Pharmacotherapy of Posterior Segment DiseasePharmacotherapy of Posterior Segment Disease Joseph J. Pizzimenti, OD, FAAO [email protected] Sam Snead Quotes "Keep close count of your

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Pharmacotherapy ofPharmacotherapy ofPosterior Segment DiseasePosterior Segment Disease

Joseph J. Joseph J. PizzimentiPizzimenti, OD, FAAO, OD, FAAOpizzimen@[email protected]

Sam Snead QuotesSam Snead Quotes"Keep close count of your"Keep close count of yournickels and dimes, stay awaynickels and dimes, stay awayfrom whiskey, and neverfrom whiskey, and neverconcede a putt.concede a putt.””"If a lot of people gripped a"If a lot of people gripped aknife and fork the way they doknife and fork the way they doa golf club, they'd starve toa golf club, they'd starve todeath.death.””"Thinking instead of acting is"Thinking instead of acting isthe number-one golf disease.the number-one golf disease.

Financial DisclosureFinancial DisclosureI have received honoraria from, participated inI have received honoraria from, participated inadvisory boards and speaker panels for:advisory boards and speaker panels for:–– AlconAlcon–– Carl Carl Zeiss MeditecZeiss Meditec–– ReichertReichert–– VSPVSP–– ZeavisionZeavision

I have no proprietary interest in any product, andI have no proprietary interest in any product, andmy affiliations have no influence on the contentmy affiliations have no influence on the contentof this lecture.of this lecture.

Course GoalsCourse GoalsRapid-fire clinical roundsRapid-fire clinical rounds–– Vitreo-retinal Vitreo-retinal casescases

Audience participationAudience participationEmphasis on current andEmphasis on current andemerging treatmentsemerging treatmentsNew knowledge fromNew knowledge fromclinical studies and trialsclinical studies and trials–– Impact on clinical practiceImpact on clinical practice

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Functional Anatomy of Posterior SegmentFunctional Anatomy of Posterior Segment

Clinical Landmark - EquatorClinical Landmark - Equator Peripheral vs Central RetinaPeripheral vs Central Retina

Approx 6DiscDiameters

CentralRetina

3

Exit Site of

Vortex Ampulla

Cent. R

et. →Equator

Peripheral vs Central RetinaPeripheral vs Central Retina

PosteriorPole

“Mid-Periphery”

OSOSIS/OSIS/OSELMELM RPERPEISIS

NFL: Nerve Fiber LayerNFL: Nerve Fiber Layer OPL: Outer OPL: Outer Plexiform Plexiform Layer Layer IS/OS: Junction of inner and outerIS/OS: Junction of inner and outerILM: Inner Limiting MembraneILM: Inner Limiting Membrane ONL: Outer Nuclear LayerONL: Outer Nuclear Layer photoreceptor segmentsphotoreceptor segmentsGCL: Ganglion Cell LayerGCL: Ganglion Cell Layer ELM: External limiting membraneELM: External limiting membrane OS: Photoreceptor Outer SegmentOS: Photoreceptor Outer SegmentIPL: Inner IPL: Inner Plexiform Plexiform Layer Layer IS: Photoreceptor Inner Segment IS: Photoreceptor Inner Segment RPE: Retinal Pigment EpitheliumRPE: Retinal Pigment EpitheliumINL: Inner Nuclear Layer INL: Inner Nuclear Layer

ILMILM GCLGCLNFLNFL

ChoroidChoroid

IPLIPL INLINL OPLOPL ONLONL

SD-OCT Healthy MaculaSD-OCT Healthy Macula The The ChoriodChoriodLoose connective tissueLoose connective tissueMelanocytesMelanocytesChoriocapillarisChoriocapillaris–– Fenestrated endotheliumFenestrated endothelium

allows diffusion of proteinsallows diffusion of proteins–– S__________ S__________ regulationregulation–– High blood flowHigh blood flow–– Very little O-2 extracted, soVery little O-2 extracted, so

high venous O-2high venous O-2BM

CC

Mel.

thicknessRPE

sclera

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Metallic FBMetallic FB Anatomic Anomaly #1Anatomic Anomaly #1

Cilioretinal artery• 10-30% have it

• May spare centralvision in CRAO

• If occluded, centralvision loss

Cilioretinal Artery in CRAO Cilioretinal Artery Occlusion

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Cilioretinal Artery Occlusion Venous System AnatomyVenous System Anatomy

Central Retinal VeinCentral Retinal Vein–– Retinal veins join atRetinal veins join at

disc to form CRVdisc to form CRV–– Drains into superiorDrains into superior

ophthalmic v.ophthalmic v. CRA

CRV

Anatomic Anomaly #2Anatomic Anomaly #2

"Dual Trunk" anomaly2 central retinal veinsCV Dx. can lead to aspecial type of sup orinf hemispheric RVO

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Identifying the Signs ofIdentifying the Signs ofRetinal DiseaseRetinal Disease

Signs of vascular diseaseSigns of vascular diseaseSigns of degenerativeSigns of degenerativediseasediseaseSigns of other diseaseSigns of other disease–– InfectiousInfectious–– InflammatoryInflammatory–– Retina/Optic N.Retina/Optic N.–– HereditaryHereditary–– NeoplasticNeoplastic–– TraumaTrauma

Mystery MaculaMystery Macula

SubjectiveSubjective–– 35 35 y/o y/o WMWM–– sudden, unilateral blur ODsudden, unilateral blur OD–– no pain or traumano pain or trauma–– ““Type AType A””

ObjectiveObjective–– VAVA

OD 20/60OD 20/60OS 20/20OS 20/20

–– Hyperopic shiftHyperopic shift

DFE shows large, serous elevationDFE shows large, serous elevationFFocal detachment of sensory retinaocal detachment of sensory retina

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What other tests would you likeWhat other tests would you liketo perform?to perform?

OCTOCT

What is your assessment?What is your assessment?

What is your plan?What is your plan?

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Idiopathic Central SerousIdiopathic Central SerousChorioretinopathyChorioretinopathy

(ICSC)(ICSC)

ICSCICSC

ObjectiveObjective–– Breakdown of Breakdown of outer blood-retina barrierouter blood-retina barrier–– FA shows classic FA shows classic ““smoke-stacksmoke-stack””

Pooling beneath RPE detachmentPooling beneath RPE detachmentDye ascends vertically, then laterally in SRSDye ascends vertically, then laterally in SRS

Differential DiagnosisDifferential Diagnosis–– TumorTumor–– RPE detachmentRPE detachment–– Steroid-induced CSCSteroid-induced CSC

““SmokestackSmokestack”” FA in CSC FA in CSC Retina QuizRetina Quiz

In ICSC, fluid leakage most likely occurs atIn ICSC, fluid leakage most likely occurs atthe level of:the level of:a.a. nerve fiber layernerve fiber layerb.b. inner retinainner retinac.c. outer retinaouter retinad.d. choroidchoroid

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PlanPlan

ObservationObservation–– 60% regain 20/20 w/no intervention60% regain 20/20 w/no intervention–– monitor q4wks for 6 monitor q4wks for 6 monmonFocal LaserFocal Laser–– if unresolved after 4-6 if unresolved after 4-6 monmon–– if recurrentif recurrent–– Focal, direct treatmentFocal, direct treatment–– Leak must be outside FAZLeak must be outside FAZ ( (500 um)500 um)

OutcomeOutcome

• VA recovered to 20/25at week 12

• Reduction of fluid,20/40 VA at week 5

Photodynamic Therapy for CSCPhotodynamic Therapy for CSC

Serousdetachmentbefore PDT.

Resolution ofdetachment with residualRPE mottling after PDT.

