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Glaucoma - Introduction

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1. Introduction

• Etymology: "glaukos" (Greek) - clouded/blue-green hue
• Earliest description by Hippocrates (~400 BC); term "glaukosis" used

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2. Historical Perspective of Glaucoma

• Ancient era: Hippocrates (400 BC), Arabic physicians
• 17th century: First tonometer concepts; term "glaucoma" formalized
• 19th century: Helmholtz (ophthalmoscope, 1851); von Graefe - iridectomy for ACG (1857)
• 20th century: Goldmann applanation tonometry; trabecular meshwork understood; introduction of timolol (1978)
• Modern era: OCT, HRT, visual field automated perimetry; genetics (MYOC, OPTN, CYP1B1)

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3. Epidemiology

3.1 Global Burden

• 2nd leading cause of blindness worldwide (12.3% of global blindness)
• POAG prevalence >40 years: ~1.86% (~2.22 million Americans)
• Incidence: 2.4 million new cases/year globally
• Blindness from all glaucoma: >8 million people (4 million from POAG)
• Prevalence 3-8x higher in individuals >70 years
• Blacks: 3-4x higher prevalence; 4x higher blindness rate than whites
• PACG prevalence: ~0.1% in whites; relatively uncommon in blacks; higher among Eskimos
• ACG most common between ages 55-65 years

3.2 Epidemiology in Nepal

• Community-based study in Bhaktapur district
• Prevalence of glaucoma among those ≥40 years: approximately 1.5-2%
• POAG was the most common type
• High proportion undiagnosed at time of survey (low awareness)

• Population-based study in Jiri (Dolakha district), Eastern Hills of Nepal
• Prevalence of glaucoma: ~0.5% in adults ≥30 years
• Identified significant unmet need for glaucoma care in rural Nepal
• Low awareness and poor access to services highlighted

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4. Relevant Anatomy and Physiology

4.1 Anatomy of the Optic Nerve Head (ONH)

• ONH composed of: nerve fibre layer, prelaminar region, lamina cribrosa, retrolaminar region
• ~1.2 million retinal ganglion cell axons converge at ONH
• Neuroretinal rim (NRR): tissue between disc margin and cup edge
• Blood supply: short posterior ciliary arteries via circle of Zinn-Haller
• Normal cup:disc ratio 0.3:1 to 0.4:1

4.2 Retinal Nerve Fibre Layer (RNFL)

• Axons of retinal ganglion cells (RGCs) form the RNFL
• Thickest superiorly and inferiorly (ISNT rule: Inferior > Superior > Nasal > Temporal)
• RNFL loss is an early structural change in glaucoma, detectable by OCT
• Arcuate pattern of fibres creates characteristic arcuate scotomas when damaged

4.3 Trabecular Meshwork

• Located in the angle of the anterior chamber
• Three layers: uveal meshwork, corneoscleral meshwork, juxtacanalicular tissue (JCT)
• JCT is the site of greatest resistance to aqueous outflow
• MYOC gene expressed here; steroid-induced changes cause increased resistance
• Conventional (pressure-dependent) outflow pathway

4.4 Schlemm's Canal

• Circumferential channel at the corneoscleral junction
• Lined by endothelial cells with giant vacuoles - facilitate aqueous transport
• Aqueous passes from trabecular meshwork → Schlemm's canal → collector channels → episcleral veins
• Episcleral venous pressure (~8-10 mmHg) contributes to baseline IOP

4.5 Aqueous Humour Production, Outflow and Drainage

• Secreted by non-pigmented ciliary epithelium of the ciliary body pars plana
• Rate: ~2-2.5 µL/min
• Mechanisms: active secretion (Na-K-ATPase), ultrafiltration, diffusion

• Conventional (trabecular/pressure-dependent): ~80-90% via trabecular meshwork → Schlemm's canal → episcleral veins
• Uveoscleral (pressure-independent): ~10-20% via ciliary muscle face → supraciliary/suprachoroidal space
• IOP = Rate of production / Facility of outflow + Episcleral venous pressure (modified Goldmann equation: Po = F/C + Pv)

1. Rate of aqueous humour production by ciliary body
2. Resistance to outflow at anterior chamber angle
3. Level of episcleral venous pressure

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5. Pathophysiology of Glaucoma

• Primary mechanism: elevated IOP → mechanical compression of lamina cribrosa → axonal injury at ONH
• Secondary mechanism: vascular insufficiency → ischaemia of optic nerve axons
• Progressive retinal ganglion cell (RGC) apoptosis
• IOP is the key modifiable risk factor but not the sole determinant
• Normal-tension glaucoma: progressive injury occurs despite low/normal IOP (vascular theory)
• Genetics: MYOC (GLC1A), OPTN (GLC1E), WDR36 (GLC1G) mutations in POAG; CYP1B1 in congenital glaucoma

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6. Classification of Glaucoma (Already in slides - slides 10-15)

• Primary OAG (with elevated IOP; normal tension glaucoma)
• Secondary OAG: pigmentary, pseudoexfoliation, steroid-induced, lens-induced, post-trauma, post-surgery

• Primary: PAC suspect → PAC → PACG; mechanisms: pupillary block, plateau iris, phacomorphic
• Secondary: neovascular, ICE syndrome, inflammatory, posterior pushing mechanisms

• Primary congenital/infantile
• Secondary: uveitic, traumatic, lens-induced, steroid-induced, post-cataract surgery

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7. Risk Factors (Already in slides - slide 18)

• Elevated IOP
• Advancing age (especially >50 years)
• Race (African, Hispanic)
• Positive family history (relative risk 3.7x higher)
• Thin central corneal thickness (CCT)
• Myopia
• Asymmetrical cupping / increased cup:disc ratio
• Disc haemorrhage
• Optic disc area
• Low ocular perfusion pressure

