Richard B. Rosen

Assessment of Perfused Foveal Microvascular Density and Identification of Nonperfused Capillaries in Healthy and Vasculopathic Eyes

PURPOSEnTo analyze the foveal microvasculature of young healthy eyes and older vasculopathic eyes, imaged using in vivo adaptive optics scanning light ophthalmoscope fluorescein angiography (AOSLO FA).nnnMETHODSnAOSLO FA imaging of the superficial retinal microvasculature within an 800-μm radius from the foveal center was performed using simultaneous confocal infrared (IR) reflectance (790 nm) and fluorescence (488 nm) channels. Corresponding IR structural and FA perfusion maps were compared with each other to identify nonperfused capillaries adjacent to the foveal avascular zone. Microvascular densities were calculated from skeletonized FA perfusion maps.nnnRESULTSnSixteen healthy adults (26 eyes; mean age 25 years, range, 21-29) and six patients with a retinal vasculopathy (six eyes; mean age 55 years, range, 44-70) were imaged. At least one nonperfused capillary was observed in five of the 16 healthy nonfellow eyes and in four of the six vasculopathic eyes. Compared with healthy eyes, capillary nonperfusion in the vasculopathic eyes was more extensive. Microvascular density of the 16 healthy nonfellow eyes was 42.0 ± 4.2 mm(-1) (range, 33-50 mm(-1)). All six vasculopathic eyes had decreased microvascular densities.nnnCONCLUSIONSnAOSLO FA provides an in vivo method for estimating foveal microvascular density and reveals occult nonperfused retinal capillaries. Nonperfused capillaries in healthy young adults may represent a normal variation and/or an early sign of pathology. Although limited, the normative data presented here is a step toward developing clinically useful microvascular parameters for ocular and/or systemic diseases.

Classification of Human Retinal Microaneurysms Using Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography

PURPOSEnMicroaneurysms (MAs) are considered a hallmark of retinal vascular disease, yet what little is known about them is mostly based upon histology, not clinical observation. Here, we use the recently developed adaptive optics scanning light ophthalmoscope (AOSLO) fluorescein angiography (FA) to image human MAs in vivo and to expand on previously described MA morphologic classification schemes.nnnMETHODSnPatients with vascular retinopathies (diabetic, hypertensive, and branch and central retinal vein occlusion) were imaged with reflectance AOSLO and AOSLO FA. Ninety-three MAs, from 14 eyes, were imaged and classified according to appearance into six morphologic groups: focal bulge, saccular, fusiform, mixed, pedunculated, and irregular. The MA perimeter, area, and feret maximum and minimum were correlated to morphology and retinal pathology. Select MAs were imaged longitudinally in two eyes.nnnRESULTSnAdaptive optics scanning light ophthalmoscope fluorescein angiography imaging revealed microscopic features of MAs not appreciated on conventional images. Saccular MAs were most prevalent (47%). No association was found between the type of retinal pathology and MA morphology (P = 0.44). Pedunculated and irregular MAs were among the largest MAs with average areas of 4188 and 4116 μm(2), respectively. Focal hypofluorescent regions were noted in 30% of MAs and were more likely to be associated with larger MAs (3086 vs. 1448 μm(2), P = 0.0001).nnnCONCLUSIONSnRetinal MAs can be classified in vivo into six different morphologic types, according to the geometry of their two-dimensional (2D) en face view. Adaptive optics scanning light ophthalmoscope fluorescein angiography imaging of MAs offers the possibility of studying microvascular change on a histologic scale, which may help our understanding of disease progression and treatment response.

Optical Coherence Tomography Angiography Analysis of Perfused Peripapillary Capillaries in Primary Open-Angle Glaucoma and Normal-Tension Glaucoma

PurposenTo compare perfused peripapillary capillary density in primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and normal patients using optical coherence tomography angiography (OCT-A).nnnMethodsnA retrospective review of POAG, NTG, and normal patients imaged with OCT-A was performed. En face OCT angiograms identifying peripapillary vessels were obtained using a spectral-domain OCT system (Avanti RTVue-XR). A custom image analysis approach identified perfused peripapillary capillaries, quantified perfused capillary density (PCD), and generated color-coded PCD maps for 3.5- and 4.5-mm-diameter scans. We compared PCD values, PCD maps, standard automated perimetry (Humphrey visual field [HVF]) parameters, and OCT retinal nerve fiber layer (RNFL) thickness analyses across all groups.nnnResultsnForty POAG, 26 NTG, and 26 normal patients were included. Annular PCD in POAG (34.24 ± 6.76%) and NTG (37.75 ± 3.52%) patients was significantly decreased compared to normal patients (42.99 ± 1.81%) in 4.5-mm scans (P < 0.01 and P < 0.01, respectively). Similar trends and statistical significances were seen in 3.5-mm scans. Linear regression analysis resulted in moderate correlations between annular PCD values and other glaucomatous parameters. Pearson coefficients comparing annular PCD from 4.5-mm scans in POAG and NTG groups to HVF mean deviation, HVF pattern standard deviation, and average RNFL thickness all showed statistical significance (P < 0.05). Color maps showed that POAG and NTG patients had a reduction of perfused capillaries that progressed in size when comparing early, moderate, and severe glaucoma groups.nnnConclusionsnOptical coherence tomography angiography can uniquely identify changes in peripapillary PCD in glaucoma patients. Optical coherence tomography angiography may offer insights into the pathophysiology of glaucomatous damage and risk factors for disease progression.