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Treatments for CSCTreatments for CSC

Thermal laserThermal laser

PhotodynamicPhotodynamicTherapyTherapy–– Visudyne Visudyne ((VerteporfinVerteporfin))–– A light-activated drugA light-activated drug

Limitations of LaserLimitations of LaserPhotodynamic (Photodynamic (VisudyneVisudyne) Therapy: A) Therapy: A

2-Step Process2-Step Process

Step 1

Step 2

10 Min Infusion

83 Sec ActivationA treatment odyssey

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A 38-year-old Caucasian male

Subjective– migraine-like headaches and sudden-onset

distortion OS– symptoms began 5 days after lumbar epidural

injection of methylprednisolone acetate 120mg x 5 days

– to treat chronic lower back pain associatedwith spondylosis.

– no other diseases/drug therapy.

ObjectiveObjectiveBest-corrected VA was 20/20 OD and 20/60 OS.Amsler testing revealed a large, gray area ofcentral visual distortion OS.OS VA improved to 20/25 within 4 weeks.One month later, the patient received anotherepidural steroid injection of methylprednisoloneacetate 120 mg.Five days later, he experienced acute visualblurring in the OS, headache, retinal sequelaesimilar to those in the first episode.His visual acuity recovered within several weeks,and the condition resolved without treatment.

38 38 y/o y/o WM:DFEWM:DFE

“dome” of elevatedretina involving theinferior aspect ofthe left macula.

38 38 y/o y/o WM: FAWM: FA

Small spot of focalhyperfluorescencewith early,transit,and late-stagefeatures of CSC.

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ConclusionsConclusions

Importance of a thorough medical history.Patients in whom CSC develops afterepidural analgesia with steroids should bealerted to the possible relationshipbetween CSC and this treatment.Clinicians should advise all patients withCSC to avoid systemic corticosteroidsadministered by any route, unless theyhave a compelling medical indication.

81 year old Caucasian female

CC: Decreased vision OU but OS getting much worse

Ocular History: + “Dry”AMD OU x 15 years, +Cataracts OU

Medical History: + Hypertension x 27 years (controlled with meds)

Allergies: +Sulfa drugs Meds: Ocuvite

VA: 20/100 OD 10/400 FB OS

EOMS: smooth/full TA: 12 mm Hg OU

Pupils: PERRLA – APD BP: 135/90 RAS

CF: Full periphery OU Central scotoma OU, confirmed w/Amsler

SLE: Unremarkable Vitreous: PVD OU

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Fluorescein AngiographyFluorescein AngiographyOutcome:

• Diagnosis:• Geographic Atrophy (End-stage Dry AMD) OD• Choroidal Neovascularization (Wet AMD) OS

• FA ordered

• Avastin injections OS

• Subsequent PDT (“double therapy”)

• 20/200 VA (OD) 20/200 (OS) at 1 year

• Low Vision Referral

• D/C Ocuvite; switch to BS MV w/L & Z

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Soft DrusenSoft Drusen

Soft, confluent more inclined to lead toSoft, confluent more inclined to lead to_______________ AMD *_______________ AMD *

soft drusen

Stages of AMD

EarlyAMD

Intermed.AMD

AdvancedAMD

“wet”

“dry”

Retina QuizRetina Quiz

The clinical feature of Wet AMD thatThe clinical feature of Wet AMD thatdistinguishes it from Dry is:distinguishes it from Dry is:a.a. Geographic atrophy of the RPEGeographic atrophy of the RPEb.b. soft, confluent soft, confluent drusendrusenc.c. vision 20/60 or worsevision 20/60 or worsed.d. Choroidal neovascular Choroidal neovascular membranemembrane

(CNVM) formation(CNVM) formation

AMD Risk FactorsAMD Risk FactorsAgeAge

Gender - Gender - F > MF > M

SmokingSmoking

Iris Color - Iris Color - lighter irislighter iris

ObesityObesity

CV DiseaseCV Disease

AMD Family HistoryAMD Family History

Poor nutritionPoor nutrition

Low Macular PigmentLow Macular Pigment

Dietary and Serum Levels -Dietary and Serum Levels -Complex analyses (most, butComplex analyses (most, butnot all) show a relationship.not all) show a relationship.

MPOD-MPOD- Most (but not all)Most (but not all)studies have shown reducedstudies have shown reducedMPOD in AMD (by multipleMPOD in AMD (by multiplemeasurement techniques).measurement techniques).

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AREDS 2AREDS 2 AREDS 2: PurposeAREDS 2: PurposeTo study effects of high supplemental doses of dietaryTo study effects of high supplemental doses of dietaryxanthophylls xanthophylls ((lutein lutein and and zeaxanthinzeaxanthin)) and and omega-3 omega-3 long-long-chain polyunsaturated fatty acids on development ofchain polyunsaturated fatty acids on development ofadvanced AMD.advanced AMD.To study the effects of these supplements on To study the effects of these supplements on cataractcataractand moderate vision loss.and moderate vision loss.To study the effects of To study the effects of eliminating beta-caroteneeliminating beta-carotene from fromoriginal AREDS formulation on development andoriginal AREDS formulation on development andprogression of AMD.progression of AMD.To study the effects of To study the effects of reducing zincreducing zinc in the original in the originalAREDS formulation on the development and progressionAREDS formulation on the development and progressionof AMD.of AMD.To contribute data for validation of the To contribute data for validation of the photographicphotographicAMD scalesAMD scales developed from the Age-Related Eye developed from the Age-Related EyeDisease Study.Disease Study.

AREDSAREDS 2 Formulation2 Formulation

Lutein at 10 mg/dayLutein at 10 mg/day

Zeaxanthin Zeaxanthin at 2 mg/dayat 2 mg/day–– and/or omega-3 fatty acids at a total of 1and/or omega-3 fatty acids at a total of 1

g/dayg/day

Zinc at 40 mg/dayZinc at 40 mg/day

Is There a Strategy ?Is There a Strategy ?USDA Food TriangleUSDA Food Triangle5+ daily portions of fruits &5+ daily portions of fruits &veggiesveggies–– at least 1 dark green, leafy vegat least 1 dark green, leafy veg

(spinach, kale)(spinach, kale)

Low fat, low cholesterolLow fat, low cholesterolAntioxidant for Antioxidant for ““nutritionally-nutritionally-challenged challenged ““Address CardiovascularAddress CardiovascularDisease, exerciseDisease, exerciseAvoid smoking, UVAvoid smoking, UV

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Approximately what percentage of dryApproximately what percentage of dry((non-exudativenon-exudative) AMD eyes progress to wet) AMD eyes progress to wet((exudativeexudative) AMD?) AMD?

a. 37 %a. 37 %b. 50 %b. 50 %c. 2 %c. 2 %d.d. 15-20 %15-20 %

Clinical Features of Clinical Features of ExudativeExudative(Wet) AMD(Wet) AMD

______________________*______________________*________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Available technologies for earlyAvailable technologies for earlydetection and monitoring of AMDdetection and monitoring of AMD

Non-invasive MethodsNon-invasive MethodsMacular Pigment Optical DensityMacular Pigment Optical Density–– MPODMPODPreferential Preferential Hyperacuity Hyperacuity PerimetryPerimetry–– PHPPHP Optical Coherence Tomography Optical Coherence Tomography–– OCTOCT

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Optical Coherence Tomography

Subfoveal Subfoveal CNVM w/ret thick, serous RDCNVM w/ret thick, serous RD

TD-OCTTD-OCT

CysticCysticchange inchange inWet AMDWet AMD

SD-OCTSD-OCT

Wet AMD: Earlier Detection,Wet AMD: Earlier Detection,Better TreatmentsBetter Treatments

