COPYRIGHT AND USE OF THIS THESIS This thesis must be used in accordance with the provisions of the Copyright Act 1968. Reproduction of material protected by copyright may be an infringement of copyright and copyright owners may be entitled to take legal action against persons who infringe their copyright. Section 51 (2) of the Copyright Act permits an authorized officer of a university library or archives to provide a copy (by communication or otherwise) of an unpublished thesis kept in the library or archives, to a person who satisfies the authorized officer that he or she requires the reproduction for the purposes of research or study. The Copyright Act grants the creator of a work a number of moral rights, specifically the right of attribution, the right against false attribution and the right of integrity. You may infringe the author’s moral rights if you: - fail to acknowledge the author of this thesis if you quote sections from the work - attribute this thesis to another author - subject this thesis to derogatory treatment which may prejudice the author’s reputation For further information contact the University’s Director of Copyright Services sydney.edu.au/copyright Retinal Measurements by Spectral Domain Optical Coherence Tomography: Normative Data and Associations in Adolescents Yasser M Tariq BSc MBBS (Hons) This thesis is submitted in fulfillment of the requirements for the degree of Doctor of Philosophy at the University of Sydney Department of Clinical Ophthalmology and Eye Health University of Sydney October 2013 1 Table of Contents Preface……………………………………………………………………………........... 4 Executive Summary…………………………………….………………………….......... 6 Acknowledgements…………………………………………………………………....... 12 Candidate’s Contribution………………………………………………………….......... 13 Publications and Presentations……………………………………………….................. 14 List of Tables………………………………………………………………………......... 19 List of Figures………………………………………………………………………....... 22 Abbreviations…………………………………………………………………….…....... 23 Introduction……………………………………………………………………………… 24 Chapter 1: Brief Literature Review………………..…...……………………….............. 27 Chapter 2: Methods……………………………………………………………………... 56 Chapter 3: Retinal Nerve Fiber Layer and Optic Disc Measurements in Young Adults.. 63 Chapter 4: Retinal Nerve Fiber Layer and Optic Disc Parameters in Children ………… 84 Chapter 5: Macular Measurements in Young Adults…………………………………… 99 Chapter 6: Macular Measurements in Children……………………………………..…... 115 Chapter 7: Ethnic Differences in Macular Thickness…………………………….…….. 130 2 Chapter 8: Ethnic Differences in the Correlation of Retinal Parameters with Axial Length…………………………………………………….………………… 144 Chapter 9: Association of Birth Parameters with Time Domain OCT Measured Macular and Retinal Nerve Fiber Layer Thickness....………………….….. 160 Chapter 10: Spectral Domain OCT Measured Macular Parameters and Prematurity ..… 178 Chapter 11: Retinal Thickness in Children from Diabetic Pregnancies........................... 186 Chapter 12: Conclusions, Implications and Future Direction.......................................... 197 References……………………………………………………………………………...... 203 Appendix: SAVES Examination Booklet....................................................................... 238 Appendix: SAVES Parent Questionnaire …………………………………………….. 252 Appendix: SAVES Student Questionnaire...................................................................... 286 3 PREFACE This thesis describes the candidate’s work on the measurement of retinal parameters in adolescents using OCT. These retinal measurements were obtained from the older cohort of the Sydney Myopia Study (SMS, older cohort was predominantly 12 years of age) and all participants of the Sydney Adolescent Vascular and Eye Study (SAVES, age range 10 to 19 years). In the SMS time domain OCT technology was used, and these data were used to perform analysis of associations of retinal thickness. The SAVES examined retinal parameters with spectral domain OCT, and these data were used to determine the normative distribution of retinal parameters in a normal adolescent population, as well as assess associations of these parameters. The first chapter of this thesis reviews existing publications of OCT measurements of retinal parameters in normal eyes. It provides normative data from these publications and comments on previous findings of variations of retinal thickness with age, ethnicity, axial length and myopia. Chapter 2 outlines the methodology of the thesis, encompassing the protocols for the SMS and the SAVES. Chapters 3 and 4 provide Cirrus HD-OCT measured retinal nerve fiber layer for a mixed ethnic population of young adults and children from the Sydney metropolitan area. Chapters 5 and 6 provide data and analysis for macular parameters. Together these four chapters are the first to describe normative spectral domain OCT values in such a large cohort, as well as the first studies to provide comprehensive childhood data using this technology. 