Handbook of Nutrition, Diet, and the Eye 9780128152461, 012815246X, 9780128152454

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Handbook of Nutrition, Diet, and the Eye

Handbook of Nutrition, Diet, and the Eye Second Edition Edited By Victor R. Preedy Ronald Ross Watson

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-815245-4 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Nikki Levy Acquisition Editor: Natalie Farra Editorial Project Manager: Carlos Rodriguez and Aleksandra Packowska Production Project Manager: Sruthi Satheesh Cover Designer: Alan Studholme Typeset by SPi Global, India

Contributors Winsome Abbott-Johnson School of Medicine, University of Queensland, Brisbane, Australia Niyazi Acar Eye and Nutrition Research Group, Centre des Sciences du Gouˆt et de l’Alimentation, AgroSup Dijon, CNRS, INRA, Universit
e Bourgogne Franche-Comt
e, Dijon, France Asaf Achiron Department of Ophthalmology, Edith Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Vaishali Agte Agharkar Research Institute, Pune, India R.A. Armstrong Vision Sciences; Optometry School, Aston University, Birmingham, United Kingdom Bahri Aydın Department of Ophthalmology, Gazi University Medical School, Ankara, Turkey Fereshteh Bahmani Department of Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran ˆ t et de Lionel Bretillon Eye and Nutrition Research Group, Centre des Sciences du Gou l’Alimentation, AgroSup Dijon, CNRS, INRA, Universit
e Bourgogne Franche-Comt
e, Dijon, France Alain M. Bron Eye and Nutrition Research Group, Centre des Sciences du Gouˆt et de l’Alimentation, AgroSup Dijon, CNRS, INRA, Universit
e Bourgogne Franche-Comt
e; Department of Ophthalmology, University Hospital, Dijon, France Zvia Burgansky-Eliash Department of Ophthalmology, Edith Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Pramila Chaubey SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Mithibai College Campus, Mumbai, India  Emina Colak Institute of Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia Damian Cole Centre for Public Health, Queen’s University Belfast, Institute of Clinical Science A, Belfast, Ireland

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CONTRIBUTORS

Marc Comaratta Associated Retina Consultants, Phoenix, AZ, United States M. Cossenza Program of Neurosciences; Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Nitero´i, Brazil Catherine P. Creuzot-Garcher Eye and Nutrition Research Group, Centre des Sciences du
Bourgogne FrancheGouˆt et de l’Alimentation, AgroSup Dijon, CNRS, INRA, Universite
Comte; Department of Ophthalmology, University Hospital, Dijon, France R.C. Cubbidge Vision Sciences, Aston University, Birmingham, United Kingdom R.P. Cubbidge Vision Sciences, Aston University, Birmingham, United Kingdom Carlo Alberto Cutolo Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Science, University of Genoa, Polyclinic San Martino Hospital, Genoa, Italy Alexandra P M de Koning-Backus Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands Maria Cristina de Oliveira Izar Federal University of Sao Paulo, Sa˜o Paulo, Brazil Patricia Coelho de Velasco Laborato´rio de Plasticidade Neural, Departamento de ^ncias, Instituto de Biologia, Neurobiologia, Programa de Po´s-Graduac¸a˜o em Neurocie
de Castro, Universidade Federal Fluminense, Nitero´i; Instituto de Nutric¸a˜o Josue Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil I. Domith Program of Neurosciences; Department of Neurobiology, Institute of Biology, Fluminense Federal University, Nitero´i, Brazil T.G. Encarnac¸ a˜o Program of Neurosciences, Fluminense Federal University, Nitero´i, Brazil Mesut Erdurmuş Kudret Eye Hospital, Ankara, Turkey Hamed Esfandiari Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States ´ rea de Ciencia Gastrono´mica, Facultad de Ciencias Jurı´dicas y
vez-Santiago A Rocı´o Este Empresariales, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarco´n, Madrid, Spain Asghar Farajzadeh Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran Silvia C. Finnemann Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, NY, United States Francisco Antonio Helfenstein Fonseca Federal University of Sao Paulo, Sa˜o Paulo, Brazil

Contributors

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Christopher Fortenbach Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States Peter L. Gehlbach Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States Snehal Gite Agharkar Research Institute, Pune, India Elissa Goldman Eye Monitoring Center, Kaiser Permanente Southern California; Department of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park, CA, United States Paweł Grieb Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland Julia A. Haller Wills Eye Hospital, Jefferson Medical College, Philadelphia, PA, United States Sang Beom Han Department of Ophthalmology, Kangwon National University Medical School, Kangwon National University Hospital, Chuncheon, South Korea Rijo Hayashi Department of Ophthalmology, Saitama Medical Center, Dokkyo Medical University, Saitama, Japan Idan Hecht Department of Ophthalmology, Edith Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Tatiana Helfenstein Federal University of Sao Paulo, Sa˜o Paulo, Brazil Ruth E Hogg Centre for Public Health, Queen’s University Belfast, Institute of Clinical Science A, Belfast, Ireland Joon Young Hyon Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea Yao Jin Nanjing Medical University Eye Hospital, Nanjing, People’s Republic of China Kim Jiramongkolchai Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States Rahul K. Reddy Associated Retina Consultants, Phoenix; School of Medicine, University of Arizona, Tucson, AZ, United States Frances H. Kazal Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, NY, United States Paul Kerlin Gastroenterology and Liver Group, Wesley Hospital, Brisbane, Australia

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CONTRIBUTORS

Jessica C Kiefte-de Jong Department of Epidemiology, Erasmus Medical Center, Rotterdam; Leiden University College; Department of Public Health and Primary Care, Leiden University Medical Center/LUMC Campus, The Hague, The Netherlands Amar U. Kishan Department of Radiation Oncology, University of California, Los Angeles, CA, United States Caroline C W Klaver Department of Epidemiology, Erasmus Medical Center, Rotterdam; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands Kimitoshi Kohno Kurate Hospital, Fukuoka, Japan Dingbo Lin Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, United States Nils A. Loewen Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States Idit Maharshak Department of Ophthalmology, Edith Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Shilpa Mathew UC Davis Eye Center, Sacramento, CA, United States Francesca Mazzoni Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, NY, United States Naoya Miyamoto Miyamoto Eye Clinic, Fukuoka, Japan Bobeck S. Modjtahedi Eye Monitoring Center, Kaiser Permanente Southern California; Department of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park, CA, United States Lawrence S. Morse UC Davis Eye Center, Sacramento, CA, United States Manikanta Murahari Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India Nara Naranjit Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States Robert Kelechi Obi Department of Microbiology, Federal University of Technology, Owerri, Nigeria ˜ a Olmedilla-Alonso Department of Metabolism and Nutrition, Institute of Food Begon Science, Technology and Nutrition (ICTAN-CSIC), Madrid, Spain R. Paes-de-Carvalho Program of Neurosciences; Department of Neurobiology, Institute of Biology, Fluminense Federal University, Nitero´i, Brazil

Contributors

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Adela Pintea University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania ´ de and Instituto de Biologia C.C. Portugal Instituto de Investigac¸a˜o e Inovac¸a˜o em Sau Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal Jiang Qin Nanjing Medical University Eye Hospital, Nanjing, People’s Republic of China Marina Roizenblatt Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Ophthalmology; Vision Institute, IPEPO, Department of Ophthalmology, Paulista Medical School, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil Tommaso Rossi Department of Head/Neck Pathologies, Polyclinic San Martino Hospital, Ophthalmology Unit, Genoa, Italy Dumitrit¸a Rugina˘ University of Agricultural Sciences and Veterinary Medicine, ClujNapoca, Romania Sergio Claudio Sacca` Department of Head/Neck Pathologies, Polyclinic San Martino Hospital, Ophthalmology Unit, Genoa, Italy Poliana Capucho Sandre Laborato´rio de Plasticidade Neural, Departamento de ^ncias, Instituto de Biologia, Neurobiologia, Programa de Po´s-Graduac¸a˜o em Neurocie ´ Universidade Federal Fluminense, Niteroi, Brazil Preeti C. Sangave Department of Pharmaceutical Sciences, School of Pharmacy & Technology Management, SVKM’s NMIMS, MPTP, Shirpur, Dhule, India Megha Sarkar SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Mithibai College Campus, Mumbai, India Claudio Alberto Serfaty Laborato´rio de Plasticidade Neural, Departamento de ^ncias, Instituto de Biologia, Neurobiologia, Programa de Po´s-Graduac¸a˜o em Neurocie Universidade Federal Fluminense, Nitero´i, Brazil Horacio M. Serra Department of Clinical Biochemistry, Faculty of Chemical Science, National University of Co´rdoba, Co´rdoba, Argentina Juliet Adamma Shenge Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria € seyin Simavlı Kudret Eye Hospital, ˙Istanbul, Turkey Hu R. Socodato Instituto de Investigac¸a˜o e Inovac¸a˜o em Sau´de and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal Marco Spinazzi Neurology and Neuromuscular Diseases Center, Centre Hospitalier Universitaire d’ Angers, Angers, France

xxvi

CONTRIBUTORS

Krishnapura Srinivasan Department of Biochemistry, CSIR—Central Food Technological Research Institute, Mysore, India Philip P. Storey Retina Department, Wills Eye Hospital, Philadelphia, PA, United States Marı´a Fernanda Sua´rez Department of Clinical Biochemistry, Faculty of Chemical Science, National University of Co´rdoba, Co´rdoba, Argentina Vasanti Suvarna SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Mithibai College Campus, Mumbai, India Mehmet Tosun Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States Jade Vargas Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, NY, United States Jayne V Woodside Centre for Public Health, Queen’s University Belfast, Institute of Clinical Science A, Belfast, Ireland Lei Wu Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, United States Chen Xi Nanjing Medical University Eye Hospital, Nanjing, People’s Republic of China € Ramazan Yag˘cı Ozel Denizli Tekden Hospital, Denizli, Turkey Ji Yong Department of Pathophysiology, Nanjing Medical University, Nanjing, People’s Republic of China S. Zahra Bathaie Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran ˇ ori
c Ophthalmology Department, Faculty of Medicine, University of Pristina, Lepsˇa Z Kosovska Mitrovica, Serbia

