Ophthalmology (Eye & Ear Hospital) - Theses
Permanent URI for this collection
Search Results
1 - 4 of 4
-
ItemTopographic rod function in intermediate age-related macular degeneration( 2019)Background Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the elderly. In the early stages of disease, dark adaptation problems are more significant for patients than visual acuity impairment. For decades, studies of rod function related to dark adaptation issues suggested that rod function could be useful as a functional marker for differentiating AMD severity and monitoring disease progression. However, there remains many unanswered questions about how best to investigate rod function in the early stages of AMD. Earlier studies were not able to phenotype AMD cases to the extent we can today as they relied only on colour fundus photographs to determine AMD subgroups. We now have the opportunity to look at different AMD phenotypes using multimodal imaging techniques. These advances have added clarity to the phenotyping of AMD, as high-risk features such as reticular pseudodrusen (RPD), hyperreflective foci (HRF), and nascent geographic atrophy (nGA) can now be identified. At the same time as the advances in detecting anatomical changes were made, instruments that could measure rod function in a more thorough way were improving. Previously, instruments measured rod function at only a single retinal location, or could only detect large losses in sensitivity due to a lack of dynamic range. Recent advances have seen perimeters that are able to measure rod function at multiple locations in the one setting and also have a larger dynamic range to detect subtle rod dysfunction. I have used one of these new tools in my studies. Aims Two-color dark-adapted chromatic perimeter (DACP) is a novel device, designed and manufactured in Melbourne, Australia. It was first used in 2015 when I commenced my PhD. This perimeter measures rod function at multiple locations with sufficiently large range of stimulus intensities to detect subtle changes seen in early AMD. My thesis aimed to investigate the ability of the DACP to reliably detect and record rod sensitivities. I then utilized this new perimeter to investigate the ability of rod function to act as a robust functional biomarker that could be used to determine AMD disease severity and to monitor disease progression, and to compare rod function in AMD cases to normal control participants. I was also able to separate my AMD cohort into those with or without RPD, a high-risk AMD phenotype, to investigate the impact of this phenotype on rod function. Both static and dynamic rod functional changes were recorded at baseline visits and then again at 6- and 12-months. The results of this study will contribute to our understanding of functional loss in AMD and help clinicians and researchers when designing research protocols aiming to evaluate rod functional impairment before vision loss. Methods This study was conducted between 2015 and 2018 at the Macular Research Unit, Centre for Eye Research Australia. During that time, three main studies were completed. An initial assessment of test-retest reliability of the DACP was followed by a cross-sectional study comparing the severity of rod dysfunction based on point wise sensitivity (PWS) and point wise sensitivity difference (PWSD) of two color sensitivities. AMD cases were divided into an AMD group with traditional drusen only and an RPD group, and rod function was evaluated at multiple ring eccentricities within 24º of the central macula. A further 12-months evaluation of static (PWSD) and dynamic rod functional changes (rod intercept time (RIT) and rod recovery rate (RRR)) within the central 12º was conducted in participants with intermediate AMD with and without RPD as well as normal control eyes. Results The DACP did not have ceiling or floor issues during the intrasession and intersession testing, with a coefficient of repeatability of ± 5 dB. Intermediate AMD (iAMD) with the presence of RPD was found to be associated with poorer rod function compared with iAMD without RPD and normal control eyes, but only within the central macular 8º. Rod dysfunction was more significant if the eyes were prebleached before undertaking the sensitivity measurements. In a longitudinal study, dynamic rod functional changes, ie. RRR, was the only parameter that changed over 12 months, and only in the iAMD without RPD group. Change was found only at the peripheral 12º ring eccentricities. Conclusion The DACP offers a great opportunity to evaluate topographic rod function when eyesight is still normal. The findings from this study support that concept of rod function being impaired in the early stages of AMD. The presence of RPD in cases of iAMD were associated with further reductions in rod function. Measuring dynamic rod function offers a more sensitive functional marker in determining severity of AMD within the central 8 degrees of the macula, but changes over time were only detected at more peripheral locations. Longer follow-up will be beneficial to determine how rod function deteriorates over time and correlates with progression to vision loss.
