Ophthalmology (Eye & Ear Hospital) - Theses

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    Ocular manifestations of neurologic disease in early childhood
    Billson, Francis ( 2017)
    Neuro-ophthalmology is a medical discipline focusing on diseases of the central nervous system that may affect the visual sensory or motor systems or pupillary reflexes. Neuro-ophthalmologists are often part of the academic medical team and the eyes may be involved in a variety of medical disciplines. Paediatric ophthalmology adds precision to diagnostic challenges arising from the complexity of foetal and early development of the visual system. The first chapter of this thesis deals with normal neuronal, vascular and immunological development of the retina. The second chapter deals with a selection of visuo-motor disturbances in the neonate and early childhood, including the difficulties faced by the paediatric neuro-ophthalmologist in diagnosis in the context of children, particularly in the early years of life where development adds a profound challenge to the interpretation of conditions and determining whether conditions are progressive or static: • Chapter 2.1 deals with the objective measurement of visual fields by directly recording from the visual (occipital) cortex. • Chapter 2.2 deals with confusion and possible mismanagement of visual path glioma and the importance of objective perimetry in clarifying diagnosis and determining management, particularly in early childhood. • Chapter 2.3 deals with the further problem of regional giantism associated with neurofibromatosis and presenting in early childhood with buphthalmos. • Chapter 2.4 discusses the publication of an early series of cases of optic nerve hypoplasia at a time when there were relatively few reported in the literature, however the condition is now recognised as the commonest cause of blindness at birth. • Chapter 2.5 discusses optic neuropathy and the importance of distinguishing ‘functional’ loss of vision from pathologic conditions such as drug toxicity. • Chapter 2.6 discusses two unusual cases of pathological papilledema in childhood, treated with sheath splitting surgery in its early developmental phase. • Chapter 2.7 deals with a series of cases of Aicardi’s syndrome, the first to appear in the English literature. • Chapter 2.8 deals with strabismus and amblyopia and demonstrates the vulnerability of the developing visual system to abnormal visual environmental influences and motor disturbances. • Chapter 2.9 deals with congenital nystagmus and its differential diagnosis. • Chapter 2.10 discusses the developmental causes of supra-nuclear disturbances of gaze, their differential diagnosis and the importance of excluding tumours of the visual path in early childhood. The final chapter highlights and summarises the major contributions to paediatric neuro-ophthalmology of the topics covered in this thesis and the importance of development adding complexity to the interpretation of diagnosis.
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    Retinal vascular changes in children: exploring the genesis of microvascular disease
    Cheung, Ning ( 2015)
    BACKGROUND: Technological advances in computer-based analysis of retinal images have allowed reliable and precise measurements of subtle differences or changes in the retinal vascular geometry. One of the most well studied geometric parameters of the retinal vasculature is the caliber of the retinal vessels. Variations in retinal vascular caliber have been associated with a range of vascular risk factors, and may independently predict the risk of cardiovascular events (e.g., stroke, coronary heart disease) and ocular diseases (e.g., diabetic retinopathy, glaucoma). It is therefore believed that altered retinal vascular caliber could be an early sign of not only microvascular disease in the eye, but also subclinical systemic microvascular dysfunction, preceding the development of clinical cardiovascular diseases. However, previous studies have mostly focused on middle-aged to older adult populations, in which confounding effects of pre-existing systemic and ocular diseases are sometimes difficult to be completely adjusted for. Less is known about this important vascular parameter in children. In this project, we examined retinal vascular caliber in generally healthy children, and sought to further our fundamental understanding of the genesis of ocular and systemic microvascular disease. PURPOSE: The overall objective of this project is to examine retinal vascular caliber in generally healthy children, and determine its systemic and ocular associations. RESEARCH DESIGNS AND METHODS: The data used to assess the pattern and associations of retinal vascular caliber was from the Singapore Cohort Study of Risk Factors for Myopia (SCORM; mostly Asian Chinese) and the Sydney Childhood Eye Study (SCES; mostly Caucasians). The SCORM is a study of children aged 7 to 9 years recruited from 3 schools in Singapore. The SCES is a population-based study of 1,740 6-year-old children in