School of Optometry and Vision Sciences Cardiff University Low-Level Night-Time Light Therapy for Age-Related Macular Degeneration David Grant Robinson 2017 A thesis submitted to Cardiff University for the degree of Doctor of Philosophy Supervisors: AM Binns TH Margrain Advisor: A Wood For Catherine i Declaration This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed: (candidate) Date: 11/9/2017 STATEMENT 1 This thesis is being submitted in partial fulfilment of the requirements for the degree of PhD. Signed: (candidate) Date: 11/9/2017 STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated, and the thesis has not been edited by a third party beyond what is permitted by Cardiff University’s Policy on the Use of Third Party Editors by Research Degree Students. Other sources are acknowledged by explicit references. The views expressed are my own. Signed: (candidate) Date: 11/9/2017 STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed: (candidate) Date: 11/9/2017 ii Acknowledgements Firstly, I would like to thank my two inspirational supervisors, Dr Ali Binns and Prof Tom Margrain for their guidance and encouragement throughout this PhD. I would also like to thank Dr Ashley Wood and Dr Matt Dunn for their help and advice over the years. Many thanks also go to the office staff at the Optometry department, especially the wonderful Sue Hobbs who has provided fantastic support since day one. A huge thank you to everyone in the Bristol Eye Hospital Clinical Research and Retinal Imaging Units for all of the hard work you have contributed to this PhD. In particular, I would like to thank Ms Clare Bailey and my fantastic trial manager Gemma Brimson. I would also like to extend my gratitude to all of the participants that agreed to take part in my studies. A heartfelt thanks goes to my fellow post-graduate friends, especially those in office 2.10. Thank you all for putting up with my distracting antics and grumpiness over the last 3 years. A special thanks goes to Nikki Cassels, who has been a constant source of encouragement and friendship since we first sat next to each other in 2013. Finally, I would like to express my love and gratitude to my family. Especially to my wife Catherine, my parents, my siblings and to David for their enduring support and encouragement. You have always believed in me, for which I will forever be grateful. iii Table of contents Dedication…………………………………………………………………………………...i Declaration.... .......................................................................................................... ii Acknowledgements ............................................................................................... iii Table of contents ................................................................................................... iv List of tables .......................................................................................................... xi List of figures ...................................................................................................... xiii Acronyms……..................................................................................................... xvii Summary……. ....................................................................................................... xx Chapter 1. Introduction ....................................................................................... 1 1.1. Normal retinal structure .............................................................................. 1 Blood supply to the retina .................................................................... 3 The effect of luminance on retinal oxygen demand ............................. 5 Bruch’s membrane .............................................................................. 7 The retinal pigment epithelium ............................................................ 7 The photoreceptor layer ...................................................................... 9 1.2. Light and dark retinal physiology .............................................................. 11 Visual phototransduction cascade ..................................................... 12 Recycling of visual pigment ............................................................... 13 Alternative method of visual pigment regeneration ............................ 15 The dark current ................................................................................ 16 1.3. Age-related macular degeneration ........................................................... 17 Risk factors for AMD ......................................................................... 19 iv AMD pathogenesis ........................................................................... 23 Clinical features of AMD ................................................................... 27 AMD grading scales ......................................................................... 32 Prevention and treatment ................................................................. 35 Clinical investigation of AMD ............................................................ 41 1.4. Visual psychophysics ............................................................................... 52 Classical psychophysical methods.................................................... 52 Adaptive psychophysical methods .................................................... 54 1.5. PhD objectives ......................................................................................... 58 Pilot study aims ................................................................................ 58 Cross-sectional study aims ............................................................... 59 Longitudinal clinical trial (the ALight trial) aims ................................. 59 1.6. Conclusion ............................................................................................... 60 Chapter 2. Evaluating the role of hypoxia in the pathogenesis of AMD: a literature review ................................................................................................... 61 2.1. Introduction .............................................................................................. 61 2.2. Literature review methods ....................................................................... 63 Literature searching methods ........................................................... 64 2.3. Results .................................................................................................... 65 Direct evidence of hypoxia in AMD ................................................... 66 2.4. Indirect evidence of hypoxia in AMD ........................................................ 70 Choroidal blood flow volume and velocity ......................................... 70 Structural changes to the choroid ..................................................... 72 v Changes to choroidal blood flow perfusion ........................................ 74 Bruch’s membrane and RPE dysfunction .......................................... 76 Mitochondrial damage ....................................................................... 78 2.5. Discussion ................................................................................................ 79 Chapter 3. General methods and protocol development ................................ 82 3.1. Overview of original protocol .................................................................... 82 3.1.1. Primary outcome measures ............................................................... 83 3.1.2. Secondary outcome measures .......................................................... 85 3.1.3. Participant eligibility criteria ............................................................... 86 3.1.4. Recruitment strategy ......................................................................... 87 3.1.5. Withdrawal from trial: criteria and loss to follow-up ............................ 88 3.1.6. Registration ....................................................................................... 88 3.2. Intervention .............................................................................................. 88 Determining the optimum light level for the intervention .................... 91 Maintenance of the light level ............................................................ 92 Circadian rhythm ............................................................................... 93 Ocular position during sleep .............................................................. 94 3.3. Trial procedures ....................................................................................... 95 Informed consent and screening ....................................................... 95 Screening assessment ...................................................................... 95 Baseline assessment ........................................................................ 96 Enrolment .......................................................................................... 99 Monthly assessment of medical records ............................................ 99 vi Monthly follow-up