AHISTORYOFDIABETICRETINOPATHY:ANOBSCUREENTITYBECOMESAN

INTERNATIONALPUBLICHEALTHDILEMMA

byCharlesPattonWilkinson,MD

AthesissubmittedtoJohnsHopkinsUniversityinconformitywiththerequirementsfortheDegreeofMasterofArts

Baltimore,MarylandFebruary,2020

©2020CharlesP.Wilkinson

AllRightsReserved

ii

Abstract

Diabeticretinopathyisadisorderthatwasunknownuntilthelate19thcenturyand

thatdidnotbecomeimportantuntilatleastthe1940’s.Thisstudydescribesthe

disorder’shistoryandprovidessupportforthethesisthatmostoftheworld’s

healthcaresystemshaverespondedinadequatelytothesubsequentepidemicsof

diabeticretinopathyanditscause,diabetesmellitus,particularlyinviewofthewell

documentedavailabilityofevidence-basedmanagementstrategiesthathavebeen

developedoverdecades.Theglobaldistributionofhealthcaresystemstocombat

thesedisordersisexceptionallylimited,andalthoughcontemporaryexemplary

plansareavailableinmostcornersoftheworld,theyarelimitedinthepercentages

ofpopulationsthatcanbeappropriatelymanaged.Ingeneral,optimalsystemsare

availableonlyinenvironmentscontainingsophisticatedequipmentandpersonnel

inwhichonlypatientswithappropriatemedicalinsuranceorfundingaremanaged.

Manycaregiversremainunabletoprovideexemplarysupportbecauseof

inadequateaccesstopatients,funding,oreducation,andfewpatientsaregenuinely

compliantinmanagingtheirdiabetes.Eachofthesefactorsisamplifiedinregionsof

relativepovertyandpoorhygiene.Itcurrentlyappearsthatmostoftheworld’s

diabeticpatientswithretinopathywillremainunderserved.

PrimaryReaderandAdvisor:GrahamMooney

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Contents

Abstractii

Contentsiii

ListofFiguresv

1.Introduction1

2. Adescriptionofdiabeticretinopathyandareviewofitscause8

2.1Diabeticretinopathyinanutshell8

2.2Diabetesmellitus10

2.2.1Thepre-insulinera11

2.2.1Theintroductionofinsulin13

2.2.2Glucosecontrolandtheproblemofmedicalcomplications14

3.Theepidemiologicalburdenofdiabetesandretinopathy19

3.1 Theimpactofsocialdeterminantsofhealthupondiabetesmellitus28

4.DiabeticRetinopathy:recognitionandmanagement31

4.1Thediagnosisofdiabeticretinopathy31

4.2 Earlytreatmentofdiabeticretinopathy35

4.3Developmentoftheevidencebasefortreatmentofdiabeticretinopathy44

5.Developmentofhealthcaresystemsformanagementofretinopathy54

5.1RetinopathycareinEngland61

5.2RetinopathycareintheUnitedStates 64

5.3RetinopathycareinIndia70

5.4Observationsregardinginternationalhealthcaresystems74

6.Conclusions84

iv

TableofContents(Continued)

CurriculumVitae89

v

ListofFigures

1.DiagramoftheHelmholtzOphthalmoscope

2.TheDiabeticRetinopathyStudy:Initialoutcomesfortreatmentofseverediabetic

retinopathy

1

Chapter1.

Introduction

Diabeticretinopathy(DR),amajorandgrowingcauseofimpairedvision

worldwide,waslargelyunknowntoeyespecialistsuntilwellintothe20thcentury

becauseidentificationandsubsequentawarenessofthedisorderrequiredits

appearanceasaclinicalentity,thedevelopmentofrelevantdiagnosticequipment,

andthetrainingofappropriatecaregivers.Priortoinsulin’sintroductioninto

clinicalpracticeinthe1920’s,diabeticpatientsalmostneverlivedsufficientlylong

tolosevisionfromDR,sotherewasnoneedtoidentifyitasasignificantdisorderor

todeveloprelevantteachinginstitutions,specialistclinicians,andtherapeutic

strategiestocombatit.Butaspatientswithdiabeteslivedlonger,andtheirnumbers

grewprecipitously,microvascularcomplicationsofthissystemicdisease

(retinopathy,nephropathy,andneuropathy)assumedepidemicproportionsinall

partsoftheworld.

Inthisthesis,IconcentrateuponahistoryofDRanditsbecomingrecognized

asanimportantentity,anduponthemedicalandsocietalresponsesthatfollowed.I

emphasizethatthedisorderwasgenerallyunappreciatedasapotentialpublic

healthproblemuntilatleastthemid-1930’sandthatreactionstoitsbecomingso

havebeensignificantlydelayedforadditionaldecadesinmostpartsoftheworldby

failuresofnationalandinternationalhealthcaresystemsindevelopingoptimal

measurestopreventorretardboththesystemicdiseaseandthisocular

2

complication.1Asatraineeinthelate1960’sandthenapractitionerintheretina

subspecialtyofophthalmology,IwitnessedheateddebatesaboutDRtherapy.

Blindnesswasgenuinelyunpreventableinmanycases,2andthesituationwas

sufficientlydismalthatalongwithcontemporarytherapeuticstrategiesmentioned

below,abortionsfornewlypregnantdiabeticpatientswithretinopathywere

sometimesrecommendedtopreventitsprogressiontoblindness.3

Hypophysectomieswithsurgeryorirradiationwerealsowidelyaccepted

therapeuticalternatives.Athoroughaccuratenarrativeregardingboththeearly

historyofDRandthestepsthatleadtocurrentmanagementstrategiesisneededto

exploreboththeadequateandinsufficientstatesofcarethatexistinmostcountries

today.Thishistoryisintendedtoprovidereaderswithinformationthattheyneedto

knowaboutthepast.4Thisstoryofdiabeticretinopathycanserveasametaphorfor

avarietyofadditionaldiabetes-relatedchronicdiseasesthatimpactmillionsof

patientsaroundtheworld.

HistorianKeithWailoohasstated“onecanthinkoftwentieth-century

specialtiesasbeingorganizedaroundoneoffourprimaryfeatures-tools,patients,

organs,ordiseases.”5ThecontemporaryspecialtyofDR-relatedophthalmology

1DiIorioDT,CarincIF,BenedettiMM.Thediabeteschallenge:Fromhumanandsocialrightstothe2Afamousophthalmichistorian,SirStewartDuke-Elder,wrotein1967“Diabeticretinopathyisoneofthemajortragediesofophthalmologyinourpresentgeneration;alwayscommonandrapidlybecomingstillmorecommon,affectingtheyoungaswellastheaged,predictablebutnotpreventableandrelativelyuntreatable,chronicandprogressiveinitscourseandleadingtoblindnessinadistressingpercentageofcases.”(Duke-ElderS,DobreeJH.SystemofOphthalmology:Volume10.DiseasesoftheRetina.1967,St.Louis,C.V.Mosby,p.410)3ReportbyB.M.A.Committeeontherapeuticabortion.Indicationsforterminationofpregnancy.BritMedJ1968;1:171-5.4MazaSC.ThinkingAboutHistory.2017,Chicago,UniversityofChicagoPress,p.6.5WailooK.Notestopages9-12,inWailooK.DrawingBlood.TechnologyandDiseaseIdentityinTwentieth-CenturyAmerica.Baltimore,TheJohnsHopkinsUniversityPress,1997,p.204.

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encompassesallfourofthesevariables:theevolutionofdiagnosticandtherapeutic

toolshavebeencriticalinthemanagementofpatientswiththediseases,diabetes

mellitus(DM)andDR;althoughDR,diabeticnephropathy,diabeticneuropathy,and

variouscardiacproblemsareallcomplicationsofDM,Iconcentrateontheorganas

theeye.6

Priortothedevelopmentofthosecriticaltools,thepre-20thcenturyspecialty

ofophthalmologywasrelativelyprimitive.7Although ocular therapy including

oculoplastic and cataract surgery had existed for millennia, treatment was primarily

confined to disorders of the outer eye; and non-physicians treated most ocular problems

in a variety of ways in evolving fashions.8,9 Thebirthofamorespecificspecialtywas

initiallysparkedbythereappearanceofChlamydiatrachomatis,anorganism

subsequentlydesignatedas“trachoma”.Thiswasknownasasourceofexternaleye

infectioninancientsocietiesofChina,Egypt,andGreece,anditstimulatedthe

establishmentofophthalmologyinthewesternworld.10,11(Still,andconsistentwith

“retrospectivediagnoses”,12itshouldbenotedthatsomecasesof“Egyptian

6Thedisease,DMdatestoantiquity,buttheorganbecameinvolvedwithDRonlyafteraffectedpatientslivedformanyyears,whereastoolstodetectDRdevelopedlater.7Ophthalmoscope(1851),slitlamp(1911),diagnostic3-morrorcontactlens(1948)8Cataractsurgerywasliterallyintraocularandperformed(“couched”)withasingleneedlestabincisionintotheeyeposteriortotheiris.9HubbellAA.TheDevelopmentofOphthalmologyinAmerica,1800-1870.Chicago,AMAPress1908:18-27.10DavidsonL.Identitiesascertained:Britishophthalmologyinthefirsthalfofthe19thcentury.SocHistMed1996;9(3):313-33.11FeibelL.JohnVetchandtheEgyptianophthalmia.SurvOphthalmol1983;28(2):128-34.12MitchellPD.Retrospectivediagnosisandtheuseofhistoricaltextsforinvestigatingdiseaseinthepast.IntJofPaleopath2011;1:81–8.

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ophthalmia”wereapparentlyduetoHemophilusaegypticus,Neisseriagonorrheae,

andadenoviruses.13)

TheEgyptiancampaignoftheNapoleonicwarendedtemporarilyin1802,

andbythenasubstantialpercentageofreturningsoldiershaddevelopedtrachoma,

adisordercharacterizedbyacuteinflammationoftheexternaleyeandeyelids

followedbyeyelidmalfunctionandsecondarycornealscarringleadingto

permanentlossesofvision.Althoughmilitaryhospitalshadbeenestablished

specificallyforinfectedpatientsaswellasforeyetrauma,theincidenceofthe

formercontagiousproblemgrewprofoundly,magnifiedbythecrowdingofthe

ever-enlargingimmigrantpopulationsthathadmovedintolivingconditionsdevoid

ofadequatehygiene.Theneedforadditionalstudyofoculardisordersstimulated

theestablishmentofacademiccentersdevotedtoeyecare.Previously,

ophthalmologyhadbeenregardedas“anuncoordinatedoffshootofsurgery,largely

peddledbyillegitimatepractitionersandquacks,anditwasforthefirsttimegiven

thedignityofanacademicspecialtyandsciencewiththeAustrianroyalty’s

establishmentoftheworld’sfirstChairinOphthalmologyinViennain1812”.14,15

Workingindependentlybutinfluencedbytheepidemicof“ophthalmia”,John

SaundersestablishedandopenedaneyedepartmentastheLondonDispensaryfor

12WagemansM,VanBijsterveldOP.TheFrenchEgyptiancampaignanditseffectsuponophthalmology.DocOphthalmologica1988;68:135-44.14Duke-ElderS.MoorfieldsandBritishophthalmology.LangLecture.ProcRoySocMed1965;58(7):541-5.15ThisfirstChairwasestablishedafterGeorgJosephBeer,the“fatheroftheViennaOphthalmologicalschool”,whohadby1806demonstratedthatophthalmologyshouldbeconsideredasalegitimatespecialtywithinthehouseofmedicine(LeskyE.TheViennaMedicalSchoolofthe19thCenturyBaltimore,TheJohnsHopkinsPress,1976,60-1.

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CuringDiseasesoftheEye(laternamedMoorfieldsEyeHospital)in1805.16

Americanphysiciansstudyingatthelatterinstitutionineffortstoimprovetheir

self-describedminimalknowledgeofoculardisordersreturnedin1820toestablish

thefirstcharityeyehospitalintheU.S.tobecomealastinginstitution,17theNew

YorkEyeandEarInfirmary(NEEI).Otherearlyandenduringophthalmology

centersincludedtheMassachusettsEyeandEarInfirmaryinBoston,alsofounded

byLondonalumniandfoundedin1824;andPhiladelphia’sWillseyeHospital,

establishedin1834.18,19TheseVienna,London,andAmericaneyeinstituteswereall

initiallyfoundedascharityclinicsfundedbyphilanthropicindividualsinthe

respectivecitiestotreatindigentpatients,althoughtheirophthalmologistswere

alsoabletoestablishprivatepracticeswithhopesofsignificantremunerations.

Globally,London-trainedphysiciansestablishedtheRegionalInstituteof

OphthalmologyandGovernmentOphthalmicHospitalinMadras(nowChennai),

India,in1819.20ThefirstAmericanophthalmologytextbookwaspublishedin1823

andauthoredbyBaltimoreanGeorgeFrick,whoreceivedspecialtytrainingin

ViennaaftergraduatingfrommedicalschoolinPhiladelphiain1815.21Itofcourse

containednoreferencestoDR.

16CollinsET.TheHistoryandTraditionsoftheMoorfieldsEyeHospital.London,HKLewisandCo,1929,1-226.17TheliteralfirsteyeinfirmarywastheestablishedastheNewLondon(Connecticut)EyeInfirmarybyElishaNorthin1817,butitremainedinplaceonlyafewyears;similarly,twoshort-lastinginstitutionsinPhiladelphiawerefoundedin1821and1822(HubbellAA.TheDevelopmentofOphthalmologyinAmerica,1800-1870.Chicago,AMAPress,1908,16-27.18Ibid.19SnyderC.MassachusettsEyeandEarInfirmary.StudiesonitsHistory.Boston,MassachusettsEyeandEarInfirmary,1986,19.20Collins,Opcit.,36-7.21Hubbell,Op.cit.,96-8.

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Rosen22,Rosenberg23andothershavestressedthatmedicalspecialties

developinresponsetoscientificandtechnicalimprovementscoupledwith

contemporarysocialinfluencesandhumanneeds.Theimpactoftrachomaupona

substantialnumberofveteransreturningtocivilianlifewasacriticalfactorinthe

establishmentofophthalmologyasaspecialty,asnoted,andtheestablishmentof

eyehospitalsexpandedthenumberofstudentsandphysiciansinterestedinthe

profession.Butimportantly,managementoftrachomaandadditionalocular

disordersduringthefirsthalfofthe19thcenturycouldnotincludeevaluationsof

theeyes’interiors,anditwasnotuntiltheintroductionoftheinvaluabletoolthe

ophthalmoscopeinthemid-19thcenturythatagenuinelydistinctandnovel

comprehensiveeyespecialtywasestablished.24Andintheyearsthatfollowed,a

greatnumberof“new”oculardisorderssuchasretinaldetachmentsandretinal

venousobstructivedisorderswereidentified,althoughDRwasnotamongthe

earliestofspecificdiagnoses,duetotherealitythatitscommonappearance

requiredyearsofpatientslivingwiththesystemicdisease,andthisbecameof

practicalimportanceonlyaftertheintroductionofinsulin.

ThegrowthofDR-relatedvisionlossworldwidehasbeenfueledbythe

systemicdiseaseDM,theriseofwhichhasbeentheresultofcomplexsocialand

culturalfactors.Clearly,DRrepresents“…anoccasionandagendaforanongoing

discourseconcerningtherelationshipamongstatepolicy, medicalresponsibility,22RosenG.TheSpecializationofMedicinewithParticularReferencetoOphthalmology.NewYork,1944,FrobenPress,30-49.23RosenbergCE.TheCholeraYears:TheUnitedStatesin1832,1849and1866.Chicago:TheUniversityofChicagoPress,1962.Reprintedinpaperback,UniversityofChicago,PhoenixBooks,1968;seconded.withanewafterword.24Rosen,op.cit.,23-4.

7

andpersonalculpability”.25.Itisanexampleofthemultifactorialcriteriafor

“disease”articulatedbyRosenbergandGoldenintheirclassicbook,Framing

Disease.26

InthenextChapter,IprovideadescriptionofthepathophysiologyofDR

followedbyabriefhistoryofthediabetesmellitus,includingtheintroductionof

insulinandrecognitionoftheimportanceofserumglucosecontrol.InChapter3,I

discusstheepidemiologyofDMandDRandinChapter4,theevolutionof

techniquestodiagnoseDR,earlytherapeuticefforts,anddevelopmentofthe

evidencebaseforitscontemporarymanagement.InChapter5Ireportmorerecent

internationalrecognitionofDRasagrowinghealthcareissueandsubsequent

attemptstoestablishmanagementgoalsandalsorecountseffortsofspecificeye

careprogramstocombatDR-relatedvisionlossinIndiaandtheU.S.,comparing

themtomoreadvancedstrategiesavailableinEngland.27TheConclusion

emphasizestheimportanceofthecontemporaryevidencebaseregardingmeasures

topreventvisionlossfromDRandthestepsthatshouldbetakeninternationallyto

improvefuturecareforthisimportantdisorder.

25RosenbergCE.ExplainingEpidemicsandOtherStudiesintheHistoryofMedicine.Cambridge,CambridgeUniversityPress1992,p.317.26“Diseaseisatonceabiologicalevent,ageneration-specificrepertoireofverbalconstructsreflectingmedicine’sintellectualandinstitutionalhistory,anoccasionofandpotentiallegitimizationforpublicpolicy,anaspectofsocialroleandindividual–intrapsychic-identity,asanctionforculturalvalues,andastructuringelementindoctorandpatientinteractions”(RosenbergCE,GoldenJ(eds)FramingDisease.StudiesinCulturalHistory.1992,NewBrunswick,NJ,RutgersUniversityPresspxiii).27EnglandwasselectedasanexampleofacountrywithanadvancedDRmanagementsystem;theU.S.asacountryinwhichmostresearchonDRcarehasbeenconductedbutonewithafragmentedhealthcarenetwork;andIndiawaschosenasanexampleofahugelowerincomecountrycomparabletoChina(bothofwhichhaveevenmoredisconnectedhealthcarestructures)inwhichEnglishistheprimarylanguage.AppropriateresearchdataareavailableforallthreeEnglish-speakingcountries.

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Chapter2.

Adescriptionofdiabeticretinopathyandareviewofits

cause.

Ascientificdescriptionofretinopathyanditsresponsiblecause,diabetes

mellitus,isnecessaryforathoroughunderstandingofthisthesis.

Diabeticretinopathyinanutshell

DRisamicrovascularcomplicationofdiabetes,occurringintheeyes(with

similaralterationsinkidneysandseveralperipheralnerves).Theprecise

mechanismsleadingtoretinopathyareunclearandapparentlymultifactorial,but

thereisagreementthatsmall(25–100µm)roundredspotsobservedwithan

ophthalmoscopeandtermed“micro-aneurysms”areusuallythefirstclinicalsignof

thedisorder;theyaresmalloutpouchingsofthecapillarywallsintheposterior

retinalvasculature.Astheyincreaseinnumber,alterationsinthepermeabilityof

thecapillariesleadtoleakageofserumintotheinterstitialspacesandthickeningof

theretina,andthefocalareasofleakageareeasilydetectablewiththephotographic

techniquesofopticalcoherencetomography(OCT)andfluoresceinangiography

(thelatterinvolvesanintravenousinjectionofdyeandsubsequentphotography

employingappropriatefilters).Thislocalizedormorediffusethickeningdueto

leakageinthebackoftheeyeistermed“diabeticmacularedema”(DME),and

patientsdousuallynotrecognizeitssymptomsuntiltheswellinginvolvesthe

9

centralretinaor“macula”.Theretinalthickeningisfrequentlyassociatedwith“hard

exudates”whicharelocalizeddepositsofextracellularlipidandproteinmaterials

duetovascularleakage.DMEistodayresponsibleformostvisionlossindiabetic

patients,butitistypicallynotcatastrophicandrarelyinitselfleadstogenuine

blindness.AsDRprogresses,manyinvolvedcapillariesceasetocarryblood,a

processknownas“capillarydrop-out”or“vascularnon-perfusion”.Thiscausesfocal

areasofretinalischemiaandsignificantvisionlossifocclusionsinvolvethemacula.

Moreimportantly,retinalischemiacausesproductionof“vascular

endothelialgrowthfactors(VEGF)”andadditionalalterationsintheretinal

vasculature;theseinturnareassociatedwithbothincreasedpermeabilityofretinal

capillariesandthedevelopmentof“neovascularization”,thegrowthofabnormal

vesselsupontheinnersurfaceoftheretinaandontheopticnerve.Oncethese

becomevisible,“proliferativeDR”ispresent,andthesituationbecomesquite

ominous.DRpriortotheappearanceofneovascularizationistermed“non-

proliferativeDR”;oncenewvesselsareidentified,“proliferativeDR”becomesthe

properdiagnosis,anditfrequentlyisaccompaniedbyDMEaffectingthemacula.

Signsofnon-proliferativediseasealwaysprecedetheproliferativeform.

Thevitreousgelfillingtheeyespacebetweentheretinaandthelensisof

fundamentalimportanceasDRprogresses.Inlocationsinwhichneovascularization

develops,adhesionsbetweenthesevesselsandtheposteriorsurfaceofthevitreous

gelbecomemanifest,andwhenthevitreousgelsubsequently“contracts”(shrinks,

movinganteriorly),proliferativeDRentersamoreserious3-dimentionalphasein

whichtractionuponthevesselscausesbleedingintothevitreouscavity;andsimilar

10

tractionforcesupontheretinaleadtoretinaldetachment.Intravitrealhemorrhages

andretinaldetachmentsareresponsibleformostcasesofliteralblindnessdueto

DR.Astheretinopathyprogresses,collagenislaiddowninareasofvitreoretinal

adhesions,makingthemmuchmorevisibleas“fibrotic”areas,andthisstagewas

recognizedbyearlyobserverswhotermedtheentity“retinitisproliferans”.Both

non-proliferativeandproliferativeDRhavebeencategorizedwithevidence-based

standardizedclassificationschemesthatallowcomparisonsofnaturalhistorywith

varioustherapeuticefforts,andthesearediscussedlater.

ThebestmethodofpreventingDRremainsoptimalcontrolofDM,asnotedin

multicentercollaborativetrialstobediscussedlaterinthischapter.OnceDR

develops,proventherapiestopreventvisionlossfromDRhaveincludedattemptsat

preventionandreductionoreliminationofDMEandneovascularization.Blindness

fromDRcancurrentlybepreventedinasmanyas98%ofcasesifdetectedina

timelyfashion.28

Diabetesmellitus(DM)

ThefundamentalcauseofDRisofcourseDM.Individualaswellas

generalizedsocialfactorshaveplayedmajorrolesasdeterminantsofthesystemic

disease’scourse.Inthissection,Idescribeabriefhistoryofdiabetes,includingpre-

andpost-insulinerasandstudiesregardingtheimportanceofglucosecontrol.The

epidemiologyofthesystemicdiseaseamongvariousethnicandsocietalgroups,and

28FerrisFL.Howeffectivearetreatmentsfordiabeticretinopathy?JAMA1993;269(10):1290-1.

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theimportanceofsocialrealitiesasinfluentialfactorsregardingtheappearanceand

progressionofdiseasewillalsobediscussed.

SymptomsofDMwereknownformillennia,butthepathophysiologyofthe

diseaseandsuccessfulformsofmanagementrequiredstudiesthatextendedover

centuries.Oneofmedicine’smostimportanttriumphswastheidentificationand

productionofinsulin,anagentthatconvertedanaffectedpatient’santicipatedbrief

lifespanintothepossibilityofalongexistencewithameaningfulquality-of-life.But

priortothatachievement,thesystemicdiseasewaswellknownasasignificant

problemforboththoseafflictedandtheircaregivers.

Thepre-insulinera

UnlikeDR,DMhasalonghistorythathasbeenthoroughlydescribedby

manyauthors.Nwaneri,29Poulson,30andothers,notedthatthediseaseDMmay

havebeendocumentedbytheyear1550BC,asrevealedinEbers’ancientEgyptian

papyrus.Later,theIndianphysicianSushrutadescribedthesweeturineof

glycosuria,andinthesecondcenturyADamorethoroughdescriptionofthe

problemwasintroducedbytheGreekphysicianAretaeus,whoemphasizedthe

excessivethirst,urinevolume,andfrequencyassociatedwiththesystemicdisorder

andwhoemployedtheterm“diabetes”todescribethephenomenonofingested

fluidssimplypassingthroughthebodyontheirwaytothebladder.(Interestingly,

29NwaneriC.Diabetesmellitus:acompleteancientandmodernhistoricalperspective.WebmedCentralDiabetes2015;6(2):WMC00483130PoulsonJE.FeaturesoftheHistoryofDiabetology.Philadelphia1982,Lee&Fibiger,11.