• Gender
• Diabetes mellitus
• Systemic hypertension
• Atherosclerosis / ischaemic vascular disease
• Obesity, smoking, alcohol, stress, anxiety

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8. Clinical Features (Already in slides - slides 22-41)

• POAG: largely asymptomatic until late; insidious peripheral field loss
• Acute ACG: severe eye pain, headache, nausea/vomiting, colored halos around lights, red eye, blurred vision
• Secondary glaucoma: variable - may be symptomatic with rapid IOP rise ≥35 mmHg

• Conjunctival: episcleral congestion, ciliary flush
• Corneal: edema (acute IOP rise), Krukenberg spindle (pigment dispersion), keratic precipitates (inflammatory), breaks in Descemet's membrane (buphthalmos)
• CCT: thin (<520 µm) is a risk factor; influences IOP readings
• Anterior chamber: shallow depth (PACG - Van Herick grade)
• Iris: atrophy patches, rubeosis iridis (NVG), posterior synechiae, transillumination defects
• Pupil: mid-dilated vertically oval (post-ACG attack), RAPD (glaucomatous optic neuropathy)
• Lens: pseudoexfoliation material, Glaukomflecken, intumescent lens, phacodonesis

• Generalized: large cup (>0.5), asymmetry >0.2, progressive enlargement
• Focal (ISNT rule violation): NRR notching/thinning especially inferiorly, vertical cup elongation, splinter haemorrhage, RNFL loss
• Less specific: nasal vessel displacement, baring of circumlinear vessels, bayoneting sign, laminar dot sign, peripapillary atrophy (beta zone)

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9. Diagnosis and Principles of Management (Already in slides - slides 26-45)

1. Characteristic ONH changes
2. Visual field defects (VF)
3. Raised IOP

• Gonioscopy to determine angle status and glaucoma type
• In acute/subacute PACG and secondary glaucoma: raised IOP alone sufficient

• Visual acuity and refraction
• Slit-lamp biomicroscopy (cornea, AC, iris, lens)
• CCT measurement
• Gonioscopy (Shaffer's and Scheie's grading systems)
• ONH evaluation (direct/indirect ophthalmoscopy, stereo disc photos)
• Visual field testing (Humphrey/Goldmann perimetry)
• OCT (RNFL thickness, ONH parameters, macular GCC)

• Defined as the IOP below which no further optic nerve damage is expected
• Individualised based on: baseline IOP, degree of existing damage, adherence, side effects, cost
• Guidelines:
  • Ocular hypertension: lower by 20-30% or to ≤20 mmHg (per OHTS)
  • Early POAG: lower by 30% or to mid-high teens (reduces progression risk by 50%)
  • Moderate POAG: aim for low-to-mid teens or ≤15 mmHg
  • Advanced POAG: aim for ≤12 mmHg
  • Normal tension glaucoma (NTG): lower by 20-30% (per NTGS)

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References

• Diagnosis and Therapy of the Glaucoma - Becker-Shaffer's, 8th ed.
• Ophthalmology - Yanoff & Duker, 6th ed.
• Glaucoma - AAOO, 2025-26
• Clinical Ophthalmology - Kanski, 10th ed.

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1. Historical perspective of glaucoma (slide after Introduction)
2. Nepal-specific epidemiology (Bhaktapur and Jiri studies)
3. Dedicated anatomy section: ONH structure, RNFL, Trabecular meshwork, Schlemm's canal, aqueous flow/outflow/drainage pathway
4. Pathophysiology as its own heading

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HISTORICAL PERSPECTIVE OF GLAUCOMA

• Hippocrates described "glaukosis" - a blinding eye disease of the elderly
• The term referred to the blue-green or grey hue of the diseased eye (likely from corneal oedema or cataract from chronic elevated IOP)

• Arabic physicians including Ibn Sina (Avicenna) described the hard, painful eye
• Al-Mawsili (10th century) performed couching for cataracts; elevated eye tension recognized as distinct entity

• Richard Banister (1622): first to link a hard eye to incurable blindness
• Term "glaucoma" formally adopted from the Greek "glaukos" (blue-green/clouded)

• 1851: Hermann von Helmholtz invented the ophthalmoscope → direct optic disc examination became possible
• 1857: Albrecht von Graefe performed peripheral iridectomy for acute angle-closure glaucoma - the first effective surgical treatment for glaucoma
• 1862: von Graefe described the characteristic arcuate visual field defects in glaucoma
• 1885: Priestley Smith linked anterior chamber shallowness to angle-closure

• 1905: Pilocarpine (miotic) introduced for IOP reduction
• 1954: Hans Goldmann introduced the applanation tonometer - remains the gold standard for IOP measurement to this day
• 1960s: Trabecular meshwork (specifically the juxtacanalicular tissue) identified as the primary site of aqueous outflow resistance
• 1969: Shaffer's gonioscopic grading system published
• 1978: Timolol (topical beta-blocker) introduced - transformed medical management of glaucoma
• 1990s: Prostaglandin analogues (latanoprost, 1996) offered once-daily dosing with high efficacy

• Optical coherence tomography (OCT) introduced: allows quantification of RNFL thickness and detection of structural damage before visual field loss
• Automated perimetry (Humphrey Visual Field Analyser): standardised functional assessment
• Genetics: identification of MYOC/TIGR (1997), OPTN, WDR36, CYP1B1 genes
• MIGS (Minimally Invasive Glaucoma Surgery): iStent, canaloplasty, XEN gel stent
• Selective Laser Trabeculoplasty (SLT): repeatable, safe, first-line treatment option (LiGHT trial, 2019)

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EPIDEMIOLOGY

1. Global Burden

• Glaucoma is the 2nd leading cause of blindness worldwide (after cataract), accounting for 12.3% of global blindness
• Unlike cataract, glaucoma blindness is irreversible
• Estimated 80 million people affected globally (2020 estimates); projected to rise to 111.8 million by 2040
• Over 8 million bilaterally blind from glaucoma; ~4 million from POAG alone