-
ItemNovel clinical biomarkers of disease in early stages of age-related macular degeneration( 2014)Background: The lack of effective disease biomarkers in the early stages of age-related macular degeneration (AMD) is a major impediment to the ability to sensitively identify individuals at risk of progression to the late stages where vision is threatened, and thus also the development and evaluation of novel interventions that aim to slow or prevent such progression. Aims: To investigate and identify potential anatomical and functional biomarkers that can be effectively used for clinical studies in the early stages of AMD. Methods: Functional markers including low luminance visual acuity (LLVA), microperimetry and multifocal electroretinography (mfERG) were examined in participants with the early stages of AMD at cross-section and longitudinally over a 12-month period. Structural measures were then developed via identification on spectral-domain optical coherence tomography (SD-OCT), and their relationship with functional changes was examined. Results: The intrasession test-retest variability of microperimetry was improved by discarding the first examination for participants who had not previously performed microperimetry before, since it was subject to a learning effect. LLVA was on average no more effective than best-corrected visual acuity (BCVA), in detecting functional changes in the early stages of AMD, with microperimetry detecting a greater extent than both acuity measures. The magnitude of measured functional deficit was also greater on microperimetry than mfERG. When examined longitudinally, microperimetry was able to detect subtle functional changes over the 12-month period in intermediate AMD eyes that was not detected by LLVA or BCVA, especially in the parafoveal region. Longitudinal changes on mfERG were insignificant for implicit time and unclear for response amplitudes. In AMD eyes, the relative intensity of the inner-segment ellipsoids (ISe) band on SD-OCT correlated with mfERG implicit time and was reduced compared to control participants. The degree of retinal pigment epithelium (RPE) band elevation and ISe band integrity on SD-OCT were found to be independent predictors of microperimetric retinal sensitivity. In a retrospective, longitudinal analysis, a unique series of features that preceded the development of atrophy on SD-OCT was described as “nascent geographic atrophy (nGA)”. These features were present in a notable percentage of intermediate AMD eyes when examined in a cross-sectional study. The microperimetric retinal sensitivity in areas of nGA were reduced on average compared to surrounding areas of drusen and/or pigmentary abnormalities, but were not consistently the worst performing point in an eye. Conclusions: These findings show that microperimetry can be a potentially useful functional biomarker in the early stages of AMD. The structural parameters determined on SD-OCT can also provide rapidly acquired, more objective biomarkers, some of which correlate with the functional measures. Unique anatomical features detected on SD-OCT that were defined as nGA, appears to be the most specific marker to predict the development of atrophy. These novel clinical biomarkers can now be exploited to better understand the disease severity and progression for eyes with the early stages of AMD, and to improve the evaluation of novel interventions for these stages.
