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BLOOD FLOW IN GLAUCOMA – INSIGHTS AND PERSPECTIVES
Leo Semes, OD
Colorado Vision Summit 2017
DisclosuresCommercial Interest
Nature of Relevant Financial Relationship
Maculogix Honorarium Speaker Science Based Health Honorarium Speaker OptoVue Honorarium Speaker B&L Honorarium Advisor Allergan
Genentech
Regneneron
Shire
ZeaVision
Reichert/Ametek
HPO
Honorarium
Honorarium
Honorarium
Honorarium
Honorarium Honorarium
Stock options
Advisor
Advisor
Speaker
Speaker
Advisor
Speaker
Advisor
OcularBloodFlowandglaucoma?Stateofthescience2009
“AtthepresentCme,noSINGLEbloodflowimagingdeviceiscapableofevaluaCngocularbloodflowrelevanttoglaucoma.
“Acomprehensiveapproach,uClizingmulCpleimagingtechnologiesisrequiredformeaningfulinsightintothemulCplevascularbedsoftheeye.”
Consensusstatement
oftheWGA2009
Seriously...
ì Primaryopen-angleglaucoma(POAG)isachronic,progressiveopCcneuropathyinadultsinwhichthereisacharacterisCcacquiredatrophyoftheopCcnerveandlossofreCnalganglioncellsandtheiraxons.ThiscondiConisassociatedwithanopenanteriorchamberanglebygonioscopy.
–alaAAOPPP,January2016[Whatisconspicuousbyitsabsence?]
OurworkingdefinitionofPOAG
ì Primaryopen-angleglaucoma(POAG)isachronic,progressiveopCcneuropathyinadultsinwhichthereisacharacterisCcacquiredatrophyoftheopCcnerveandlossofreCnalganglioncellsandtheiraxons.ThiscondiConisassociatedwithanopenanteriorchamberanglebygonioscopy.
ì Primaryopen-angleglaucomarepresentsaspectrumofdiseaseinadultsinwhichthesuscepCbilityoftheopCcnervetodamagevariesamongpaCents.AlthoughmanypaAentswithPOAGpresentwithelevatedintraocularpressure(IOP),nearly40%ofthosewithotherwisecharacterisAcPOAGmaynothaveelevatedIOPmeasurements.ThevastmajorityofpaCentswithPOAGhavediscchangesordiscandvisualfieldchanges,buttherearerarecaseswheretheremaybeearlyvisualfieldchangesbeforetherearedetectablechangestotheopCcnerve.
–alaAAOPPP,January2016
Seriously...POAGisaprogressive,chronicopCcneuropathyinadultsinwhichintraocularpressure(IOP)andothercurrentlyunknownfactorscontributetodamageandinwhichthereisacharacterisCcacquiredatrophyoftheopCcnerveandlossofreCnalganglioncellsandtheiraxons.ThiscondiConisassociatedwithananteriorchamberanglethatisopenbygonioscopicappearance.–alaAAOPPP“CanglaucomatousopCcneuropathybeinducedbyaprimarynon-IOP-relatedinsult...alone??”-ClaudeBurgoyne
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MaybeagoodintroducCon
Whendoyouthinkthiseditorialappeared?
DX: POAG, ??? Is there a blood-flow problem here???
MaybeagoodintroducCon
2009
OcularBloodFlowandglaucoma?Stateofthescience2009
“AtthepresentCme,noSINGLEbloodflowimagingdeviceiscapableofevaluaCngocularbloodflowrelevanttoglaucoma.
“Acomprehensiveapproach,uClizingmulCpleimagingtechnologiesisrequiredformeaningfulinsightintothemulCplevascularbedsoftheeye.”
ConsensusstatementoftheWGA2009
40o3DEnFaceReference
WideFieldEnfaceOCTTM
OptovueWidefield-EnfaceOCT
WidefieldVS6mmx6mm3D
MulC-layerassessmentofpathology–evenintheperiphery
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OptovueWidefield-EnfaceOCT SLO/LSLO2DImage
Choroidenface ChoroidTopographicalview
Widefield3DOCTVSWidefieldSLO
ILMenface ILMTopographicalview
MulC-layerassessmentofpathology–evenintheperiphery
IPLenface IPLTopographicalviewRPEenfaceRPETopographicalview
OCTwillrevoluConizethediagnosis,management&understandingofglaucoma…
• HigherresoluCon• DifferenCaldepthscans• O/RapplicaCons• Smartphoneapp• OCTangiography!!!
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XRAvanCMCTwithOCTA1
OCTEnfaceimageSSADA/OCTAImagingSSADA/OCTAImaging
Flowratedirectlyrelatestoappearance(brightness)ofvesselintheimage2
*ImagescourtesyofDavidHuang,M.D.OHSU.
1OCTA(SSADA)isnotyetcommerciallyavailable.