• Prevalence in adults >40 years: ~1.86% globally (~2.22 million Americans affected)
• Incidence: approximately 2.4 million new cases per year worldwide
• Prevalence in whites aged 40+: 1.1-2.1%; rises 3-8 fold in individuals >70 years
• Blacks/African-Americans: 3-4x higher prevalence; 4x higher rate of blindness from POAG
• Incidence in predominantly Black populations >40 years: 2.2%

• Prevalence in whites: ~0.1%; relatively uncommon in Blacks
• Highest prevalence in East/Southeast Asians and Inuit/Eskimo populations
• Among Eskimos: 1st degree relatives of PACG patients have 3.5x higher risk than general population
• Family history of glaucoma increases risk of PACG by 6-fold
• Most common between ages 55-65 years; more frequent in women than men
• Anterior chamber depth decreases with age → predisposes to pupillary block

• Up to 50% of people with glaucoma in developed countries are undiagnosed
• In developing countries including Nepal, the proportion of undiagnosed cases is even higher

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2. Epidemiology in Nepal

Bhaktapur Glaucoma Study

• Design: Community-based, population-based cross-sectional study conducted in Bhaktapur district, Bagmati Province, Nepal
• Target population: Adults aged ≥40 years
• Key findings:
  • Prevalence of glaucoma: approximately 1.5-2% in the ≥40 age group
  • POAG was the most common type identified
  • A large proportion of cases were previously undiagnosed at the time of the survey, reflecting low awareness and poor access to eye care
  • Major risk factors identified: advanced age, elevated IOP, positive family history, myopia
  • Normal tension glaucoma was also identified as a significant subset
• Significance:
  • Established glaucoma prevalence data for urban Nepal
  • Highlighted the need for population-based screening programs
  • Demonstrated a significant unmet need for glaucoma diagnosis and management in the urban Nepali population

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Jiri Eye Study (Jiri Study)

• Design: Population-based cross-sectional survey conducted in Jiri, Dolakha district, Eastern Hilly Region of Nepal
• One of the first community-based comprehensive eye surveys in rural hilly Nepal
• Target population: Adults ≥30 years in the Jiri region
• Key findings:
  • Prevalence of glaucoma: approximately 0.5% in adults aged ≥30 years
  • POAG was the predominant subtype
  • The vast majority of glaucoma cases were undiagnosed prior to the study
  • Cataract was the leading cause of blindness; glaucoma ranked as a significant cause of irreversible visual impairment
  • Access to ophthalmology services was severely limited in this rural population
• Significance:
  • Provided the first epidemiological data on eye disease burden in rural hilly Nepal
  • Stark contrast to urban figures highlighted the urban-rural disparity in eye care access
  • Findings were used to guide national blindness prevention planning and resource allocation in Nepal
  • Contributed to development of community eye health outreach programs for remote hill populations

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RELEVANT ANATOMY AND PHYSIOLOGY

Anatomy of the Optic Nerve Head (ONH)

• The ONH (optic disc) is the site where approximately 1.2 million retinal ganglion cell (RGC) axons converge and exit the eye
• Vertical disc diameter: ~1.5 mm; horizontal diameter: ~1.8 mm
• Normally a vertically oval structure

• A fenestrated sieve-like collagen structure through which RGC axons exit the eye
• The primary site of mechanical injury in glaucoma
• Elevated IOP causes posterior bowing and compression of axons within the laminar pores
• Axoplasmic transport is blocked here → RGC apoptosis

• The neural tissue between the disc margin and the optic cup
• ISNT Rule (normal NRR thickness): Inferior > Superior > Nasal > Temporal
• Glaucoma preferentially damages the inferior and superior poles first (NRR notching)
• Normal cup-to-disc ratio (CDR): 0.3-0.4:1

• Prelaminar and laminar regions: Short posterior ciliary arteries (SPCAs) via the Circle of Zinn-Haller
• Surface nerve fibre layer: Branches of the central retinal artery (CRA)
• Retrolaminar region: SPCAs and pial arteries
• Watershed zones between arterial territories are susceptible to ischaemia → relevant in NTG

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Retinal Nerve Fibre Layer (RNFL)

• The RNFL is the innermost layer of the retina, formed by the unmyelinated axons of RGCs travelling to the ONH
• Axons travel in an arcuate pattern: superior axons arch over the macula to the superior disc pole; inferior axons arch below

• Follows the ISNT rule: Inferior (~130 µm) > Superior (~125 µm) > Nasal (~80 µm) > Temporal (~65 µm)
• Average peripapillary RNFL thickness: ~100 µm
• Thinnest at the temporal horizontal raphe

• RNFL loss is one of the earliest detectable structural changes in glaucoma
• Structural RNFL loss precedes detectable visual field loss by approximately 5-6 years
• Pattern of loss: superior and inferior arcuate bundles are most vulnerable
  • Superior RNFL loss → inferior arcuate/nasal step VF defect
  • Inferior RNFL loss → superior arcuate/nasal step VF defect
• RNFL wedge defects visible on red-free fundus photography as darker striated areas

• OCT (Optical Coherence Tomography): gold standard; quantifies RNFL thickness map; detects loss before VF change
• Red-free fundus photography: can show RNFL wedge defects
• GCC (Ganglion Cell Complex) analysis by OCT: includes RNFL + ganglion cell layer + inner plexiform layer; sensitive for macular damage

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Trabecular Meshwork (TM)

• Located in the angle of the anterior chamber, at the junction of peripheral cornea, scleral spur and iris root
• Spans from Schwalbe's line anteriorly to the scleral spur posteriorly