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The Eye and Vision: An Overview R.A. Armstrong, R.C. Cubbidge VISION SCIENCES, ASTON UNIVERSITY, BIRMINGHAM, UNITED K INGDOM

CHAPTER OUTLINE Introduction ...................................................................................................................................... 4 Development of the Eye .................................................................................................................. 4 The Ocular Adnexa .......................................................................................................................... 5 Eyebrows .......................................................................................................................................5 Eyelids ...........................................................................................................................................6 Eyelashes .......................................................................................................................................6 Lacrimal Gland ..............................................................................................................................6 Orbit ..............................................................................................................................................6 Extraocular Muscles ......................................................................................................................7 The Anterior Structures of the Eye ................................................................................................. 7 Conjunctiva ...................................................................................................................................7 Cornea ...........................................................................................................................................8 Sclera .............................................................................................................................................8 Iris ..................................................................................................................................................8 Ciliary Body ...................................................................................................................................9 Crystalline Lens .............................................................................................................................9 Aqueous Humor .........................................................................................................................10 The Posterior Structures of the Eye .............................................................................................. 10 Vitreous Body .............................................................................................................................10 The Choroid ................................................................................................................................11 The Retina ...................................................................................................................................11 Visual Pathway ............................................................................................................................... 13 Summary Points ............................................................................................................................. 14 References ...................................................................................................................................... 14

List of Abbreviations Ah AMD BV C CH Co EB

aqueous humor age-related macular degeneration blood vessel conjunctiva choroid cornea eyebrow

Handbook of Nutrition, Diet, and the Eye. https://doi.org/10.1016/B978-0-12-815245-4.00001-6 © 2019 Elsevier Inc. All rights reserved.

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EL GCL I INL IOP L La LGN Lv Me OC OD ON/O ONL Or OS P PE PVD R R/C Sc SE VB

eyelid ganglion cell layer iris inner nuclear layer intraocular pressure crystalline lens eyelashes lateral geniculate nucleus lens vesicle meninges optic cup optic disk optic nerve outer nuclear layer orbit optic stalk pupil pigment epithelium posterior vitreous detachment retina rods and cones sclera surface ectoderm vitreous body

Introduction Vision is the sense that we rely on most to inform us of the state of the world. For this reason, more is known about the scientific basis of vision than any of our other senses.1 The major organ of vision, the eye, is highly specialized for photoreception. It focuses light from an object onto the light-sensitive part of the eye, the retina. Changes in specialized neurons in the retina result in nerve action potentials, which are relayed to the brain via the optic nerve. Visual processing by the brain results in “visual perception,” the construction of a sensory image, which is then consciously appreciated as vision.2,3 All other structures of the eye are subsidiary to this function, either by facilitating focusing of light rays or supporting the tissues of the eye. This chapter is an introduction to the different parts of the eye and their various functions in achieving a visual image.

Development of the Eye The eyes develop from outgrowths of the brain called the optic vesicles (Fig. 1).4 Five weeks after conception, the optic vesicle has emerged from the neural ectoderm of the brain and begins to fold inwards producing an inner and an outer layer separated by a cavity. The retina and smooth muscle of the iris will develop from this structure. The optic vesicle also induces the formation of the lens placode that develops from an invagination of surface ectoderm in front of the vesicle and ultimately will develop into the

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FIG. 1 The figure shows the lens vesicle, optic cup, and optic stalk, which will develop into the lens, retina, and optic nerve, respectively (Lv, lens vesicle; OC, optic cup; OS, optic stalk; SE, surface ectoderm). Image courtesy: R.A. Armstrong.

crystalline lens. In addition, the hyaloid artery ramifies on the back of the developing lens while the outer surface of the optic vesicle develops a network of blood vessels in the mesoderm eventually forming the choroid. Outside this, the mesoderm forms the sclera and the extraocular muscles. Eight weeks after conception, the thicker inner layer of the optic cup has detached from the thinner outer layer thus illustrating the weak attachment that exists between inner and outer layers of the developing retina. Within the vitreous chamber, the hyaloid blood vessels have developed that nourish the developing vitreous and the crystalline lens. These vessels normally disintegrate before birth but remnants of them may persist into childhood. The crystalline lens has developed at this stage and the primary lens fibers have now filled the cavity of the lens vesicle. The cornea develops from the surface ectoderm and mesoderm and the anterior chamber is formed between the developing cornea and lens. The fused eyelids can be seen at this stage, their skin and glands developing from the surface ectoderm, while connective tissue and muscle develop from the mesoderm.

The Ocular Adnexa The ocular adnexa refer to the accessory or adjoining parts of the eye and comprise several structures including the eyebrows, eyelids, eyelashes, lacrimal gland, and orbit. Many of these structures are illustrated in the anterior view of the eye shown in Fig. 2.

Eyebrows Each eyebrow is a thickened area of skin with accompanying hairs, which are directed both upwards and toward the temporal side of the head. The hairs function to prevent sweat formed on the forehead from entering the eyes. In many cultures, the eyebrows are also important in facial expression.

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FIG. 2 The figure shows various parts of the anterior eye including the lids, cornea, sclera, and pupil (Co, cornea; EB, eyebrow; EL, eyelid; P, pupil; Sc, sclera). Image courtesy: R.A. Armstrong.

Eyelids The eyelids are moveable folds of skin, which function to protect the eye from particulate matter in the air. They also reduce the amount of light entering the eyes and provide some of the constituents making up the tears. The ocular surface can usually resist ocular infection both as a result of the mechanical action of the eyelids, which physically remove potential pathogens, and the washing effect of tears.5

Eyelashes There are two or three rows of eyelashes located on the upper edge of the upper and lower lids, the lashes numbering approximately 150 on the upper lid and 75 on the lower lid. They function to protect the eye against small particles but are vulnerable to infection, especially by bacteria, a condition called “blepharitis.”

Lacrimal Gland The lacrimal gland lies inside the eye socket above the eye and functions to produce the tears. It is divided into a large “orbital” and a smaller “palpebral” portion connected by a canal. In the orbital part, ducts join with those from the palpebral portion entering the upper temporal part of the conjunctiva. Excess tears are drained via the canaliculi into the lacrimal sac and ultimately the nasal cavity. Tears contain lysozymes, lactoferrin, B-lysin, and immunoglobulin A, which are important in defense against infection.

Orbit The orbit is the bony socket, which contains the eye. The eye is situated in the anterior portion of the orbit closer to its lateral surface than the medial wall and nearer the roof

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of the orbit than the floor.6 It comprises seven bones, including the ethmoid and sphenoid bones, and bones that make up the structure of the face such as the maxilla, frontal, and zygomatic. The purpose of the orbit is to protect the eye and to act as an anchorage point for the extraocular muscles and other ocular tissues.

Extraocular Muscles There are six extraocular muscles, which are attached to the eye by tendons at the sclera (the white outer coat of the eye). They function to move the eyes through 360 degree of gaze and are coordinated so that the two eyes move in unison, thus preventing double vision (diplopia). There are four rectus muscles: medial, lateral, superior, and inferior, which are attached to a common tendon ring at their posterior ends (the annulus of Zinn), which in turn, is attached to the posterior surface of the orbit. The primary action of the medial rectus is to pull the eye horizontally in the nasal direction, whereas the lateral rectus pulls the eye horizontally in the temporal direction. The primary action of the superior rectus is to pull the eye upwards and the inferior rectus to pull the eye downwards. The two remaining muscles, the superior and inferior oblique muscles, are inserted more “obliquely” into the upper and lower posterior temporal quadrants of the orbit. The inferior oblique, and superior, inferior, and medial recti muscles are controlled by the third cranial nerve (the oculomotor nerve) and the lateral rectus by the sixth cranial nerve (the abducens nerve). In addition, the superior oblique muscle is supplied by the fourth cranial nerve (the trochlear nerve). The primary actions of the superior and inferior oblique muscles are also to pull the eyes in an upward or downward direction, respectively. Nevertheless, only the primary muscle actions have been described, and several of the muscles act in concert to produce secondary and tertiary actions, which can move the eyes in more complex directions. The study of muscle action of the eyes and the coordination of eye movement is called “binocular vision.”

The Anterior Structures of the Eye The human eye is approximately spherical in shape, 25 mm in diameter, has a volume of 6.5 mL, while average axial length of the globe is 24 mm (range: 21–26 mm). It actually comprises the parts of two spheres, which are represented anteriorly by the cornea, which has a greater curvature than that represented by the curvature of the posterior sclera. Hence, the eye can be divided into two functionally distinct regions, viz. the anterior eye and the posterior eye. The anterior segment comprises the cornea, iris, ciliary body, crystalline lens, aqueous humor, and the anterior part of the sclera (Fig. 3).

Conjunctiva The conjunctiva is the outer membrane of the eye covering the white fibrous sclera. It is continuous with that of the transparent cornea and extends onto the surface of the upper and lower lids. It is a mucous membrane with a nonkeratinized, stratified epithelium and

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FIG. 3 The figure shows the various structures of the eye as seen in a vertical section (C, conjunctiva; Ch, choroid; CO, cornea; I, iris; O, optic nerve; OD, optic disk; Or, orbit; R, retina; VB, vitreous body). Image courtesy: R.A. Armstrong.

subepithelial layers, which are composed of adenoid and connective tissue, a region especially vulnerable to infection (“conjunctivitis”).