Detailedvasculatureofthefovea
withoutanydyeorcontrast
enhancementinjecAon
2014
2014
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Glaucoma
RapidexplosionofinformaConinheOCTAarenaBrJOphthalmoldoi:10.1136/bjophthalmol-2016-309377Diagnos?cabilityofperipapillaryvesseldensitymeasurementsofop?calcoherencetomographyangiographyinprimaryopen-angleandangle-closureglaucoma
HarshaLRao1,SujathaVKadambi1,RobertNWeinreb2,NarendraKPuLaiah1,ZiaSPradhan1,DhanarajASRao1,RajeshSKumar1,CarrollABWebers3,RohitSheLy1DrHarshaLRao,NarayanaNethralaya,121/C,ChordRoad,1st‘R’Block,Rajajinagar,Bangalore560010,India.
PublishedOnlineFirst29November2016ConclusionsDiagnosCcabilityofperipapillaryvesseldensityparametersofOCTA,especiallytheinferotemporalsectormeasurement,wasgoodinPOAGandPACG.DiagnosCcabiliCesofvesseldensitymeasurementswerecomparabletoRNFLmeasurementsinbothPOAGandPACG.
Vesseldensity(OCTA)andVFlosscorrelaConinglaucoma
YarmohammadiA,etal.,RelaConshipbetweenOpCcalCoherenceTomographyAngiographyVesselDensityandSeverityofVisualFieldLossinGlaucoma.Ophthalmology2016;123:2498-2508
GlaucomaapplicaCon#1.• Peripapillarycapillarydensity(PCD)
– Whatthisisimportant• ONHbloodsupplyisderivedmainlyfromchoriocapillaris
– Emergingevidenceforanearlystructuralindicatoringlaucomatousdamageandanindexforprogression.
ConclusionsPCDdisplayedsignificantcorrelaConswithmorphologicalandfuncConalindicesandexhibiteddiagnosCccapabiliCescomparabletocurrentlyemployedclinicalvariables.OurpreliminaryresultssuggestthatPCDanalysismayprovetobeausefultoolinmonitoringPOAGacrossstageandidenCfyingearlyPOAG.
GeymanLS,etal.Peripapillaryperfusedcapillarydensityinprimaryopen-angleglaucomaacrossdiseasestage:anopCcalcoherencetomographyangiographystudy.BrJOphthalmoldoi:10.1136/bjophthalmol-2016-309642
PCDexample
AkilH,etal.OpCcalCoherenceTomographyAngiographyoftheOpCcDisc;anOverview.JOphthalmicVisRes2017;12(1):98‑105.
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Peripapillarycapillarydensity(PCD)
CONCLUSIONS. Diagnostic ability of peripapillary vessel density parameters of OCTA, especially the inferotemporal sector measurement, was good in POAG and PACG. Diagnostic abilities of vessel density measurements were comparable to RNFL measurements in both POAG and PACG.
RaoHL,etal.DiagnosCcabilityofperipapillaryvesseldensitymeasurementsofopCcalcoherencetomographyangiographyinprimaryopen-angleandangle-closureglaucoma.htp://bjo.bmj.com/content/early/2016/11/29/bjophthalmol-2016-309377.long
RecentreportsonOCT-Aandglaucoma
• OCT-AcorrelaCngperipapillaryvasculardensity(pVDandvisualfieldindex,meansensiCvity)
RESULTSThepVDsatsuperotemporalandinferotemporalregionsweresignificantlyassociatedwithcorrespondingVFMSinmildglaucoma(p<0.05).Inmoderate-to-advancedglaucoma,thereweresignificantassociaConsbetweenpVDandVFMS,regardlessoflocaCon.TheassociaConbetweenglobalpVDandVFMSwassignificantlystrongerthanthatbetweenglobalpRNFLthicknessandVFMSinmoderate-to-advancedstageglaucoma(p<0.05).htp://dx.doi.org/10.1136bjophthalmol-2017-310180
RecentreportsonOCT-Aandglaucoma
CONCLUSIONS.Alocalizedmicrovasculardropout(MvD)observedintheparapapillarychoroidusingOCTAcoincidedwiththeparapapillarydropout(PD)detectedbyICGA.ThesefindingsindicatethatOCTAaccuratelyimagesimpairedparapapillarychoroidalcirculaCon.
LeeEJ,etal.ParapapillaryChoroidalMicrovasculatureDropoutinGlaucoma:AComparisonbetweenOCT-AandICGAngiography.Ophthalmology.2017Apr19.pii:S0161-6420(16)32234-5.doi:10.1016/j.ophtha.2017.03.039.[Epubaheadofprint]
GlaucomaapplicaCon#3.
• RNFLcapillarydensity– Whythisisimportant
• RNFL(innerreCnalvasculaturecorrelaContoRNFLloss)• MicrovascularcompormisemayfollowRNFLdamage(NTGstudy)
– Emergingevidencecorrelateswithtwostructuralindicatorsinearlyglaucomatousdamage
IchiyamaY,etal.CapillaryDropoutattheReCnalNerveFiberLayerDefectinGlaucoma:AnOpCcalCoherenceTomographyAngiographyStudy.JGlaucoma.2016Sep2.LeeEJ,etal.MicrovascularCompromiseDevelopsFollowingNerveFiberLayerDamageinNormal-TensionGlaucomaWithoutChoroidalVasculatureInvolvement.JGlaucoma.2017Mar;26(3):216-222.doi:10.1097/IJG.0000000000000587.
