Eye Disease Diverse Populations Final 3-08-06

7/28/2019 Eye Disease Diverse Populations Final 3-08-06

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Challengesand Opportunitiesfor Preventing andTreating Blindness

Eye Diseasesin

Diverse

Populations


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Eye Diseases in Diverse

Populations

Challenges and Opportunities orPreventing and Treating Blindness

June 1214, 2005Rancho Valencia, California

Symposium Co-ChairsJ. Bronwyn Bateman, M.D.

Gerald J. Chader, Ph.D.

The Washington Advisory Groupan LECG company

1275 K Street N.W., Suite 1025Washington, D.C. 20005


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The Washington Advisory Group, ounded in 1996, serves the science

and technology advisory and institutional needs o U.S. and oreign com-

panies, universities, governmental and nongovernmental organizations,

and other interested and aected parties. The Group provides authorita-

tive advisory and other services to institutions aected by the need to

institute and improve research and education programs, by the press o

the competitive marketplace, and by changing programs and policies o

the ederal science and technology enterprise. n ctober , Gn ctober , G

orporation, a provider o expert services, acquired substantially all o

the assets o The Washington Advisory Group, which will continue to

operate as a company within G.

The directors o The Washington Advisory Group are:

Mr. rich Bloch

Dr. . Thomas askey

Dr. Purnell hoppin

Dr. Robert A. Frosch

Dr. Bruce Guile

Ms. Victoria Hamilton

Dr. Frank PressDr. Mitchell T. Rabkin

For additional inormation about The Washington Advisory Group,

please see our website at www.theadvisorygroup.com.

Dr. Frank Rhodes

Dr. Maxine Savitz

Dr. Alan Schriesheim

Dr. Daniel . Tosteson

Mr. Andrew M. Werth

Dr. Robert M. White

Mr. Joe B. Wyatt


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iii

Contents

Preace .............................................................................................................................v

Acronyms .......................................................................................................................vii

Executive Summary ..........................................................................................................1

Conclusions and Recommendations ................................................................................9verarching onclusions .....................................................................................9General mplementation Actions or cular Disease ........................................18Public ducation and utreach .........................................................................1

onclusions on ndividual ye Diseases .............................................................6

Session 1. Ethnic Dierences in Eye Diseases................................................................49What pidemiology Has Taught Us about ye Diseases in

Diverse Populations, Dr. Sheila West.................................................................9linical onsiderations: essons rom hina and the Far ast,

Dr. Robert D. Yee ...............................................................................................55Worldwide ducation and Training in the Detection and Treatment o

ye Disease, Dr. Bradley R. Straatsma...............................................................6

General Discussion on Session 1 Topics .............................................................68

Session 2. Myopia ..........................................................................................................73Quantiying Dierences in Myopia Prevalence: Findings rom the RS,

Dr. Leon B. Ellwein............................................................................................73Pathophysiology o Myopia, Dr. Earl L. Smith, III ...............................................77linical Management o Myopia: Present and into the Future,

Dr. Tien Y. Wong................................................................................................85General Discussion on Myopia ...........................................................................89

Session 3. Glaucoma......................................................................................................93pidemiology o Glaucoma, Dr. Barbara Eden Kobrin Klein................................93Pathogenesis o Glaucoma, Dr. David S. Friedman..............................................99Glaucoma linical Management: Present and into the Future,

Dr. Paul L. Kaufman ........................................................................................1General Discussion on Glaucoma .....................................................................11


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iv Contents

Session 4. Diabetic Retinopathy ..................................................................................113pidemiology o Diabetic Retinopathy, Dr. Robert N. Frank.............................113

Pathophysiology o Diabetic Retinopathy, Dr. Stephen J. Ryan..........................1linical Management o Diabetic Retinopathy: Present and into the Future,Dr. Paulus T.V.M. de Jong....................................................................................18

General Discussion on Diabetic Retinopathy ...................................................13

Session 5. Degenerative Diseases o the Macula ........................................................137Aging Macular Disease Worldwide, Dr. Peter A. Campochiaro .........................137The Pathogenesis o AMD, Dr. Alan C. Bird ....................................................11linical Management o AMD: Present and into the Future, Dr. Yasuo Tano ....17linical Management o Polypoidal horoidal Vasculopathy:

Present and into the Future, Dr. Eugene de Juan ............................................15General Discussion on Degenerative Diseases o the Macula and

Neovascularization .........................................................................................158

Business Perspectives on Transitioning New Treatments into Practice ........................161Paths to Treating Diverse ye Diseases in the Future, Dr. Ronald Klein...........161An ntrepreneurial Perspective on Transitioning Research into Delivered

Health are Products, Mr. Alfred E. Mann....................................................166

Reerences ...................................................................................................................169

Appendix A. Symposium Participants and Observers ..................................................179

Appendix B. Symposium Agenda .................................................................................181

Tables1. Principal onclusions o the Fourth Drabkin Symposium ...............................5

. World Population in by Region ..............................................................63. Sites nvolved in the RS ............................................................................7. rigins o Hispanic Americans, .............................................................975. Prevalence, ncidence, and Progression o Diabetic Retinopathy ................1156. Recommended Follow-up ntervals or evels o NPDR ..............................197. Prevalence o PV in Patients nitially Diagnosed with AMD ....................15

Figures1. Gene Pool Ancestry or Hispanic Americans ................................................13. Blindness in U.S. Adults over Years o Age ...............................................63. Myopia Prevalence by Age .............................................................................75. Prevalence o pen Angle Glaucoma by Sex, Age, and Race/thnicity .......965. Ten-Year Progression o Retinopathy by Quartile o Glycosylated

Hemoglobin ....................................................................................................1166. Polypoidal horoidal Vasculopathy ..............................................................15


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v

Preace

The ourth in a series o symposia on accelerating the implementation

o research results on eye disease was held on June 111, 5, at Ran-

cho Valencia, aliornia. The theme o this Fourth Drabkin ye Disease

Symposium was an exploration o the special challenges and treatment

prospects or dealing with the ways in which chronic blinding eye dis-

eases present in subgroups o a heterogeneous population. The diversity

o the American population with respect to ethnic and cultural ances-

try provided a starting point or considering implications o a hetero-

geneous population or understanding and treating potentially blinding

eye diseases. Many o the symposium recommendations address issues o

public health and the burden o visual impairment in the United States.

However, in matters o health and illness, as in so many other areas o

modern lie, we reside in a global village. The diversity within the U.S.

population relects our increasingly important role as one crossroads, one

multicultural neighborhood, within that larger village, with its global

array o peoples and cultures.

A guiding theme emerged early in the context-setting presentations

that opened the symposium and resonated through to its closing discus-

sions. For complex diseases o the eye, the diversity o the American peo-

ple presents clinical medicine with challenges or which evidence-based

practice will need the research opportunities available in the worldwide

diversity o genetic, environmental, cultural, and personal liestyle ac-

tors. n this context, progress in American public health depends on theeicacy o partnering across national borders.

The 19 symposium participants (listed in appendix A) were selected

to provide crosscutting expertise on our complex ocular diseases or


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vi Preface

which population diversity presents acknowledged challenges: glaucoma,

diabetic retinopathy, degenerative diseases o the macula, and myopia.

Within each o the our subsequent sessions devoted to a speciic ocular

disease, the presenters ocused on disease epidemiology, pathophysiology,

or current practice and uture trends in clinical management o the dis-

ease. n addition, three participants provided context-setting presenta-

tions on the broad topic o ethnic dierences in eye diseases worldwide

and within the United States. (The symposium agenda is in appendix B.)

ach session included ample time or discussion o the presentations in

these three areas.n the inal morning o the symposium, each session group pro-

posed conclusions and recommendations or consideration by the partic-

ipants. The results o that discussion provided the basis or the con-

clusions listed in table 1 (pp. 58); supporting discussion and detailed

suggestions or each o these principal conclusions ollow the table.

ike the prior symposia on glaucoma, age-related macular degen-

eration, and emerging therapies or diseases o the retina and opticnerve [1, 2, 3], this symposium was made possible by the endeavors o

Mr. Robert Drabkin o os Angeles, aliornia, and supported by the

University o aliornia, os Angeles, Support Group o the Jules Stein

ye nstitute. t was organized and conducted by the Washington Advi-

sory Group. This report was prepared with the guidance and supervi-

sion o the symposium co-chairs, who are responsible or its technical

content.