Management of Exudative AMDManagement of Exudative AMDUV/blue WL protectionUV/blue WL protectionHome AmslerHome AmslerAntioxidants/Nutrition/Diet/Antioxidants/Nutrition/Diet/Smoking/ExerciseSmoking/ExerciseFA - Stat ! (ICG - as indicated) *FA - Stat ! (ICG - as indicated) *Retinal Consult and TreatmentRetinal Consult and Treatment–– Laser PhotocoagulationLaser Photocoagulation–– Photodynamic TherapyPhotodynamic Therapy–– Anti-angiogenic Anti-angiogenic TherapyTherapy–– Surgical or Other MedicalSurgical or Other Medical

InterventionInterventionLow Vision ConsultLow Vision Consult

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Combination Treatments

• Anti-VEGF agents

• Steroids

• PDT

Antiangiogenic Antiangiogenic Drugs: VEGFDrugs: VEGFInhibitorsInhibitors

VEGF binds to receptorVEGF binds to receptor

Targeting Vascular EndothelialGrowth Factor (VEGF)

• Macugen

• Lucentis

• Avastin

VEGF InhibitorsVEGF InhibitorsPegaptanib sodium-Pegaptanib sodium-MacugenMacugen ((Pfizer/Eyetech)Pfizer/Eyetech)–– FDA ApprovedFDA Approved–– AptamerAptamer (decoy): (decoy): inhibits protein activityinhibits protein activity

Ranibizumab- Ranibizumab- Lucentis Lucentis (Genentech) (Genentech) $2,000.00$2,000.00–– FDA ApprovedFDA Approved–– Antibody-basedAntibody-based–– Compared favorably to PDT in ANCHOR studyCompared favorably to PDT in ANCHOR study

Bevacizumab- Bevacizumab- AvastinAvastin (Genentech) $40.00(Genentech) $40.00–– Off labelOff label–– Anti-neoplasticAnti-neoplastic–– Intravitreal injectionIntravitreal injection–– 1 1 injection/mon injection/mon x 3 x 3 monmon

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Treatments for Wet AMDTreatments for Wet AMD Intravitreal Intravitreal InjectionInjection

Wet AMDWet AMD

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VEGF Inhibition for Wet AMDVEGF Inhibition for Wet AMD

VA 55 L

VA 78 L

Pre and Post Avastin Treatment

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Combination Treatments

• Anti-VEGF agents

• Steroids

• PDT

Which therapy(Which therapy(iesies) is/are ) is/are ““off-off-labellabel”” for Wet AMD? for Wet AMD?

a.a. Argon Laser PhotocoagulationArgon Laser Photocoagulationb.b. Visudyne Visudyne Photodynamic TherapyPhotodynamic Therapyc.c. Intravitreal Ranibizumab Intravitreal Ranibizumab ((LucentisLucentis))d.d. Intravitreal Bevacizumab Intravitreal Bevacizumab ((AvastinAvastin))e.e. Intravitreal Triamcinolone Intravitreal Triamcinolone ((KenalogKenalog))

Wet AMD Treatments onWet AMD Treatments onthe Horizonthe Horizon

VEGF InhibitorsVEGF InhibitorsSqualamine Squalamine lactate- lactate- Envizon Envizon ((GenaeraGenaera): Phase II): Phase II–– Isloated Isloated from dogfish shark tissuefrom dogfish shark tissue–– Originally developed for oncologyOriginally developed for oncology–– AminosterolAminosterol

Inhibits plasma membrane ion channelsInhibits plasma membrane ion channelsBlocks proliferation of endothelial cellsBlocks proliferation of endothelial cells

–– Administered IntravenouslyAdministered IntravenouslyWWeekly x 4 wkseekly x 4 wks

–– Small sample showed improved or stabilized VASmall sample showed improved or stabilized VA–– Low systemic toxicityLow systemic toxicity

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Squalamine Squalamine lactate- lactate- EnvizonEnvizon((GenaeraGenaera))

Squalamine works INSIDE endothelial cells to blockmultiple intracellular pathways generated by the bindingof VEGF and PDGF! to receptors.

VEGF Inhibitor not yet approvedVEGF Inhibitor not yet approved

VEGF-TrapVEGF-Trap ( (RegeneronRegeneron))–– Intravitreal Intravitreal injection completed Phase IIinjection completed Phase II

No adverse effectsNo adverse effects

–– Now entering Phase IIINow entering Phase III–– Binds tightly to VEGF receptorsBinds tightly to VEGF receptors–– Rapid decrease in foveal thickening,Rapid decrease in foveal thickening,

improved VAimproved VA

Case From NSU Macula ClinicCase From NSU Macula Clinic

65 65 yo yo BMBMHealthy, recent physicalHealthy, recent physical–– (-) DM, HTN(-) DM, HTNCC:CC: gradual centralgradual central blur OS x 1 wkblur OS x 1 wkVA:VA: OSOS 20/40020/400

–– Acknowledgement: Dr. Acknowledgement: Dr. Sherrol Sherrol ReynoldsReynolds

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What is your plan? What is your plan?


Idiopathic Idiopathic JuxtafovealJuxtafovealTelangectaisiaTelangectaisia


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OCTOCT Thickness MapThickness Map

OCTOCT Another cutAnother cut……

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Fluorescein angiogramsFluorescein angiograms

perifoveal intraretinal telangiectasias with leakage

Idiopathic Juxtafoveolar RetinalTelangiectasia (IJRT)

A condition characterized byA condition characterized byexudation or diffusion abnormalitiesexudation or diffusion abnormalitiesfrom from ectatic ectatic (dilated and tortuous)(dilated and tortuous)blood vessels and blood vessels and incompetent retinalincompetent retinalcapillaries in the capillaries in the juxtafoveolarjuxtafoveolar regionregion

S/P S/P Intravitreal KenalogIntravitreal KenalogVA 20/60-20/80VA 20/60-20/80 Describe That Fundus!Describe That Fundus!

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Questions and Comments?Questions and Comments?

74 year old WM:74 year old WM:SubjectiveSubjective

CCCC: Blurred : Blurred ““centralcentral”” vision (OD) @ distance and near vision (OD) @ distance and near–– Onset gradual, over 3-4 daysOnset gradual, over 3-4 days–– Last visit 3 weeks prior showed 20/25 VA ODLast visit 3 weeks prior showed 20/25 VA OD

Ocular HistoryOcular History: 7 weeks s/p uneventful cataract surgery: 7 weeks s/p uneventful cataract surgerywith IOL ODwith IOL ODMedical HistoryMedical History: + HTN x 12 years,: + HTN x 12 years,+ Hypercholesterolemia (both under control w/meds)+ Hypercholesterolemia (both under control w/meds)Family Ocular HistoryFamily Ocular History: + AMD (mother): + AMD (mother)AllergiesAllergies: None: NoneTopical MedsTopical Meds: artificial tears: artificial tears

Exam Findings:Exam Findings:ObjectiveObjective

VAVA: c Rx : c Rx OD 20/70 PHNIOD 20/70 PHNI OS 20/30 PHNIOS 20/30 PHNI

PupilsPupils: (-)APD, PERRLA: (-)APD, PERRLA Refraction OD:Refraction OD: 1.25D hyperopic shift1.25D hyperopic shift

EOMSEOMS: Smooth / Full: Smooth / Full

SLESLE: : Well-centered IOL ODWell-centered IOL OD, 1+ CC OS, 1+ CC OS

IOPIOP: 12 mm Hg OD, 14 mmHg OS: 12 mm Hg OD, 14 mmHg OS

CFCF: Full OU (periphery): Full OU (periphery) Central blurCentral blur OD/Amsler +OD/Amsler +

VitreousVitreous: Clear OU: Clear OU

Fundus EvaluationFundus Evaluation

DFE shows macularDFE shows maculardetail obscurationdetail obscuration““HoneycombHoneycomb”” lesion lesionw/cystic spacesw/cystic spacesMacular elevationMacular elevation

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Are there any other tests youAre there any other tests youwould perform?would perform?