GlaucomaapplicaCon#2.
• Macularcapillarydensity– Whythisisimportant
• Ganglion-celllayerthicknessisameasurableparameterandnowdemonstratedtocorrelatewithcapillaryinvestment
– Emergingevidencecorrelatestwostructuralindicatorsinearlyglaucomatousdamage
IchiyamaY,etal.CapillaryDropoutattheReCnalNerveFiberLayerDefectinGlaucoma:AnOpCcalCoherenceTomographyAngiographyStudy.JGlaucoma.2016Sep2.
RecentreportsonOCT-Ainglaucoma
RESULTS.VesseldensitymapsofsuperficialanddeepreCnallayersweresignificantlyreducedatthe7and11o'clockposiConsinglaucomatouseyes.Insuperficiallayer,vesseldensitysignificantlydecreasedasthedistancefromtheopCcdiscmarginincreased,exceptintheinnermostcircle.
ShinJW,etal.OpCcalcoherencetomographyangiographyvesseldensitymappingatvariousreCnallayersinhealthyandnormaltensionglaucomaeyesGraefesArchClinExpOphthalmol.2017Apr20.doi:10.1007/s00417-017-3671-4.[Epubaheadofprint].
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GlaucomaapplicaCons• Choroidalcapillarydensity
– Whythisisimportant• Choroidal(choriocapillaris)circulaConcanbevisualizedbyOCT-AandcorrelateswithPCD
CONCLUSIONS.FAZandCCVDareinterchangeablebetweenthe3Å~3mmand6Å~6mmmacularscansizes.TheVDdifferencesbetweenthetwodifferentscansizesarenotclinicallymeaningful.Themacularperfusionparameterspresentedgoodbutnotperfectreliability,whichshouldbeacknowledgedinclinicalpracCce.
DongJ,etal.InterchangeabilityandreliabilityofmacularperfusionparametermeasurementsusingopCcalcoherencetomographyangiography.htp://bjo.bmj.com/content/early/2017/03/23/bjophthalmol-2016-309441
Generalizedandlocaleffects....
2014
Maybethishelpsexplaintheasymmetrythatissoprevalentinglaucoma.Think:VF,rimCssue,PPA....
2012
Proposedmechanisms
ReducedbloodflowcouldbeaconsequenceofneuralCssuelossarisingfromelevatedIOP
Proposedmechanism
ReducedbloodflowandelevatedIOPcouldbothleadtoneuralstructureloss
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Proposedmechanism
ReducedbloodflowcouldbeanindependentcauseofVFloss
Andjustlatelastyear…
• AstudyfromaregistryinEnglandsuggestedanassociaConbetweenglaucoma*andvasculardemenCa*butnotbetweenglaucomaandAlzheimerdisease*.
• [*AlzheimerandvasculardemenCaarebothneurodegeneraCvediseasesandglaucomaisnowbeinglumpedintothatbucket,too.]
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Perfusion
Pressure Blood Pressure
IOP
Lower Diastolic, Systolic, or
Mean Pressure Reduces Perfusion
Pressure
Higher IOP
Negatively Impacts Perfusion Pressure
Perfusion Pressure Is a Result of
A Delicate Balance Between IOP
and Blood Pressure
Lower Perfusion Pressure Is Associated with Increased Risk for
Open Angle Glaucoma Leske MC, et al. Ophthalmology 2007; 114,: 1965-72 Leske MC, et al. Ophthalmology 2008;115, 65-93. Hayreh SS. Trans Am Acad Ophthalmol 1974;78:240-54
OcularPerfusionPressure&GlaucomaProgression–emergingparadigms
DX: POAG, ??? Is there a blood-flow problem here???
OpCcNerveHEADanatomy–bloodflowconsideraCons
HayrehSS.IschemicopCcneuropathy.ProgRetEyeRes.2009;28:34–62
Structural evaluation - Diagnosis enhanced depth imaging [choroid] • Choroidal thickness and perfusion/flow evaluation
• Age, axial length, CCT, and diastolic ocular perfusion pressure are significantly associated with choroidal thickness in glaucoma suspects and glaucoma patients.
• Degree of glaucoma damage was not consistently associated with choroidal thickness.