J. Bronwyn Bateman, M.D. Gerald J. Chader, Ph.D.

o-chair o-chairDepartment o phthalmology Doheny Retina nstituteThe hildrens Hospital University o SouthernRocky Mountain ions ye nstitute aliornia Medical SchoolUniversity o olorado os Angeles, aliornia

School o MedicineAurora, olorado


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vii

Acronyms

AG angle closure glaucoma

AG advanced glycation endproducts

AMD age-related macular degeneration

ARDS Age-Related ye Disease Study

BDNF brain-derived neurotrophic actor

D enters or Disease ontrol and Prevention

NV choroidal neovascularization

DT Diabetes ontrol and omplications Trial

DRR.net Diabetic Retinopathy linical Research Network

TDRS arly Treatment Diabetic Retinopathy Study

FDM orm deprivation myopia

G indocyanine green [a luorescent dye used or angiography]

P intraocular pressure

NHP National ye Health ducation Program

NHANS National Health and Nutrition xamination Survey

NH National nstitutes o Health

NPDR nonprolierative diabetic retinopathyT optical coherence tomography

PV polypoidal choroidal vasculopathy

PDR prolierative diabetic retinopathy

PDF pigment epithelium-derived actor

PAG primary open angle glaucoma

RS Reractive rror Study in hildren

RP retinal pigment epithelium

TMP tissue inhibitor o metalloproteinasesUKPDS United Kingdom Prospective Diabetes Study

VGF vascular endothelial growth actor

WSDR Wisconsin pidemiologic Study o Diabetic Retinopathy

WH World Health rganization


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1

Executive Summary

Many serious and relatively common diseases or which straightorward

cures are lacking aremultifactorial, meaning that a number o genetic and

environmental actors aect their onset and progression. Both anecdotal

reports and bone ide epidemiologic studies indicate that these diseases

vary in at least some characteristics within diverse populations. For mul-

tiactorial diseases o the eye, the evidence, although incomplete, indi-

cates some substantial dierences exist in how these potentially blinding

diseases present in groups that dier in ethnic, socioeconomic, or other

measurable parameters. These dierences hold important general lessons

or American health care, as well as engendering both challenges and

opportunities or translating new research more quickly into eective

treatments or potentially blinding diseases.

The irst 1 conclusions in table 1 convey general lessons drawn

by the 19 participants in the Fourth Drabkin ye Disease Symposium.

Table 1 also lists 1 conclusions the participants reached on major

vision-threatening diseases: glaucoma, diabetic retinopathy, retinal neo-

vascularization and macular diseases, myopia, and cataract.

GlaucomaWorldwide, glaucoma is a common cause o irreversible vision loss. t is

the second most common cause o irreversible vision loss in the United

States and the most common cause among Arican Americans. Themost common orm o glaucoma in the United States is primary open

angle glaucoma. Glaucoma prevalence in Americans o predominantly

uropean ancestry (uropean Americans) is about percent or adults

over years o age. By comparison, Americans o Arican ancestry


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2 Executive Summary

may have as much as ive times that risk. The risk or Hispanic popula-

tions is also greater than that observed in populations o predominantly

uropean ancestry. The data are inadequate to estimate risk in Asian

Americans. No basis has yet been identiied or the observed dierences

among Arican, Hispanic, and uropean Americans. Prevalence increases

with age; or those 75 years o age or older, prevalence increases to 5 per-

cent in people o uropean ancestry, to 11 percent in Arican Ameri-

cans, and to 5 percent in those o aribbean and Arican ancestry.

Angle closure glaucoma is more common in many Asian populations

than in populations o predominantly uropean or Arican ancestry. ,as current data suggest, speciic groups have ar higher susceptibility to

glaucoma (or to dierent orms o glaucoma) than does the American

population in general, then dierent emphases in diagnosis, prevention,

and treatment may be necessary or eective management o this public

health menace.

Diabetic RetinopathyDiabetic retinopathy is the leading cause o poor vision in young adults.

The causes are complex, but the risk is directly proportional to control

o blood sugar and, to a lesser extent, blood pressure (established only

or type diabetes). As with glaucoma, persons with diabetes who are

o Arican or Hispanic ancestry are at increased risk or severe vision

loss and blindness compared with Americans o predominantly uro-

pean ancestry. At least part o this elevated risk can be attributed to

dierences in health care among the groups with respect to risk actors

such as glycemia and blood pressure. However, genetic actors and envi-

ronmental/liestyle actors such as diet (particularly in type diabetes)

require urther detailed evaluation o actor interactions. omparative

studies are needed to ensure that high-quality care can be ocused and

tailored to decrease risk in speciic population groups.

Degenerative Diseases o the Macula

Age-related macular degeneration (AMD) is the leading cause o severe

loss o vision in Americans 65 years o age or older, particularly those


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Eye Diseases in Diverse Populations

o uropean ancestry. t appears that Arican Americans and Hispanic

Americans may be at lower risk or the more severe orms o this disease.

However, the data or these groups are sparse, and even less is known

about the risk or Asian Americans. Given the social, inancial, and

quality-o-lie ramiications o this trend, comparative data or the major

subgroups within the U.S. population will be essential to a cost-eective

public health strategy.

Another disease o the macula characterized by neovascularization,

leakage, and scarring is polypoidal choroidal vasculopathy (PV). This

disease has been studied primarily in Asian populations, but its preva-lence among Asian Americans and other U.S. population subgroups is

unknown.

Myopia

The prevalence o myopia is high and increasing in parts o ast Asia.

Still unknown is whether this high prevalence relects primarily geneticactors or a more complex response to intense environmental stimula-

tion (such as extended periods o visual concentration on details within

an arms distance, callednear work) occurring on a susceptible genetic/

ethnic background. This ast Asian experience has potentially serious

implications or lietime visual impairment in the more diverse popula-

tion o American youth and also or adults o all ethnic backgrounds.

To assess these implications, a concerted eort is needed to determinewhether the same causal actors related to the high-prevalence ast

Asian groups are present in groups within the U.S. population.

Summary

n any disease, each patient must be evaluated as an individual. How-

ever, useul clues or this evaluation can be ound in the ethnic andcultural heritage o the patient because o the agglomeration o genetic,

cultural, and environmental conditions that underlie shared heritages.

Ultimately, it is these still unknown (or just emerging) actors that aect

the outcome o multiactorial diseases. There are ethnic and cultural di-


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4 Executive Summary

erences in the requencies o several vision-threatening conditions that

aect millions o Americans and millions more in other countries around

the world. Studies can now be designed to yield deinitive data to help

health care planners provide accessible and aordable diagnostic and

treatment modalities or these vision-impaired patients.


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5

Overarching Conclusions

Epidemiological research into the prevalence, incidence, riskactors and determinants, treatment, and outcomes o eyedisease in diverse populations continues to be a valuable andnecessary endeavor. There is now an urgent need to identiy anddocument the dierences in how ophthalmic disorders presentin the diverse American population and to understand whichpotentially relevant actors (genetic, cultural, environmental)inuence these dierences. Worldwide, the major causes oblindness in many countries vary by degree o socioeconomicactors, as well as by customary ethnic designations.Understanding the causal actors underlying these observablemarkers o population diversity can improve eective delivery opreventive and therapeutic health care to high-risk groups withinthe diverse U.S. population.

1.

To guide intervention strategies, urther research into theseunderlying actors can make use o evidence on diseasedisparities among population groups.

2.

