current challenges and concepts in the …dme.ap.nic.in/glaucoma.pdfdr.pulijala venkateshwar rao...

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Dr.PULIJALA VENKATESHWAR RAO

CURRENT CHALLENGESCURRENT CHALLENGESANDAND

CONCEPTS IN THE MANAGEMENT OF GLAUCOMACONCEPTS IN THE MANAGEMENT OF GLAUCOMA

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A NEW BEGINNING TO AN OLD DISEASEA NEW BEGINNING TO AN OLD DISEASEThis watermark does not appear in the registered version - http://www.clicktoconvert.com


DEFINITIONDEFINITION

l “ Multifactorial optic neuropathy “ in which there is a characteristic acquired loss of optic nerve fibres.

AAO 1996



PRESSURE SENSITIVE PRESSURE SENSITIVE OPTIC NEUROPATHYOPTIC NEUROPATHY



RISK FACTORSRISK FACTORS

l I.O.P.DEPENDENT

l NON I.O.P. DEPENDENT

Increasing age

Family History

African Heritage

Hypertension

Vascular & Endocrine disorders

Myopia

Diabetes



Newly identified Risk factorsNewly identified Risk factors

l Systemic hypotension.

l Nocturnal hypotension.

l Cardio vascular disease.

l Vasospasm.(Migraine.Raynoud disease).

l Dis regulation.

l Sleep apnea.

l Auto immune disease.

l Hemorrhagic abnormalities.

l Cerebral micro vascular ischaemia.



Current ConceptsCurrent Concepts

Glaucoma pathology



TheoriesTheories

l Mechanical theory.

l Vascular theory.

l Combined mechanism.



Glaucoma Pathogenesis.Glaucoma Pathogenesis.

l Interruption of axoplasmic flow at lamina cribrosa..

l Elastin present at L.C. Protects it from backward excavation.

l I.O.P.Damages it and facilitates backward stretching leading to poor capillary blood flow which inhibits axonal transport.

l In NTG defective elastin is seen,lowvasular flow may also contribute.



GLAUCOMA: OPTIC NERVE DAMAGE

Rise in IOP > 21 mm Hg

Mechanical back pressure

On the junction of optic nerve/retina

Reduce the blood supply to the optic nerve

(prolonged AVP time)

Loss of blood supply (< in pOBF)

Ischaemia

RGC cell loss



A HYPOTHESIS FOR GANGLION CELL DEATH IN GLAUCOMA

Release of glutamate

and potassium

Insult spread to all astrocytes

in retina. Astrocytes electrically

couple-spreading depression

Hypoxia to

astrocytes

Glutamate and GABA receptors on

ganglion cell overactivated and rate of

death depends on numbers and type of

receptors becom "overworked'

Muller cells no longer functionnormally

so cannot inactivate 'released'transmiters like glutamate and GABA

Released glutamate inactivated

by Muller cell. These eventuall

become "overworked'

Release of

glutamate

Insult (lack of nutrients

eventually affects all ganglion

cell bodies

Hypoxia to

axons

Microcirulation in optic

nerve head affected

Glutamate / GABA eventuallyDeposited in vitreous

Hypoxiato lamina cribrosa

Hypoxiato to blood vessels



R e t i n a l G a n g l i o n C e l l D e s t r u c t i o n

R i s k F a c t o r s

Primary Insult

Glutamate being releasedinto surrounding medium

Toxic response in adjacent retinal ganglion cells(Secondary degeneration)

Excito toxicity Block the Excito toxicity

Over stimulation ofN-methyl –D-asparate (NMDA)Receptors

Excessive levels of intra cellularC a l c i u m

Activation of Nitric Oxide Synthatase

Excess free radicals accumulationActivation of catabolic enzymes cellDeath (Apoptosis)

Ganglion CellsG l u t a m a t e

Delivery ofN e u r o t r o p i n s( B D N T F )

