Ophthalmology (Eye & Ear Hospital) - Theses
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ItemPredicting progression in age-related macular degeneration( 2023-08)Background: Predicting which individuals will develop vision-threatening complications of age-related macular degeneration (AMD) is a challenging task, as traditional models based on colour fundus photography (CFP) correctly identify less than half of those who subsequently develop late AMD at 95% specificity. Thus, there is a great need to improve risk stratification for individuals with the early stages of AMD. Aims: To examine the prognostic significance of novel pathological characteristics related to drusen phenotypes and pigmentary abnormalities in the early stages of AMD. Methods: Retinal imaging data from 280 eyes from 140 individuals with bilateral large drusen enrolled in a longitudinal observational study was evaluated. Individuals underwent multimodal imaging (MMI) and microperimetry at baseline and then 6-monthly for up to 3-years. Disease progression was primarily evaluated based on the development of MMI-defined late AMD, and secondarily based on the rate of visual sensitivity decline on microperimetry prior to late AMD development. Four retinal specialists assessed the likelihood that each eye at baseline would progress with CFP, and then with MMI, to determine if MMI improves their ability to predict late AMD development. Baseline images were assessed for the: (i) presence of cuticular drusen, and extent of (ii) hyporeflective cores within drusen (HCD), (iii) hyperpigmentary abnormalities (HPAs), and (iv) hyperreflective foci (HRF) that do not spatially correspond to HPAs [HRF(OCT+/CFP-)]. The association with progression and impact on visual sensitivity of each feature was examined, including adjustments for well-established risk factors for progression (drusen volume from optical coherence tomography, presence of pigmentary abnormalities on CFP, and age). Results: The prediction of late AMD development by retinal specialists was improved when using MMI compared to CFP. However, a basic prediction model (age, presence of pigmentary abnormalities, and drusen volume) outperformed clinicians. In this cohort, neither the presence of cuticular drusen nor extent of HCD were significantly associated with an increased rate of progression to late AMD, reduced mean visual sensitivity at baseline, or an increased rate of visual sensitivity decline, after adjusting for well-established risk factors of progression. The quantification of HPA extent did not significantly improve the prediction of late AMD development compared to HPA presence, and the addition of HRF(OCT+/CFP-) extent to HPA extent also did not improve performance. Both HPA and HRF(OCT+/CFP-) extent were independently associated with reduced sector-based visual sensitivity, with the latter also associated with a significantly faster rate of visual sensitivity decline. Conclusions: Accounting for drusen phenotypes such as cuticular drusen and HCD, or the quantity of HPAs and HRF(OCT+/CFP-), did not significantly improve the prediction of late AMD development above what could be achieved by well-established risk factors. However, a basic prediction model using these parameters – drusen volume, presence of pigmentary abnormalities and age – outperformed retinal specialists, suggesting that such a model could improve counselling and monitoring of individuals in clinical practice. Such a model could also be used to better identify an enriched cohort to improve feasibility of future interventional trials, and thus help expedite the discovery of preventative treatments in the early stages of AMD.
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ItemNew approaches to the photopic negative response of the electroretinogram in glaucoma( 2022)Background: Glaucoma is an optic neuropathy characterised by the progressive loss of retinal ganglion cells (RGCs) and is a leading cause of blindness worldwide. Prior to irreversible cell death, RGCs exhibit functional changes that if detectable, could aid in predicting the disease trajectory and help better guide the management of this condition. The photopic negative response (PhNR) of the electroretinogram (ERG) shows potential as such a functional test, but its utility has been limited due to problems with repeatability and interpretation. Purpose: To explore novel techniques to improve the repeatability of the electroretinogram in glaucoma, describe new feature extraction techniques, and to develop models that predict glaucoma severity from the ERG. Methods: Normal controls and individuals with glaucoma were recruited for these studies. ERGs were collected with red flashes on a blue background or with a white-on-white stimulus. Various novel denoising techniques were evaluated on the normal control group to improve measurement repeatability, and complexity measures were used as new features to better discriminate between those with and without glaucoma. Novel predictive models informed by novel features extracted with time-frequency techniques were trained evaluated and compared to models using various amplitude markers from the ERG. Results: The denoising technique termed complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) was shown to be effective and efficient in removing baseline drift and wander of the ERG, thus significantly improving the repeatability of the recordings. Eyes with and without glaucoma showed significant differences based on novel complexity measures of the ERG, beyond the standard PhNR measure. New models informed by time-frequency features significantly added to the predictive performance for glaucoma severity when used alongside conventional amplitude markers of the ERG. Conclusion: This body of work developed a new method of denoising of the ERG, which also could have wider application in electrophysiology. New features based on complexity showed potential for providing important additional measures of RGC dysfunction useful for disease discrimination. Time frequency features extracted from the ERG also showed that there is substantial information in the ERG beyond what is captured by standard amplitude markers that could aid in better detecting early RGC dysfunction.
