Giant cell arteritis: diagnostic prediction models, temporal artery biopsy and epidemiology

Giant cell arteritis (GCA) is the most common primary vasculitis in the elderly and can cause irreversible blindness, aortitis, and stroke. Diagnostic confirmation of GCA usually entails temporal artery biopsy (TABx) – a time-consuming and invasive test, or ultrasound. The primary treatment of GCA is with high dose glucocorticoids that have numerous potential side effects. Glucocorticoids are initiated prior to the TABx result, due to the risk of interim blindness. By 2050 the cost of blindness from GCA in the United States is estimated at $76 billion with an additional$6 billion from glucocorticoid-induced fractures. This thesis examines knowledge gaps in the diagnosis and epidemiology of GCA. Needed refinements in the diagnosis of GCA included: i) the optimization of diagnostic prediction models (PMs) and ii) clarification of the contemporary utilization parameters of TABx. With regards to i) previous PMs are usually based on limited sample size, do not leverage sufficient clinical predictors, or include continuous variables, and not compliant with the transparent reporting guidelines for diagnostic PMs (TRIPOD). Using multicentre data of consecutive patients undergoing TABx, the largest (n=1,201) and most comprehensive logistic regression and, neural network PMs for GCA were formulated. Age, platelet level, jaw claudication and vision loss eventuated as the key predictor variables. An online risk calculator was developed from the PM and could decrease both the number of ABx performed on low-risk patients, and the morbidity from unneeded glucocorticoids. Regarding ii) although TABx has long been acknowledged as the gold standard test for GCA the current preference for TABx versus ultrasound amongst neuro-ophthalmologists and the utility rate of TABx are unknown. The thesis survey revealed that 91% of neuroophthalmologists preferred TABx over ultrasound as the confirmatory test for GCA. The first systematic review for the utility rate of TABx disclosed a median positive yield of 25% and provides a benchmark for institutions performing this procedure. Knowledge gaps in the epidemiology of GCA important for public health planning included the incidence of GCA in Ontario, Canada, and the controversial role of herpes zoster in the development of GCA given the advent of zoster vaccines. Pathology audit and an assay of billing data revealed the incidence of biopsy-proven GCA in Ontario to be 4.9 per 100,000 individuals 50 years of age or older. On ecologic analysis, the inverse relationship of the incidence rates of herpes zoster versus GCA per country suggested zoster is not a major immunopathogenic trigger for GCA. In summary, this thesis advances the diagnosis and epidemiology of GCA, most notably in the area of clinical prediction models that aid in the triage of patients with suspected GCA

The Retinal Microvasculature in Secondary Progressive Multiple Sclerosis

In light of new data regarding pathology of multiple sclerosis (MS), more research is needed into the vascular aspects of the disease. Demyelination caused by inflammation is historically thought of as the main cause of disability in the disease. Recent studies, however, have suggested that MS is in fact a spectrum of overlapping phenotypes consisting of inflammation, oxidative damage and hypoperfusion. The microvasculature plays an important role in all of these pathogenic processes and its dysfunction may therefore be of crucial importance to the development and progression of the disease. This thesis focuses on investigating the microvasculature of the retina as a surrogate for the brain by assessing the vascular structure, blood flow dynamics and oxygen transfer of the retinal blood vessels in secondary progressive multiple sclerosis (SPMS). Studying the retinal microvasculature using a multimodal imaging approach has allowed us to develop a more detailed understanding of blood flow in MS and to identify new imaging markers for trials into neuroprotective drugs in MS. The work done in this thesis demonstrated; i) a higher rate of retinal microvascular abnormalities in MS which progresses with disease severity, ii) evidence of retinal vascular remodelling in SPMS and iii) changes in blood velocity and flow in the retina in SPMS. These observations pave the way for future investigations into the mechanisms of vascular alterations and vascular dysfunction in MS, and provide a set of imaging markers to further explore other cerebrovascular diseases through the retina