Induction cells inthe retina or toproduce Neurotropinswith gene therapy

M e m a n t i n e

A m i n o g u a n i d i n e

Blockade orr e c e p t o rm e d i a t o r sExcito toxicity

M e l a t o n i n / A n t i o x i d a n t sV i t . E

Scavenging of reactiveOxygen species



l There is no POAG without vascular risk factors.

l Ganglion cell apoptosis is increased by ischaemia.

l Vascular disregulation makes the eye more sensitive to increased IOP or decreased blood pressure.

l With normal auto regulation GON developed only if perfusion pressure is markedly decreased.

l When disregulation occurred GON can occur without reduction in perfusion pressure.



Types of Neuronal deathTypes of Neuronal death

l Necrotic.

l Apoptotic.



Mechanism of RetinalMechanism of RetinalGanglion cell death Ganglion cell death

l Neuroprotection with drawl due to retrograde axoplasmic transport block.

l Glutamate induced excitotoxicity.

l Free radical generation.

l Nitric oxide neurotoxicity.

l Apoptosis.



Steps Of Neuronal DeathSteps Of Neuronal Death

l Axonal death.

l Death of injured neuron.

l Injury and death of previously intact neurons, through secondary degeneration.



Conceptual Aspects of Ganglion Conceptual Aspects of Ganglion Cell Death in GlaucomaCell Death in Glaucoma

l Not all axons of O.N.Nor RGC die at the same time.

l This occurs over a period of decades.

l Groups of RGC similarly susceptible.

l Field defects will not develop till 30% loss of axons.



Challenges in Diagnostic ToolsChallenges in Diagnostic Tools

l Goldman appl.tonometry Vs central corneal thickness.

l SITA Vs SWAP / FDP.

l Estimation of RNF layer thickness.

l Measurement of ocular circulation.



Modes of ApproachModes of Approach

l Lowering I.O.P.

l Increase out flow facility.

l Neuro protection.

l Vaso protection



Glaucoma Management PerceptsGlaucoma Management Percepts

l Quantify the damage

l Set an I.O.P. Goal

l Lower the I.O.P.

l Follow the course to establish that low IOP is maintained and damage is stationary



Patient ConsiderationsPatient Considerations

l Is the elevated pressure significant?

l Will the patient develop visual loss if untreated?

l Is treatment worth the risk of side effects?



Strongly RECCOMENDED For Strongly RECCOMENDED For TreatmentTreatment

l Poor reliability on visual field examination

l One eyed patient

l Poor compliance

l Patient whose optic nerve is difficult to visualize

l H/O of vascular occlusion

l OHT with IOP > 28 mmHg

l IOP progression is successive



Managing IOP Dependent Managing IOP Dependent Risk FactorsRisk Factors

l Decreasing aqueous formation

l Increasing outflow facility

l Increasing uveoscleral outflow



Aqueous Suppressors Outflow Facilitators

Medical Treatment



Relationship Between IOP andRelationship Between IOP andField LossField Loss

l Pts with IOP>30mm.Hg were over 38 times more likely to have glaucoma than with pts whose IOP is<15mm.Hg.

l 4.7 times higher in patients with an IOP >21mm.Hg.

l Odds of developing glaucoma were 2.8 times more in patients with IOP asymmetry between rt. And lt.Greater than 3mm.Hg.



Importance of lowering IOP

For every 1mm Hg drop in IOP, a 10%

reduction in risk of glaucomatous

progression is observed

Reducing IOP in glaucoma patients limits

disease progression & slows visual field

loss

Survey Of Ophthalmol 2003; 48 (Suppl 1)



Relationship between IOP & glaucomatous visual loss (Baltimore Eye Survey)

Risk of POAG at different IOP levels

0

1020

3040

50

< 15 16-18 19-21 22-24 25-29 > 30

IOP (mm Hg)

Rel

ativ

e ri

sk o

f P

OA

G

Eye 1996;10;295 -301Survey Of Ophthalmol 2003, 48 ( Suppl 1), S3 -S7



Target Pressure RangeTarget Pressure Range

l “ A range of IOP enough to limit progression of visual field loss to a rate that will preserve the patient visual function and maintain their individual patterns of daily living.”