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ItemThe global socioeconomics of vision impairment and cataract surgery( 2019)The overwhelming majority of the world’s vision impaired reside in low-income settings. Cataract is the leading cause of blindness and the second-leading cause of moderate to severe vision impairment (MSVI). Proxy measures of cataract disease burden and access to cataract surgery services include cataract surgery rate (CSR) and cataract surgery coverage (CSC) rates. The present research aims to evaluate and model associations between the scale of vision loss and burden of cataract disease with socioeconomic indices, drawing comparisons with other countries globally to identify key country policies, practices and initiatives that have resulted in significant improvements to service delivery. A meta-analysis was conducted using CSR data between 2005 and 2014 from published literature and unpublished literature. A systematic review of Rapid Assessment of Avoidable Blindness (RAAB) studies from 1995 to 2015 extracted information on the prevalence and causes of blindness, rate of cataract blindness, cataract surgery coverage (CSC), and visual acuity outcomes of cataract surgery (CSO). HDI and GDP data were collected from the United Nations Development Program (UNDP) and World Bank repositories respectively. Estimates of age-standardised prevalence data of vision impairment and blindness were collected from the 2010 Global Burden of Disease Study (GBD). CSR was found to be closely associated with GDP and GNI using data throughout the study period. HDI levels accounted for the majority of global variance in the prevalence of moderate-severe VI and blindness. Of the three HDI components, education was identified as the most influential factor, accounting for two-thirds of the global variance in MSVI and blindness prevalence. Lower total health expenditure per capita, and as a proportion of total GDP, were associated with a higher prevalence of moderate-severe VI and blindness. A strong association exists between socioeconomic factors as indicated by GDP, GNI and HDI and the quality and quantity of cataract surgery. This suggests there are strong relationships between resource availability and healthcare delivery. Low-cost and innovative services as well as strategic investment in capacity development is important to address cataract surgery needs in low-resource settings.
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ItemThe role and benefits of collaborative care through task sharing in eye health service delivery( 2015)This thesis demonstrated the role of collaborative care in eye health service delivery through task sharing and the anticipated benefits of utilising existing workforces to meet future demands. The research evaluated a model of collaborative care between ophthalmology and optometry and an exploratory study to understand the occasions of service required for the three chronic eye conditions age-related macular degeneration, diabetic retinopathy and glaucoma. It is anticipated the findings and conclusions will potentially inform future models of care and management guidelines in Australia.
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ItemFunctional and structural changes in the visual pathway associated with ageing and glaucoma( 2013)Glaucoma is a leading cause of irreversible blindness. While early treatment is beneficial, diagnosis and monitoring are problematic: values of anatomical indicators of potential damage in the visual pathway vary with age, and values in glaucoma patients overlap substantially with the normal physiological range. A potential solution to this dilemma may exist if certain pathway structures are resistant to the disease and could provide an indication of pre-morbid anatomy. Aim: The first aim of my thesis was to identify the normal range of anatomical variation and establish the profile of normal ageing for structures in the visual pathway. The second aim was to use this normal characterisation as an age-stratified comparator for glaucoma patients to identify structures which were resistant to the disease and may provide an indication of pre-morbid anatomy. The final aim was to correlate an objective measure of cortical response by functional MRI with both subjective measures of visual function and anatomical change in glaucoma patients. Method: Normal controls (n = 83) and glaucoma patients (n = 42) with a range of disease severity were recruited for the study. The anterior visual pathway was imaged in vivo using conventional clinical techniques to obtain measures of the retinal nerve fibre layer and optic nerve head. 3T MRI was used to image the posterior visual pathway in vivo by T1, T2, diffusion imaging and functional scanning. Measurements of the retrobulbar optic nerve were taken directly from T2 scans and statistical parametric mapping software used to calculate brain volumes including visual cortices. High angular diffusion imaging was used to identify and quantify the optic radiations using spherical deconvolution and tracking software. Functional assessment was carried out by Humphrey 24-2 visual field evaluation and by functional MRI scanning with novel software developed for analysis. Results: An age stratified characterisation of the visual pathway was developed with ageing changes found for the retinal nerve fibre layer, optic nerve head parameters and the optic radiations. Visual cortex volume was only found to change in males with ageing, and the retrobulbar optic nerve did not exhibit any age-related anatomical loss. Glaucoma patients showed a gradually increasing loss of anterior anatomy and retrobulbar optic nerve diameter related to disease severity. However, optic radiations only showed a significant difference with more advanced disease, while visual cortex volumes were unaffected by disease state. Functional MRI scanning showed significantly less activation for moderate and severe glaucoma patients compared to normal controls and there was a significant correlation between functional activation and visual field mean defect scores for binocular and left eye viewing. Conclusion: Glaucomatous damage in the visual pathway is related to disease severity as assessed by functional loss, however changes in the posterior pathway lag those which occur anteriorly. This thesis presents an age-stratified characterisation of the normal visual pathway which can be used on an individual basis for glaucoma patients to assess anatomical status and amount of anatomical redundancy for each pathway structure which may give an indication of the relative risk of further progression.