� Maul EA, Friedman DS, Chang DS, Boland MV, Ramulu PY, Jampel HD, Quigley HA. Choroidal thickness measured by spectral domain optical coherence tomography: factors affecting thickness in glaucoma patients. Ophthalmology. 2011 Aug;118(8):1571-9. 42
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Hey! Maybe its choroidal blood flow after all Choroidal blood flow (arbitrary units)
Hey! Maybe its choroidal blood flow. After all that seems to be the case in AMD
ImplicaConsofBFalteraConswithÛÛIOP
Note: increased IOP induces • posterior rotation of the peripapillary sclera • flattening of the cup floor • thinning of the lamina cribrosa and the prepapillary neural tissue and • anterior movement of the central optic nerve relative to the LC
Which may be complementary to reduced blood flow OR a result of same
Sigal I, Ethier CR. Biomechanics of the optic nerve head. Exp Eye Res. 2009; 88,799-807 .
StructuralevaluaCon–diagnosisenhanceddepthimaging
• LaminacribrosaevaluaCon
• EmerginginvesCgaCons:CSFpressure(see:later)
ParkHY,JeonSH,ParkCK.Enhanceddepthimagingdetectslaminacribrosathicknessdifferencesinnormaltensionglaucomaandprimaryopen-angleglaucoma.Ophthalmology.2012Jan;119(1):10-20.ParkSC,DeMoraesCG,TengCC,TelloC,LiebmannJM,RitchR.EnhanceddepthimagingopCcalcoherencetomographyofdeepopCcnervecomplexstructuresinglaucoma.Ophthalmology.2012Jan;119(1):3-9. 47
Bloodsupplysummary• InterindividualvariaCon*• ReCnalnervefiberlayer
– CRA/CRV
• OpCcnervehead– SPCaa– choroidalplexus– bloodsupplyissegmental
v UlAmatebloodsupplytoRNFLandONHisfromtheophthalmicartery,abranchoftheinternalcaroAdartery
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VascularTheoryofGlaucomaChangesinocularbloodflow(OBF)
• Reducedperfusionpressure(beyondautoregulatorycapacity)leadingto...– SecondaryvasculardegeneraConfollowingganglioncell/RNFLloss
VascularTheoryofGlaucomaChangesinocularbloodflow(OBF)
• PeripheralvasculardysregulaCon-PVD– whichcanresultinreperfusioninjury(RI)
• AllcanbeIOPindependentandmayinvolveboththere9nalandchoroidalcirculatorysystems.
* Some variability and controversy exist over blood supply
Lamina
Glaucomatous damage cascade 1. IOP compromises perfusion
pressure
2. Resulting in ischemia @ ONH
3. Growth factors from LGN fail to reach ganglion cells
4. Cell bodies, lacking growth factors, initiate apoptosis
Glaucomatous damage cascade 5. Cell death by apoptosis
6. Glutamate release from ganglion cells
7. Death of adjacent axons in bundle from neurotoxicity from amino acids such as glutamate and NMDA (N-methyl D-aspartate).
(Zombies)
Distribution of IOP in a general population*
N=nonglaucoma;G=glaucoma.*Dotedlinesrepresentareasofuncertainty.ShieldsMB.TextbookofGlaucoma.1998.
ImplyinganIOP-independentcomponentinglaucoma(“NTG”???)
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WhatarethepossibiliCesintheabsenceofelevatedIOP?
• Primary/PeripheralvasculardysregulaCon
• InadequateONHperfusion
Let’stryandconnectthedots
RelaConshipofperfusiontoglaucoma
• LowdiastolicocularperfusionpressuremaybeassociatedwithincreasedriskforPOAG.
• ThisassociaConwasconfirmedinsubjectstreatedforsystemichypertensioninsubgroupanalysis.Thismaysupportthehypothesisthattheconceptofocularperfusionpressurestatusmaybemorerelevanttoglaucomapathogenesisthanocularperfusionpressurealone.
ConsultthepaCent’sbeta-blockerprescriberinthecontextofprogressiveglaucomadamagewith“good”IOPcontrol.AmJOphthalmol2013;155:843–851.
PrimaryOBFcomponent• Riskfactors(RF)for
atherosclerosisarelargelyparalleltoincreasedIOP– age– smoking– dyslipidemia– systemichypertension– malesex– obesity
Flammer J, Mozaffariaeh M. What is the present pathogenetic concept of glaucomatous optic neuropathy? 2007. Surv Ohthalmol 52: S162-173.
PrimaryOBFcomponent• Riskfactors(RF)for
atherosclerosisarelargelyparalleltoincreasedIOP– age– smoking– dyslipidemia– systemichypertension– malesex– obesity
• ThereforereducingtheseRFreducesIOP(slightly)– physicalexercise– weightloss– treatmentofdyslipidemia
• Andmayincreasebloodflowandaqueousou\lowthroughtheTM
Flammer J, Mozaffariaeh M. What is the present pathogenetic concept of glaucomatous optic neuropathy? 2007. Surv Ohthalmol 52: S162-173.
• GlaucomatousdiscandfieldchangeswithIOPconsistently<22
20%ofnewlydiagnosedglaucomapaAentshaveIOP<21mmHgatpresentaAon
• CAUSE??Decreasedperfusionofdisc(arteriosclerosis,lowBP)
‘NormalTensionGlaucoma?’