Optical Coherence TomographyOptical Coherence Tomography

Additional TestingAdditional Testing

FA demonstratesFA demonstratestypical p________typical p________appearanceappearanceNo scanning lasers atNo scanning lasers atthe timethe time


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Irvine-Gass SyndromeIrvine-Gass Syndrome

Post-operative CystoidPost-operative CystoidMacular Edema (CME)Macular Edema (CME)

Hypothesis of MechanismHypothesis of MechanismOperative Irritation/Inflammation

AgingSystemic Vasculopathy

Glaucoma

Breakdown of theBlood/AqueousBarrier & Blood/Retina Barrier

Prostaglandins

in Aqueous &Vitreous

Cystoid Macular Edema

Adapted from Miyake K, et al. Jpn J Ophthalmol 2000;44:58-67.


Actual Treatment and OutcomeActual Treatment and Outcome

Ketorolac (Acular) 0.5%Ketorolac (Acular) 0.5%–– 1 gt qid x 8 weeks1 gt qid x 8 weeksMinimal improvement in VA, fundusMinimal improvement in VA, fundusPatient referred back to cataract surgeonPatient referred back to cataract surgeon–– sub-Tenonsub-Tenon’’s steroid injections steroid injectionVA eventually improved to 20/30VA eventually improved to 20/30

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Irvine-Gass Syndrome (CME)Irvine-Gass Syndrome (CME)Most frequent cause of visualMost frequent cause of visualdecline after uncomplicateddecline after uncomplicatedcataract cataract SxSx..Late onset (4 to 6 weeks post-Late onset (4 to 6 weeks post-operatively) operatively) 11

Occurs in 12% of low-riskOccurs in 12% of low-riskcataract casescataract cases22

Due to p____________-mediatedDue to p____________-mediatedbreach of blood-retinal barrierbreach of blood-retinal barrier33

1. Samiy N, Foster CS. The role of nonsteroidalantiinflammatory drugs in ocular inflammation. Int OphthalmolClin. 1996;36(1):195-206. 2. McColgin AZ, Raizman MB.Efficacy of topical Voltaren in reducing the incidence of postoperative cystoid macular edema. Invest Ophthmol Vis Sci.1999; 40 S289. 3. Mishima H, Masuda K, et al. The putativerole of prostaglandins in cystoid macular edema. Prog ClinRes 1989;31:251-264.

Risk Factors for CMERisk Factors for CME

Pre-existing ocular inflammationPre-existing ocular inflammationEpi-retinal or vitreo-retinal interfaceEpi-retinal or vitreo-retinal interface________ retinopathy________ retinopathyOcular vascular or cardiovascular diseaseOcular vascular or cardiovascular diseaseTopical prostaglandin useTopical prostaglandin useHistory of r________ p___________History of r________ p___________

Treatment of CMETreatment of CME

Topical NSAID x 3-4 monTopical NSAID x 3-4 monTopical steroidTopical steroidTopical NSAID + topical steroidTopical NSAID + topical steroidYAG laserYAG laser–– lysis of postoperative vitreous strands presentlysis of postoperative vitreous strands present

in the wound or pupil (limited success)in the wound or pupil (limited success)

Treatment of CMETreatment of CME

Sub-TenonSub-Tenon’’s Kenalog injections Kenalog injectionIntra-vitreal Kenalog injectionIntra-vitreal Kenalog injectionIntra-vitreal Anti-VEGF drugsIntra-vitreal Anti-VEGF drugs–– Decreases vascular permeabilityDecreases vascular permeabilitySurgical therapySurgical therapy–– Pars plana vitrectomy (PPV)Pars plana vitrectomy (PPV)

30

Reduction of InflammationReduction of InflammationNSAIDs work s____________ with steroidNSAIDs work s____________ with steroidtherapy to minimize inflammation followingtherapy to minimize inflammation followingocular surgeryocular surgery1,21,2

NSAIDs primarily act on COX1 and COX2NSAIDs primarily act on COX1 and COX233

–– Minimize prostaglandin formationMinimize prostaglandin formationSteroids primarily act on phospholipase ASteroids primarily act on phospholipase A22

33

–– Inhibit the release of arachidonic acidInhibit the release of arachidonic acid

1. Heier JS, Topping TM, et al. Ketorolac versus Prednisolone versus Combination Therapy in Treatment of Acute PseudophakicCystoid Macular Edema. American Academy of Ophthalmology. 2000;107(11):2034-9. 2. Flach AJ. Discussion: ketorolac vsprednisolone vs combination therapy in the treatment of acute pseudophakic CMD. Ophthalmology 2000;107:2039. 3. JampolLM. Pharmacologic therapy of aphakic cystoid macular edema. Ophthalmology 1982; 89:894.

NSAIDsNSAIDsMechanism ofMechanism of

ActionAction

Phospholipids

Phospholipase A2

Inhibited by Corticosteroids

Arachidonic Acid

Leukotrienes

Lipoxygenases

Inhibited by NSAIDs

Cyclooxygenase

Endopreoxides(PGG2 PGH2)

Prostacyclin(PGI2)

PGE2 PGF2!PGD2

Thromboxane A2

Jampol LM. Pharmacologic therapy of aphakic cystoidmacular edema. Ophthalmology 1982; 89:894.

Review of Common NSAIDsReview of Common NSAIDs

Diclofenac 0.1% and Ketorolac 0.5%Diclofenac 0.1% and Ketorolac 0.5%shown to be equally effective in:shown to be equally effective in:–– Treating post-operative CMETreating post-operative CME11

–– Treating post-operative inflammationTreating post-operative inflammation22

1. Rho DS. Treatment of Acute Pseudophakic Cystoid Macular Edema: Diclofenac versus Ketorolac CataractRefract Surg. 2003;29(12):2378-84.

2. Flach AJ et al. Comparative Effect of diclofenac 0.1% and ketorolac 0.5% on inflammation after cataract.Ophthalmology. 1998. 105: 1775-1779.

Adverse Events Associated withAdverse Events Associated withConventional NSAID TherapyConventional NSAID Therapy

Mild/Moderate corneal side effectsMild/Moderate corneal side effects11::–– Burning and irritationBurning and irritation–– Superficial punctate keratitisSuperficial punctate keratitis–– Delayed wound healingDelayed wound healing

Severe corneal issuesSevere corneal issues22

–– ThinningThinning–– Perforation due to meltsPerforation due to melts

1. Flach, AJ. Topical nonsteroidal antiinflammatory drugs in ophthalmology. IntOphthalmol Clin. 2002;42(1):1-11. 2. Mah et al. ASCRS 2000. 2. Prescribing Information: VOLTAREN; ACULAR; ACULAR LS.

31

New NSAIDNew NSAID

Xibrom Xibrom ™™ (ISTA Pharm.) (ISTA Pharm.)–– Claims enhanced ocularClaims enhanced ocular

penetrationpenetration–– Unique Unique bidbid dosing dosing

Appropriate use of NSAIDs inAppropriate use of NSAIDs inprevention of CMEprevention of CME

RecommendedNSAID Dosing

At-Risk PatientsPreoperative: 1 weekPostoperative: 4 weeks to several months

Not At-Risk PatientsPreoperative: 1-2 DaysPostoperative: 4 weeks

O’Brien TP. Emerging Guidelines for Use of NSAID Therapy to Optimized Cataract Surgery PatientCare. Curr Med Res & Opin. 2005; Vol. 21, No. 7, 1131-1137

That was thenThat was then……In 1998, the older conventional In 1998, the older conventional NSAIDsNSAIDsdid not work on our CME patient.did not work on our CME patient. A Novel ClassA Novel Class

of Non-Steroidalof Non-SteroidalAnti-Inflammatory TherapyAnti-Inflammatory Therapy

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Nepafenac Ophthalmic Suspension 0.1%Nepafenac Ophthalmic Suspension 0.1%(NEVANAC(NEVANAC™™))