Importance of steady IOP.Importance of steady IOP.

l A diurnal variation of more than 11.8 mm.Hg 88% develop further field loss,when compared to D.V <7.7mm. With 57% loss.

l Large variation of IOP on multiple days found to be a significant risk factor for Glaucoma progression.

l Patients who have periodic or sporadic pressure spikes can lose visual field due to cumulative effects.



FACTORS CAUSING INCREASED FACTORS CAUSING INCREASED RESISTANCE TO OUTFLOWRESISTANCE TO OUTFLOW

l Anatomical / Histopathological changes

l Altered Corticosteroid metabolism.

l Dysfunctional adrenergic control.

l Abnormal immunologic process.

l Oxidative damage of Trabecular meshwork.



CLASSIFICATIONCLASSIFICATION

n Inflow regulating Agents Reduces Aqueous

Humor production

Beta Blocker TimololBetaxololCarteolol

CAIsDorzolamideBrinzolamideAcetazolamide



CLASSIFICATIONCLASSIFICATION

Trabecular OutflowPilocarpine

Prostamides

Uveo ScieralOutflow

LatanoprostProstamides

BothAlphagan

Outflow regulating agents (Increases drainage of Aq. Humor)



THERAPEUTIC AGENTS SUMMARY


Non selective BBs

Xalatan/AlphaganSelective BBS

High

Invisible / irreversible Side effects

LOW Efficacy High





Beta blockers

(Non –Selective )

XalatannSelective Beta

blockers

AlphaganHigh

Visible / Reversible Side effects

LOW Efficacy High



MEDICAL MANAGEMENT OF GLAUCOMA

SystemicCAIs (Carbonic Anhydrase Inhibitors)- Acetazolamide Tablets

Prostaglandin analogues - Latanoprost- Bimatoprost

Adrenergics - Dipivefrin

a2 agonists- Brimonidine

Cholinergics/ Miotics - Pilocarpine

b blockers- Timolol- Betaxolol- Levobunolol

TopicalTopical

Outflow facilitators Aqueous Suppressors

Drugs 2000 Mar; 59(3): 411 -434



Calculations(AAO Guidelines)Calculations(AAO Guidelines)

l MILD DAMAGE ( early or no field loss).

75-80% of IOP at which presenting damage occurs.

l MODERATE DAMAGE( both hemi fields involved).

70-75% of IOP at which presenting damage occurs.

l ADVANCED damage(fixation involved).

I.O.P.< 15mmhg.



ADJUSTMENTSADJUSTMENTS

l DOWNWARD : For high risk factors

High myopia,family history

african, one eyed

l UPWARD : For mild damage in some patients



AAO GuidelinesAAO Guidelines

l IN NTG 30% reduction in base line pressure.

l In OHT patients whose IOP is >30mm

Hg with no signs of OD damage a target pressure low 20s with at least 20% reduction in baseline may be accepted.



Trial MedicationTrial Medication PeriodPeriod

ASSESSMENT

l Efficacy

IOP reduction during initial 2-3 weeks.

Following with diurnal variability.

l Safety

Ocular side effects

Systemic side effects

Acquiescence of primary care physician

l Compliance

Technique of applying drops

Use of medication schedule

Rate of defaulting

Affordability



Guidelines For Follow UpGuidelines For Follow Up

3-121-61-30Not

applicable

YESNO

3-122-67-90Not

applicable

NONO

3-122-67-90Not

applicable

YESYES

6-246-1890-365>6NOYES

6-126-1230-180<6NOYES

VF

Evaluation

(months)

ONH

evaluation

(months)

Follow up

Interval

(days)

Duration of

Control

(months)

Progress

of damage

Target IOP

Achieved



Therapeutic ChallengesTherapeutic Challenges

l Anti glaucoma treatment in pregnancy and lactation.

l Tailoring the treatment to the patient.

l Switching the therapy.

l First line of therapy.

l Improving compliance.