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Recentevidence...
‘NormalTensionGlaucoma’
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Recentevidence...
‘NormalTensionGlaucoma’
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Perfusion
Pressure Blood Pressure
IOP
Lower Diastolic, Systolic, or
Mean Pressure Reduces Perfusion
Pressure
Higher IOP
Negatively Impacts Perfusion Pressure
Perfusion Pressure Is a Result of
A Delicate Balance Between IOP
and Blood Pressure
Lower Perfusion Pressure Is Associated with Increased Risk for
Open Angle Glaucoma Leske MC, et al. Ophthalmology 2007; 114,: 1965-72 Leske MC, et al. Ophthalmology 2008;115, 65-93. Hayreh SS. Trans Am Acad Ophthalmol 1974;78:240-54
OcularPerfusionPressure&GlaucomaProgression
POAG Risk Factors 9-year BES
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Leske MC, Wu SY, Hennis A, Honkanen R, Nemesure B; BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology. 2008 ; 115: 85-93.
mean perfusion pressure = 2/3(mean arterial pressure) - IOP Where mean arterial pressure = diastolic BP + 1/3 (systolic BP – diastolic BP)
PerfusiontotheONH• DOPP(Diastolicocularperfusionpressure) =DBP–IOP
(Whatisthenumber?)
<40issignificant*-talktothePCP)
– ReducedinPOAG
AlternaCvely,meanperfusionpressure
*LeskeMC,WuSY,HennisA,HonkanenR,NemesureB;BESsStudyGroup.Riskfactorsforincidentopen-angleglaucoma:theBarbadosEyeStudies.Ophthalmology.2008;115:85-93.
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PerfusiontotheONH
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ExamplecomparingDOPPandmeanOPP120/80IOP=20;DOPP=60[80-20]WhatIOPdowemeasure?diastolic
Significantdifference Whichtouse???
MOPP=2/3[DBP=1/3(SBP-DBP)-IOP2/3[80+1/3(40)]–20resultsin42
2014(monkeys)
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RecentassociaConbetweenBP/OPPandstructuralglaucomaprogression
• Twogreatestriskfactors– Olderage– LowerdiastolicBP
• Structuralelementsassessed–ONH(rimCssue),RNFLthickness.
McGlynnMM,ErlichJR,MarlowED,etal.AssociaConofbloodandocularperfusionpressurewithstructuralglaucomatousprogressiionbyflickerchronoscopy.BrJOphthalmol2013.PublishedonlineSeptember24,2013
EmergingimportanceofdiastolicBP
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• LowmeandiastolicBPisconsistentlyassociatedwithstructuralglaucomaprogression(RimCssue,RNFL)
McGlynnMM,ErlichJR,MarlowED,etal.AssociaConofbloodandocularperfusionpressurewithstructuralprogressioninglaucomaasmeasuredbyflickerchronoscopy.BrJOphthalmol.2013.
*SignificantlylowerdiastolicperfusionpressurewasobservedinthosetakingoralhypotensivemedicaCons(asinbeta-blockers)
2013,
CurrentOpinioninPharmacology2013,13:36–42www.sciencedirect
2013,
Modelofprimary&secondaryinsultsinglaucomaduetolowOPP
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InfluencesofabnormalautoregulaConinglaucoma(proposedscheme)
ContribuCngfactorstoabnormalneurovascularcouplinginglaucoma
Conclusionsfromprevious 2014
So,whichismoreimportant,loweredBPorelevatedIOP?
Conclusions• TheresultsshowthatopCcnerveheadbloodflowismoresuscepCbletoanocularperfusionpressuredecreaseinducedbyloweringthebloodpressurecomparedwiththatinducedbyincreasingtheintraocularpressure.
• ThisbloodflowautoregulaConcapacityvulnerabilitytolowbloodpressuremayprovideexperimentalevidencerelatedtothehemodynamicpathophysiologyinglaucoma.
2014
NOCTURNALHYPOPERFUSIONASAGLAUCOMARISKFACTOR
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2014
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Conclusionsandguidance
• Inconclusion,themagnitudeandduraConofnocturnalhypotensionidenCfypaCentswithNTGwhohaveVFprogression.
• AmbulatorymonitoringofsystemicBPshouldbecomepartofrouCneassessmentofpaCentswithNTG,parCcularlyamongthosewhoconCnuetoprogressdespiteIOPlowering.
Conclusionsandguidance
• NocturnalBPshouldbeconsideredamodifiableriskfactorinNTG.
• RandomizedtrialswillberequiredtoassesstheefficacyofdifferentintervenConsdesignedtoavoidnocturnalhypotensiontopreventVFlossinpaCentswithNTG,aswellastotesttheeffectofmoreaggressiveIOP-loweringtherapyinthesecases.
ConclusionsandGuidance
• BloodflowmeasurementscouldguidechangesintreatmentprotocolwithemphasisonnormalizaConofcirculatoryalteraConratherthanjustIOP.