Cornea The cornea is the most anterior structure of the eye and comprises one-sixth of the circumference of the globe. It is a curved, transparent structure with a radius of 7.8 mm. The anterior surface is continually bathed by tears while the posterior surface is bathed by aqueous humor. The surface of the cornea together with the associated tear film is responsible for most of the refractive power of the eye. Hence, the function of the cornea is to refract light rays so that they eventually come to a focus on the retina. The main thickness of the cornea is composed of regularly arranged collagen fibers, which together with the regular smooth epithelium and lack of blood vessels, is responsible for its transparency.

Sclera With the exception of the cornea, the sclera forms the outermost layer of the eye. It is thickest in its posterior region and thinnest at the point of attachment of the tendons to the ends of the extraocular muscles. It comprises collagen fibers, which unlike the cornea, are irregularly arranged resulting in an opaque appearance. The sclera is highly fibrous and provides protection, support, and anchorage for structures within and outside the eye such as the musculature, and also maintains the shape of the globe.

Iris The iris is a 12-mm-diameter structure, which functions to regulate the amount of light entering the eye and also separates the eye into anterior and posterior chambers. It is analogous in action to the diaphragm of a camera. The pupil is an aperture in the center of the iris through which light rays pass on route to the retina. The iris also contains muscle,

Chapter 1 • The Eye and Vision: An Overview

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which contracts in response to bright light, making the pupil smaller and reducing the amount of light entering the posterior segment. By contrast, dim light will cause the pupil to dilate thus increasing the light entering the posterior segment. The iris is controlled by branches of the autonomic nervous system. Hence, parasympathetic stimulation, supplied by the oculomotor nerve, will constrict the pupil while sympathetic stimulation, originating from the superior cervical ganglion, acts to dilate the pupil. The posterior surface of the iris is covered in cells, which contain the pigment melanin and which prevent light from entering the eye through the iris. The remaining part of the iris has varying amounts of pigment resulting in its characteristic color. Hence, an iris with relatively little pigment appears blue and progressively more pigment leads successively to green, hazel, and brown eyes. The amount of pigmentation present and therefore, the resulting eye color, is genetically determined. Albinism is a genetically determined condition, which results in a lack of pigment in cells in the body. In humans, pigmentation on the back surface of the iris is never completely absent, so the eyes of humans with albinism often appear blue. In animals that are albino, however, no pigmentation is present and the eyes appear pink as for example, in white mice.

Ciliary Body The ciliary body is a 5–6 mm wide ring of tissue extending from the scleral spur anteriorly to the ora serrata posteriorly and is the anterior continuation of the choroid. It can be further divided into the pars plicata and pars plana. It consists of the ciliary muscle and a tissue, which secretes the aqueous humor. In addition, it provides attachment to the zonular fibers, which attach to the peripheral region of the crystalline lens thus maintaining it in position. Contraction and relaxation of the ciliary muscle can change the thickness of the lens, which simultaneously alters its curvature thus enabling the eye to change power and focus at different distances, a process called “accommodation.” The action of the ciliary body is also controlled by the oculomotor nerve.

Crystalline Lens The lens consists of specialized surface ectoderm cells and is a highly elastic, circular, biconvex, transparent body lying immediately behind the pupil. It is suspended from the ciliary body by the zonular fibers and enclosed within a transparent capsule. The lens has less refractive power than the cornea and contraction of the ciliary muscle during accommodation relaxes the tension exerted by the zonular fibers on the lens, causing it to bulge, thus increasing its thickness and refractive power. This variable power enables us to focus from distant to near objects in the visual scene. The microscopic appearance of the lens is of long, thin cells, which are regularly arranged in layers, essentially like an onion. These cells are continually produced through life as a result of mitotic cell division at the periphery of the lens,7 such that the thickness of the lens increases during a person’s lifetime. Eventually the lens may become so thick that it is no longer able to support its own metabolism, leading to increased opacity and ultimately cataract.7 The lens also

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becomes yellower with age as a result of pigment cells building up within its structure. These cells are thought to be a protective mechanism against ultraviolet light. As the lens becomes thicker, it also becomes less elastic and this loss in elasticity and therefore, ability to focus, is thought to be responsible for a loss in reading ability in the middle years of life, a condition called “presbyopia.”

Aqueous Humor The aqueous humor is a transparent liquid produced by the ciliary body and which passes through the pupil, thus filling the anterior chamber. It ultimately passes through a fine meshwork at the cornea-sclera-iris junction called the trabecular meshwork into Schlemm’s canal, and then drains into the venous system. Aqueous humor has a consistency much like water and functions to provide nutrients to, and remove waste products of metabolism from the transparent cornea and crystalline lens, both of which do not possess a blood supply. The continuous production of the aqueous humor and drainage through the trabecular meshwork results in a fluid pressure, which has a range in normal individuals of 10–20 mm of mercury. This pressure serves to maintain the shape of the eye. In some individuals, the trabecular meshwork can suddenly or more gradually become blocked leading to an increase in intraocular pressure (IOP) in the anterior chamber. This increase in IOP may be transferred to the retina damaging its function, leading to a condition called glaucoma.8

The Posterior Structures of the Eye The posterior part of the eye consists largely of the vitreous body, the choroid, retina, and optic disk (Fig. 3).

Vitreous Body The vitreous cavity is the largest cavity in the eye comprising approximately two-thirds of its volume. It is bounded anteriorly by the lens and ciliary body and posteriorly by the retinal cup. It comprises two regions, viz. a cortical zone of densely packed collagen fibers and a more liquid central region. Unlike the aqueous humor, the vitreous is a transparent, gel-like liquid with a relatively thick consistency. It is largely water (98%), with salts and collagen fibers making up the remainder. The vitreous fills the posterior eye and is only loosely attached to the retina, its function being mainly to maintain the shape of the eye. Vitreous is not continually produced, but remains fairly constant during life. Sometimes individuals complain of seeing particles or “floaters” in their visual field. Floaters are a consequence of the aggregations of collagen fibers, which circulate around the vitreous due to convection currents arising from body heat. When these particles are close to the retina, they cast a shadow, which is perceived as floaters. In some older individuals, the loose attachment of the vitreous to the retina can break leading to a posterior vitreous detachment (PVD), a process that may cause a retinal tear.

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The Choroid The choroid lies between the sclera and retina and lines the posterior portion of the inner surface of the sclera. It is rich in blood vessels and a deep chocolate brown in color due to the dense pigmentation by melanin and serves to absorb stray light within the eye. The choroid also provides a vascular supply to structures of the anterior segment and provides nutrients and removes waste products from the retinal photoreceptor cells.

The Retina The retina is the innermost layer of the posterior eye, lining approximately three-quarters of the eyeball. It is thickest at the back of the eye and thins out anteriorly ceasing just behind the ciliary body. The retina is the light-sensitive part of the eye and responsible for converting the focused image into nerve action potentials, which are then relayed to the brain via the visual pathway. There are many layers of nerve cells within the retina, which provide complex connections between the light-sensitive cells located toward the posterior parts of its surface. The most posterior layer of the retina is the pigment epithelium (Fig. 4), which supplies metabolites and removes waste products from the light-sensitive cells embedded within it. The light-sensitive cells are of two types, viz. rods and cones. Rods are highly specialized cells made up of an outer segment containing the photosensitive pigment rhodopsin, an inner

FIG. 4 The figure shows the various layers of the light-sensitive retina (CH, choroid; GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; PE, pigment epithelium; R/C, rods and cones). Image courtesy: R.A. Armstrong.

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segment containing large numbers of mitochondria, a nuclear region, and special synaptic structures. When exposed to light, rhodopsin causes a chemical cascade reaction, which converts light energy into electrical energy. Rods are most active at low light intensities and, therefore, are responsible for vision in dim light and for night vision. Rods are only sensitive to the intensity of light and not to its wavelength, so they can only represent an image in black and white. The other type of light-sensitive cell, the cones, is much less numerous than rods but capable of color detection. Hence, there are three types of cones sensitive to red, green, and blue light. Perception of a colored image is similar to that constructed on a television screen, where the red, green, and blue pixels interact to produce all colors of the visible spectrum. When light enters the eye, it is brought to a focus by the cornea and crystalline lens on to the retina. This point of focus is called the macula lutea and located in its center is a depression called the fovea centralis. The density of cones is greatest at the macula while at the fovea centralis only cones are present. The density of cones is responsible for visual acuity, i.e., the level of detail that an individual is capable of perceiving, which is analogous to the pixel resolution of a digital camera. Hence, the greater the number (and density) of pixels, the more detailed the image that the camera is able to resolve. In addition, at the fovea centralis, there is a layer of pigment, which absorbs ultraviolet light and is therefore protective to the eye. This macular pigment can sometimes be observed with an ophthalmoscope as a tiny dot of yellow at the fovea centralis. An image of the retina, termed the fundus, can be achieved by using an ophthalmoscope and several important features are visible. First, the retinal nerves, which are generally too small to be seen individually, collect together and leave the eye at the optic disk (Fig. 5). There are no rods or cones present within the optic disk and hence this region is also known as the “blind spot.” Second, the optic disk is the entry point for the major blood supply to the anterior surface of the retina. The eye is one of the few places in the body where the capillary network can be directly observed without an invasive procedure.

FIG. 5 The figure shows the optic disk and nerve in section (BV, blood vessel; CP, cribriform plate; OD, optic disk; ON, optic nerve; Me, meninges). Image courtesy: R.A. Armstrong.