Guidelines of AAOGuidelines of AAO

l Hypotensive lipid drugs as first line.

l Non selective B blockers should not be used in NTG.

l Switching over to another drug,in the same class is recommended if there is no adequate response to initial therapy.If no response adjunctive therapy is advised.



Categories of Ganglion Cells Categories of Ganglion Cells in Glaucoma Patientin Glaucoma Patient

l Normal healthy cells.

l Sick cells.

l Dead cells.

l Died and decayed .



MANAGING NON IOP DEPENDENT RISK MANAGING NON IOP DEPENDENT RISK FACTORSFACTORS

l Delivery of neurotrophins

l Blockade of receptor mediated Excitotoxicity

l Scavenging of reactive oxygen species



Neuroprotection.Neuroprotection.

l Pharmacological intervention.

l Immunological intervention.

l Future possibilities.



Pharmacological InterventionPharmacological Intervention

l Protection of undamaged cells.

l Rescue of marginally damaged cells.

l Regenerate/Regrowth/replacement of axons.



Protection of Undamaged CellsProtection of Undamaged Cells

l Blocking retinal exitotoxicity mediated by glutamate.

l Administration of neurotrophic factors.(BDNF).

l Neuronal resistance to insult.

l Inhibition of nitricoxide synthatase2 which will prevent axonal injury at LC.

l Ca2 channel blockers.



Rescue of marginally damaged Rescue of marginally damaged ganglion cellsganglion cells

l Lazaroids/21-aminosteroids.

l UP-Regulation of antideath genes.(bcl-2/bcl-x;viral vectors).

l Antioxidents/Free radical scavengers.

l Ca2 channel blockers.

l Nitric oxide synthatase inhibitors.



Regeneration/Regrowth/Regeneration/Regrowth/ReplacmentReplacmentOF AXONSOF AXONS

l Spanner neural grafts.

l Growth factors.

l Transglutaminases/Interleukin-2 Dimerizers/Oligodendrocytotoxins.

l Macrophage/cytokine/neuro immunological related factors.

l Astrocyte related factors.



Immunological InterventionImmunological Intervention

l Recently it has been suggested that COPL,a synthetic copolymer composed of aminoacids is knowntobe an immuno suppressive drug which can evoke t-cell mediated immunity that is neuro protective.



FUTURE POSSIBILITIESFUTURE POSSIBILITIES

l Gene therapy.

l The hepatocyte growth factor.

l Heat shock proteins.

l Stem cell graft.

l Peripheral nerve graft.

l Optic nerve transection.



NeuroprotectionNeuroprotection

l By glutamate antagonists.

l Prevent calcium influx.

l Prevent sodium influx.

l Reduce formation of free radicals.

l Stopping formation of nitric oxide and preventing lipids peroxidation.



Neuro Neuro protecting agents.protecting agents.

l Antiglaucoma agents.

l Calcium channel blocking agents.

l Anti oxidants.

l Ginkgo bilopa extract.

l Cannabinoids.

l Melatonin.

l Aspirin.



Ginkgo Ginkgo biloba biloba extractextract

l 60 known bioactive substances half of which are found nowhere in nature.

l Protective action against free radicals,and lipid per oxidation.

l Preserves mitochondrial metabolism,and ATP production in various tissues.

l Scavenges nitric oxide and reduce glutamate induced calcium conc.



Neuro Neuro rescuerescue

l Restoration of viability of dead cells or sick cells.

l Under trials;Aminoguanidine an inhibitor of nitricoxide synthetase.