Indication:Indication:Treatment of pain and inflammationTreatment of pain and inflammationfollowing cataract surgeryfollowing cataract surgeryDosing:Dosing:–– One drop One drop TIDTID one day pre-op, DOS, one day pre-op, DOS,

14 days post-op14 days post-op

Nepafenac Ophthalmic Suspension 0.1%Nepafenac Ophthalmic Suspension 0.1%(NEVANAC(NEVANAC™™))

Formulation:Formulation:First and only ophthalmic non-First and only ophthalmic non-steroidal ___-_____steroidal ___-_____Preservative: 0.005% BAKPreservative: 0.005% BAKpH: 7.4 (physiologic)pH: 7.4 (physiologic)

Prodrug Structure: MetabolicProdrug Structure: MetabolicConversionConversion

Nepafenac is converted to Nepafenac is converted to amfenac, amfenac, a COXa COXinhibitor, by intraocular hydrolasesinhibitor, by intraocular hydrolases–– Amfenac exhibits potent anti-inflammatory activity withAmfenac exhibits potent anti-inflammatory activity with

greatly reduced toxicitygreatly reduced toxicity

1 Ke, TL, et al, Inflammation. 2000;24(4):371-84.

Nepafenac Amfenac sodium

Novel Pro-Drug StructureNovel Pro-Drug StructureOptimizes PenetrationOptimizes Penetration–– Upon dosing, nepafenacUpon dosing, nepafenac

rapidly penetrates therapidly penetrates theintraocular tissuesintraocular tissues11

Target-Specific EfficacyTarget-Specific Efficacy–– Nepafenac is converted toNepafenac is converted to

amfenacamfenac for optimal for optimalefficacyefficacy22::–– CorneaCornea–– Iris/CBIris/CB–– Retina/ChoroidRetina/Choroid

Nepafenac

Amfenac

Amfenac

Amfenac

1. Ke, TL, et al, Inflammation. 2000;24(4):371-84.

2. Ke, TL, et al, Inflammation. 2000;24(4):371-84.

NepafenacAmfenac

33

Take Home Points - CMETake Home Points - CMETopical NSAIDs pre/post-surgery helpTopical NSAIDs pre/post-surgery helpmaximize surgical outcomes.maximize surgical outcomes.NSAIDs work synergistically withNSAIDs work synergistically with________ to prevent/control CME.________ to prevent/control CME.Must have appropriate duration ofMust have appropriate duration oftreatment for routine and high risktreatment for routine and high riskpatients.patients.Ideal topical NSAID maximizes intraocularIdeal topical NSAID maximizes intraocularefficacy while minimizing corneal toxicity.efficacy while minimizing corneal toxicity.

QuestionsQuestions

Do patients taking topical prostaglandinsDo patients taking topical prostaglandinsfor glaucoma need to be d/cfor glaucoma need to be d/c’’d or switchedd or switchedto another med before/after cataractto another med before/after cataractsurgery?surgery?


70 year old Caucasian male

CC: Blurred “central” vision (OD) x 2 days @ distance and near

Ocular History: +Corneal abrasion OS x 15 years ago +Anterior Cortical Cataracts / NS 1 OU

Medical History: + Hypertension x 20 years (under control) – with meds + Hypercholesterolemia (not under control) – with meds

Family Ocular History: + Primary Open Angle Glaucoma (mother)

Allergies: +Penicillin +Keflex

VA: c Rx OD 20/70 OS 20/30

Pupils: (+) APD Grade 1 OD

EOMS: Smooth / Full

SLE: Unremarkable OU

CF: Full OU (periphery) Central blur OD

Vitreous: Clear OU BP: 140 / 90 RAS

IOP: 15 mm Hg OU

34

Are there any other tests youAre there any other tests youwould perform?would perform? Fluorescein AngiographyFluorescein Angiography

35



36

Outcome:

•Diagnosis: Branch Retinal Artery Occlusion OD

•Vision remained 20/70 x 1 year

•Carotid Studies revealed 75% obstruction Right Side

•Carotid Studies revealed 70% obstruction Left Side

•Echocardiogram – no abnormalities

•Patient has not reported any new ocular complaints

•Patient did have a “TIA” x 8 months post BRAO

•Now taking “Baby Aspirin”

•Cholesterol was lowered by PCP

39 year old Hispanic female

CC: Total loss of vision x 1 hour ago OD @ distance and near

Ocular history: + Glasses and Contact lenses x 20 years + Ocular Hypertension x 7 years

Systemic History: + Hypertension x 3 years ( Controlled with Meds ) ? + Diabetes x 3 months ( Controlled with Meds ) + Hypercholesterolemia x 3 years ( Controlled with meds )

Social History: +Smokes 1 pack of cigarettes a day / Patient takes BCP

Allergies: No know drug allergies / No environmental allergies

VA: CF OD 20/25 OS

EOMS: Smooth / Full

PUPILS: PERRLA + APD Grade 4 OD

CF: Restricted OD Full OS SLE: Unremarkable

TA: 25 OD 26 OS

Vitreous: Clear OU

BP: 155 / 95 RAS

Describe That Fundus!Describe That Fundus!

37


What is your plan? What is your plan?


In CRAO of < 24 hrs duration, best initialIn CRAO of < 24 hrs duration, best initialmanagement is:management is:a.a. digital ocular massage, STAT retinaldigital ocular massage, STAT retinal

consultconsultb.b. IV IV methylprednisonemethylprednisonec.c. po po steroidsteroidd.d. observe without treatment; prognosisobserve without treatment; prognosis

excellent for visual recoveryexcellent for visual recovery


In CRAO of < 24 hrs duration, best initialIn CRAO of < 24 hrs duration, best initialmanagement is:management is:a.a. digital ocular massage, STAT retinaldigital ocular massage, STAT retinal

consultconsultb.b. IV IV methylprednisonemethylprednisonec.c. po po steroidsteroidd.d. observe without treatment; prognosisobserve without treatment; prognosis

excellent for visual recoveryexcellent for visual recovery

The Real Deal on BRAOThe Real Deal on BRAO

Usually Usually e_________e_________–– cholesterol, calcific, fibrincholesterol, calcific, fibrinFA shows delayed filling of affected arteryFA shows delayed filling of affected arteryand hypofluorescence in surrounding areaand hypofluorescence in surrounding area–– Retinal infarct results in permanent VF defectRetinal infarct results in permanent VF defect80-90% improve to a VA of 20/40 or better80-90% improve to a VA of 20/40 or better–– No acute interventionNo acute intervention

Observe closely for NVI/NVAObserve closely for NVI/NVASystemic co-management with PCPSystemic co-management with PCP

38

Clinical Significance of Clinical Significance of RAOsRAOs

Thrombus– A hardened clump of blood within a vessel.

Embolus– Sudden blockage of an artery by a blood clot (thrombus) or

a_____________ material.Both are common causes of stroke.

