Zaid Mammo

Label-Free Density Measurements of Radial Peripapillary Capillaries in the Human Retina

Radial peripapillary capillaries (RPCs) comprise a unique network of capillary beds within the retinal nerve fibre layer (RNFL) and play a critical role in satisfying the nutritional requirements of retinal ganglion cell (RGC) axons. Understanding the topographical and morphological characteristics of these networks through in vivo techniques may improve our understanding about the role of RPCs in RGC axonal health and disease. This study utilizes a novel, non-invasive and label-free optical imaging technique, speckle variance optical coherence tomography (svOCT), for quantitatively studying RPC networks in the human retina. Six different retinal eccentricities from 16 healthy eyes were imaged using svOCT. The same eccentricities were histologically imaged in 9 healthy donor eyes with a confocal scanning laser microscope. Donor eyes were subject to perfusion-based labeling techniques prior to retinal dissection, flat mounting and visualization with the microscope. Capillary density and diameter measurements from each eccentricity in svOCT and histological images were compared. Data from svOCT images were also analysed to determine if there was a correlation between RNFL thickness and RPC density. The results are as follows: (1) The morphological characteristics of RPC networks on svOCT images are comparable to histological images; (2) With the exception of the nasal peripapillary region, there were no significant differences in RPC density measurements between svOCT and histological images; (3) Capillary diameter measurements were significantly greater in svOCT images compared to histology; (4) There is a positive correlation between RPC density and RNFL thickness. The findings in this study suggest that svOCT is a reliable modality for analyzing RPC networks in the human retina. It may therefore be a valuable tool for aiding our understanding about vasculogenic mechanisms that are involved in RGC axonopathies. Further work is required to explore the reason for some of the quantitative differences between svOCT and histology.

Quantitative Noninvasive Angiography of the Fovea Centralis Using Speckle Variance Optical Coherence Tomography

PURPOSE To demonstrate the utility of speckle variance optical coherence tomography (svOCT), a noninvasive angiographic technique, for evaluating the foveal vasculature. METHODS Twelve normal human eyes were imaged with svOCT (1060-nm, 100-kHz custom-built system) and fluorescein angiography (FA; Topcon TRC-50DX with 5.0 megapixel resolution camera). Manual tracing techniques were used to quantify the foveal vasculature, including foveal avascular zone (FAZ) metrics (area, perimeter, greatest diameter, and lowest diameter). Reproducibility of these measurements was determined. The FAZ was imaged in 25 normal eyes using svOCT and 15 donor eyes using confocal scanning laser microscopy. Retinal capillary plexuses in donor eyes were perfusion-labeled with phalloidin conjugated to Alexa Fluor 546. RESULTS Speckle variance OCT is able to stratify the foveal circulation into inner and deep capillary plexuses as well as reliably quantify and assess the morphometric dimensions of the human FAZ. Capillary density measurements were significantly greater in svOCT than FA (31.2 ± 1.6% vs. 19.3 ± 1.9% of total tissue area; P < 0.001). Measurements were highly reproducible (all P > 0.366). All FAZ metrics were significantly lower in histology than svOCT (all P < 0.001). CONCLUSIONS Speckle variance OCT permits precise, reproducible, and noninvasive visualization of the human foveal vasculature. Speckle variance OCT may become an important adjunct in evaluating patients with retinal vascular diseases.

In vivo optical imaging of human retinal capillary networks using speckle variance optical coherence tomography with quantitative clinico-histological correlation

Retinal capillary networks are critically linked to neuronal health and disease. The ability to perform accurate in vivo examination of human retinal capillary networks is therefore valuable for studying mechanisms that govern retinal homeostasis and retinal vascular diseases. Speckle variance optical coherence tomography (svOCT) is a non-invasive imaging technique that has the capacity to provide angiographic information about the retinal circulation. The application of this technology for studying human retinal capillary networks however has not been validated in a quantifiable manner. We use a custom-built svOCT device to qualitatively and quantitatively study the various capillary networks in the human perifovea. Capillary networks corresponding to the nerve fibre layer (NFL), the retinal ganglion cell/superficial inner plexiform layer (RGC/sIPL), the deep inner plexiform layer/superficial inner nuclear layer (dIPL/sINL) and the deep inner nuclear layer (dINL) are imaged in 9 normal human subjects. Measurements of capillary diameter and capillary density are made from each of these networks and results are compared to post-mortem histological data acquired with confocal scanning laser microscopy. Additionally, retinal capillary measurements from high-resolution fundus fluorescein angiogram (FA) are directly compared with svOCT images from 6 eyes. We demonstrate that svOCT images of capillary networks are morphologically comparable to microscopic images of histological specimens. Similar to histological images in svOCT images, the capillaries in the NFL network run parallel to the direction of RGC axons while capillaries in the dINL network comprise a planar configuration with multiple closed loops. Capillaries in remaining networks are convoluted with a complex three-dimensional architecture. We demonstrate that there is no significant difference in capillary density measurements between svOCT and histology images for all networks. Capillary diameter was significantly greater in svOCT images compared to histology for all networks. Capillary density measurements were also higher in svOCT compared to FA. The results of this study suggest that in vivo svOCT imaging allows accurate morphometric assessment of capillary networks in the human perifovea and may provide an improved ability to render microvascular detail compared to FA. Therefore, svOCT may have broad clinical applications in the study of human retinal physiology and disease. The difference in quantitative measurements between svOCT and histology may reflect dynamic variations in the retinal microcirculation and warrants further investigation.