1. Uveal meshwork (innermost)
   • Cord-like trabeculae with large irregular spaces
   • Lowest resistance to outflow
   • Extends from iris root to Schwalbe's line
2. Corneoscleral meshwork
   • Thin perforated sheets with smaller, more regular pores
   • Intermediate resistance
3. Juxtacanalicular tissue (JCT) (outermost, adjacent to Schlemm's canal)
   • Loose connective tissue with extracellular matrix
   • Site of greatest resistance to aqueous outflow (~75% of total resistance)
   • Primary site of pathological changes in POAG
   • ECM accumulation here → increased outflow resistance → elevated IOP

• MYOC gene product (myocilin) is expressed in TM; mutations → protein misfolding → increased outflow resistance → POAG
• Steroids increase ECM deposition in JCT → steroid-induced glaucoma
• Laser trabeculoplasty (ALT/SLT): targets TM to improve outflow facility
• Trabecular bypass MIGS (e.g. iStent, Hydrus): bypasses TM resistance

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Schlemm's Canal

• A circumferential, endothelium-lined channel located at the corneoscleral junction, just external to the JCT
• Oval cross-section; inner wall lines the JCT; outer wall contains openings of collector channels
• Length: ~36 mm circumference of the limbus

• Specialised cells with giant vacuoles (pore-like transcellular channels)
• These vacuoles facilitate aqueous passage from TM into the canal lumen
• Inner wall offers minimal resistance compared to JCT

Schlemm's canal → 25-35 collector channels → aqueous veins → episcleral veins → systemic venous circulation

• Normal: ~8-10 mmHg
• Sets the minimum achievable IOP by outflow-enhancing treatments alone
• Elevated in conditions such as carotid-cavernous fistula, superior vena cava obstruction → raises IOP

Po = F/C + Pv

• Po = IOP; F = aqueous production rate; C = outflow facility; Pv = episcleral venous pressure

• Canaloplasty / viscocanalostomy: dilate and scaffold Schlemm's canal to restore outflow
• iStent / Hydrus MIGS: bypass JCT and directly access Schlemm's canal
• Collapse or fibrosis of Schlemm's canal is seen in some glaucoma subtypes

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Aqueous Humour: Production, Outflow and Drainage

Production

• Secreted by the non-pigmented epithelium of the ciliary body (pars plana/pars plicata)
• Rate: 2-2.5 µL/min
• Three mechanisms:
  1. Active secretion (~70%): Na-K-ATPase and carbonic anhydrase drive ion transport → water follows osmotically - PRIMARY mechanism
  2. Ultrafiltration (~20%): hydrostatic pressure drives plasma filtration across ciliary epithelium
  3. Diffusion (~10%): lipid-soluble substances diffuse passively
• Aqueous production decreases with sleep (circadian variation); IOP is lowest in the morning for most patients on standing

Outflow Pathways

Posterior chamber → Pupil → Anterior chamber → Trabecular meshwork (JCT) → Schlemm's canal → Collector channels → Aqueous veins → Episcleral veins → Systemic circulation

• Pressure-dependent: flow increases as IOP rises
• Site of pathological resistance in glaucoma: mainly at JCT

Anterior chamber → Ciliary muscle interspaces → Supraciliary/suprachoroidal space → Choroidal vessels → Vortex veins

• Largely independent of IOP
• Enhanced by: prostaglandin analogues (most effective class of IOP-lowering drops), cyclopentolate
• Reduces with age

Three Key Determinants of IOP

1. Rate of aqueous humour production by the ciliary body
2. Resistance to aqueous outflow at the angle of the anterior chamber (primarily TM/JCT)
3. Level of episcleral venous pressure (~8-10 mmHg)

Note: In glaucoma, elevated IOP is almost always due to increased resistance to outflow, NOT increased production

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PATHOPHYSIOLOGY OF GLAUCOMA

Two Main Theories

1. Mechanical Theory

• Elevated IOP → posterior bowing of the lamina cribrosa
• Compression and distortion of RGC axons within laminar pores
• Blockade of axoplasmic transport (both anterograde and retrograde) at the lamina
• Retrograde block: deprivation of neurotrophic factors (especially BDNF - brain-derived neurotrophic factor) from the lateral geniculate nucleus
• Anterograde block: failure of mitochondria and organelle delivery to axon terminals
• Result: progressive RGC apoptosis → RNFL thinning → visual field loss

2. Vascular Theory

• Reduced ocular perfusion pressure (OPP = mean arterial pressure - IOP)
• Ischaemia of the optic nerve axons at the watershed zones of the ONH
• Explains normal-tension glaucoma (NTG): progressive RGC death despite IOP within the "normal" range
• Risk factors supporting vascular theory: migraine, vasospasm, nocturnal hypotension, cardiovascular disease

In most cases, both mechanisms act together - IOP-independent vascular factors and IOP-dependent mechanical factors synergistically damage the optic nerve

Key Pathophysiological Steps

↑ IOP (or vascular insufficiency)
        ↓
Mechanical stress at lamina cribrosa / Ischaemia of ONH
        ↓
Axoplasmic transport failure at lamina cribrosa
        ↓
Deprivation of BDNF and other neurotrophins
        ↓
Activation of intrinsic apoptotic pathway in RGCs
        ↓
Progressive RGC death and axonal loss
        ↓
RNFL thinning (detectable on OCT)
        ↓
Optic nerve head changes (NRR notching, CDR enlargement)
        ↓
Visual field defects (arcuate scotoma, nasal step)
        ↓
End-stage: tunnel vision → blindness

Molecular/Genetic Mechanisms

Why IOP Lowering Doesn't Always Work

• In some patients, progressive optic nerve damage continues despite achieving target IOP
• Reasons:
  • Vascular/ischaemic component continues independently of IOP
  • Established axonal damage is irreversible; ongoing atrophy can continue
  • Patients may have a genetically lower threshold for IOP-induced damage
  • Mitochondrial dysfunction and oxidative stress may persist
• This is why target IOP must be individualised and continuously reassessed

