.

Introduction: This study tested whether multiple traumatic brain injuries (TBIs) alter the structure of the Henle fiber layer (HFL) and degrade cell-specific function in the retinas of human participants. Methods: A cohort of case participants with multiple TBIs and a cohort of pair-matched control participants were prospectively recruited. Directional optical coherence tomography and scanning laser polarimetry measured HFL thickness and phase retardation, respectively. Full-field flash electroretinography (fERG) assessed retinal function under light-adapted (LA) 3.0, LA 30 Hz, dark-adapted (DA) 0.01, DA 3.0, and DA 10 conditions. Retinal imaging and fERG outcomes were averaged between both eyes, and paired t-tests or Wilcoxon signed-rank tests analyzed inter-cohort differences. Results: Global HFL thickness was significantly (p = 0.02) greater in cases (8.4 ± 0.9 pixels) than in controls (7.7 ± 1.1 pixels). There was no statistically significant difference (p = 0.91) between the cohorts for global HFL phase retardation. For fERG, LA 3.0 a-wave amplitude was significantly reduced (p = 0.02) in cases (23.5 ± 4.2 µV) compared to controls (29.0 ± 8.0 µV). There were no other statistically significant fERG outcomes between the cohorts. Discussion: In summary, the HFL thickens after multiple TBIs, but phase retardation remains unaltered in the macula. Multiple TBIs may also impair retinal function, indicated by a reduction in a-wave amplitude. These results support the potential of the retina as a site to detect TBI-associated pathology.

Structure and function of retinal ganglion cells in subjects with a history of repeated traumatic brain injury.

This study tested whether repeated traumatic brain injuries (TBIs) alter the objective structure or the objective function of retinal ganglion cells (RGCs) in human subjects recruited from an optometry clinic. Case subjects (n = 25) with a history of repeated TBIs (4.12 ± 2.76 TBIs over 0-41 years) and healthy pair-matched control subjects (n = 30) were prospectively recruited. Retinal nerve fiber layer (RNFL) thickness was quantified with spectral-domain optical coherence tomography, and scanning laser polarimetry measured RNFL phase retardation. Measurements of the photopic negative response were made using full-field flash electroretinography. There was no statistically significant difference (p = 0.42) in global RNFL thickness between the case cohort (96.6 ± 9.4 microns) and the control cohort (94.9 ± 7.0 microns). There was no statistically significant difference (p = 0.80) in global RNFL phase retardation between the case cohort (57.9 ± 5.7 nm) and the control cohort (58.2 ± 4.6 nm). There were no statistically significant differences in the peak time (p = 0.95) of the PhNR or in the amplitude (p = 0.11) of the PhNR between the case cohort (69.9 ± 6.9 ms and 24.1 ± 5.1 µV, respectively) and the control cohort (70.1 ± 8.9 ms and 27.8 ± 9.1 µV, respectively). However, PhNR amplitude was more variable (p < 0.025) in the control cohort than in the case cohort. Within the case cohort, there was a strong positive (r = 0.53), but not statistically significant (p = 0.02), association between time since last TBI and PhNR amplitude. There was also a modest positive (r = 0.45), but not statistically significant (p = 0.04), association between time since first TBI and PhNR amplitude. Our results suggest that there were no statistically significant differences in the objective structure or in the objective function of RGCs between the case cohort and the control cohort. Future large, longitudinal studies will be necessary to confirm our negative results and to more fully investigate the potential interaction between PhNR amplitude and time since first or last TBI.

Foveal Phase Retardation Correlates With Optically Measured Henle Fiber Layer Thickness.

This study quantified and compared phase retardation distribution in the central macula with the thickness of the Henle fiber layer (HFL). A scanning laser polarimeter (SLP) was used to acquire 20° × 40° macular-centered images, either with fixed corneal compensation or with variable corneal compensation, in two cohorts of clinically normal subjects (N = 36). Phase retardation maps from SLP imaging were used to generate a macular cross pattern (fixed compensation) or an annulus pattern (variable compensation) centered on the macula. Intensity profiles in the phase retardation maps were produced using annular regions of interest at eccentricities from 0.25° to 3°. Pixel intensity was averaged at each eccentricity, acting as a surrogate for macular phase retardation. Directional OCT images were acquired in the horizontal and vertical meridians in all subjects, allowing visualization of the HFL thickness. HFL thickness was manually segmented in each meridian and averaged. In both cohorts, phase retardation and HFL thickness were highly correlated in the central 3° assessed, providing further evidence that the source of the phase retardation signal in the central macula is dominated by the HFL and that the center of the macula on cross sectional imaging corresponds closely with the center of the macular cross on SLP imaging.

Association between Vision Impairment and Physical Quality of Life Assessed Using National Surveillance Data.