Chapter 1 • The Eye and Vision: An Overview

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Consequently, it is possible to observe structural changes within the blood vessels associated with disease such as aneurysm, embolism, and atherosclerosis.9 In addition, the signs of malignant hypertension (high blood pressure) can be observed, a potentially life-threatening condition. The pattern of blood vessels across the retina is unique to each individual, much like a fingerprint. Third, the photoreceptor layer at the macula is thicker and has a greater and finer blood supply, resulting in a darker appearance. The increase in thickness is due to the greater packing density of the rods and cones. The background color of the fundus is red-orange color, due to its blood supply. Because capillary vessels in the retina are particularly fine, they are also prone to damage from various diseases such as diabetes, which can cause leaking from the blood vessels. Other diseases result in degeneration of the photoreceptors as in age-related macular degeneration (AMD). In addition, the retina itself is a delicate structure and easily dislodged by trauma, a condition resulting in a detached retina.

Visual Pathway The visual pathway describes the anatomical pathway by which electrical signals generated by the retina are sent to the brain (Fig. 6). The nerve fibers of the retina, representing the axons of the ganglion cells, collect together at the optic disk before passing out of the eye through the orbital bones and into the brain via the optic nerve (the second cranial nerve). The nerve fibers from different areas of the retina become more organized as they pass down the optic nerve. The optic nerves from each eye meet at the optic chiasm, a structure at the base of the brain. At this point, the nerve fibers, which are associated with the nasal half of the retina from each eye cross over, so that on leaving the optic chiasm and passing into the optic tracts, the nerve fibers from the nasal retina of one eye travel

FIG. 6 The figure shows the pathway connecting the eyes to the brain, fibers form the temporal halves of each eye pass to the brain on the same side while those from the nasal halves of each eye cross over at the optic chiasm (L, left; R, right). Image courtesy: R.A. Armstrong.

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down the optic tract with the nerve fibers originating in the temporal retina of the other eye. At the end of each optic tract, the retinal nerve fibers connect with other visual pathway nerves in a structure called the lateral geniculate nucleus (LGN) located in the midbrain. Some processing of the electrical signals occurs in the LGN before a series of radiating nerve fibers, the optic radiation, convey the information to the visual cortex in the posterior portion of the occipital lobe. Perception of sight ultimately derives from processing within this and adjacent areas of brain.

Summary Points 1. The eye is highly specialized for photoreception and focuses light from an object onto the retina. 2. Visual processing by the brain results in “visual perception,” the construction of a sensory image in the brain, which is then consciously appreciated as vision. 3. The surface of the cornea together with the associated tear film is responsible for most of the refractive power of the eye. 4. The lens has less refractive power than the cornea and contraction of the ciliary muscle during accommodation relaxes the tension exerted by the zonular fibers on the lens, causing it to bulge, thus increasing its thickness and refractive power. 5. The retina is the light-sensitive part of the eye and is responsible for converting the focused image into electrical signals, which are then sent to the brain via the visual pathway. 6. There are several important landmarks visible on the fundus of the eye including the optic disk, the capillary network of the retina, and the macula. 7. The visual pathway describes the anatomical pathway by which electrical signals generated in the retina are sent to the brain. 8. Perception of sight ultimately derives from processing within the visual cortex and adjacent areas of brain.

References 1. Smith CUM. Biology of Sensory Systems. New York: John Wiley & Sons Ltd; 2000. 2. Hubel DH. Eye, Brain, and Vision. New York: Scientific American Library; 1988. 3. Valberg A. Light, Vision, Color. New York: John Wiley; 2005. 4. Armstrong RA. Developmental anomalies of the eye: the genetic link. Optom Today. 2006;2006:29–32. 5. Armstrong RA. Fungal infection of the eye (ocular mycoses). Microbiologist. 2013;(June):9–13. 6. Forrester J, Dick A, McMenamin P, Lee W. The Eye: Basic Sciences in Practice. London/Toronto/Tokyo: W.B. Saunders Co. Ltd; 1996. 7. Armstrong RA, Smith SN. The genetics of cataract. Optom Today. 2000;33–35. 8. Armstrong RA, Smith SN. The genetics of glaucoma. Optom Today. 2001;30–33. 9. Hamilton AMP, Gregson R, Fish GE. Text Atlas of the Retina. London: Martin Dunitz; 1998.

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Overview of Risk Factors for Age-Related Macular Degeneration R.A. Armstrong*, R.P. Cubbidge† *O P T OM E T R Y SC HO OL , A S T ON U N I V E R SITY, BIRMINGHAM, UNI TED KINGDOM † V IS I ON SCIENCES, ASTON UNIVERSITY, BIRMINGHAM, UNITED K INGDOM

CHAPTER OUTLINE Introduction .................................................................................................................................... 18 Genetic Risk Factors ....................................................................................................................... 19 Dietary Risk Factors ........................................................................................................................ 19 Cardiovascular Risk Factors ........................................................................................................... 22 Sunlight .......................................................................................................................................... 22 Smoking .......................................................................................................................................... 22 Alcohol ............................................................................................................................................ 23 Discussion and Conclusions ........................................................................................................... 24 Summary Points ............................................................................................................................. 25 References ...................................................................................................................................... 25

List of Abbreviations aAMD ABCR ACE AMD APOE ARDES ARM ARMS2 BDES BES BMES BMI C3 CACNG3 CBWS CC CFB CFH

advanced AMD ATP-binding cassette rim protein angiotensin-converting enzyme age-related macular degeneration apolipoprotein E age-related eye disease study age-related maculopathy age-related maculopathy susceptibility protein 2 Beaver Dam Eye Study Beijing Eye Study Blue Mountain Eye Study body mass index factor 3 voltage-dependent calcium channel 3 Chesapeake Bay Waterman Study case-control study complement factor B complement factor H

Handbook of Nutrition, Diet, and the Eye. https://doi.org/10.1016/B978-0-12-815245-4.00002-8 © 2019 Elsevier Inc. All rights reserved.

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CI dGI DHA EDCCSG ERCC6 FGF2 HDL HR HTRA1 LOX1 MPCC OR PHS POLA PS RR SA SELP SERPING1 SiMES

95% confidence interval dietary glycemic index docosahexanoic acid Eye Disease Case-Control Study Group DNA excision repair protein fibroblast growth factor 2 high-density lipoprotein hazard ratio HTRA serum peptidase 1 lysyl oxidase-like 1 matched pairs case-control study odds ratio Physician’s Health Study es a` l’Age study Pathologies Oculaires Lie prospective study relative risk survival analysis selectin-P serpin peptidase inhibitor Singapore Malay Eye Study

Introduction Age-related macular degeneration (AMD) is the most important cause of blindness in industrialized countries in individuals over 65 years of age. In the United Kingdom, for example, overall prevalence of late stage AMD is 2.4% of the population and approximately 10% of patients 66–74 years of age exhibit some evidence of macular degeneration, prevalence increasing to 30% in patients 75–85 years of age.1 According to the most recent estimates, there are 513,000 individuals currently in the United Kingdom with the visual impairment characteristic of AMD suitable for registration as seriously visually impaired. This figure is predicted to rise to 679,000 by 2020 as the proportion of older individuals in the population continues to increase, a phenomenon likely to be repeated in many countries. There are two forms of AMD, viz. the “atrophic” or “dry” form and the “exudative” or “wet” form. The dry form is characterized by degeneration of the macular pigment epithelium, choriocapillaris, and photoreceptor cells. Larger areas of degeneration result from the merging of small areas of atrophy and this state is often referred to as “geographic atrophy.” By contrast, in the wet form, new choroidal vessels are formed (neovascularization) and ultimately retinal detachment, edema, and hemorrhage may occur followed by macular degeneration. Age-related maculopathy (ARM) is a further term often used to describe the early stages of AMD and is characterized by the presence of discrete drusen and increased deposition of retinal pigment in individuals over 50 years of age. Multiple risk factors are likely to be involved in AMD including genetics, diet, cardiovascular disease, sunlight, smoking, and alcohol.2–4 There are also likely to be synergistic effects among these risk factors, which will ultimately determine the overall risk of disease

Chapter 2 • Overview of Risk Factors for Age-Related Macular Degeneration

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for an individual. The objective of this chapter is to review the major risk factors associated with AMD and their interactions and to assess their relative contribution to AMD risk.

Genetic Risk Factors Genetic factors play a highly significant role in AMD, 52 individual gene associations having been detected, including common and rare variants, across 34 gene loci.5 The most important genes linked to AMD are involved in immune modulation and in the complement system such as complement factor H (CFH),6–8 complement factor B (CFB),9 factor 3 (C3),10 and serpin peptidase inhibitor (SERPING1)11 strongly suggesting that inflammatory processes are important. Hence, CFH, C3, and SERPING1 together with HTRA serum peptidase 1(HTRA1), which may regulate the availability of insulin-like growth factor, could account for 45% of the total AMD risk.11 Genes associated with membrane transport such as ATP-binding cassette rim protein (ABCR),12 and voltage-dependent calcium channel 3 (CACNG3),12 the vascular system, for example, fibroblast growth factor 2 (FGF2),13 Lysyl oxidase-like 1 (LOX1),14 and selectin-P (SELP),7 and with lipid metabolism, for example, apolipoprotein E (APOE),15 and LOX116 may also be involved. Genes associated with the vascular system are of particular interest as a result of the neovascularization characteristic of wet AMD. Furthermore, various genes of more uncertain function are also involved in AMD especially age-related maculopathy susceptibility protein 2 (ARMS2),17 ATP synthase,18 and DNA excision repair protein (ERCC6)19 and it is likely that further genes will be identified. A “genetic risk score” for AMD based on 13 “at risk” variants of eight individual genes suggested that AMD patients younger than 75 years of age have a significantly higher score compared with those older than 75.20