The eye diseases on which this symposium ocused have geneticcomponents. In studying population dierences to identiyand understand these genetic actors, one cannot assumethat the standard demographic categories or ethnicity defnepopulations with relevantly similar genetic characteristics. Inshort, the common ethnic categories should not be assumedto be adequate markers or disease phenotypes and theirunderlying disease genotypes.

3.

Studies that target populations both inside and outside the

United States may cost-eectively increase the value o resultsdirectly applicable to specifc American groups. Inclusion o studypopulations rom outside the United States can be a easibleway to collect the data needed to answer both basic scientifcand clinical research questions about the contributions o andinteractions among environmental and genetic actors.

4.

General Implementation Actions or Ocular Disease

Standard defnitions and terminologies or the major blindingeye diseases should be agreed on and used by majorophthalmology centers. These standards should includeclinical signs or diagnosis, disease stages, and measurementtechniques.

5.

Table 1. Principal Conclusions o the Fourth Drabkin Symposium


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Table 1. Principal Conclusions of the Fourth Drabkin Symposium

An economic plan or progress in cost-eective treatment (a

roadmap to a cure) should be constructed or each o themajor eye diseases considered in this report.

6.

For all the diseases considered in this symposium, prevention ordelay o disease progression should be a priority or researchand clinical management. An emphasis or uture treatments,once a disease condition is present, should be on delivering theactive agent to the target site.

7.

Public Education and Outreach

Increased support is warranted or research into public outreach

on eye health that is tailored or diverse populations. Supportor public health education on eye care has a high ratio osocietal beneft to cost. Improving the eective delivery o knownprevention and treatment strategies, particularly to underservedpopulations at increased risk, is likely to increase the returns orsociety, measured in the economic value o health benefts tohealth benefts tohealth benefts toboth individuals and the public good.

8.

A coordinated approach is essential to public education aboutdisease prevention strategies. Public health education should

be coordinated or all diseases, not just those o the eye. Thiscoordinated approach should include messages and outreachactivities specifcally tailored or population groups that are notyet being eectively treated.

9.

Training or eye care proessionals should reect the growingdiversity o the U.S. population. A cost-eective way to combinethis training with the need or research on diverse populations isto oster the international exchange o U.S.-based and oreign-based eye care proessionals.

10.

Glaucoma

Research is needed into eective methods or identifcation oglaucoma in high-risk populations. As the U.S. population ages,early diagnosis o all orms o glaucoma will help to preservevision. Treatments such as medical and surgical options to lowerintraocular pressure are available or most orms o glaucoma, ithe disease process is identifed and treated early enough.

11.

A better understanding is needed o the dierences in glaucomapathophysiology within and between population groups.Mechanisms may dier within and between population groups

defned by customary demographic or cultural criteria.

12.

Opportunities exist or improved glaucoma treatments in theuture, but stronger support is needed to bridge the gaps inresearch necessary to develop and test them.

13.


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Diabetic Retinopathy

Prevention is the most important strategy or dealing withdiabetic retinopathy. The principal prevention goal is tomaintain normal, or at least near-normal, glycemic levels. Otherprevention goals include maintaining normal blood pressureand serum lipid levels.

14.

Population studies or diabetic retinopathy should be designedto: (1) ensure that results can be generalized to populations atelevated risk; (2) allow meaningul comparisons across studies;and (3) make use o results rom current population studies,

particularly those in which DNA sampling allows or analysesthat support genotype characterization.

15.

Innovative approaches are needed or improving complianceand patients understanding o their disease, on whichcompliance dependsacross ethnocultural boundaries. Patientcompliance is the single biggest driver in determining theoutcome o known prevention strategies.

16.

Degenerative Diseases o the Macula

Future epidemiological studies o macular diseaseincluding

polypoidal choroidal vascularization (PCV) as well as the wetand dry orms o age-related macular degeneration (AMD)and precursor conditionsneed a common basis or interstudycomparisons based on uniorm defnition and classifcation. Thisstandardization should reect the need to match phenotypes withgenotypes o macular disease.

17.

More population-based studies are needed that are careullydesigned to test specifc hypotheses regarding the roles ogenetic and environmental actors in AMD and PCV initiationand progression.

18.

Better treatments and therapeutic agents or neovascularizationaecting the macula are needed. Treatments are also needed ordry AMD. A better understanding o AMD progression is needed,on which to base decisions and techniques or treating earlyprecursor stages o AMD.

19.

Population-based studies, such as the Beaver Dam Study and theRotterdam Eye Study, have ound that smoking is a risk actor or

AMD. Two major studies have reported association o dietary sup-plements, including antioxidant vitamins and zinc, with reduced

incidence o AMD in the elderly and reduced rate o progressionto advanced AMD. Further study is needed on these actors (e.g.,mechanisms o action), as well as on additional risk actors andprotective actors or degenerative diseases o the macula.

20.


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Table 1. Principal Conclusions of the Fourth Drabkin Symposium

Myopia

Epidemiologic data rom dierent countries with diversepopulations indicate that both environmental and genetic riskactors inuence the development o myopia and o ocularmorbidity associated with childhood myopia. Understanding therespective roles and interactions among these actors is essentialto cost-eective intervention strategies. Thus, population-based studies are needed to identiy these risk actors and theirinteractions.

21.

A better understanding o the pathophysiology o myopia

as a disease o eye growth and reractive development willcomplement the eort to resolve the genetic and environmentalactors through population-based studies.

22.

Prospective population-based studies are needed to determinethe predictors or progression o juvenile myopia and to identiyuture treatment opportunities.

23.

Cataract

A high priority or urther research on cataract should be tounderstand the disparities among populations worldwide in

patient access to and outcomes o cataract surgery. Althoughsurgery is a cost-eective intervention worldwide or visual lossdue to cataract, research to understand population disparitiesin cataract onset may aid in preventing or delaying this disease,which blinds more than a million people each year.

24.


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9

Conclusions and Recommendations

The June 5 Drabkin ye Disease Symposium began with two days

o presentations rom the participating medical research scientists and

clinical physicians. (The meeting agenda is in appendix B.) An open-

ing session o high-level views on ethnic dierences in eye diseases was

ollowed by sessions ocusing on one eye disease or which population

diversity presents special challenges. n the morning o the third day,

the presenters or each session proposed major conclusions and recom-

mendations or all the symposium participants to consider. The conclu-

sions listed in table 1 are based on the results o those lively discussions.

This chapter presents key arguments and reasons, drawn rom the sym-

posium discussions, supporting the principal conclusions.

Overarching Conclusions

1. Epidemiological research into the prevalence, incidence, risk actors and

determinants, treatment, and outcomes o eye disease in diverse populations

continues to be a valuable and necessary endeavor. There is now an urgent

need to identiy and document the dierences in how ophthalmic disorders

present in the diverse American population and to understand which

potentially relevant actors (genetic, cultural, environmental) infuence these

dierences. Worldwide, the major causes o blindness in many countries

vary by degree o socioeconomic actors, as well as by customary ethnicdesignations. Understanding the causal actors underlying these observable

markers o population diversity can improve eective delivery o preventive

and therapeutic health care to high-risk groups within the diverse U.S.

population.


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10 Conclusions and Recommendations

Many chronic diseases or which we lack straightorward cures are

thought to bemultifactorial: they are inluenced by a number o genetic

and environmental actors. For most o these complex diseases, both

anecdotal reports and epidemiologic studies indicate that disease preva-

lence, incidence, and other characteristics vary within diverse popula-

tions. n particular, or complex diseases o the eye, much tantalizing but

incomplete evidence suggests that substantial dierences exist in how

these diseases present in groups that dier on the basis o ethnic, envi-

ronmental, or cultural actors.

These dierences in how a complex eye disease presents in diverse

populations conront the practical arts o medicine and public health

with both a challenge and an opportunity. Until we understand the how

and why o a complex diseaseits etiology and pathophysiologywe

cannot be sure that what is known about its behavior in one group will

be equally valid or a dierent group. ndeed, mounting evidence shows

that substantial dierences do exist or several important eye diseases

in diverse groups o Americans. Thus, we must be careul in presum-ing that what has been learned or proven in the context o a general, or

generic, population will apply to a subgroup whose ethnic, environ-

mental, or cultural characteristics diverge rom the norms o the larger

population. Which dierences are relevant, which o themmay be rel-

evant, and which can be ignored? This is the challenge in preventing or

treating complex diseases in a diverse population.