The Real Deal on CRAOThe Real Deal on CRAO

CRAO can be CRAO can be embolic or thromboticembolic or thrombotic–– Atherosclerotic changes, inflammatory endarteritisAtherosclerotic changes, inflammatory endarteritis–– BP, carotid auscultationBP, carotid auscultation

Acute management (< 24 hours)Acute management (< 24 hours)–– Ocular Massage: 10 seconds/release Ocular Massage: 10 seconds/release !! Retinal consult ** Retinal consult **

AC paracentesis (<24 hr)AC paracentesis (<24 hr)IV AcetazolamideIV AcetazolamideCarbogen Carbogen (95% O-2, 5% CO-2)(95% O-2, 5% CO-2)

–– Medical evaluation to ID and treat underlying causeMedical evaluation to ID and treat underlying causeCarotid, cardiac studiesCarotid, cardiac studiesESR if > 55 y/o, no visible emboliESR if > 55 y/o, no visible emboliIf suspect GCA, hi-dose steroidsIf suspect GCA, hi-dose steroids

Follow-upFollow-up–– Monitor for NVI/NVA Monitor for NVI/NVA !!PRPPRP

69 year old Caucasian Female

CC: Reduced central vision OD x 3 weeks @ distance and near

Ocular History: Unremarkable

Systemic History: Unremarkable ; Last PCP exam 15 years ago

Social History: Smokes " pack of cigarettes a day Alcohol 5-10 drinks a day

Meds: Multivitamin

Allergies: +Penicillin

VA: s Rx 20/60 OD 20/20 OS

EOM: Smooth / Full

Pupils: PERRLA - APD

CF: Central blur OD Full Periphery OU

SLE: Unremarkable OU

TA : 20 mm Hg OU

Vitreous: PVD OU

BP: 168 / 98 RAS

Describe That Fundus!Describe That Fundus!

39

Fluorescein AngiographyFluorescein Angiography

40

What is your assessment?What is your assessment?Hemispheric RetinalHemispheric Retinal

Vein OcclusionVein Occlusion


BRVOBRVO CRVOCRVO

41

1

2

Outcome:

•Diagnosis: Inferior Hemi-Central Retinal Vein Occlusion OD

•Treated as a non-ischemic CRVO (Why?)

•Follow-Up in 1 month

•Patient sent to PCP to rule out Diabetes, Hypertension, Cholesterol

•Hypertension diagnosed

•Patient received intravitreal injection of Kenalog at 4 months for CME

•Patient had IOP spike after Kenalog injection – given Alphagan P

•No NVD or NVE occurred

•Vision at 1 year was OD 20/25

Hemi-Central Retinal Vein Occlusion

Uncommon type of Uncommon type of hemispherichemispheric RVO RVO–– Occurs in "Dual Trunk" anomalyOccurs in "Dual Trunk" anomalySame Same pathophysiology pathophysiology as CRVO.as CRVO.May affect either the superior or inferiorMay affect either the superior or inferiorCRV before they unite into commonCRV before they unite into commoncentral retinal vein.central retinal vein.Usually occurs at or near the optic disc.Usually occurs at or near the optic disc.

The Real Deal on The Real Deal on BRVOsBRVOsCaused by Caused by a______________ofa______________of overlying artery overlying arteryBRVO StudyBRVO Study–– Observe monthly for first 6 monObserve monthly for first 6 mon

DFE, OCTDFE, OCTGonioGonio

–– Chronic findings include ME, collateral BVsChronic findings include ME, collateral BVs–– Macular grid laser helpful for ME >6 monMacular grid laser helpful for ME >6 mon–– After initial 6 mon, observe q 3-4 mon for RNV, NVI/AAfter initial 6 mon, observe q 3-4 mon for RNV, NVI/A–– Scatter laser for RNV, Scatter laser for RNV, VHemeVHeme–– IV Kenalog, IV Kenalog, Avastin Avastin off-label for MEoff-label for ME

Medical workupMedical workupCV Dx, DM, hyperviscosity, lipidsCV Dx, DM, hyperviscosity, lipids

42

Arteriosclerosis with calcification ofArteriosclerosis with calcification ofvessel wallvessel wall The Real Deal on The Real Deal on CRVOsCRVOs

T__________ in CRV at laminaT__________ in CRV at laminaCRVO StudyCRVO Study–– Prophylactic PRP did not prevent NVI/NVA in ischemic CRVOProphylactic PRP did not prevent NVI/NVA in ischemic CRVO

Therefore, wait for development of NVI/NVA before PRPTherefore, wait for development of NVI/NVA before PRP–– No real benefit of macular grid laser for MENo real benefit of macular grid laser for ME

Follow-upFollow-up–– Observe monthly for first 4-6 monObserve monthly for first 4-6 mon–– Angiography when heme, retinal edema reducesAngiography when heme, retinal edema reduces–– Monitor for NVI/NVA Monitor for NVI/NVA !!PRPPRP–– Medical workupMedical workup

CV Dx, DM, hyperviscosity, lipidsCV Dx, DM, hyperviscosity, lipids–– Non-ischemic CRVO may convert to ischemic (30%)!Non-ischemic CRVO may convert to ischemic (30%)!


In an ischemic CRVO, which is In an ischemic CRVO, which is falsefalse??a.a. it carries high risk of NVI/NVAit carries high risk of NVI/NVAb.b. complications may include ME,complications may include ME,

ischemic damageischemic damagec.c. risk of NVG is 5%risk of NVG is 5%d.d. it carries some risk for NVD, NVE,it carries some risk for NVD, NVE,

leading to vitreous leading to vitreous hemeheme

Non-ischemic vs. Ischemic CRVONon-ischemic vs. Ischemic CRVO

Functional TestsFunctional Tests

VAVAPupil testingPupil testingVisual fieldsVisual fieldsElectroretinographyElectroretinography

Structural TestsStructural Tests

OphthalmoscopyOphthalmoscopy–– SL SL FundoscopyFundoscopy–– BIOBIO

FluoresceinFluoresceinangiographyangiography

43

Ischemic CRVOIschemic CRVO

• Note disc edema, several CWS

• Capillary non-perfusion on FA

• VA < 20/200, +APD, retinal/macular edema

• More likely to result in NVI/NVA than non-ischemic

• 45% of cases result in NVG

Blood Flow in the Optic NerveBlood Flow in the Optic Nerve::

•• Blood Flow = Perfusion Pressure / Resistance to flow Blood Flow = Perfusion Pressure / Resistance to flow

•• Perfusion Pressure = Mean BP Perfusion Pressure = Mean BP –– IOP IOP

•• Mean BP = Diastolic BP + 1/3 (systolic BP Mean BP = Diastolic BP + 1/3 (systolic BP –– diastolic BP) diastolic BP)

Retinal Blood Flow = Retinal Arterial Pressure – Retinal Venous Pressure

To improve retinal blood flow in CRVO there are two options:Lower the venous pressure or increase the arterial pressure

No scientific basis for lowering IOP in to improve retinal blood flow

Should Ischemic VenousShould Ischemic VenousOcclusions be Referred to aOcclusions be Referred to a

Retinologist BeforeRetinologist BeforeNVI/NVA?NVI/NVA?

Macular Edemain CRVO

44

Emerging Treatments forEmerging Treatments forBRVO/CRVOBRVO/CRVO

Intravitreal KenalogIntravitreal Kenalog–– Intravitreal injection for MEIntravitreal injection for ME–– The The SStandard Care versus tandard Care versus COCOrticosteroid forrticosteroid for

REREtinal Vein Occlusion (SCORE) Study: tinal Vein Occlusion (SCORE) Study: TwoTwoRandomized TrialsRandomized Trials to Compare the Efficacy and to Compare the Efficacy andSafety of Intravitreal Injections(s) ofSafety of Intravitreal Injections(s) ofTriamcinolone Acetonide with Standard Care toTriamcinolone Acetonide with Standard Care toTreat Treat Macular EdemaMacular Edema

–– One for One for CRVOCRVO and One for and One for BRVOBRVO–– IVK found useful for ME in CRVO, not BRVOIVK found useful for ME in CRVO, not BRVO

when compared to standardwhen compared to standard

SCORE – Standard Care vs. Corticosteroid for Retinal Vein Occlusion

To evaluate the clinical benefits of triamcinolone for treating macular edemaassociated with vein occlusion.

84 clinics and sponsored by the National Eye Institute

One group received the standard clinical care for the conditionOne group got 4 milligramOne group got 1 milligram

Results: SCORE (CRVO) – 27%(1milligram) group and 26%(4milligram) groupExperienced a substantial visual gain of 3 or more lines. The results up to 2 years.

