glaucoma dr.gosiengfiao dr.pangalanan

PartnersEye Care Specialists

GlaucomaGlaucoma

Dr. David GosiengfiaoDr. David Gosiengfiao

Dr. Ernesto PangalanganDr. Ernesto Pangalangan


What is Glaucoma?What is Glaucoma?

A family of diseases having in common A family of diseases having in common characteristic progressive optic neuropathy and characteristic progressive optic neuropathy and an associated visual field lossan associated visual field loss Retinal ganglion cell lossRetinal ganglion cell loss Characteristic optic nerve head changesCharacteristic optic nerve head changes Characteristic visual field changesCharacteristic visual field changes


Why is Glaucoma important?Why is Glaucoma important?

Potentially blindingPotentially blinding

Causes irreversible optic nerve damageCauses irreversible optic nerve damage

Largely manageable when caught earlyLargely manageable when caught early


Visual pathwayVisual pathwayPhotoreceptor cellsPhotoreceptor cellsBipolar cellsBipolar cellsRetinal ganglion cellsRetinal ganglion cellsNerve fiber layerNerve fiber layerOptic nerve headOptic nerve headOptic nerveOptic nerveOptic chiasmOptic chiasmLateral geniculate bodiesLateral geniculate bodiesOptic radiationsOptic radiationsOccipital cortexOccipital cortex


Changes in glaucomaChanges in glaucomaNormal Glaucomatous


ApoptosisApoptosis

Programmed cell deathProgrammed cell death

Cell shrinkageCell shrinkage

Chromatin clumpingChromatin clumping

DNA fragmentationDNA fragmentation


ApoptosisApoptosis

SignalSignal Neurotrophin deprivationNeurotrophin deprivation Glutamate toxicityGlutamate toxicity

Activation p53Activation p53 bcl-2 (inhibits apoptosis)bcl-2 (inhibits apoptosis) bax (promotes apoptosis)bax (promotes apoptosis)

Activation cytochrome cActivation cytochrome c


ApoptosisApoptosis

Activation caspacesActivation caspaces Digest cellular componentsDigest cellular components

Cellular debris phagocytosed by glial cellsCellular debris phagocytosed by glial cells


NeurotrophinsNeurotrophins

BDNFBDNF <50% in acute glaucoma<50% in acute glaucoma Upregulated Trk B receptor in chronic glaucomaUpregulated Trk B receptor in chronic glaucoma

bFGFbFGFNT-3,4NT-3,4NGFNGFCNTFCNTFInterruption Interruption Mechanical obstructionMechanical obstruction Impaired transport mechanismImpaired transport mechanism


ExcitotoxicityExcitotoxicity

May trigger cell death in adjacent cellsMay trigger cell death in adjacent cells


Reduction of blood flowReduction of blood flow

Depletion of cellular energy storesDepletion of cellular energy stores

NaNa++/K/K++ pump failure pump failure Acidosis Acidosis

Membrane depolarizationMembrane depolarization

Opening of voltage-operatedOpening of voltage-operated

calcium channelscalcium channels

Elevation of intracellular CaElevation of intracellular Ca2+2+

Activation of:Activation of: lipaseslipases

NO synthaseNO synthase

proteases - calpainsproteases - calpains

endonucleasesendonucleases

Releases of glutamate

Activation of NMDA, AMPA, kainate and metabotropic

receptors

NO Free radicalformation

Cell death

Reperfusion

Inflammation

Glutamate cascadeGlutamate cascade


Role of glial cells and ECMRole of glial cells and ECM

Glial cellsGlial cells AstrocytesAstrocytes Muller cellsMuller cells Have glutamate transporters that buffer Have glutamate transporters that buffer

extracellular glutamateextracellular glutamateGLT-1GLT-1

GLASTGLAST Modulate ECMModulate ECM


Role of IOPRole of IOP

Direct effect on retinal ganglion cells Direct effect on retinal ganglion cells (RGC)(RGC)

Mechanical effect on optic nerve headMechanical effect on optic nerve head

Blood flow effectBlood flow effect


Direct effect on RGCDirect effect on RGC

Somatic shrinkageSomatic shrinkage

Dendritic changesDendritic changes

Heat shock responseHeat shock response


Mechanical effect on optic nerve Mechanical effect on optic nerve headhead

Optic nerve head is weakest point in eyeOptic nerve head is weakest point in eye Greatest stressGreatest stress

Astrocyte remodeling and migrationAstrocyte remodeling and migration Elastin depositionElastin deposition

Posterior bowing and thinning of cribriform Posterior bowing and thinning of cribriform plateplate


Effect on blood flowEffect on blood flow

PP = MAP – IOPPP = MAP – IOPPP:PP: Perfusion pressurePerfusion pressureMAP:MAP: Mean arterial blood pressureMean arterial blood pressureIOP:IOP: Intraocular pressureIntraocular pressure