Sydney, Australia. Retinal photographs from these two studies were used to measure retinal arteriolar and venular caliber using a semi-automatic computer-based program according to a validated and standardized protocol. All the participants from the SCORM and SCES undertook comprehensive and standardized medical history questionnaires, physical and eye examinations, and various other ophthalmic investigations, including optical coherence tomography and ocular response analyzer (for corneal biomechanical properties; in SCORM only). RESULTS: Retinal vascular caliber in children is normally distributed. The mean retinal arteriolar and venular caliber were 156.4μm (95% confidence interval [CI]: 155.4-157.3) and 225.4μm (95% CI: 224.1-226.8), respectively, in the SCORM; and 162.7μm (95% CI: 161.9-163.4) and 226.8μm (95% CI: 225.9-227.8), respectively, in the SCES. In both SCORM and SCES, narrower retinal arteriolar caliber was cross-sectionally associated with higher blood pressure, higher body mass index and indicators of poor in-utero growth (lower birth weight, lower birth length, smaller head circumference and/or preterm birth), whereas wider retinal venular caliber was associated with higher body mass index. For ocular associations, narrower retinal arteriolar and venular caliber were associated with smaller optic discs, thinner optic disc rims and retinal nerve fiber layer in both SCORM and SCES. Narrower retinal arteriolar caliber was associated with lower corneal dysteresis and corneal resistance factor in the SCORM. Axial length was not associated with retinal vascular caliber after correction of ocular magnification, and there was no association between retinal vascular caliber and intraocular pressure in the SCORM. CONCLUSIONS: Variations in retinal vascular caliber are associated with a range of ocular and systemic factors in generally healthy children. In view of the findings from studies of adult populations, the pattern of these associations seen in children suggests that retinal arteriolar narrowing and venular widening could be signs of physiological microcirculatory adaptation or subclinical microvascular dysfunction related to these ocular and systemic factors in early life.
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    Progress in uveitis: novel treatments, new disease associations, and imaging applications
    LIM, LYNDELL ( 2014)
    Although an uncommon disease, due to its peak incidence in young adults and the often sight-threatening complications that result from it, uveitis accounts for a high socioeconomic cost to our society. Further research is therefore required to increase our knowledge regarding the pathogenesis of this disease, which will ultimately lead to the development of novel treatments, that will in turn help reduce the economic burden of visual loss that often results. AIM: To investigate 3 areas of uveitis research: potential novel treatments in uveitis, new disease associations and disease patterns, and finally, the application of cutting edge imaging modalities in ocular inflammatory disease. METHOD: A combination of prospective cohort studies and retrospective studies focusing on each of these three research areas. RESULTS: Key findings include the discrepancy in efficacy between different TNF-inhibitors in the treatment of uveitis, where infliximab and, to a lesser extent, adalimumab, were associated with a lower incidence of uveitis episodes than etanercept. New disease associations were also discovered between uveitis and other autoimmune diseases – particularly with autoimmune hepatitis and primary sclerosing cholangitis. With regards to new disease patterns, another major finding was that uveitis activity tends to ameliorate during pregnancy, only to return to pre-pregnancy levels after delivery, which will have clear management implications, in addition to opening up further avenues of research regarding the immune mechanisms of non-infectious uveitis. Finally, confocal microscopy has provided us with the opportunity to image in-vivo processes in living tissue at a cellular level, allowing us to measure leucocyte diapedesis (leucocyte rolling and sticking), which was found to occur at much higher levels in scleritis in comparison to subjects with allergic conjunctivitis and normal controls. CONCLUSION: Novel treatments in uveitis, particularly biologics, hold the promise of more targeted treatment with greater efficacy and fewer side effects. However, our mixed experience with TNFα inhibitors in uveitis suggests that the ideal target for ocular autoimmune disease remains elusive. Hence our efforts to better understand the pathogenesis of uveitis through studies with other related autoimmune diseases, better in-vivo imaging of live disease processes, and larger genetic studies that will help us establish genetic predispositions to developing each of the various types of uveitis. Such knowledge will form the foundation of further work to find the key targets for “switching off” the inflammatory cascade that results in autoimmune diseases such as uveitis.