Adaptive optics imaging of healthy and abnormal regions of retinal nerve fiber bundles of patients with glaucoma.

PURPOSEnTo better understand the nature of glaucomatous damage of the macula, especially the structural changes seen between relatively healthy and clearly abnormal (AB) retinal regions, using an adaptive optics scanning light ophthalmoscope (AO-SLO).nnnMETHODSnAdaptive optics SLO images and optical coherence tomography (OCT) vertical line scans were obtained on one eye of seven glaucoma patients, with relatively deep local arcuate defects on the 10-2 visual field test in one (six eyes) or both hemifields (one eye). Based on the OCT images, the retinal nerve fiber (RNF) layer was divided into two regions: (1) within normal limits (WNL), relative RNF layer thickness within mean control values ±2 SD; and (2) AB, relative thickness less than -2 SD value.nnnRESULTSnAs seen on AO-SLO, the pattern of AB RNF bundles near the border of the WNL and AB regions differed across eyes. There were normal-appearing bundles in the WNL region of all eyes and AB-appearing bundles near the border with the AB region. This region with AB bundles ranged in extent from a few bundles to the entire AB region in the case of one eye. All other eyes had a large AB region without bundles. However, in two of these eyes, a few bundles were seen within this region of otherwise missing bundles.nnnCONCLUSIONSnThe AO-SLO images revealed details of glaucomatous damage that are difficult, if not impossible, to see with current OCT technology. Adaptive optics SLO may prove useful in following progression in clinical trials, or in disease management, if AO-SLO becomes widely available and easy to use.

Acircularity index and axis ratio of the foveal avascular zone in diabetic eyes and healthy controls measured by optical coherence tomography angiography

&NA; Given the complexity of the current system used to stage diabetic retinopathy (DR) and the risks and limitations associated with intravenous fluorescein angiography (IVFA), noninvasive quantification of DR severity is desirable. We examined the utility of acircularity index and axis ratio of the foveal avascular zone (FAZ), metrics that can noninvasively quantify the severity of diabetic retinopathy without the need for axial length to correct for individual retinal magnification. A retrospective review was performed of type 2 diabetics and age‐matched controls imaged with optical coherence tomography angiography (OCTA). Diabetic eyes were divided into three groups according to clinical features: No clinically observable diabetic retinopathy (NoDR), nonproliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). OCTAs of the superficial and deep vascular layers centered at the fovea were superimposed to form a full vascular layer on which the FAZ was manually traced. Acircularity index and axis ratio were calculated for each FAZ. Significant differences in acircularity index were observed between all groups except for controls vs. NoDR. Similar results were found for axis ratio, although there was no significant difference observed between NPDR and PDR. We demonstrate that acircularity index and axis ratio can be used to help noninvasively stage DR using OCTA, and show promise as methods to monitor disease progression and detect response to treatment. HighlightsAcircularity index and axis ratio can quantify FAZ abnormalities in diabetics.They do not require axial length measurement.They can be used to noninvasively stage severity of diabetic retinopathy using OCTA.These metrics show promise as methods to monitor disease over time.

Imaging Foveal Microvasculature: Optical Coherence Tomography Angiography Versus Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography.

Purpose To compare the use of optical coherence tomography angiography (OCTA) and adaptive optics scanning light ophthalmoscope fluorescein angiography (AOSLO FA) for characterizing the foveal microvasculature in healthy and vasculopathic eyes. Methods Four healthy controls and 11 vasculopathic patients (4 diabetic retinopathy, 4 retinal vein occlusion, and 3 sickle cell retinopathy) were imaged with OCTA and AOSLO FA. Foveal perfusion maps were semiautomatically skeletonized for quantitative analysis, which included foveal avascular zone (FAZ) metrics (area, perimeter, acircularity index) and vessel density in three concentric annular regions of interest. On each set of OCTA and AOSLO FA images, matching vessel segments were used for lumen diameter measurement. Qualitative image comparisons were performed by visual identification of microaneurysms, vessel loops, leakage, and vessel segments. Results Adaptive optics scanning light ophthalmoscope FA and OCTA showed no statistically significant differences in FAZ perimeter, acircularity index, and vessel densities. Foveal avascular zone area, however, showed a small but statistically significant difference of 1.8% (P = 0.004). Lumen diameter was significantly larger on OCTA (mean difference 5.7 μm, P < 0.001). Microaneurysms, fine structure of vessel loops, leakage, and some vessel segments were visible on AOSLO FA but not OCTA, while blood vessels obscured by leakage were visible only on OCTA. Conclusions Optical coherence tomography angiography is comparable to AOSLO FA at imaging the foveal microvasculature except for differences in FAZ area, lumen diameter, and some qualitative features. These results, together with its ease of use, short acquisition time, and avoidance of potentially phototoxic blue light, support OCTA as a tool for monitoring ocular pathology and detecting early disease.