Reducedperfusion-MoreRiskfactors
• AutoregulaCondisturbances• VasospasCcDisorder• Migraine• Increasedresistance
• ✔Reducedbloodflow(20lowBP)→Nocturnalhypoperfusion
• Sleepapneasyndrome84
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SASandNormalTensionGlaucoma• 50sleepapneapaCentswerecomparedwith40normals
• PrevalenceofNTGamongSASptswas5.9%(and0%amongthecontrols)
• SeverityofSASwascorrelatedposiCvelywith[structuralandfuncAonalelements]– IOP– MD– C/D– meanNFLthickness(HRTII)
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Sergi M, Salerno DE, Rizzi M, et al.. Prevalence of Normal Tension Glaucoma in Obstructive Sleep Apnea
Syndrome Patients. J Glaucoma. 2007; 16: 42-46.
SAS–GlaucomaconnecCon(addiConalevidence)
� TheprevalenceofglaucomainpaCentswithobstrucCvesleepapneaisanesCmated27%!
BendelRE,etal.PrevalenceofglaucomainpaCentswithobstrucCvesleepapnoea-across-
secConalcase-series.Eye.2007.
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OcularbloodflowandObstrucCveSleepApneaSyndrome(OSAS)
• 31paCentswithprovenOSAS/25controls
• 12.4%ofOSASandnoneofthecontrolswerediagnosedwithglaucoma
• NodifferencesinreCnalcirculaConmeasuresorIOP(implyingIOP-independentrisks)
• PosiCvecorrelaConbetweenMDandLV&reCnalcirculatorymeasures
Karakucuk S, et al. Ocular blood flow in patients with obstructive sleep apnea. Graefes Arch Clin Exp Ophthalmol. 2008; 246: 129-134.
SAS–GlaucomaconnecCon(furtherevidence)
� InpaCentswithOSAS,ahighprevalenceofglaucomawasfound.
� VisualfielddefectsmaybeduetoopCcnerveperfusiondefectsandthesefielddefectsalsoincreaseastheRI(resistanceindex)increases.
KarakucukS,etal.OcularbloodflowinpaCentswithobstrucCvesleepapneasyndrome(OSAS).GraefesArchClinExpOphthalmol.2008Jan;246:129-34.
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And,morerecentlyraisedquesCons...
• ShouldOSAHSbeincludedintheDDxofglaucoma?
• IsOSAHSanotherglaucomaoracontributor?
• DoesloweringIOPinOSAHSarresttheprogressionofopCcneuropathy?
LinPW,FriedmanM,LinHC,ChangHW,PulverTM,ChinCH.DecreasedreCnalnervefiberlayerthicknessinpaCentswithobstrucCvesleepapnea/hypopneasyndrome.GraefesArchClinExpOphthalmol.2011Apr;249(4):585-93.Epub2010Oct19.
Glaucoma - Glaucoma + Total Apnea - 64,825
(95.0%) 3,410 (5.0%) 68,236
Apnea + 2,497 (91.6%) 228
(8.4%) 2725
Total 67,322 3,638 70,960 Limitations and confounders * Boyle-WalkerM,SemesLP,ClayOJ,FuhrP,LiuL.SleepApneaSyndromeRepresentsaRiskforGlaucomainaVeterans’AffairsPopulaCon.ISRNOphthalmology.Volume2011,doi:10.5402/2011/920767.
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“Fairandbalanced”
• FoundthatthereISarelaConshipbetweenIIHandAIONandthoseusingaC-PAPbutnotbetweenglaucomaandC-PAPuse.
SteinJD,etal.TheAssociaConbetweenGlaucomatousandOtherCausesofOpCcNeuropathyandSleepApnea.AmJOphthalmol.2011Aug17.[Epubaheadofprint]
2013,
2013
2013
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Anewissue-translaminarintracranialpressure
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SiaudvytyteL1,JanulevicieneI,RagauskasA,etal.UpdateinintracranialpressureevaluaConmethodsandtranslaminarpressuregradientroleinglaucoma.ActaOphthalmol.2014Jul18.doi:10.1111/aos.12502.[Epubaheadofprint]
Conclusionsabouttheroleoftranslaminarpressureinglaucoma
Inconclusion,CSFpressureastranslaminarcounterpressureagainstIOPseemstobeofmajorimportanceinglaucoma,andfutureinvesCgaConsareneededtoelucidatetheinvolvementofCSFpressureanditsfluctuaConsinthedevelopment,progressionandmanagementofglaucoma.UptothepresentCme,researchinglaucomawaslimitedduetoinvasiveICPmeasurementmethods.
Conclusionsabouttheroleoftranslaminarpressureinglacuoma
Theroleofthetwo-depthtranscranialDopplerbasednon-invasivetechnologyformeasuringabsoluteICPinglaucomapaCentswouldbeinnovaCveandmayprovideanimportantaspectcurrentlymissinginformaConinglaucomapathologyassessmentandevenchangeourwholeunderstandingaboutglaucoma.Importantly,todate,thisnon-invasiveabsoluteICPmeasurementmethodistheonlyavailablemethodthatdoesnotneedanindividualpaCent-specificcalibraCon.