Optical coherence tomography angiography

Optical coherence tomography (OCT) was one of the biggest advances in ophthalmic imaging. Building on that platform, OCT angiography (OCTA) provides depth resolved images of blood flow in the retina and choroid with levels of detailed far exceeding that obtained with older forms of imaging. This new modality is challenging because of the need for new equipment and processing techniques, current limitations of imaging capability, and rapid advancements in both imaging and in our understanding of the imaging and applicable pathophysiology of the retina and choroid, and the requirement for understanding the origins of image artifacts. These factors lead to a steep learning curve, even for those with a working understanding dye-based ocular angiography. All for a method of imaging that is a little more than 10 years old. This review begins with a historical account of the development of OCTA, and the methods used in OCTA, including signal processing, image generation, and display techniques. This forms the basis to understand what OCTA images show as well as how image artifacts arise. The anatomy and imaging of specific vascular layers of the eye are reviewed. The integration of OCTA in multimodal imaging in the evaluation of retinal vascular occlusive diseases, diabetic retinopathy, uveitis, inherited diseases, age-related macular degeneration, and disorders of the optic nerve is presented. OCTA is an exciting, disruptive technology. Its use is rapidly expanding in clinical practice as well as for research into the pathophysiology of diseases of the posterior pole

Glaucoma

This book addresses the basic and clinical science of glaucomas, a group of diseases that affect the optic nerve and visual fields and is usually accompanied by increased intraocular pressure. The book incorporates the latest development as well as future perspectives in glaucoma, since it has expedited publication. It is aimed for specialists in glaucoma, researchers, general ophthalmologists and trainees to increase knowledge and encourage further progress in understanding and managing these complicated diseases

Deep learning in ophthalmology: The technical and clinical considerations

The advent of computer graphic processing units, improvement in mathematical models and availability of big data has allowed artificial intelligence (AI) using machine learning (ML) and deep learning (DL) techniques to achieve robust performance for broad applications in social-media, the internet of things, the automotive industry and healthcare. DL systems in particular provide improved capability in image, speech and motion recognition as well as in natural language processing. In medicine, significant progress of AI and DL systems has been demonstrated in image-centric specialties such as radiology, dermatology, pathology and ophthalmology. New studies, including pre-registered prospective clinical trials, have shown DL systems are accurate and effective in detecting diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), retinopathy of prematurity, refractive error and in identifying cardiovascular risk factors and diseases, from digital fundus photographs. There is also increasing attention on the use of AI and DL systems in identifying disease features, progression and treatment response for retinal diseases such as neovascular AMD and diabetic macular edema using optical coherence tomography (OCT). Additionally, the application of ML to visual fields may be useful in detecting glaucoma progression. There are limited studies that incorporate clinical data including electronic health records, in AL and DL algorithms, and no prospective studies to demonstrate that AI and DL algorithms can predict the development of clinical eye disease. This article describes global eye disease burden, unmet needs and common conditions of public health importance for which AI and DL systems may be applicable. Technical and clinical aspects to build a DL system to address those needs, and the potential challenges for clinical adoption are discussed. AI, ML and DL will likely play a crucial role in clinical ophthalmology practice, with implications for screening, diagnosis and follow up of the major causes of vision impairment in the setting of ageing populations globally

Evaluation and Correlation of Morphological, Blood Flow and Physiological Retinal Changes in a Rat Model of Glaucoma with a Combined Optical Coherence Tomography and Electroretinography System