12

theformerdescribedDMasassociatedwithobesity,whereasthelattermentionedit

asa“wastingdisease”.)

Aretaeus’writingswerenotrecognizedintheWestatthetimetheywere

written,butGalen(c.130–210AD)brieflydescribedDMasadiseaseofthe

kidneys,abeliefthatpersistedbeyond1800.In1674,Willis“re-discovered”the

sweeturineassociatedwiththe“pissingevil”butdidn’tassociatethesweetness

withglucose,andmorethan100yearspassedbeforeDobsonidentifiedthe

presenceofsugarinboththeurineandbloodofaffectedpatients.31In1798,Rollo

coinedtheterm“mellitus”,meaning“honey”,innotingthesweetnessofdiabetic

glycosuria.Hisadditionaleffortsincludedtheintroductionofradicaldietsto

improvethelongevityoftheinflicted.32

Thefirstscreeningtesttodetectthepresenceofglucoseintheurinewas

publishedbyTrommerin1841,33butthiswasquitecumbersome,andamore

practicalmethodwaslaterdevelopedandpresentedbyRobertsin1862,although

thiswasapparentlyemployedonlyrarely.34Still,itstimulatedfurtherstudiesof

dietarymanipulations,oneofwhichwasdescribedinOsler’s1909textbook35aimed

ateliminatingglycosuria.Although,asnotedabove,DMhadbeenpreviously

recognizedinobesepatientswithdiabetes,Frenchphysicianswerecreditedwith

31Ibid,14.32Ibid,34.33Tattersall,Op.Cit.,19.34Ibid,19-20.35OslerW.ThePrinciplesandPracticeofMedicine7thEdition.NewYork,Appleton,1909,421.

13

distinguishingdiabetesmaigre(thin)fromdiabetesgros(big)intheearly20th

century.36

Andforhundredsofyears,dietarymanipulationsweretheprimaryformsof

therapyfordiabetes.37,38Notably,Bouchardathasbeencreditedwiththe

observationthatsevererestrictionsoffoodintake,suchasoccurredduringasiege

ofParisin1870,causedamarkedreductionofglycosuriainsomediabeticpatients,

andhealsoclaimedthatphysicalexercisewasbeneficial.39Intheearly20thcentury,

theso-called“starvationdiet”(high-fatandlow-carbohydrate)becamefavoredby

leadingexpertsofthetimeincludingFredericAllenandEliotJoslinintheU.S.;40all

dietstrategiessharedthegoalofloweringserumglucoselevelsbylimitingcaloric

input.Eachoftheseprogramswassupersededbytheintroductionofinsulinin1922,

eventhoughdietcontinued(andcontinues)tobeacriticalvariableinthe

managementofthesystemicdisease.

Theintroductionofinsulin

TheworkofVonMeringandMinkowskiprovedconclusivelytheimportance

ofthepancreasinthepathophysiologyofDM.Serendipitously,theseinvestigators

haddiscoveredthatcompleteremovalofthepancreasproducedclinicaldiabetes

36LancereauxE.Noteetreflexionsàproposde2casdediabètesucréavecaltérationdupancréas.BullAcadMedParis.1887;2(Sér6)1215-1240.CitedinNwaneri.37SeePoulson,Nwarni.38FeudtnerC.Ideas,ideas,andinnovationinthehistoryofdiabetes.ArchPediatAdolesMed2011;165(3):195-6.39BouchardatA.DeLaglycosuricouDiabeteSucre.é,sontraetementhygienique,.Germer-Baillière.Paris,1875.citedinNwaneri.40WestmanAC,YancyWSJr.,HumphreysM.Dietarytreatmentofdiabetesmellitusinthepre-insulinera(1914-1922).PerspBiolMed2006;49(1):77-83.

14

mellitusinthecaninemodel,41andsubsequenthistopathologicalevaluationsof

specimensfrombothlaboratorycaninesanddiabeticpatientsidentified

abnormalitiesinthepancreaticisletcellsthathadbeeninitiallydescribedby

Langerhansinthelater19thcentury.42,43Tattersallreportedthatbetween1900and

1921,atleastfiveinvestigatorsalmostdiscoveredahypotheticalsubstance,termed

“insulin”bydeMeyerin1909,butitwastheMontrealgroupofBanting,Best,

Mcloud,andCollipthatsuccessfullysucceededinextractinganeffectivepancreatic

extracttotreatDMin1922.44Thatpathtowardsthediscoveryofinsulinprofoundly

transformedthereconfigurationandmanagementofDM,andithasbeenwell

describedbymanyauthors.45,46,47

Glucosecontrolandtheproblemofmedicalcomplications

Theuseofinsulinresultedinrecognitionthattherelativelygoodhealth

enjoyedbyinsulin-dependentdiabeticpatientswasbeingalteredbythelateronset

ofmicrovascularcomplicationsofretinopathy,nephropathy,andneuropathy.

Controversyregardingthevalueofglucosecontrolinretardingthesedisordersas

41vonMeringJ&MinkowskiO.Diabetesmellitusnachpancreasexstirpation.ArchExpPathPharmacol1890;26371-87.42MedveiVC.Historyofclinicalendocrinology:Acomprehensiveaccountofendocrinologyfromearliesttimestothepresentday.1993,London,TaylorandFrancis,1-538.43LangerhansP.Uberdienervendermenschlichenhaut.ArchivesofPathologicalAnatomy1868;44:325–37.44Tattersall,Op.cit.,42.45Poulson,Op.cit,44.46BlissM.TheDiscoveryofInsulin.25thAnniversaryEdition.Chicago,2007,ChicagoUniversityPress,1-304.47BestHBM.MargaretandCharley:ThePersonalStoryoftheCo-DiscovererofInsulin.Ontario,2003,H.D.M.Best,1-542.

15

wellasintheoverallhealthofthepatientsragedforover60years.48Joslin

pioneeredstrictglucosecontrolinthepreventionofmicrovascularcomplications,49

whileJackson,apediatricianattheUniversityofIowaSchoolofMedicine,provided

substantialevidenceofthevalueofglucosecontrolinpreventingDRin1956.50

However,itwasnotuntiltheProspectiveDiabetesStudy(UKPDS)trial51in

theUnitedKingdomregardingType2DMandtheDiabetesComplicationsand

ControlTrial(DCCT)52concerningType-1DMthatthevalueofglucosecontrolwas

firmlyestablished.Thesewillbemorethoroughlydescribedlater.(Anditshouldbe

notedthatastudythatprecededboththeDCCTandUKPDS,theUniversityGroup

DiabetesProgramme(UGDP),suggestedmacrovascularharmfromglucose

reductiontreatmentwithtolbutamide;53thiswasahighlydebatedstudythatnever

satisfactorilyresolvedthequestionsregardingglucosecontrol.)Additionalevidence

ofthevalueofstrictglucosecontrolcamewiththe2010ACCORDstudy.54

TheDiabetesComplicationsandControlTrial(DCCT)55evaluatedthe

outcomesofintensiveglucosecontroluponthedevelopmentofretinopathy,

48GuthieRA.Controversiesofthesweeturinedisease.DiabSpec2003;16(3):133-4.49JoslinEP.Statusoflivingdiabeticswithonsetunderfortyyearsofage.JAMA1951;147(3):209-13.50HardinRC,JacksonRL,JacksonTL,etal.Thedevelopmentofdiabeticretinopathy:effectsofdurationandcontrolofdiabetes.Diabetes1956;5(5):397-405.51UKProspectiveDiabetesStudy(UPDS)Group.Intensivebloodglucosecontrolwithsulphonyureasorinsulincomparedwithconventionaltreatmentandrisksofcomplicationsinpatientswithtype2diabetes.Lancet1988;352:837-53.52TheDCCTResearchGroup:Theeffectofintensivetreatmentofdiabetesondevelopmentandprogressionoflong-termcomplicationsininsulindependentdiabetesmellitus.NEnglJMed1993;329:977–86,1993.53UniversityGroupDiabetesProgramme.Astudyontheeffectsofhyperglycaemicagentsonvascularcomplicationsinpatientswithadult-onsetdiabetes.I:Design,methods,andbaselinecharacteristics.Diabetes1970;93(suppl2):747-83.54TheACCORDstudygroupandACCORDeyestudygroup.EffectsofmedicaltherapiesonretinopathyprogressioninType-2diabetes.NEJM2010;363(3):233-44,55TheDCCTResearchGroup.Op.cit.

16

nephropathy,andneuropathyinpatientswithinsulin-dependentDM.Patientswere

randomlyassignedtointensivetherapywiththreeormoredailyinsulininjections

orwithinsulinpumpsortoconventionalmanagementwithoneortwodailyinsulin

injections.Thestudycohortincluded1,441patients,726withnoDRatbaselineand

715withmildretinopathy.Overameanfollow-upperiodof6.5years,intensive

therapyreducedtheriskofdevelopingDRby76%;andimportantly,inthosethat

alreadyhadretinopathy,significantprogressionwasreducedby54%,andthe

chanceofdevelopingseverenon-proliferativeorproliferativeDRwasreducedby

47%.Themajorcomplicationofintensivetreatmentwasasignificantincreasein

thelikelihoodofhypoglycemicepisodes.Additionalstudiesprovidedsubstantiation

ofthevalueofglucosecontrol.

Anotherimportanttrial,theUKProspectiveDiabetesStudy(UKPDS)56

studiedtheeffectsofintenseglucosecontroluponthesubsequentdevelopmentof

complicationsofdiabetesinnewlydiagnosedpatientswithtype2DM.Between

1977and1991,5,102patientsfrom23centerswererecruitedandfollowedforan

averageof10years.Abloodpressurearmwasaddedinthecourseofthestudyand

comparedrigorousvs.lessintensebloodpressurecontrolinhypertensivepeople

withdiabetesandalsotherelativebenefitsofanACEinhibitor(captopril)orβ-

blocker(atenolol)inachievinghypertensioncontrol.MedianHbA1cwas7.9%with

conventionaltreatmentand7.0%withintensifiedtherapy,andthiswasassociated

witha25%reductionintheratesofretinopathy,nephropathyand(possibly)

neuropathy.Therewasanon-significant16%reductioninmyocardialinfarctionor56UKProspectiveDiabetesStudy(UPDS)Group.Op.cit.

17

suddendeathwithintensifiedtherapy,anda25%reductionintheriskofdeathfor

every1%dropinHbA1c.Antihypertensivetherapymarkedlyreducedallend-

points,macro-aswellasmicrovascularcomplications.A10-yearfollow-upstudyof

theoriginalUKPDSdemonstratedacontinuedbenefitofreducedriskwithimproved

glucosecontrol.57Andanadditionalstudy,ACCORD58,providedadditional

documentationofthevalueofreducinghyperglycemia.

TheACCORDstudyrecruited10,251diabeticpatientsat77clinicalcenters

inanefforttoevaluatethevalueofintensiveglucose,anti-dyslipidemia,andblood

pressurecontrolinreducingtherateofprogressionofretinopathy.Asubgroupof

2,856patientswithbaselineand4-yearfollow-upprotocolretinalphotographswas

includedinthisproject,andintensiveglucosecontrolandanti-dyslipidemiatherapy

significantlyreducedtherateofprogressionofDR,whereasthevalueofintensive

anti-hypertensivetreatmentwasofnoapparentbenefit.

Clearly,theDCCT,UKPDRS,andACCORDstudieshighlightedtheimportance

ofglucosecontrolinthemanagementofbothDMandDR.Thelatterdisordercan

literallybepreventedoritsprogressionsignificantlyreducedwithoptimaltherapy.

ThusallstrategiestoreducetheimpactofvisionlossduetoDRmustinclude

recognitionofthecriticalvariableofchronichyperglycemia.However,inspiteofthe

overwhelmingevidenceregardingthevalueofglucosecontrol,theincreaseofDR,

duebothtothegrowthinnumbersofpatientswiththesystemicdiseaseandtheir

poorbutlife-sustainingcontrol,hasreachedepidemicproportions,clearlyan

57HolmanRR,PaulSK,BethelAA,etal.10-yearfollow-upofintensiveglucosecontrolintype2diabetes.NEJM2008;359:1577-89.58TheACCORDstudygroupandACCORDeyestudygroup.Op.cit.

18

exampleofthelimitationsofthebodytoadapttochangesinsocialcircumstances

suchasdiet.59Theglobalperspectivehaschangedasnotedina2017addressbythe

Director-GeneraloftheWHO,whostated“injustafewdecadestheworldhas

movedfromanutritionalprofileinwhichtheprevalenceofthoseunderweightwas

morethandoublethatofobesitytothecurrentsituationinwhichinwhichmore

peopleworldwideareobesethanunderweight”.60Thestrainthatsuchchangeshave

causedisexploredinthefollowingchapter.

59RosenbergCE.Pathologiesofprogress.Theideaofcivilizationatrisk.BullHistMed1998;72:714-730.60ChanM.Obesityanddiabetes:theslow-motiondisaster.Keynoteaddressatthe47thmeetingoftheNationalAcademyofMedicine,Washington,D.C.,October17,2017.

19

Chapter3.

Theepidemiologicalburdenofdiabetesandretinopathy

DRduetoDMhasbecomeamajorcauseofvisualdisabilityinallcornersof

theworldduetotheprofoundincreaseintheincidenceandsurvivalrateofthe

systemicdiseaseresponsibleforDR’sdevelopment.61Iprovideacondensed

literaturereviewofsociety’s“post-insulin”responsestothegrowingprevalenceof

thesystemicdiseaseanditscomplicationsbyexamininghistoricalcomparisonsof

figuresintheU.S.,India,andEngland.62

TheWorldHealthOrganization(WHO)didnotissueitsfirstreportonDM

until1965,over40yearsafterinsulin’sintroduction,andthispublicationstressed

thealarmingworldwideincreaseinthedisease’sprevalencebutonlybriefly

mentionedtheappearanceofmicrovascularcomplications(andnotmentioningDR

byname)“aftersomeyears[ofthedisorder]”.63Still,thereportwasprescientin

notingthatmanynewcasesofDMcouldbepreventedthrough“educationand

practicalpublichealthmeasures”;thatthepercentageofundetectedpatientswith

DMwaslarge;andthatthedisorderwouldcauseanincreasingburdenon

healthcareresourcesaroundtheworld.Fifteenyearslaterin1980,asecondWHO

61Theissueregardingthe“shiftingdiagnosticcriteria”ofDMassociatedwiththeintroductionoforalhypoglycemicagents(GreenJA.PrescribingbyNumbers:DrugsandtheDefinitionofDisease.Baltimore2007,JohnsHopkinsUniversityPress,pp.82-148.)willnotbediscussedinthismanuscript.62Asnotedearlier,EnglandwasselectedasanexamplewithanadvancedDRmanagementsystem;theU.S.asacountryinwhichmostresearchonDRcarehasbeenconductedbutonewithafragmentedhealthcarenetwork;andIndiaasanexampleofahugelowerincomecountryinwhichEnglishistheprimarylanguage.AppropriateresearchdataareavailableforallthreeoftheseEnglish-speakingcountries.63DiabetesMellitus.ReportofaWHOexpertcommittee.WldHlthOrgtechRepSer,1965,310.

20

reportwaspublished,64andthisstatedthatatleast30millionpatientswere

affectedwithDMworldwideandthatprevalencewasgrowingprecipitously.65Sure

enough,in2006,theWHOreportedthatin1980therewere108milliondiabetic

patientsintheworldbutthatthenumberwouldgrowto422millionbytheyear

2014;66(thisinspiteofthefactthatthissameorganizationhadtwoyearsearlier

predictedthattherewouldbe“only”366millionsuchpatientsbytheyear2030).67

Ina2016WHOReport68,the422millionfigurewasreaffirmedalongwiththe

observationthattheprevalenceofDMhadincreasedfrom4.7%to8.5%amongthe

world’sadultpopulation.

TheInternationalDiabetesFederation(IDF),anorganizationofmorethan

230nationaldiabetesassociationsin170countriesandterritories,publisheda

periodicDiabetesAtlas,andinthe2015seventhedition69theirestimateofthe

worldwideprevalenceofdiabeteshadgrownto415millionwithanexpected

increaseto642millionby2040.Clearly,thedisorderassumedepidemic

proportionsoverarelativelybriefperiodoftime.

Regardingretinopathy,the1980WHOreportcitedabovenotedthat

“retinopathyisthecommonestsinglecauseofblindnessregistrationinthemiddle-64WHOExpertCommitteeondiabetesmellitus.Secondreport.WldHlthOrgtechRepSer,1980,pp.1-64.65Ibid.ThisreportmentionedDRbynameandnotedthatphotocoagulationtherapyhadbeenprovenasaneffectivetreatment.Italsosuggestedthat“diabeticoutpatientclinics”mightbeestablished.Nospecificscreeningstrategieswererecommended,althoughitsuggested“diagnosticandtherapeuticfacilitiesshouldbemadeavailablewhereverpossible”.66MatthersCD,LuncorD.projectionsofglobalmorbidityandburdenofdiseasefrom2002to2030.Pl0SMedicine2006;3(11):2011-30.67WildG,RoglicG,GreenA,etal.Globalprevalenceofdiabetes.Estimatesfortheyear2000andprojectionsfor2030.Diabcare2004;27(5);1047-53.68WHOGlobalReportonDiabetes.2016,GenevaSwitzerland,WorldHealthOrganization,pp.1-87.69InternationalDiabetesFederation(IDF).DiabetesAtlas,SeventhEdition.Brussels2015,InternationalDiabetesFederation,pp.1-144.

21

agedinmosteconomicallyadvancedcommunities”,andapublishedmeta-analysis

ofvisualdisabilityduetoDRfrom1990-2010revealedthatover800,000adults

worldwideweretotallyblindandanadditional3.7millionvisuallydisabled;these

figuresrepresentedincreasesoverthosetwodecadesof27%and69%,

respectfully.70Avarietyofracial,genetic,environmental,andsocialfactorshave

beeninstrumentalintheepidemicofDM.Thesearebrieflydiscussedbelow,butitis

clearthattheincreasedprevalenceofDMandassociatedretinopathy,nephropathy,

andneuropathyhaveoccurredmorefrequentlyamongindigenouspeoplesinlow

andmiddle-incomecountries.Poverty,poorhygiene,inadequatediet,substandard

housing,andlackofeducationareallsocialdeterminantsofbothDMandDR.71

Society’shealthcarestructuresrepresentsystemicattemptstocombat

diseasesascontemporaryhealthworkersunderstandthematthattime.Awareness

ofthenumberoflivingpatientsbecameapparentvirtuallyimmediatelyfollowing

insulin’sintroductionalthoughthesubsequentglobalimpactofDMremained

underappreciated.Fortheimportanceoflocalizedvasculardiseasesretinopathy,

nephropathy,andneuropathy,the“diabetictriadofcomplications”72requiredmore

timetobecomeappreciated.73Patientswhopreviouslymighthaveworriedabout

70LeasherJL,BourneRRA,FlaxmanSR,etal.Globalestimateofthenumberofpeopleblindandvisuallyimpairedbydiabeticretinopathy:Ameta-analysisfrom1990-2010.DiabCare39(9):1643-7.71Hill,J,NielsenM,FoxMH.Understandingthesocialfactorsthatcontributetodiabetes:Ameansofinforminghealthcareandsocialpracticesforthechronicallyill.PermJ2013;17(2):67-72.72RootHF,PoteJrWH,FrehnerH.Triopathyofdiabetes.Sequenceofneuropathy,retinopathy,andnephropathyin150patients.AMAArchIntMed1954;94(6):931-41.73Asomewhatsimilarstorytothatregardinginsulinemergedfollowingtheintroductionofrespiratorsinlowerincomecountrieswithlimitedaccesstooptimalpracticesformanagementofprematurebabies.Thus,thosewhowouldhavediedwithoutatleastoxygenarenowliving,andamajorincreaseinratesofretinopathyofprematurity(ROP)isbeingobserved.(KhalidAM,HaiderAA,FatimaT,etal.Retinopathyofprematurity:anexperienceinatertiarycarehospital.PakistanPedJ2018;42(2):97-102;andpersonalcommunicationwithAnthonyCapone,M.D.July20,2018.

22

survivingwithDMthereforehadtobecomeawareofthecomplicationsthatwould

beexpectediftheycontinuedtolive.74,75

ResponsestotheepidemicsofbothDMandDRhavefeaturedabroadvariety

oftherapeuticrecommendationsandcountermeasuresofdifferenttypesandin

variouslocations,buteffectivepublichealthstrategiestocombatbothdisorders

wereandcontinuetobeunfortunatelyslowinmostareasoftheworld.The

importanceofdetectingaffectedpatientshasbeenrepeatedlystressed,although

optimalscreeningmethodsforeachproblemcontinuetobedebated.Still,the

impactofbothdisordersupontheworldstageoverabrieftimeperiodhasbeen

remarkable,asisthefactthatanadequatepublichealthresponsetothemremains

delayedinmostregions.

Theincreaseinobesity(a“plagueofplenty”76,“apathologyofclinical

progress”77)hasbeenamajordriverinfluencingthegrowthofbothDMandDR.

Theiralteredprevalenceismostclearlyduetochangesintheenvironmentsas

reflectedinselectedpopulations,andsubsetsofaffectedcohortsprovideexcellent

examplesofthephenomenaamongvarioussomewhatgeneticallydissimilargroups.

Iincludebriefdescriptionsofnative-AmericansoftheU.S.,citizensofthePacificand

Indianoceans,andinhabitantsofIndia,theU.K.,andtheU.S.inaneffortto

documentepidemiologicalvariationsamongsocialgroups.Inallofthese,the

prevalenceofDRcloselyfollowsthatofDM,whichisinfluencedbysocietal

74FeudtnerC.Bittersweet.DiabetesandtheTransformationofIllness.ChapelHill,NC,UniversityofNorthCarolinaPress2004,pp.1-320.75TattersallR.Diabetes.TheBiography.Oxford,NY.OxfordUniversityPress,2009,pp.1-231.76PhrasefromBailyJ.TheEndofHealing.MemphisTN2017,TheHealthyCity,Kindlep.997.77Rosenberg1998,Op.cit.

23

evolutionsto“westerndiets”containingexcessivefatsandsugar-sweetened

beveragesandtophysicalinactivity.78

IndigenousNative-Americansserveasexcellentexamplesoftherolesofboth

geneticandsocialfactorsinpromotingthedevelopmentofDMandits

complications.Anunderlyingthemeofthishistoryisthatthespikeinobesityand

thereforeDMandDRlevelsamongNativeAmericantribesfollowingWorldWarII

wasduetoevolutionfromahunter-gathererenvironmenttowardanadoptionofa

Westernstyledietandlifestyle.79Thereisincreasingevidencethatthesefactors

begantooccurearlier-inthemid-andlate19thcentury.80Forinstance,thePima

Indianshavebeenstudiedfordecades,andtheirDMisalmostexclusivelyType2(as

istrueofallthetribes);thisgrouphasthehighestrecordedprevalenceand

incidenceofdiabetesintheworld–19timesthatofcitizensofRochester,

Minnesota.81In1940,only21casesofdiabeteswereidentifiedamongthePima

livingintheSonoranDesertinArizona,82whereasin2006,38%ofadultsinthe

tribeaged≥20yearshadacquiredthedisease.83Althoughthereclearlyaregenetic

predispositionstothedisorderasevidencedinthefindingofageneticmarker

78HuFB.Globalizationofdiabetes.Theroleofdiet,lifestyle,andgenes.DiabetesCare2011;34(6):1249-1257.79MihesuahDA,DiabetesinIndianTerritory:revisingKellyM.West’stheoryof1940.AmIndCultResJ2016;40(4):1-21.80Ibid.81NarayanKMV.DiabetesmellitusinNorthAmericans:Theproblemanditsimplications.InSandefurGD,RindfussRR,CohenB(eds.).NationalResearchCouncil(US)CommitteeonPopulation.Washington,D.C.1996.NationalAcademicsPress,262-88.82JoslinEP.Theuniversalityofdiabetes:asurveyofdiabeticmortalityinArizona.Diabetes1940;115:2033-8.83SchulzLO,BennettPH,RavussinE,etal.Effectsoftraditionalandwesternenvironmentsonprevalenceoftype2diabetesinPimaIndiansinMexicoandtheU.S.Diabetescare2006;29:1866-71.

