Diabetic Retinopathy Evaluationat the Fundus Photograph

Reading Center –past, present,Jane Armstrong

History of the Reading Center

UW-Madison, Medical SchoolDept. of Ophthalmology &

Visual SciencesFundus Photograph Reading Center

History of Trials• 1961-65 Natural Course of PDR• 1968 Airlie House Symposium• 1970-76 191 Study• 1972-79 Diabetic Retinopathy Study• 1979-1989ETDRS• 1983-1993DCCT• 1993-now EDIC• Pharmaceutical trials begin (Lilly, Novartis, Genentech,

UW-FPRC Background

• 1961-65 Natural Course of PDR– 1300 University Avenue– MDD and YLM– Fundus diagrams– Stereo photos– Exhibits 1964, 1965– Archives 1965

Vitreous contraction in proliferative diabetic retinopathy

Retinal drawing circa 1962

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UW-FPRC Background• 1968 Airlie House Symposium

– Photocoagulation– Pituitary ablation– Classification of retinopathy

Historical Perspective

September 291968

Careful observational experience lead to thedescription of various retinopathy features andthe natural history of the disease Symposium on the Treatment of DiabeticRetinopathy is organized by Drs. Morton F.Goldberg and Stuart L. Fine and held at theAirlie House Conference Center in Warrenton,Virginia

Airlie House 1968

Historical Perspective The original Airlie House Classification SystemStandardized photographic protocol (5 fields)Classification of retinopathy features

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Historical Perspective The Modified Airlie House fields areused for the Diabetic RetinopathyStudy (DRS) in 1971

4 6

75

123

Historical Perspective The Modified Airlie House fields are furthermodified to their current configuration inthe early 1990s to better capture DME

4 6

75

1M23M

Abnormalities Graded• H/Ma – hemorrhages and/or microaneurysms• HE – hard exudates• SE – soft exudates (cotton-wool patches)• IRMA – intraretinal microvascular abnormalities• VB – venous beading• NVD – new vessels 1 DD from disc• NVE – new vessels elsewhere• VH – vitreous hemorrhage• PRH – preretinal hemorrhage• FPD,FPE – fibrous proliferations

Features of DiabeticRetinopathy

Venousbeading

HemorrhagesMicroaneurysms

NVD

Evaluation of PhotographicsetsBy the Reading Center

Determination ofAppropriateRetinopathy level

Assessment of MacularEdemaCharacteristics

Step 4 (Ma + H, HE &/or SE)Step 1 (no retinopathy)

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Step 5 (HE both eyes) Step 8 (VB one fld, one eye)

Dec 1964

AUG 1965

Featureless retina

APR 1966

JUL 1966

Sep 1966

Jul 1966

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UW-FPRC Background• 1970-76 191 Study

– Local MD’s offices and eye clinic annex– Retinopathy severity levels– Progression rates by level

191 Levels1. No DR2. Ma only3. HMa < Std. 2A

– HE < Std. 3– SE, IRMA, VB Q

4. HMa Std. 2A– HE Std. 3– SE, IRMA, VB definite

5. (DRS) 3 of following (Flds. 4-7)– HMa 2A > 1 Fld.– SE 2 Flds.– IRMA 2 Flds.– VB 2 Flds.

or– IRMA 4 Flds., 8A in 2

1. PDR, pc scars, VH

UW-FPRC Beginning• 1972-79 Diabetic Retinopathy Study

(DRS)– More photos, space, dollars– More staff– More moving

• “Green” house (Charter & Johnson)• “Old” WARF• New WARF

UW-FPRC DRS 1972-79• Grader training• Quality control• Deadlines• External monitoring• Impact

Diabetic Retinopathy Study (DRS)RCT, NEI, 1972-1979 (n = 1742)

• Eligibility– Type 1 or 2 diabetes– PDR in at least 1 eye or SNPDR in both eyes– VA 20/100 or better in each eye

• Design– 1 eye argon or xenon photocoagulation, other no

treatment– VA and eye exam every four months (masked examiner,

standard protocol)– Visual fields and fundus photographs at 4 months and

Diabetic RetinopathyStudy

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Diabetic Retinopathy (DR) Stages

Vitrectomy80, 85Severe VH, Traction RD*Early Treatment Diabetic Retinopathy Study

Prompt Laser71, 75High-risk PDR (HR-PDR)Consider Laser61, 65“Mild” PDR

Consider Laser53Very Severe NPDR(Pre-proliferative)

35, 43, 47NPDR (Moderate to severe)

Current TreatmentETDRS*Severity

LevelBroad Agreement

20Microaneurysms (Ma) onlyControl of:glycemia, bloodpressure, lipids

10No DR

DCCTThe study showed that keeping blood glucoselevels as close to normal as possible slows theonset and progression of the eye, kidney, andnerve damage caused by diabetes. In fact, itdemonstrated that any sustained lowering of bloodglucose, also called blood sugar, helps, even if theperson has a history of poor control.