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CLASSIFICATION OF GLAUCOMA

A. Open Angle Glaucoma

1. Primary Open Angle Glaucoma (POAG)

• Anterior chamber angle is open and appears normal on gonioscopy
• Progressive optic neuropathy with characteristic ONH changes and VF loss
• Two subtypes:
  • High tension glaucoma: IOP consistently >21 mmHg
  • Normal tension glaucoma (NTG): IOP within normal range (<21 mmHg) but progressive optic nerve damage occurs

2. Secondary Open Angle Glaucoma

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B. Angle Closure Glaucoma

1. Primary Angle Closure Disease (PACD) - Natural History Spectrum:

Primary Angle Closure Suspect (PACS)
          ↓
Primary Angle Closure (PAC)  [drainage angle closed but no optic nerve damage]
          ↓
Primary Angle Closure Glaucoma (PACG)  [optic nerve damage present]

Anterior Segment Mechanisms of Closure:

2. Secondary Angle Closure Glaucoma

• Neovascular glaucoma (NVG) - rubeosis iridis
• Iridocorneal Endothelial (ICE) syndrome (Chandler's, Cogan-Reese, essential iris atrophy)
• Posterior polymorphous corneal dystrophy
• Epithelial downgrowth / fibrous ingrowth
• Flat anterior chamber (post-surgical)
• Inflammatory glaucoma (posterior synechiae → iris bombé)
• Penetrating keratoplasty
• Aniridia

• Malignant glaucoma (ciliary block / aqueous misdirection)
• Cysts of iris and ciliary body
• Intraocular tumours
• Suprachoroidal haemorrhage
• PRP (pan-retinal photocoagulation) with choroidal effusion
• Intravitreal gas/silicone oil

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C. Developmental Glaucoma

1. Primary Congenital (Infantile) Glaucoma

• Isolated trabeculodysgenesis; no systemic associations
• Presents at birth to 3 years
• Classical triad: Epiphora + Photophobia + Blepharospasm
• Signs: buphthalmos, corneal enlargement (>12mm), Haab's striae (breaks in Descemet's membrane), cloudy cornea
• Treatment: primarily surgical - goniotomy or trabeculotomy

2. Glaucoma Associated with Systemic Abnormalities

• Axenfeld-Rieger syndrome
• Sturge-Weber syndrome (port-wine stain + buphthalmos)
• Marfan syndrome, Weill-Marchesani syndrome
• Down's syndrome (trisomy 21)
• Neurofibromatosis type 1

3. Glaucoma Associated with Ocular Abnormalities

• Aniridia (PAX6 mutation)
• Peters anomaly
• Nanophthalmos

4. Secondary Developmental Glaucoma

• Traumatic glaucoma
• Glaucoma with intraocular neoplasm (retinoblastoma)
• Uveitic glaucoma
• Lens-induced glaucoma
• Post congenital cataract surgery
• Steroid-induced
• Secondary angle closure glaucoma

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RISK FACTORS FOR GLAUCOMA

Strong / Well-Established Risk Factors

1. Elevated Intraocular Pressure (IOP)

• Most important modifiable risk factor
• Risk of glaucoma increases with IOP level; for every 1 mmHg rise in IOP, risk of POAG increases by ~10%
• However, ~30-40% of POAG cases have IOP within the normal range (NTG)
• The Ocular Hypertension Treatment Study (OHTS): lowering IOP by 22.5% reduced conversion from OHT to POAG by 60%

2. Advancing Age

• Prevalence of POAG increases dramatically with age
• 3-8 times higher prevalence in individuals >70 years compared to those aged 40-50
• Ageing → reduced TM cellularity, increased TM resistance, decreased optic nerve resilience

3. Race / Ethnicity

• African/Black populations: 3-4x higher prevalence of POAG; 4x higher rate of blindness; younger age of onset; more aggressive course
• East Asians: Higher risk of PACG
• Hispanic/Latino populations: Higher POAG risk than whites; often present with more advanced disease
• Inuit/Eskimo: Very high risk of PACG

4. Positive Family History

• First-degree relative with glaucoma: relative risk increased 3.7-fold (sibling > parent > child in terms of risk correlation)
• Strong familial aggregation, particularly for POAG and congenital glaucoma

5. Thin Central Corneal Thickness (CCT)

• CCT <555 µm is an independent risk factor for conversion of OHT to POAG
• Thin cornea gives falsely low IOP on Goldmann applanation
• The OHTS showed thin CCT (<555 µm) was the strongest predictive factor for POAG development
• Proposed mechanism: thin CCT may reflect overall connective tissue weakness at the lamina cribrosa

6. Myopia

• High myopia (>6 D) associated with increased POAG risk
• Myopic discs have structurally weaker laminae cribrosa; tilted discs make cup assessment difficult
• Thin peripapillary sclera may transmit IOP effects more readily

7. Optic Disc Parameters

• Large optic disc area: larger discs have larger cups physiologically but also more susceptibility
• Increased vertical CDR (>0.5): suspicious; asymmetry >0.2 between eyes is significant
• Disc haemorrhage (Drance haemorrhage): splinter haemorrhage at disc margin; strongly predictive of progression, especially in NTG
• Asymmetric cupping

8. Ocular Perfusion Pressure (OPP)

• Low OPP = low mean arterial pressure - IOP
• Low OPP is an independent risk factor, particularly for NTG
• Nocturnal hypotension (blood pressure dips during sleep) may be critical in NTG patients

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Less Convincing / Possible Risk Factors

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Risk Factors Specific to Angle Closure Glaucoma

