THE WAY PATIENTS SEE FLOATERS: Widefield Dynamic Scanning Laser Ophthalmoscopy Imaging of Vitreous Abnormalities.

PURPOSE: To investigate the use of dynamic widefield scanning laser ophthalmoscopy (SLO) and B-scan ultrasonography in imaging vitreous abnormalities in patients with complaints of floaters. METHODS: Twenty-one patients underwent both dynamic SLO and B-scan ultrasonography to image their vitreous abnormalities. After reviewing these videos, patients graded each imaging technique on a scale of 1 to 10, based on how closely it represented their visual perception of floaters. RESULTS: The mean age of the patients (12 women and nine men) was 47.7 ± 18.5 years. The patients graded a median score of nine for SLO imaging (mean = 8.43) compared with a median score of 5 (mean = 4.95) for ultrasound ( P = 0.001). Widefield SLO imaging demonstrated three-dimensional interconnectivity within the condensations of the formed vitreous that exhibited translational and rotational movements with eye saccades. CONCLUSION: Floaters are a common complaint, but it is difficult to know whether imaging findings of the vitreous correlate to what patients perceive. Widefield SLO seems to image vitreous abnormalities related to how patients perceive their own floaters better than B-scan ultrasonography. Despite the term "floaters", the vitreous abnormalities in the videos seemed to be manifestations of a complex three-dimensional degeneration of the vitreous framework.

DENOISING SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY VOLUMETRIC SCANS USING A DEEP LEARNING MODEL.

PURPOSE: To evaluate the use of a deep learning noise reduction model on swept source optical coherence tomography volumetric scans. METHODS: Three groups of images including single-line highly averaged foveal scans (averaged images), foveal B-scans from volumetric scans using no averaging (unaveraged images), and deep learning denoised versions of the latter (denoised images) were obtained. We evaluated the potential increase in the signal-to-noise ratio by evaluating the contrast-to-noise ratio of the resultant images and measured the multiscale structural similarity index to determine whether the unaveraged and denoised images held true in structure to the averaged images. We evaluated the practical effects of denoising on a popular metric of choroidal vascularity known as the choroidal vascularity index. RESULTS: Ten eyes of 10 subjects with a mean age of 31 years (range 24-64 years) were evaluated. The deep choroidal contrast-to-noise ratio mean values of the averaged and denoised image groups were similar (7.06 vs. 6.81, P = 0.75), and both groups had better maximum contrast-to-noise ratio mean values (27.65 and 46.34) than the unaveraged group (14.75; P = 0.001 and P < 0.001, respectively). The mean multiscale structural similarity index of the average-denoised images was significantly higher than the one from the averaged--unaveraged images (0.85 vs. 0.61, P < 0.001). Choroidal vascularity index values from averaged and denoised images were similar (71.81 vs. 71.16, P = 0.554). CONCLUSION: Using three different metrics, we demonstrated that the deep learning denoising model can produce high-quality images that emulate, and may exceed, the quality of highly averaged scans.

SUBRETINAL DRUSENOID DEPOSITS AND SOFT DRUSEN: Are They Markers for Distinct Retinal Diseases?

PURPOSE: Soft drusen and subretinal drusenoid deposits (SDDs) characterize two pathways to advanced age-related macular degeneration (AMD), with distinct genetic risks, serum risks, and associated systemic diseases. METHODS: One hundred and twenty-six subjects with AMD were classified as SDD (with or without soft drusen) or non-SDD (drusen only) by retinal imaging, with serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke. RESULTS: There were 62 subjects with SDD and 64 non-SDD subjects, of whom 51 had CVD or stroke. SDD correlated significantly with lower mean serum high-density lipoprotein (61 ± 18 vs. 69 ± 22 mg/dL, P = 0.038, t-test), CVD and stroke (34 of 51 SDD, P = 0.001, chi square), ARMS2 risk allele (P = 0.019, chi square), but not with CFH risk allele (P = 0.66). Non-SDD (drusen only) correlated/trended with APOE2 (P = 0.032) and CETP (P = 0.072) risk alleles (chi square). Multivariate independent risks for SDD were CVD and stroke (P = 0.008) and ARMS2 homozygous risk (P = 0.038). CONCLUSION: Subjects with subretinal drusenoid deposits and non-SDD subjects have distinct systemic associations and serum and genetic risks. Subretinal drusenoid deposits are associated with CVD and stroke, ARMS2 risk, and lower high-density lipoprotein; non-SDDs are associated with higher high-density lipoprotein, CFH risk, and two lipid risk genes. These and other distinct associations suggest that these lesions are markers for distinct diseases.