24

linkedtoinsulinresistance,84obesityisthemajordeterminantofDMinthisgroup,

andtheinteractionofthisvariablewithgeneticsusceptibilityisstriking:individuals

withaffectedparentsareprofoundlymorelikelytodevelopDMatrelativelyearly

ages.85TheincidenceofDRisdirectlyrelatedtodegreesofobesityandlevelsof

glucosecontrol,86asisgenerallytrueforallpatientswithdiabetes.

PlainsIndiansappeartobelesslikelytodevelopDMthanthePima.Although

incidencefiguresamongvariousNorthAmericantribesvaryconsiderably,the

figuresforplainsIndiansareonlyapproximatelyathirdthoseofthePima.87Still,

theclearassociationbetweenenvironmentalfactorsandtheoddsofdevelopingDM

arestrikinglyapparentinallgroups.West88andothershavedocumentedthatthe

apparentlowprevalenceofDMinplainsIndianspriortoWWIIwasfollowedbya

dramaticincreasethereafter,eventhoughthepreciseincidenceofDRindiabetic

patientsvariedamongdifferentOklahomatribes.

Internationally,similarpatternsareapparent.Studiesregardingthe

primarilyPolynesianpopulationofNauruinthePacificOcean,theislandof

MauritiusintheIndianOcean,andAustraliaprovideadditionalevidenceofthe

epidemicofDMaroundtheworld.OnNauru,theprevalenceofDMamongthe

primarilyPolynesiancitizensisalmost35%,withevidencethatthefigureincreased

84ProchazkaM,LilloyaS,TaietJE,etal.Linkageofchromosomalmarkerson4qwithaputativegenedeterminingmaximalinsulinactioninPimaIndians.Diabetes1993;42:514-9.85GohdesD.DiabetesinNorthAmericanIndiansandAlaskanatives.InHarrisMI,CowieCC,SternMP,etal(eds.).DiabetesinAmerica.2ndEdition.WashingtonD.C.1995;DHHSpublicationno.(NIH)95-1468.86PettitDJ,KnowlerWC,BennettPH.Developmentofretinopathyandproteinuriainrelationtoplasma-glucosecontrolinPimaIndians.Lancet1980;15;2(8203):1050-2.87Ghodes,Op.cit.88WestK.DiabetesinAmericanIndiansandothernativepopulationsofthenewworld.Diabetes1974;23:841-55.

25

significantlyoverthepastdecade.89OnMauritius,witharelativelysmallpopulation

ofapproximately1.2millionpeoplethatincludesthreemajorethnicgroups,Asian

IndiansfromIndia,Creole-SouthAfricanBlacks,andChinese,theprevalenceof

diabetesgrewfrom14.6%to23.6%from1997-2009,a62%increase,thatwas

similarineachethnicgroup.90InAustralia,theDMprevalencehasalsogrown

precipitously,andtheIndigenouspopulationsthereweredisproportionately

affectedbydiabetesanditscomplications,witha4-foldhigherprevalence

comparedtothegeneralAustralian,mainlyEuropeanpopulation.91Inthefirst

Australiannationalsurveytodeterminethemajorcausesofvisualimpairmentand

blindness,DRwasrecognizedastheculpritin5.5%ofIndigenousAustraliansbutin

only1.5%inthenon-Indigenouspopulation.92Inalloftheseregions,amodifiedlife

stylefeaturingwesterndietsandlowphysicalactivityplayedamajorroleintheDM

epidemic,butadditionaldifferencesareduetogeneticvariability;andsocialfactors

includingpovertyandpoornutritionhavealsobeenimportant.

AndinIndiatherewasanincreaseofdiabetesprevalenceofnearly5%

betweentheyears2000and2006,morenotablyincitiesthaninruralvillages.93An

additionalstudydocumentedsimilargrowthwithadditionalinformationthat

improvedsocioeconomicstatuswithitsgreaterexposuretoWesterndietswasan

89ZimmetPZ.Diabetesanditsdrivers:thelargestepidemicinhumanhistory?ClinDiabandEpidemiol2017;3:190Ibid.91GuestCS,O’DeaK.DiabetesinAboriginesandotherAustralianpopulations.AustJPublicHealth.1992;16:340–9.92CentreforEyeResearchAustraliaandVision2020Australia.TheNationalyehealthSurvey2016.Melbourne,2016,Vision2020Australia,1-32.93RamachandranA,MaryS,YamunaA,etal.HighprevalenceofdiabetesandcardiovascularriskfactorsassociatedwithurbanizationinIndia.DiabetesCare.2008;31:893–8.

26

importantvariableimpactingprevalencerates,especiallyinurbanareas.94Inthe

latterstudy,theprevalencerateofDMinrelativelyaffluentpatientsinhabitingcities

ofmoreeconomicallydevelopedstateswashigherthaninthoseindividualsof

relativelylowsocioeconomicclass,whereastheoppositewastrueinurbanregions

thathadexperiencedlessdevelopment,suggestingarecurringthemethat

increasingaccesstomorewesterndietsmayincreasetherateofdiabetes.

Regardless,theprevalencerateofdiabetesinIndia,currentlysecondonlytoChina,

nowincludes80–90millionpeoplelivingwiththesystemicdisorder,representing

over10%intheadultpopulation;95andIndiaisprojectedtooutnumberChinain

numberofaffectedpatientsby2030.96TheIndiaDRmarketsizeiscurrentlyvalued

ateightbillionUSdollarsandisexpectedtogrowbyalmostsevenpercentannually

to12billionby2025.97Factorsresponsiblefortheprevalenceinclude(asnoted

previously)thegeneticinfluencescoupledwithenvironmentalvariablessuchasthe

obesityassociatedwithrisinglivingstandards,steadyurbanmigration,andlifestyle

changes.98

RetinopathyratesamongIndianpatientswithDMappeartobeconsistent

withotherregionsoftheworldmentionedabove.A2014nationwidesurveyofover

5,000diabeticindividualsrevealedaDRprevalenceofalmost22%,andthetypical

94AnjanaRM,DeepaM,PradeepaR,etal.Prevalenceofdiabetesandpre-diabetesin15statesofIndia:resultsfromtheICMR-INDIABpopulation-basedcrosssectionalstudy.TheLancet.DiabetesandEndocrinology.2017;5(8):585-96.95InternationalDiabetesFederation2015DiseaseAtlasOp.cit.96NadarajanB,SayaGK,KrishnaRB,etal.PrevalenceofdiabeticretinopathyinruralareaofVillupuramdistrictofTamilNadu,India.JClinDiagRes2017;11(7);LC23-6.97SankritayanR.Diabeticretinopathymarket2019share,trends,andforecast,2019-2025.www.express-journal.com/july26,2019.AccessedAugust9.2019.98KaveeshwarSA,CornwallJ.ThecurrentstateofdiabetesmellitusinIndia.AusMedJ2004;7(1):45-8.

27

variablesofdurationofsystemicdisease,age,andglucosecontrolqualitywere

significantlyassociatedwiththelikelihoodofdevelopingtheseretinalvascular

changes.99Specificprevalencefiguresvarysomewhatfromregiontoregionand

studytostudy,butitisquiteclearthatincreasingnumbersofpatientswithDM

leadstomorecasesofDR,andthatbothdisorderswillincreasethehealthcare

burdenofthecountry.100

IntheUnitedKingdom,theoverallprevalenceofDMamongcitizensis

approximately6.2%,representingadoublingofthenumberofaffectedindividuals

between1996and2014,andanestimated50%additionalincreaseisexpectedby

2025.101Onceagain,theincreasedrateofobesityinthepopulationisamajor

determinant.RatesofDRareconsistentwiththoseinothercountriesinbeing

associatedwithage,durationofdisease,andpoorcontrolofserumglucose.

However,theUKisintheforefrontofthosetakingmeasurestoidentifyandmanage

thisdisorder,asdescribedlater.

IntheUnitedStates,theprevalenceofDMvariesamongdifferentethnic

groups.NativeAmericanswerementionedaboveduetotheirrepresentationasa

relativelydistinctgroup,andcomparedtotheCaucasianAmericanpatients,DMis

almosttwoand1.6timesascommoninLatino-AmericanandAfrican-Americans,

respectively.102Inadditiontotheseracial/geneticvariables,additionalmajorsocial

99GadkariSS,MaskatiQB,NayakBK.PrevalenceofdiabeticretinopathyinIndia:Theall-IndiaOphthalmologicalSocietydiabeticretinopathyscreeningstudy2014.IndJOphthalmol2016;64(1):38-44.100Nadarajan2017,Op.cit.,25.101DiabetesUK(formerlytheBritishDiabeticAssociation).FactsandStats,Version4,2015,p.1.102HarrisMI,FlegalKM,CowieCC,etal.Prevalenceofdiabetes,impairedfastingglucose,andimpairedglucosetoleranceinU.S.adults.DiabCare1998;21:518-24.

28

determinantsofthesystemicdisease(describedbelow)aresimilararoundthe

globe:obesityandreducedphysicalactivitiesassociatedwithcontemporarylife

styles.Similarly,ratesofDRarestronglyrelatedtothecontrolofserumglucose

levelsanddurationofdisease.Andthereareadditionalfactorsofimportance.

Theimpactofsocialdeterminantsofhealthupondiabetesmellitus

Inadditiontotheethnicandgeneticvariablesmentionedabove,the

influencesofpoverty,education,andadditionalsocioeconomicfactorsuponthe

incidenceandcourseofDMhasbeenclearlyandextensivelyarticulatedinthe

literature,andanyvariablecorrelatedwiththeprevalenceofDMaswellas

inadequatecareofthissystemicdisorderisreflectedinanincreasedpresenceand

severityofDR.Lacksofincomeandeducation(thetwomostcommondimensionsof

poverty103)aretwopredictivevariablesforlifeexpectancy,104butconsiderationsof

thesefactorsalonemaymissdataregardingtheextremesofpovertyandsqualor

thatexist,especiallyinmanylowerincomecountrieswithgrowingpopulationsof

diabeticpatients.Asnotedearlier,patientsofloweconomicstatusinhigh-income

countriesaremuchmorelikelytohaveahigherchronicdiseaseburdenthan

individualsofahighereconomicstatus,andobesityamongothervariables

increasesamongtherelativelypoorasexposuretowesterndietaryincreases

(anotherexampleofSigerist’s1933statement“Eachchangeofculturalconditions103TheLancettaskforceonNCDsandeconomics2.Tacklingsocioeconomicinequalitiesandnon-communicablediseasesinlow-incomeandmiddle-incomecountriesundertheSustainableDevelopmentagenda.PublishedonlineApril4,2018,http://dx.doi.org/10.1016/S0140-6736(18)30482-3.104KnickmanJR,KovnerAR.(eds).JonasandKovnar’sHealthcareDeliveryintheUnitedStates,11thEdition.NewYork,2015,SpringerPublishing,86.

29

hasadefiniterepercussiononthediseasesofthetime”.105)Majordietarychanges

thathaveoccurredinAsiainthelastseveraldecadeshaveincludedashiftfrom

consumptionofcoarsegrainstopolishedriceandrefinedwheat;reduceddietsof

cerealsparticularlyamongurbanpopulationsandhigher-incomegroups;increased

consumptionofdairyproductsandaddedsugar;andhigherenergyintakeamong

thepoor,lowerenergyintakeamongtherich,andgreaterconsumptionoffatinall

incomegroups.106Andofcoursetheabilitytoaccessandpayforcontemporarycare

includingpatienteducationmaybequiteimpossibleforimpoverishedindividuals.

OnecontemporarystudyoftheinfluenceofsocioeconomicstatusuponDM

prevalencerevealedthatregionalareasofrelativedeprivationmaycontributeto

theeffectsuponindividuals,evenaftercontrollingforthelatter’spersonal

characteristics.107Lowerincomedictatedareducedaccesstooptimalfoodsand

increasedinsecurityregardingtheiravailability;108andalsothequalityofdiets

availabletopatientsindifferingregions.109Highereducationalattainmentwouldbe

expectedtobeassociatedwithincreasedcompetenceinmanaginghealthissues,

includingtheunderstandingofinstructionsregardingoptimaldietaryhabitsandthe

necessityofperiodicevaluations.

105SigeristHE.Problemsofhistorical-geographicalpathology.BullInstHistMed1933;1(1):10-18.106HuFB.Globalizationofdiabetes.Theroleofdiet,lifestyle,andgenes.DiabCare2011;34(6):1249-1257.107MaierW,HolleR,HungerM,etal.Theimpactofregionaldeprivationandindividualsocioeconomicstatusoftheprevalenceoftype-2diabetesinGermany.Apooledanalysisoffivepopulation-basedstudies.DiabMed2013;30(3):e78-e86.108SeligmanHK,LavatiaBA,KushelMB.Foodinsecurityinassociationwithchronicdiseaseamonglow-incomeNHANESparticipants.JNutr2010;140:304-10.109DarmanN,DrewnowskiA.Doessocialclasspredictdietquality?AmJClinNutr2008;1109-17.

30

InthischapterIsetouttodescribeabriefhistoryofDMduringpost-insulin

eras.Theimpactofstudiesregardingtheimportanceofglucosecontrolthatwas

emphasizedinthelastchapterwereexplored.Inaddition,theepidemiologyofthe

systemicdiseaseamongvariousethnicandsocietalgroupsandtheimportanceof

socialdeterminantsasinfluentialvariablesweredescribed.Mostpatientsthathave

acquiredthesystemicdiseaseultimatelydevelopsignsofDR.Effectiveclinical

practicesthatreducetheincidenceofboththesystemicandoculardisordershave

beendeveloped,buttheyremainpoorlyinstitutedinmostpartsoftheworld.Inthe

followingchapterIdiscussretinopathyinmoredetail.

31

Chapter4.

DiabeticRetinopathy:recognitionandmanagement

InthischapterIreviewhistoricalandcontemporarymethodsforthe

detectionandtreatmentofDR,includingthedevelopmentoftheophthalmoscope,

earlytherapeuticattempts,anddescriptionsoftrialsthatestablishedtheevidence

baseforcontemporarytherapeuticstrategies.Thisinformationisimportantforan

understandingofthestepsthatthathaveoccurredasevidence-basedtreatment

maneuvershavebeendeveloped.

Asnotedpreviously,ittooksometimeforconceptsoflocalizedvascular

diseasesduetoDMtoemerge.110Anyvariableassociatedwithanincreased

prevalenceofDMandinadequatemanagementofthesystemicdisorderwillbe

reflectedinanincreasedpresenceandseverityofDR;thusthedataregarding

developmentofthesystemicdiseaseareconsistentwithstudiesregardingthe

prevalenceofretinopathy.

Thediagnosisofdiabeticretinopathy

ThestoryofDRdidnotbeginuntilitcouldbedetectedclinicallywithan

ophthalmoscope–aliteral“knowledge-producingtool”111.Theclinicaldiagnosisis

purelymorphologic,constructeduponitsappearance:someonehastoobserveit(or

110Rosen,Op.Cit.,16.111Wailoo,Op.cit..13.

32

animageofit)beforeadiagnosiscanbemade,andthisbecamepossibleonlyafter

theintroductionoftheophthalmoscope,whichhastenedtheevolutionofspecialties

inmedicineinadditiontoprovidingthefirstmeansofvisuallyassessinghuman

pathophysiologyinvivo.Thedevicewasinitiallyverydifficulttoemploy,thereby

addingtotheauthorityofthosewhomastereditsuse.

Anumberoftextbookshavedescribedthedevelopmentofthe

ophthalmoscopeanditsroleintheestablishmentofsubspecialties.112,113,114Allthat

wasultimatelyrequiredforanophthalmoscopewasfortheproperlensestobe

placedinfrontoftheluminouspupil,theobservertobeappropriatelypositioned,

andameansofseparatingthelightenteringtheeyefromthatemergingfromit.The

developmentoftheophthalmoscopewasalmostaccomplishedbyseveralscientists,

butHermannHelmholtzhasbeenrightfullycreditedastheoriginator.

TheinventionoftheophthalmoscopewasannouncedtotheBerlinPhysical

Societyin1850,anddescriptionsoftheinstrumentwerepublishedthefollowing

year.Hisdeviceemployedthreeplatesofglassthatsimultaneouslyactedasamirror

toreflectlightintotheeyewhileallowingtheobservertoseeanimagethrough

them;tothiswasattachedalenstofocustheemerginglightrays(Figure1).115The

earlydeviceswerecumbersomeanddifficulttouse,andacoupleofdecadespassed

beforemorepracticalmodelsweredeveloped.Eventhen,onlyafewinvestigators

usedthem,promptingan1871quote“thenumberofphysicianswhoareworking

112Rosen,Op.Cit.113RuckerWC.Ahistoryoftheophthalmoscope.Rochester,Minnesota:WhitingPrintersandStationers,1977;127.114ShermanSE.Theinventionoftheophthalmoscope.DocOphthalmologica1989;71:221-8.115Ibid.

33

withtheophthalmoscopeinEnglandmay…becountedonthefingersofone

hand”.116Butthissituationdidnotpersistasinstrumentsimproved.

Formorethanadecade,illuminationforreflectingophthalmoscopy

employedcandles,oillamps,and(later)gaslights.Electricbulbsforillumination

wereadaptedinthelater19thcentury,butreflectedlightcontinuedtobeusedwell

intothe20th.By1913,over200differentreflectingophthalmoscopeshadbeen

developed.Theavailabilityofelectricitypromptedaneedforsmalllightbulbs,and

althoughthefirstelectricophthalmoscopewithself-containedilluminationwas

demonstratedin1885,morepracticaldevicesdidnotreachthemarketplaceuntil

theseconddecadeofthe20thcentury.

Retinalchangesassociatedwithdiabeteswereobservedsoonafterthe

ophthalmoscopewasinvented.Jaegerin1856describedtheretinalvascular

anomaliesthathehadobservedandprovidedadrawing,whichalthoughnot

pathognomonicofDR,wasunequivocallythefirstpublicationdescribingretinal

vascularlesionsintheeyeofapatientwithDM.117Twentyyearslater,Manz

publishedanillustrationandpaperthatdescribedadvancedproliferativeDRas

“retinitisproliferans”.118However,theconceptofthediseaseentity“diabetic

retinopathy”remainedelusiveformanymoredecades.Blurryvisionassociated

withDMhadbeenrecognizedforcenturies,butitwasusuallyduetovariableserum

glucoselevelsorcataracts.Whenthesevariablesbecameruledoutand

116Ibid.117JaegarE.BeiträgezurPathologiedesAuges.2.Lieferung,S.33,TafelXII.K.K.Hof-undStaatsdruckerei,Wien1855.118ManzW.Retinitisproliferans.GraefesArchClinExpOphthalmol.1876;22:229.

34

ophthalmoscopeswereavailable,visiblelesionsintheretinabecamesuspectedas

thecauseofvisionloss.AlthoughsomeauthorshavestatedthatHirshbergfirst

claimedthatDRwasadistinctentity,119debatesregardingthespecificityofthe

findingsversusthoseof“albuminuricretinopathy”associatedwithrenalfailure

continuedfordecadesbecausethetwoconditionssofrequentlycoexisted,andboth

featuredintraretinalhemorrhagesandswellingintheposteriorretina.120

Bouchut121(1866)andDesmarres122(1864)reportedthatsignsof“glycosuric”

(diabetic)retinopathywereidenticaltothoseof“albuminuricretinopathy”;

Galezowski123(1875)regardedtheformertobeonlyrarelydistinguishedfromthe

latter;whereasNoyes124(1868)andNettleship125(1872)describedcasesofDR

unassociatedwithalbuminuria.Still,therelativerolesofhyperglycemia,

arteriosclerosis,andrenalfailureinthepathogenesisofretinalvascularchanges

longdelayedacceptanceofDRasaspecificentity,andwellintothe20thcenturyit

wasincorrectlyframedasacomplicationofrenalfailureand/orhypertension.

Thisdiagnosticdilemmawasclearlydemonstratedinsequentialpapersfrom

theMayoClinicthatwerepublished13yearsapartbythesamegroupof

119Pouslon,Op.cit.,120.120ContrarytoDR,albuminuricretinopathyhasbecomeanexceedinglyunusualdiagnosticentityinthewesternworldprimarilybecauseoftheavailabilityofdialysis.Theauthorlastobservedacasein1972inanon-diabeticteenagerwithrenalfailuresecondarytochronicpyelonephritis.121BouchutE.DuDiagnosticdesMaladiesduSystemNerveuxParsL-Ophthalmoscopic.1866,Paris,GermerBailliere,pp.442-6.122DesmarresLA.TraiteTheoriquebetPractiquedesMaladiesDesYeux,3rdEdition.1864,Paris,GermerBailliere,pp.642-6.123GalezowskiX.TraitedesMaladiesDesYeux,2ndEdition.Paris,GermerBailliere,pp.642-6.124NoyesHD.Retinitisinglycosuria.TransAmOphthalmolSoc.1869;4:71–75.125NettleshipG.Onoedemaorcysticdiseaseoftheretina.RoyOphthLondHospRep.1872;7(3):343–51.

35

investigators.Inthefirst,publishedin1921,44casesof“diabeticretinitis”126were

identifiedinacohortof300patients(15%),andtheretinalalterationswere

consideredtobeduetosystemicarteriosclerosisortorenaldisease.127Theauthors

stated“…retinitischaracteristicordiagnosticofdiabetes,comparabletotheretinitis

ofnephritis,muststillberegardedasunproven”.128Subsequentlyin1934,1052

diabeticpatientswereevaluated(evidenceofthegrowingprevalenceofbothDM

andDR),andretinalchangeswereidentifiedin187(17.7%).Fifteenpercentof

diabeticpatientswereunderage40years,butDRwasevidentinonly4,3%,

whereasitwaspresentinover20%ofpatientsolderthanthat,anditoccurred

exclusivelyinthosewithmild,easy-to-controlDM(i.e.,thosewhocontinuedtolive

withDM).Inthispublication,theauthorsstatedthatDRfeaturedadistinctpicture

thatwassolelyduetothesystemicdisease,129andthisviewcametobeaccepted

worldwide.

Earlytreatmentofdiabeticretinopathy

Inthespringof1967,Janetwasa27year-oldCaucasianfemalewitha17-year

historyoftype-1diabetesmellitus130;shehadbeenpregnantfortenweeks.In

theprecedingdays,shehadexperiencedblurredvisionassociatedwithdark

126Theterm“retinitis”wasinitiallyemployedtodescriberetinalvascularchangesduetoDMeventhoughaninflammatorybasiswasnot(andhasnotbeen)established.Itgraduallywasreplacedbytheterm“retinopathy”,stimulatedbyapublicationdescribingthehistopathologyofthedisorder(BallantyneAJ,LoewensteinA.Diseasesofretina:pathologyofdiabeticretinopathy.Tr.Ophth.Soc.UK1943:63:95.)127WagenerHP,WilderRM.Theretinitisofdiabetesmellitus.JAMA1921;75:515-17.128Ibid,515.129WagenerHP,Dry,TJS,WilderRM.Retinitisindiabetes.NEJM1934;211(25):113-17.130“Janet”isapseudonym,butthetruehistorywaswitnessedbytheauthor.

36

floatingimagesinhervisualfieldsandwassubsequentlydiagnosedwith

intraocularhemorrhagesandlocalizedretinaldetachmentsduetodiabetic

retinopathy.Fortheseproblems,whichwerenotamenabletorecently

availablephotocoagulationtherapy,shewasofferedacceptedalternative

treatmentsofeitherabortionorbrainsurgerytoremoveherpituitarygland;

butsherejectedtheseoptions.Overthefollowingfivemonths,Janetlostall

visionincludinglightperceptioninbotheyes.