4 Chapter 7 provides side-by-side macular thickness data for four distinct ethnic groups, and chapter 8 is a novel study describing ethnic differences in the association of retinal parameters with axial length. Chapters 9, 10 and 11 investigate how perinatal factors are associated with changes in retinal parameters in adolescence. Chapter 12 concludes the thesis with a brief discussion and the implications of the major findings. The exam booklet and the two questionnaire booklets for SAVES are included in the appendix. 5 Executive Summary The objectives of this thesis were to: 1. Determine the distributions and develop a normative database for spectral domain OCT measured macular and optic disc parameters in healthy children and young adults 2. Investigate the association of gender and ethnicity with macular and optic disc parameters 3. Determine if OCT parameters are associated with AL and SER 4. Determine if prematurity and low birth weight are associated with macular and RNFL parameters 5. Investigate if an association exists between maternal diabetes and retinal parameters measured by OCT The Sydney Childhood Eye Study comprises 3 separate studies, including the Sydney Myopia Study (SMS), the Sydney Paediatric Eye Disease Study (SPEDS) and the Sydney Adolescent Vascular and Eye Study (SAVES). SMS and SAVES were carried out in 2003 to 2005 and 2009 to 2011, respectively and conducted ocular exams on two cohorts of school children. Data from the school year 7 SMS children (predominantly 12 years old) and SAVES were utilised in the preparation of this thesis. During SMS 2367 Year 7 children were examined. During SAVES 2818 participants underwent examination. As part of both of these studies Optical Coherence Tomography (OCT) scanning was performed. The first commercially available OCT machines applied time domain technology. 6 The newer spectral domain OCT allows faster scanning, with higher scanning density and higher scanning resolution than time domain OCT. In the SMS the time domain Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA) was used, and in SAVES the spectral domain Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, California, USA) was used. Major findings from this thesis 1. Normative values and associations of spectral domain OCT RNFL and optic disc measurements in young adults and children In the SAVES older cohort (aged 16 to 19 years) the mean value of average RNFL for this population was 99.4 ± 9.7µm with a range of 61 to 138µm. The RNFL was thickest at the inferior (128.5 ± 17.2µm) and superior (124.8 ± 15.9µm) quadrants. The average RNFL was normally distributed based on the Kolmogorov-Smirnov test. The mean disc area in this population was 1.98 ± 0.38mm2 with a mean rim area of 1.50 ± 0.30 mm2 and a mean CDR of 0.44 ± 0.18. CDRs ranged from 0.05 to 0.80. The temporal RNFL was found to be thinner in males as compared with females in data adjusted for age, height, AL and ethnicity (P = 0.0008). Females had smaller disc areas, cup volumes and cup disc ratios (all P ≤ 0.004). Individuals of Caucasian (European) ethnicity had thinner RNFL parameters than East Asian children (all P ≤ 0.005, data adjusted for age, sex, height, AL and clustered sampling) except for the nasal quadrant which was significantly thicker in Caucasians (P < 0 .0001). The optic disc rim area was smaller (mean difference 0.08mm2, P = 0.0007) and optic disc area was greater (mean difference 0.14mm2, P < 0.0001) in East Asian than in Caucasian children resulting in overall greater cup disc ratio in East Asian (mean difference 0.11, P < 0.0001). Increased AL and more severe myopia were associated with decreased RNFL thickness (Ptrend < 0.0001). 7 In the younger cohort of the SAVES study (age range 10 – 15 years) the average RNFL was 100.3 ± 10.2µm. The pattern of relative quadrant thickness was similar to the older cohort. The disc area in this population had a mean value of 2.01 ± 0.38mm2 and the rim area was 1.57 ± 0.32mm2. The cup disc area ratio ranged from 0.05 to 0.82. There was no inter-sex difference in average RNFL; however girls had a significantly thinner nasal quadrant RNFL than boys in analysis adjusted for age, height, AL and ethnicity. Boys had marginally larger disc area (mean difference 0.07mm2, P = 0.002) and cup volume (mean difference 0.02mm3, P = 0.01) compared with girls, in analysis adjusted for age, height, AL and ethnicity. Average RNFL was thicker in East Asian children compared with white children (mean difference 6.1µm, CI 4.0 – 8.1, P < 0.0001, data adjusted for age, sex, height, AL