The 4 milligram group had the highest rates of cataract formation, cataractSurgery, and elevated pressure. The 1 milligram dose is safer for patients.

SCORE (BRVO) – 29%(laser), 26%(1mg), 27%(4mg) gained 3 or more lines. 3 yr.Laser treatment may have fewer side effects for patients.


Dexamethasone Dexamethasone Drug Delivery SystemDrug Delivery System–– OZURDEX (OZURDEX (intravitreal intravitreal implant) 0.7mgimplant) 0.7mg

((AllerganAllergan))–– Intraocular, biodegradable implant for theIntraocular, biodegradable implant for the

treatment of persistent MEtreatment of persistent ME–– Clinical trial underwayClinical trial underwayAnti-VEGF drugsAnti-VEGF drugs–– LucentisLucentis–– AvastinAvastin

45

DR: CSME DR: CSME TreamentTreamentIluvien Iluvien (formerly known as(formerly known asMedidureMedidure))–– Tube 3.5mm x 0.37mm containingTube 3.5mm x 0.37mm containing

fluocinolonefluocinolone–– Implanted into vitreousImplanted into vitreous w/ w/ 25g25g

(~0.5mm) inserter(~0.5mm) inserterSuturelessSutureless

–– Designed to provideDesigned to provide sustained sustainedeffect up to 24 monthseffect up to 24 months

–– FAMEFAME ( (fluocinolone acetonide fluocinolone acetonide ininDME) trial under wayDME) trial under way


BRAVO and CRUISE studies BRAVO and CRUISE studies –– Lucentis Lucentis clinical trials for RVOclinical trials for RVO

BRAVOBRAVO –– Phase III study (12 month study) 0.3 or 0.5 mg of Phase III study (12 month study) 0.3 or 0.5 mg of LucentisLucentis

Safety and effectiveness of Safety and effectiveness of Lucentis Lucentis in macular edema secondary to BRVOin macular edema secondary to BRVO

CRUISECRUISE –– Phase III study (12 month study) 0.3 or 0.5 mg of Phase III study (12 month study) 0.3 or 0.5 mg of LucentisLucentis

Safety and efficacy of Safety and efficacy of Lucentis Lucentis in macular edema secondary to CRVOin macular edema secondary to CRVO

An analysis of the 6 month data from both studies showed a safety profileAn analysis of the 6 month data from both studies showed a safety profileconsistent with previous consistent with previous Lucentis Lucentis Phase III trials in wet ARMD.Phase III trials in wet ARMD.

As early as seven days after the first injection, patients who received monthlyAs early as seven days after the first injection, patients who received monthlyinjections of injections of Lucentis Lucentis had, on average, a statistically significant improvementhad, on average, a statistically significant improvementin their vision that lasted 6 month.in their vision that lasted 6 month.

Final thoughts on CRVOFinal thoughts on CRVOWhen NV occurs in When NV occurs in ischemicischemic CRVO, it most CRVO, it mostoften occurs in the often occurs in the anterioranterior segment.segment.Neovascular Neovascular glaucoma is seen in glaucoma is seen in ~ 45%~ 45% of eyes of eyeswith ischemic CRVO.with ischemic CRVO.M______ e_____ may occur in either ischemicM______ e_____ may occur in either ischemicor non-ischemic CRVO, leading to permanentor non-ischemic CRVO, leading to permanentcentral scotoma.central scotoma.Non-ischemic CRVO may convert to ischemicNon-ischemic CRVO may convert to ischemic(30%)!(30%)!2/3 of non-ischemic CRVO will have 20/40 or2/3 of non-ischemic CRVO will have 20/40 orbetter w/o ocular better w/o ocular TxTx..

46


54 year old Asian male

CC: +Intermittent blurred vision OU @ distance and near x 5 months

Ocular History: + mild cortical cataracts OU

Systemic History: + DM x 12 years ( controlled with meds) HbA1c = 9% + Hypertension x 10 years ( controlled with 2 meds)

Family History: +POAG ( mother and father )

No known drug or environmental allergies / Pt. smokes 5-7 cigarettes a day

VA: 20/25 OD/OS c Rx Dist. / Near TA:16 mm OU

EOM: Smooth / Full Vitreous: Clear OU

Pupils: PERRLA – APD BP: 145 / 90 RAS

CF: Full OU SLE: Unremarkable OU

47

FluoresceinFluorescein Angiography Angiography

Outcome:

Diagnosis:

OD Proliferative Diabetic RetinopathyOS Severe Non-Proliferative Diabetic Retinopathy

• No macular edema OD/OS

• FA performed

• Photos taken

• PRP given (OD) over 4 sessions

• Letter written to PCP

• F/U Q 3 mon

Diabetes MellitusDiabetes Mellitus

DM is the most frequent cause of newDM is the most frequent cause of newcases of blindness in the USA. (Preventcases of blindness in the USA. (PreventBlindness America 2003)Blindness America 2003)Severe vision loss from DR is oftenSevere vision loss from DR is oftenpreventable with timely detection andpreventable with timely detection andtreatment. (ETDRS)treatment. (ETDRS)2 million2 million people people w/DM w/DM in CNin CNType 2 on the rise in CNType 2 on the rise in CN

48

Risk Factors for DRRisk Factors for DR

________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Risk Factors for DRRisk Factors for DR

AgeAgeRaceRaceSmokingSmokingObesity (BMI)Obesity (BMI)Early Age at Initial Diagnosis of DMEarly Age at Initial Diagnosis of DMLong Duration of DMLong Duration of DMCV Dx.CV Dx.Poor glycemic controlPoor glycemic control

Anatomy Review: Retinal CapillariesAnatomy Review: Retinal Capillaries

Capillary NetworkCapillary Network–– Pericytes Pericytes surroundsurround

each endothelial celleach endothelial celland provide supportand provide support

–– Tight junctionsTight junctionsbetween between endoendo. cells. cells

–– Pericytes Pericytes + tight+ tightjunctions form innerjunctions form inner_____________._____________.

normal mouse retina in whichpericytes marked by ng2 staining(blue) and endothelial cells aremarked by PECAM (red).

DIABETIC RETINOPATHYDIABETIC RETINOPATHY(pathogenic mechanisms)(pathogenic mechanisms)

Capillary hypertensionCapillary hypertensionSystemic hypertensionSystemic hypertensionInsulin resistanceInsulin resistanceEndothelial dysfunctionEndothelial dysfunctionHyperglycemic pseudohypoxiaHyperglycemic pseudohypoxiaNon-enzymatic Non-enzymatic glycosylationglycosylationIncreased vascular permeabilityIncreased vascular permeability

49

Capillary damage

Pericyte necrosis(capillaries and veins)

Endothelial damage

Capillary non-perfusion

Retinal ischaemia

Vasoactive factors

Hyperperfusion Abnormal autoregulation

Hypertension

New vesselsGrowth factors

Hyperglycemia

Pathogenesis of DiabeticPathogenesis of DiabeticRetinopathyRetinopathy

Pericyte Pericyte lossloss!!ThickeningThickening(occlusion) and weakening(occlusion) and weakening!!(leaking) vessels(leaking) vessels


What is the distinguishing feature of PDR?What is the distinguishing feature of PDR?

a.a. MAsMAsb.b. CWSCWSc.c. IRMAIRMAd.d. NVD or NVENVD or NVE

50

NPDRNPDR MICROANEURYSMS MICROANEURYSMS and and

blot-and-dot hemorrhagesblot-and-dot hemorrhages INCREASED VASCULAR INCREASED VASCULAR

PERMEABILITYPERMEABILITY (hard (hardexudates)exudates)

ISCHEMIA ISCHEMIA (cotton-wool(cotton-woolspots)spots)

–– damage to damage to axoplasmicaxoplasmic flow flowin the nerve fiber layerin the nerve fiber layer

–– focal infarctfocal infarct

NPDRNPDR Venous Venous ““beadingbeading””

IRMA ( IRMA (intraretinalintraretinalmicrovascularmicrovascularanomalies)anomalies)

Extensive capillary Extensive capillaryocclusion and ischemiaocclusion and ischemia

PDRPDR

CHARACTERIZED BY CHARACTERIZED BYNEWLY FORMED VESSELSNEWLY FORMED VESSELS!!

