Topic presentation- POAG

Dr.Lhacha WangdiR3, JDWNRH/KGUMSB

2016

Objectives Aqueous formation and drainage systemGlaucoma overviewPOAG: Pathophysiology of raised IOP Glaucomatous optic neuropathy Clinical manifestation Investigations and interpretation of the results Management principles

Aqueous humor

Formation: Aqueous is secreted by the bilayer ciliary epithelium

at the pars plicata of ciliary body

Aqueous productionThree Mechanism

1. Ultrafiltration ultrafiltration of plasma through the fenestrated capillaries into the ciliary stroma

2. Active transport (main mechanism)Number of solutes are actively transported from ultrafiltrated across the CE(PE+NPE) into the PC

3. Simple diffusionPassive transport of H2O to PC facilitated by the Osmotic gradient created by active transport

Active transport Three mechanism:

1. Loading of major ions/solutes occurs through the Basolateral membrane (BLM) of PE

Na-K-2cl and Na-HCO3 cotransporter / Na/H+ counter exchanger= uptake of of Na+, K+, CL- from stroma to PE coupled with anti-transport of H+ and HCO3- by Na/H+ and CL-/HCO3 antiports located in BLM of PE

2. Active transport of Na+ by Na+,K+ ATPase located at the BLM of NPE

3. Shifting of fluid and solutes from PE to PC is facilitated by the concentration gradient

Aqueous dynamics Secretion of aqueous balanced with drainage Secretion flow rate:2-3 uL/min. Aqueous volume(AC+PC)= (200ul+60ul)=260ul Maintains IOP of 11-21mmHg (average=16mmHg)

Diurnal variation – morning rise( 7.mmHg is considered normal upper limit)

Asymmetry of IOP >4mmHg is significant

Aqueous flow

1. Passes from PC to AC via pupil

2. About 90% of aqueuos flows through Trabecular meshwork which drain through Schlemm canal to episcleral vein

10% of aqueuos drain through Uveoscleral route across the face of ciliary body into the suprachoroidal spaces

Ctn..Angle structure

1. Schwalbe line (SL)2. Trabecular meshwork(TM)3. Schlemm’s canal(SC)4. Scleral spur(SS)5. Anterior border of the ciliary

body(CB)1. (where its longitudinal fibers insert

into the scleral spur)

6. Iris (I)

Trabecular meshwork (TM)

TM Circular spongework of connective tissue lined by

trabeculocytes Triangular in cross section. Apex at Schlemm’s canal Base formed by the scleral spur and the Ciliary body

Trabecular meshwork3 parts:

1. Uveal Contains large and circular cordlike trabeculae Diameter of pores-70pm in diameter

2. Corneoscleral Series of thin, flat, perforated connective tissue sheets arranged in

a laminar pattern Pores-35pm in diameter (moderate resistance

3. Juxtacanalicular Pericanalicular connective tissue-a multilayered collection of cells

forming a loose network- Pores -7pm in diameter (highest resistance to flow)

Glaucoma Definition:

Glaucoma is a group of acute and chronic, progressive, multifactorial optic neuropathies in which intraocular pressure (IOP) and other contributing factors are responsible for a characteristic, acquired loss of retinal ganglion cell axons leading to atrophy of the optic nerve with demonstrable visual field defects

The word glaucoma came from the ancient Greek word glaucosis, meaning clouded or blue-green hue, most likely describing a patient having corneal edema or rapid evolution of a cataract precipitated by chronic elevated pressure

Glaucoma

When to suspect?1. Glaumatous optic neuropathy2. Characteristic visual field loss3. Raised IOP

Other clinical signs will depend on the Type of glaucoma

Glaucoma

Classification

Congenital Acquired

Angle closure Open angle

Primary Secondary

Acute Chronic

Primary open angle glaucoma(POAG)

Definition: Multifactorial optic neuropathy that is chronic and

progressive with a characteristic acquired visual field loss in presence of open anterior chamber angle.

Commonly bilateral disease of adult onsetCharacteristics:

1. Primary glaucomatous optic neuropathy2. >IOP 21mmHG at some stage3. Characteristic visual field loss4. Absence of secondary cause of glaucoma

POAG variants

Primary open-angle glaucoma (POAG)

Not associated with known ocular or systemic disorders that cause increased resistance to aqueous outflow or damage to optic nerve;usually associated with elevated IOP

Normal-tensionglaucoma ( NTG)

Considered in continuum of POAG; terminology often used when IOP is not elevated

Juvenile open-angleglaucoma (JOAG)

Terminology often used when open-angle glaucoma diagnosed at young age (typically 4-35 years of age)