2. To guide intervention strategies, urther research into these underlying actors

can make use o evidence on disease disparities among population groups.

The opportunity comes rom the potential value o dierences in disease

characteristics among diverse populations to help us unravel the multi-

actorial nature o a complex disease. areully documented population

dierences provide an acceptable surrogate or the kinds o controlledexperimentation that we cannot ethically perorm on human subjects.

When aced with an outcome or which there appears to be multiple

causal actors, the scientiic approach is to study what happens when

one or more o these actors are varied in a systematic way, while all the


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Eye Diseases in Diverse Populations 11

others are held constant. However, ethical medical scientists cannot

do this. For example, they cannot create genetic strains or knockout

models o humans to test or a genetic actor. They cannot deliberately

expose human subjects to long-term environmental or liestyle condi-

tions i there is evidence that those conditions may be harmul, just or

the sake o a controlled experiment. Faced with multiactorial diseases,

medical research requires scientiically sound study methods, such as

those provided by epidemiology, to detect putative actors without vio-

lating the canons o medical ethics. pidemiological studies o diverse

populations rom around the world may permit urther inerences regard-ing relationships o genetic and environmental risk actors to diseases.

Where population groups with well-documented dierences in actors

suspected o causing or inluencing a complex disease can be identiied,

the epidemiologist, geneticist, and biomedical scientist can cooperate

to conduct appropriate studies. Population diversity thus provides an

opportunity or research not otherwise easible.

The need to identiy and document dierences in how ophthalmicdisorders present in diverse populations is rooted in both the challenge

and the opportunity posed by complex diseases o the eye. For example,

there is suggestive evidence that Arican and Hispanic Americans may

be at greater risk or glaucoma and diabetic retinopathy than are Ameri-

cans o predominantly uropean ancestry. 1 How large is the risk di-

erential, and what actors account or it? What are the cost-eective

public health responses to address these risks, i they exist? Are AsianAmericans more susceptible to angle closure glaucoma (AG) and high

(severe) myopia than are Americans o predominantly uropean ances-

try? s polypoidal choroidal vasculopathy (PV) a greater risk or Ari-

can and Asian Americans than or Americans o other ancestry, and i

so, what actors are responsible? These are just a ew o the challenges

1For purposes o this report, Arican Americans are U.S. citizens with Aricanancestry and Asian Americans are U.S. citizens with Asian ancestry. Hispanic Amer-icans are U.S. citizens whose ancestry traces to Mexico, entral or South America,or the Spanish-speaking islands o the aribbean. These categories, along withuropean American, are not mutually exclusive; a large and growing number oAmericans have ancestors rom several o these locations.


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related to reducing the risk o visual impairment rom eye diseases in the

diverse U.S. population. n the opportunity side, sorting out genetic

versus environmental and liestyle dierences may be diicult or dis-

eases that occur relatively inrequently, i the study populations are lim-

ited to the United States only. Data regarding incidence and risk actors

derived rom well-designed studies using careully selected populations

outside our national boundaries may be beneicial to understanding and

preventing loss o vision in U.S. citizens. Speciic instances o this oppor-

tunity are included in the symposiums conclusions or speciic eye dis-

eases. Given current knowledge about these diseases, such studies may

acilitate learning which actors are relevant to uture prevention and

treatment.

Studies o the prevalence, incidence, treatment, and outcomes o

eye diseases in diverse populations rom around the world, as well as

rom our own diverse American population, can enhance our ability to

prevent and treat these potentially blinding diseases. That is the princi-

pal, overarching theme on which the Drabkin Symposium participants

agreed. However, even beyond their relevance to complex diseases o the

eye, the above arguments on the challenge and opportunity in popula-

tion diversity apply as well to other similarly complex diseases such as

cardiovascular disease and cancer. The illustrations given below or spe-

ciic eye diseases thus contain signiicant general lessons or American

health care.

3. The eye diseases on which this symposium ocused have genetic components. In

studying population dierences to identiy and understand these genetic actors,

one cannot assume that the standard demographic categories or ethnicity deine

populations with relevantly similar genetic characteristics. In short, the common

ethnic categories should not be assumed to be adequate markers or disease

phenotypes and their underlying disease genotypes.

ne o these general lessons or health care is that the classic mea-

sures o diversity used by demographersethnicity, age, and gender,

or instanceare not reliable markers or disease risk actors. A demo-

graphic category such as Hispanic American or Arican American covers


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a wide range o potentially relevant environmental, sociocultural, and

economic actors, as well as genetic actors. Age and gender dierences

can relect liestyle dierences, which are inluenced by social actors.

For example, the Hispanic population in the United States is par-

ticularly likely to be genetically heterogeneous because this culturally

deined group consists o individuals whose ancestors typically came

rom diverse populations in widely separated regions (Native Americans

rom South and entral America, Spanish and Portuguese immigrants

rom the berian Peninsula, Aricans transported to the New World asslaves, and other uropeans who emigrated in response to amine or

wars). Figure 1 illustrates the gene pool diversity among Hispanic Amer-

icans who emigrated rom three areas: Mexico, Puerto Rico, and uba.

A similar caveat about genetic diversity applies to Arican Ameri-

cans, many o whom have some uropean ancestry and whose Arican

ancestors may have come rom dierent areas o Arica. aribbean

populations o Arican descent oten have ancestors rom dierent areaswithin Arica than do many Arican Americans.

Figure 1. Gene Pool Ancestry or Hispanic Americans

Source: [4].

0

10

20

30

40

50

60

70

Mexico Puerto Rico Cuba

African Native American Spanish

Percent


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Great caution must thereore be exercised when making inerences

rom data or any customary demographic category to the speciic ac-

tors underlying the disease experience o that population group. , or

example, Hispanic Americans have a dierent prevalence o a disease

rom the general population (e.g., open angle glaucoma or late-stage

macular disease), one cannot simply assume that a genetic (or cultural,

or environmental) actor is responsible or the dierence. n the popula-

tion geneticists language o diseasegenotypes andphenotypes (see box),

one must be cautious about assuming that commonly used racial or

ethnic categories, even those used in demographic studies, are accu-

rate, ully representative phenotypes o a disease genotype.

n addition to this genetic heterogeneity in a demographically

deined group, one must also consider the complicating role o suscep-

tibility genes (both their presence and absence), gene-environment

interactions, gene-gene interactions, and nongene-based regulation o

Genotypes and Phenotypes o a Complex Disease

A genotype is the genetic constitution o an organism, usually in reer-

ence to one or a ew genes relevant to a specifc context. In discussing

multiactorial diseases, a disease genotype consists o the specifc gene

or set o genes (along with other non-gene genetic components) associ-

ated with one variant o the disease condition. The disease conditions

diagnosed as glaucoma, or example, can arise rom dierent geno-

types. Macular degeneration and probably the other ocular diseases

discussed in this report are similarly complex in genetic constitution.

The phenotype o an organism is the set o observable characteristics

that depend on a genotype o the organism in interaction with its envi-

ronment. Similar observable characteristics need not reect the same

genotype. Culturally signifcant characteristics, such as skin color or

acial eatures, are unreliable as markers or phenotypes o a disease.

Even clinically observed dierences in disease conditions may not cor-

respond to dierent disease genotypes and thereore may not represent

distinct disease phenotypes.


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gene expression. Much additional research on these underlying actors

is needed so that dierences with respect to probable causal actors can

be scientiically established through population studies. The good news

is that this work o identiying risk actors or development o any o the

eye diseasesis likely to produce results applicable to multiple diseases

and health-related conditions and issuesnot just with respect to the

eye and vision but also relevant to other areas o public health and clini-

cal medicine.