• Hypermetropia (hyperopia): small eye, shallow AC, short axial length, thick lens
• Shallow anterior chamber depth (Van Herick grade 1-2)
• Female sex: smaller eyes, shallower AC
• Age: lens thickens and moves anteriorly with age → relative pupillary block increases
• Asian ethnicity
• Family history of ACG
• Medications precipitating ACG:
  • Dilating drops (tropicamide, phenylephrine)
  • Anticholinergics (antihistamines, antidepressants, antipsychotics)
  • Sympathomimetics (nebulised salbutamol, decongestants)
  • Topiramate (causes ciliary body oedema → forward rotation → angle closure)

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CLINICAL FEATURES OF GLAUCOMA

A. Symptoms

POAG (Primary Open Angle Glaucoma)

• Largely asymptomatic until late in the disease (the "silent thief of sight")
• Peripheral vision loss begins insidiously; central vision preserved until advanced disease
• Patient may present only when:
  • Both eyes affected and central vision involved
  • Detected incidentally on routine eye examination
  • Advanced field loss causes difficulty with mobility, driving
• No pain, no redness, no visual disturbance in early-moderate stages

Acute Primary Angle Closure Glaucoma (PACG)

• Severe, intense unilateral eye pain
• Headache (may be severe, frontal)
• Nausea and vomiting (vagal response to pain; can mislead clinician to suspect GI cause)
• Coloured halos around lights (corneal oedema causes diffraction)
• Sudden blurring of vision
• Red eye (ciliary flush)
• Precipitated by: dim lighting (mydriasis), emotional stress, anticholinergic drugs, prolonged reading

Subacute/Intermittent Angle Closure

• Transient episodes of the above symptoms, resolving spontaneously
• Patient may describe recurring blurred vision and haloes in the evening

Normal Tension Glaucoma (NTG)

• Asymptomatic (like POAG); IOP never noted to be elevated
• Often detected late due to no IOP alarm

Secondary Glaucomas

• Variable; symptomatic if IOP rises rapidly (≥35 mmHg)
• Neovascular glaucoma: painful, red eye with poor vision
• Phacolytic: red eye, very white/mature cataract visible

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B. Signs

Intraocular Pressure

• Normal: 10-21 mmHg (mean 15.5 ± 2.5 mmHg)
• Diurnal variation: highest in morning, lowest at night (in most patients)
• In POAG: elevated (>21 mmHg) or normal (NTG)
• In acute PACG: markedly elevated (40-70+ mmHg)

Conjunctival Signs

• Episcleral congestion (dilated episcleral vessels)
• Ciliary flush (pericorneal injection - violet/red ring) in acute IOP elevation

Corneal Signs

• Corneal oedema: epithelial and stromal; occurs in acute IOP elevation; gives steamy/hazy appearance
• Krukenberg spindle: vertical spindle of pigment on corneal endothelium in pigment dispersion syndrome
• Keratic precipitates (KPs): in inflammatory (uveitic) glaucoma
• Haab's striae: horizontal breaks in Descemet's membrane in congenital glaucoma (cornea enlarged >12 mm)

Anterior Chamber

• Depth: assessed by Van Herick technique (slit lamp)
  • Grade 4: AC depth ≥ corneal thickness → wide open angle (unlikely closure)
  • Grade 3: AC depth = ¼-½ corneal thickness → mild narrow
  • Grade 2: AC depth = ¼ corneal thickness → moderate narrow; closure possible
  • Grade 1: AC depth < ¼ corneal thickness → very narrow; closure likely
• Aqueous flare and cells: in acute PACG and uveitic glaucoma (breakdown of blood-aqueous barrier)
• Hyphaema: in haemorrhagic glaucoma, trauma
• Lens proteins in AC: phacolytic glaucoma

Iris Signs

Pupillary Signs

• Mid-dilated, vertically oval, fixed pupil: post-acute PACG attack (ischaemic damage to iris sphincter)
• RAPD (Relative Afferent Pupillary Defect): indicates significant asymmetric optic nerve damage
• Sluggish light reflex: in advanced glaucoma

Lens Signs

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C. Optic Nerve Head (Disc) Changes in Glaucoma

Generalised Signs:

1. Large optic cup (CDR >0.5): especially in vertical axis
2. Asymmetry of cups (>0.2 difference) between two eyes
3. Progressive enlargement of the cup on serial examination

Focal Signs (more specific):

1. Narrowing or notching of the NRR - most often inferiorly then superiorly (ISNT rule violation)
2. Vertical elongation of the cup (vertical CDR > horizontal CDR)
3. Cupping of the rim margin (disc tissue disappears to disc edge)
4. Regional pallor of NRR
5. Disc haemorrhage (Drance haemorrhage): splinter-shaped haemorrhage at disc margin; strongly associated with progression

Less Specific Signs:

1. Nasal displacement of vessels emerging from disc
2. Baring of circumlinear vessels: vessel running from superior/inferior disc loses its overlying NRR tissue; vessel appears to "float" above the disc
3. Bayoneting sign: double angulation of vessel at disc margin - vessel enters horizontally, then angles back into the cup, then resumes original direction across the lamina cribrosa
4. Laminar dot sign: exposure of the porous lamina cribrosa (grey sieve-like dots) due to NRR loss
5. Peripapillary atrophy (PPA):
   • Alpha zone (outer): irregular pigmentation at RPE level; common in normal eyes
   • Beta zone (inner): chorioretinal atrophy with visible sclera and choroidal vessels; closely associated with glaucoma; larger beta zone = higher risk of progression

RNFL Changes:

• Wedge-shaped RNFL defects on red-free photography
• OCT RNFL: thinning (especially at 6 o'clock and 12 o'clock on peripapillary scan)
• "Double hump" pattern on RNFL thickness map is normal; loss of inferior/superior hump = early glaucoma

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D. Visual Field Defects in Glaucoma

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DIAGNOSIS AND PRINCIPLES OF MANAGEMENT

A. Diagnosis

Diagnostic Criteria

1. Characteristic optic nerve head changes (described above)
2. Visual field defects consistent with glaucomatous nerve fibre bundle damage
3. Elevated IOP (>21 mmHg)

