Date post: | 01-Nov-2014 |
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GlaucomaGlaucoma
Dr. David GosiengfiaoDr. David Gosiengfiao
Dr. Ernesto PangalanganDr. Ernesto Pangalangan
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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
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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
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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
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Changes in glaucomaChanges in glaucomaNormal Glaucomatous
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ApoptosisApoptosis
Programmed cell deathProgrammed cell death
Cell shrinkageCell shrinkage
Chromatin clumpingChromatin clumping
DNA fragmentationDNA fragmentation
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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
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ApoptosisApoptosis
Activation caspacesActivation caspaces Digest cellular componentsDigest cellular components
Cellular debris phagocytosed by glial cellsCellular debris phagocytosed by glial cells
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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
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ExcitotoxicityExcitotoxicity
May trigger cell death in adjacent cellsMay trigger cell death in adjacent cells
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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
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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
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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
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Direct effect on RGCDirect effect on RGC
Somatic shrinkageSomatic shrinkage
Dendritic changesDendritic changes
Heat shock responseHeat shock response
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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
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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
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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
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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
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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
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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
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Pseudoexfoliative glaucomaPseudoexfoliative glaucoma
Basement membrane Basement membrane diseasedisease
Exfoliated material Exfoliated material obstruct TMobstruct TM
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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
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Increased episcleral resistanceIncreased episcleral resistance
Sturge Weber Sturge Weber syndromesyndrome
AV fistulaAV fistula
Orbital floor fractureIOP + 6 mmHg
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Angle closure glaucomaAngle closure glaucoma
AcuteAcute SymptomaticSymptomatic
PainPain
RednessRedness
Blurred visionBlurred vision
HaloesHaloes
Nausea or vomitingNausea or vomiting
ChronicChronic May be asymptomaticMay be asymptomatic
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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
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Plateau irisPlateau iris
Central iris flat Central iris flat centrally and convex centrally and convex peripherallyperipherally
Angle closes on Angle closes on dilationdilation
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Supraciliary effusionsSupraciliary effusions
UveitisUveitis
Drug effectDrug effect SulfaSulfa TopiramateTopiramate
Malignant glaucomaMalignant glaucoma
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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
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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
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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