BreakingNewsParaphrasingtheconclusionsoftheauthors,…consideringONLYCSFPandIOPwithoutconsideringlaminacribrosaproperCes,orbitalCssue,piamaterandsubarachnoidspaceproperCesisunlikelytoadequatelycharacterizepathologicalprocessesindiseaseslikeglaucomaandidiopathicintracranialhypertension.
NewdirecConsinglaucomatreatment
• Yes,treatment• BeyondIOPreducCon,regulaConofbloodflow...– Systemically(regulaCngbloodpressureandmonitoringperfusionpressure)
– Locally–endothelial-cellacCvitybymodulaCngNitricOxide(NO)ThisistheNEXTBIGTHING!
• RegulaConofaqueousdynamicsatthetrabecularmeshworkbyvascularmodulaCon
• InaddiCon,theapplicaConofNO-donaCngcompoundsfortheloweringofIOPdirectly
Howshouldglaucomabemanagedcomprehensively?
• First,lowerIOP
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Howshouldglaucomabemanagedcomprehensively?
• Second,considerincreasingperfusion(maybeaconsequenceofloweredIOP)– Topicaltreatments?(betaxolol,brimonidine,brinzolamide,GingkoBiloba)
– Exercise,weightloss– Lowercholesterol,bloodsugarlevels– Treatunderlyingvasculardisorders(HT,SAS,CVD)– Etc.
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Howshouldglaucomabemanagedcomprehensively?
• Third,reduceoxidaCvestress(Ca++blockade[BUT,notsystemicβ-blockers],supplements)
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NON-SELECTIVEBeta-blockers:SignificantaddiAonalprecauAon
Topicalβ-blockersadministeredatnighttothosetakingsystemicβ-blockersmayreduceperfusiontotheONHplusβ-blockertherapytoreduceIOPisineffecCveatnight.
Whichbringsusto...
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Hayreh SS. Effect of nocturnal blood pressure reduction on retrobulbar hemodynamics in glaucoma. Graefes Arch Clin Exp Ophthalmol. 2002; 240: 867-8.
RelaConshipbetweenNocturnalHypotensionandOPP(ocularperfusionpressure)
• LowBPatnight,coupledwithhighIOPinsupineposiCon,compromiseOPP
• UsesystemicBPmedsintheAMtominimizenocturnalhypotenCon
• UseIOPloweringdrugsthatlowerIOPduringthediurnalandnocturnalperiod
• AvoidIOPmedsthatlowersystemicBPatnight(betablockers,alphaagonists)
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Graham,Drance.SurvOphthalmol.1999;43(suppl1):S10-16Hayreh,Zimmerman,Podharsky.AmJOphthalmol.1994;117:603-624Colligan,Dewe,Guillaume,Colligan-Brach.IntOphthalmol1998;22:19-25
Summary:OPP&Glaucomaprogression
• Lowocularperfusionpressure(OPP)isanimportantriskfactorforglaucoma
• OPPisamenabletomodificaConbyloweringIOPandimprovingperfusionpressure
• Newstrategiesneededtotakeadvantageofthismodifiableriskfactor
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QuigleyHA,WestSK,RodriguezJ,etal.ArchOphthalmol.2001;119:1819-26
QuarantaL,GandolfoF,TuranoR,etal.InvestOphthalmolVisSci2006;47:2917-23.
Let’slookatsomepracAcalaspectsofIOPcontrol/bloodflow...
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Let’slookatsomepracCcalaspectsofIOPcontrol...
• PGAs• AddiCvity• Efficacyofβ-blockers• Efficacyofα-agonists• ConCnuousIOPcontrol
Brimonidine24-hrProfilesof24-hourIOPinthehabitualbodyposiCons.Measurementsweretakenfrom15subjectssi�ngduringthediurnalperiodandsupineduringthenocturnalperiod.
OpencirclesrepresentthebaselineSolidcirclesrepresentthebrimonidinetreatment.
Errorbarsrepresentstandarderrorofthemean.IOP=intraocularpressure.BoLomline:brimonidinedoesnotworkatnight
LiuJH,MedeirosFA,SlightJR,WeinrebRN.Diurnalandnocturnaleffectsofbrimonidinemonotherapyonintraocularpressure.Ophthalmology.2010Nov;117(11):2075-9.Epub2010Jul21.
Brimonidine24-hrProfilesof24-hoursupineIOP.Opencirclesrepresentbaselinesolidcirclesrepresentbrimonidinetreatment.Datawerefromthesame15subjectsaspreviously.Botomline:brimonidinedoesnotworkwhenpa?entsareinthesupineposi?on
Cmolol,brinzolamide24-hr(addedtolatanoprostmonotherapy)
Profilesof24-hourIOPinthehabitualbodyposiCons.Measurementsweretakensi�ngduringthediurnalperiodandsupineduringthenocturnalperiodfrom26subjects.Latanoprostmonotherapy(opencircles),brinzolamidet.i.d.add-ontreatment(solidtriangles),andCmolol(GFS)qAM.add-ontreatment(solidsquares).