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    Predictors of outcome of anti-VEGF treatment in neovascular age-related macular degeneration
    ABEDI, FARSHAD ( 2013)
    Purpose: To identify the predictors of visual acuity (VA) outcome of intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment in neovascular age-related macular degeneration (nAMD). Methods: A review was conducted on all treatment naïve eyes (459 eyes of 398 patients >50 years old) that received intravitreal ranibizumab or bevacizumab injections for nAMD at the Royal Victorian Eye and Ear Hospital from 2006 to 2010. 201 consecutive patients treated with an as-required regimen were genotyped for seven tagged single nucleotide polymorphisms (SNPs) in VEGFA gene. 224 patients were also genotyped for seventeen AMD risk-associated SNPs in the CFH, CFHR1-5, LOC387715/ARMS2, C3, C2, CFB and F13B genes. Multivariate data analysis, adjusted for age, sex, baseline VA, lesion type and size, and patients‘ smoking status examined the role of genetic variants on VA outcome of treatment. 120 treatment naive patients were treated with an “Inject and Extend” regimen comprising three initial monthly injections, followed by an extension phase of 9 months, where the interval to the subsequent injection was extended by two weeks if the extension criteria were met. Results: Mean baseline VA of the 459 eyes was 46.5±19 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores. Mean change in VA from baseline was +3.0±15.6, -1.0±18.3, -7.3±21.5 and -11.7±22.7 letters after 12, 24, 36 and 48 months, respectively. The mean number of injections was 5.6 ±2.6 in year one, 3.1±3.1 in year two, 2.9±3.2 in year three and 3.2±3.0 in year four. A higher number of injections and worse baseline VA led to significantly greater improvement in VA. Outcomes significantly improved for patients who commenced treatment after 2008. In 120 patients treated with an “inject and extend” protocol, mean change in VA from baseline after 12 months was +9.5±10.9 letters with a mean number of injections and clinic visits of 8.6±1 over 12 months. Of the seven examined SNPs in the VEGFA gene, SNP rs3025000 was the only SNP significantly associated (p value < 1x10-4) with visual outcome at 6 months. The presence of the T allele at this SNP predicted a better outcome of +7 letters at 6 months. Analysis of the seventeen AMD risk-associated SNPs revealed that the AA genotype at rs11200638 - HTRA1 promoter SNP (p =0.001) and GG genotype at rs10490924 (A69S) in LOC387715/ARMS2 (p=0.002) were significantly associated with poorer VA outcome at 12 months. The mean change in VA from baseline in patients with AA genotype at rs11200638 was -2.9±15.2 letters after 12 months, compared with +5.1±14.1 letters in patients with AG or GG genotypes at this SNP. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (LD, r2 = 0.92). Conclusion: Overall, patients with a lower baseline VA showed a greater increase in VA with treatment. An “inject and extend” regimen achieved significant improvement in VA over 12 months. Variants in VEGFA, HTRA1 and LOC387715/ARMS2 genes were significantly associated with treatment outcome. This may suggest a pharmacogenetic association and lead to a personalised treatment regimen, based on genotype to achieve optimal outcome in certain groups of patients.