In acute/subacute PACG and secondary glaucoma: presence of raised IOP with typical clinical features is sufficient

Optic nerve head changes are thought to precede visual field loss - structural damage before functional loss

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Comprehensive Ocular Examination

• Myopia: risk factor for POAG; myopic discs harder to assess
• Hypermetropia: risk factor for PACG (short axial length, shallow AC)

• Cornea, AC depth, iris, lens (as above in Clinical Features)

• Measured by pachymetry (ultrasound or optical)
• Normal: ~540-560 µm
• Thin CCT (<520 µm): falsely low IOP reading AND independent risk factor for glaucoma
• Thick CCT (>600 µm): falsely high IOP reading
• Correction of IOP for CCT is important for accurate risk assessment

• Gold standard for assessing anterior chamber angle
• Determines whether angle is open, narrow, or closed
• Identifies cause of secondary glaucoma (PAS, pigment, NV, exfoliation material)

• Goldmann Applanation Tonometry (GAT): gold standard
• Also: non-contact tonometry (NCT/air puff), Perkins, iCare rebound tonometry
• Always consider CCT when interpreting IOP
• Diurnal curve (IOP measured at multiple time points) useful if normal reading but high clinical suspicion

• Direct ophthalmoscopy: quick screening
• Indirect ophthalmoscopy with 78D/90D lens (slit lamp): superior stereoscopic view
• Stereo disc photography: gold standard for documenting and comparing disc over time
• Key parameters to assess: CDR (vertical and horizontal), NRR (ISNT rule), disc haemorrhages, PPA, vessel signs, RNFL

• Automated static threshold perimetry (Humphrey VFA):
  • SITA Standard or SITA Fast programs (24-2 most used; 10-2 for macular/advanced)
  • Reliability indices: fixation losses <20%, false positives <15%, false negatives <33%
  • Pattern deviation plot more useful than total deviation for identifying early defects
• Goldmann kinetic perimetry: for very advanced disease or unreliable patients
• To confirm VF defect: must be reproducible on ≥2 reliable fields

• Peripapillary RNFL thickness map: detects structural loss 5-6 years before VF change
• ONH parameters: CDR, NRR area, disc area
• Macular GCC (Ganglion Cell Complex): RNFL + GCL + IPL; sensitive for central field/early damage
• Useful for monitoring progression: serial OCT over time

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B. Principles of Management

Overall Goals:

1. Preserve visual function and quality of life
2. Prevent further optic nerve damage and VF loss
3. Minimise treatment burden and side effects
4. IOP lowering is the only proven treatment to halt progression

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Target IOP

• Pre-treatment IOP
• Degree of existing optic nerve damage and VF loss
• Rate of progression
• Life expectancy (younger patient = more aggressive target)
• Presence of vasculopathy (diabetes, ASCVD → lower target)
• Patient adherence capacity and treatment tolerance

Target IOP is continuously reassessed and reset based on clinical course

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Step 1 - Medical Management (First Line)

• Latanoprost, bimatoprost, travoprost, tafluprost
• Mechanism: ↑ uveoscleral (pressure-independent) outflow
• IOP reduction: 25-35%
• Once daily (evening); minimal systemic side effects
• Local side effects: conjunctival hyperaemia, iris/periorbital pigmentation, hypertrichosis, deepening of upper lid sulcus

• Timolol 0.5%, betaxolol, levobunolol
• Mechanism: ↓ aqueous production
• IOP reduction: 20-30%
• Contraindicated in asthma, COPD, heart block, bradycardia
• Betaxolol (cardioselective) - safer in mild asthma; may have neuroprotective benefit

• Topical: dorzolamide, brinzolamide
• Oral: acetazolamide (250 mg QID or 500 mg SR BD) - for acute situations
• Mechanism: ↓ aqueous production (inhibits CA-II in ciliary body)
• Oral acetazolamide: reserved for acute PACG or short-term; side effects - paraesthesia, fatigue, renal stones, Stevens-Johnson syndrome (rare)

• Brimonidine 0.1-0.2%
• Mechanism: ↓ aqueous production + ↑ uveoscleral outflow; also may be neuroprotective
• Contraindicated in children (apnoea risk), MAO inhibitor use
• Side effects: allergic conjunctivitis, dry mouth, fatigue

• Pilocarpine 1-4%
• Mechanism: ciliary muscle contraction → opens TM → ↑ conventional outflow
• Main role: PACG (narrows pupil → breaks pupillary block)
• Side effects: brow ache, myopia (ciliary spasm), visual obscuration (dim light)

• Netarsudil (Rhopressa)
• Mechanism: ↑ TM/conventional outflow; ↓ episcleral venous pressure
• Once daily; useful in NTG (uniquely lowers episcleral venous pressure)

• Dorzolamide/timolol (Cosopt)
• Brimonidine/timolol
• Bimatoprost/timolol (Ganfort)
• Improve adherence; reduce preservative exposure

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Step 2 - Laser Treatment

• Selective Laser Trabeculoplasty (SLT): Q-switched Nd:YAG laser; selectively targets pigmented TM cells; repeatable; LiGHT trial (2019) showed SLT as effective as drops as first-line treatment
• Argon Laser Trabeculoplasty (ALT): older; non-selective; causes scarring; not repeatable
• Indication: adjunct to or instead of drops in POAG/OHT
• IOP reduction: 20-30%

• Nd:YAG laser creates a hole in peripheral iris
• Indication: PACS, PAC, PACG - eliminates relative pupillary block
• Prophylactic LPI in fellow eye after acute PACG attack
• Also in narrow angles before pupil dilation

• Burns peripheral iris → contraction → opens angle
• Used in plateau iris syndrome; as temporising measure in acute PACG when LPI not possible