–– originate from vessels of theoriginate from vessels of theoptic nerve or from theoptic nerve or from thesurface of the retinasurface of the retina

Newly formed vessels are Newly formed vessels areabnormal, extremely fragile!abnormal, extremely fragile! Matrix

Central 4 degree threshold

1.5 min per eye

51

Management Guidelines: NPDRManagement Guidelines: NPDRFor Mild and Moderate NPDRFor Mild and Moderate NPDR–– Observe patient q3-12 monthsObserve patient q3-12 months–– Visual function testingVisual function testing–– DFE, photography, OCT, gonioDFE, photography, OCT, gonio–– DM educationDM education

For Severe and Very Severe NPDRFor Severe and Very Severe NPDR–– More frequent observationMore frequent observation–– Visual function testingVisual function testing–– DFE, photography, OCT, gonioDFE, photography, OCT, gonio–– Angiography/retina consultAngiography/retina consult–– DM educationDM education

4-2-1 Rule4-2-1 RuleSevere NPDRSevere NPDRAt least one of :At least one of :

–– intraretinalintraretinal hemorrhages in hemorrhages in fourfour quadrants quadrants

–– venous beading invenous beading in two two quadrants quadrants

–– intraretinalintraretinal microvascularmicrovascular abnormalities in abnormalities in 1 quadrant1 quadrant

Standard photographs available at:Standard photographs available at:eyephoto.ophth.wisc.edu/ResearchAreas/Diabeteyephoto.ophth.wisc.edu/ResearchAreas/Diabetes/DiabStds.htmes/DiabStds.htm

IntraretinalIntraretinal hemorrhages in hemorrhages in fourfourquadrantsquadrants

Venous Beading and Venous Beading and IntraretinalIntraretinalMicrovascularMicrovascular Anomalies (IRMA) Anomalies (IRMA)

Venousbeading IRMA

52

Management Guidelines: PDRManagement Guidelines: PDRR/O NVI/NVAR/O NVI/NVA–– Co-manage if NVGCo-manage if NVG

AngiographyAngiographyRetina consult for treatmentRetina consult for treatmentof NVof NV–– Laser photocoagulationLaser photocoagulation

FocalFocalGridGridScatterScatterPRPPRP

–– Vitrectomy if massive VH orVitrectomy if massive VH orpre-retinal membrane atpre-retinal membrane atmaculamacula

Management Guidelines: CSMEManagement Guidelines: CSME

Establish whether CSME existsEstablish whether CSME exists–– Stereoscopic fundoscopyStereoscopic fundoscopy–– AngiographyAngiography–– OCT may be helpfulOCT may be helpfulCan have DME that is non-clinicallyCan have DME that is non-clinicallysignificant, CMEsignificant, CMEETDRS demonstrated that laser Tx.ETDRS demonstrated that laser Tx.significantly reduced risk of vision loss insignificantly reduced risk of vision loss inCSME.CSME.

DIABETIC MACULAR EDEMACSME DefinedCSME Defined

CSME, as defined by the ETDRS, existsCSME, as defined by the ETDRS, existswith any of the following findings:with any of the following findings:–– Retinal thickening within 500 mm of the centerRetinal thickening within 500 mm of the center

of the foveaof the fovea–– Hard exudates within 500 mm of the center ofHard exudates within 500 mm of the center of

the fovea with adjacent retinal thickeningthe fovea with adjacent retinal thickening–– At least 1 disc area of retinal thickening, anyAt least 1 disc area of retinal thickening, any

part of which is within 1 disc diameter of thepart of which is within 1 disc diameter of thecenter of the foveacenter of the fovea

53

Diagnosing CSME: Choose OneDiagnosing CSME: Choose One

Diabetic Macular EdemaDiabetic Macular Edema Important DM StudiesImportant DM Studies

DCCT showed that intensive glycemic control waseffective in delaying the onset, as well as slowingthe progression, of diabetic retinopathy inpatients with type 1 diabetes.

DCCT–DiabetesControl andComplicationsTrial, 1993[16]

DRVS findings showed that an early vitrectomywas beneficial in restoring and preserving visionin patients with proliferative DR (PDR) with orwithout associated vitreous hemorrhage.

DRVS–DiabeticRetinopathyVitrectomyStudy, 1981[22,23]

PRP was beneficial only in cases that haddeveloped proliferative changes or in which it wasimminent. It also showed that focal or gridphotocoagulation was beneficial in reducingvisual loss due to macular edema.

ETDRS–EarlyTreatment forDiabeticRetinopathyStudy, 1984[19-21]

54

Vitreous HemorrhageVitreous Hemorrhage Emerging Treatment for VHEmerging Treatment for VH

In phase III clinical trials, In phase III clinical trials, intravitrealintravitrealinjections of ovine injections of ovine hyaluronidasehyaluronidase ((VitraseVitrase))have been shown to be safe and to havehave been shown to be safe and to havemodest efficacy for the clearance ofmodest efficacy for the clearance ofsevere vitreous hemorrhage.severe vitreous hemorrhage.More recently, More recently, bevacizumabbevacizumab ((AvastinAvastin)) has hasbeen used to treat vitreous hemorrhage.been used to treat vitreous hemorrhage.

DR: Emerging TreatmentsDR: Emerging Treatments

Minimum-intensity PhotocoagulationMinimum-intensity Photocoagulation–– Laser w/o scarLaser w/o scar

low levels of argon laser energy for PDRlow levels of argon laser energy for PDR

Pegaptanib and Ranibizumab (Anti-VEGF)Octreotide– Somatostatin analog and insulin-like growth

factor 1 antagonistIntravitreal Corticosteroids for DME

PKC Inhibition for NPDR, CSMEPKC Inhibition for NPDR, CSME

Protein Protein kinasekinase C (PKC) enzymes, upon C (PKC) enzymes, uponactivation, may cause hyperglycemia-activation, may cause hyperglycemia-related related microvascularmicrovascular damage damageRuboxistaurinRuboxistaurin MesylateMesylate–– popo med med–– initial results from the PKC-DRS showinitial results from the PKC-DRS show

improved vision and reduced risk of CSME inimproved vision and reduced risk of CSME inpatients treated with 32 mg.patients treated with 32 mg.

55

PKC InhibitionPKC Inhibition

(Retinopathy)

Diabetes is a Risk Factor for:

•___________________•___________________•___________________•___________________

Diabetes is a Risk Factor for:

StrokeHeart DiseaseCRVOBRVOSleep Apnea


56

ConclusionsConclusionsWe have an important roleWe have an important rolein the diagnosis andin the diagnosis and(co-)management of(co-)management ofposterior segmentposterior segmentvascular, degenerative,vascular, degenerative,and other diseases.and other diseases.DonDon’’t miss the telltalet miss the telltalesymptoms and signs.symptoms and signs.Used evidence-basedUsed evidence-basedguidelines.guidelines.Medical retinal care isMedical retinal care isexpanding!expanding!

Thank You!Thank You!For the opportunity to meet and discuss theseFor the opportunity to meet and discuss thesecases with you.cases with you.

Joe PizzimentiJoe Pizzimenti–– [email protected]@nova.edu

Documents

Pharmacotherapy of Posterior Segment DiseasePharmacotherapy of Posterior Segment Disease Joseph J. Pizzimenti, OD, FAAO [email protected] Sam Snead Quotes "Keep close count of your