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A -R ge elAted M AculAR d egeneRAtion A -R ge elAted M AculAR d egeneRAtion S e econd dition Edited by Jennifer I. Lim, M.D. University of Illinois School of Medicine, Department of Ophthalmology Eye and Ear Infirmary, UIC Eye Center Chicago, Illinois, USA InformaHealthcareUSA,Inc. 52VanderbiltAvenue NewYork,NY10017 q2008byInformaHealthcareUSA,Inc. InformaHealthcareisanInformabusiness NoclaimtooriginalU.S.Governmentworks PrintedintheUnitedStatesofAmericaonacid-freepaper 10987654321 InternationalStandardBookNumber-10:0-8493-7214-3(Hardcover) InternationalStandardBookNumber-13:978-0-8493-7214-8(Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission,andsourcesareindicated.Awidevarietyofreferencesarelisted.Reasonableeffortshavebeenmadetopublish reliabledataandinformation,buttheauthorandthepublishercannotassumeresponsibilityforthevalidityofallmaterialsor fortheconsequenceoftheiruse. 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Includesbibliographicalreferencesandindex. ISBN-13:978-0-8493-7214-8(hardcover:alk.paper) ISBN-10:0-8493-7214-3(hardcover:alk.paper) 1.Retinaldegeneration–Agefactors. I.Lim,JenniferI.,1962- [DNLM:1. MacularDegeneration.WW270A264912007] RE661.D3A3222007 617.7’35–dc22 2007023317 VisittheInformaWebsiteat www.informa.com andtheInformaHealthcareWebsiteat www.informahealthcare.com I wish todedicatethis book tomystudents, myfamily, and especially mydaughter, Bernadette. Foreword to the Second Edition Five years ago, Jennifer Lim, MD, and her expert undercontrol,asprovedbyappropriateclinicaltrials. colleagues published the first edition of Age-Related The invention and development of automated pars Macular Degeneration, a state-of-the-art summary of plana vitrectomy in the 1970s and 1980s represented knowledge about this frequently blinding disease. In another quantum leap forward. This innovative theForewordtothatedition,InotedthatDr.Limhad surgery has restored vision to innumerable patients “fashioned this valuable compendium of the way who were blind from a variety of retinal diseases, things are—for now!” It is relevant to ask, therefore, including proliferative diabetic retinopathy. Such if the state of the art and level of knowledge have exciting therapeutic advances come infrequently in progressedintheintervalsincethen.Whyindeedthey modern medicine—often they are decades apart. have, and, in the vernacular of the day, they have Attheiroutset,theyrequirebrilliantinsightsfollowed evolved“bigtime!”Themostimportantdevelopment, by painstaking, time-consuming, and expensive ofcourse,hasbeentheclinicalproofthatagentsaimed clinical trials for adequate proof of both efficacy and at inhibiting vascular endothelial growth factor not safety.Whensuccessful,suchactivityisclearlyworth- only preserve visual acuity in the neovascular (wet) while,asmeasuredbyenormousimprovementinboth form of age-related macular degeneration, but also personal and public health. improvevisualfunctioninginasubstantialpercentage Have the beneficial results of age-related ofpatients.Thisclassofcompoundsis,therefore,truly macular degeneration therapy yet reached their revolutionaryandofmajorbenefittopatientswithwet asymptote? Far from it! Although the frustrating age-related maculardegeneration. state of therapeutic affairs at the time of the first There have been numerous additional develop- edition has been substantially ameliorated in the mentsinboththeunderstandingandtreatmentofage- interim, there is much about age-related macular related macular degeneration since the first edition, degeneration that is yet to be understood and yet to and they are very well described in this new book. be accomplished. Even the relatively “established” Some of them are briefly mentioned subsequently in worlds of photocoagulation and vitrectomy are this Foreword, but none compares with the monu- characterized by useful, ongoing refinements. Analo- mentalimpactoftheanti–vascularendothelialgrowth gous events will undoubtedly characterize the factor approach to therapy of wet macular degener- evolution of the anti–vascular endothelial growth ation. The discoverers of key knowledge related to factor approach. We will certainly see a “dramatic vascular endothelial growth factor and its antagon- flourishing of new hypotheses, experiments, and ism—Drs. Harold