Ocular hypertension

Normal optic disc and visual field associated with elevated I O P

Glaucoma suspect

Suspicious optic disc or visual field regardless of I O P

POAGEpidemiology: Prevalence of 6% in white populations, 16% in black

populations and around 3% in Asian populations. Most common type of glaucoma

Globally:Glaucoma affects more than 67 million persons worldwide10%, or 6.6 million, are estimated to be blind Glaucoma is responsible for 14% of all blindness

POAGRisk factors: The higher the IOP/Asymmetry of IOP of 4 mmHg or more Older age More common in black individuals than in whites Genetics Steroid usages Diabetes mellitus Myopia Contraceptive pill Vascular disease Translaminar pressure gradient. Large discs

Genetics of POAG Inheritance:

Most POAG pedigrees do not show a simple Mendelian pattern of inheritance- largely unknown

A minority of POAG pedigrees do demonstrate a Mendelian pattern of inheritance:

1. Autosomal recessive- commonest type2. Autosomal dominant pedigrees have also been described, with

a degree of penetrance varying from 60% to 100%3. Rare pedigrees showing possible sex linked inheritance have

been reported

Genetics of POAGMolecular genetic: Gene expression analysis has found out 26 genetic

loci in the region of the long arm of chromosome 1, 1q21-q31 associated with POAG

Out of these only three gene has been discovered till date:

1. Myocilin (MYOC)2. Optineurin3. WDR36

Ctn..MYOC(myocilin)-Most studied gene:

Also called TIGR(trabecular meshwork induced glucocorticoid response protein)Normally myocilin protein is secreted by TM cells into aqueous

Mutated myocilin protein is not secreted and retained within TM cells:

Interferes with TM function Causes TM cell death Obstruction of aqueous drainage- raised IOP

Ctn…

Optineurin &WDR36:

It is expressed in a variety of ocular tissues, including the ciliary body, TM, and retina.

Itsrole in glaucoma pathogenesis is still unclear

Pathogenesis of raised IOP in PAOG Mechanism:

ComplexMain mechanism:

Obstruction of aqueous through open angle Pathological changes in the angle structures

Cause of aqueous obstruction: Multifactorial: Genetic Aging Race Ocular risk systemic risk factors Drugs

Ctn…

Thickening and sclerosis of trabecular meshwork with faulty collagen tissue

Narrowing of intertrabecular spacesDeposition of amorphous material in the

juxtacanalicular space

Collapse of schlemm’s canal and absence of giant vacuoles in the cells lining it

Reduced aqueous outflow facility occurs due to failure of aqueous outflow pump mechanisms:

Pathogenesis of raised IOP in POAG

obstruction of aqueous outflow

High risk groups

Transforming growth factors (TGFs)• Inhibition of epithelial cell growth• excessive amounts of extracellular matrix

materials - GAGs

Alteration of TM:• increase in extracellular matrix and

an accumulation of “plaque material.”

• Thickening of basement membrane

• disrupt TM cell actin microfilaments

Thickening of juxtacanalicular connective tissue

Decreased in Pores and giant vacuoles in the inner wall endothelium of the Schlemm canal Collapse of the Schlemm Canal

Alterations of the Intrascleral Channels• due to a swelling of

glycosaminoglycans in the adjacent sclera

Steroid responsiveness

“Steroid Responder” Around one in three individuals develop some

degree of elevation of IOP in response to a course of potent topical steroid

“Non-responders” IOP is not affected by steroid

Steroid responderMechanisms:

1. Glycosaminoglycans Theory:Cortico — steroids stabilize the lysosome membrane of TM cells► reduced catabolic enzyme►reduces GAGs catabolism► increased polymerised form of GAGs► increases resistance to aqueous outflow.

2. Phagocytosis Theory:Suppress the phagocytic activity of endothelial cells lining the trabecular►buildup of material that could account for the amorphous layer in the juxtacanalicular connective tissue meshwork

3. Cyclic-Adenosine Monophosphate Theory:Altering cyclic-adenosine monophosphate- mechanism poorly defined

Glaucomatous optic neuropathyPathogenesis:

1. Direct mechanical damage to retinal nerve fibres

2. Ischaemic damage3. Common pathways of

damage

1 2

3

MECHANICAL

mechanical pressure on the lamina cribrosa

mechanical pressure on the lamina cribrosa

altering capillary blood flow backward displacement and

compaction of the laminar plates narrows the openings through which

the axons pass

GANGLION CELL DEATH

VASCULAR

rise in intraocular pressure

mechanical pressure on the lamina cribrosa

decrease the capillary blood flow

mechanical compression of vessels at the lamina

cribrosa

GANGLION CELL DEATH

POAG- clinical menefestation

The Silent thief of sight

Clinical features Symptoms:

Insidious and asymptomatic disease Gradual painless loss of vision Mild headache, eye ache Visual field defect(SCOTOMA) Frequent change in presbyopic glasses Delayed dark adaptation Significant loss of vision and blindness

Ctn…Specific enquiry:

Refractive status(e.g myopia)Causes of secondary glaucoma (trauma/surgery/inflammation/tumour)Family history- glaucomaPast medical history-Asthma, heart failure/migraine and Raynaud phenomenon, DM/HTN.Drugs -Steroids/OCP/beta blockersSocial history- smoking/alcohol/nutrition-dietAllergies

Examination Work up:

1. Visual acuity2. Pupils-regularity/reaction/asymetry/RAPD/

APD3. Color vision assessment4. Visual field- confrontation test5. Slit lamp examination- detail examination of

anterior segment/fundus

Visual field examination

Screening tests …Confrontational visual field testing Amsler grid (assesses the central 10° the visual field ) .