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ItemThe heritability of optic disc shape( 2012)Aim: Morphologic appearance is an important aspect of the structural integrity of the optic disc. While factors influencing the size of the optic disc have been studied, there is relatively little information explaining underlying causes of variation in its shape. Recent work has suggested that the shape may be heritable and this has implications for disorders of the optic nerve head that have a genetic basis. The aim of my thesis was to disentangle and quantify the relative contributions of genetic and environmental factors to the variation in optic disc shape in the population. Methods: Stereoscopic optic disc photographs were obtained from twins (n = 1,858) and their non-twin siblings (n = 194), recruited through the Australian Twins Eye Study. The two-dimensional contours of the optic cup and disc were planimetrically delineated using specialised imaging instrumentation and the outline information converted to coordinate data. A novel method of shape analysis employed in geometric morphometric studies of biological form was then used to normalise optic cup and disc configurations for position, size and orientation, thereby removing all non-shape-related geometric variation. The remaining shape information was subjected to principal components analysis in order to describe the main features of shape variation and quantify the magnitude of each. The heritability of three optic disc shape phenotypes was evaluated: optic disc shape, optic cup shape and a combined shape phenotype (cup and disc outlines analysed simultaneously). The proportion of phenotypic variance attributable to genetic factors in each case was estimated by structural equation modelling applied within a multivariate framework. Genome-wide association studies were also conducted for optic cup and disc shape in an effort to identify prospective genes related to these traits. Results: The principal mode of shape variation for both the optic cup and disc was interpreted as differences in vertical/horizontal ovality of the configuration outline and accounted for 52.1% and 56.7% of the total shape variance, respectively. For the combined shape phenotype, covariation of cup and disc size explained 65% of the total variance and represented the dominant shape characteristic. Of the three shape traits considered, the combined shape phenotype was the most heritable, followed by the optic disc and optic cup shapes (maximum additive heritabilities - 0.87, 0.70 and 0.43, respectively). The best-fitting genetic model in each case was the AE model, with the residual variance in each trait due to unique environmental factors. The dominant heritable shape features reflected those of the phenotypic shape analysis. The genome-wide association study failed to identify any molecular variants either reaching conventional thresholds of significance or with a plausible biological basis for association. Conclusions: Genetic factors influence inter-individual shape variation of the optic nerve head in humans. However, the results of my work indicate that when looking for associated genes, it is better to focus on the shape of optic disc rather than the optic cup, for which environmental factors play a greater role. This is important information in the study of all disorders of the optic disc, especially those underpinned by genetic differences. My thesis is directly relevant for studying glaucoma, a complex disease with a genetic architecture that can be distilled into a simpler form by evaluating individual, underlying traits. Thus, by unravelling the genetic epidemiology of optic disc shape, my work fits into place one piece of that metaphorical jigsaw puzzle.
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ItemTrabeculectomy: methods to improve safety, optimise outcomes, and assess filtering blebs( 2010)Trabeculectomy is the most commonly performed incisional glaucoma procedure worldwide. This thesis incorporates a compilation of papers with the aims of improving the surgical approach to trabeculectomy, and via improved assessment of results of surgery, optimising outcomes. In the first weeks after surgery, success of trabeculectomy hinges on the absence of complications, with the more important complications resulting from loss of control of intraocular pressure. The interactions between aqueous flow, scleral flap construction, and the placement and tension of sutures in the scleral flap can effectively control IOP, and are under the control of the surgeon. The surgical approach, independent of antimetabolite use, also affects bleb morphology. Via papers that are included in this thesis, I describe how I and coworkers have tested, modeled, and validated a ‘Safe Surgery System’ for trabeculectomy, an approach initiated by Professor Peng Khaw at Moorfields Eye Hospital, with excellent results and external validation and recognition. Later in the postoperative course, once the sclera in the trabeculectomy site has started to heal and remodel, the scleral component effectively becomes a fistula*; the functional component and the important determinant of long term success is the filtering bleb. In addition to descriptions of some minor complications of filtering blebs that had not previously been described, this thesis contains the story of the development and testing of a bleb grading system that became the Moorfields Bleb Grading System (MBGS). Although the current MBGS has flaws as described in the included publications, I believe it is still the best available tool for bleb grading since it captures important information that others ignore. My interest in the surgical and post-surgical management of blebs has led to related projects including textbook chapters regarding bleb assessment and management, and also to investigate the possibility of in-vivo imaging of blebs at tissue and cellular levels. Two papers at the end of this thesis show the potential for fluorescence-mode confocal microscopy to be applied to bleb and other wound healing research, perhaps with practical applications once suitable methods for selective fluorescent labelling become available.