CHORIOCAPILLARIS VASCULAR PARAMETERS IN NORMAL EYES AND THOSE WITH PACHYCHOROID WITH AND WITHOUT DISEASE.

PURPOSE: To evaluate the vascular characteristics of the choriocapillaris in eyes with pachychoroid as compared with normal controls. METHODS: Eyes with pachychoroid disease were defined as those with a history of central serous chorioretinopathy or peripapillary pachychoroid syndrome. Pachychoroid without disease was defined as eyes with no history of disease with a subfoveal choroidal thickness ≥ the age-adjusted 95th percentile thickness. Frame-averaged optical coherence tomography angiography images of the choriocapillaris obtained with a Zeiss Plex Elite were binarized, skeletonized, and evaluated for vascular branching parameters. RESULTS: There were 7 normal control subjects, 10 subjects with pachychoroid without disease, and 17 pachychoroid disease subjects. Mean choriocapillaris vessel segment length was 12.19 µm in eyes with pachychoroid disease as compared with 11.48 µm in normal controls and 11.62 µm in pachychoroid without disease (P = 0.003 and P = 0.006, respectively). The branches per square millimeter were fewer in pachychoroid disease (1,215), as compared with normal controls (1,471) or pachychoroid without disease (1,384; P < 0.001, and P = 0.002, respectively). The choriocapillaris vessel diameter was larger, but the fractal dimension was smaller in pachychoroid disease eyes as compared with normal eyes or pachychoroid without disease eyes. There was no statistically significant difference between normal controls and pachychoroid without disease for any measured vascular parameter of the choriocapillaris. CONCLUSION: Choriocapillaris vascular parameters suggest that pachychoroid is not necessarily pathologic. It is possible that choroidal thickening is an epiphenomenon, and there are more significant vascular parameters that are related to disease. These concepts may help guide future prospective studies.

SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGING OF THE CHORIOCAPILLARIS.

PURPOSE: To analyze swept-source optical coherence angiography images acquired at different depths above and below the default location of the Zeiss PLEX Elite 9000. METHODS: Normal eyes of subjects in their 20s and 30s were evaluated. Angiographic slab images were taken at the default location of 29 µm to 49 µm below the retinal pigment epithelium and 21 µm to 41 µm through 52 µm to 72 µm below in steps. The images were processed using the projection removal function from the device's software. Raw images were evaluated, as were images that underwent a published compensation technique that adjusts for light penetration to the sampled layer. RESULTS: Eleven eyes of 11 subjects were evaluated for the uncompensated and the compensated sets with the projection removal function turned off and on. The default location, 29 µm to 49 µm below the retinal pigment epithelium, showed a granular choriocapillaris appearance. This appearance remained in all slabs from each group, differing slightly throughout depth. The projection removal function modified the grayscale values and diminished projection from overlaying retinal vessels. The compensation technique altered the appearance of flow deficits, and the changes induced by it were more evident on the images were the projection removal function was turned on. CONCLUSION: Flow images in swept-source optical coherence angiography of the choriocapillaris from varying levels are similar in appearance, suggesting projection from the choriocapillaris is important in image formation, although layers of vessels in the inner choroid may contribute by various amounts. A model explaining the prominent projection artifacts observed in the choroid with swept-source optical coherence angiography imaging is presented.

INTERVORTEX VENOUS ANASTOMOSIS IN Pachychoroid-RELATED DISORDERS.

PURPOSE: To evaluate the choroidal vascular patterns of patients with pachychoroid-related diseases in eyes images with wide-field indocyanine green angiography. METHODS: Retrospective study of wide-field indocyanine green angiographic images of patients with pachychoroid, peripapillary pachychoroid syndrome, central serous chorioretinopathy, and pachychoroid-associated neovascularization that were evaluated for anastomoses between vortex vein systems, which are ordinarily separated by a watershed zone. RESULTS: There were 21 subjects with a mean age of 57.4 years and 15 were male. Among the 42 eyes evaluated, central serous chorioretinopathy was found in 24 eyes (57.1%), peripapillary pachychoroid syndrome in 5 (11.9%), pachychoroid associated neovascularization in 7 (16.7%), and pachychoroid in 6 (14.3%). Every eye showed anastomosis between the superonasal, superotemporal, and inferotemporal vortex vein systems. The inferonasal vortex vein system was less likely to demonstrate anastomosis except for peripapillary pachychoroid syndrome, which showed anastomosis in all eyes. The anastomotic connections were prominent in the central macula in the central serous chorioretinopathy and pachychoroid-associated neovascularization cases, and around the nerve in the peripapillary pachychoroid syndrome cases. Although the large choroidal veins were particularly prominent in the neovascular cases, the number was fewer in the macular region than in other pachychoroid-related diseases in this series. Compared with a control group of nine eyes, the inferotemporal-superotemporal-superonasal anastomotic connections were more common in the case group (P < 0.001) and inferonasal quadrant (P = 0.023 right eye; P = 0.01, left eye). CONCLUSION: Intervortex venous anastomosis is common in pachychoroid, central serous chorioretinopathy, peripapillary pachychoroid syndrome, and pachychoroid-associated neovascularization. This finding has important implications concerning pathogenesis and classification of disease.