A second general lesson is that population-based research can ben-

eit rom the comparability across studies provided by judicious oversight

and guidance rom cognizant national and international authorities. At

the national level, these authorities include the enters or Disease on-

trol and Prevention (D) and the National nstitutes o Health (NH).

At the international level, an obvious example is the World Health

rganization. onsultation with national and international proessional

societies with relevant expertise may also be o beneit in conducting

such research. specially important is oversight or longitudinal studies,to ensure optimal use o data rom each study to gain insights into the

underlying actorswhether genetic, environmental, or culturaland

to ensure comparability across studies. With respect to interventions,

surveillance o the populations health by population-based surveys and

objective measurements sponsored by the D or NHor example,

the National Health and Nutrition xamination Surveyare important

to determine whether practice differences introduced to address presumedgenetic, cultural, or socioeconomic (environmental) dierences in act

have the desired impact on patient outcomes in the population groups

to which these dierential practices are targeted. For example, does

introduction o a new treatment or preventive therapy in act reduce the

requency o unctional loss rom the treated condition? Does it improve

patients quality o lie? n the United States, the National enter or

Health Statistics, a branch o the D, has conducted such surveys overtime. The National ye nstitute has ostered population-based studies

through its unding priorities.

These general lessons or American health care can be illustrated

with speciics o the chronic, vision-threatening diseases considered at


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the Drabkin Symposium. As mentioned above, it is generally accepted

that the prevalence o glaucoma is higher or Arican Americans and

Hispanic Americans than or Americans o non-Hispanic uropean

ancestry. However, data rom these populations are inadequate to detect

the risk actors explaining the higher prevalence rates or glaucoma.

Variations among studies notwithstanding, results rom studies such

as the Baltimore ye Study do show that prevalence in all population

groups increases with age and with increased intraocular pressure (P).

Beyond these undamental risk actors, close comparison o groups or

which genetic, environmental, and cultural dierences are known and

quantiied becomes diicult, even speculative.

4. Studies that target populations both inside and outside the United States may

cost-eectively increase the value o results directly applicable to speciic

American groups. Inclusion o study populations rom outside the United States

can be a easible way to collect the data needed to answer both basic scientiic

and clinical research questions about the contributions o and interactionsamong environmental and genetic actors.

onclusion expands on the general point made above that studies tar-

geting speciic populations outside the United States may provide data

relevant to understanding ocular disease in the diverse U.S. population.

Studies o complex eye diseases need large enough numbers o subjects

experiencing the underlying candidate causal actors to yield observabledierences that are statistically signiicant. The more individual ac-

tors and combinations o actors to be compared, the larger the target

population must be to have suicient numbers o subjects with dier-

ent exposures. deally, those designing such studies will want to select

a population that will maximize the diversity with respect to potential

risk actors. Going across national borders to select a study population

may increase the number o participants in treatment groups o interest,compared with relying on subpopulations within the larger general popu-

lation o a single country. ne reason is that populations in other coun-

tries may be more homogeneous with respect to one or more risk actors

o interest than the highly heterogeneous American population, even


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within a demographic ethnic category. A second reason is that groups

in dierent countries but with similar ancestry may dier with respect to

potential environmental and cultural risk actors.

To return to an example already mentioned, Hispanic Americans

have a broad range o ancestry in terms o relative amounts o His-

panic and non-Hispanic uropean ancestry, Native American ancestry,

and Arican ancestry. To understand the interplay among genetic and

cultural/environmental actors in the incidence o glaucoma among

Hispanic Americans, a study that examines selected participants rom

speciic areas in the United States and rom targeted areas in atin

American countries may be more cost-eective. A similar situation

holds or studying the higher incidence o glaucoma in Arican Ameri-

cans than in the general population. n some circumstances, a smaller

study population, but with higher proportions o risk actors o interest,

might provide the same statistical power or some questions as a larger

but more heterogeneous study population. To test some questions, such

as on interactions among potential risk actors, the only easible way toenroll enough participants with the relevant combinations o character-

istics may be to include subjects rom outside the United States.

Americans o Asian ancestry provide a third example. This rapidly

growing segment o the U.S. population includes persons with ancestry

rom ast Asia (hina, Japan, Korea, etc.), South Asia (ndia, Pakistan,

Bangladesh, etc.) and Southeast Asia (Vietnam, ndonesia, Thailand,

etc.). onsidering the diversity o the history and peoples indigenousto these areas o Asia, one can expect a great deal o genetic diversity

within their American-dwelling descendents, as well as divergences

between these Americans and others o primarily uropean or Arican

ancestry. However, there have been ew Asian American populations

studied to date. There is evidence, or example, o an increase in the

incidence o high myopia and o angle closure glaucoma in ast Asian

countries, but data on Americans o ast Asian ancestry are nonexis-tent. Studies o myopia in Asians living in their ancestral country o

origin need to be compared with studies o Americans with ancestry

rom these same origins. To make such comparisons, the studies must

use similar methods and deinitions. Multi-nation studies could provide


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valuable inormation or understanding the risk actors o a disease or all

populations, much as has already resulted rom studies comparing car-

diovascular disease in Japanese living in Japan with Japanese Americans.

Dierences (or similarities) in myopia among Asians living in Asia and

in America could similarly shed light on risk actors or all populations.

General Implementation Actions or Ocular Disease

Given the challenges and the opportunities posed by the presence o

complex ocular diseases in a diverse population, what should be done to

overcome the ormer and embrace the latter? The three conclusions in

this section describe actions relevant across most or all o the diseases

discussed at the symposium. n many instances, detailed recommenda-

tions made in later sections o this summary or a speciic disease are

extensions and reinements o the broad actions advocated here.

5. Standard deinitions and terminologies or the major blinding eye diseases

should be agreed on and used by major ophthalmology centers. These standards

should include clinical signs or diagnosis, disease stages, and measurement

techniques.

To have precise, objective, and reproducible data on dierences in eye

disease characteristics in a diverse population (whether the target popu-

lation resides in one country or geographical region, or comes romseveral), researchers should use the same disease descriptors. This meth-

odological requirement is routinely solved within individual studies, but

the lack o standard deinitions and terminologies hampers comparisons

across studies. Standardization in the areas o clinical signs or diagno-

sis, disease stages, and measurement techniques will enable comparative

assessments o patient populations by both the public sector (govern-

ment entities) and the private sector (e.g., pharmaceutical companies).Deinitions, diagnostic criteria, and diagnostic methods or the dierent

orms o glaucoma, or example, should be standardized, where possible,

to enable valid comparisons o prevalence and incidence across multiple

studies.


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However, lexibility to respond to new medical knowledge must be

built into the deinitions. are must be taken that standard deinitions and

measurements do not become obstacles to new research and insights that

advance older approaches. As new knowledge is acquired on such topics

as genetic mutations and the role o environmental and cultural actors,

the deinitions must allow or incorporation o that new knowledge.

Population studies on age-related macular degeneration (AMD) are

another area where additional standardization and test method evalua-

tion are warranted. nternationally accepted standardized protocols have

been adopted or deining and grading AMD stages. These protocols

have been successully used in large population-based studies. Although

severity scales such as the one used in the Age-Related ye Disease

Study (ARDS) have been based on these standard protocols, they

are qualitative classiications and are relatively insensitive or tracking

changes in the location and extent o macular lesions over time. A quan-

titative grading system is needed, which could be adapted to computer-

based grading or scoring disease progression rom early to late stages.Standard deinitions or the earliest stages o AMD are needed, coupled

with detection methods that make application o the deinitions easible

and practical in population studies. The easibility o using newer detec-

tion and monitoring technologies, such as optical coherence tomography

or autoluorescent imaging, should be evaluated.

n the United States, ederal unding agencies should support and

work with representative bodies rom the clinical and research commu-nities to produce newer grading standards that could be implemented

as computer-assisted approaches or scoring severity and progression

or AMD and other complex ocular diseases. The standards should be

widely circulated and readily accessible. For example, they should be

available on the public nternet website o the National ye nstitute.

