NEWEST -Blood Flow in Glaucoma (2) - Colorado Home Flow in Glaucoma.pdf6/6/17 1 BLOOD FLOW IN GLAUCOMA – INSIGHTS AND PERSPECTIVES Leo Semes, OD Colorado Vision Summit 2017 Disclosures

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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’

61

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

65

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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•  Second,considerincreasingperfusion(maybeaconsequenceofloweredIOP)–  Topicaltreatments?(betaxolol,brimonidine,brinzolamide,GingkoBiloba)

–  Exercise,weightloss–  Lowercholesterol,bloodsugarlevels–  Treatunderlyingvasculardisorders(HT,SAS,CVD)–  Etc.

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•  Third,reduceoxidaCvestress(Ca++blockade[BUT,notsystemicβ-blockers],supplements)

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NON-SELECTIVEBeta-blockers:SignificantaddiAonalprecauAon

Topicalβ-blockersadministeredatnighttothosetakingsystemicβ-blockersmayreduceperfusiontotheONHplusβ-blockertherapytoreduceIOPisineffecCveatnight.

Whichbringsusto...

105

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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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.


Example

Moderatereproducibilityina59GSfortwoovernightsblue&yellow.


Example

Poorreproducibilityina20GSfortwoovernightswithspikes(n.b.,pthaspoorsleephabits).[apponyouriPhone]


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?

128

SchemaCcofimplantableconCnuousIOPmonitoringdevice Recently

•  AnImplantableIntraocularPressureTransducerImplantedatcataractsurgery

130Implandata,GMBH

•  AnImplantableIntraocularPressureTransducer

131>/=3measurements(eachdevice)

Thank You

Documents

NEWEST -Blood Flow in Glaucoma (2) - Colorado Home Flow in Glaucoma.pdf6/6/17 1 BLOOD FLOW IN GLAUCOMA – INSIGHTS AND PERSPECTIVES Leo Semes, OD Colorado Vision Summit 2017 Disclosures