Glaucoma is a chronic disease associated with progressive dysfunction of the retinal ganglion cells (RGC), reduction of the retinal blood flow, thinning of the retinal nerve fiber layer (RNFL) and deformation of the optical nerve head (ONH). It is the second leading cause of blindness worldwide, with an estimate of 64.3 million people between the ages of 40 to 80 years affected in 2013, 76.7 million by 2020, and 111.8 million by 2040. Currently, there is no cure for glaucoma and any clinically available pharmaceutical or surgical approaches to treating the disease can only slow its progression. Therefore, early detection and treatment are essential for managing the glaucoma progression. Elevated intraocular pressure (IOP) is one of the most well studied and documented pathogenic risk factors for open-angle glaucoma (OAG), and as such, numerous animal models have been developed to study the acute and chronic IOP elevation effect on the ONH structure, retinal blood perfusion and RGC function. However, most of these studies utilized static chronic IOP elevation, while the relation between the IOP dynamics and the progression of glaucoma is still poorly understood. Joos et al proposed a rat model of glaucoma that utilized a dynamic approach to IOP elevation by use of a vascular loop that consists of short duration (~1h), intermittent IOP elevation. This model resembles closely the daily IOP spiking observed in glaucomatous patients, especially during the early stages of the disease. Better understanding of how the retina (human and animal) responds to such intermittent spikes of the IOP can provide ophthalmologists with valuable information on the origins and early stages of glaucoma development when treatment would be most efficient, as well as insights into developing new therapeutic approaches for glaucoma. Over the past few decades, a number of ex-vivo and in-vivo optical imaging modalities ranging from histopathology to confocal microscopy and optical coherence tomography (OCT) have been used to image changes in the morphology of the retina and the optic nerve head (ONH) in human subjects and animal models of OAG. Laser Doppler Flowmetry, Doppler OCT (DOCT) and Optical Coherence Angiography (OCTA) have been utilized to image and quantify changes in the total retinal blood flow and the blood perfusion in retinal capillaries during IOP elevation. Furthermore, electroretinography (ERG) has been used to assess changes in the retinal function (response to visual stimulation) during elevated IOP. However, all previous studies collected information about the morphological, functional and blood flow / perfusion changes in the retina during elevated IOP separately, at different time points, which prevented the researchers from correlating those changes and uncovering the relationship between them, typically referred to as neurovascular coupling. Since OCT provides both intensity and phase information in a single acquisition, this imaging technology is able to assess changes in the retinal morphology, function and blood flow/perfusion in-vivo and simultaneously. Therefore, the main goals of this PhD project were to: • Develop a combined OCT+ERG imaging system that can image in-vivo and record simultaneously, changes in the retinal morphology, retinal response to visual stimulation and retinal blood flow / perfusion at normal and elevated IOP. • Test the performance of the OCT+ERG system in a rat model of glaucoma. • Utilize the OCT+ERG technology and the dynamic IOP rat model of glaucoma based on the vascular loop, to investigate the effects of acute and chronic IOP elevation to ischemic and non-ischemic IOP levels on the rat retina. • Utilize the OCT+ERG technology to investigate neurovascular coupling in the rat retina at normal and abnormal IOP levels. Results from this PhD research have been published or summarized in manuscripts that are currently under review. Therefore, this PhD thesis was prepared in such a way that individual manuscripts represent separate thesis chapters

Evaluation of Macular and Peripapillary Choroidal Thickness using Enhanched Depth Imaging Optical Coherence Tomography in Patients with Essential Hypertension

PURPOSE: To measure the macular and peripapillary choroidal thickness using Enhanced Depth Imaging (EDI) Spectral Domain optical coherence tomography in patients with essential hypertension. MATERIALS AND METHODS: This was a case–control, cross-sectional prospective study. A total of 25 patients with systemic hypertension, and 25 healthy controls over 30 years of age, were included. Macular and peripapapillary choroidal thickness (SFCT) was measured using a Heidelberg SD-OCT platform operating in the enhanced depth imaging mode. All study participants had best corrected visual acuities of 20/25 or more, a refractive error in the range +3.0 to –3.0 diopters and intraocular pressure (IOP) lower than 21 mmHg. Those with systemic or ocular disease (glaucoma, uveitis, high myopia, age-related macular degeneration, diabetes mellitus, etc.) or a history of ophthalmic surgery that may have affected the choroidal vascular network were excluded. RESULTS: The subfoveal choroidal thickness was significantly thicker in the hypertension group compared to the normal participants (P<0.015). The macular choroidal thickness was significantly thicker in the superior, inferior and temporal quadrants among the hypertensive patients (Superior- P <0.08, inferior P<0.014, temporal P < 0.0003). Though the choroid thickness in the nasal quadrant was also thicker in nasal quadrant in the hypertensive patients the difference was not statistically significant (P<0.067). The peripapillary choroidal thickness in superior, inferior and temporal quadrants was significantly thicker in the hypertensive group (Superior-P<0.023, inferior-P<0.033, nasal-P<0.447, temporal-P<0.008). CONCLUSION: The choroidal thickness was significantly thicker in the hypertensive patients in our study. However further larger population-based studies are required to better understand the effect of systemic hypertension on choroidal thickness