VARYING OPTICAL COHERENCE TOMOGRAPHY APPEARANCE OF THE INNER CHOROID WITH AGE: Possible Explanation and Histologic Correlate.

PURPOSE: To investigate the reflectivity of the structural optical coherence tomography images of the inner choroid as it relates to potential structural composition. METHODS: The reflectivity of slab images 29 to 49 µm and 45 to 65 µm below the retinal pigment epithelium, obtained with the Zeiss Plex Elite 9000, was evaluated. The mean and SD of a group of subjects with no ocular disorders were determined. Binarization of the images was performed and a threshold level established at the mean plus one SD for each slab depth. The proportion of area binarized was evaluated with generalized estimating equations. Representative histologic images obtained from autopsy donors were stained with Masson's trichrome, a staining method helpful in evaluating collagen and ground substance of tissue. RESULTS: There were 67 eyes of 38 subjects with a mean age of 44.5 (range 22-82) years. Using generalized estimating equations, age was found to be a significant predictor for the proportion of binarized pixels in both the 29 to 49 µm (P = 0.034) and the 45 to 65 µm (P < 0.001) slabs. The histologic specimens illustrated the loss of ground substance with increasing compaction of collagen fibers in the choroidal stroma with advancing age. CONCLUSION: The reflectivity from the inner choroid is not uniform and changes with age. As suggested by the histologic specimens, we propose the optical coherence tomography reflectance from the inner choroid is related, in part, to the packing density of collagen fibers present there.

CLINICAL UTILITY OF MORPHOFUNCTIONAL CORRELATION OF MICROPERIMETRY AND OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To demonstrate the clinical and research value of a simplified technique enabling alignment of functional microperimetry data with retinal structure imaged by eye-tracked optical coherence tomography (OCT) in eyes with macular disease. METHODS: Normal and diseased eyes underwent sequential Spectralis OCT macular raster scans and Macular Integrity Assessment microperimetry using both standard central 10° analysis and custom scan patterns. The microperimetry data were imported into Spectralis research software program, which was automatically registered to the scanning laser ophthalmoscopy near-infrared reflectance image obtained during OCT acquisition. The OCT B-scans were directly correlated with the microperimetry data so that retina sensitivity and retinal microstructure at corresponding points could be evaluated simultaneously. RESULTS: Seventy eyes of 41 patients (110 studies) aged 22 years to 95 years (mean 63.5 ± 18.0 years) with both normal and pathologic macular changes were included. The mean Macular Integrity Assessment retina sensitivity of all 110 studies was 22.2 ± 4.9 (range: 0.1-30.3). Retinal sensitivity showed good correspondence in structural changes seen on OCT B-scans. CONCLUSION: We demonstrate a practical method to align retina sensitivity data to anatomical tomographic findings. This technique provides data not obtainable with standard visual acuity measures.

NOVEL METHOD FOR IMAGE AVERAGING OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGES.

PURPOSE: To develop a method of averaging optical coherence tomography (OCT) angiography to improve visualization of choriocapillaris structure. METHODS: A stack of OCT angiographic data from vascular layers were placed into the red-green-blue channels of a conventional digital color image. The superficial plexus was placed in the blue channel, choriocapillaris in the green, and deep vascular plexus in the red channel. The red-green-blue images derived from nine separate OCT angiographic scans were registered using an automatic registration sequence and the images were averaged. The averaged red-green-blue image was then split into the three averaged component layers. The technique is flexible and any vascular layer, such as macular neovascularization, can be used as well. RESULTS: The utility of the imaging method was demonstrated by showing the imaging of two different diseases. A patient with a history of familial amyloidosis, hypertension, kidney failure, kidney transplantation, and prednisone use, followed by central serous chorioretinopathy treated by photodynamic therapy. She had alterations in retinal pigment epithelial pigmentation and widespread abnormalities of autofluorescence. She showed remarkably decreased vascular density and vessel configuration of her choriocapillaris. A patient with pseudoxanthoma elasticum with subretinal drusenoid deposits at an early age also showed marked decreased choriocapillaris density and vascular configuration. These findings were compared with healthy controls of similar age with no abnormalities. CONCLUSION: The detailed method is capable of averaging choriocapillaris OCT angiographic images using a simple automatic method. Image averaging offers opportunity to improve the noisy OCT angiographic images such that actual vascular structure is visible.

SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGE COMPENSATION OF THE CHORIOCAPILLARIS INDUCES ARTIFACTS.

PURPOSE: To analyze swept-source optical coherence angiography slab images acquired at the default level for the choriocapillaris from the Zeiss PLEX Elite 9000 before and after using a previously described imaging compensation technique. METHODS: Eyes of normal subjects, in their 20 seconds and 30 seconds, were evaluated. Angiographic slab images, 20 µm in thickness, were taken at the default location of 29 to 49 µm below the retinal pigment epithelium. These images were evaluated, as were images that underwent a published compensation technique that adjusts for light penetration to the sampled layer. Each set of images was threshold at 1 SD below the mean. Visual comparison of the swept-source optical coherence angiography images along with a quantitative analysis using a novel parameter known as multiscale structural similarity index, a measure of image similarity, was performed. RESULTS: Eleven eyes of 11 subjects were evaluated. The default location, 29 µm to 49 µm below the retinal pigment epithelium, showed the granular choriocapillaris appearance. Visual comparison showed that the compensation technique altered the appearance of the thresholded images, creating the appearance of new deficits while causing others to disappear. The mean multiscale structural similarity index for the original versus thresholded images and original versus thresholded compensated was 0.49 and 0.34, respectively, representing a statistically significant difference. CONCLUSION: The findings of this study show that the use of a commonly used imaging compensation technique can have undesired effects on the image, and its use should be carefully considered. A model explaining the cause of such changes in the choriocapillaris swept-source optical coherence angiography images is presented.

PAX6 allelic heterogeneity in Mexican congenital aniridia patients: expanding the mutational spectrum with seven novel pathogenic variants.

IMPORTANCE: The importance of the study was to describe the clinical characteristics and mutational analysis of Mexican patients with aniridia. BACKGROUND: Aniridia is a panocular hereditary eye disease caused by mutations in the PAX6 transcription factor. Mutation detection rate is highly variable ranging from 30% to 90% in different populations. Very few studies have been published about the PAX6 mutational analysis in aniridia patients from Mexico. In order to establish a more representative PAX6 mutational frequency in the country, a cohort of 22 Mexican unrelated aniridia probands were analysed in this study. DESIGN: Case series. PARTICIPANTS: A total of 22 Mexican probands with bilateral isolated aniridia and their available relatives were included. METHODS: Sanger sequencing was used for the mutational analysis of all coding exons and flanking intronic regions of PAX6. MAIN OUTCOME MEASURES: Clinical characteristics and results of PAX6 mutational analysis in probands with aniridia and available family members. RESULTS: Molecular analysis of PAX6 in 22 index cases with aniridia allowed the identification of a total of 16 different mutations. Seven of these pathogenic variants are novel, including c.183C>G, p.(Y61*); c.718delC, p.(R240Efs*3); c.1149_1152delTCAG, p.(P385Wfs*139); c.257_266delAAATAGCCCA, p.(K86Sfs*35); c.836_843dupGCAACACA p.(P282Afs*86); c.1032+2_1032+3insT; and c.141+2T>A. Inter and intrafamilial phenotypic heterogeneity was found. CONCLUSIONS AND RELEVANCE: The mutational diagnostic rate in this series was 77%, which is comparable with reports from other populations. Importantly, no founder mutations were identified in this case series. Our results add 7 novel PAX6 pathogenic variants to the aniridia-related mutational spectrum and reveal considerable PAX6 allelic heterogeneity in this population.

Macular atrophy and focal choroidal excavation in a patient with JAG1- related alagille syndrome.

INTRODUCTION: Alagille syndrome (AGS) is a genetic disease with multisystemic affection, including ocular manifestations. Recently, a high frequency of posterior segment findings, including macular changes, has been reported. This publication aims to report an unusual finding of macular atrophy and a focal choroidal excavation in a patient with JAG1 related AGS. METHODS: Case report. RESULTS: This publication describes an atypical presentation of focal choroidal excavation (FCE) and unilateral macular atrophy in a 7-year-old male with Alagille syndrome (AGS). Genetic analysis revealed a pathogenic variant in the JAG1 gene. Ophthalmological examination and imaging findings demonstrated characteristic ocular manifestations of AGS, including posterior embryotoxon, chorioretinal atrophy, and thinning of the choroid. CONCLUSION: The presence of FCE in AGS is uncommon, and the underlying mechanisms remain unclear. Further exploration of similar cases is necessary to better understand the evolution and visual prognosis in patients with AGS and FCE.