Quantitative measurements using manual or automated perimetry

Cnt..

Anterior segment:

Corneal haze AC depth and any reaction Pupil- syniechae Evidences of secondary

cause

Ctt..The van Herick method: gross estimation

Uses the slit lamp alone to estimate the AC angle width:

Funduscopy

• Fundus :1. Optic disc

assessment2. Parapapillary

changes3. Vessels 4. Nerve fiber

Optic disc- surface anatomy

Around the optic cup is neuroretinal rim (NRR):• Pink and sharp peripheral margin• Contain nerve axon• Broad inferior rim followed by superior> nasal>temporal ( ISNT

rule)

Disc: Vertically oval Vertical diameter-1.8mm

Horizontal diameter- 1.5 mm Pale center area-physiological cup Horizontally oval Free of nerve axon(cup)-0.3mm Normal CDR= 0.4

Inferior

superior

Nasal temporal

Glaucomatous Optic neuropathy

Glaucomatous damages in three regions:(a) the optic nerve head(b) the peripapillary area and (c) the retinal nerve fibre layer.

There are specific sings and non specific signs

Ctn…

Optic nerve:

Specific signs: Focal ischaemic discs Myopic disc with glaucoma Sclerotic discs Concentrically enlarging discs

Focal ischaemic – inferior notch and disc haemorrhage

myopic;scleroticconcentrically enlarging

Glaucomatous ON

Nonspecific signs glaucomatous damages: Disc haemorrhages Baring of circumlinear blood vessels Bayoneting Collaterals Loss of nasal NRR The laminar dot sign ‘Sharpened edge’ or ‘sharpened rim’

baring of inferior circumlinearblood vessel

bayoneting of blood vesselscollateral vessels

loss of nasal neuroretinal rim and laminar dot sign

Ctn…Peripapillary changes

1. Alpha (outer) zone is characterized by superficial retinal pigment epithelial changes

2. Beta (inner) zone is characterized by chorioretinal atrophy

Ctn..

Retinal nerve fibre layer1. Localized wedge-shaped defects and

2. Diffuse defects that are larger and have indistinct borders

INVESTIGATIONS1. Tonometry2. Central corneal thickness(CCT)3. Diurnal variation test4. Gonioscopy5. Perimetry to detect the visual field defects6. Nerve fibre layer analyzer (NFLA)7. Provocative tests

Water drinking test

TONOMETRYThe intraocular pressure (IOP) is measured with the help of an instrument called tonometer

Indentation tonometerySchiotz tonometer

Applanation tonometryGoldmann tonometerPerkin’s applanation tonometerPneumatic tonometerPulse air tonometerTono-Pen

Rebound tonometry - icare Schiotz tonometer

Technique of Schiotz tonometry

Technique of applanation tonometry

End point of applanation tonometry. (A) too small; (B) too large; (C) end point.

Gonioscopy

The technique of biomicroscopic examination of the angle of the anterior chamber using a goniolens.

The angle structures seen from behind forward are:1. Root of the iris2. Ciliary body band3. Scleral spur4. Trabecular meshwork5. Schwalbe’s line

Schaffer’s grading

Grade 0

Grade 1Grade 2

Grade 3

Grade 4

Grade 4 (35–45°) is the widest angle, the ciliary body can be visualized. Grade 3 (25–35°) is an open angle, scleral spur is visible. Grade 2 (20°) is an angle in which the trabeculum but not the scleral spur can be seen. Grade 1 (10°) is a very narrow angle in which only the Schwalbe line and perhaps the top of the trabeculum can be identified. Slit angle is one in which there is no obvious iridocorneal contact but no angle structures can be identified. Grade 0 (0°) is closed due to iridocorneal contact.