The DCCT involved 1,441 volunteers, ages 13 to39, with type 1 diabetes and 29 medical centers inthe United States and Canada. Volunteers had tohave had diabetes for at least 1 year but no longerthan 15 years. They also were required to have no,or only early signs of, diabetic eye disease.

Advancement of Medical Understandingand New Treatments Drives the Types of

Trial Outcome

DRS Severe Vision Loss(functional)

ETDRS, many others Moderate Vision Loss(functional)

Lilly PKC inhibitor,DRCR.net protocols

Prevention of progression ofDME (morphologic)

DCCT/EDIC, UK PDS,others

Prevention of progression ofDR (morphologic)

Modified Airlie House Classification &ETDRS Retinopathy Severity Scale

• Developed in the DRS and ETDRS• Modified from an original 6 level scale• Greater detail (and complexity) added based

upon the predictive value of various gradedfeatures

• Accepted as a clinically important outcome• Progression of > 3 steps on this scale is a

principal outcome for the DCCT/EDIC and

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ETDRS DR Severity Scale• Highly detailed description of disease level• Employed to describe disease level for

inclusion and exclusion criteria for clinicalresearch studies

• Predictive value and extensive experiencewith it in the research arena makesprogression along this scale a robustendpoint for some clinical trials

Severity Scales: Conclusions• Scales are built to be highly descriptive and have

predictive value and are therefore valuable inclinical trials

• Standardized data capture and assessment isessential for their research application

• Extent of lesions such as H/Ma, VB and IRMAprovide severity scale for NPDR

• Extent and location of RT and HE providemeasures of severity of DME

Current Studies

DRCRnet• Laser Photocoagulation for Diabetic

Macular Edema• Intravitreal Triamcinolone Acetonide

Versus Laser Study• OCT Diurnal Variation Study• Peribulbar Triamcinolone Acetonide Study• PRP Study• Subclinical Diabetic Macular Edema Study

Grading fundus photographs forretinopathy severity and

• Characteristic abnormalities classified withModified Airlie House system

• Grades for various abnormalities summarizedinto ETDRS severity scale

• Developed in the DRS and ETDRS tocategorize patients according to risk ofdeveloping sight-threatening PDR

• Progression defined as movement on thescale

The FPRC Team

Dr. Ronald Danis,Director

Ruth Susman,Ocular Disease Evaluator

Kathy Glander,Project Manager

Katie Nigl,Digital Imaging Specialist

Vonnie Gama,Data Manager

Hugh Wabers,Imaging Consultant

Amy Remm,Quality Assurance

DirkNorman,Computing

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GradingGraders use stereo viewers on

upright light boxes to evaluatefilm fundus photos.

Digital imagesare graded fromour server

Quality control of grading

• Multi-step process– Preliminary grading for ME status and level– Detailed grading– Comparison for important differences– Adjudication to yield grading of record

• Direct longitudinal review if adverse event

Central subfield = 4/9 disc areas (DA)Inner subfields = 8/9 DA eachOuter subfields = 3 DA eachTotal grid = 16 DA

Stereo Fundus Photography remains the standardfor evaluation of area and proximity to center inclinical trials – for NON-center-involved DME

New Technology for RetinalEvaluation in Clinical Trials

• Requires standardized data captureacross clinical sites

– Availability of instrumentation– Quality of instrumentation– Training of personnel capturing the images

• Requires standardized display andprotocols for interpretation

• Requires demonstrable reproducibility andutility

However, OCT (10 um axial resolution)clearly issuperior to photographic estimation toquantifycenter involvement

Additionalmorphologicfeatures suchas cystoidspaces canbe more easilydiscerned byOCT

Future Diabetic Evaluation

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Future Evaluation• Integrated approach with overlay of OCT• One step grading with outcome review and

continuous quality control• Use of a mosaic for assessment• Spectral Domain OCT• Use of the green channel• Use of optimization for digital photos

Color photo and OCT of DME

M.D. Davis, A. Glassman, L.P. Aiello, et al.Comparison of OCT and Fundus Photographic Assessments of Macular EdemaInvest Ophthalmol Vis Sci 2005 46: E-Abstract 397.

Red-free images favorable forDR

But may need contrastenhancement

Integrated Approach

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