6. An economic plan or progress in cost-eective treatment (a roadmap to a cure)should be constructed or each o the major eye diseases considered in this report.

The symposium participants agreed that having an economic plan or

making progress in cost-eective treatment was essential or the major,


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complex eye diseases discussed at the Drabkin Symposium. The com-

plexity o each disease is too great to expect a magic bullet or easy

solution to emerge rom an undirected process. The aim o this planning

or roadmapping approach should be to enhance public health. t should

also ocus research and clinical intervention programs on the most

eective prevention and treatment options or a diverse U.S. population,

including targeted delivery to higher-risk groups. The economic roadmap

to a cure or a given disease should show the expected societal beneit

rom proposed studies or treatment approaches. The beneits should be

suicient to justiy the cost o those studies, including the clinical trials

necessary to demonstrate treatment proo o principle, saety, and eicacy.

7. For all the diseases considered in this symposium, prevention or delay o disease

progression should be a priority or research and clinical management. An

emphasis or uture treatments, once a disease condition is present, should be on

delivering the active agent to the target site.

The irst priority or eye health care must be on primary prevention o

the disease processor example, prevention o diabetes on a systemic

level. The second line o eye care treatment or disease conditions, such

as diabetes, that have systemic origins and systemic treatment regimens,

is prevention o ocular maniestations o the disease, such as diabetic ret-

inopathy. As an example, normalization o blood glucose levels can slow

or halt diabetic retinopathy (secondary prevention), as well as other con-sequences o the underlying diabetic condition. nce a disease condition

is present in the eye itsel, eicient and eective delivery o an active

agent to the ocular target should be the preerred third line o treatment.

n the case o diabetic retinopathy, this might be intravitreal injection o

agents that prevent bleeding (tertiary level o prevention).

For glaucoma treatment strategies ocusing on preventing the per-

manent loss o retinal ganglion cells (neuroprotection and neural rescuestrategies), as well as or other diseases o the retina and choroid, conclu-

sion 7 means delivering therapeutic agent to the back o the eye. ven

more precisely, the active agent should be targeted to speciic tissues and

cell types in the posterior segment o the eye. With respect to diabetes,


31/194


medical research should continue to target the local mechanisms that

make ocular tissues such as the retina so susceptible to diabetic damage,

as well as continuing the search or improved treatment o developing

or progressive diabetic retinopathy. For glaucoma, this principle should

be applied to mechanical (e.g., surgical), biological, and pharmacological

interventions. Fundamental disease mechanisms, such as inlammation

and neovascularization, may be more successully targeted locally (at the

site o ocular damage), rather than systemically. The symposium presen-

tations and discussions included numerous examples o this principle or

a range o treatment prospects: pharmacological and biological suppres-

sion or blocking o vascular endothelial growth actor (VGF), suppres-

sion o retinal neovascularization with agents such as pigment epithe-

lium-derived actor (PDF), antioxidants to reduce oxidative damage in

retinal tissue, neuroprotectants, laser treatment o vascularization on the

retinal surace, treatments combining laser photocoagulation with anti-

neovascularization drugs, and drug combinations (drug cocktails).

Public Education and Outreach

This Drabkin Symposium, like the three preceding it, sought ways to

improve the transition o research results into positive consequences or

patients and those at risk or developing a complex ocular disease. The

participants attention to the interplay o environmental and cultural

actors in these complex diseases led to three general action-orientedconclusions on improving public education and outreach. The sympo-

sium conclusions or individual eye diseases extend and elaborate on the

crosscutting actions recommended here.

8. Increased support is warranted or research into public outreach on eye health

that is tailored or diverse populations. Support or public health education

on eye care has a high ratio o societal beneit to cost. Improving the eectivedelivery o known prevention and treatment strategies, particularly to

underserved populations at increased risk, is likely to increase the returns or

society, measured in the economic value o health beneits to both individuals

and the public good.


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The complex eye diseases considered at this symposium develop over

time. Their progressionand in some cases their onsetoten depends

on risk actors that can be managed, i not absolutely controlled. For the

more common orms o glaucoma, patient involvement in lowering intra-

ocular pressure is the oundation o current treatment strategy, short

o surgery. For diabetic retinopathy, maintenance o blood sugar levels

within a near-normal range appears to be eective in slowing or halt-

ing onset and progression. ultural and socioeconomic actors related

to excessivenear workthat is, extended periods o visual ocus at dis-

tances typical o reading or benchworkduring childhood are suspected

in the development o myopia and, in particular, the relatively high

prevalence o high myopia in ast Asian populations o hinese ances-

try. hanging these environmental actors to avoid extended periods o

near work or young children may be necessary to deal with this disease.

Smoking is a well-established environmental risk actor or AMD.

However, a vast gap exists between the medical proessions under-

standing o manageable risk actors and the application o that knowl-

edge to eective patient care. Best practices or getting treatment knowl-

edge into the hands o patients at risk must be identiied and properly

applied or all population groups. n particular, outreach to groups at

heightened risk will be essential to educate them about the risks and

what they can do to reduce them. eective, such outreach can pro-

duce substantial societal beneits, in addition to aiding individuals at

risk. The beneits o eective public education will endure even i the

most promising o new therapeutic concepts prove successul beyond

expectation. n act, several participants at the symposium surmised

that the practical value o putting all that we now know into eective

health care regimens, maintained by patient and care provider work-

ing together, would have greater societal beneit at lower cost than

can be expected rom any new biomedical breakthroughs in treatment.Whether or not this surmise is literally true, it underscores the substan-

tial beneits still unreaped rom past advances in medical knowledge.

ective public education and outreach must be included in the road-

maps to a cure advocated by conclusion 6.


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9. A coordinated approach is essential to public education about disease prevention

strategies. Public health education should be coordinated or all diseases, not

just those o the eye. This coordinated approach should include messages and

outreach activities speciically tailored or population groups that are not yet

being eectively treated.

To the participants in this symposium, the most eective way to reap the

societal beneits rom public education about the major eye diseases is

to communicate an integrated and consistent message. This basic message

to the public should not be about any one disease or even just about eyediseases collectively. The message should begin with the responsibility

that each individual has to sel and loved ones to learn about disease

risks and make the eort to manage them. Beyond this uniying theme,

however, the message must target detailed, practical inormation to those

who need it. normation on risk actors and the relative risks o speciic

population groups must be tailored to reach those groups. The participants

discussed the diiculty o eective public outreach and education, evenor a condition as common and debilitating as type diabetes. There have

been many attempts and only limited successes in substantially improving

compliance rates. ne suggestion was to convene groups o health econo-

mists and others with practical and specialist knowledge to pinpoint eec-

tive practices or improving public health inormation delivery. Another

was to compile lessons learned about how to do eective public out-

reachand about what does not workeither in the general populationor in speciic groups. Since the time o the irst warning rom the U.S.

Surgeon General, anti-smoking campaigns provide a case study worth

exploring or both successes and obstacles in educating the public. Heart

disease, hypertension, and cholesterol are other public health issues that

should be studied or lessons on eective public education.

The symposium discussions o ways to improve patient compliance

with risk management regimens raised several associated issues. Arethere policy changes that could improve compliance? What changes to

preerred practice guidelinessuch as the preerred practice patterns

o the American Academy o phthalmologyare needed to improve

compliance? How do socioeconomic and cultural actors inluence com-


34/194


pliance with treatment regimens in groups at increased risk rom diseases

such as glaucoma or diabetic retinopathy?

Rather than attempting to guess at answers to these large questions,

the symposium participants agreed that systematic, concerted eorts

should be directed to identiying and substantiating practical responses

to them. ne suggestion was to mine the data rom recent and ongoing

studies o diabetic retinopathy, including those unded by the National

ye nstitute, or evidence o practical improvements in public outreach

that could be incorporated into government policies and programs at all

levels (e.g., ederal, state, and local within the United States). Another

suggestion was that voluntary organizations at the community level,

championed by an acknowledged community leader, may be more eec-

tive in reaching disadvantaged groups than the usual top-down public

education programs. A third suggestion was that the search or better

practices in public outreach should explicitly call attention to barriers to

compliance and seek the most eective ways to overcome them.