Dietary Risk Factors There is increasing evidence that diet is involved in AMD21 (Table 1), recent research suggesting both “at risk” and “beneficial” foods. Hence, beneficial foods such as fruit and green leafy vegetables may reduce the incidence of large drusen, while at risk foods such as those characterized as having high fat or sugar are slightly associated with large drusen.22 In addition, diets with a “low healthy score” were associated with AMD, while an unhealthy lifestyle in combination with CFH risk alleles increased the risk of early AMD.56 In particular, the “Mediterranean diet,” i.e., a diet rich in vegetables, fruits, fish, and olive oil may be protective against AMD.57 Hence, the age-related eye disease study (AREDS) suggested that a high Mediterranean diet score was strongly associated with reduced risk of progression to advanced AMD.57 Moreover, when the influence of American dietary patterns was studied, an “oriental” diet was associated with a lower risk and a “western diet” with a higher risk of early and advanced AMD.24 Specific components of the diet have also been identified as influencing AMD risk. Hence, AMD has been linked to the consumption of carbohydrates and lipids, diets with a high dietary glycemic index (dGI) being associated with a greater risk.25 Furthermore, an

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Table 1 A Selection of Epidemiological Studies Relating Diet and Cardiovascular Factors, Exposure to Sunlight, and Smoking and Alcohol to Age-Related Macular Degeneration (AMD) Factor

Type

OR/RR/HR (CI)

Effect on AMD

References

Diet (protective foods) Diet (poor health behaviors)

CC CC CC SA CC CC CC CC PS CC PS PS PS CC SA CC CC CC CC CC PS PS PS CC PS PS CC PS PS CC CC CC CC CC CC CC CC CC CC CC CC MPCC PS

0.93 (0.89–0.90) 5.14 (1.04–25.45) 29.53 (2.72–321.16) 0.74 (0.61–0.91) 0.74 (0.59–0.91) 0.38 (0.27–0.54) 1.56 3.70 (2.31–5.90) 1.10 (1.00–1.20) 1.42 (1.09–1.84) 1.54 (1.17–2.01) 1.49 (1.15–1.94) 0.70 (0.52–0.93) 0.41 (0.22–0.75) 0.60 (0.43–0.81) 0.44 (0.21–0.91) 1.37 (1.04–1.79) 3.26 (1.02–5.07) 1.58 (1.06–2.35) 2.26 (1.06–4.81) 3.17 (1.24–8.11) 2.14 (0.99–4.61) 3.17 (1.24–8.11) 1.36 (1.00–1.85) 1.53 (1.19–1.97) 0.58 (0.41–0.82) 3.5 (1.2–10.4) 1.53 2.14 (0.99–4.61) 2.6 – 2.6 – – 2.5 3.92 2.97 (1.00–8.84) 2.09 (0.71–6.13) 3.6 (1.1–12.4) 2.39 (1.02–5.57) 5.03 (1.0–25.47) 1.02 (1.01–1.04) 2.4(1.40–4.0)

Large drusen (+) Any AMD (+) Late AMD (+) Late AMD ( ) Early AMD ( ) aAMD ( ) Early AMD (+) aAMD(+) AMD (+) Large drusen (+) AMD (+) AMD (+) AMD ( ) ARM( ) Wet AMD ( ) aAMD ( ) AMD (+) AMD (+) Soft drusen (+) AMD (+) Retinal pigment (+) ARM(+) Retinal pigment (+) aAMD (+) Soft drusen (+) Pigment degen ( ) No effect Soft drusen (+) Early ARM (+) AMD in males (+) AMD (+) Wet AMD (+) Wet AMD (+) AMD ( ) Dry AMD (+) Wet/dry AMD (+) Wet AMD (+) Wet AMD (+) AMD (+) AMD (+) Late AMD (+) Wet AMD (+) Wet/dry AMD (+)

22 23 23

Diet (Mediterranean) Diet (Oriental) Diet (Western) Diet (dGI) Diet (dGI) Diet (total fat) Diet (linolenic acid) Diet (DHA) Diet (Omega-3) Diet (vitamin D) Diet (olive oil) CV (BP) CV (AHM) Retinal signs Sunlight (time outdoors) Sunlight (summer sun) Sunlight (summer sun) Sunlight (summer sun) Sunlight (blue light) Sunlight (brown eyes) Sunlight (brown eyes) Sunlight (fair skin) Sunlight (iris color) Sunlight (sun exposure) Smoking (C) Smoking Smoking (C) Smoking Smoking Smoking Smoking (C) Smoking (C) Smoking (E) Smoking (C) Smoking Smoking (C) Smoking Smoking (C)

24 24 24 24 25 26 27 27 27 28 21 29 30 31 32 33 34 34 35 36 35 35 37 35 35 38 39 40 41 42 43 44 45 45 3 31 46 47 48

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Table 1 A Selection of Epidemiological Studies Relating Diet and Cardiovascular Factors, Exposure to Sunlight, and Smoking and Alcohol to Age-Related Macular Degeneration (AMD)—cont’d Factor

Type

OR/RR/HR (CI)

Effect on AMD

References

Smoking (C) Smoking (C) Alcohol (beer) Alcohol Alcohol (light) Alcohol (heavy) Alcohol (heavy) Alcohol (heavy) Alcohol (heavy)

PS PS CC CC PS CC PS CC CC

2.5 (1.60–3.79) 6.6 1.03 (1.02–1.28) 1.41 (1.05–1.88) 0.97 (0.78–1.21) 1.57 (1.18–2.11) 9.2 (1.7–51.2) 5.8 12.7

AMD (+) Wet AMD (+) Retinal pigment (+) Early AMD (+) No effect Early AMD (+) Dry AMD (+) Wet AMD (+) Dry AMD (+)

49 50 51 51 52 53 54 55 55

Abbreviations: AHM, antihypertensive medication; aAMD, advanced age-related macular degeneration; ARM, age-related maculopathy; BP, blood pressure; C, current smokers; CC, case-control study; CI, 95% confidence intervals; CV, cardiovascular; DHA, docosahexanoic acid; dGI, dietary glycemic index; E, ex-smokers; MPCC, matched pairs case-control study; OR, odds ratio; RR, relative risk; PS, prospective study; SA, survival analysis. (+) indicates an enhanced risk and ( ) a reduced risk of AMD.

association between high dGI, the frequency of large drusen, and the severity of AMD has been observed.26 Regular consumption of olive oil, an important constituent of the Mediterranean diet, and which consists of a mixture of lipids and antioxidants, may also be associated with a lower risk of late AMD.29 Studies have also linked AMD to specific types of lipid or lipid-related compounds. Hence, raised levels of C-reactive protein have been associated with increased frequency of ARM,58 and with enhanced consumption of lard and solid fat.30 By contrast, high triglyceride levels were associated with a lower risk and could be protective against AMD. In a prospective study, total fat intake in the highest consumers was associated with increased risk of AMD.27 Linolenic acid consumption was the specific fatty acid associated with AMD, whereas docosahexanoic acid (DHA) had a modest inverse relationship with AMD.27 In the “Blue Mountain Eye Study” (BMES) study, older Australians with high omega-3 fat intake had the lowest risk.28 No association was found, however, between ARM and butter, margarine, or a variety of nutrients. When AMD patients were subdivided into five clinical groups and differences in the ratio of omega-6 to omega-3 fatty acids examined, significant differences were found in all stages of wet AMD suggesting a decreased ratio may be protective.59 AMD risk may also be related to macular carotenoids and vitamin intake. Hence, consumption of lutein and zeaxanthin, dietary constituents of dark green vegetables and orange/yellow fruits, may be protective.60 Furthermore, low intake of α-tocopherol, zinc, vitamin D, and β-carotene was associated with increased risk of wet AMD whereas no relationship was found with retinol and cryptoxanthin.61 Association between wet AMD and serum 25 hydroxy vitamin D, together with genetic variants associated with the vitamin D pathway, has been also reported.62

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Cardiovascular Risk Factors A high mean arterial blood pressure is associated with increased AMD risk30 (Table 1) whereas in the Singapore Malay Eye Study (SiMES), no significant association between retinal arteriolar wall signs and early AMD has been observed.32 Nevertheless, arteriolar wall opacification was associated with the presence of soft drusen especially in the eyes of nonstatin users. By contrast, no association between ARM and hypertension has been observed.63 Of 19 cardiovascular risk factors studied, none were statistically associated with AMD but it was concluded that beta-fibrinogen and apolipoprotein E should be studied further as possible risk factors.64Associations have also been studied between past physical activity and AMD risk. However, no association was found between total recreational past physical activity and AMD but an inverse relationship was observed with intermediate-stage AMD in females suggesting a possible protective effect.65

Sunlight The significance of exposure to sunlight as a risk factor for AMD remains controversial (Table 1).66 In the Beaver Dam Eye Study (BDES), time spent outdoors was positively associated with AMD.33 In addition, exposure to summer sun (>5 h per day in the teenage years) increased retinal pigment and early ARM.34 In the Chesapeake Bay Waterman Study (CBWS), long-term high exposure to blue light was associated with advanced AMD.36 A study of sun exposure and visual field damage in a region of Russia concluded that increased exposure represented an important risk factor for AMD and suggested that the eyes of children should be protected by taking vitamin A and antioxidants.67 Finally, the effect of visible blue light was studied in an experimental rat model of dry AMD concluding that short-wavelength blue light induced retinal injury.68 Several other casecontrol studies, however, have failed to show associations between sunlight exposure and AMD.4,39,69,70 A study of 446 subjects suggested that sunlight was not a risk factor for AMD.71 In addition, no associations were found between iris or hair color and early or late ARM37 although fair skinned individuals may have had increased risk of developing dry AMD. Nevertheless, in the BDES study, brown eyes were significantly more likely to develop soft indistinct drusen compared with blue eyes, but less likely to develop retinal pigment epithelial degeneration.35

Smoking The earliest studies of smoking and AMD often reported inconsistent results (Table 1). A Baltimore study reported a significant relationship between AMD and smoking in males,38 a Maryland study an increased risk of AMD in smokers,39 while a hospital-based study carried out in London, United Kingdom, and a study carried out in Finland72 found no relationship.42 In addition, the Eye Disease Case-Control Study Group (EDCCSG) (1992) found