SIGNIFICANCE: Physically unhealthy days assessments in national health surveillance datasets represent a useful metric for quantifying quality-of-life differences in those with and without vision impairment. Disproportionately poorer physical health in the visually impaired population provides further rationale for the inclusion of vision care in multidisciplinary approaches to chronic disease management. PURPOSE: This study aimed to assess the association between vision impairment and health-related quality of life using data from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System. METHODS: Data from each of the 50 states were extracted from the 2017 Behavioral Risk Factor Surveillance System data set. Self-report of difficulty seeing was used to categorize visually impaired versus nonvisually impaired populations. Self-report number of physically unhealthy days in the previous 30 days was used to quantify quality of life. The number of unhealthy days was calculated for the visually impaired and nonvisually impaired cohorts for each state. The ratio of the number of physically unhealthy days in the visually impaired versus nonvisually impaired population was calculated for each state and for different age cohorts. RESULTS: Mean numbers of physically unhealthy days among persons with and without severe vision impairment across all states were 10.63 and 3.68 days, respectively, and demonstrated considerable geographic variability. Mean ratios of physically unhealthy healthy days in the visually impaired versus the nonvisually impaired population were 2.91 in the 18- to 39-year-old cohort, 2.87 in the 40- to 64-year-old cohort, and 2.16 in the ≥65-year-old cohort. CONCLUSIONS: National surveillance data demonstrate a greater number of physically unhealthy days in the visually impaired population, indicating a need to improve our understanding of causes that lead to reduced physical health among those with vision impairment. Additional research is needed to better understand how individuals perceive vision as part of their overall health.

Retinal dysfunction in a presymptomatic patient with Huntington's disease.

PURPOSE: Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Studies have shown retinal abnormalities in patients and mouse models with HD; however, to our knowledge, no prior research papers evaluated retinal structure and function in a presymptomatic patient with HD. The aim of this report is to present a case of retinal dysfunction in a presymptomatic patient with HD. METHODS: We investigated retinal structure and function in a 25-year-old male who tested positive for the gene that causes HD, but did not have any symptoms normally associated with HD. Vision and ocular testing included a comprehensive dilated ophthalmic examination, 24-2 full-threshold Humphrey visual field, spectral-domain optical coherence tomography (SD-OCT), fundus photography, full-field electroretinogram (ERG), and multifocal electroretinogram (mfERG). RESULTS: Visual electrophysiology testing showed rod and cone functional anomalies in both eyes. Full-field ERG amplitudes were subnormal in both eyes for the dark-adapted (DA) 0.01 ERG, DA 3 ERG, DA 3 oscillatory potentials (OPs), DA 10 ERG, light-adapted (LA) 3 ERG, and LA 30 Hz flicker, but peak times for the six standard ERG responses were not significantly different from normals. mfERGs revealed functional anomalies of the central retina with attenuated P1 amplitudes for five of the six concentric rings in the right eye and all six rings in the left eye. mfERG P1 peak times were normal at all eccentricities. Dilated fundus examination, SD-OCT, and fundus photography were unremarkable in both eyes. The visual field was normal in the right eye, but there was a mild paracentral field defect in the left eye. CONCLUSIONS: Our results illustrate that the ERG and mfERG detected early retinal dysfunction in a presymptomatic patient with HD consistent with electroretinogram findings in animal models of HD. However, our report was limited to one patient and additional studies are needed to verify whether the ERG and/or mfERG can uncover neural dysfunction before motor, behavioral, and cognitive abnormalities are discernible in patients with HD.

Polarization Variability in Age-related Macular Degeneration.

SIGNIFICANCE: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss. Complementary imaging techniques can be used to better characterize and quantify pathological changes associated with AMD. By assessing specific light-tissue interactions, polarization-sensitive imaging can be used to detect tissue disruption early in the disease process. PURPOSE: The aim of this study was to compare variability in central macular polarization properties in patients with nonexudative AMD and age-matched control subjects. METHODS: A scanning laser polarimeter (GDx, LDT/CZM) was used to acquire 15 × 15-degree macular images in 10 subjects diagnosed with nonexudative AMD and 10 age-matched control subjects. The coefficient of variation (COV, SD/mean) was used to quantify variability in pixel intensity in the central 3.3° of the macula for custom images emphasizing multiply scattered light (the depolarized light image) and polarization-retaining light (the maximum of the parallel detector image). The intensity COV was compared across subject categories using paired t tests for each image type. RESULTS: The COV in the central macula was significantly higher in the AMD subject group (average, 0.221; 95% confidence interval [CI], 0.157 to 0.265) when compared with matched control subjects (average 0.120; 95% CI, 0.107 to 0.133) in the depolarized light image (P = .01). The COV in the maximum of the parallel detector image was not statistically different between the two subject groups (AMD average, 0.162 [95% CI, 0.138 to 0.185]; control average, 0.137 [95% CI, 0.115 to 0.158]; P = .21). CONCLUSIONS: Variability in multiply scattered light is higher than that of light that is more polarization preserving in patients with nonexudative AMD. Multiple scattering may act as an early indicator representing disruption to the macula in early AMD.