Retinal angiography with real-time speckle variance optical coherence tomography

This report describes a novel, non-invasive and label-free optical imaging technique, speckle variance optical coherence tomography (svOCT), for visualising blood flow within human retinal capillary networks. This imaging system uses a custom-built swept source OCT system operating at a line rate of 100 kHz. Real-time processing and visualisation is implemented on a consumer grade graphics processing unit. To investigate the quality of microvascular detail acquired with this device we compared images of human capillary networks acquired with svOCT and fluorescein angiography. We found that the density of capillary microvasculature acquired with this svOCT device was visibly greater than fluorescein angiography. We also found that this svOCT device had the capacity to generate en face images of distinct capillary networks that are morphologically comparable with previously published histological studies. Finally, we found that this svOCT device has the ability to non-invasively illustrate the common manifestations of diabetic retinopathy and retinal vascular occlusion. The results of this study suggest that graphics processing unit accelerated svOCT has the potential to non-invasively provide useful quantitative information about human retinal capillary networks. Therefore svOCT may have clinical and research applications for the management of retinal microvascular diseases, which are a major cause of visual morbidity worldwide.

Quantitative Comparison of Retinal Capillary Images Derived By Speckle Variance Optical Coherence Tomography With Histology.

PURPOSE The purpose of this study was to correlate human retinal capillary network information derived from a prototype speckle variance optical coherence tomography (svOCT) device with histology to determine the utility of this instrument for quantitative angiography. METHODS A retina location 3 mm superior to the optic disk was imaged with svOCT in 14 healthy human eyes. Qualitative and quantitative features of capillary networks, including capillary diameter and density, were compared with perfusion-labeled histological specimens from the same eccentricity. Twelve human donor eyes with no history of eye disease were used for histological comparisons. RESULTS svOCT was able to clearly distinguish the morphological features of the nerve fiber layer capillary network, the retinal ganglion cell (RGC) layer capillary network, the capillary network at the border of the inner plexiform layer and superficial boundary of the inner nuclear layer, and the capillary network at the boundary of the deep inner nuclear layer and outer plexiform layer. The morphological features of these networks were highly comparable to those in previous histological studies. There were no statistical differences in mean capillary diameter between svOCT images and histology for all networks other than the RGC capillary network. Capillary density measurements were significantly greater in svOCT images, except in the RGC capillary network. CONCLUSIONS svOCT has the capacity to provide histology-like anatomical information about human retinal capillary networks in vivo. It may have great potential as a research and diagnostic tool in the management of retinal vascular diseases. Further work is required to clarify the cause of some quantitative differences between svOCT and histology.

Segmentation of the foveal microvasculature using deep learning networks

Abstract. Accurate segmentation of the retinal microvasculature is a critical step in the quantitative analysis of the retinal circulation, which can be an important marker in evaluating the severity of retinal diseases. As manual segmentation remains the gold standard for segmentation of optical coherence tomography angiography (OCT-A) images, we present a method for automating the segmentation of OCT-A images using deep neural networks (DNNs). Eighty OCT-A images of the foveal region in 12 eyes from 6 healthy volunteers were acquired using a prototype OCT-A system and subsequently manually segmented. The automated segmentation of the blood vessels in the OCT-A images was then performed by classifying each pixel into vessel or nonvessel class using deep convolutional neural networks. When the automated results were compared against the manual segmentation results, a maximum mean accuracy of 0.83 was obtained. When the automated results were compared with inter and intrarater accuracies, the automated results were shown to be comparable to the human raters suggesting that segmentation using DNNs is comparable to a second manual rater. As manually segmenting the retinal microvasculature is a tedious task, having a reliable automated output such as automated segmentation by DNNs, is an important step in creating an automated output.