Dvorak, Judah Folkman, Napoleon clinical procedures,” as predicted in the Foreword to Ferrara, and others—deserve enormous credit and thefirstedition.Newdeliverysystemsandschedules, gratitude for their ingenuity and scientific contri- for example, will undoubtedly enhance the inconve- butions. These achievements have directly lead, over nientandinvasiveintravitrealtreatmentregimensthat a decades-long evolutionary process of basic and are now utilized. Moreover, new combinations of applied research, to the initial, successful pharma- therapeuticagents(bothpharmacologicandphysical) cologic treatment techniquesof today. willbeproposedandevaluated.Manywillinevitably Inthehistoryoftherapyforotherblindingretinal flounder(ashavesomeotherformsofinitiallypromis- diseases, have there been other clinical advances ing treatments for age-related macular degeneration, that compare favorably with the tremendous impact such as irradiation, submacular surgery, and photo- of the anti–vascular endothelial growth factor coagulationofdrusen),butsomewillindeedsucceed. approach to age-related macular degeneration? In We have just embarked on a new era in the my personal experience, photocoagulation, and treatment of wet age-related macular degeneration. particularly laser photocoagulation, had analogous But what of dry age-related macular degeneration therapeutic effects when fully developed in the 1960s (and its major variants, including geographic and 1970s. With the advent of photocoagulation, atrophy), for which prophylaxis, such as that with anotherirreversiblyandcommonlyblindingdisorder, antioxidants, is in its formative phases and for diabeticretinopathy,suddenlyanddramaticallycame which restoration of lost vision does not yet exist? vi FOREWORDTOTHESECONDEDITION And what of wet age-related macular degeneration Finally, what of visual rehabilitation and its and an understanding of its etiology, pathogenesis, newer techniques? Clinicians must be well informed and prophylaxis? We remain in the infancy of these about developments that impact patients with low subjects.Fortunately,numerouschaptersinthissecond vision. The relevant chapter in this edition has prac- edition provide up-to-the-minute summaries of tical, currentinformation. relevant knowledge. For example, allele associations, Despite the extraordinary advances of the last such as those related to complement factor H and five years, and despite the superlative therapeutic others,andsinglegenemutations,suchasthoseinvol- armamentarium that we now possess, too many ving ABCR, ELOVl4, VMD2, TIMP3, peripherin/RDS, patients still lose their vision to both dry and wet and Fibulin3/EFEMP1, represent discoveries that are forms of age-related macular degeneration. Their largely new since the appearance of the first edition. well-being must remain at the forefront of our They are well described herein, and clinicians must consciousness. knowaboutthem.Cliniciansmust,ofcourse,alsoknow Ifprogressoverthelastfiveyearscanbeusedas about advances in fundus imaging. Much of the apredictorforthefuture,wecanassumethatongoing valuable, pragmatic information on optical coherence clinicalcarewillcontinuallyevolve—untilthepassage tomography, for example, has appeared since the of time (and hopefully another edition) permits first edition and is well described in this book. identification of those ideas that can safely be Additional new information on avant-garde subjects, discarded and those that herald better vision for our such as artificial vision, retinal prostheses, retinal patients. pigment epithelial transplantation, and new surgical techniques, are also reported by Dr. Lim and her Morton F. Goldberg collaborators. Thus, this second edition plays a The Joseph GreenProfessorof Ophthalmology pivotal role in educating those individuals concerned Former Director,the Wilmer Eye Institute with the diagnosis and treatment of age-related JohnsHopkins University Schoolof Medicine maculardegeneration. Baltimore,Maryland,U.S.A. Foreword from the First Edition Age-relatedmaculardegeneration(AMD)hasbecome the presence of choroidal neovascularization and a scourge of modern, developed societies. In such related phenomena in AMD, despite having been groups, where improved living conditions and developed almost half a century ago.) What are the medical care extend