Decrease PPDecrease PP PP dependent axonal transport of BDNFPP dependent axonal transport of BDNF


Mechanisms of elevated IOPMechanisms of elevated IOP

IOP = F / C + PIOP = F / C + Pee

F = aqueous flow F = aqueous flow (uL/min)(uL/min)

C = outflow facility C = outflow facility (uL/min/mmHg)(uL/min/mmHg)

PPee = episcleral venous pressure = episcleral venous pressure

(mmHg)(mmHg)

Increased aqueous Increased aqueous productionproduction

Impaired aqueous Impaired aqueous outflowoutflow

Elevated episcleral Elevated episcleral venous pressurevenous pressure


Anataomy and physiology of Anataomy and physiology of aqueous flowaqueous flow

Produced via active Produced via active transport in non-transport in non-pigmented epithelium of pigmented epithelium of the ciliary processesthe ciliary processes

Outflow Outflow Trabecular Trabecular UveoscleralUveoscleral

Elevated IOPElevated IOP Open angleOpen angle Closed angleClosed angle


Primary open angle glaucomaPrimary open angle glaucoma

SenescenseSenescense Decreased number of pores in TMDecreased number of pores in TM Decreased cellularity of TMDecreased cellularity of TM

Helicobacter pyloriHelicobacter pylori 88% in POAG88% in POAG Treatment associated with + responseTreatment associated with + response

OptineurinOptineurin VasoregulationVasoregulation apoptosisapoptosis


Steroid induced glaucomaSteroid induced glaucoma

Myocilin / Tigr protein expressionMyocilin / Tigr protein expression

Increased aqueous viscosityIncreased aqueous viscosity

Triggered by Myoc/Tigr geneTriggered by Myoc/Tigr gene


Pseudoexfoliative glaucomaPseudoexfoliative glaucoma

Basement membrane Basement membrane diseasedisease

Exfoliated material Exfoliated material obstruct TMobstruct TM


Pigmentary glaucomaPigmentary glaucoma

Reverse pupillary blockReverse pupillary blockPosterior bowing of irisPosterior bowing of irisPigment epithelium contact with lensPigment epithelium contact with lensPigment released causing Krukenberg spindlesPigment released causing Krukenberg spindlesPigment phagocytosed by TM causing decreased TM Pigment phagocytosed by TM causing decreased TM functionfunction


Increased episcleral resistanceIncreased episcleral resistance

Sturge Weber Sturge Weber syndromesyndrome

AV fistulaAV fistula

Orbital floor fractureIOP + 6 mmHg


Angle closure glaucomaAngle closure glaucoma

AcuteAcute SymptomaticSymptomatic

PainPain

RednessRedness

Blurred visionBlurred vision

HaloesHaloes

Nausea or vomitingNausea or vomiting

ChronicChronic May be asymptomaticMay be asymptomatic


Pupillary block glaucomaPupillary block glaucoma

Resistance at irido-Resistance at irido-lenticular interfacelenticular interface

Pressure bows iris Pressure bows iris anteriorlyanteriorly

Dilation causes angle Dilation causes angle to closeto close

May be lens / cataract May be lens / cataract inducedinduced


Plateau irisPlateau iris

Central iris flat Central iris flat centrally and convex centrally and convex peripherallyperipherally

Angle closes on Angle closes on dilationdilation


Supraciliary effusionsSupraciliary effusions

UveitisUveitis

Drug effectDrug effect SulfaSulfa TopiramateTopiramate

Malignant glaucomaMalignant glaucoma


Role of ocular blood flow and Role of ocular blood flow and oxygenationoxygenation

IschemiaIschemia triggers glutamate cascadetriggers glutamate cascade May impair axonal transportMay impair axonal transport

Impaired compensation in OAGImpaired compensation in OAG

Dysautoregulation in NTGDysautoregulation in NTG

Nocturnal hypotension and NTGNocturnal hypotension and NTG

Sleep apnea and NTGSleep apnea and NTG

Migraine and NTGMigraine and NTG


Immunologic mechanismsImmunologic mechanisms

T cell mediated modulation of glutamate T cell mediated modulation of glutamate toxicitytoxicity Cop-1 induced immunityCop-1 induced immunity

C-terminal cross reactivityC-terminal cross reactivity CaspacesCaspaces HspHsp


ConclusionConclusion

Glaucoma is a multi-faceted and multi-Glaucoma is a multi-faceted and multi-factorial diseasefactorial disease

Can occur at any intraocular pressureCan occur at any intraocular pressure

Misdiagnosis can be visually devastatingMisdiagnosis can be visually devastating

A high index of suspicion is necessaryA high index of suspicion is necessary

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