Thecasecitedabovedemonstratesthefrustrationlevelthatpatientsand

theircaregiversfacedwithuntreatableretinopathy.EarlyattemptstomanageDR

wereinitiallytopicsofclinicalresearchonlocallevels.Suchtherapiesincluded

dietaryrestrictions,x-irradiationoftheretina,systemicadministrationofvitamins

CandB12,clofibrate(Atromid),para-aminosalicyclicacid,anticoagulants,

testosterone,andlater,inductionofglaucomawithtopicaluseoftopical

corticosteroids.131TheimportanceofarapidlyincreasingprevalenceofDR

appeared(totheauthor)tobeofmoreimportancetotheeyecarecommunitythan

tobroadbasedhealthcaresystems.Responsestomanyepidemicsareslowto

developincommunitiesofaffectedpatients,132andtimeisrequiredforwidely

acceptedrecognitionofadiseaseentity;soitwaswithDR,aproblemthat

implicatedbothpersonalbehaviorofaffectedpatientsandmanagementstrategies

131GoldbergMF,JampolLM.KnowledgeofdiabeticretinopathybeforeandeighteenyearsaftertheAirlieHouseSymposiumontreatmentofdiabeticretinopathy.Ophthalmology1987;94:741-6.132RosenbergCE.ExplainingEpidemicsandOtherStudiesintheHistoryofMedicine.Cambridge,CambridgeUniversityPress1992,p.281.

37

acceptedbythemedicalcommunity.Theformervariableremainsaformidablegoal,

andthelatterwasasourceofmajorcontroversythatprecededtheestablishmentof

evidence-basedtherapies.

Themostimportanthistoricaltechniques—pituitaryablationand

photocoagulation—bothbecameviableoptionsviaserendipitousroutes,andtheir

relativevalueswerehotlydebatedamongphysiciansintheretinacommunity.Very

importantly,untiltheywereproperlyevaluated,therewerevirtuallynoevidence-

proventherapiestopreventblindnessfromproliferativeDR.Minkowskiandco-

workersdemonstratedtherelationshipbetweenthepancreasandDMbeforethe

endofthe19thcentury:removalofthecaninepancreascauseddiabetesmellitusto

develop,andthisstimulatedaflurryofsubsequentresearch.(Interestingly,

Minkowski’sinitialpancreatectomyhadbeenperformedforthephysicianvon

Meringinanefforttostudylipidabsorption,andthesubsequentpolyuriaof

diabeteswasunexpected.133)

In1930Houssay134,employingadiabeticcanine(followingpancreatectomy)

model,describedaremarkableincreaseininsulinsensitivityfollowingremovalof

thedog’spituitarygland,andadditionalcasereportsinthemid-30’sdescribed

improvementofDMcontrolinhumandiabeticpatientsfollowinglossofpituitary

function.135Later,in1953,Poulsonreportedaserendipitouscaseinwhich

spontaneousnecrosisoftheanteriorpituitarygland(Sheehan’ssyndrome)had133Editor’sNote.Diabetes.AMedicalOdyssey.USVpharmaceuticalcorporation1971,Tuckahoe,NY,p.111.134Houssay,BA,Biasotti,AA:Diabetespancreaticadelosperroshipofisoprivos,RevSocArgentBiol1930;6:251-69.135HernbergCA,afBjorkestenG,VannassS.Hypophysectomyinthetreatmentofdiabeticretinopathyandnephropathyinseverejuvenilediabetes.Diabetologica1959;3:241-60.

38

occurredinapostpartumpatientwithestablishedDR,followingwhichthe

retinopathyresolvedoveralengthyfollow-upperiod.136However,evenpriortothis

publication,Oliveron(aneurosurgeon)andLuft(aphysicianfriendofPoulsonwho

knewabouthiscase)beganstudyingthevalueofhypophysectomyforproliferative

DR.In1955theyreported20suchcases;somehadpoorlydefinedimprovementsin

retinopathy,butthemortalityratesweredisappointinglyhigh.137Nevertheless,with

nohopesforvisioninpatientswithsevereDR,itwaswidelyproposedthatstudies

ofpituitaryablationshouldbeinitiatedinspiteofthefactthatthediseaseof

hypopituitarismwouldbesuperimposeduponthatofDM.

Pituitaryablationwasaccomplishedwithavarietyofsurgicalandirradiation

maneuvers,andby1967over1,200patientsinthewesternworldhadundergone

thetherapy.138Andcontrarytoopinionsinsomecontemporarypublications

regardingDM,139,140thesetechniqueswereclearlyofvalueinsomepatientswith

certainstagesofsevereDR.Resultsfromalargeanddiversegroupofparticipating

investigatorswerereportedalongwiththoseregardingphotocoagulationata

pivotalmeetingatAirlieHouse,Virginia,in1967andpublishedin1968141(the

meetingismorethoroughlydiscussedbelow).Dataregardingablationsat11

centersinvolving599eyeswerereported,andofthese,63%exhibitedan“arrest”of

136PoulsonJE:Houssayphenomenoninman:RecoveryfromretinopathyinacaseofdiabeteswithSimmonds’disease.Diabetes1953:2:7-12.137LuftR,OlivercronaH,IkkosD,etal.Hypophysectomyinman.Furtherexperiencesinseverediabetesmellitus.BrMedJ1955;2:752-6.138DavisMin:FineSL,GoldbergMF(Eds).Symposium:TreatmentofDiabeticRetinopathy.Washington,D.C.1969,U.S.DeptofHealth,Education,andWelfare,pp.1-913.139Feudtner,Bittersweet,opcit,192.140Tattersall,opcit,99-100.141FineSL,GoldbergMF.(Eds)Symposium:TreatmentofDiabeticRetinopathy.Washington,D.C.1969,U.S.DeptofHealth,Education,andWelfare,pp.1-913.

39

retinopathy,whereastheremaining37%progressed.Therewasunanimous

agreementthatthe“angiopathicaspectofretinopathyrespondedwelltopituitary

ablation”.142Compellingly,onereportdocumentedadirectrelationshipbetweenthe

degreeofpituitaryablationandthelikelihoodofretinopathyregression.143Still,

concernsregardingtheexpectedcomplicationsofsecondaryhypopituitarismwere

recognizedasnegativeoutcomes,144andthesuccessratesofphotocoagulation

describedbelowresultedinageneralizedabandonmentofpituitaryablationwith

rareexceptions.145

Photocoagulationwasaresultofanadditionalserendipitousobservationand

subsequentpublicationsbyasingleGermaninvestigator,GerhardMeyer-

Schwickerath.Solarburnsoftheretinahadbeenrecognizedsinceantiquity,and

suchacasewasreportedsoonafterthedevelopmentoftheophthalmoscope;andin

thelater19thcenturyCzernyandothersdescribedeffectsofretinalburnsfromthe

sunontheeyesofexperimentalanimalsafterfocusingsunlightupontheir

retinas.146,147Thefirstreportoftheeffectsoffocusedsunlightonthehumanretina

(ineyeswithtumorsthatwerescheduledforenucleation)waspublishedinthe

142McMeelJW.Summaryofpapersonocularaspectsofpituitaryablation.In:FineSL,GoldbergMF(Eds).Symposium:TreatmentofDiabeticRetinopathy.Washington,D.C.1969,U.S.DeptofHealth,Education,andWelfare,pp.375-379.143JoplinGF,OakleyNW,HillDW,etal.DiabeticretinopathyII.ComparisonofdiseaseremissioninducedbyvariousdegreesofpituitaryablationbyY90.Diabetelogica1967;3:406-412.144Physiciansmanagingthesepatientswereburdenedwithmanyacutemetabolicproblemsaswellasthelong-termfutureissues.“Thepsychosocialdimensions{inthesepatients}arethemissinglinkinthesereports.Ibecameburdenedwithofferingtheoperation{pituitaryablation}toaless-than-40-yearsagegroupwhowouldbemadeoldovernight.”(Personalcommunication,BurnettD(anendocrinologyfellowattheJoslinInstitutefrom1960-62),April2,2017)145KohnerEM,HamiltonAM,JopkinGF,etal.Floriddiabeticretinopathyanditsresponsetotreatmentbyphotocoagulationorpituitaryablation.Diabetes1976;25:104-10.146CzernyV.Uberblendungdernetzhautdurchsonnenlicht.BerWienAcadWiss1867,56:II.147DeutschmannR.Klinisch-ophthalmologischemiscellen.GraefesArchfOphthalmol1882;28:241.

40

Italianliteraturein1927,anditwasnotuntil1949thatMeyer-Schwickerath

publishedhisinitialexperiences.148Hehadbeenstimulatedbyhisobservationofa

scarintheretinaofapatientwhohadwitnessedaneclipse,andheinitiated

experimentstoestablishameansoftherapeuticphotocoagulationofthehuman

retina.Heinitiallydevelopeda“heliostat”tofocusthesun’sraysbutthenbegan

experimentswithahigh-intensitycarbonlamp.Subsequently,axenonarcdevice

wasdevelopedin1956,andthiswasemployedasaphotocoagulationdevice

worldwideuntillasertherapywasintroducedadecadelater.

Thephysicssurroundingthedevelopmentofthelaserwillnotbediscussed,

butresearchonrubylaserphotocoagulationwasinitiatedinexperimentalanimals

in1961andtwoyearslaterinhumaneyes.149Butredlightwasnotgenerally

effectiveforredretinalvascularlesions,andsearchesforalternativewavelengths

werecontinued,andtheargongreenlaserquicklybecametheinstrumentofchoice

formany,particularlyafterthedevelopmentofabinocularstereoscopicobservation

systemsinthelate‘60s.150Commerciallyavailableargonlasersbecamewidely

distributedgloballybeginningin1970.

Photocoagulationtherapywasinitiallydirectedatvisibleretinalvascular

lesions,othersitesofapparentleakageofserum(unusual),orareasof

neovascularization(common).Amajorproblemwasthatnewvesselsarisingonthe

opticnervecouldnotbetreatedforfearofdamagingthisvitalstructure.Asdata148Meyer-SchwickerathG.Koagulationdernetzhautmitsonnenlicht.BerDtschOphthalmolGes1949;55:256.149KapenyNS,PeppersNA,ZwengHC,etal.Retinalphotocoagulationbylaser.Nature1963;199:146-149.150LittleHL,ZwengHC,PeabodyRR.Argonlaserslitlampretinalphotocoagulation.TransAmAcadOphthalmolOtolaryngol1970;74:85-NEEDPAGE.

41

accumulatedregardingphotocoagulation,anironicoutcomebecameapparent:eyes

inwhichalargenumberofburns(initiallywithxenonlight)hadbeenplaced

seemedtohavebetteroutcomesthanthosewithfewerspotsoftherapybecauseof

lesssevereproliferativeDR.Regardlessoftreatmenttechnique,eyesinwhicha

genuine“involution”occurredwerecharacterizedbywidespreadnarrowingof

retinalvessels,mildopticatrophy,and(ofcourse)alargenumberofpigmented

burnscars.Coincidentally,Beethamiscreditedwithrecognizingthatsuchcases

weresimilartothosewithwidespreadchorioretinitsoropticatrophydueto

vascularaccidents;151itwaswidelyacceptedbutpoorlydocumentedthatsuchcases

providedapparentprotectionfromretinopathyprogressionwhentheyoccurredin

asingleeyeofapatientwithdiabetesinwhichthe“unaffected”eyewithDR

continuedtoprogress.152Thisinturnleadtothedevelopmentofasecond

photocoagulationtechnique,“scattertherapy”,inwhichlargenumbersofburns

wereplacedrandomlyintheposteriorretina,avoidingthemacula,anddisregarding

thelocationsofneovascularization.Theoriginatorsofthistechniqueinitially

employedarubylaser,butbothxenonarcandargongreentherapieswerelater

employedincollaborativestudiesdiscussedbelow.Resultsofphotocoagulation

werecollectedinadvanceoftheAirlieHouseSymposiummentionedbothabove

andbelow.Atotalof1,635eyeshadbeentreated,andtherewasgeneralagreement151AielloLM,BeethamWF,BalodimosMC,etal.Rubylaserphotocoagulationintreatmentofdiabeticproliferatingretinopathy:preliminaryreport.In:FineSL,GoldbergMF(Eds).Symposium:TreatmentofDiabeticRetinopathy.Washington,D.C.1969,U.S.DeptofHealth,Education,andWelfare,p.438.152Thisappearancewasalsorecognizedinrarecasesinwhichextensiveretinalburnshadbeencreatedforretinaldetachmentinoneeyeofadiabeticpatient,andsevereproliferativediseasedevelopedonlyintheothereye.OkunE.Discussionofvisualandanatomicresults.In:FineSL,GoldbergMF(Eds).Symposium:TreatmentofDiabeticRetinopathy.Washington,D.C.1969,U.S.DeptofHealth,Education,andWelfare,pp.619.

42

thatthetreatmentwassignificantlybetterthannotherapy.Still,theneedforbetter

studiescomparingtreatedandcontroleyeswithsimilarstagesofDRwasalso

expressed.153

TheprofoundincreaseinDRasamajorcauseofvisualdisabilitystimulated

theU.S.PublicHealthServicetosponsorasymposiumatAirlieHouse,Virginiain

theautumnof1968.154InadvanceofthemeetinginJune,1968asmallgroupof

sevenexpertsmetinChicagoneartheO’Hareairportinanefforttoestablishanovel

DRgradingsystembaseduponahandfulofpriorreports155;thiswasnecessaryto

establishastandardclassificationofdiseasesothatclinicallyequivalentcasescould

becomparedfollowingtreatmentsofvarioustypesandafterlengthsoftimewithno

therapy.156Aselectgroupofapproximately55experiencedophthalmologistsanda

similarcohortofneurosurgeons,epidemiologists,andendocrinologistswereinvited

tothesymposiumandaskedtopreparereportsoftheirsuccessesandfailures

utilizingtheirpreferredtechniquesandemployingtheO’Hareclassification.The

outcomedatainattendees’manuscriptswerethendistributedtoallinadvanceof

themeetingsothatmeaningfuldiscussionswouldoccurwhenthesymposiumtook

place.ThisInternationalSymposiumonTreatmentofDiabeticRetinopathywasheld153DavisMD.SummaryofpersonalimpressionsofAirlieHousesymposiumondiabeticretinopathy.In:FineSL,GoldbergMF(Eds).Symposium:TreatmentofDiabeticRetinopathy.Washington,D.C.1969,U.S.DeptofHealth,Education,andWelfare,pp.718-719.154Personalcommunication,StuartFine,MD,September2017.155HistorianHenryMarksstated“…clinicalresearchisintrinsicallyasocialprocess”.(MarksHM.TheProgressofExperiment.ScienceandTherapeuticReformintheUnitedStates,1900-1990.1997,Cambridge,CambridgeMedicalPress,p.240),inwhich“endlessnegotiationstookplace”.Still,theacademicretinacommunitywasverysmallin1968,andthemembersofthisgroup,leadmyMathewD.Davis,wasrecognizedascomposedoftheleadinglegitimateexpertsonDR.Similarly,thoseinvitedtotheAirlieSymposiumwereacknowledgedexpertsintheirrespectivefields.156DavisMD,NortonEWD,MyersFL.TheAirlieclassificationofdiabeticretinopathy.In:FineSL,GoldbergMF(Eds).Symposium:TreatmentofDiabeticRetinopathy.Washington,D.C.1969,U.S.DeptofHealth,Education,andWelfare,pp.

43

atAirlieHouseSeptember29-October1,1968.Sixsessionsincluded:classification

ofDR;naturalhistoryandvisualprognosis;relationshipofDRtoglucosecontrol;

pituitaryablation;photocoagulation;andmiscellaneoustopics.Thismeetingwas

thecriticaleventinthepathtowardmorescientificevaluationsregardingtreatment

forDRbecausethepresenteddatahaddemonstratedthatphotocoagulationwas

moreeffectivethanhypophysectomy,and(moreimportantly)itstimulatedthe

developmentofseveralrandomizedtrialsoftheformertherapy.

ThemethodsdescribedintheAirlieHousepublicationhadbeendifficultto

interpretbecauseofaninsufficiencyofdataregardingthepredictabilityofanygiven

case.Bothhypophysectomyandphotocoagulationproducedavarietyofoutcomes

thatmadecomparisonsofthetwomodalitiesandalsoofthenaturalcoursesof

untreatedeyesquiteuntenable.Clearly,experiencedphysiciansofhighintegrityhad

recordedsuccesseswithbothphotocoagulationandpituitaryablation,butfailures

alsohadoccurred.Thesituationwasperhapsbestexemplifiedbyaleadingexpert

onthesubjectwho,whenaskedtodiscussphotocoagulationatasymposium,stated

thatofcoursehewouldbepleasedtocommentbutthathewouldneedtoknowifhe

shouldplantodeliverthespeechonthesuccessofthemodalityorhowdangerousit

appearedtobe;157forphotocoagulationhadwell-knownseverecomplications,

especiallywhenappliedtoeyeswithadvancedDR,anditwasnotalwayssuccessful,

eveninnon-advancedcases.

Thus,inspiteofthemanycaseseriesreportsregardingphotocoagulation

andpituitaryablation,itwasclearthatby1968therewasnounequivocalanswerto157Fine2017Opcit.

44

thequestion“whatisthebestwaytotreatadvancedDR?”inspiteofthefactthat

over1,200reportedpituitaryablationsand1,600recordedphotocoagulation

procedureshadbeenperformedinthedecade1958-1968.158Buttheimplicationsof

theAirlieHouseSymposiumhadstimulatedanacceptanceofphotocoagulationas

preferabletopituitaryablationeventhoughquestionsremainedaboutthegenuine

efficacyoftheformeralternative,andthisstimulatedinterestbybothpractitioners

andthegovernmenttomoveawayfromthepersonalexperiencesandopinionsof

expertsandinitiatethedevelopmentofarandomizedtrial(RCT)toprovide

conclusiveevidenceregardingthebenefitsorlackofefficacyofphotocoagulation

therapy.

Developmentoftheevidencebasefortreatmentofdiabeticretinopathy

ThereisarichliteratureonthehistoryofRCT’s.159,160,161,162Accordingto

Lilienfeld,163thefirsttrialfeaturingrandomizationbeganin1931inregardtothe

useofsanocrysinfortuberculosis,andthisstudywasalsothefirsttoemploya

double-blindstrategy.164Still,itappearstobewidelyacceptedthattraditional

randomizationoflargenumbersofpatientsbeganinEnglandinthe1940’swiththe158FineSL,GoldbergMF,TasmanW.Historicalperspectivesonthemanagementofmaculardegeneration,diabeticretinopathy,andretinaldetachment.Personalreminiscences.Ophthalmology2016;123:S64-S77.159MarksHM.TheprogressofExperiment.ScienceandTherapeuticReformintheU.S,1900-1990.NewYork,1997,CambridgeUniversityPress.160BothwellLE,GreeneJA,PodolskySH,etal.Assessingthegoldstandard-lessonsfromthehistoryofRCT’s.NEJM2006;374(22):2175-81.161ChalmersTC.Randomizationofthefirstpatient.MilbankMemFndQuart1981;59(3):.324-9.162ChalmersTC.Theclinicaltrial.MedClinNAmer1975;59(4):1035-8.163LilienfeldAM.Ceterisparibus.Theevolutionofthecontrolledtrial.BullHistMed1982;56(1):1-18.164AmersonJB,McMahanBT,PinnerM,AmersonJB.Aclinicaltrialofsanocrysininpulmonarytuberculosis.AmRevTuberculosis1931;24:401-35.

45

workofA.B.HillandtheMedicalResearchCouncilinregardtoStreptomycinfor

tuberculosis165,althoughananalysisofattemptstodemonstratetherapeutic

efficacy,forerunnersofRCT’s,revealedthatlesssophisticatedmethodswere

initiatedmuchearlier.166,167TheearlyRCT’swereemployedintheevaluationsof

medicalratherthansurgicaltherapy,andsomeauthoritiesstatedthatthereexisted

a“doublestandard”,withsurgicalproceduresnothavingtomeettherigidcriteria

forefficacydemandedbyagenciessuchastheFDA.168However,thisopinion

contrastedwithanalternativeexplanationthatthemanualskills,experiences,and

intraoperativevariablesdemandedofsurgeonsmadeacomparisonofsurgicaland

medicaltherapeuticoutcomesquiteunrealistic.169Still,surgicalRCT’sbecame

important,inspiteoftheirinherentpotentialdifficultiesregardingsurgeon

experienceandexpertise,170,171althoughthemajorityofthesefollowedthestudies

mentionedbelow.

Inhistextonthedevelopmentofclinicaltrialsinmedicine,Marksnoted

“newtherapeuticswasaproductoftwoinstitutions:thelaboratoryandthe

165 Streptomycinintuberculosistrailscommittee.Streptomycintreatmentofpulmonarytuberculosis.BrJMed1948;2:769-782.166BothwellLE,PodolskySH.Theemergenceoftherandomized,controlled,trial.NEJM2006;375(6):501-4.167GreeneJA.Therapeuticproofsandmedicaltruths:theenduringlegacyofmedicaldrugtrials.BullHistMed2017;91(2):420-9.168SpodickDH.Numeratorsanddenominators.ThereisnoFDAforthesurgeon.JAMA1975;232(1):35-6.169LoveJW.Drugsandoperations.Someimportantdifferences.JAMA1975;232(1):37-8.170RomanH,MocrpeauL,HulseyTC.Surgeons’experienceandinteractioneffectinrandomizedcontrolledtrialsregardingnewsurgicaltechniques.AmJObstandGynec2008;199(2):108.e1-108.e6.171TangCL,SchlichT.Surgicalinnovationandthemultiplemeaningsofrandomizedcontrolledtrials:thefirstrandomizedcontrolledtrialonminimallyinvasivecholecystectomy.JHistMedAlliedSci2017(72(2):117-41.

46

market”.172Althoughthereclearlywasa“market”foreffectivetherapyforDR,I

believethattheformervariable(thelaboratory)wasnotrelevantatthetimeRMT’s

werebeingformulated,foralthoughnumerouspreclinicallaboratoryresearch

studiesregardingphotocoagulationhadbeenperformedbythetimethatclinical

trialsofthetreatmentmodalities(XenonandArgon)werebeingconsidered,the

deviceshadbecomestandardsoftherapyforbothDRandseveralnon-diabetic

retinalvascularandretinaldetachmentdisorders,andthephysicalskillsnecessary

fortreatmentwerenotextraordinary-expertisewasacquiredinresidency

programs.Priortoestablishmentofrandomizedtrials,avarietyoftherapeutic

photocoagulationstrategieswereroutinelypracticedontheaboveconditions

worldwideasphysiciansacquiredthedevicesinthelatter1960’s.Thestudiestobe

describedbelowwerefundedbytheNationalEyeInstitute(NEI)oftheNIH,andthe

randomizationprocessintheDiabeticRetinopathyStudywassimplyamatterof

selectingoneofapairofeyeswithsimilarstagesofretinopathyfortreatmentand

theotherasacontrol.Theestablishmentofappropriatetrialsrequiredextensive

preparation.

TheDiabeticRetinopathyStudy(DRS)173wasthefirstformalrandomized

andcontrolledstudyinophthalmology,althoughapriortrialoftheeffectsofoxygen

uponprematurebabieshadfeaturedcomparisonsbetweengroupsofsimilar

172Marks,Op.Cit.173TheDiabeticRetinopathyStudyResearchGroup:Preliminaryreportoneffectsofphotocoagulationtherapy.AmJOphthalmol1976;81:383-396.

47

patients.174TheDRSrequiredagroupeffortthatincludedthecountry’sleading

authorities,andthiswasparticularlyimportantintheestablishingofamore

sophisticatedDRclassificationsystemregardingtheseverityofretinopathy.

TheHammersmithgroupintheUKhadestablishedaschemeforgradingDR

severityin1966,andthisservedasastimulusforlaterclassifications.175InJune,

1968,asnotedabove,asmallgroupofexpertsmetneartheO’Hareairportand

producedaschemeforthemeetingatAirlieHouseinVirginiaalsomentioned

above.176Publicationsofthepapersanddiscussionsappearedsoonthereafter,and

minormodificationsoftheO’Hareclassificationresultedinthe“AirlieHouseDR

classification”thatwasemployedduringthesubsequentDRS.177

TheNIH-fundedDRSwasbegunin1971;patientswererecruitedfrom15

clinicalcenters;initialoutcomeswerepublishedin1976.178Thestudyincluded

patientswithrelativelyadvancedDRandvision20/100orbetterinbotheyes;thus

oneeyecouldserveasacontrol.Thestudy’sprimaryend-pointwasthe“severeloss

ofvision”(lessthan5/200andwelllessthanthedefinitionoflegalblindnessas

20/200)ontwoconsecutive4-monthfollow-upvisits.Therapeuticstrategies

includedeitherXenonorArgontreatmentwithphotocoagulationburnsapplied

174PatzA,HoeckLE,DeLaCruzE.Studiesontheeffectofhighoxygenadministrationinretrolentalfibroplasia.1,Nurseryobservations.AmJOphthalmol1952;35(9):1248-53.175OakleyN,HillDW,JoplinGF,etal.Diabeticretinopathy.I.Theassessmentofseverityandprogressbycomparisonwithasetofstandardfundusphotographs.Diabetalogia1967;3(4):402-5.176EventhoughIwasaretinafellowatthetime,ipersonallykneworhadmeteachoftheseindividualsthroughtheircontactswithmyChairmaninMiami,andIwasfamiliarwiththestateofclassifications.Theseophthalmologistswereindeedtheleadingauthoritiesatthetime.AlthoughIwasnotpresentatanyofthesemeeting,itwasmyimpressionthatdebatesabout“finepoints”weremanagedinanequitableandamicablefashion.177Fine,Goldberg,Tasman2016,op.cit.178TheDiabeticRetinopathyStudyResearchGroup,1996,Op.Cit.

