1. Partners
Eye Care Specialists
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 commonA family of diseases having in common
characteristic progressive optic neuropathy andcharacteristic 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 pathway
Photoreceptor cellsPhotoreceptor cells
Bipolar cellsBipolar cells
Retinal ganglion cellsRetinal ganglion cells
Nerve fiber layerNerve fiber layer
Optic nerve headOptic nerve head
Optic nerveOptic nerve
Optic chiasmOptic chiasm
Lateral geniculate bodiesLateral geniculate bodies
Optic radiationsOptic radiations
Occipital cortexOccipital cortex

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Changes in glaucomaChanges in glaucoma
Normal 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
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Upregulated Trk B receptor in chronic glaucomaUpregulated Trk B receptor in chronic glaucoma
bFGFbFGF
NT-3,4NT-3,4
NGFNGF
CNTFCNTF
InterruptionInterruption

Mechanical obstructionMechanical obstruction
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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 failurepump failure AcidosisAcidosis
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 radical
formation
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
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Muller cellsMuller cells
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Have glutamate transporters that bufferHave glutamate transporters that buffer
extracellular glutamateextracellular glutamate
GLT-1GLT-1
GLASTGLAST

Modulate ECMModulate ECM

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Role of IOPRole of IOP
Direct effect on retinal ganglion cellsDirect 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 nerveMechanical 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 cribriformPosterior bowing and thinning of cribriform
plateplate

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Effect on blood flowEffect on blood flow
PP = MAP – IOPPP = MAP – IOP
PP:PP: Perfusion pressurePerfusion pressure
MAP:MAP: Mean arterial blood pressureMean arterial blood pressure
IOP: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 flowF = aqueous flow (uL/min)(uL/min)
C = outflow facilityC = outflow facility (uL/min/mmHg)(uL/min/mmHg)
PPee = episcleral venous pressure= episcleral venous pressure
(mmHg)(mmHg)
Increased aqueousIncreased aqueous
productionproduction
Impaired aqueousImpaired aqueous
outflowoutflow
Elevated episcleralElevated episcleral
venous pressurevenous pressure

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Anataomy and physiology ofAnataomy and physiology of
aqueous flowaqueous flow
Produced via activeProduced via active
transport in non-transport in non-
pigmented epithelium ofpigmented epithelium of
the ciliary processesthe ciliary processes
OutflowOutflow
 TrabecularTrabecular
 UveoscleralUveoscleral
Elevated IOPElevated IOP
 Open angleOpen angle
 Closed angleClosed angle

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Primary open angle glaucomaPrimary open angle glaucoma
SenescenseSenescense
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Decreased number of pores in TMDecreased number of pores in TM
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Decreased cellularity of TMDecreased cellularity of TM
Helicobacter pyloriHelicobacter pylori

88% in POAG88% in POAG
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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 membraneBasement membrane
diseasedisease
Exfoliated materialExfoliated material
obstruct TMobstruct TM

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Pigmentary glaucomaPigmentary glaucoma
Reverse pupillary blockReverse pupillary block
Posterior bowing of irisPosterior bowing of iris
Pigment epithelium contact with lensPigment epithelium contact with lens
Pigment released causing Krukenberg spindlesPigment released causing Krukenberg spindles
Pigment phagocytosed by TM causing decreased TMPigment phagocytosed by TM causing decreased TM
functionfunction

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Increased episcleral resistanceIncreased episcleral resistance
Sturge WeberSturge Weber
syndromesyndrome
AV fistulaAV fistula
Orbital floor fracture
IOP + 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 irisPressure bows iris
anteriorlyanteriorly
Dilation causes angleDilation causes angle
to closeto close
May be lens / cataractMay be lens / cataract
inducedinduced

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Plateau irisPlateau iris
Central iris flatCentral iris flat
centrally and convexcentrally and convex
peripherallyperipherally
Angle closes onAngle closes on
dilationdilation

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Supraciliary effusionsSupraciliary effusions
UveitisUveitis
Drug effectDrug effect
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SulfaSulfa
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TopiramateTopiramate
Malignant glaucomaMalignant glaucoma

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Role of ocular blood flow andRole of ocular blood flow and
oxygenationoxygenation
IschemiaIschemia

triggers glutamate cascadetriggers glutamate cascade
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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 glutamateT cell mediated modulation of glutamate
toxicitytoxicity
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Cop-1 induced immunityCop-1 induced immunity
C-terminal cross reactivityC-terminal cross reactivity
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CaspacesCaspaces
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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