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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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Retina QuizRetina Quiz
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 assessment?What is your assessment?
What is your plan? What is your plan?
What is your assessment?What is your assessment?
Idiopathic Idiopathic JuxtafovealJuxtafovealTelangectaisiaTelangectaisia
What is your plan?What is your plan?
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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
What is your assessment?What is your assessment?
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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.
What is your plan?What is your plan?
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)
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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
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–– 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.
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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?
Questions and Comments?Questions and Comments?
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
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Are there any other tests youAre there any other tests youwould perform?would perform? Fluorescein AngiographyFluorescein Angiography
35
What is your assessment?What is your assessment?
What is your plan?What is your plan?
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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 assessment?What is your assessment?
What is your plan? What is your plan?
Retina QuizRetina Quiz
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
Retina QuizRetina Quiz
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
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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!
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Fluorescein AngiographyFluorescein Angiography
40
What is your assessment?What is your assessment?Hemispheric RetinalHemispheric Retinal
Vein OcclusionVein Occlusion
What is your plan?What is your plan?
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%)!
Retina QuizRetina Quiz
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.
Emerging Treatments forEmerging Treatments forBRVO/CRVOBRVO/CRVO
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
Emerging Treatments forEmerging Treatments forBRVO/CRVOBRVO/CRVO
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
Questions and Comments?Questions and Comments?
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
Retina QuizRetina Quiz
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
Questions and Comments?Questions and Comments?
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
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