48

directlytoflatareasofneovascularizationandalsototheretinaperipheryina

“scatter”(random)pattern.

Intheinitialreportregarding1,727patients,869eyeshadreceivedXenon

therapyand858,Argon.Aftertwoyears,16.3%ofuntreatedeyeshadexperienced

severevisualloss,butthisoccurredinonly6.4%oftreatedcases,areductionof

61%(Fig.2).Thesesignificantdifferencesresultedintreatmentforthefelloweyes

tobeoffered,andphotocoagulationbecameacceptedworldwideasthetreatmentof

choiceforproliferativeretinopathy.

ThesignificanceoftheDRSshouldnotbeunderestimated.Upuntilthetime

ofitspublication,practitionershadnoevidence-baseddataregardinghowtotreat

anincreasingnumberofeyeswithadvancingproliferativeDR.Forexample,in1972

asayoungretinaspecialistinanacademiccenterbutnotparticipatingintheDRS,I

adaptedthepremiseoftheprotocolsincethevalueofphotocoagulationremained

undocumented.Irecalla38-yearoldwomanwitha21-yearhistoryoftype1DM

withseverebutsymmetricalproliferativediseaseineacheye.SheandIliterally

flippedacoinanddecidedtotreatherrighteyewiththelaserandfollowtheleft.

Shedidwellwithphotocoagulationtherapybutbecameblindinherlefteyeduetoa

seriesofvitreoushemorrhagesoverthefollowing15months.Ultimately,theblood

wasremovedwithavitrectomy(seebelow)andusefulvisionwasrestored.

Fortunately,furtherguidelinesformanagementweredevelopedinadditionaltrials.

AsecondDRSreportwaspublishedin1978anddescribedachangeinstudy

protocoltorequiretheconsiderationofuntreatedcasesofPDRwithselected

49

featuresthatweretermed“highriskcharacteristics”.179Themajorconclusionsin

thispublicationwerethatphotocoagulationtreatmentcontinuedtodemonstrate

significantefficacyforhighriskcasesandthatthexenon-treatedeyesweremore

likelytosuffercomplicationsoftreatment,includinglossesofbothcentralvision

andperipheralvisualacuity,thanwerethosetreatedwithargonlaser.AthirdDRS

reportcorroboratedthesefindinganddescribedthecumulativeeffectsoffourrisk

factors:thepresenceofvitreousorpreretinalhemorrhage;thepresenceofnew

vessels;alocationofnewvesselsonorneartheopticdisc;andtheseverityofthe

newvessels.180Asthenumberofthesefactorsincreasedinaneye,sodidthe

chancesofit’ssufferingaseverelossofvisionwithouttreatment.

AdditionaltrialsfurthercontributedguidelinesformanagementofDR.The

EarlyTreatmentDiabeticRetinopathyStudy(ETDRS)181wasthesecondprospective

randomizedcontrolledmulti-centerclinicalstudyregardingDR,initiatedin1980

andfundedbytheNationalEyeInstitute(NEI)oftheNIH.Theoriginalintentofthe

effortwasthree-fold:tolearntheoptimaltimetobeginscatterphotocoagulationfor

“lessthansevere”DR;todiscoverifaspirintherapywashelpfulorharmful

regardingDR;andtoestablishthevalueofphotocoagulationfordiabeticmacular

edema(DME).Thefirstpublishedreportin1985wasinregardtoonlythisthird

issue.Severalpriorstudieshadclaimedabenefitfromthistreatment,buttheywere

179TheDiabeticretinopathyresearchgroup.Photocoagulationtreatmentofproliferativediabeticretinopathy:Thesecondreportofdiabeticretinopathystudyfindings.Ophthalmology1978(1):82-106.180TheDiabeticretinopathyresearchgroup.Severevisuallossindiabeticretinopathy.Thethirdreportfromthediabeticretinopathystudy.ArchOphthalmol1979;97(4);654-5.181EarlyTreatmentDiabeticRetinopathyResearchGroup.Earlytreatmentdiabeticretinopathyreportnumber1.ArchOphthalmol1985;103(12):1796-1806.

50

inconclusiveduetodeficienciessuchasnon-randomization,smallcohortsize,

incompletedescriptionsoftechniques,andavarietyofmethodologicalissues.For

thepurposesoftheETDRS,“clinicallysignificantDME”wasdefined,butnovisual

acuitylevelswereincludedinthesedefinitions.

FromApril,1980throughAugust,1985,3,928patientsat23clinicalcenters

wererecruitedfortheETDRS.Atfollow-up,eyesassignedtoimmediatefocallaser

treatmentforDMEwereapproximatelyhalfaslikelytolosevisualacuityasthose

assignedtodeferral,andthedifferencesbetweengroupsincreasedwithtime(5%

vs.8%atoneyearoffollow-upand12%vs.24%atthreeyears).The

recommendationsofthestudywerethatfocallaserphotocoagulationtherapy

shouldberecommendedforalleyeswithclinicallysignificantDME.Patientswere

usuallyadvisedthattherapywasmoreeffectiveinpreventingfurtherlossofvision

thaninimprovingvisualacuity.

InregardtothefirstofthreegoalsfortheETDRS,the2,052patientswithno

DMEhadeyesrandomized50:50tolasertherapyorobservation.Theseeyeshad

moderatetoseverenon-proliferativeorearlyproliferativeretinopathy,andlaser

treatmentincludedeither"full"or"mild"scatterlasertreatment.182Ultimately,data

demonstratedincreasingvalueofphotocoagulationasthestageofnon-proliferative

DRapproachedthe“severe”stage,withearlytherapyappearingtobeofparticular

valueintype-2patients.183RegardingthesecondgoaloftheETDRS,thevalueof

aspirintreatment,thestudydemonstratedthataspirinusedidnotalterthecourse

182FerrisFL.EarlyphotocoagulationineyeswitheithertypeIortypeIIdiabetes.TransAmOphthalmolSoc1996;94:5065-537.183Ibid.

51

ofDR.184AnadditionalandveryimportantcontributionoftheETDRSwasthe

productionofaDRseverityscalethatrangedfrom“noretinopathy”to“verysevere”

disease.185Thisscalewassubsequentlyemployedinnumerousstudiesandtrials

regardingtheappearanceandprogressionofDR.

Vitreoussurgerywasdevelopedintheearly1970’s,anditbecamethefirst

intraocularmethodtomanageDR,andsubsequentstudieswereperformedto

assessitsvalue.Itwasconsideredfordiabeticeyesinwhichnootherformof

therapywasavailable;laserburnscouldnotpenetratevitreousbloodandwere

ineffectivefordetachedretinas.TheDiabeticRetinopathyVitrectomyStudy

(DRVS)186,187,188wasaNEI-supportedrandomizedtrialofvitrectomyforadvanced

DRwitheithermassivevitreoushemorrhageorretinaldetachment.Thegoalsof

thisDRsurgeryincludedtheremovalofallbloodandtheposteriorcorticalsurface

ofthevitreousgel,thuseliminatingtractionforcesuponboththenewvesselsand

theretina.Additionally,improvedtechnologyallowedintraocularlasertreatment

neartheendoftheprocedure.Thisrandomizedtrialdemonstratedabenefitof

surgery:vitrectomyimprovedtheprognosisforgoodpostoperativevisionwithout

184EarlyTreatmentDiabeticRetinopathyResearchGroup.Effectsofaspirintreatmentondiabeticretinopathy.ETDRSreportnumber8.Ophthalmology1991;98:757-65.185ETDRSstudygroup.Fundusphotographicriskfactorsforprogressionofdiabeticretinopathy.ETDRSreportnumber12.Ophthalmology1991;98:823-33.186TheDiabeticretinopathyvitrectomystudyresearchgroup.Two-yearcourseofvisualacuityinsevereproliferativediabeticretinopathy.Diabeticretinopathyvitrectomystudy(DRVS)reportnumber1.Ophthalmology1985;92:492-502.187TheDiabeticretinopathyvitrectomystudyresearchgroup.Hemorrhageindiabeticretinopathy.Two-yearresultsofrandomizedtrial.Diabeticretinopathyvitrectomystudyreportnumbertwo.ArchOphthalmol1985;103(11):1644-52.188TheDiabeticretinopathyvitrectomystudyresearchgroup.Earlyvitrectomyforsevereproliferativediabeticretinopathyineyeswithusefulvision.Resultsofarandomizedtrial.Diabeticvitrectomystudyreportnumber3.Ophthalmology1988;95(10):1307-20.

52

increasingoddsofreducingvisualacuity.ManysubsequenttrialsregardingDR

continuetobepublished.

TheDRCRNetwork(DRCR.net)wasandisacollaborativeNEI-supported

networkthatwasfoundedin2002tofacilitateandexpediteresultsofmulticenter

clinicalresearchregardingDRandavarietyofadditionalretinaldisorders.Although

onlyfourstudysitesarelocatedoutsideoftheU.S.andCanada,theprogramhas

producedresultsthathaveprofoundlyalteredDRcarearoundtheworld.Byearly

2018,theNetworkincludedover400investigatorsat115clinicalcenters,both

academiccenter-basedandcommunitypractice-based.TheDRCR.netsupportsthe

identification,design,andimplementationofmulticenterclinicalresearchinitiatives

withestablishedprotocolsthatallowapoolingofdatainrandomizedtrialsfromthe

separateclinicalcenters;variousclinicsareinvolvedinseparatetrials,andthe

protocolsarereadilyaccessibletoophthalmologistsuninvolvedintheprogram.

Sinceitsinception,andasofJanuary2018,theDRCR.netgrouphascompleted18

studyprotocolsandcontinuestorecruitforseveralothers.

Over80DRCR.netmanuscriptshavebeenpublishedinpeer-reviewed

journals,andseveralotherpapershavebeenacceptedforpublication.Inregardto

DR,themostimportantreportshavedemonstratedthatanti-vascularendothelial

growthfactor(anti-VEGF)agents(ranabizumab,bevacizumab,aflibercept)were

moreefficaciousthanlasertherapyinthetreatmentofDME,andthemorerecent

trialshaveindicatedthatthesedrugsareaseffectiveasPRPforselectedformsof

PDR.Atthepresenttime,bothranabizumabandafliberceptinjectionshavebeen

53

approvedbytheFDAfortreatmentofallformsofretinopathy.189However,they

requireintravitrealinjectionsona4-6weekscheduleforvaryinglengthsoftime

andtheyareexpensive,sotheirrolesintheinternationalmarkets,especiallyin

lowerincomesocieties,remainunknown.Ongoingresearchregardingdevicesfor

sustainedreleaseofeffectivecompoundsovermanymonthswillhopefullyimprove

thesituation.

Thischapterhasdiscussedtheearlydevelopmentofinstrumentstodetect

DRandmostimportantlyreviewedacondensedhistoryofresearchtrialsthat

establishedtheevidencebaseforitscontemporarymanagement.Clearly,the

developmentofanevidence-basedalgorithmforrecognitionandtreatmentofDR

hasoccurred;strongevidenceexistsregardingboththeidentificationofstagesof

retinopathyinneedoftherapyandtheoptimaltherapeuticstrategiesthatshouldbe

employed190.Thedevelopmentofaninternationallyacceptedsequenceof“whatto

do”stepsforvariousstagesofDRhasbeendemonstrated.

However,itdoesnotnecessarilyfollowthatknowledgeregardingthemost

appropriatetreatmentmodalitieswillbefollowedbytheadoptionofoptimal

practicesglobally.Indeed,despitetheconvincingdataforDRphotocoagulation

treatment,effortsbynationalandinternationalhealthcaresystemstocombatthe

disorderhaveprovedsuccessfulonlyinpatchyregions.Thenextchapterexplores

thisdilemmainmoredetail.189DiabeticRetinopathyClinicalResearchNetwork.Intravitreousanti-VEGFtreatmentforpreventionofvisionthreateningdiabeticretinopathyineyesathighrisk.JaebCenterforHealthResearchwebsite.https://public.jaeb.org/drcrnet/stdy/340.AccessedJune27,2019.190Still,researcheffortscontinuetoevolve.Inparticular,theappropriaterolesofanti-VEGFinjectionsforallformsofDRcomparedtopreviouslydevelopedevidencebasedlasertherapiescontinuetobeexplored,especiallyforlowerincomecountries.

54

Chapter5.

Developmentofhealthcaresystemsformanagementof

retinopathy

Inthepriorchapter,DRwasdescribedalongwiththeresearchleadingtoan

algorithmforitseffectivetreatment.AndinChapter2,theimportanceofglucose

controluponthecomplicationsofDMwasdocumented.Inthepresentchapter,I

describethedevelopmentofsubsequenteffortstoreducetheglobalimpactofDR-

relatedvisionloss,includingtheintroductionoftelemedicaltechnology.

Thetrialsandsubsequentpublicationsdescribedinthepreviouschapter

demonstratedthatevidence-basedtreatmentfordiabeticretinopathycouldreduce

therisksofDRblindnessinover90%ofcases,andiftreatmentwereinitiatedat

relativelyearlystages,thisfigurecouldriseto98%.191,192Althoughsuchsuccess

rateswererecognizedbyatleast1985,biomedicaladvancesregardingdiagnosis

andtreatmentwerenotreflectedbytheabilitytomanageaffectedpatients,asthe

prevalenceofvisualdisabilityduetoDRcontinued(andcontinues)togrow

worldwide.

Investigatorsinmostpartsoftheworldhavebecomemoreawareofthe

epidemicofDManditsmanycomplications,includingDR,asattestedtobyhuge

numbersofbothscientificandlayarticles.Contemporarymanagement

191WorldHealthOrganization.ReportofaWHOConsultationinGenevaSwitzerland9-11November2005.Geneva2006,WHO,pp.1-39.192FerrisFL.Howeffectivearetreatmentsfordiabeticretinopathy.JAMA1993;269(10):1290-1.

55

(identificationandtreatment)hasreapedrewardsinpreventingvisionlossinsome

selectedregions,especiallythosewithuniversalhealthcare,butratesofvisionloss

havecontinuedtoincreaseinlowerincomecountries,inwhichidentificationof

patientswithdiabetes,letaloneretinopathy,isdifficult,andtreatmentfacilitiesare

sparselydistributediflocatedawayfromofmedicalcenters.

TheimportantSt.VincentDeclarationofOctober,1989(13andfouryears,

respectively,followingpublicationsoftheDRSandETDRS)wasaneffortto

stimulateEuropeanprogramstocombatDMandDR.193TheDeclarationwasthe

productofameetingofgovernmenthealthdepartments,concernedpatient

organizations,anddiabetesexpertsinSt.Vincent,ItalyundertheaegisoftheWHO

andIDF.TherewasaconsensusthatDMrepresentedanincreasingmajorhealth

probleminallcountriesandthatareductionintheburdensofthediseaseshouldbe

amajorgoal,asitwouldreducehumanmiseryandresultinmassivesavingsofboth

humanandmaterialresources.Therewasaunanimousresolutionthatincludedasa

majorgoalthereductionofblindnessduetoDRbyone-thirdinthefollowingten

years.194Thisgoalprovedtobeoverlyoptimisticandwasnotachievedinmost

areasoftheworld:asof2009,only13oftheEU’sthen28memberstateshad

developedandimplementedanationalframeworkorplantohelpreduceDR-

relatedvisionloss.195

193StVincentDeclaration.DiabetescareandresearchinEurope.ActaDiabetelogia1989;10(suppl):143-4.194TheStVincentDeclaration.DiabetesinEurope:aproblemofallagesinallcountries.ActaOphthalmolScand1997;75(suppl):223.195FeltonA-H,HallMS.Diabetes—fromStVincenttoGlasgow.Haveweprogressedin20years?BritJDiabVascDis2009;9(4):142-144.

56

Additionally,theWHOin2006(approximately30yearsafterresultsofthe

DRSwerepublished)issueditsveryfirstreportaimedspecificallyatDR,

“PreventionofBlindnessfromDiabetes”.196Itwasdevelopedbyapanelofwidely

distributedinternationalexpertsinGenevainNovember,2005,andsectiontitles

included“Globalpresenceofdiabetesanditscomplications”,“Evidencebasefor

preventionandtreatmentofDR”,“Principlesineyecareforpeoplewithdiabetes”,

and“PrinciplesfororganizinganeyehealthcaresystemforthecareofDR”.These

recommendationswereconsistentwiththeevidence-basedmanagement

documentedinthe“DRPreferredPracticePatterns”publishedandupdated

regularlybytheAmericanAcademyofOphthalmology,buttheyincluded

recognitionthatrealitiesofsituationaldifferencesamongcountrieswouldlimit

abilitiestoachieveallgoals.

Asnotedearlier,optimalcontemporarymanagementstrategiesforbothDM

andDRarebaseduponevidence-basedtrials.However,theabilitytoimplement

goodpracticeshasbeenhamperedinmostregionsoftheworldbyacombinationof

variables,includingavailabilitiesofphysicians,equipment,andpharmaceutical

resources;financingofcare;andcomplianceofpatientsmanagingtheirsystemic

diseaseandDRinprescribedfashions197.Thesevariablesinturnareprofoundly

affectedbytherespectivestatesofhealthcaresystemsingivencountriesor

territories,andthesevaryconsiderably,asnotedbelow.

196WHO.PreventionofBlindnessfromDiabeticRetinopathy.Geneva2006,WHO,pp1-40.197Holtz,GlodalHealthcare,Opcit.

57

TheWHOperiodicallyratestheoverallperformancesofinternational

healthcaresystems,anda2017publicationrankedthecountriesdiscussedhereas

18th(UK),37th(U.S.),and112th(India).198Similarly,inanearlierCommonwealth

Fundanalysisofthecomparativeperformanceinhighlydevelopedcountries199,the

U.S.underperformedtheothers,failingtoachievebetterhealthoutcomesinspiteof

itsbeingthemostexpensivehealthcaresystem200.Inanotherreport,theU.S.was

rankedasthe“worsthealthcaresystemintheindustrializedworld”withthemost

privatizedcompensationschemes201.Thus,althoughthevastmajorityofstudies

thatdocumentedthevalueofDRmanagementwereperformedintheU.S.,and

althoughpatientswithappropriatehealthinsurancearegenerallywelltreated

there,theabsenceofaninstitutionalizedsocialwelfaremedicalcareinsurance

systemsimilartothoseinotherindustrializedcountriesresultsinmanydiabetic

patientsnotreceivingoptimalcare.

InalowerincomecountrysuchasIndia,themaldistributionofpatients,

caregivers,andresourceshascompromisedmanagementinregionsunassociated

withcontemporaryfacilities.Still,inallregionsoftheworld,theintroductionof

telemedicaltechnologytofacilitatetheidentificationandgradingofDRindiabetic

patientsrepresentsapotentialmajorimprovementinthehealthcareprocess,

althoughthisiscurrentlyavailableinonlyafewregions.198TandonA,MurrayCJL,LauerJA,etal.Measuringoverallhealthcaresystemperformancefor191countries.GenevaSwitzerland2017,WorldHealthOrganization.199ThecountriesincludedAustria,Canada,France,Germany,theNetherlands,NewZealand,Norway,Sweden,theUK,andtheU.S.200DavisK,StremikisK,SquiresD,etal.HowtheperformanceoftheU.S.healthcaresystemcomparesinternationally.NewYork2004,TheCommonwealthfund,pp.1-31.201Sanchez-SerranoI.TheGlobalHealthcareCrisis.FromtheLaboratoryBenchtothePatientBedside.Elsevier,London2011.

58

Todate,theEnglishDiabeticScreeningProgram(andsimilarprogramsina

fewnearbyEuropeancountries)representsthegoldstandardregardingthe

identificationandmanagementofDR.Admittedly,thiswasfacilitatedbythe

existenceofanestablished“universal”nationalhealthcareprogram.IntheU.S.,

healthcareplansareerraticallyandincompletelydistributed,asnouniversalhealth

careisavailable;andinIndia,allprogramsareinadevelopmentalstageinmost

regions.ThecontemporaryevidenceforDRcareiswellrecognizedbyretina

specialistsaroundtheworld,andthemajordilemmainthetherapeuticprocessisan

inabilityofpatientstophysicallyinteractwithappropriatecaregivers.

Therelativelyrecentdevelopmentoftelemedicaltechnologythatfacilitates

connectivitybetweenpatientandcaregiver,thusreducingtheinabilitytolink

patientswithoptimaldiagnosticandtherapeuticentities,hasimprovedthe

potentialforeffectivecare.Earlyeffortsintelemedicinewereimproved

exponentiallybytheintroductionandimplementationofInternetcapabilities.

Theearliestdocumentedtelemedicalapplicationsdatetotheearly20th

century202-203,andamultitudeofsubsequentresearcheffortshaveresultedin

progressivelymoresophisticatedmeansofcombiningmedicalinformationwith

communicationtechnology204.SincetheclinicalmorphologyofDRcanbe

categorizedatvariouslevelsofriskforvisualloss,stagesofthedisordercanbe

capturedphotographicallyfromanyclinicalcarefacilitywitheffectiveresources

202StrehleEM,ShabdeN.One-hundredyearoftelemedicine:doesthisnewtechnologyhaveaplaceinpaediatrics?ArchDisChild2008;91(12):956-9.203EinthovenW.Letelecardiogramme.ArchIntdePhysiol1906;4:132-64(translatedintoEnglishAmHeartJ1957;53:602–15).204Strehle,Op.Cit.,8.

59

andtransmittedtoremotegradingcentersfromwhichappropriatetreatment

strategiescanberelayedbacktophysiciansattreatmentfacilities.Theoretically,

thistelemedicalschememayappeartobestraightforwardandeasilyperformed,

butitsaccomplishmenthasrequiredmajoreffortsonavarietyoflevels.

TheestablishmentofseverityscalesofDRanddiabeticmacularedema

requiredprogressivemodificationsofschemesbeginningwiththeO’Hare

classificationandevolvingintotheETDRSseverityscale,bothofwhichwere

mentionedpreviously.Theimagesemployedinthosegradingswerecapturedon

filmandthenemployedtocreatetheanalysisofDRimagestageversusrisk.These

picturesrequiredastandardizedprotocolthatultimatelyconsistedofseven

standardcolorstereo30°fields,developedas35-mmslides.Thetransferand

analysesofthefilmimageswasquitecumbersome,sotheprocesswasprofoundly

improvedwiththeintroductionofdigitalfundusphotographyin1987;anda

subsequentstudycomparingfilmanddigitalprocessingofprotocolfieldsthrough

dilatedpupilsdemonstratedequivalenceofthetwotechniques205.

Thetechnologyadvancesthatprogressedtotherealityofmodern

contemporarydigitalcamerasandtelemedicalsystemsarenotdescribed,buttwo

significantvariablesare:first,thenecessityofdilatingthepupilsformoreoptimal

picturesandsecond,thenumberandlocationoffieldsoftheretinathatshouldbe

photographedtoobtainareliablepictureofthestatusofDR.Compromiseshave

beenrequired:theuseofvastlyimprovednon-mydriaticcameraswouldresultin

191FransenSR,Leonard-Martin,TC,FeuerWJ,etal.Clinicalevaluationofpatientswithdiabeticretinopathy.AccuracyoftheInoveondiabeticretinopathy-3DTsystem.Ophthalmology2002;109(3):595–601.