TherewasnodifferenceinnocturnalIOPbetweenthe?mololadd-ontreatmentandthebaseline.Addi?onofbrinzolamideloweredtheAMpeak.
LiuJH,MedeirosFA,SlightJR,WeinrebRN.ComparingdiurnalandnocturnaleffectsofbrinzolamideandCmololonintraocularpressureinpaCentsreceivinglatanoprostmonotherapy.Ophthalmology.2009Mar;116(3):449-54.Epub2009Jan20.
Cmolol,brinzolamide24-hr(addedtolatanoprostmonotherapy)
Profilesof24-hoursupineIOP.IOPunderthelatanoprostmonotherapy(opencircles),brinzolamidet.i.d.add-ontreatment(solidtriangles),andCmolol(GFS)qAM.add-ontreatment(solidsquares).Datawerefromthesame26subjects.
TherewasnodifferenceinnocturnalIOPbetweentheCmololadd-ontreatmentandthebaseline.Duringthenocturnalperiod,thesupineIOPunderbrinzolamideadd-ontreatmentwassignificantlylowerthanboththebaselineandthe?mololadd-ontreatment.
ExplanaConforwhybrimonidinefailstolowerIOPinthesupineposiCon
Studydesign
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ExplanaConforwhybrimonidinefailstolowerIOPinthesupineposiCon
ExplanaConforwhybrimonidinefailstolowerIOPinthesupineposiCon
CONTINUOUSIOPMEASUREMENT
Theholygrailofglaucomawhetheritisdiagnosisormanagementis...
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SENSIMED Triggerfish – temporary continuous IOP monitoring Not currently FDA approved
ConAnuousIOPmonitoringwithawirelessoculartelemetrysensor:iniAalclinicalexperienceinpaAentswithOAG.
MansouriK,ShaarawyT.BJO2011;95:627.(April)
• Resultsfrom15paCents(single24-hourmonitoringperiod)– Peaks(>1hr)observedin12/15(80%)ofpaCents
– Managementwaschangedin11/15(73%)basedonthedata!
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Example
53yotreatedglaucomapaCent(PGAqhs+Cmolol/tCAIcomb);excellentreproducibilityfortwoovernightsblue&yellow.
MansouriK,MedeirosFA,TafreshiA,WeinrebRN.ConCnuous24-HourMonitoringofIntraocularPressurePaternsWithaContactLensSensor:Safety,Tolerability,andReproducibilityinPaCentsWithGlaucoma.ArchOphthalmol.2012;13:1-6.
Example
52YOAsianfemaleglaucomasuspect(PGAqhsRx’dbutmayhavebeennoncompliant);goodreproducibilitypaternfortwoovernightsblue&yellow.
MansouriK,MedeirosFA,TafreshiA,WeinrebRN.ConCnuous24-HourMonitoringofIntraocularPressurePaternsWithaContactLensSensor:Safety,Tolerability,andReproducibilityinPaCentsWithGlaucoma.ArchOphthalmol.2012;13:1-6.
Example
Moderatereproducibilityina59GSfortwoovernightsblue&yellow.
MansouriK,MedeirosFA,TafreshiA,WeinrebRN.ConCnuous24-HourMonitoringofIntraocularPressurePaternsWithaContactLensSensor:Safety,Tolerability,andReproducibilityinPaCentsWithGlaucoma.ArchOphthalmol.2012;13:1-6.
Example
Poorreproducibilityina20GSfortwoovernightswithspikes(n.b.,pthaspoorsleephabits).[apponyouriPhone]
MansouriK,MedeirosFA,TafreshiA,WeinrebRN.ConCnuous24-HourMonitoringofIntraocularPressurePaternsWithaContactLensSensor:Safety,Tolerability,andReproducibilityinPaCentsWithGlaucoma.ArchOphthalmol.2012;13:1-6.
LS
Andonerecentcomment
ThereisnogoodevidencetosuggestthatIOPvariabilityisanappropriatesubsCtuteformeasuringtruediurnalIOP(i.e.,24-hourfluctuaCon).Paraphrasedfrom:SinghK,SitAJ.(Editorial)Intraocularpressurevariabilityandglaucomarisk:complexandcontroversial.ArchOphthalmol.2011Aug;129(8):1080-1.
2013,
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2013,
Closingthoughts
• How can IOP be monitored continuously?
• What impact may this have on management?
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SchemaCcofimplantableconCnuousIOPmonitoringdevice Recently
• AnImplantableIntraocularPressureTransducerImplantedatcataractsurgery
130Implandata,GMBH
• AnImplantableIntraocularPressureTransducer
131>/=3measurements(eachdevice)
Thank You