R e t i n a l G a n g l i o n C e l l D e s t r u c t i o n

R i s k F a c t o r s

Primary Insult

Glutamate being releasedinto surrounding medium

Toxic response in adjacent retinal ganglion cells(Secondary degeneration)

Excito toxicity Block the Excito toxicity

Over stimulation ofN-methyl –D-asparate (NMDA)Receptors

Excessive levels of intra cellularC a l c i u m

Activation of Nitric Oxide Synthatase

Excess free radicals accumulationActivation of catabolic enzymes cellDeath (Apoptosis)

Ganglion Cells

G l u t a m a t e

Delivery ofN e u r o t r o p i n s( B D N T F )

Induction cells inthe retina or toproduce Neurotropinswith gene therapy

M e m a n t i n e

A m i n o g u a n i d i n e

Blockade orr e c e p t o rm e d i a t o r sExcito toxicity

M e l a t o n i n / A n t i o x i d a n t sV i t . E

Scavenging of reactiveOxygen species



VASOPROTECTIONVASOPROTECTION



While reduction of IOP remains the

mainstay of medical therapy of

glaucoma, other ocular effects of

topical medications remain important.



Reduction of IOP is not always sufficient to prevent further optic disc changes and vision loss.

There is a direct evidence for deficient blood supply to the choroid, retina and optic nerve head in glaucoma patients.

Am J of Ophthalmol 2003; 135(2), 144 -147



Evidence suggests that vascular defects

may be associated with optic nerve head

damage in both normal tension and

primary open angle disease

Acta Ophthalmol Scand 1996; 74: 569 -572



“Vasoprotection”

– May be effective in preventingdamage resulting from vasculardysfunction of eye

– Can lead to improved visual function



VASOPROTECTION

• AVP time (Arteriovenous passage time):Difference between the time of appearance ofblood in arteries and its appearance in theircorresponding veins. (normal value= 1.45 secs)

• Optic nerve head blood flow: Blood flow to opticnerve

• Pulsatile ocular blood flow (pOBF): Bloodsupply to retinal layers

• Ocular perfusion: Passage of blood throughocular vessels



Contrast sensitivityTreatment can be better managed if C.S is added to the evaluation process.(visual field, IOP, optic disc appearance)

Causes of improvement in C.S

Clinicians note changes in C.S following treatment are not correlated to changes in IOP.

- improvement in ocular circulation are related to improvements inContrast sensitivity.

- Dorzolamide, besides improving ocular circulation, is thought to improve perifoveal circulation ( nourishing RGCs near fovea), thereby improving visual function.

J of Ocular Pharmacology & Therapeutics 1999, 15, 189-197

www.vectorvision.com (31/01)

Parsons’ Diseases of the Eye,19, 103-104



Dorzolamide: Vasoprotection

Results

Patients visual fields significantly improved from MD –11.71 to 8.06 dB (p < 0.05)

Optic nerve head blood flow increased from 508 AU at baseline to 644 AU

Pulsatile ocular blood flow improved from 542 to 676 ml/min (p < 0.05)

Conclusion

Dorzolamide has a significant effect on visual fields

and pOBF in POAG patients and may significantly

improve visual functionwww.mednet.ca/html



HYPOTHESIS FOR GLAUCOMA HYPOTHESIS FOR GLAUCOMA MANAGEMENTMANAGEMENT

M A I N T A I N A N C E

NEURO RESCUE

N E U R O P R O T E C T I O N

CONTROL I.O.P

ELIMINATE RISK FACTORS



THERAPEUTIC GOALSTHERAPEUTIC GOALS

l Reduction in IOP

l Improvement in Blood flow of Optic nerve head and Retina

l Decreasing the damage caused by toxic metabolites such as Glutamate



A NEW BEGINNING TO AN OLD DISEASEA NEW BEGINNING TO AN OLD DISEASE



current challenges and concepts in the …dme.ap.nic.in/glaucoma.pdfdr.pulijala venkateshwar rao...

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