Visual field defects

Relative paracentral scotoma

Roenne’s nasal step

Seidel scotoma

Arcuate scotoma

Double arcuate / ring scotoma

End stage / near total field defect

A paracentral scotoma- loss of nerve fibers ininferotemporal retina

The arcuate scotoma-10-20° from fixation-Bjerrum scotoma

Nasal stepAltitudinal defectAdvanced glaucomatous V. Field loss

SEIDEL SCOTOMAstarts at the poles of the blind spot , arches over the macular area without reaching the horizontal meridian nasally

Treatment of PAOG

Medical

LASER

Surgery

ManagementPrinciple:

Determine TARGET PRESSURE – Reduction of IOP by at least 30% appears to have the best chance of preventing optic nerve damage

Starting drugs-Monocular Therapeutic Trial (MTT) Reexamination in 3 to 6 weeks to check for

effectiveness. Exception to MMT:

IOP > 40 mm Hg impending loss of central fixation),

MEDICAL

MECHANISM

Decreased aqueous production

Increased facility of outflow (trabecular / uveoscleral)

Intraocular osmotic fluid reduction

Anti-glaucoma drugs# Agents Mechanism of action Drugs

1 Prostaglandins enhancementof uveoscleral aqueous outflow

Latanoprost(0.005%) - ODTravoprost(0.04%) -ODBimatoprost(0.03%) -ODTafluprost(0.04%) -OD

2 Beta-blockers

block β receptors in ciliary processes aqueous production

Timolol (0.25%/0.5%)-BDBetaxolol(0.25%,0.5%) -BDLevobunolol(0.5%)-BD Carteolol(1%, 2%) -BDMetipranolol(0.1%, 0.3%, 0.6%)-BD

3 carbonic anhydrase inhibitors

Inhibition of carbonic anhydrase- reduce aqueous production

Dorzolamide(2%) –BD-TDSBrinzolamide (1%)-BD-TDST-Acetazolamide (250mg),BD-QIDT-Dichlorphenamide(50mg) BD-TDST-Methazolamide(50 mg) BD-TDs

# Agents Mechanism of action Drugs 4 Alpha-2

agonistsOcular alpha-2 receptor stimulation decreases aqueous synthesisvia an effect on the ciliary epithelium, and increases uveoscleral outflow.

Brimonidine(0.2%)BD-TDS dosageApraclonidine (0.5%,1%)BD-TDSClonidine (0.125%,0.25%) BD

5 Miotics cholinergic agonists-reduce IOP by contraction of the ciliary muscle, also opens angle by miosis

Pilocarpine 0.5%, 1%, 2%, or 4% solution as four timesCarbachol(0.75%,1.5%,3%)BD-TDS dosage

6 Osmotic agents

lower IOP by creating an osmotic gradient so thatwater is ‘drawn out’ from the vitreous into the blood

Mannitol IV(20% solution1-2g/kg over 20-30 minutes,Glycerol is an oral agent (1 g/kg body weight or 2 ml/kgbody weight of a 50% solution)Isosorbide is a metabolically inert oral agent

Prostaglandin Side affects

Systemic :1. Upper respiratory tract symptoms (flu like )2. Headache and precipitation of migraine in

susceptible individuals3. Muscle and joint pains4. Skin rash

Prostaglandin side affects Ocular Side Effects

1. Conjunctival hyperaemia and foreign body sensation2. Eyelash lengthening, thickening, hyperpigmentation, increase

in number3. Iris hyperpigmentation4. Increase in severity and recurrence of herpetic keratitis5. Anterior uveitis6. Cystoid macular edema

Beta- blocker side effects Systemic

1. Cardiovascular effects – bradycardia, arrhythmia, heart failure, syncope

2. Respiratory reactions – bronchospasm and airway obstruction, especially in asthmatics

3. CNS effects – depression, anxiety, confusion, drowsiness, disorientation

4. Others – nausea, diarrhoea, decreased libido, skin rashes, alopecia

Beta-bockers Ocular side affects:

Conjuctival hyperaemia Superficial punctate keratopathy Corneal anaesthesia

1. Contraindications: Bronchial asthma Chronic obstructive pulmonary disease Heart blocks Congestive heart failure Cardiomyopathy

Carbonic anhydrase inhibiters Systemic side affects:

1. Paraesthesias, numbmness, lethargy, depression, malaise2. Metabolic acidosis, hypokalemia, increased serum urate

level3. Urinary frequency4. Anorexia, cramps, flatulence, weight loss, diarrhoea5. Sulfonamide related – blood dyscrasias, renal calculi,

steven-Johnson syndrome

Topical agents are less likely to induce systemic side effects

LASER THERAPY

Argon laser trabeculoplasty

Selective laser trabeculoplasty

Surgical

TRABECULECTOMY:

Involves creation of fistula between angle of anterior chamber and sub Tenon’s space

Trabeculectomy

Indications:Failure of conservative therapy to achieve adequate IOP control.Avoidance of excessive polypharmacyProgressive deterioration despite seemingly adequate IOP control (including poor compliance with medical treatment).Patient preference

DRAINAGE SHUNTSShunts using episcleral explantsGlaucoma Drainage Devices(GDD)= creates communication between AC and sub tenon space

THANK YOU