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an increased risk of wet AMD in current smokers,40 while in the BDES,41 no correlation between dry AMD and smoking was observed, although a positive association with ARM was detected in both males and females. In a Copenhagen study,43 a close relationship was found between smoking and dry AMD while the BMES observed that smoking was strongly associated with both wet and dry AMD, current smokers having the highest risk.73 es a` l’Age study (POLA) reported that The population-based Pathologies Oculaires Lie AMD risk in current smokers and also in ex-smokers remained up to 20 years after cessation of smoking. In Japan, AMD risk was greater for current smokers compared with exsmokers.45 Moreover, when patients were divided into five groups based on the severity of AMD, a significant relationship with smoking was found in only one group.74 Using matched pairs of patients, 73 sibling pairs were studied in which one member of each pair exhibited wet AMD in at least one eye while the unaffected sibling was normal and was past the age at which their partner was diagnosed with AMD,47 a 2% increase in the risk of wet AMD being reported with each pack-year of smoking. In prospective studies, female registered nurses 50–59 years of age were investigated in the United States and it was found that individuals who smoked more than 25 cigarettes a day had an increased risk of AMD.48 In a study of male doctors, smoking enhanced AMD risk, a 2–3 time increase being observed in men who were currently smoking 20 or more cigarettes a day.49 For the wet form of AMD, smoking appeared to double the risk. In a Rotterdam study, however, the risk of wet AMD was 3.2 times for former smokers, and 6.6 times for current smokers.50 In a prospective study carried out in retinal practice,75 261 individuals greater than 60 years of age were clinically examined for signs of nonadvanced AMD, or a visual acuity of 20/200 or better in at least one eye with an average follow-up time of 4.6 years, but no significant association was observed.

Alcohol In one of the earliest studies (BDES),51 consumption of beer was associated with retinal pigment degeneration and wet AMD, but neither wine nor spirits appeared to be related to either early or late ARM (Table 1). Smith and Mitchell,44 however, concluded that there may be an association between the consumption of spirits and AMD. In a study of smoking and alcohol,53 alcohol consumption was associated with early AMD with a particularly increased risk in older smokers. By contrast, in the Physician’s Health Study (PHS),52 no appreciable signs of AMD were observed in individuals consuming one or more alcoholic drinks a week. Similarly, in the Beijing Eye Study (BES)76 and a prospective Rotterdam study,77 no evidence was found that alcohol was a significant factor. Nevertheless, a weak relationship between heavy alcohol consumption and AMD risk has been reported78 while in a prospective BDES study,54 heavy drinking, defined as more than four alcoholic drinks per day, was related to dry AMD, moderate drinking showing no relationship. In addition, heavy consumption of alcohol in Latinos was found to be associated with an increase in both wet and dry AMD.55

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Discussion and Conclusions A significant proportion of AMD cases can be explained by genetics, especially in individuals younger than 75, genome-wide scans suggesting that ARMS279 and genes of the complement cascade are strongly related to AMD.80 Nevertheless, genetic variation is unlikely to explain all of the variability in AMD.81 Of the modifiable risk factors, smoking appears to be the most consistent,82 studies taken collectively suggesting long-term smoking is associated with approximately a doubling of the risk of late-onset AMD. Combining data from the BDES, Rotterdam, and BMES studies smoking was the only consistent risk factor.83 Of the remaining modifiable risk factors, there is evidence that diet influences risk but less evidence to support specific types of diet, with the possible exception of the Mediterranean diet, or individual dietary constituents. Exposure to sunlight and alcohol remains more controversial. As AMD is multifactorial, synergistic effects among the various risk factors are likely. Hence, it was concluded that a combination of smoking, previous cataract surgery, and a family history of the disease were important factors.84 In addition, the major risk factors in a Spanish population were identified as possession of light colored irides, smoking in males, female gender, and a variety of cardiovascular risk factors.85 Of multiple risk factors studied by Butt et al.86 only age was significantly associated with AMD in men and women. In women alone, however, multivitamin use also had a significant inverse association with AMD, whereas sun exposure and high-density lipoprotein (HDL) cholesterol had positive associations. In addition, age, smoking, and angiotensin-converting enzyme (ACE), an antihypertensive drug, were identified in older Australians (>40 years).31 Kawasaki et al.46 found that increasing age, and current cigarette smoking were the principal factors associated with late AMD in Japan. In a Swiss study,87 smoking explained 7% of late AMD cases while Bai et al.88 found no gender effect but reported that advancing age and smoking had the strongest associations. The collective influence of physical activity, diet, smoking, and alcohol consumption has also been studied indicating that “poor health behaviors” were associated with greater odds of any or late AMD.23 Hence, it is likely to be the collective effects of many factors acting over a lifetime, which determine the overall risk of AMD. Of particular interest is whether there are interactions between genetics and the modifiable risk factors.89 Hence, a reduced risk of the development of advanced AMD has been reported in individuals carrying the lower risk CFH (Y420H) allele suggesting that the effects of the Mediterranean diet may be modified by genetic susceptibility.57 By contrast, an increasing Mediterranean diet score was associated with reduced odds of wet AMD but without evidence of genetic susceptibility.9 Nevertheless, the interactions between genetics and diet are poorly understood and require further study.90 A number of risk assessment models have been developed for AMD. A model for advanced AMD is available for online use and based on data from 2846 AMD patients observed over 9.3 years.91 Cox proportional hazard analysis was used in this study to assess the significance of demographic, environmental, phenotypic, and genetic covariates. The final model included age, smoking, family history, and allelic variation (especially of

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CFH and ARMS2) to predict the risk of AMD. A second model incorporates 10 genetic loci, which alone accounted for 80% of AMD cases, in combination with age, sex, education, body mass index (BMI), smoking, and the presence of baseline AMD signs to predict AMD risk.92 Many studies have suggested lifestyle changes to reduce the lifetime risk of AMD. Smoking is the most established modifiable risk factor, some studies suggesting that giving up smoking could reduce the risk of recurrence, especially of the wet form of the disease. In addition, as high fat intake may be associated with an increased risk of AMD, a diet deriving closer to 20%–25% of total food energy from fat is probably healthier. More controversial is whether consumption of various antioxidants and antioxidant cofactors, vitamins, zinc, and antifree radicals such as lutein, and zeaxanthin could reduce AMD risk.93 Evans and Lawrenson,94 however, reviewed all randomized controlled trials, which compared antioxidant vitamins and concluded that there was no benefit of taking any combination of these compounds. Nevertheless, the possible beneficial effects of antioxidant and vitamin supplements or dietary changes may be modified by genetic factors,95 and therefore genetic testing may identify those individuals who would benefit most from vitamin use.96 Chew,97 however, has argued that genetic testing for the efficacy of various therapies is not likely to be clinically useful.

Summary Points 1. AMD is a multifactorial disorder and identification of possible risk factors for the disease enables individuals to make lifestyle choices that may reduce disease risk. 2. Genetics plays a significant role in AMD especially in younger patients. 3. Smoking is the modifiable risk factor most consistently associated with AMD with current smokers having a two to three time higher risk of AMD than nonsmokers. 4. There is increasing evidence that diet influences the risk of AMD but less support of associations with specific diets, with the possible exception of the Mediterranean diet, or with individual dietary constituents. 5. Whether the risk of AMD is increased by exposure to sunlight or alcohol is controversial. 6. There are synergistic effects of the various risk factors and therefore, cessation of smoking, eye protection, dietary changes, and regular use of dietary supplements may all need to be considered to reduce the lifetime risk of AMD especially in those individuals with “at risk” genetic alleles.

References 1. Owen CG, Jarrar Z, Wormald R, Cook DG, Fletcher AE, Rudnicka AR. The estimated prevalence and incidence of late stage age related macular degeneration in the UK. Br J Ophthalmol. 2012;96:752–756. 2. Yoshida A, Yoshida M, Yoshida S, Shiose S, Hiroishi G, Ishibashi T. Familial cases with age-related macular degeneration. Jpn J Ophthalmol. 2000;44:290–295.

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3. Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L. Smoking and age-related macular degeneration: the POLA study. Arch Ophthalmol. 1998;116:1031–1035. 4. Delcourt C, Carriere I, Ponton-Sanchez A, Fourrey S, Lacroux A, Papoz L. Light exposure and the risk of age-related macular degeneration. Arch Ophthalmol. 2001;119:1463–1468. 5. Fritsche LG, Igl W, Bailey JNC, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48:134–143. 6. Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421–424. 7. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227–7232. 8. Nischler C, Oberkofler H, Ortner C, et al. Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age related macular degeneration. Acta Ophthalmol. 2011;89:E344–E349. 9. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458–462. 10. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553–561. 11. Gibson J, Cree A, Collins A, Lotery A, Ennis S. Determination of a gene and environment risk model for age-related macular degeneration. Br J Ophthalmol. 2010;94:1382–1387. 12. Spencer KL, Olson LM, Schnetz-Boutaud N, et al. Dissection of chromosome 16p12 linkage peak suggest a possible role for CACNG3 variants in age-related macular degeneration susceptibility. Invest Ophthalmol Vis Sci. 2011;52:1748–1754. 13. Maller J, George S, Purcell S, et al. Common variation in three genes, including a variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006;38:1055–1059. 14. Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992–993. 15. Adams MKM, Simpson JA, Richardson AJ, et al. Apolipoprotein E gene associations in age-related macular degeneration. Am J Epidemiol. 2012;175:511–518. 16. Seddon JM, Reynolds R, Rosner B. Associations of smoking, body mass index, dietary lutein, and the LIPC genetic variant rs10468017 with advanced age-related macular degeneration. Mol Vis. 2010;16: 2412–2424. 17. Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML. Association of CFH Y420H and LOC3877515 A69S with progression of age-related macular degeneration. JAMA. 2007;297:1793–1800. 18. Nordgaard CL, Karunadharma PP, Feng X, Olsen TW, Ferrington DA. Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49:2848–2855. 19. Baas DC, Despriet DD, Gorgels TGMF, et al. The ERCC6 gene and age-related macular degeneration. PLoS ONE. 2010;5e13786. 20. Grassmann F, Fritsche LG, Keilhauer CN, Heid IM, Weber BHF. Modeling the genetic risk in age related macular degeneration. PLoS ONE. 2012;7e37979. 21. Merle BMJ, Silver RE, Rosner B, Seddon JM. Dietary folate, B vitamins, genetic susceptibility and progression to advanced non-exudative age-related macular degeneration with geographic atrophy: a prospective cohort study. Am J Clin Nutr. 2016;103:1135–1144. 22. Piermarocchi S, Tognetto D, Piermarocchi R, et al. Risk factors and age-related macular degeneration in a Mediterranean-basin population: the PAMDI (prevalence of age-related macular degeneration in Italy) study: Report 2. Ophthalmic Res. 2016;55:111–118.