Effects of Intraframe Distortion on Measures of Cone Mosaic Geometry from Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose To characterize the effects of intraframe distortion due to involuntary eye motion on measures of cone mosaic geometry derived from adaptive optics scanning light ophthalmoscope (AOSLO) images. Methods We acquired AOSLO image sequences from 20 subjects at 1.0, 2.0, and 5.0° temporal from fixation. An expert grader manually selected 10 minimally distorted reference frames from each 150-frame sequence for subsequent registration. Cone mosaic geometry was measured in all registered images (n = 600) using multiple metrics, and the repeatability of these metrics was used to assess the impact of the distortions from each reference frame. In nine additional subjects, we compared AOSLO-derived measurements to those from adaptive optics (AO)-fundus images, which do not contain system-imposed intraframe distortions. Results We observed substantial variation across subjects in the repeatability of density (1.2%–8.7%), inter-cell distance (0.8%–4.6%), percentage of six-sided Voronoi cells (0.8%–10.6%), and Voronoi cell area regularity (VCAR) (1.2%–13.2%). The average of all metrics extracted from AOSLO images (with the exception of VCAR) was not significantly different than those derived from AO-fundus images, though there was variability between individual images. Conclusions Our data demonstrate that the intraframe distortion found in AOSLO images can affect the accuracy and repeatability of cone mosaic metrics. It may be possible to use multiple images from the same retinal area to approximate a “distortionless” image, though more work is needed to evaluate the feasibility of this approach. Translational Relevance Even in subjects with good fixation, images from AOSLOs contain intraframe distortions due to eye motion during scanning. The existence of these artifacts emphasizes the need for caution when interpreting results derived from scanning instruments.

Macular pigment in retinal health and disease

Lutein and zeaxanthin, two carotenoid pigments of the xanthophyll subclass, are present in high concentrations in the retina, especially in the macula. They work as a filter protecting the macula from blue light and also as a resident antioxidant and free radical scavenger to reduce oxidative stress-induced damage. Many observational and interventional studies have suggested that lutein and zeaxanthin may reduce the risk of various eye diseases, especially late forms of AMD. In vitro and in vivo studies indicate that they could protect various ocular cells against oxidative damage. Recent research has shown that in addition to traditional mechanisms, lutein and zeaxanthin can influence the viability and function of cells through various signal pathways or transcription factors: for instance, they can affect immune responses and inflammation, and have anti-angiogenic and anti-tumor properties. This review covers the basic aspects and results of recent studies regarding the effects of lutein, zeaxanthin and other carotenoids, such as meso-zeaxanthin, on the eye in different clinical and experimental models and the management of various ocular diseases using these molecules.

En Face Optical Coherence Tomography Analysis to Assess the Spectrum of Perivenular Ischemia and Paracentral Acute Middle Maculopathy in Retinal Vein Occlusion

PURPOSEnTo assess the spectrum of perivenular ischemia in eyes with retinal vascular obstruction (typically central or hemicentral retinal vein obstruction) using en face optical coherence tomography (OCT).nnnDESIGNnRetrospective observational case series.nnnMETHODSnEyes with recent retinal vascular occlusion illustrating paracentral acute middle maculopathy (PAMM) in a perivenular fern-like pattern with en face OCT were evaluated in this study. Multimodal retinal imaging including en face OCT segmentation of the inner nuclear layer was performed in all patients. Color fundus photography and fluorescein angiography (FA) images were used to create a vascular overlay of the retinal veins vs the retinal arteries to map the distribution of PAMM with en face OCT analysis.nnnRESULTSnMultimodal retinal imaging was performed in 11 eyes with acute retinal vascular obstruction. While 7 eyes demonstrated obvious findings of retinal vein obstruction (5 with central and 2 with hemicentral retinalxa0vein occlusion), 4 eyes were unremarkable at presentation. En face OCT analysis demonstrated a spectrum of perivenular PAMM illustrating a fern-like pattern with sparing of the periarteriolar area in all cases.nnnCONCLUSIONnEn face OCT may illustrate a remarkable perivenular pattern of PAMM in eyes with retinal vascular obstruction even in the absence of significant funduscopic findings. Perivenular PAMM with en face OCT demonstrates a wide spectrum of variation with narrow fern-like perivenular lesions at the mildest end and more diffuse lesions with only periarterial sparing at the most severe end of the spectrum. Arterial hypoperfusion secondary to outflow obstruction from a central retinal vein obstruction appears to be the most common cause of this presentation, although primary arterial hypoperfusion may also be an etiology.

Longitudinal imaging of microvascular remodelling in proliferative diabetic retinopathy using adaptive optics scanning light ophthalmoscopy

To characterise longitudinal changes in the retinal microvasculature of type 2 diabetes mellitus (T2DM) as exemplified in a patient with proliferative diabetic retinopathy (PDR) using an adaptive optics scanning light ophthalmoscope (AOSLO).