60

morenon-gradableimages(butwithasimplifiedprocessthatwasmorepatient-

friendly)206;andalternativefieldchoicestothe7-field30°standardsoftheDRS

couldmisssitesofsignificantdisease.Still,non-mydriaticcamerasthatemployed

three45°fieldsbecamethestandardfortheJoslinVisionNetworkemployedinthe

IndianHealthServiceandVeterans’Administration207andmentionedbelow,

whereastheEnglishNationalHealthServiceutilizedmydriaticcamerasthat

documenttwo45°retinalfields208.Anumberofadditionaltelemedicalprograms

havebeendevelopedforscreeningofdiabeticpatients,andtheAmerican

TelemedicalAssociation(ATA)publishedareviewofthese,includingvariouslevels

ofvalidation,in2015209.Theessentialpointregardingthesetelemedicalscreening

programsisthattheyofferedthepotentialtodetectlargenumbersofpatientswith

significantDRwhowouldotherwiseremainundiagnosed.

Theintroductionofartificialintelligence(AI)intoscreeningalgorithmshas

constitutedapotentiallymajoradvanceinremotetelemedicalscreeningforDR,and

inApril,2018,theU.S.FoodandDrugAdministration approvedmarketingofthe

firstmedicaldevicethatemployedAI;approvalwasbaseduponaclinicalstudyof

retinalimagesfrom900diabeticpatientsat10primarycaresites.TheAIdevice,

termed“IDX-DR”wasabletoidentifythepresenceofmorethanmilddiabetic

192ScanlonPH,MalhotraR,ThomasG,etal.Theeffectivenessofscreeningfordiabeticretinopathbydigitalimagingphotographyandtechnicianophthalmoscopy.DiabeticMedicine2003;20:467–74.207Bursell,S,CavalleroJD,CavellaroAA,etal.Stereonon-mydriaticdigital-videocolorretinalimagingcomparedtoEarlyTreatmentDiabeticRetinopathyStudysevenstandardfield35-mmstandardcolorphotosfordetermininglevelofdiabeticretinopathy.Ophthalmology2001;108(3):572-85.208HardingS,GreenwoodR,AldingtonS,etal.GradinganddiseasemanagementinnationalscreeningfordiabeticretinopathyinEnglandandWales.Diabeticmedicine.2003;20(12):965-71.209TozerK,WoodwardMA,Newman-CaseyPA.Telemedicineanddiabeticretinopathy:Reviewofpublishedscreeningprograms.JEndocrinolDiab2015;2(4):1-10.DOI:http://dx.doi.org/10.15226/2374-6890/2/4/00131.

61

retinopathy87.4percentofthetimeandtocorrectlyidentifypatientswhodidnot

havemorethanmilddiabeticretinopathy89.5percentofthetime210.Connecting

suchdiagnosticcapabilitieswithpatientsintheofficesofprimarydiabetes

caregiversthatcontainthesecameraswouldsignificantlyincreasethepercentages

ofpatientswithDMwhoarescreenedforDR,althoughcostscouldbeexcessivefor

small“captured”populations,asnotedbelow.Asecondcriticalstepinthecare

process,linkingthoseinneedoftreatmentwiththerapeuticfacilitiesandpersonnel

remainsaproblematicvariableinmanylocationsoftheworld.Iwillnowpresent

descriptionsofthecomparativehistoriesofpertinenthealthcaresystemsin

England,India,andtheU.S.

RetinopathycareinEngland

TheEnglishnationalscreeningprogramfordiabeticretinopathywas

initiatedin2003inanefforttoreducetheburdenofretinopathyonbothaffected

individualpatientsandthenation211.InspiredbytheSt.VincentDeclaration

mentionedearlierandtheexistenceoftheNationalHealthService(NHS),the

programextendedcoverageoverallofEnglandby2008,andby2016,over80%of

patientswithdiabeteshadagreedtobescreenedwithannualphotographs,thereby

ultimatelydisplacingDRasthenumberonecauseofcertifiableblindnessamong

England’sworkingagegroup.

210U.S.FoodandDrugAdministration,FDANewsRelease,April11,2018.211ScanlonPH.TheEnglishnationalscreeningprogrammefordiabeticretinopathy2003-2016.ActaDiabetologica2017;54:515-25.

62

Initially,aUKNationalScreeningCommitteeconsideredWHOscreening

principlesinappraisingtheviability,effectivenessandappropriatenessofa

proposedscreeningprogram212,213.Theseprinciplesincluded:first,screeningisa

publichealthprogram,notadiagnostictest;second,largenumbersofapparently

healthyindividualsareinvitedforretinopathyscreening,and,iftheirtestispositive,

theyareofferedfurtherdiagnosticinvestigation;third,somepeoplemaybeharmed

bytheprocess,orfalselyreassured;fourth,thereisanethicalandmoral

responsibilitytoensurethattheprogramsareofhighquality;andfinally,quality

assuranceofscreeningprogramsisessentialtoensurethattheprogramachieves

thehighestpossiblestandardsandminimizesharm214.Subsequently,digital

photographythroughdilatedpupilswasdemonstratedtoachieveanapproximate

85%sensitivityand95%specificity,andtheUK’sNationalInstituteforClinical

Excellence(NICE)initiallyapprovedthebasicsofsuchaprogramin2002,andithas

providedperiodicannualupdatesastreatmentoptionsgrowinnumber215.

Veryimportantly,theNHSinEnglandprovidedmajoradvantagesovernon-

“socialized”healthcaresystems,especiallyregardingpatientswithdiabetes.A

NationalDiabetesAudit(NDA)providedacomprehensiveoverviewofdiabetescare

inUnitedKingdomandWales.Thisauditcollectedinformationfrombothprimary

andsecondarycarefromapproximately4,700generalpractitioners(GP)officesand212WilsonJ,JungnerG(1968)Theprinciplesandpracticeofscreeningfordisease.PublicHealthPapers34.PublicHealthPapers,WHO,Geneva,GPEdiscussionpapernumber30.213ScanlonPH(2008)TheEnglishnationalscreeningprogrammeforsight-threateningdiabeticretinopathy.JMedScreen15:1–4.214Scanlon2017,Op.cit.215NationalInstituteforClinicalExcellence(2002)Managementoftype2diabetes,retinopathy-screeningandearlymanagement.NICEInheritedClinicalGuidelineE.London:NationalInstituteforClinicalExcellence.Availablefromwww.nice.org.uk

63

100specialistservices;andinthe2014–2015NDAreport,datawereacquiredon

roughly1.9millionpeoplewithdiabetes.

NICEhasrecommendedannualstudiesforalldiabeticpatientsaged12years

andoldertoincludebloodtests(glycatedhemoglobin(HbA1c),serumcreatinine,

andcholesterol),bloodpressure,urinealbumin,footsurveillance,bodymassindex,

andsmokinghistory.Schedulingandcollatingresultsofthesestudiesarethe

responsibilityofDiabetesCareProviders.Finally,annualdigitalphotographyretinal

screeningisrecommendedbyNICE,andthisisconductedunderanNHSDiabetic

EyeScreeningprogramonanannualbasis216.

Thealgorithmofthemanagementstrategyisasfollows:peoplenewly

diagnosedwithdiabetesareinvitedannuallyfordigitalretinalphotography

screening(usuallyinthecaregivers’offices),andimagesaregradedusingascale

quitesimilartothatdevelopedbyaninternationalcommitteeofretinopathyexperts

thatinturnwasbasedupontheETDRSdatamentionedpreviously217.Patients

foundtohavepotentiallysight-threateningretinopathyarereferredto

ophthalmologysurveillanceclinicsortotheNHSHospitalEyeService.Patients

withoutsignsofDRorwithonlynon-severeretinalchangesarescheduledfor

annualrescreeningphotographicevaluations.Asnoted,thenationalscreening

programhasprogressivelyevolvedtocovermorethan80%ofthediabetic

population.In2014–2015,therewere83screeningentitiesincludingbothNHSand

privateprovidersinUnitedKingdom,andinthatyear,2.5millionpeoplewith

216Scanlon,2017,op.cit.217WilkinsonCP,FerrisFLIII,KleinRE,etal.Proposedinternationalclinicaldiabeticretinopathyanddiabeticmacularedemadiseaseseverityscales.Ophthalmology2003;110:1679-xx

64

knowndiabeteswereofferedscreeningappointments,and2.1million(84%)were

screened218.Asaresult,DRnolongerwastheleadingcauseofseverevisual

impairmentamongworkingageadults.Still,ithasbeennotedthatanumberof

diabeticpatientsdonotappearfortheirretinalphotographs,andabsenceshave

beenduetoavarietyofissues,asdiscussedbelow.

TheoverallsuccessoftheEnglishscreeningprograminidentifyingand

managingdiabeticpatientswithDRhasbeenpossibleonlybecauseoftherealityof

theNHSanditsassociatedprograms.TheabilitiestoidentifythosewithDM,

regardlessofage,andtoentertheirmedicalrecordsandretinalphotographslocally

(usuallyintherespectiveGPoffice)forgradingandindicatedtreatmentare

impossibleinotherhealthcaresystemsthatdonotprovidemeansofplacing

patientsofallagesinanationaldatabaseandstronglyencouragingthemanagement

ofidentifiedcomplicationsofthesystemicdisease.Thesuccessesofthisprogram,a

productofanationaluniversalhealthcaresystem,couldserveasamodelforall

countries,butitsadaptationhasbeenaccomplishedonlyinselectedEuropean

countiesintheUK,Scandinavia,andIceland,allofwhichhavecontemporaryDR

screeningservicesasportionsofcentralizednationalhealthcaresystems.

RetinopathycareintheUnitedStates

Astheonlyindustrializedcountryintheworldtonotprovideuniversal

healthcare,thediagnosisandmanagementofDMandDRintheU.S.isquite

fragmented;theMedicareprogramcanprovideadatabaseofpatientsoverage65218Scanlon,2017,op.cit.

65

withdiabetes,andsocanavarietyofadditionalinsuranceprograms.Butamajor

“disconnect”intheU.S.istheinabilityforoptimalperiodiceyeexaminationstobe

performed,eventhoughtheyarerequiredasaHEDISmeasurementofquality

performance.Althoughsuchevaluationsareroutinelysuggestedbyphysicians

managingpatientswithdiabetes,anunfortunatelysignificantpercentageofthe

latterdonotfollowthroughforthoseeyevisits,especiallyiftheyareuninsured,

destituteandmembersofminoritygroups,allofwhicharemorelikelytobe

associatedwithgreaterlikelihoodsofDMandDRprevalence219.Butevenina“best

case”situationinwhichpatientshaveadequateinsurance,patientadherenceis

frequentlypoor.Inone2019studyofover298,000patientswithtype-2diabetes

andcontinuous5-yearcommercialoremployee-sponsoredhealthinsurance,only

15%metAmericanDiabeticAssociationguidelinesforannualorbiannualeye

screening.220

Individualhealthcareprogramsthatthatprovide“universalcare”toallofits

members,suchasthose(mentionedbelow)withintheIndianHealthService(IHS),

theVeterans’Administration(VA),andisolatedprivateinsuranceprograms,have

providedstrongevidencethatimprovedsystemsformanagementofDMand

associatedDRcouldbemadepossibleforall.

TheprevalenceofDMandDRinAmericanIndiansandAlaskanNatives,who

represent1.5%ofthepopulationoftheU.S.wasdiscussedearlier,and

219BarsegianA,KotlyarB,LeeJ,etal.Diabeticretinopathy:focusonminoritypopulations.IntJClinEndocrinolMetab2017;3(1):34-45.220BenoitSR,SwenorB,GeissLS,etal.EyecareutilizationamonginsuredpeoplewithdiabetesintheU.S.,2010-2014.DiabCare2019;42(3):427-433.

66

approximately60%ofthemrelyontheIHS221.ThisisadivisionofHealthand

HumanServices(HHS)thatisresponsibleforprovidinghealthcaretofederally

recognizedtribesandAlaskanNativesthroughits33hospitals,59healthcenters,

and50healthstations222.Asubstantialpercentageoftheseentitiesarelocated

rurally,makingthedeliveryofservicesrelativelyproblematic.Asmentionedearlier,

thereisconsiderablediversityinpreciseprevalenceratesofDMandDRamongthe

tribalcommunities,butallshareanincreasedlikelihoodofthesystemicdiseaseand

itsmicrovascularcomplications.Inspiteofthegeneralpoorhealthinthis

population,selectedIHShospitalshavedevelopedstate-of-the–artprogramsto

diagnoseandtreatDRthatcanserveasexamplesofoptimalcarerivalingthatofthe

EnglishScreeningprogrammentionedearlier.

Asagoodexample,thePhoenixIndianMedicalCenter(PIMC)wasthesiteof

apilotstudyconductedintheirprimarycaremedicineclinicatwhichdiabetic

patientswereseenatnopersonalexpense.In2000,thePIMCaddedaretinaldigital

surveillancemodalityorchestratedbytheJoslinVisionNetwork(JVN)223toevaluate

DRstatusinpatientsatthisclinic,sothatreferralstoeyecareprofessionalswere

notnecessarilyrequired;onlypatientswithungradableimagesorworrisomeDR

wouldneedsuchappointments.TheJVNincludesastereoscopic,non-mydriatic,

digitalcolorretinalimagingacquisitionsystem.Digitalimagesoftheretinaand

221CenterforDiseaseControlandPrevention2014.HealthyPeople2020.Retrievedfromhttp://www.cdc.gov/nchs/healthy_people/hp2020.htm.222HoltzC.GlobalHealthCare.IssuesandPolicies.ThirdEdition.BurlingtonMA2017,JonesandBartlettLearning,p.40.223AielloLM,CavalleranoJD,CavalleranoAA,etal:Preservinghumanvision:theJoslinVisionNetwork(JVN)innovativetelemedicinecarefordiabetes.OphthalmolClinNorthAm2000;13:213–23.

67

pertinentpatienthealthdataareforwardedtoacentralizedimagereadingcenter,

whereadiagnosisandtreatmentplantailoredtothepatient’slevelofDR,

determinedbyanexpertphotographicanalyzer,canbemade,andpatientswith

significantstagesofDRcanbepromptlyreferredfortreatment.Intheyearthat

PIMCaddedtheJVNprogram,DRannualretinopathysurveillanceratesamong

diabeticpatientswereapproximately50%,afigurecomparabletomanyhealthcare

systemsintheU.S.;butithadincreasedtoapproximately75%by2003,a50%

increase;andevidence-basedtreatmentofDRalsogrewby50%eventhoughthe

rateoftherapyperpatientscreenedremainedstable,thusdemonstratingthat

improvedscreeningleadtogreaternumbersthatreceivedneededtherapy.

AnIHS-JVNTeleophthalmologyProgramwassubsequentlyformally

established,andby2005,itwasdeployedin97healthcarefacilitiesin25states,

whereapproximately18,000patientswerescreenedannually224.In2014,a

modificationinthescreeningcameraswasevaluated,andultrawidefieldretinal

imagingwithscanninglaserophthalmoscopywascomparedtothestandard

nonmydriatictechnique.Theultra-widescreeningcuttherateofungradableimages

by81%,thusreducingthenumberofpatientsthatwouldhavetobereferredforeye

examinationsbyanestimated4,000casesperyear225.Inaddition,theidentification

ofthepresenceofbothDRandDRneedingreferralswereincreasedsignificantly.

224SilvaPS,HortonMB,ClaryD,etal.Identificationofdiabeticretinopathyandungradableimageratewithultrawidefieldimaginginanationalteleophthalmologyprogram.Ophthalmology2016;123(6):1360-7.225Ibid.

68

ThisHIS-JVNProgramispracticallyalmostidenticaltotheEnglishscreening

programdescribedabove,asignificantdifferencebeingthattheEnglishpatients

havetheirpupilsdilatedpriortophotography,ameasurethatreducesthe

percentageofungradableimages.Theessentialfeatureofbothstrategiesisthat

diabeticpatientsvisitingtheirrespective“diabetescaregivers”,whichtheydo

relativelyreliably,arealsoabletohavetheirretinalstatuscapturedbyexpert

gradersatthissamesiteofcare,thusavoidingtheissuesassociatedwithadditional

referralappointmentsforeyeevaluations,whicharenotoriouslyinadequatefora

varietyofreasons.

TheU.S.VeteransHealthAdministration(VHA,VA)isanadditionalexample

ofthevalueofDRscreeninginaprimarycaresetting.TheVAhasbecomeoneofthe

largesthealthcaresystemsintheworld,growingfrom54hospitalsin1930,to

include152hospitals,800community-basedoutpatientclinics,and126nursing

homecareunits.ApproximatelyaquarterofitspatientshaveDM226.In2014,over

9,100,000veteranswereenrolledintheprogram,andmorethan6,000,000usedits

services227.

ThesameJoslinVisionNetwork(JVN)associatedwiththeIHSwas

instrumentalindevelopingatelemedicalDRscreeningprogramintheVA.In1999,

theVeteransHealthAdministration(VHA)collaboratedwiththeJoslinDiabetes

Centertoimplementapilotteleretinalimagingprogram.Itincludedthesame

nonmydriaticdigitalretinalimagingplatformemployedintheIHS,andcameras

226Https://www.va.gov227BagalmanE.ThenumberofveteransthatuseVAhealthcareservices.Washington,D.C.,2014,Congressionalresearchservice,pp.1-3.

69

wereinstalledatVAmedicalcentersandcommunity-basedoutpatientclinicsin

NewEnglandandthePacificNorthwest.Imagescapturedattheseremoteimaging

stationsweretransmittedtoreadingcentersattheJVNandtheVAPugetSound

HealthcareSysteminSeattle.Thispilotprogramwasquitesuccessfulinidentifying

patientsinneedoftimelyfurthercareforDRwhileatthesametimerecommending

eyecareatappropriateintervalsforthosewithlittleornoriskfactorsfor

retinopathyprogression228.

In2001,theVHAconvenedanexpertpaneltoaddressissuesofclinical

application,qualityandtraining,informationtechnology,andhealthcare

infrastructureneedsregardingtheimagingprogram,anditwassubsequently

deployedonasystemwidebasisin2006229.Costeffectivenessoftheprogramwas

reportedin2013:amodelwasemployedinanevaluationof900patientrecordsto

estimatetheprogressionofDRanddetermineaveragequality-adjustedlifeyears

(QALYs)savedandtheaverageadditionalcostincurredbythetelemedicine

screeningprogram.Thestudyresultsindicatedthattheprogramwasquitecost-

effectiveforDR,butonlyinpatientpopulationsof3500ormoreandinpatientsless

than80yearsofage.Telemedicineloweredtheaverageageofthosescreened,

increasedthenumberofknowndiabeticpatients,andreducedtheaveragenumber

ofmilestravelledbypatientsforscreening.Participationintheprogramwas

observedtobeincreasing.ThustheVAscreeningprogramisanadditionalexample

228ConlinPR,FischBM,OrcuttJC,etal.FrameworkforanationalteleretinalimagingprogramtoscreenfordiabeticretinopathyinVeteransHealthAdministrationpatients.JRehabResDev2006;43:741-8.229TsanGL,HobanKL,JunW,etal.AssessmentofdiabeticteleretinalimagingprogramatthePortlandDepartmentofVeteransAffairsMedicalCenter.JRehabResDev2015;52(2):193-200.

70

ofaneffectivestrategytoreducetheprevalenceofbothsight-threateningvisualloss

andblindnessamongAmericancitizens.Itisofcourseanotherexampleofthe

benefitofsystemssimilartotheEnglishNHS.

IntheU.S.,privatecompanies,stimulatedbyneedstoimproveHEDISDR

screeningscoresaswellasopportunitiesforprofits,havebeendevelopedto

provideDRscreeningprogramsineffortstoprovidehigherpercentagesofdiabetic

patientswhoareevaluatedforDRinamannersimilartotheHISandVAdescribed

above.Buttheseprogramsarelimitedtothosepatientscapableoffundingwith

theirinsurance,andevenMedicarerequiresaco-paymentunaffordabletomany.

RetinopathycareinIndia

Asmentionedearlier,a2014nationwidesurveyofover5,000diabetic

individualsinIndiarevealedaDRprevalenceofalmost22%,andthetypical

variablesofdurationofsystemicdisease,age,andglucosecontrolqualitywere

significantlyassociatedwiththelikelihoodofdevelopingretinalvascular

changes230.Specificprevalencefiguresvarysomewhatfromregiontoregionand

studytostudy,butitisquiteclearthatincreasingnumbersofpatientswithDMwill

leadtomorecasesofDR,andthatbothdisorderswillincreasethehealthcare

burdenforIndia’spopulationof1.24billionpersons231.SeventypercentofIndian

citizensliveinruralareaswhereaverageincomesarelessthanoneUSdollar/day

andtheratioofphysicianstopatientsissixtimeslowerthanintheurbanareas,so

230Gadkari2014,Op.cit.,p.58.231Holtz,Op.cit.,87.

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thediagnosisandmanagementofbothDMandDRarecompromised232.In2015the

InternationalCouncilofOphthalmologypublishedrecommendedguidelinesforthe

screeningandtreatmentofDRwhilerecognizingtherealitiesofthediffering

environments233.Thus,abroadspectrumofeyecaregiversrangingfrom

ophthalmologistsandoptometriststoprimaryphysicianstoanyfieldworkeror

healthvolunteerwhohadsignificanttraininginretinopathygradingweredeemed

capableofscreeningofdiabeticpatients.However,theimpactofthe

recommendationsremainsunclear,asasubstantialgapbetweenplansand

outcomespersists.

In2013,arealisticoverviewofDRcareinIndiawaspublished234.Awareness

ofDRasaseriousentitywasgenerallypoor,andlittlehadbeendonetoinitiate

massawarenessprogramsacrossthenation.Asanexampleofasystemic

“disconnect”,apriorpopulation-basedstudywascitedinwhich80%ofnon-medical

respondersstatedabeliefthatannualeyeexamswereessentialbutlessthanhalf

hadevervisitedaneyecareprofessional,andonly10%knewthatuncontrolledDM

wasariskfactorforDR235.InanadditionalstudyfromChennaiitwasnotedthat

63%ofdiabeticpatientsinruralareasand75%inurbanenvironmentshadnever

232CentralIntelligenceAgency.TheWorldFactbook:India.Retrievedfromhttp://www.cia.gv/cia/publications/factbook/goes/ind.html.233InternationalCouncilofOphthalmology.Vision2020TheRighttoSightIndia.GuidelinesforDiabeticCareinIndia.SanFrancisco2015,InternationalCouncilofOphthalmology,pp.1-40.234RamasamyK,RamanR,TandonM.CurrentstateofcarefordiabeticretinopathycareinIndia.CurrDiabRep2013;13:460-8.235NamperumalsamyP,KimR,KaliaperumalK,etal.Apilotstudyonawarenessofdiabeticretinopathyamongnon-medicalpersonsinSouthIndia.Thechallengeforeyecareprogamsintheregion.IndJOphthalmol.2004;52:247–51.

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hadaneyeexamforDR,whereas45%ofruraland50%ofurbandiabeticswith

sight-threateningDRhadneverbeenevaluatedpreviously236.

Inamorerecentreportregardingdiabeticpatientsbeingfollowedina

tertiaryeyehospitalinsouthernIndia,theimportanceofknowledgeregardingboth

DMandDRwasfurtherdocumented237.A45-pointquestionnairewasadministered

verballyto288diabeticpatientsinoutpatientclinicsandinpatientwards.Forty-two

percenthad“goodknowledge”regardingDM,butonly10%regardingDR;72%

wereawarethatDMcouldaffecteyes,butonly17%wereawareofDRasaspecific

entity,thelatterfigurebeingconsistentwithadditionalpriorreports238.

Importantly,amongtherelativelysmallpercentageofdiabeticpatientswith

awarenessofDR,theiroddsofhavinggoodpracticepatternsregardingthesystemic

diseaseweremuchbetterthanthoseofpatientsunawareofit.Similarly,theoddsof

patientswithgoodknowledgeregardingDMalsohavinggoodDRpracticepatterns

werefourtimesthosewithlittleknowledgeregardingthesystemicdisease.