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23. Gopinath B, Liew G, Flood VM, Joachim N, Burlutsky G, Mitchell P. Combined influence of poor health behaviours on the prevalence and 15-year incidence of age-related macular degeneration. Sci Rep. 2017;74359. 24. Chiu CJ, Chang ML, Zhang FF, et al. The relationship of major American dietary patterns to age-related macular degeneration. Am J Ophthalmol. 2014;158:118–127. 25. Chiu CJ, Milton RC, Klein R, Gensler G, Taylor A. Dietary carbohydrate and the progression of agerelated macular degeneration: a prospective study from the age-related eye disease study. Am J Clin Nutr. 2007;86:1210–1218. 26. Chiu CJ, Milton RC, Gensler G, Taylor A. Association between dietary glycemic index and age-related macular degeneration in non-diabetic participants in the age-related eye disease study. Am J Clin Nutr. 2007;86:180–188. 27. Cho E, Hung S, Willett WC, et al. Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr. 2001;73:209–218. 28. Chua B, Flood V, Rochtchina E, Wang JJ, Smith W, Mitchell P. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. 2006;124:981–986. 29. Cougnard-Gregoire A, Merle BMJ, Korobelnik JF, et al. Olive oil consumption and age-related macular degeneration: the Alienor study. PLoS ONE. 2016;11e0160240. 30. Ngai LY, Stocks N, Sparrow JM, et al. The prevalence and analysis of risk factors for age-related macular degeneration: 18 year follow-up data from the Speedwell eye study, United Kingdom. Eye. 2011;25:784–793. 31. McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR. Risk factors for age-related maculopathy: the visual impairment project. Arch Ophthalmol. 2001;119:1455–1462. 32. Cheung CMG, Cheung CYL, Yang EL, Mitchell P, Wang JJ, Wong TY. Retinal arteriolar wall signs and early age-related macular degeneration: the Singapore Malay Eye Study. Am J Ophthalmol. 2011;152:108–113. 33. Cruickshanks KJ, Klein R, Klein BEK, Nondahl DM. Sunlight and the 5-year incidence of early agerelated maculopathy: the Beaver Dam eye study. Arch Ophthalmol. 2001;119:246–250. 34. Tomany SC, Cruickshanks KJ, Klein R, Klein BEK, Knudtson MD. Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam eye study. Arch Ophthalmol. 2004;122:750–757. 35. Tomany SC, Klein R, Klein BEK. The relationship between iris color, hair color, and skin sun sensitivity and the 10-year incidence of age-related maculopathy: the beaver dam eye study. Ophthalmology. 2003;110:1526–1533. 36. Taylor HR, West S, Munoz B, Rosenthal FS, Bressler SB, Bressler NM. The long-term effects of visible light on the eye. Arch Ophthalmol. 1992;110:99–104. 37. Wang JJ, Jakobsen K, Smith W, Mitchell P. Five-year incidence of age-related maculopathy in relation to iris, skin or hair colour, and skin sensitivity: the blue mountains eye study. Clin Exp Ophthalmol. 2003;31:317–321. 38. Hyman LG, Lilienfeld AM, Ferris FL, Fine SI. Senile macular degeneration: a case-control study. Am J Epidemiol. 1983;118:213–227. 39. West SK, Rosenthal FS, Bressler NM, et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol. 1989;107:875–879. 40. Yannuzzi LA, Sorenson JA, Sobel RS, et al. Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol. 1992;110:1701–1708. 41. Klein R, Klein BEK, Linton KLP, De Mets DL. The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol. 1993;137:190–200. 42. Pauleikhoff D, Wormald RP, Wright L, Wessing A, Bird AC. Macular disease in an elderly population. Ger J Ophthalmol. 1992;1:12–15.

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43. Vinding T, Appleyard M, Nyboe J, Jensen G. Risk factor analysis for atrophic and exudative age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmol. 1992;70:66–72. 44. Smith W, Mitchell P. Alcohol intake and age-related maculopathy. Am J Ophthalmol. 1996;122:743–745. 45. Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y. Smoking and the neovascular form of age-related macular degeneration in late middle aged males: findings from a case-control study in Japan. Br J Ophthalmol. 1997;81:901–904. 46. Kawasaki R, Wang JJ, Ji GJ, et al. Prevalence and risk factors for age-related macular degeneration in an adult Japanese population. Ophthalmology. 2008;115:1376–1381. 47. De Angelis MM, Lane AM, Shah CP, Ott J, Dryja T, Miller JW. Extremely discordant sib-pair study design to determine risk factors for neovascular AMD. Arch Ophthalmol. 2004;122:575–580. 48. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and agerelated macular degeneration in women. JAMA. 1996;276:1141–1146. 49. Christen WG, Glynn RJ, Manson JE, Ajan UA, Buring JE. A prospective study of cigarette smoking and the risk of age-related macular degeneration in men. JAMA. 1996;276:1147–1151. 50. Vingerling JR, Hofman A, Grobbee DE, De Jong PTVM. Age-related macular degeneration and smoking: the Rotterdam study. Arch Ophthalmol. 1996;114:1193–1196. 51. Ritte LL, Klein R, Klein BEK, Maresperlman JA, Jensen SC. Alcohol-use and age-related maculopathy in the Beaver Dam Eye Study. Am J Ophthalmol. 1985;120:190–196. 52. Ajani UA, Christen WG, Manson JE, et al. A prospective study of alcohol consumption and the risk of age related macular degeneration. Ann Epidemiol. 1999;9:172–177. 53. Coleman AL, Seitzman RL, Cummings SR, et al. The association of smoking and alcohol use with agerelated macular degeneration in the oldest old: the study of osteoporotic fractures. Am J Ophthalmol. 2010;149:160–169. 54. Knudtson MD, Klein R, Klein BEK. Alcohol consumption and the 15-year cumulative incidence of agerelated macular degeneration. Am J Ophthalmol. 2007;143:1026–1029. 55. Fraser-Bell S, Wu J, Klein R, Azen SP, Varma R. Smoking, alcohol intake, estrogen use, and age-related macular degeneration in Latinos: the Los Angeles Latino eye study. Am J Ophthalmol. 2006;141:79–87. 56. Meyers KJ, Liu Z, Millen AE, et al. Joint associations of diet, lifestyle, and genes with age-related macular degeneration. Ophthalmology. 2015;122:2286–2294. 57. Merle BMJ, Silver RE, Rosner B, Seddon JM. Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study. Am J Clin Nutr. 2015;102:1196–1206. 58. Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N. Association between C-reactive protein and AMD. JAMA. 2004;291:704–710. 59. Mance TC, Kovacevic D, Alpeza-Dunato Z, Stroligo MN, Brumini G. The role of omega-6 to omega-3 ratio in development and progression of age-related macular degeneration. Coll Antropol. 2011;35:307–310. 60. Bernstein PS. The role of lutein and zeaxanthin in protection against age-related macular degeneration. Acta Hortic. 2015;1106:153–159. 61. Aoki A, Inoue M, Nguyen E, et al. Dietary n-3 fatty acid, alpha-tocopherol, zinc, vitamin D, vitamin C, and beta-carotene are associated with age-related macular degeneration in Japan. Sci Rep. 2016;620723. 62. McKay GJ, Young IS, McGinty A, et al. Associations between serum vitamin D and genetic variants in vitamin D pathways and age-related macular degeneration in the European eye study. Ophthalmology. 2017;124:90–96.