Strip-based registration of serially acquired optical coherence tomography angiography

Abstract. The visibility of retinal microvasculature in optical coherence tomography angiography (OCT-A) images is negatively affected by the small dimension of the capillaries, pulsatile blood flow, and motion artifacts. Serial acquisition and time-averaging of multiple OCT-A images can enhance the definition of the capillaries and result in repeatable and consistent visualization. We demonstrate an automated method for registration and averaging of serially acquired OCT-A images. Ten OCT-A volumes from six normal control subjects were acquired using our prototype 1060-nm swept source OCT system. The volumes were divided into microsaccade-free en face angiogram strips, which were affine registered using scale-invariant feature transform keypoints, followed by nonrigid registration by pixel-wise local neighborhood matching. The resulting averaged images were presented of all the retinal layers combined, as well as in the superficial and deep plexus layers separately. The contrast-to-noise ratio and signal-to-noise ratio of the angiograms with all retinal layers (reported as average±standard deviation) increased from 0.52±0.22 and 19.58±4.04  dB for a single image to 0.77±0.25 and 25.05±4.73  dB, respectively, for the serially acquired images after registration and averaging. The improved visualization of the capillaries can enable robust quantification and study of minute changes in retinal microvasculature.

Oral Bisphosphonates and Risk of Wet Age-Related Macular Degeneration

PURPOSE To examine the risk of age-related macular degeneration (AMD) with oral bisphosphonates. DESIGN Three study designs were used: (1) disproportionality analysis; (2) case-control study; (3) self-controlled case series (SCCS). METHODS setting: (1) Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) Database; (2) 2 patient cohorts from British Columbia, Canada. STUDY POPULATION (1) All reports of AMD to the FDA with oral bisphosphoantes; (2) patients with wet AMD in British Columbia (2009-2013) and 1 million controls (2000-2007). INTERVENTION Oral bisphosphonates. MAIN OUTCOME MEASURES (1) Reports of AMD to the FDA; (2) first diagnosis of wet AMD verified by a retina specialist in British Columbia. RESULTS In the disproportionality analysis there were 133 cases of AMD reported with alendronate, 20 with ibandronate, and 14 with risedronate. The reported odds ratios (RORs) for alendronate, ibandronate, and risedronate were 3.82 (95% CI: 2.94-4.96), 2.40 (95% CI: 1.49-3.86), and 2.87 (95% CI: 1.58-5.19), respectively. In the case-control analysis there were 6367 cases and 6370 corresponding controls. The adjusted OR for wet AMD among regular users of bisphosphonates in the 1, 2, and 3 years prior to the index date were 1.24 (1.12-1.38), 1.38 (1.22-1.56), and 1.59 (1.38-1.82), respectively. In the SCCS analysis there were 198 cases of wet AMD on continuous bisphosphonate therapy. The rate ratio for wet AMD for continuous bisphosphonate use was 1.99 (95% CI: 1.41-2.79). We did not have information on intravenous bisphosphonates. CONCLUSIONS Continuous users of oral bisphosphonates are at a higher risk of developing wet AMD. Given the observational nature of this study and limitation of the data, future studies are needed to confirm these findings.

Vascular endothelial growth factor inhibitor use and treatment approach for choroidal neovascularization secondary to pathologic myopia.

ABSTRACT Introduction: Myopic choroidal neovascularization (CNV) is the most common cause of CNV in those under 50 years of age. It is a significant cause of visual loss in those with pathologic myopia. The current standard of care involves therapy with intravitreal inhibitors of vascular endothelial growth factor (VEGF). Areas Covered: The epidemiology of myopia, high myopia, pathologic myopia, and myopic CNV is reviewed, along with a brief discussion of historical treatments. The pharmacology of the three most commonly used anti-VEGF agents is discussed, with an emphasis on the licensed drugs, ranibizumab and aflibercept. A comprehensive clinical approach to diagnosis and treatment of myopic CNV is presented. Expert Opinion: The current standard of care for myopic CNV is intravitreal inhibition of VEGF, with ranibizumab and aflibercept licensed for intraocular use. The diagnosis, OCT features of disease activity and retreatment algorithm for myopic CNV is different from wet age-related macular degeneration. In the long-term, myopic CNV may be associated with gradual, irreversible visual loss due to progressive chorioretinal atrophy, for which there is currently no treatment.

Comparison of ophthalmic training in 6 English-speaking countries

OBJECTIVE To compare key characteristics of ophthalmology training programs in 6 different English-speaking countries: Australia, New Zealand, Canada, Ireland, the United Kingdom, and the United States. PARTICIPANTS Seven ophthalmologists with personal knowledge of all 6 systems contributed. METHODS The main features examined were career pathway, duration of training, surgical training, governing bodies, and examination structure. Data were collected from the literature, online resources, and personal experience. RESULTS Several differences were highlighted, including length of training (ranging from 4 to 9 years after medical school), number of surgical procedures such as cataracts (ranging from minimum 86 to approximately 600), and structure of fellowship training. CONCLUSIONS As trainees increasingly seek international experience to enhance their knowledge and skills, the similarities and differences between training programs in different countries have become more relevant. Some of these differences may reflect differing needs of different patient populations and different healthcare delivery systems across the globe. However, these differences should also prompt educators to more carefully scrutinize their own training system and search for potential improvements.