This case report highlights the presence of focal choroidal excavation and unilateral macular atrophy in a patient with Alagille syndrome. The genetic analysis identified a pathogenic variant in the JAG1 gene.

Quantifying cardiac dysfunction and valvular heart disease associated with subretinal drusenoid deposits in age-related macular degeneration.

BACKGROUND/AIMS: Demonstrate through objective multidisciplinary imaging that subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are linked to both coexistent valvular heart disease (VHD) and reduced systemic perfusion via cardiac index (CI). METHODS: Post-hoc analysis of cross-sectional study. 200 intermediate AMD (iAMD) subjects were assigned by masked readers to two groups: SDD (with or without drusen) and drusen (only) based on multimodal ophthalmic imaging. 65 transthoracic echocardiograms (TTEs) reports were available for cardiologist evaluation of VHD severity of the four cardiac valves and the presences of precursor lesions of aortic sclerosis (ASc) and mitral annular calcification (MAC). Necessary parameters to calculate CI were also obtained. Univariate testing was performed using Fisher's Exact test and t-test. RESULTS: 82.6% (19/23) of the iAMD subjects with at least one moderate/severe VHD had concurrent SDDs (p = 0.0040). All cases of aortic regurgitation (6/6, p = 0.0370) and mitral regurgitation (13/13, p = 0.0004) were found with coexisting SDDs. Stenotic VHD was not significantly associated with SDDs, however 70.7% of subjects with ASc (29/41, p = 0.0108) and 76.0% of subjects with MAC (19/25, 0.0377) had coexisting SDDs. CI was available in 48 subjects and was significantly below normal levels in the SDD cohort (mean CI SDD 1.95 ± 0.60 L/min/m2, non-SDD 2.71 ± 0.73 L/min/m2, p = 0.0004). CONCLUSIONS: Several specific VHDs have been found associated with the SDD form of AMD. Decreased systemic perfusion as measured by CI was also associated with SDDs, which supports a perfusion hypothesis of SDD pathogenesis. Further research is warranted to understand the relationship between cardiovascular disease and SDDs.

Correlation between ellipsoid zone thickness and the presence of subretinal drusenoid deposits in age-related macular degeneration.

PURPOSE: Subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are associated with systemic vascular diseases that compromise ocular perfusion. We demonstrate that SDDs are associated with decreased ellipsoid zone (EZ) thickness, further evidence of hypoxic damage. METHODS: Post hoc analysis of a cross-sectional study. 165 AMD subjects (aged 51-100; 61% women). Spectral-domain optical coherence tomography was obtained in both eyes. Masked readers assigned subjects to three groups: drusen only, SDD+drusen (SDD+D) and SDD only. EZ thickness was measured subfoveally and 2000 µm nasally, temporally, superiorly and inferiorly from the fovea. Univariate testing was performed using two-tailed t-tests with Bonferroni correction. RESULTS: The mean EZ thickness differences between the SDD+D and drusen-only groups were (in µm) 1.10, 0.67, 1.21, 1.10 and 0.50 at the foveal, nasal, temporal, superior and inferior locations, respectively (p=0.08 inferiorly, otherwise p≤0.01); between the SDD-only and drusen-only groups, the differences were 3.48, 2.48, 2.42, 2.08 and 1.42 (p≤0.0002). Differences in EZ thicknesses across all subjects and between groups were not significantly different based on gender, race or age. CONCLUSION: Subjects with SDDs (±drusen) had thinner EZs than those with drusen only, and the inferior EZ was least affected. EZs were thinnest in SDD-only subjects. This thinning gradation is consistent with progressive destruction of highly oxygen-sensitive mitochondria in the EZ from hypoxia. These findings support the reduced ophthalmic perfusion hypothesis for the formation of SDDs secondary to high-risk systemic vasculopathy.

Subretinal drusenoid deposits, age-related macular degeneration, and cardiovascular disease.

Decades of studies on age-related macular degeneration (AMD), cardiovascular disease and stroke have not found consistent associations between AMD and systemic vascular disease. This study suggests that there is in fact no general relationship, but instead a strong, specific association between only the subretinal drusenoid deposit (SDD) phenotype of AMD on retinal imaging and certain co-existent vascular diseases that are high risk for compromised cardiac output or internal carotid artery stenosis. Future screening initiatives for these high -risk vascular diseases (HRVDs) with fast, inexpensive retinal imaging could make a significant contribution to public health and save lives. Likewise, screening patients with known HRVDs for unrecognized AMD of the SDD form could enable needed treatment and save vision.