ImprovingknowledgeandawarenessofDManditsmicrovascular

complicationsisafundamentalgoalinimprovingthehealthofdiabeticpatientsand

inreducingtheimpactofvisualimpairmentduetoDR.But,bearinginmindthat

blindnesscanbepreventedinthevastmajorityofpatientswhoaretreatedina

236RaniPK,RamanR,PaulPG,etal.Useofeyecareservicesbypeoplewithdiabetes–SouthIndianexperience.BrJOphthalmol.Lettertotheeditor,PublishedonlineMay18,2005.Available:http://bjo.bmj.com/content/82/4/410/reply#bjophthalmol_el_756.237SrinivasanNK,DeepaJ,RebekahG,etal.Diabetesanddiabeticretinopathy:Knowledge,attitude,practice(KAP)amongdiabeticpatientsinatertiaryeyecarecenter.JClinDiagRes2017;11(7):1-7.238SeeDandonaR,DandonaL,JohnRK,McCartyCA,RaoGN.AwarenessofeyediseasesinanurbanpopulationinsouthernIndia.BullWorldHealthOrgan.2001;79(2):96-102.,MaheshG,EliasA,SandhyaN,etal.ChengamanadDiabeticRetinopathyAwarenessStudy(CDRAS).KeralaJOphthalmol.2006;28:14-21.

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timelyfashion,whataboutthecareprocessfortheIndiandiabeticpatient?Since

treatmentcanonlybeappliedwhenpatientsinneedareidentified,patientswith

DMmustbescreened.CurrentlythereisnonationalscreeningprogramforDR,and

differentad-hocmethodshavebeenemployedindiverselocations239.Lessthantwo

percentofprimarycarephysiciansusedirectophthalmoscopes,andonlyhalfof

thosedilatepatients’eyes,soscreeninginthatfashionisineffective240.Eyecamps

fordiabeticpatientshavebeenemployedinpartsofIndiaforseveralyears,andthey

provideanadditionalbenefitofcommunityawarenessintheregion241;andinone

report,approximately20%ofscreeneddiabeticpatientsexhibitedsignsofDR,

althoughonlysixpercentofthosehadanyevidenceofpriorDRtreatment242.A

morerecentplanforDRscreeninginIndiainvolvedtheuseoftelemedicine

conductedbycamerasenclosedinmobilevans;imageswereproducedand

conveyedtoacentralizedreadingcenterforanalysis,andareportreturnedtothe

patientwithinanhour243.Thissystemwasdemonstratedasquitecost-effectiveif

employedonabiannualbasis244

OncepatientswithDMandretinopathyaredetected,whataboutthedelivery

oftherapy?Again,theissuesofdistributionofbothpatientsandcaregivershavea

239Ramasamy2013,Op.cit,460.240RamanR,PaulPG,PadmajakumariR,SharmaT.KnowledgeandattitudeofgeneralpractitionerstowardsdiabeticretinopathypracticeinSouthIndia.CommunEyeHlth2006;19(57):13–4.241RaniPK,RamanR,AgarwalS,etal.Diabeticretinopathyscreeningmodelforruralpopulation:awarenessandscreeningmethodology.RuralRemoteHeal.2005;5:350.242NamperumalsamyP,NirmalanPK,RamasamyK.Developingascreeningprogramtodetectsight-threateningdiabeticretinopathyinsouthIndia.DiabetesCare.2003;26:1831–5.243LiesenfeldB,KohnerE,Piehlmeier,etal.Atelemedicalapproachtothescreeningofdiabeticretinopathywithdigitalfundusphotography.DiabetesCare2000;23:345–48.244RachapelleS,LegoodR,AlaviY,etal.Thecost-utilityoftelemedicinetoscreenfordiabeticretinopathyinIndia.Ophthalmology2013;120:566-73.

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majorimpactthatremainsuncorrected. Nationally, there is an approximate ratio of 1

ophthalmologist for every 107,000 people, but this ranges from 1:9,000 in urban areas to

1:608,000 in more rural locations245; and the percentages of ophthalmologists that

manage DR is unclear, although there were 585 ophthalmologists who had become

members of the Vitreoretinal Society of India by 2012246. Once patients reach a location

with appropriate facilities, state-of-the-art DR management is generally practiced, and

only minor practice pattern discrepancies exist between India practitioners and those

surveyed by the American Society of Retina Specialists247

Observationsregardinginternationalhealthcaresystems

Atthetimeofthiswriting,“tools”forstate-of-thearttherapyforDRare

availableinthemajorityoflocationsaroundtheworld,buttheyareemployedonly

intertiarycenterswithappropriatefacilities,andthereforetheiruseisquitelimited

inmostregions,especiallylow-middleincomecountries.Althoughtheabilitiesto

detectsight-threateningDRhavebeenprofoundlyexpandedbytheintroductionof

mobiletelemedicaldevices,“tools”forprovidingthemeansofconnecting

appropriatepatientswiththerapeuticfacilitiesremainproblematic.Clearly,most

societieshaveyettoconstructsatisfactoryapproachestotheepidemicofDMand

DRalongwithnephropathyandneuropathy.248,249Theproverbial“elephantinthe

245KumarR.OphthalmicmanpowerinIndia—needforaseriousreview.IntOphthalmol.1993;17:269–75.246Ramasamy2013,Op.Cit.,463.247Ibid,467.248Hossain P, Kawar B, El Nahas M: Obesity and diabetes in the developing world--a growing challenge. N Engl J Med. 2007;356(3):213–5.

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room”istheincreasinglygiganticnumberofdiabeticindividualsintheworld,

especiallyinlow-middleincomecountriesinwhich80%ofdiabeticpatientsare

living.250Regardlessofprecisediagnosticcriteria,thenumbercontinuestogrowin

associationwithobesity,whichinturnisduetodietarymodificationsasdescribed

earlier.AndroughlyaquarterofdiabeticpatientswithoutoptimalHemoglobinA1c

levelswillultimatelydevelopsignificantDR.

Whatwouldconstituteanideal(orsignificantlyimproved)healthcare

systemforDR?CriteriawouldincludeuniversalaccesstoadequateDM

managementwithoutexcessivefinancialburdentopatients;currently,amongthe

threecountriesunderdiscussion,thisisavailableinEngland,saidtobeinforcein

Indiabutnotfunctional;andunavailableintheU.S.Second,programsforpatient

educationregardingtheimportanceofoptimalDMmanagementandtherealitiesof

DR;currently,theseareavailableinallthreecountriesbutunderutilized.Third,

capabilitiestoscreenremotelylargenumbersofdiabeticpatientsforDR;inthe

threecountriesbeingdiscussed,theseareroutinelyavailableonlyinEngland.

Fourth,ameansofconnectingallpatientsinneedofDRtreatmenttoappropriate

caregiversofferingoptimaltherapeuticfacilities;thiscurrentlyismostoptimalin

England.Finally,establishmentofefficientlinesofcommunicationbetweenDM

caregiversandthoseinvolvedineyecare;again,althoughfarfromperfect,itismost

availableinEnglandbutfragmentedintheU.S.andIndia.Inallcountries,theroles

249BelloAK,LevinA,LunneyM,etal.Statusofcareforendstagekidneydiseaseincountriesandregionsworldwide:internationalcrosssectionalsurvey.BMJ2019;367:5873.250SabanayagamC,YipW,TingDSW,etal.Tenemergingtrendsintheepidemiologyofdiabeticretinopathy.OpyhalmicEpidemiol2016;23(4):209-222.DOI: 10.1080/09286586.2016.1193618

76

ofsocialandenvironmentalcircumstancesincludingpovertyandpublichealth

realitiesshouldberecognized,astheyareimportantdeterminantsofthequalityof

carethatcouldbeprovided.

CreationofoptimalhealthcaresystemsforDMandDRwillrequire

improvementsintheclassiclinkagesofstatepolicies,patientengagementand

compliance,andinvolvementofmedicalpersonnel–asystemthatbrings

acknowledgedcontemporarystate-of-the-artdiagnosticandtreatmentcapabilities

tocombatthecurrentmaldistributionofaffectedpatientswiththeircaregivers.

Thesethreevariablesarediscussedinsequenceinthefollowingparagraphs.

Regarding“statepolicies”,a2000UNGeneralCommentNo.14“Rightto

Health”251specifiedthat“thehighestattainablestandardofphysicalandmental

health”shouldbebroadlyinterpretedandnotlimitedtotherighttohealthcarebut

toextendtorecognitionandimprovementsintheunderlyingsocioeconomic

determinantsofhealthsuchassafewater,adequatefood,reasonablesanitation,and

accesstohealthcareinformation.Therighttohealthwasstatedtobecomposedof

fourelements:availability,accessibility,acceptability,andquality252.

A2006UNResolution61/225253askedfor“allnationstodevelopnational

policiesfortheprevention,careandtreatmentofdiabetes…takingintoaccount

251UnitedNations(2000)GeneralCommentNo.14:Therighttothehighestattainablestandardofhealth.NewYork,UnitedNations,pp.1-22.Citedin:DiIorioCT,CarinciF,BenedettiMM.Thediabeteschallenge:fromhumanandsocialrightstotheempowermentofpeoplewithdiabetes.In:DeFranzoRD,FerranniniE,ZimmetP,etal(eds),InternationalTextbookofDiabetesMellitus,4thEd,Hoboken,NJ,JohnWileyandSons,2015p1105.252Ibid.253UnitedNationsResolution61/225:WorldDiabetesDay.NewYork2007,UnitedNations83rdPlenarysession,pp.1-2.CitedinDiIorioCT,CarinciF,BenedettiMM.Thediabeteschallenge:fromhumanandsocialrightstotheempowermentofpeoplewithdiabetes.In:DeFranzoRD,FerranniniE,

77

internationallyagreeddevelopmentgoals,includingtheMillenniumDevelopment

Goals.”DelegatesparticipatingattheWHO65thWorldHealthAssembly“approved

thedevelopmentofaglobalmonitoringframeworkforthepreventionandcontrolof

noncommunicablediseases(NCDs),includingindicatorsandasetofglobaltargets.”

Atthesamemeeting,theAssemblyapprovedaglobaltargetofa25%reductionof

deathsfromNCDs.

IntheU.S.inSection403ofthe2010AffordableCareAct,anopportunityto

identifypopulationsatriskfortype-2DMwaspresented,andin2012,theInstitute

ofMedicine(IOM)recognizedtheneedforimprovedpublichealthmeasuresto

manageagrowingtollofchronicdiseasesincludingDMandcalledfordata

acquisitionregardingsuchillnessesandtheirdeterminants.254Threeyearslater,a

reviewofNIHfundingtopreventchronicdiseasewaspublished.255Nevertheless,

althoughacquisitionofsuchdatamaybeworthwhileglobally,mostpatientswith

DMliveincountriesinwhichimplementationofpracticesformostpatientsremains

impossible.

Inamorerecent2106report256,theDirector-GeneraloftheWHOdescribed

a“2030Agendaforsustainabledevelopment”,inwhichmemberstatessetatarget

toreduceprematuremortalityfromNCD’sincludingdiabetesbyone-third,to

achieveuniversalhealthcoverage,andtoprovideaccesstoaffordableessential

ZimmetP,etal(eds),InternationalTextbookofDiabetesMellitus,4thEd,Hoboken,NJ,JohnWileyandSons,2015p1105.254InstituteofMedicine.LivingWellwithChronicIllness.ACallforPublicAction.2012,Washington,D.C.255CalitzC,PollackKM,MillardC,etal.NationalInstituteofHealthfundingforbehavioralinteractionstopreventchronicdiseases.AmJPrevMed2015;48(4):462-471.256WHO2016,Op.cit.

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medications.InthesamereportandregardingDM,technologies“generallyavailable

inpublically-fundedprimaryhealthcarefacilities”wereassessed,andthe

percentagesofcountrieswithcapabilitiesforofferingaccessibledilatedretinal

evaluationsvariedenormously,rangingfrom26%inthe“Africanregion”to

approximately45%inthe“westernPacific”and“regionoftheAmericas”regionsto

75%inthe“Europeanregion”.Theincomelevelsinvariousglobalregionswere

majorfactorsthatinfluencedthisdisparity.Dilatedretinalexaminationswere

availableinonly19%oflow-incomecountriescomparedto29%in“lowermiddle”

incomelevelsto48%in“uppermiddle”incomelevelsto67%in“highincome”

regions.Thismaldistributionofcapabilitiestodeliveroptimalevidence-basedcare

forDRandDMisnotuniqueforthesetwodisorders.But,hopefully,theeconomic

impactofthecomplicationsofdiabeteswillstimulatestrategiesforstatesto

improvetherecognitionandmanagementofdiabeticpatients.Inspiteofworthybut

ambitiousWHOrecommendations,Ihavedemonstratedthattheabilitiesof

individualnationstoimplementthemhavevariedconsiderably.Differences

betweenthreediscussedcountries’abilitiestodelivercontemporarycareforDR

havebeenprovided.Currently,optimalcareforDRisavailableintertiarymedical

centersinmosturbanareasoftheworld,butavastpercentageofpatientswithDM

andDRremainunmanaged,especiallyiftheyarepoorandliveinalow-income

country.

Regarding“patientengagement”,personalculpabilityisamajorfactor

impactingmanyifnotmostcasesofDR.PatientsdiagnosedwithDMenterthe

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proverbial“kingdomofthesick”,257aregionfromwhichnoexittonormalityexists.

Still,althoughthisrealityshouldbeacknowledged,thepersonalresponsibilitiesof

patientswithDMcannotbeoverestimated,becauseadequatecontrolofserum

sugarlevelsremainsanessentialfeatureofstrategiestoreducetheimpactofDR

andtheadditionalmacro-andmicrovascularcomplicationsofDM.Acritical

componentofthismanagementistherecognitionofthediseaseinquestion,and

unfortunatelyasubstantialpercentageofpatientswithDMareunawareofits

presence;andmanywithknownDMhavelittleknowledgeregardingoptimal

processesofcare258.Andthecostsaswellasavailabilityofdiabeticmedicinesare

additionalvariablesthatimpactself-management.Soalthoughsuchindividuals

shouldnotbeblamedforalldeficienciesinpersonalhealthpractices,optimal

patientself-careremainsacornerstoneofthetherapeuticprocess,astatement

validatedinstudiesmentionedpreviously.

TheSt.VincentDeclarationmentionedearlierstatedthatareductioninthe

burdenofdiabeteswouldrequireactivepartnershipbetweenpatientswithdiabetes

andcareproviders,particularlyincategoriesofdiseasemanagementand

education259.Thispolicyadvocatedafundamentalprincipleof“patient

empowerment”,definedas“theabilityofapersonaffectedbyadiseasetobean

257SontagS.IllnessasaMetephorandAIDSanditsMetaphors.1978,NewYork,PicadorUSA.258IntheU.S.theepidemicofDMhasresultedtotheubiquitousappearanceofmultitudesofmediaadvertisementsofdrugstolowerhemoglobinA1C,whereasinformationregardingthecriticalimportanceofdietsremainsrelativelyunavailabletothepublic.259DiIorioCT,CarinciF,BenedettiMM.Thediabeteschallenge:fromhumanandsocialrightstotheempowermentofpeoplewithdiabetes.In:DeFranzoRD,FerranniniE,ZimmetP,etal(eds).InternationalTextbookofDiabetesMellitus,FourthEdition,2015,HobokenNJ,JohnWiley&Sons,1105-12.

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activememberofhis/hermanagementteam”260.Itaddresseddifferentdimensions

ofcareincludingeducationregardingbothmedicalandpublichealthconditionsand

theabilityofapersontomakedecisionsontreatments.Optimalpatient

empowermentshouldallowapersontoeffectivelyself-managebothDMandDRby

adherencetoagreedself-careregimensincludingmaintenanceofoptimalserum

glucoselevels,normalbloodpressure,andmeaningfulweightloss.Chronicdisease

programsthatrelyonself-managementeducationhavebeentestedinrandomized

controlledtrialsthathavedemonstratedsignificantimprovementsintheareasof

healthybehaviorsandcommunicationwithhealthcareproviders261.

Conceptsofpatientempowermentaremostdifficultinregionscharacterized

bypoorsanitaryfacilities,malnutrition,poverty,andthelackofeducation.Still,

eveninanexcellentsystemsuchastheEnglishDiabetesScreeningProgram

mentionedearlier,patientwillingnesstoparticipateisacriticalvariable.Ina2016

report262,reasonsfornon-attendanceatDRscreeningprogramsinLondonwere

tabulated.Avastmajorityofthoseofferedscreeningacceptedit,but258who

registeredbutneverappearedforscreeningwerelateridentified,andanattempt

wasmadetocontactthemtolearnwhy.Asubstantialnumberofpatientscouldnot

bereached,butreasonsfornon-attendanceweredocumentedfor146(57%).

Personalexplanationsfornon-acceptanceincludedconflictingcommitments,

260SanturriLE:Patientempowerment:improvingtheoutcomesofchronicdiseasesthroughself-managementeducation.TheMPHP439OnlineTextBook,,2006,CaseWesternReserveUniversity,at:http://www.cwru.edu/med/epidbio/mphp439/Patient_Empowerment.htm261Ibid.262StrattonR,DuCheminA,StrattonM,etal.System-levelandpatient-levelexplanationsfornon-attendanceatdiabeticretinopathyscreeninginSuttonandMerton(London,UK):aqualitativeanalysisofaserviceevaluation.BMJOpen2016;6:e010952.

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anxietyregardingthescreeningtest,disengagementwithdiabetescareingeneral,

andforgetting.System-levelfactorsincludedinaccurateregistrationdata,untimely

communications,eligibilityerrors,andpracticalproblemssuchasalackof

recognitionofhomeboundpatients.Theessentialpointisthatpatientresponsibility

isnecessaryforoptimalcaretooccur.Andunfortunately,non-attendingpatients

havebeenshowntohaveagreaterlikelihoodofsight-threateningDR263.

Regarding“involvementofmedicalpersonnel”,caregiverresponsibility

remainsacornerstoneofDMandDRmanagement.TheIOMhaslistedsix

characteristicsofoptimalmedicalcare:itshouldbesafe,effective,patient-centered,

timely,efficient,andequitable264;andtheAgencyforHealthcareResearchand

Quality(AHRQ)hasestablishedqualityindicatorsandguidelinesforgood

healthcare265.Theessentialfeaturesofcontemporaryevidence-basedcarefor

patientswithDMandDRhavebeenmentionedearlier.Caregiversshouldknow

whatshouldbedonetomanagethesedisorders.Themajorlimitationinthecare

processistheinadequatematchingofpatientswiththosecapableofrecognizingDR

andprovidingcare,andprofounddifferencesincapabilitiestodosoarequite

evident,asmentionedearlier.Manyofthementionedcontemporarystrategieshave

distancedpatientsfromspecialists,andtrainingmoreprimaryhealthcareworkers

toacquirescreeningandcounselingskillscouldalleviatesomeofthecurrent

263ForsterAS,ForbesA,DodhiaH,etal.Non-attendanceatdiabeticeyescreeningandriskofsight-threateningdiabeticretinopathy:apopulation-basedcohortstudy.Diabetologia2013;56(10):2187-93.264InstituteofMedicine.CrossingtheQualityChasm:ANewHealthSystemforthe21stCentury.Washington,D.C:NationalAcademyPress;2001.265AgencyforHealthcareResearchandQuality.

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problems.Bondingofdiabeticpatientswithpersonalcaregiversisrecognizedasa

criticalvariableinthetherapeuticprocess.

ThestoryofDRdoesnotendhere.Inadditiontomakingdesirable

improvementsinsocietalprogramsdescribedabove,biologicresearchforbetter

therapiesneedstocontinuetobeexplored.Inparticular,theappropriateroleof

anti-VEGFmedicationsrequiresconsiderablymorestudy.Still,effortstoreducethe

prevalenceofDManditsmanydeterminantsarefundamentalgoalstoprevent

vascularcomplications.

Inthischapter,Idescribedahistoryofincreasingawarenessoftheepidemic

ofDMandDRbyinternationalhealthcareentitiesandplansforstrategiesto

combatthedisorders,includingtheimportantimplementationoftelemedicine.This

wasfollowedbyacomparativeanalysisofhealthcaresystemsinEngland,theU.S.,

andIndiaandanoverviewoftheirefforts.ThishistoryofDRmanagementsystems

inthreecountriesdemonstratedthatscientific“medical”studiesregardingthe

disorderhavefaroutpacedglobalcapabilitiestomanageit.Optimalevidence-based

careisavailableinalloftheregions,butitislimitedbyavarietyofsocialand

economicfactors.Generalizing:InEngland,anexcellentprogramisinplace,anda

majorImpedimenttocareappearstobepatientcompliance.IntheU.S.,care

remainsfragmentedduetomanypatients’lackoffinancialresourcesandtheir

compliance.InIndia,excellentprogramsexistinmajormedicalcentersthatfeature

contemporaryeyehospitals,butthepercentagesofpatientswithoutaccesstocare

areenormousandmaybegrowing.Thus,althoughthescientificbasisforreducing

visionlossandadditionalcomplicationsofdiabeteshasbeenwellestablished,the

83

implementationofthesecareprocessesremainsinadequate,withresponsibilities

continuingtofalluponallthreecontributingfactors:the“state”,thepatients,and

thecaregivers.Iwillnowpresentaconcludingchaptersummarizingthesefactsas

variablessupportingmythesis.

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Chapter6.

Conclusions

Thismanuscriptwaswritteninanefforttosupportthethesisthatmostof

theworld’shealthcaresystemshaverespondedinadequatelytotheepidemicsof

DRanditscause,DM,especiallyinviewofavailabilityofevidence-based

managementstrategiesthathavebeendevelopedoverdecades.Idrewuponmy

personalexperiencetodescribethemanifestationsofDRbutconductedathorough

literaturesearchregardingtheadditionalaspectsofthisefforttosupportmyclaims.

Myanalysisdemonstratedthattheglobaldistributionofhealthcaresystems

tocombatDMandDRisexceptionallylimited.Althoughcontemporaryexemplary

plansareavailableinmostcornersoftheworld,theyarelimitedinthepercentages

ofpopulationsthatcanbeserved.Ingeneral,theyareavailableonlyin

environmentscontainingsophisticatedequipmentandpersonnelinwhichonly

patientswithappropriatemedicalinsuranceorfundingaremanaged.Anexception

tothisgeneralityexistsintheUK,Iceland,andselectedwesternEuropeancountries,

butinIndia,theU.S.,andregionscontainingmostoftheworld’spopulations,it

remainstrue.

Theimplicationsofthisresearcharethatalthoughoptimalstrategiesto

managethedisordersinquestion(aswellasnephropathy,neuropathy,andmany

additionalchronicdiseases)areavailableinselectedpartsoftheworld,their

broaderimplementationwillrequirethedevelopmentof“universal”nationalhealth

caresystemsthatareappropriatelyfundedandcapableofidentifyingaffected

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patientsandprovidingthemeansforcare.Theseofcourseareoptimalgoalsandthe

likelihoodoftheirbeingaccomplishedwilldependuponthepoliticalenvironments

andfundingcapabilitiesamongthemanynations.Intheopeningsectionofthis

dissertation,ImentionedthatthisstoryofDRcouldrepresentametaphorforother

chronicdiseases.State-of-the-arttherapiesforbothnephropathyandneuropathy

havebeendevelopedinafashionparalleltothatofDR.266,267268AndtheInstituteof

Medicinehasrecognizedtheneedforpublichealthactionforimproved

managementstrategiesforchronicdiseases.269

Ialsoearlierquotedthatdiseaserepresented“anoccasionandagendaforan

ongoingdiscourseconcerningtherelationshipamongstatepolicy,medical

responsibility,andpersonalculpability”.270Myresearchhassupportedthis

impression:adequatestatepoliciesarenecessaryforoptimaluniversalhealthcare;

evidence-basedmedicineshouldbeunderstoodandpracticedbyavailable

caregivers;andpatientshaveresponsibilitiestoappropriatelymanagetheir

systemicdisease.Itissaidintheidiomthat“talkischeap”,271andsoitiswiththese

threevariables.Relativelyfewcountriesprovideoptimalfundingofhealthcare

systems,evenwhentheyareself-designatedas“universalhealthcare”.Many

caregiversremainunabletoprovideexemplarycarebecauseofinadequateaccess266BlaggCR.TheearlyhistoryofdialysisforchronicrenalfailureintheUnitedStates:AviewfromSeattle.AmJKidDis2007;49(3):482-496.267BelloAK,LevinA,LunneyM,etal.Studiesofcareforendstagekidneydiseaseincountriesandregionsworldwide.Internationalcrosssectionalsurvey.BMJ2019;367:5873.268SkljarerskiV.Historicalaspectsofdiabeticneuropathies.InVevesA,MalikRA(eds).DiabeticNeuropathy.ClinicalManagement(2ndEd).2007,TotawaNJ,HumanaPress,pp.1-5.269InstituteofMedicine.LivingWellwithChronicDisease.ACallforPublicAction.2012,WashingtonD.C,InstituteofMedicine.270Rosenberg1992,Op.cit.271Originoftheidiomisuncertain.