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    Pathology of the lacrimal system and its treatment
    McNab, Alan A. ( 2011)
    The lacrimal system comprises the lacrimal glands, the tear film and the lacrimal drainage system (the lacrimal puncta, canaliculi, lacrimal sac and nasolacrimal duct). The lacrimal system is essential in maintaining a healthy ocular surface and therefore optimal visual function. This thesis presents a compilation of papers on the lacrimal system, its pathology and surgical treatment. The lacrimal system is subject to a wide variety of congenital anomalies, some with a clearly established genetic basis. This thesis commences with a small series of papers describing congenital anomalies of the lacrimal drainage system. The lacrimal glands comprise the main lacrimal gland and the accessory lacrimal glands. The main lacrimal gland is analogous to the salivary glands in terms of the range of pathological processes that occur within it. Several papers in this thesis are devoted to pathological entities occurring in the lacrimal gland. Infection within the lacrimal system is a common clinical entity. Two brief papers describe less common infections of the lacrimal system. The commonest cause of lacrimal drainage system obstruction is so-called Primary Acquired Naso-lacrimal Duct Obstruction (PANDO). However there is a large variety of secondary causes of lacrimal obstruction and the third section of the thesis presents several papers on this group of conditions. Tumours of the lacrimal outflow system are rare and their management presents a number of challenges. This thesis includes three significant publications on the pathology, clinical features and surgery of these rare tumours. The largest section of the thesis comprises papers published on various aspects of the surgical management of the lacrimal excretory system, including anaesthetic techniques, methods to reduce blood loss, secondary haemorrhage after dacryocystorhinostomy (DCR) and late failure of DCR. The final section of the thesis comprises reproductions of book chapters written on lacrimal surgery, which include sections on the management of more complex and challenging lacrimal cases where previous surgery has failed or where lacrimal obstruction occurs in the canalicular system. Their inclusion serves also to emphasise the importance of the role of the surgeon as educator.
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    Trachoma in the Pacific Islands
    Mathew, Anu A. ( 2011)
    The presence of trachoma in the Pacific Islands came in to question when the global distribution of trachoma was mapped by WHO and the London School of Hygiene and Tropical Medicine in 2005. Modified Trachoma Rapid Assessment (TRA) methodology was used in Kiribati, Nauru, Vanuatu, Solomon Islands and Fiji to establish the presence or absence of trachoma in the Pacific Island region. Advised by key informants, high-risk communities were chosen from each country. All available children aged 1-9 years and adults ≥ 40 years were examined. Risk factor information was also collected. A total of 903 adults ≥ 40 years and 3,102 children aged 1-9 years were screened at 67 sites. 64 of 82 (78%) communities/schools examined in the five Pacific Island countries had rates of active trachoma of greater than 10% in children. Rates of trichiasis surgery are suggestive of blinding trachoma in the region. Risk factor analysis showed that the most common association with active trachoma in children was the presence of a ‘dirty face’ (p<0.01, odds ratios 1.53 to 4.15) and the most common association with blinding trachoma in adults was increasing age (p=0.01, odds ratios 1.05-1.11). Logistic regression modelling indicated that conventional risk factors such as distance to water supply that are usually predictors of trachoma do not completely explain the rates of trachoma. Communities in all the surveyed countries had access to some water source and were often surrounded by pristine ocean. Hygiene practices and cultural beliefs may be contributing to rates of trachoma in the region. As the study indicated that trachoma is a public health problem in the Pacific Island region that will need to be addressed, qualitative research methodology was used in Fiji, the Solomon Islands, Vanuatu and Kiribati to assess perceived barriers to trachoma control. Semi-structured interviews were carried out on 26 participants involved in governance, service delivery or non-governmental organization aspects of primary eye care. The questionnaires revealed that besides the common problem of lack of resources, cultural factors and behavioural attitudes are major barriers to address. Based on the findings of this study and a literature review, a model for implementation of the SAFE (Surgery; Antibiotics; Facial cleanliness; Environmental improvement) strategy for trachoma control in the Pacific Island region was developed. The model recommends a regional approach to trachoma as the communities share similar risk factors and experience similar barriers to implementation of the SAFE strategy. Other principles of the strategy include individual country ownership allowing modification of the strategy to match individual country’s characteristics, a horizontal approach allowing collaboration with different sectors and community involvement and integration with other disease control strategies. One could recast the SAFE strategy as the FASE strategy to emphasise the appropriate public health importance on each component. In these countries where water is apparently plentiful, the behaviour change aspect of the “F” components needs to focus most importantly on the cultural factors that appear to be a major factor contributing to the persistence of trachoma. The goal of global elimination of blinding trachoma by the year 2020 has been set and a number of countries are already eligible for certification of trachoma elimination. Equipped with new evidence from this study, the Pacific can now join the global fight against trachoma.
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    Trabeculectomy: methods to improve safety, optimise outcomes, and assess filtering blebs
    Wells, Anthony Philip (Tony) ( 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.