human longevity, degeneration best therapies of today and how might we improve of bodily tissues slowly but relentlessly occurs as the them in the future? At present, we think primarily of life spanincreases.Soonerorlater,the‘‘warranty’’on thermal laser photocoagulation and photodynamic such tissues expires, and so do critically important therapy. How can they be enhanced? What roles, if cells that, in the case of the macula, would have any, will other techniques play? Will they include allowed normal visual function if they had survived. low-power transpupillary thermal or x-irradiation, Those cells occupy a tiny area having a diameter of antiangiogenic drugs, genetic manipulation, or only about 2 to 3 mm in human eyes. When the cells surgery? Will combinations of these or even newer losetheirfunctionordieanddisappear,sharpcentral modalities be demonstrated to be both safe and effec- visualacuityfails,andlifestyleiscompromised—often tive? Will wide-scale population-based preventive severely.Theability toread,drive,recognizefaces,or measures, including antioxidants, for example, watch television can be impaired or lost. This group be more important than therapeutic intervention of diseases—AMD—has become the leading cause of expostfacto? visual impairment in those countries where increas- Clairvoyance is an imperfect attribute, but the ingly large numbers of individuals live to a so-called largely palliative and incompletely successful treat- ‘‘ripe old age.’’ Most of these senior citizens had ments of today are quite frustrating. There is a anticipated, with pleasure, the opportunity to enjoy compelling mandate for intense and sustained efforts their mature and less frenetic years, but too many of toimprovebothtreatmentandprophylaxis.Thecrystal theseindividuals,ravagedphysicallyandemotionally ball for AMD suggests that the immediate futurewill with AMD, frequently and understandably complain be characterized by refinements in today’s favored that the golden years are not quite so golden. This is interventions, especially photodynamic therapy, but the human and emotional side of AMD, a group of no one can really hope or believe that the therapeutic disorders now under intense scientific and clinical status quo will be preserved. Substantial change is scrutiny, as ably summarized herein by Dr. Jennifer a certainty. Physicians and patients appropriately Lim and herexpert groupof coauthors. demand more. The intermediate and long-range The chapters in this book are devoted to patho- futurewillprobablyincludealargenumberofdefini- physiology, clinical features, diagnostic tests, current tive clinical trials devoted to fascinating new and experimental therapies, rehabilitation, and pharmacological agents, many of which are now in research. They represent what we know today. They theevaluativepipeline,butmanyofwhichhavenotyet also tell usexplicitly or by inferencewhat we need to even been conceived. Classes of drugs will include know tomorrow. In effect, they are cross-sectional antiangiogenicorangiostaticsteroidswithglucocorti- analysesofthepresentstateofknowledge,analogous coidandnonglucocorticoidqualities,aswellasdiverse tophotosinanalbum,forexample.Here,inthisbook, agents to bind and inactivate cytokines and chemo- wehavecomprehensive,definitive,analyticreviewsof kines at different points in the angiogenic and the current state of macular affairs. Such albums and vasculogeniccascades.Manywillinvolveblockage of booksareofteninformativeandbeautiful,buttheybest the actions of vascular endothelial growth factor realize their inherent potential, as does this book, by (VEGF). Ingenious surgical approaches will also whetting our appetite for more information, both for come, and some will then go, as more and more new today as wellas for tomorrow.Forexample,whatare approaches of this nature undergo clinical evaluation the precise etiology and pathophysiology of andgaineitherwidespreadacceptanceorrejection. AMD?Willtheychange?Whatarethebestdiagnostic Today’s requirements for ‘‘evidence-based’’ testsfordifferentformsofAMD?(Parenthetically,itis medical decisions invoke Darwinian selection historically noteworthy to realize that fluorescein processes for numerous known, as well as currently angiographyremainsthedefinitivetestfordiagnosing unknown, diagnostic and therapeutic approaches to