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topatients,funding,oreducation.Andfewpatientsaregenuinelycompliantin

managingtheirdiabetes.Eachofthesefactorsisamplifiedinregionsofrelative

povertyandpoorhygiene.

Myresearcheffortsdescribeddifferencesamongthreenationalhealthcare

systems,buttheycanbeextrapolatedtoadditionalregions.Basedonmyanalysis,it

appearslikelythattheepidemicofDR-relatedvisionlosswillbesignificantly

reducedonlyinlocationsthatprovidecomprehensivehealthcareservicestomost

diabeticpatientsandthatthemajorityoftheworld’sdiabeticpatientswillremain

underserved.272

272CavanD,MarakoffL,FernandesJdeR,etal.Thediabeticretinopathybarometerstudy:globalperspectivesonaccesstoandexperiencesofdiabeticretinopathyscreeningandtreatment.DiabResClinPrac.2017:129:16-24.

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Figure1.DiagramoftheHelmholtzOphthalmoscope,(courtesyoftheWellcome

Collection)

88

Figure2.TheDiabeticRetinopathyStudy17:InitialOutcomesfortreatmentofsevere

diabeticretinopathy.The“event”wasaseverelossofvisionontwoconsecutive4-

monthfollow-upvisits.

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CURRICULUM VITAE

Charles Patton “Pat” Wilkinson, MD PERSONAL DATA Address: Dec-May 380 Gulf of Mexico Dr, Apt 521 Longboat Key, FL, MD, 34228 Phone : 941-387-8481 (mobile) Email: cwilkins117@verizon.net May-Nov: 7707 Rider Hill Rd Baltimore, MD, 21204 Phone: 410-832-8855 Birth date: 8/16/40, Syracuse, New York Domestic status: Married: Alice Roberts Michels (Married 11/13/92) Children: Laura Wilkinson Gable, born 2/9/66 Melinda Wilkinson Lee, born 11/29/67 Stepchildren:JamesRandolph“Randy”Michels,born1/31/76 Allison Michels Pettinelli, born 10/2/78 EDUCATION HISTORY Undergraduate Stanford University, 1958-1962; BA (Psychology) 1962 Medical School Johns Hopkins University Medical School, 1962-1966; MD 1966 Postgraduate Training: Internship: Johns Hopkins Hospital (Medicine), 1966-1967 Residency: Wilmer Institute, Johns Hopkins (Ophthalmology), 1967-1970 Fellowship: Bascom Palmer Eye Institute (Vitreoretinal), 1970-1971 Harvard School of Public Health “Program for Chiefs of Clinical Services”, 1993 Johns Hopkins Department of the History of Medicine (M.A. track) 2016-present. Certification: American Board of Ophthalmology, 1972-present, including 2010 “recertification” Maryland State Medical Association, 1966 - present Oklahoma State Medical Association, 1971-2002 PROFESSIONAL ACTIVITIES

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Current Academic Appointments: Chairman Emeritus, Ophthalmology, Greater Baltimore Medical Center, 2016- present. Emeritus Status at Johns Hopkins University, pending. Past Academic Appointments Chairman, Dept. of Ophthalmology, Greater Baltimore Medical Center, 1992-2016. Professor, Dept. of Ophthalmology, Johns Hopkins University, 1996 – 2016 Associate Professor, Dept. of Ophthalmology, Johns Hopkins University, 1993 - 1996 Clinical Professor, Dept. of Ophthalmology, University of Oklahoma, 1977-1992. Vice-Director, Dean A. McGee Eye Institute, Oklahoma City 1975-1992 Director, Vitreoretinal Service, Dean A. McGee Eye Institute, 1975-1992 Current Clinical Staff Appointments: Greater Baltimore Medical Center (Emeritus Staff), 1992 - present The Johns Hopkins Hospital (Active then Courtesy Staff), 1992 – present Additional Professional Appointments: Chair, EyeCare America Steering Committee, 2014-2019. Member, Data and Safety Monitoring Committee, Diabetic Retinopathy Clinical Research Network (DRCRnet), 2012-present. Member, EyeCare America Steering Committee, 2000-2019. Member, Data and Safety Monitoring Committee, Age Related Eye Disease Study (AREDS II), 2005-present. Past Professional Appointments Member, American Academy of Ophthalmology Seniors’ Committee, 2012-2016 Study Director, FDA LASIK Quality of Life Collaboration Project (Patient Reported Outcomes with Lasik (PROWL)) 2009-June, 2015. Member, Executive Committee, Pan American Ophthalmological Society 2009-11. Secretary for English Language, Pan American Ophthalmological Society 2009-11. President, American Ophthalmological Society, 5/2009 – 5/2010. Immediate Past President, American Academy of Ophthalmology, 2008 Member, Board of Trustees, American Academy of Ophthalmology, 1999-2002, 2006-2008, 4/1/09-12/31/09. Chairman, American Academy of Ophthalmology Eye Care America Diabetes Project Committee, 2000-2009. President, American Academy of Ophthalmology, 2007. President-Elect, American Academy of Ophthalmology, 2006. Secretary-Treasurer, American Ophthalmological Society, 1999 – 2007. Member, Board of Trustees, American Society of Retina Specialists, 2002 – 2006. President, Retina Society, 2004 & 2005. Member, Data and Safety Monitoring Committee, NAPP Trial, 2002 – 2006. Member, American Academy of Ophthalmology Committee for Research, Regulatory, and External Scientific relations, 2000 – 2005.

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Chairman, American Board of Ophthalmology, 2004. Director, American Board of Ophthalmology, 1997 – 2004. Member, American Academy of Ophthalmology Committee for Ophthalmic Technology Development, 1994-2000. Member, American Academy of Ophthalmology Committee for Research, Regulatory Agencies and Federal Systems, 1990-1998. Associate Examiner, American Board of Ophthalmology, 1986-1997. Treasurer, Retina Society, 1997 – 2000. Chairman, Credentials Committee, Retina Society, 1992-1996. Voting Consultant, FDA Ophthalmic Devices Panel, l993-2009. Chairman, Food and Drug Administration (FDA) Ophthalmic Devices Panel, 1990- 1993. Member, Food and Drug Administration (FDA) Ophthalmic Devices Panel, 1986- l993. Member, RAND/Academic Medical Center Consortium on Cataract Surgery, 1990- l992. Member, National Eye Institute Vision Research Review Committee, 1992-1993 (Brevity due to FDA conflict). Member, NEI Data and Safety Monitoring Committee, Silicone Oil Study, 1985- 1991. Professional Society Memberships: American Ophthalmological Society Retina Society Macula Society American Society of Retinal Specialists (ne Vitreous Society) Club Jules Gonin Association for Research in Vision and Ophthalmology (ARVO) Schepens International Society Pan American Ophthalmological Society Society of Heed Fellows American Eye Study Club Joseph Weil Society Bascom Palmer Alumni Association American Eye Study Club Wilmer Residents Association Current and Past Editorial Staff Appointments: Associate Editor, Retina, 2007 - present Editorial Board, Retina, 1985-present. Associate Secretary, American Academy of Ophthalmology, Modules Program, 1988-1992. Editorial Review Board, American Academy of Ophthalmology, Clinical Modules for Ophthalmologists, 1983 – 1988. Chairman, American Academy of Ophthalmology Preferred Practice Patterns: Retina

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Panel, 1992-2001. Member, American Academy of Ophthalmology Preferred Practice Patterns: Retina Panel, 1989-2001. Current Reviewer for Ophthalmology Publications: Ophthalmology American Journal of Ophthalmology JAMA Archives of Ophthalmology Retina British Journal of Ophthalmology European Journal of Ophthalmology Indian Journal of Ophthalmology Past Granted Research: Principle Investigator, Macular Photocoagulation Study, University of Oklahoma, 1979-1992. Principle Investigator, Endophthalmitis Vitrectomy Study, University of Oklahoma, 1990-1992. Current Research Interests: History of medicine Evidence-based medicine, outcomes research Diabetic retinopathy: pathogenesis, epidemiology, screening, treatment, and prevention Pathogenesis and prevention of retinal detachment Posterior segment complications of intraocular surgery Age-related macular degeneration: screening, treatment Honors and Awards: American Academy of Ophthalmology Honor Award, 1982. American Academy of Ophthalmology Senior Honor Award, 1991. Society of Heed Fellows Honor Award, 1991 Residents' Teaching Award, Greater Baltimore Medical Center, 1994 American Academy of Ophthalmology Secretariat Award, 2003 Residents' Teaching Award, Greater Baltimore Medical Center, 2005 American Academy of Ophthalmology Life Achievement Award, 2005 Gertrude Pryon Award (American Society of Retinal Specialists), 2009 Residents' Teaching Award, Greater Baltimore Medical Center, 2010 Presidential Guest of Honor, American Academy of Ophthalmology annual meeting, 2011 Inaugural recipient of the Wilkinson-Welch-Hoover Endowed Chair in Ophthalmology, GBMC, 2015 Special Recognition Award, American Academy of Ophthalmology, 2015 Retina Hall of Fame, Charter member, 2016. Named Lectures: 11th Mahlon Barlow Memorial Lectureship, Baltimore, 1982

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2nd Ronald G. Michels Memorial Lectureship, Baltimore, 1992 15th Taylor Smith Lecture, Aspen, 1994 2nd Walter J. Stark Sr. Lecture, Oklahoma City, 1994 12th Delbert P. Nachazel, Jr Lecture, Detroit, 1999 25th Tullos O. Coston Lecture, Oklahoma City, 2004. 37th Doheny Lecture, Los Angeles, 2006. 17th D. Jackson Coleman Lecture, New York, 2007. 4th Jerry and Donna Knauer Lecture, Beaver Creek, 2007. 31st Taylor Asbury Lecture, Cincinnati, 2007 8th Stanley Truhlsen Lecture, Omaha, 2009 20th Gertrude Pryon Award Lecture, New York, 2009 23rd William Holland Wilmer Lecture, Baltimore, 2011 21st Edward W. D. Norton Lecture, Miami, 2015 Visiting Professorships: Albany (NY) Medical Center University of Arkansas Bascom Palmer Eye Institute Baylor University University of California, SF Duke University University of Iowa Devers Eye Clinic, Portland University of Kansas Emory University University of Minnesota Georgetown University University of Oklahoma Mayo Clinic University of Pennsylvania Mass Eye and Ear Infirmary University of Pittsburgh Penn State University University of Southern California Royal Oak, MI University of Tenn, Memphis Tulane University University of Texas, San Antonio Vienna Eye Clinic I University of Cincinnati Wills Eye Hospital Vanberbilt University Wake Forest University PUBLICATIONS 1. Donahoo, J.S., Wilkinson, C.P., Weldon, C.S.: The Production of Lymphocytopenia by Selective Irradiation in Dogs, J Surg Res 7:475-480, 1967. 2. Duke, J.R., Wilkinson, C.P., Sigelman, S.: Retinal Microaneurysms in Leukemia, Brit J Ophthalmol 52:368-374, 1968. 3. Maumenee, A.E., Wilkinson, C.P.: A Combined Operation for Glaucoma and Cataract, Am J Ophthalmol 69:360-367, 1970. 4. Wilkinson, C.P., Welch, R.B.: Intraocular Toxocara, Am J Ophthalmol 71:921-930, 1971.

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5. Gass, J.D.M., Wilkinson, C.P.: A Follow-Up Study of Presumed Ocular Histoplasmosis, Trans Am Acad Ophthalmol Otolaryngol 76:672-694, 1972. 6. Wilkinson, C.P.: Diabetic Retinopathy, J Oklahoma State Assoc 65:399-404, 1972. Part II, 65:442-446, 1972. 7. WIlkinson, C.P.: Current Concepts in the Treatment of Macular Diseases, Southern Med J 1975, pages 914-918. 8. Wilkinson, C.P.: Stimulation of Subretinal Neovascularization, Am J Ophthalmol 81:104-106, 1976. 9. Wilkinson, C.P.: Presumed Ocular Histoplasmosis, Am J Ophthalmol 82:104-106, 1976. 10. Wilkinson, C.P., Anderson, L.S., Little, J.H.: Retinal Detachment Following Phacoemulsification, Ophthalmology 85:151-156, 1978. 11. Coston, T.O., Wilkinson, C.P.: Choroidal Osteoma, Am J Ophthalmol 86:368-372, 1978. 12. Wilkinson, C.P.: Retinal Detachment Following Phacoemulsification, Am J Ophthalmol 87:628-631, 1979. 13. Freeman, H.M., Dobbie, J.G., Friedman, M.W., Johnston, G.P., Jungshaffer, O.H., McPherson, A.R., Nicholson, D.H., Spalter, H.F., Wilkinson, C.P., Tasman, W.S.:Pseudophakic Retinal Detachment, Mod Probl Ophthalmol Vol. 20, Karger, Basel, 1979. 14. Wilkinson, C.P.: Retinal Detachment Following Phacoemulsification, Mod Probl Ophthalmol Vol. 20, Karger, Basel, 1979, pages 339-344. 15. Wilkinson, C.P.: Recurrent Macular Pucker, Am J Ophthalmol 88:1029-1031, 1979. 16. Wilkinson, C.P.: Rowsey, J.J., Closed Vitrectomy for the Vitreous Touch Syndrome, Am J Ophthalmol 90:304-308, 1980. 17. Wilkinson, C.P.: Vitrectomy for Complications Related to Elective Senile Cataract Surgery, In: Current Concepts in Cataract Surgery. Emery, J.E. and Jacobson (eds). C.V. Mosby, St. Louis, 1980, pages 272-273. 18. Wilkinson, C.P.: Update: Retinal Detachment Following Phacoemulsification, In: Current Concepts in Cataract Surgery. Emery, J.E. and Jacobson (eds). C.V. Mosby, St. Louis, 1980, pages 323-324. 19. Wilkinson, C.P.: Retinal Detachments Following Intraocular Lens Implantation, Ophthalmology 88:410-413, 1981.

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20. Wilkinson, C.P.: What Are the Highlights About Retinal Detachments Following Intraocular Lens Implantation? Highlights of Ophthalmol, Vol. IX, 1981.

21. Wilkinson, C.P.: Visual Results Following Scleral Buckling for Retinal Detachments Sparing the Macula, Retina, 1:113-116, 1981. 22. Robertson, D.M., Wilkinson, C.P., Murray, J.L., Gordy, D.D.: Metastatic Tumor to the Retina and Vitreous Cavity from Primary Melanoma of the Skin, Ophthalmology, 88:1296-1301, 1981. 23. Basta, L.L., Wilkinson, C.P., Anderson, L.S., Acers, T.E: Focal Choroidal Calcification, Ann Ophthalmol, April, 1981, pages 447-450. 24. Wilkinson, C.P.: A Long-Term Follow-Up Study of Cystoid Macular Edema in Aphakic and Pseudophakic Eyes, Trans Am Ophthalmol Soc 79:810-839, 1981. 25. Macular Photocoagulation Study Group: Argon Laser Photocoagulation for Senile Macular Degeneration: Results of a Randomized Clinical Trial. Arch Ophthalmol 100:912-918, 1982. 26. Macular Photocoagulation Study Group: Argon Laser Photocoagulation for Ocular Histoplasmosis: Results of a Randomized Clinical Trial. Arch Ophthalmol 101:1347-1357, 1983. 27. Macular Photocoagulation Study Group: Argon Laser Photocoagulation for Idiopathic Neovascularization: Results of a Randomized Clinical Trial. Arch Ophthalmol 101:1358-1361, 1983. 28. Fine, S.L., Murphy, R.P., Macular Photocoagulation Study Group: Photocoagulation for Choroidal Neovascularization, Ophthalmology 90:531-533, 1983. 29. Wilkinson, C.P.: The Natural Course of Cystoid Macular Edema Occurring in Pseudophakic Eyes, Trans XXIV International Congress Ophthalmol, 1983, pages 67-70. 30. Wilkinson, C.P., Bradford, R.H.: The Drainage of Subretinal Fluid. Trans Am Ophthalmol Soc 81:162-171, 1983. 31. Wilkinson, C.P., Bradford, R.H.: Complications of Draining Subretinal Fluid. Retina 4:1-4, 1984. 32. Macular Photocoagulation Study Group: Changing the Protocol: A Case Report from the Macular Photocoagulation Study. Controlled Clinical Trials 5:203-216, 1984. 33. The Silicone Study Group: Proliferative Vitreoretinopathy. Am J Ophthalmol 99:593-595, 1985.

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34. Wilkinson, C.P.: Pseudophakic Retinal Detachments, Retina 5:1-4, 1985. 35. Wilkinson, C.P.: The Natural Course of Pseudophakic Eyes with Cystoid Macular Edema. In: Ryan, S.J., Dawson, A.K., Little, H.L. (eds). Retinal Diseases Grune & Stratton, Orlando, FL 1985. 36. Wilkinson, C.P.: Discussion: Margherio, R.R., Cox, M.S., Trese, M.T., Murphy, P.L., et al, Removal of Epimacular Membranes. Ophthalmology 92:1082-1083, 1985. 37. Macular Photocoagulation Study Group: Early Detection of Extrafoveal Neovascular Membranes by Daily Central Field Evaluation. Ophthalmology 92:603-609, 1985. 38. Ober, R.R., WIlkinson, C.P., Fiore, J.V., Maggiano, J.M.: Rhegmatogenous Retinal Detachment After Neodymium-YAG Capsulotomy in Phakic and Pseudophakic Eyes. Am J Ophthalmol 101:81-89, 1986. 39. Wilkinson, C.P.: Retinal Detachment Following Intraocular Lens Implantation. Graefe's Arch Clin Exp Ophthalmol 224:64-66, 1986. 40. Wilkinson, C.P.: The Clinical Examination. Limitation and Over-utilization of Angiographic Services. Ophthalmology 93:401-404, 1986. 41. Macular Photocoagulation Study Group: Recurrent Choroidal Neovascularization After Argon Laser Photocoagulation for Neovascular Maculopathy. Arch Ophthalmol 104:503-512, 1986. 42. Macular Photocoagulation Study Group: Argon Laser Photocoagulation for Neovascular Maculopathy, Three-Year Results From Randomized Clinical Trials. Arch Ophthalmol 104:694-701, 1986. 43. Wilkinson, C.P.: Pseudophakic Retinal Detachments. In: Basic and Advanced Vitreous Surgery. Blankenship, G.W., Binder, S., Gonvers, M., Stirpe, M. (eds). Liviana Press, Padova, Italy, 1986, pages 157-161. 44. Wilkinson, C.P.: Closed Vitreous Surgery for Complications of Intraocular Lens Implantation. I. Indications; In: Basic and Advanced Vitreous Surgery. Blankenship, G.W., Binder, S., Gonvers, M., Stirpe, M. (eds). Liviana Press, Padova, Italy, 1986, pages 136-140. 45. Wilkinson, C.P.: Closed Vitreous Surgery for Complications of Intraocular Lens Implantation. II. Techniques. In: Basic and Advanced Vitreous Surgery. Blankenship, G.W., Binder, S., Gonvers, M., Stirpe, M. (eds). Liviana Press, Padova, Italy, 1986, pages 141-144.

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95. Wilkinson, C P: The FDA and its regulation of vitreous substitutes. Arch Ophthalmol 111: 1619-1620, l993. 96. Stirpe, M, Wilkinson, CP, Billi, B, et al: Retinal detachment in myopic and emmetropic eyes after extracapsular cataract extraction. J Vitreoret 2:17-22, 1993. 97. Aminoglycoside Toxicity Study Group: Aminoglycoside toxicity in the treatment of endophthalmitis. Arch Ophthalmology 112:48-53, 1994. 98. Macular Photocoagulation Study Group: Visual outcome after laser photocoagulation for subretinal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Arch Ophthalmol 112:480-488,1994. 99. Macular Photocoagulation Study Group: Persistent and/or recurrent choroidal neovascularization after laser photocoagulation for subfoveal choroidal neovascularization of age-related macular degeneration. Arch Ophthalmol 112: 489-499, 1994. 100. Macular Photocoagulation Study Group: Laser photocoagulation of juxtafoveal choroidal neovascularization: Five year results from randomized clinical trials. Arch Ophthalmol 112:500-509, 1994. 101. Wilkinson, CP: Ocular toxocariasis. In: Ryan, SJ, Schachat, AP, Murphy, RB (eds): Retina Volume 2, Second Edition St Louis, CV Mosby, 1994, pp 1545-1552. 102. Macular Photocoagulation Study Group: Evaluation of argon green vs. krypton red laser for photocoagulation of subfoveal choroidal neovascularization in the macular photocoagulation study. Arch Ophthalmol 112:1176 - 1184, l994. 103. Macular Photocoagulation Study Group: Laser photocoagulation for neovascular lesions nasal to the fovea. Arch Ophthalmol 113:56-61, 1995. 104. Macular Photocoagulation Study Group: The influence of treatment extent on the visual acuity of eyes treated with krypton laser for juxtafoveal choroidal neovascularization. Arch Ophthalmol 113:190-194, l995. 105. Macular Photocoagulation Study Group: Occult choroidal neovascularization: Influence on visual outcome in patients with age-related macular degeneration. Arch Ophthalmol 114: 400- 412, 1996. 106. Macular Photocoagulation Study Group: Five year follow-up of fellow eyes of individuals with ocular histoplasmosis and unilateral extrafoveal or juxtafoveal choroidal neovascularization. Arch Ophthalmol 114:677-688,l996. 107. Wilkinson, C. P., Rice, T.A.: Michels Retinal Detachment , St Louis, Mosby, 1997, 1163 pages.

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108. Macular Photocoagulation Study Group: Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degenaeration. Arch Ophthalmol 115:741-747, l997. 109. Wilkinson, C. P.: Long-term recurrent exudative serous retinal detachments associated with systemic steroid therapy. Wilmer retina update 4:37-42, l998. 110. Wilkinson, C. P.: Vitreomacular traction syndrome. Wilmer retina update. 4:56-58, 1998. 111. Wilkinson, C.P. Wanted: optimal data regarding surgery for retinal detachment. Retina 18: 199-201, 1998. 112. Wilkinson, C. P. Rhegmatogenous retinal detachment. In: Yanoff, Y, Duker, JS (eds): Ophthalmology, 1998, St. Louis, Mosby, pp 39.1-39.8. 113. Wilkinson, C.P. Scleral buckling techniques: a simplified approach. In: Guyer, DR, Yannuzzi, LA, Chang, S et al (eds): Retina-Vitreous-Macula, 1999, Philadelphia, WB Saunders, pp 1248-1271. 114. Wilkinson, C.P. Evidence-based medicine regarding the prevention of retinal detachment. Trans Am Ophthamol Soc 1999;97:307-406. 115. Wilkinson, C. P. Evidence-based analysis of prophylactic treatment of asymptomatic retinal breaks and lattice degeneration. Ophthalmology 2000;107:12-18. 116. Fekrat, S, Wilkinson, CP, Chang, B et al: Acute annular outer retinopathy: report of

four cases.Am J Ophthalmol 2000; 130:636-644. 117. Wilkinson, C. P. (Ed), Ryan, SJ (Senior Editor) Retina, (Volume 3, 3rd Edition). 2001 St. Louis, Mosby, pp 1849-2653. 118. Wilkinson, C.P. Ocular Toxocariasis. In Schachat, A.P., Ryan, SJ (Eds): Retina,

(Volume 2, 3rd Edition). 2001, St. Louis, Mosby, pp 1545 – 1552. 119. Wilkinson, C.P. Prevention of Retinal Detachment. In Wilkinson, C.P., Ryan, S.J.

(Eds): Retina, (Volume 3, 3rd Edition). 2001, St Louis, Mosby, pp 2063 – 2075. 120. Wilkinson, CP, Green, WR: Vitrectomy for retained lens material after cataract

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155.WilkinsonCP,Prevention of Retinal Detachment. In Schachat AP, Wilkinson CP, Hinton, DR, Sadda SR, Wiedemann P.(Eds). Ryan’s Retina, Volume 3, 6th Edition. 2017, New York, Elsevier Saunders, pp . 2017-2030. 156. Wilkinson CP, Wiedemann P (Eds). Ryan’s Retina, Volume 3, 6th Edition 2017, New York, Elsevier Saunders, pp 1821-2374.

Updated and signed electronically 1/25/20