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63. Klein R, Klein BEK, Marino EK, et al. Early age-related maculopathy in the cardiovascular health study. Ophthalmology. 2003;110:25–33. 64. Haas P, Aggermann T, Steindl K, et al. Genetic cardiovascular risk factors and age related macular degeneration. Acta Ophthalmol. 2011;89:335–338. 65. McGinness MB, Karahalios A, Simpson JA, et al. Past physical activity and age-related macular degeneration: the Melbourne collaborative cohort study. Br J Ophthalmol. 2016;100:1353–1358. 66. Chalam KV, Khetpal V, Rusovici R, Balaiya S. A review: role of ultraviolet radiation in age-related macular degeneration. Eye Contact Lens. 2011;37:225–232. 67. Vojnikovic B, Synek S, Micovic V, Telezar M, Linsak Z. Epidemiological study of sun exposure and visual field damage in children in Primorsko-Goranska county- the risk factors of earlier development of macular degeneration. Coll Antropol. 2010;34:57–59. 68. Wielgus AR, Collier RJ, Martin E, et al. Blue light induced A2E oxidation in rat eyes-experimental animal model of dry AMD. Photochem Photobiol Sci. 2010;9:1505–1512. 69. Wang JJ, Foran S, Mitchell P. Age-specific prevalence and causes of bilateral and unilateral visual impairment in older Australians: the blue mountains eye study. Clin Exp Ophthalmol. 2000;107: 875–879. 70. Klein R. Overview of progress in the epidemiology of age-related macular degeneration. Ophthalmic Epidemiol. 2007;14:184–187. 71. Khan JC, Shahid H, Thurlby DA, et al. Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight. Br J Ophthalmol. 2006;90:29–32. 72. Hirvela H, Luukinen H, Laara E, Laatikainen L. Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology. 1996;103:871–877. 73. Smith W, Mitchell P, Leeder S. Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol. 1996;114:1518–1523. 74. Anand R, Bressler SB, Davis MD, et al. Risk factors associated with age-related macular degeneration: age related eye disease report 3. Ophthalmology. 2007;107:2224–2232. 75. Seddon JM, Cote J, Davis N, Rosner B. Progress of age-related macular degeneration: association with body mass index, waist circumference and waist-hip ratio. Arch Ophthalmol. 2003;121:785–792. 76. Xu L, You QS, Jonas JB. Prevalence of alcohol consumption and risk of ocular diseases in a general population: the Beijing eye study. Ophthalmology. 2009;116:1872–1879. 77. Boekhoorn SS, Vingerling JR, Hofman A, de Jong PTVM. Alcohol consumption and risk of aging macula disorder in a general population—the Rotterdam study. Arch Ophthalmol. 2008;126:834–839. 78. Wang SQ, Wang JJ, Wong TY. Alcohol and eye diseases. Surv Ophthalmol. 2008;5(3):512–525. 79. Sun S, Li ZQ, Glencer P, et al. Bringing the age-related macular degeneration high-risk allele agerelated maculopathy susceptibility 2 into focus with stem cell technology. Stem Cell Res Ther. 2017;8:135. 80. Black JRM, Clark SJ. Age-related macular degeneration: genome-wide association studies to translation. Genet Med. 2016;18:283–289. 81. Persad PJ, Heid IM, Weeks DE, et al. Joint analysis of nuclear and mitochondrial variants in age-related macular degeneration identifies novel loci TRPM! And ABHD2/RLBP1. Invest Ophthalmol Vis Sci. 2017;58:4027–4038. 82. Chan D. Cigarette smoking and age-related macular degeneration. Optom Vis Sci. 1998;75:476–484. 83. Smith W, Assink J, Klein R, et al. Risk factors for AMD: pooled findings from three continents. Ophthalmology. 2001;108:697–704. 84. Chakravarthy U, Wong TY, Fletcher A, et al. A review: role of ultraviolet radiation in age-related macular degeneration. Eye Contact Lens Sci Clin Pract. 2011;37:225–232.

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85. Montero JA, Sanchez-Tocino H, Maldonado MJM, Nino CA, Bartolom RMP, Coomonte AV. Epidemiological factors associated with exudative age-related macular degeneration in Spain. Int J Ophthalmol. 2009;2:74–76. 86. Butt AL, Lee ET, Klein R, et al. Prevalence and risks factors of age-related macular degeneration in Oklahoma Indians the Vision Keepers Study. Ophthalmology. 2011;118:1380–1385. 87. Bauer P, Barthelmes D, Kurz M, Fleischhauer JC, Sutter FK. The potential effect of population development, smoking and antioxidant supplementation on the future epidemiology of age-related macular degeneration in Switzerland. Klin Monatsbl Augenheilkd. 2008;225:376–379. 88. Bai ZL, Ren BC, Yang JG, He YA, Chen L, Sun NX. Epidemiological investigation on age related macular degeneration in rural area of Shaanxi Province, China. Int J Ophthalmol. 2008;1:77–84. 89. De Angelis MM, Owen LA, Morrison MA, et al. Genetics of age-related macular degeneration (AMD). Hum Mol Genet. 2017;26:R45–R50. 90. Rowan S, Weikel K, Chang ML, et al. CFH genotype interacts with dietary glycemic index to modulate age-related macular degeneration-like features in mice. Invest Ophthalmol Vis Sci. 2014;55:492–501. 91. Klein ML, Francis PJ, Ferris FL, Hamon SC, Clemons TE. Risk assessment model for development of advanced age-related macular degeneration. Arch Ophthalmol. 2011;129:1543–1550. 92. Seddon JM, Silver RE, Kwong M, Rosner B. Risk prediction for progression of macular degeneration: 10 common and rare genetic variants, demographic, environmental, and macular covariates. Invest Ophthalmol Vis Sci. 2015;56:2192–2202. 93. Desmettre T, Lecerf JM, Souied EH. Nutrition and age-related macular degeneration. J Fr Ophtalmol. 2004;27:3S38–3S56. 94. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev. 2012;6CD000253. 95. Carneiro A, Andrade JP. Nutritional and lifestyle interventions for age-related macular degeneration: a review. Oxidative Med Cell Longev. 2017;20172435963. 96. Rojas-Fernandez CH, Tyber K. Benefits, potential harms, and optimal use of nutritional supplementation for preventing progression of age-related macular degeneration. Ann Pharmacother. 2017;51:264–270. 97. Chew EY. Nutrition, genes, and age-related macular degeneration: what we have learned from the trials? Ophthalmologica. 2017;238:1–5.

Further Reading 98. Souied EH, Ducroq D, Rozet JM, et al. ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2000;41:244–247. 99. Hogg RE, Woodside JV, McGrath A, et al. Mediterranean diet score and its association with age-related macular degeneration: the European eye study. Ophthalmology. 2017;124:82–89.

3 Age-Related Macular Degeneration Philip P. Storey*, Julia A. Haller† *RET INA DE PART MENT, WILL S E YE HO SPI TA L, PHILADELPHIA, PA, UNITED STATES † WI LLS EYE HOSPI TAL, JEF FERS ON MEDI CAL COLLEGE , P HILADELPHIA, PA, UNITED STATES

CHAPTER OUTLINE Introduction .................................................................................................................................... 32 Epidemiology ................................................................................................................................. 33 Risk Factors ..................................................................................................................................... 34 Pathogenesis .................................................................................................................................. 35 Classification .................................................................................................................................. 36 Natural History ............................................................................................................................... 37 Retinal Imaging for the Diagnosis and Management of AMD ................................................... 38 Management .................................................................................................................................. 40 Prevention ..................................................................................................................................40 Laser Photocoagulation .............................................................................................................40 Photodynamic Therapy ..............................................................................................................41 Anti-VEGF Therapy .....................................................................................................................41 Future Directions ............................................................................................................................ 42 Stem Cell Therapy ......................................................................................................................42 Gene Therapy .............................................................................................................................42 Optogenetics ..............................................................................................................................43 Summary Points ............................................................................................................................. 43 References ...................................................................................................................................... 43

List of Abbreviations AMD AREDS CATT CNV FA FAF MPGNII OCT PEDF RPE SNP VEGF

age-related macular degeneration age-related eye disease study comparisons of age-related macular degeneration treatments trial choroidal neovascularization fluorescein angiography fundus autofluorescence membranoproliferative glomerulonephritis type II optical coherence tomography pigment epithelium-derived factor retinal pigment epithelium single-nucleotide polymorphisms vascular endothelial growth factor

Handbook of Nutrition, Diet, and the Eye. https://doi.org/10.1016/B978-0-12-815245-4.00003-X © 2019 Elsevier Inc. All rights reserved.

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Introduction Age-related macular degeneration (AMD) is the primary cause of legal blindness in the developed world and the third leading cause of blindness globally.1 The two major forms of AMD are atrophic or non-neovascular (dry) and neovascular (wet). The nonneovascular form of macular degeneration accounts for 85%–90% of all cases and is characterized by thickening of the retinal pigment epithelium (RPE) and Bruch’s membrane layer underlying the neurosensory retina, with formation of drusen, or yellowish deposits of extracellular material, and atrophy of the RPE and photoreceptors (Fig. 1). The neovascular form of AMD is characterized by subretinal and sub-RPE proliferation of abnormal blood vessels that leak fluid, blood, and lipids, which leads to replacement of much of the retina by fibrous scarring (Fig. 2). While much less prevalent, the neovascular form of AMD accounts for >80% of severe vision loss.2 Our understanding of macular degeneration and its treatment options has greatly evolved from just a decade ago when the disease was treatable only by thermal laser photocoagulation or photodynamic laser therapy, in an effort to limit the size of the scarred central blind spot. A number of environmental and genetic risk factors have been identified and pharmacological interventions have been developed to help treat the disease. Pharmaceutical research targeting vascular endothelial growth factor (VEGF) has yielded treatments to suppress development of abnormal blood vessels and the subsequent decline in visual function that historically made the neovascular form of AMD so debilitating. Finally, future research to expand methods to diagnose, manage, and treat AMD holds tremendous promise.

FIG. 1 Non-neovascular age-related macular degeneration. From Wills Eye Hospital Retina Service.

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FIG. 2 Neovascular age-related macular degeneration. From Wills Eye Hospital Retina Service.

Epidemiology AMD is more common among Caucasians and Asians. The Baltimore Eye Study found that Caucasians had 10 times the prevalence of AMD compared to African-Americans.3 A recent cross-sectional study of Americans 40 years and older estimated AMD prevalence to be 6.5% and late AMD prevalence to be 0.8%.4 The study also found African-Americans were at lower risk of AMD than Caucasians with an AMD prevalence odds ratio of 0.37. An analysis of predominantly Caucasian populations in the United States, Australia, and Europe reported a prevalence of 2 mm HG compared to 23.5% of patients in the placebo group. Additionally, the mean age in those with increases of 2 mmHg IOP or more was 66 years, compared to 57.7 years in patients who had increases of