Optical coherence tomography angiography in intermediate uveitis-related cystoid macular edema

Background: Cystoid macular edema (CME) is the leading cause of permanent visual impairment in patients with uveitis, particularly in patients with intermediate uveitis (IU). This study was aimed at comparing the changes in the macular microvasculature in patients with IU with uveitic non-responsive CME and without macular edema. Methods: In this case-control study, 55 eyes of patients with IU were assessed for macular microvascular structures, including vascular density, foveal avascular zone (FAZ) measurement, and vascular morphological changes, using spectral-domain optical coherence tomography angiography (OCT-A) with the AngioVue OCT-A system. We divided patients into the following two groups: the case group, including 30 eyes with IU-related non-responsive CME, and the control group, including 25 eyes with IU without macular edema. Results: Participants in the case and control groups had comparable age (P = 0.753) and sex (P = 0.124) distributions. Superficial capillary plexus vessel density in the case group was significantly decreased in the whole image (P = 0.027) and the parafoveal area (P  = 0.001) compared to the control group. However, there were no statistically significant differences between the two groups in terms of foveal superficial vessel density, deep capillary plexus vessel density, FAZ area, FAZ perimeter, FAZ acircularity index, or foveal vessel density in a 300-µm-wide annulus around the FAZ (all P > 0.05). Vascular morphological changes, such as the capillary tuft, telangiectatic vessels, or micro-aneurism, were not different in the overview images of the OCT-A printout between the two groups. Conclusions: The mean superficial capillary plexus vessel density was lower in eyes with IU-related nonresponsive CME than in those without macular edema. We observed more cystoid spaces in SCP than in DCP. Microcystic changes in the inner retina and ischemia may be the underlying cause in eyes with nonresponsive CME. Future prospective longitudinal studies with healthy, matched controls are warranted to confirm our findings

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

Quantitative Assessment of Experimental Ocular Inflammatory Disease

Ocular inflammation imposes a high medical burden on patients and substantial costs on the health-care systems that mange these often chronic and debilitating diseases. Many clinical phenotypes are recognized and classifying the severity of inflammation in an eye with uveitis is an ongoing challenge. With the widespread application of optical coherence tomography in the clinic has come the impetus for more robust methods to compare disease between different patients and different treatment centers. Models can recapitulate many of the features seen in the clinic, but until recently the quality of imaging available has lagged that applied in humans. In the model experimental autoimmune uveitis (EAU), we highlight three linked clinical states that produce retinal vulnerability to inflammation, all different from healthy tissue, but distinct from each other. Deploying longitudinal, multimodal imaging approaches can be coupled to analysis in the tissue of changes in architecture, cell content and function. This can enrich our understanding of pathology, increase the sensitivity with which the impacts of therapeutic interventions are assessed and address questions of tissue regeneration and repair. Modern image processing, including the application of artificial intelligence, in the context of such models of disease can lay a foundation for new approaches to monitoring tissue health

Standartization of OCT Angiography Nomenclature in Retinal Vascular Diseases: First Survey Results

Purpose. To develop a consensus nomenclature for OCT angiography (OCTA) findings in retinal vascular diseases. Design. Online survey using the Delphi Method. Participants. Members of The Retina Society, the European Society of Retina Specialists, and the Japanese Retina and Vitreous Society. Methods. An online questionnaire on OCTA terminology in retinal vascular diseases was sent to members of The Retina Society, the European Society of Retina Specialists, and the Japanese Retina and Vitreous Society. The respondents were divided into 2 groups (“experts” vs. “users”) according to the number of their publications in this field. The respondents who had more than 5 publications in the field of OCTA and retinal vascular diseases were considered the OCTA “experts” group. Main Outcome Measures Consensus and near consensus on OCTA nomenclature. Results. The complete responses of 85 retina specialists were included in the analysis. Thirty-one were categorized as “experts.” There was a consensus in both groups that OCTA parameters such as foveal avascular zone (FAZ) parameters, areas of nonperfusion, and presence of neovascularization (NV) should be implemented in the identification and staging of diabetic retinopathy (DR) and that OCTA can be applied to differentiate between ischemic and nonischemic retinal vein occlusion (RVO). Diabetic macular ischemia (DMI) also can be assessed via OCTA. Further, there was consensus that the terminology should differ on the basis of the underlying causes of decreased vascular flow signal. There was disagreement in other areas, such as which terms should be applied to describe decreased OCTA signal from different causes, the definition of wide-field OCTA, and how to quantify DMI and area of decreased flow signal. These discrepancies form the basis for the upcoming expert Delphi rounds that aim to develop a standardized OCTA nomenclature. Conclusions. Although there was agreement in some areas, significant differences were found in many areas of OCTA terminology among all respondents, but also between the expert and user groups. This indicates the need for standardization of the nomenclature among all specialists in the field of retinal vascular diseases

Structural evaluation in inherited retinal diseases.