-
ItemModeling cost effectiveness of current routine treatments for neovascular age-related macular degeneration from a healthcare payer’s perspective( 2013)Neovascular age-related macular degeneration (nvAMD) is one of the leading causes of blindness in developed countries including Australia, and current gold-standard treatment is with anti-Vascular Endothelial Growth Factor (VEGF) drugs. However, cost-effectiveness (CE) of this treatment has to date only been investigated based on phase III clinical trial data, assessing treatment outcomes in only the study eye over only two years. As effectiveness as well as healthcare use are commonly overestimated in clinical trials, and patients require ongoing treatment beyond the first two years, this approach does not reflect day to day clinical reality. Thus, first the long term effectiveness and healthcare resource use in 200 patients treated with anti-VEGF drugs were assessed with up to 5 years follow-up. Mean treatment duration was 37 (±13) months and mean number of injections were 21(±11;7 in year 1-3, 6 in year 4, 5 in year 5). Visual acuity in the treated eye improved from baseline to last follow-up (49 to 56 letters read (ltrs), p<0.001). Fourty % of patients were treated in both eyes during year 1, and almost 50% by year 4. Treatment costs were highest in the first year (A$18,296 ± 7,991), and lower for uniocular (A$16,123±6,757) than for binocular treatment ($21,487±8,610). Cost decreased to A$11,420 (62%) in year five, with a much steeper decrease in uniocular treatment (to $7,698; 48%). Secondly the importance of using visual acuity (VA) in both eyes in outcomes and utility assessments in eye health were established in a large sample of over 1300 patients and controls. Using the Vision and Quality of Life (VisQOL) multi-attribute utility instrument (MAUI), utility scores decreased significantly with deteriorating vision in both the better and worse eyes when analysed separately. When stratified by 6 health states of vision impairment in both eyes, called vision states, VisQoL utilities decreased as VA declined in the worse eye despite stable VA in the better eye, demonstrating that calculating utilities based only on better eye VA is likely to underestimate the impact of vision impairment and thus treatment alleviating the impairment, particularly when the better eye has no or little VA loss and the worse eye is moderately to severely visually impaired. Thirdly, the CE of anti-VEGF treatment for nv AMD in standard medical practice in Victoria was assessed based on the collected data. In order to demonstrate the necessity of using vision states which capture VA of both eyes rather than modeling by treated or better eye only, several Markov models (MM) were built using TreeAge software, with health transition probabilities based on our real life treatment and utility inputs as described above. Costs and rewards were discounted at 3.5%/year and final results tested in probabilistic sensitivity analyses. Based on the clinical data MMs ran for 5 years, with all treatment assumed to be with ranibizumab (RBZ), the approved drug listed on the Pharmaceutical Benefits Schedule (PBS). The CE ratio was A$15,685/Quality Adjusted Life Year (QALY) for better eye, 16,296/QALY for treated eye and 15,780/QALY for both eye models, with the both eye MM generating the highest amount of QALYs (1.80 compared to 1.74 in MM1 and 1.70 in MM2). Based on these results, all subsequent MM assessing CE were based on vision states rather than treated or better eye only. The overall CE ratio was A$17,900/QALY, under the assumption that all injections were done using RBZ. Assuming that bevacizumab (BVZ, off-label use, not listed on PBS) was used instead of RBZ, the overall CE was A$ 3,196/QALY. Comparing both results for RBZ and BVZ with published CE ratios, all modelled treatment scenarios (both agents) were found to be below commonly applied cut-offs of A$ 30,000 - 70,000/QALY. In conclusion, good long-term effectiveness of anti-VEGF treatment under real life conditions was demonstrated, all relevant costs associated with this treatment were captured, and a novel method to assess the impact of vision impairment and its translation into CE modeling was developed. Based on this, anti-VEGF treatment with both, RBZ and BVZ, was found to be cost-effective over the five year period assessed.
-
ItemAssessment of environmental and genetic risk factors for age-related macular degeneration( 2012)This thesis consists of two sections. Section one presents the results of associations found between environmental factors and age-related macular degeneration (AMD) in a prospective cohort study, Section 2 presents genetic associations and interactions found between AMD risk genes and environmental risk factors from a case-control study nested in the cohort. Section One Aim: To investigate associations between environmental factors and age-related macular degeneration (AMD) in the Melbourne Collaborative Cohort Study (MCCS). Material & Methods: Participants included 21 287 men and women, who were aged 40–69 years at baseline (1990–1994 (48 to 86 years at follow up). Participant's body compositions were measured and alcohol and nutrient intakes were estimated from a food frequency questionnaire at baseline in 1990-94. At follow up from 2003-2007, digital macula photographs of both eyes were taken and evaluated for signs of early and late AMD. Section Two Aim: Associations between genotype and AMD were assessed using a nested case-control study (2,287 cases, 2,287 controls individually matched on age, sex and country-of-origin), selected from the Melbourne Collaborative Cohort Study. Statistical interactions between selected environmental and genetic risk factors were evaluated.