10. Training or eye care proessionals should refect the growing diversity o the

U.S. population. A cost-eective way to combine this training with the need or

research on diverse populations is to oster the international exchange o U.S.-

based and oreign-based eye care proessionals.

n addition to public education about risk actors, the symposium par-

ticipants agreed that eye care proessionals need more training in treat-ing a diverse population. The increasing diversity o the U.S. population

means that education about group dierences in ocular disease charac-

teristics and risks must be included in the continuing education o oph-

thalmologists. The rapid annual growth in new knowledge that medical

proessionals must assimilate is orcing a transormation at all levels o

medical education. Through proessional training at all stages in a phy-

sicians career, sensitivity o health care proessionals to diversity in theirpatient population can be enhanced, while also improving their skills

in communicating with this diverse population. n this area, the United

States can learn rom the best practices o others, as well as contributing

to improved health care worldwide.


35/194


xchange programs through which U.S. and oreign-based proes-

sionals can observe directly and participate in the practice o caring or

a dierent population than they normally see in their home practices

provide opportunities that beneit both the home and host countries.

For American doctors, on-the-job training in a country where a particu-

lar disease is more prevalent than in their home practice, or presents in

orms they do not oten see, can sharpen diagnostic expertise and stimu-

late improvements in disease management. Working within the United

States with a oreign specialist very amiliar with a disease rare in the

United States (such as PV) and its treatment provides similar training

and stimulation. The oreign-based proessional visiting in the United

States gains exposure to dierent practice patterns, new techniques, and

probably a dierent population than she or he treats at home. verall,

recognition o the challenges presented by population diversity globally,

as well as within the United States, led the symposium participants to

avor support or worldwide practice patterns and guidelines, covering

a core o knowledge and skills. vidence-based practice incorporatingthese principles can be disseminated through guidelines and practice

patterns developed by health care proessionals. nnovative distance

learning opportunities to disseminate these tools or proessional educa-

tion should be encouraged.

Another advantage o exchange programs or the American partici-

pants is the direct experience it provides in being sensitive to cultural,

ethnic, and language dierences, as well as broader exposure to age andgender as actors in patient diversity. nhancing ethnic diversity among

eye care proessionals also can contribute to greater sensitivity to popula-

tion dierences. The symposium participants also saw a need to increase

the public health component o medical training in the United States,

as part o an even broader need to ocus on prevention as a more cost-

eective alternative to treating a disease only ater it presents in health-

threatening conditions. Alternative educational experiences, includinginteractive training delivered over the nternet, are an option or tack-

ling the challenge o diagnosing and treating special population groups

within the United States, particularly when those groups may present

with eye disease inrequently seen by most American physicians.


36/194


mplementation actions in response to conclusion 1 can build on

scientiic and clinical exchanges that have already occurred or are in

progress. For example, at the time o this Drabkin Symposium in June

5, the Ministry o Science and Technology o the Republic o ndia

and the U.S. Department o Health and Human Services were close to

inal approval o an agreement on ndo-U.S. ollaboration in Vision

Research. The agreement, which will oster collaboration in various

ields o biomedical and clinical research, grew out o workshops on U.S.-

ndo ollaborative ye Research held in three cities in ndia (Hyder-

abad, hennai, and Madurai). The workshops were conducted by theAssociation or Research in Vision and phthalmology and unded by a

grant rom the National ye nstitute

Conclusions on Individual Eye Diseases

Glaucoma

The key points and recommendations on glaucoma that were discussed

in both the summary session o the Drabkin Symposium and the glaucoma

session on the irst day are presented here in relation to three broad con-

clusions. onclusion 11 addresses population issues; conclusion 1 per-

tains to medical research and pathophysiology; and conclusion 13 suggests

directions or improving early diagnosis, prevention, and treatment.

11. Research is needed into eective methods or identiication o glaucoma in

high-risk populations. As the U.S. population ages, early diagnosis o all orms o

glaucoma will help to preserve vision. Treatments such as medical and surgical

options to lower IOP are available or most orms o glaucoma, i the disease

process is identiied and treated early enough.

Worldwide, glaucoma is a leading cause o irreversible vision loss. The

epidemiology o glaucoma, especially open angle glaucoma, has beenthoroughly explored in many adult populations o uropean ancestry.

Despite variations in diagnostic criteria, glaucoma prevalence in these

study populations is about percent or adults above age . By com-

parison, persons o Arican ancestry may have as much as ive times that


37/194


risk. The risk or Hispanic populations is also greater than that observed

in populations o predominantly uropean ancestry. The data are inad-

equate to estimate risk in Asian Americans.

Although accurate and universally accepted deinitions have yet to

be established or the types o glaucoma, the orms generally recognized

as chronic angle closure glaucoma and intermittent acute angle closure glau-

coma are particularly underdiagnosed and understudied in the United

States. To assess the prevalence o these orms, studies are needed that

use consistent deinitions, accurate classiication o population groups,

and adequate sample sizes. Because glaucoma appears to have a geneticcomponent, accurate classiication o a study population will require

addressing the issues, highlighted in conclusion 3, about disease pheno-

types and genotypes.

Glaucoma is the second most common cause o irreversible vision

loss in the United States and the most common cause among Arican

Americans. The most common orm o glaucoma in the United States is

primary open angle glaucoma (PAG). Because the limited data avail-able show a much higher prevalence o glaucoma among Arican Ameri-

cans than among uropean Americans, and indicate a higher prevalence

among Hispanic Americans as well, uture glaucoma trials in the United

States must include suicient representation rom these groups to pro-

vide statistical signiicance or group-speciic results.

Angle closure glaucoma is more common in many Asian populations

than in populations o predominantly uropean or Arican ancestry.AG prevalence rates o 1 to percent have been ound in some ast

Asian populations. Rates or all orms o glaucoma in uropean Ameri-

can populations are about 1 percent or ages less than 6 years, and

perhaps 1 percent o these (roughly .1 percent overall) may be AG.

Nonetheless, PAG is probably the most common orm o glaucoma in

Asia except in Mongolia. Generally accepted risk actors or glaucoma

include:

P (the major risk actor),

Age,

A irst-order blood relative with glaucoma,

entral corneal thickness,


38/194


Diabetes mellitus (a particular concern or Hispanics, given the

high prevalence o type diabetes in this group),

High blood pressure, and

Reractive error (with qualiications: the association is clear or

high myopiareractive error greater than 6 dioptersless clear

or 36 diopters o myopia; hyperopia has been associated with

AG).

For open angle glaucoma in populations o uropean ancestry, no

dierence in risk by gender has been generally established. (However,

the Rotterdam ye Study has ound that glaucoma in that study popula-

tion has a higher prevalence in men than women [5].) AG, by con-

trast, appears more prevalent in Asian women than Asian men. For all

populations studied, glaucoma prevalence increases with age. For popula-

tions at increased risk, the age eect is dramatic. Prevalence in Arican

Americans at 6569 years o age rises to 6 percent or women and 8 per-

cent or men, rom rates o less than percent or either gender at 9

years o age.

12. A better understanding is needed o the dierences in glaucoma pathophysiology

within and between population groups. Mechanisms may dier within and

between population groups deined by customary demographic or cultural

criteria.

No explanations have been conirmed or the observed dierencesamong Arican, Hispanic, and uropean Americans. ultural and envi-

ronmental actors could be involved, as well as currently unknown

genetic actors. Given the range o orms o glaucoma, another consid-

eration is that there are likely to be multiple pathways or mechanisms

that lead to damage to the optic nerve head, the deining characteristic

o visual impairment rom glaucoma. Dierent pathways may predomi-

nate in dierent populations or groups. For example, although currentdata show glaucoma to be more prevalent among Arican Americans

than among uropean Americans, are the causal actors and disease

progression homogeneous across subgroups whose ancestors came rom

dierent regions within Arica? Some evidence exists that glaucoma in


39/194


aribbean groups o Arican descent diers in prevalence and perhaps

other characteristics rom glaucoma in urban Americans o Arican

ancestry. these dierences are substantiated, will they relect underly-

ing genetic dierences, divergent environmental/cultural dierences, or

some combination?