Ophthalmic genetics is a field that has been rapidly evolving over the last decade, mainly due to the flourishing of translational medicine for inherited retinal diseases (IRD). In this review, we will address the different methods by which retinal structure can be objectively and accurately assessed in IRD. We review standard-of-care imaging for these patients: colour fundus photography, fundus autofluorescence imaging and optical coherence tomography (OCT), as well as higher-resolution and/or newer technologies including OCT angiography, adaptive optics imaging, fundus imaging using a range of wavelengths, magnetic resonance imaging, laser speckle flowgraphy and retinal oximetry, illustrating their utility using paradigm genotypes with on-going therapeutic efforts/trials

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

Optical Coherence Tomography Angiography (OCTA) in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

Vascular changes are increasingly recognized as important factors in the pathophysiology of neuroinflammatory disease, especially in multiple sclerosis (MS). The relatively novel technology of optical coherence tomography angiography (OCTA) images the retinal and choroidal vasculature non-invasively and in a depth-resolved manner. OCTA provides an alternative quantitative measure of retinal damage, by measuring vascular density instead of structural atrophy. Preliminary results suggest OCTA is sensitive to retinal damage in early disease stages, while also having less of a "floor-effect" compared with commonly used OCT metrics, meaning it can pick up further damage in a severely atrophied retina in later stages of disease. Furthermore, it may serve as a surrogate marker for vascular pathology in the central nervous system. Data to date consistently reveal lower densities of the retinal microvasculature in both MS and neuromyelitis optica spectrum disorder (NMOSD) compared with healthy controls, even in the absence of prior optic neuritis. Exploring the timing of vascular changes relative to structural atrophy may help answer important questions about the role of hypoperfusion in the pathophysiology of neuroinflammatory disease. Finally, qualitative characteristics of retinal microvasculature may help discriminate between different neuroinflammatory disorders. There are however still issues regarding image quality and development of standardized analysis methods before OCTA can be fully incorporated into clinical practice

Eye as a window to the brain: investigating the clinical utility of retinal imaging derived biomarkers in the phenotyping of neurodegenerative disease.

Background Neurodegenerative diseases, like multiple sclerosis, dementia and motor neurone disease, represent one of the major public health threats of our time. There is a clear persistent need for novel, affordable, and patient‐acceptable biomarkers of these diseases, to assist with diagnosis, prognosis and impact of interventions. And these biomarkers need to be sensitive, specific and precise. The retina is an attractive site for exploring this potential, as it is easily accessible to non‐invasive imaging. Remarkable technology revolutions in retinal imaging are enabling us to see the retina in microscopic level detail, and measure neuronal and vascular integrity. Aims and objectives I therefore propose that retinal imaging could provide reliable and accurate markers of these neurological diseases. In this project, I aimed to explore the clinical utility of retinal imaging derived measures of retinal neuronal and vessel size and morphology, and determine their candidacy for being reliable biomarkers in these diseases. I also aimed to detail the methods of retinal imaging acquisition, and processing, and the principles underlying all these stages, in relation to understanding of retinal structure and function. This provides an essential foundation to the application of retinal imaging analysis, highlighting both the strengths and potential weaknesses of retinal biomarkers and how they are interpreted. Methods After performing detailed systematic reviews and meta‐analyses of the existing work on retinal biomarkers of neurodegenerative disease, I carried out a prospective, controlled, cross‐sectional study of retinal image analysis, in patients with MS, dementia, and ALS. This involved developing new software for vessel analysis, to add value and maximise the data available from patient imaging episodes. Results From the systematic reviews, I identified key unanswered questions relating to the detailed analysis and utility of neuroretinal markers, and diseases with no studies yet performed of retinal biomarkers, such as non‐AD dementias. I recruited and imaged 961 participants over a two‐year period, and found clear patterns of significance in the phenotyping of MS, dementia and ALS. Detailed analysis has provided new insights into how the retina may yield important disease information for the individual patient, and also generate new hypotheses with relation to the disease pathophysiology itself. Conclusions Overall, the results show that retinal imaging derived biomarkers have an important and specific role in the phenotyping of neurodegenerative diseases, and support the hypothesis that the eye is an important window to neurological brain disease

Quantifying ocular inflammation in uveitis using optical coherence tomography

Inflammation is the key underlying physiological process in uveitis. It drives the onset of acute flares, causes permanent structural damage and can result in sight-threatening complications. Being able to accurately detect and measure changes in inflammatory activity is crucial for managing uveitic flares and rationalising therapeutic decisions. Unfortunately, many of the current methods for quantifying inflammation are imperfect, due to the fact that they are based on subjective and unreliable clinician estimates. In this thesis, I evaluated the potential for imaging-based technologies such as optical coherence tomography (OCT) to measure key markers of intraocular inflammation in uveitis. Whilst several key markers of inflammation are recognised, this thesis focuses on those with an existing clinical standard, which can be used as a comparator or reference test (anterior chamber cells, anterior chamber flare and vitreous haze). I conducted a series of systematic reviews evaluating potential instrument-based techniques for measuring anterior chamber cells, anterior chamber flare and vitreous inflammation, respectively. These identified OCT and laser flare photometry as potential instruments for measuring anterior chamber cell and flare, and OCT and retinal photography for measuring vitreous inflammation. However, the interpretation of results in each review was limited by relatively few studies and the inclusion of highly heterogenous uveitic patient populations, varying severities of disease, and lack of a standardised image acquisition protocol. Second, in the prospective study, OCTAVE (OCT-assisted vitreous evaluation), I found that our custom OCT-based vitreous analysis technique (EQUIP) demonstrated good repeatability in healthy and uveitic eyes, was able to detect vitreous inflammation and was associated with the current clinical vitreous haze grading. The EQUIP measurement was able to predict visual acuity whereas the current standard method (clinician grading 3 using the National Eye Institutevitreous haze scale) could not. Whilst these results were encouraging, there remains substantial overlap in the OCT measurement between NEI vitreous haze grades. It is not clear whether this is due to poor signal-to-noise ratio of the OCT technique, or a sign of poor reliability of the comparator (clinician-based grading using the NEI vitreous haze scale). Further investigation through longitudinal studies may be able to answer this question. In summary, OCT has demonstrated potential for quantifying inflammation for multiple key measures in uveitis. However, a key limitation for the validation of all instrument-based measures has been the lack of a reliable reference test