Foveal Curvature and Asymmetry Assessed Using Optical Coherence Tomography.

PURPOSE: The aims of this study were to use cross-sectional optical coherence tomography imaging and custom curve fitting software to evaluate and model the foveal curvature as a spherical surface and to compare the radius of curvature in the horizontal and vertical meridians and test the sensitivity of this technique to anticipated meridional differences. METHODS: Six 30-degree foveal-centered radial optical coherence tomography cross-section scans were acquired in the right eye of 20 clinically normal subjects. Cross sections were manually segmented, and custom curve fitting software was used to determine foveal pit radius of curvature using the central 500, 1000, and 1500 µm of the foveal contour. Radius of curvature was compared across different fitting distances. Root mean square error was used to determine goodness of fit. The radius of curvature was compared between the horizontal and vertical meridians for each fitting distance. RESULTS: There radius of curvature was significantly different when comparing each of the three fitting distances (P < .01 for each comparison). The average radii of curvature were 970 µm (95% confidence interval [CI], 913 to 1028 µm), 1386 µm (95% CI, 1339 to 1439 µm), and 2121 µm (95% CI, 2066 to 2183) for the 500-, 1000-, and 1500-µm fitting distances, respectively. Root mean square error was also significantly different when comparing each fitting distance (P < .01 for each comparison). The average root mean square errors were 2.48 µm (95% CI, 2.41 to 2.53 µm), 6.22 µm (95% CI, 5.77 to 6.60 µm), and 13.82 µm (95% CI, 12.93 to 14.58 µm) for the 500-, 1000-, and 1500-µm fitting distances, respectively. The radius of curvature between the horizontal and vertical meridian radii was statistically different only in the 1000- and 1500-µm fitting distances (P < .01 for each), with the horizontal meridian being flatter than the vertical. CONCLUSIONS: The foveal contour can be modeled as a sphere with low curve fitting error over a limited distance and capable of detecting subtle foveal contour differences between meridians.

Corneal epithelial bullae after short-term wear of small diameter scleral lenses.

Complications of scleral lens wear are not well documented or understood. While multiple studies focus on oxygen transmission during scleral lens wear and associated corneal swelling, little is known about the effects of varying scleral lens fitting relationships, especially when there is corneal interaction. Scleral lenses, by convention, are designed to completely clear the corneal surface and rest on the conjunctival and scleral tissue. However, some designs maximize oxygen transmission by reducing the lens diameter, thickness, and recommended corneal clearance.While the modifications increase oxygen transmission in any scleral lens design, they also distribute the lens mass closer to the limbus and make visualization of corneal clearance, especially narrow in the limbal region, more difficult. The sequelae from mechanical interaction between scleral lenses and the ocular surface, in particular the cornea, remain uncertain. This case series will describe corneal epithelial bullae, molding, and epithelial erosions as unintended scleral lens complications. These corneal changes corresponded to areas of contact lens-corneal bearing confirmed utilizing a combined scanning laser ophthalmoscopy (SLO) and anterior segment OCT. This case series will discuss epithelial bullae detection, their etiology, and suggestions for application of this information into scleral lens fitting protocols.

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.

The association between the foveal avascular zone and retinal thickness.

PURPOSE: To investigate the association between the size and shape of the foveal avascular zone and retinal thickness in healthy subjects. METHODS: In vivo imaging of the foveal microvasculature was performed on 32 subjects by using an adaptive optics scanning laser ophthalmoscope (AOSLO). Motion contrast maps of the AOSLO images were used to generate a montage revealing the foveal capillary network. Foveal avascular zone (FAZ) diameters along the horizontal (FAZH) and vertical (FAZV) meridians were measured on the montages. An asymmetry index (AI) of the FAZ was then computed as the ratio of the FAZH to FAZV. Retinal thickness was investigated by using spectral-domain optical coherence tomography (SDOCT). Inner retinal layer (INLFAZ) thickness and outer nuclear layer (ONLFAZ) thickness were measured at the edges of the FAZ on the horizontal and vertical SDOCT scans on the same eye. RESULTS: The foveal capillary network was readily visualized in all subjects. As expected there was individual variation in the size and shape of the FAZ. Along the horizontal and vertical meridians, the mean±SD (µm) of the FAZ diameter was 607±217 and 574±155, respectively. The INLFAZ thickness was 68±9 and 66±9, and the ONLFAZ thickness was 103±13 and 105±11, respectively. The mean±SD of the AI was 1.03±0.27. The difference between FAZH and FAZV decreases with increasing FAZ area (P=0.004). Mean ONLFAZ was negatively correlated with FAZ effective diameter (P<0.0001). No significant correlation was found between mean INLFAZ and FAZ effective diameter (P=0.16). CONCLUSIONS: Despite large individual variations in size and shape of the FAZ, the INLFAZ has a relatively constant thickness at the margins of the FAZ, suggesting the presence of retinal capillaries is needed to sustain an INLFAZ thickness greater than 60 µm. A smaller FAZ area is associated with a vertically elongated FAZ.