For these and other reasons (such as eective treatment or nor-

mal pressure glaucoma, as well as better treatment options or advanc-

ing PAG), the mechanisms o glaucoma must be understood ar bet-

ter than at present. Among the mechanisms o this complex amily o

related disease orms that should be better explored are the ollowing:

Optic neuropathy of glaucoma. What are the relationships

among disc cupping, changes in the nerve iber layer, and visual

ield deects?

Retinal ganglion cell death. What is the biochemical cascade

leading to apoptosis? s the ganglion cell axon or the cell body the

target o the mechanism that initiates cell death?

Dependence of glaucoma optic neuropathy on elevated

IOP and the evidence for elevated IOP as a continuous and

causal risk factor. Why does reduction o P slow progression

o optical neuropathy at all P levels? s P elevation always

caused by outlow abnormalities (e.g., increased resistance to low

through the trabecular meshwork), rather than excess ormation

o aqueous humor?

Angle closure glaucoma: s this a disease pathology o smaller

eyes? Do abnormalities o unction in the anterior portion o the

eye play a role?

For some aspects o this research, animal models are extremely valu-

able or testing intervention hypotheses. The results rom studies using

these animal models provide important clues to pathophysiology and

candidate therapeutic approaches.

13. Opportunities exist or improved glaucoma treatments in the uture, but stronger

support is needed to bridge the gaps in research necessary to develop and test

them.


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As discussed under conclusion 11, some o the gaps in what we know

about glaucoma are particularly glaring when population diversity is con-

sidered. , as current data suggest, speciic groups have ar higher sus-

ceptibility to glaucoma (or to dierent orms o glaucoma) than does the

American population in general, then dierent emphases in diagnosis,

prevention, and treatment may be necessary.

From a public health perspective, earlier diagnosis o glaucoma and

its precursor conditions is more cost-eective (and reduces the risk o

visual impairment), compared with later diagnosis. The current screen-

ing approach is to monitor or elevated P. a patient has elevated P,

a hierarchy o treatment options aimed at reducing P is brought to

bear: P-lowering medications, laser trabeculoplasty, incisional surgery

including drainage shunts, and cyclophotocoagulation. This hierarchy

o treatment applies once it is established that a person has the disease,

even i P is not elevated. ncreased P is not the disease; glaucoma

is an optic neuropathy. Newer approaches in development or reducing

P include mending the trabecular pathway at the histologic level toincrease outlow (or example, with agents that relax the cytoskeleton o

cells orming the meshwork) or increasing outlow through the alterna-

tive uveoscleral pathway (or example, by targeting biochemical path-

ways such as the regulation by prostaglandinmatrix metalloproteinases

o low through the uveoscleral matrix). Another approach under study

is to provide continuous monitoring o P as the basis or more eec-

tively avoiding luctuations in P as a glaucoma risk actor.Another broad area o opportunity or new preventive and thera-

peutic approaches includes neuroprotection, neural rescue, or neural

regeneration to combat the visual impairment mechanisms in the poste-

rior region o the eye. n some novel neuroprotection approaches being

studied, the axon, rather than the cell body, o retinal ganglion cells

is the target or protection. n others, the protective strategy ocuses

on laminar glial cells, which normally eed and sustain the retinal gan-glion cells. For each o these targets or protection, there are multiple

biochemical molecules that are potential candidates or medical inter-

ventions. The local circulation or the cells in the optic nerve head is

another route being studied or protection and rescue o nerve cells.


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Among the neural regeneration approaches to treatment o advanced

glaucoma, changes in the central nervous system rom glaucoma are

under study. Research on stem cell therapy or glaucoma has the aim o

replacing lost retinal ganglion cells or other cells in the optic nerve head.

Because o the speciic type o cell lost in glaucoma (retinal ganglion

cells), this replacement strategy has a good chance o succeeding, even

though research is now at an early stage.

At present, gene therapy approaches under consideration or treat-

ing glaucoma aim at altering a target cell to do something physiologically

useul in blocking or ameliorating glaucoma-related eects, not at cor-

recting a deect in a single gene. An example o this potential approach

is gene-based pharmaceutical therapy, through which a gene or a pro-

tein regulator o neural unction (a neurotrophic agent) could be sup-

plied to cells within the eye such as retinal ganglion cells. The premise

o this approach is that increasing the supply o the neurotrophic agent

will increase the survival rate o retinal ganglion cells, slowing the loss

o visual unction. For neuroprotection and gene therapy approaches to

glaucoma, which are also still in the early research stage, a major objec-

tive is delivering the drug or active agent to the target site in the rear o

the eye, as noted in conclusion 7.

Technology and techniques to aid in understanding and monitor-

ing the physiopathology o glaucoma provide another area o active

and promising research. Visualization o retinal ganglion cell death in

a patient (in vivo visualization) would allow this aspect o glaucoma

neuropathy to be ollowed directly in patients. For structural imag-

ing and unctional testing o the anterior chamber to understand the

mechanisms o P elevation and control, in vivo visualization could

be applied to the cellular ultrastructure o the trabecular meshwork and

related histologic eatures. These visualization techniques may in the

uture aid in inding better unctional tests or signs o early indicationso glaucoma. Another application or visualization technologies, particu-

larly germane to this report, is or research on the physiological and bio-

chemical causes o the dierences in response to a particular therapeutic

approach or diverse patient populations.


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Thus, there are many solid opportunities or uture improvements

in both the diagnosis and treatment o glaucoma, which could be incor-

porated into public health programs or early detection o ocular dis-

ease and prevention o blindness. ncreased support or any number o

these promising prospects will greatly increase the likelihood o urther

improvements in treatment.

Diabetic Retinopathy

Diabetic retinopathy is the leading cause o poor vision in young adults.

The causes are complex, but the risk is directly proportional to controlo blood sugar and, to a lesser extent, blood pressure. The recommen-

dations and essential points identiied during the Drabkin Symposium

discussions on diabetic retinopathy are presented here under three con-

clusions: conclusion 1 on the primacy o prevention, conclusion 15

on population issues, and conclusion 16 on the challenges in sustaining

patient compliance with long-term regimens to reduce the risk o onset

or progression o diabetic retinopathy and other consequences o uncon-

trolled diabetes (e.g., corneal involvement).

14. Prevention is the most important strategy or dealing with diabetic retinopathy.

The principal prevention goal is to maintain normal, or at least near-normal,

glycemic levels. Other prevention goals include maintaining normal blood

pressure and serum lipid levels.

onclusion 1 represents the application o conclusion 7 to the speciiccase o diabetic retinopathy. For this ocular disease,primary preven-

tion would be prevention o the diabetic condition at a systemic level.

For type diabetes, public education programs that encourage healthy

dietary and liestyle choices beore the disease occurs are primary pre-

vention strategies. Secondary prevention strategies aim to prevent the

ocular maniestations o diabetes, once the underlying systemic disease

condition is present. The principal secondary prevention strategy or dia-betic retinopathy is to maintain glycemic levels within the near-normal

range. Maintaining blood pressure and serum lipid levels within normal

ranges appears to aid in preventing or slowing the development o reti-

nopathy. Tertiary prevention is last-resort treatment o the serious ocular


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maniestations, such as neovascularization, to prevent blindness or unc-

tional vision loss.

Public education and outreach are essential actors or the needed

improvement in preventing diabetic retinopathy through maintenance

o near-normal glycemic levels and, to a lesser extent, normalizing blood

pressure. As discussed under conclusion 9, the symposium participants

agreed that a coordinated public education campaign should address

health risks collectively. The risks, including diabetic retinopathy associ-

ated with type diabetes, the liestyle ri

Eye Disease Diverse Populations Final 3-08-06

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