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.

The use of forward scatter to improve retinal vascular imaging with an adaptive optics scanning laser ophthalmoscope.

Retinal vascular diseases are a leading cause of blindness and visual disability. The advent of adaptive optics retinal imaging has enabled us to image the retinal vascular at cellular resolutions, but imaging of the vasculature can be difficult due to the complex nature of the images, including features of many other retinal structures, such as the nerve fiber layer, glial and other cells. In this paper we show that varying the size and centration of the confocal aperture of an adaptive optics scanning laser ophthalmoscope (AOSLO) can increase sensitivity to multiply scattered light, especially light forward scattered from the vasculature and erythrocytes. The resulting technique was tested by imaging regions with different retinal tissue reflectivities as well as within the optic nerve head.

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.

Foveal phase retardation changes associated with normal aging.

This study quantified normal age-related changes to the photoreceptor axons in the central macula using the birefringent properties of the Henle fiber layer. A scanning laser polarimeter was used to acquire 15° × 15° macular images in 120 clinically normal subjects, ranging in age from the third decade to the eighth. Raw image data of the macular cross were used to compute phase retardation maps associated with Henle fiber layer. Annular regions of interest ranging from 0.25° to 3° eccentricity and centered on the fovea were used to generate intensity profiles from the phase retardation data, which were then analyzed using sine curve fitting and Fast Fourier Transform (FFT). The amplitude of a 2f sine curve was used as a measure of macular phase retardation magnitude. For FFT analysis, the 2f amplitude, as well as the 4f, were normalized by the remaining FFT components. The amplitude component of the 2f curve fit and the normalized 2f FFT component decreased as a function of age, while the eccentricity of the maximum value for the normalized 2f FFT component increased. The phase retardation changes in the central macula indicate structural alterations in the cone photoreceptor axons near the fovea as a function of age. These changes result in either fewer cone photoreceptors in the central macula, or a change in the orientation of their axons. This large sample size demonstrates systematic changes to the central cone photoreceptor morphology using scanning laser polarimetry.

Determination of foveal location using scanning laser polarimetry.

The fovea is the retinal location responsible for our most acute vision. There are several methods used to localize the fovea, but the fovea is not always easily identifiable. Landmarks used to determine the foveal location are variable in normal subjects and localization becomes even more difficult in instances of retinal disease. In normal subjects, the photoreceptor axons that make up the Henle fiber layer are cylindrical and the radial orientation of these fibers is centered on the fovea. The Henle fiber layer exhibits form birefringence, which predictably changes polarized light in scanning laser polarimetry imaging. In this study 3 graders were able to repeatably identify the fovea in 35 normal subjects using near infrared image types with differing polarization content. There was little intra-grader, inter-grader, and inter-image variability in the graded foveal position for 5 of the 6 image types examined, with accuracy sufficient for clinical purposes. This study demonstrates that scanning laser polarimetry imaging can localize the fovea by using structural properties inherent in the central macula.

Spatial distribution of macular birefringence associated with the Henle fibers.

The spatial distribution of macular birefringence was modeled to examine the contribution from the foveal Henle fiber layer, particularly cone axons. The model was tested in 20 normal subjects, age 17-55yr. Phase retardance due to Henle fibers was modeled for rings increasing in radius around the fovea, using a sinewave of two periods (2f). The 2f sinewave amplitude increased linearly with eccentricity for each individual, (p<0.004) in 19 of 20 subjects. A good fit to linearity implies regular cone distribution and radial symmetry, and the uniformly excellent fits indicate no effect of age in our sample. The peak of the 2f sinewave amplitude varied across subjects from 1.06 to 2.46deg. An increasingly eccentric peak with increasing age would indicate a relative decrease of cone axons in the central fovea, but the location of the peak was not associated with age for our sample, which did not include elderly subjects.

Imaging polarimetry in patients with neovascular age-related macular degeneration.

Imaging polarimetry was used to examine different components of neovascular membranes in age-related macular degeneration. Retinal images were acquired with a scanning laser polarimeter. An innovative pseudocolor scale, based on cardinal directions of color, displayed two types of image information: relative phases and magnitudes of birefringence. Membranes had relative phase changes that did not correspond to anatomical structures in reflectance images. Further, membrane borders in depolarized light images had significantly higher contrasts than those in reflectance images. The retinal birefringence in neovascular membranes indicates optical activity consistent with molecular changes rather than merely geometrical changes.