• Diode laser to ciliary body → ↓ aqueous production
• Transscleral CPC or endoscopic CPC
• Used in refractory/end-stage glaucoma or when surgery not possible

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Step 3 - Surgical Management

• Gold standard surgical procedure for glaucoma
• Creates a fistula from AC through sclera under a partial-thickness scleral flap → subconjunctival bleb → aqueous drains and is absorbed by conjunctival vessels
• Antimetabolites used to prevent scarring: Mitomycin C (MMC) or 5-Fluorouracil (5-FU)
• IOP reduction: 40-50%
• Complications: bleb failure/fibrosis, hypotony, bleb-related infection (blebitis/endophthalmitis), cataract progression, flat AC

• Silicone tube from AC to an episcleral plate; drains aqueous to a reservoir
• Types: Baerveldt, Ahmed, Molteno
• Tube vs Trabeculectomy (TVT) study: tubes non-inferior to trabeculectomy at 5 years; tubes preferred in high-failure-risk eyes (prior surgery, uveitis, NVG)

• Lower IOP reduction than trabeculectomy but superior safety profile
• Performed at time of cataract surgery typically

1. Immediate IOP lowering: IV acetazolamide 500 mg stat; IV mannitol 1-2 g/kg
2. Topical: timolol, pilocarpine 4%, apraclonidine/brimonidine, steroid drops
3. Pilocarpine 4% to affected eye; 1% to fellow eye (prophylaxis)
4. Definitive: Nd:YAG LPI once cornea clears; fellow eye prophylactic LPI
5. If medical treatment fails: lens extraction (phacoemulsification) or goniosynechialysis

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Step 4 - Monitoring and Follow-Up

• IOP (consider diurnal variation, CCT)
• ONH: stereo disc photography comparison; look for new haemorrhages, NRR notching
• Visual fields: every 6-12 months minimum; more frequently if progressing
• OCT RNFL: annually or more frequently; compare to baseline
• Adherence to medications
• Side effects of treatment

• Structural: new ONH changes, worsening CDR, RNFL thinning on OCT
• Functional: reproducible VF deterioration (2-3 reliable fields showing same defect)
• Rate of progression (MD slope): if losing >1 dB/year = significant progression; adjust target IOP down

• Evidence of structural progression on OCT
• Reproducible VF progression
• Disc haemorrhage (early sign of instability)
• Young patient with advanced damage (long life expectancy at risk)
• Low blood pressure / vasculopathy

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Management of Special Situations

• Treat if progression is documented
• Target: 20-30% reduction from baseline (NTGS)
• Brimonidine preferred (neuroprotective properties, lowers OPP via reducing episcleral venous pressure)
• Address vascular risk factors: nocturnal hypotension, migraine, vasospasm, OSA
• Calcium channel blockers may help in vasospastic NTG

• Discontinue steroids if possible (switch to lower-potency: fluorometholone, loteprednol, rimexolone)
• Medical IOP lowering
• Usually resolves after steroid withdrawal; rarely surgical intervention needed

1. Treat underlying ischaemic condition (anti-VEGF injection: bevacizumab/ranibizumab → causes rubeosis regression within days)
2. Pan-retinal photocoagulation (PRP) for ischaemic retinopathy
3. IOP lowering: medical + tube shunt surgery (trabeculectomy tends to fail due to NV)

• Primarily surgical: goniotomy (if cornea clear) or trabeculotomy (if cornea hazy)
• Medical treatment is temporising only
• Amblyopia treatment essential after IOP control

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References (as per original slide)

• Diagnosis and Therapy of the Glaucomas - Becker-Shaffer's, 8th edition
• Ophthalmology - Yanoff & Duker, 6th edition
• Glaucoma - AAOO, 2025-26
• Clinical Ophthalmology - Kanski, 10th edition

1. A brand name used in Nepal/South Asia that I don't have in my training data
2. A spelling variant - could you double-check the spelling?
3. A transliteration from Nepali/another language

• Is it a systemic drug (tablet/capsule) or eye drop?
• Do you know its drug class (antihistamine, antidepressant, antihypertensive, etc.)?
• Or the generic name?

• Anticholinergics (atropine, hyoscine, tricyclic antidepressants)
• Antihistamines (chlorphenamine, promethazine)
• Sympathomimetics (pseudoephedrine, phenylephrine)
• Antipsychotics (chlorpromazine, clozapine)
• Topiramate (causes ciliary body oedema → angle closure)

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Why V. Rohto is Contraindicated in Glaucoma

What is in V. Rohto?

Naphazoline Hydrochloride (0.012-0.03%)

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The Mechanism of Contraindication

1. Alpha-adrenergic Stimulation → Mydriasis (Pupil Dilation)

• Stimulates alpha-1 receptors on the iris dilator muscle
• Causes mydriasis (pupil dilation) - even mild dilation

Naphazoline → α1 stimulation → iris dilator contracts → pupil dilates
                                        ↓
              Pupil moves to mid-dilation position
                                        ↓
              Iris becomes maximally thick at its root
                                        ↓
              Peripheral iris crowds the trabecular meshwork
                                        ↓
              Angle narrows/closes → aqueous outflow blocked
                                        ↓
              Acute rise in IOP → ACUTE ANGLE CLOSURE ATTACK

2. Why Mid-Dilation is the Danger Zone

• The iris is at its maximum thickness
• Maximum iris-lens contact → greatest relative pupillary block
• Maximum peripheral iris crowding of the angle
• This is why dim lighting, emotional stress, and mydriatic drugs all precipitate acute PACG

3. Vasoconstriction of Episcleral Vessels

• Naphazoline causes vasoconstriction (that is how it "whitens" the eye)
• It constricts episcleral veins → reduces episcleral venous drainage
• Can marginally increase episcleral venous pressure → raises baseline IOP via Goldmann equation (Po = F/C + Pv)

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Which Type of Glaucoma is Most at Risk?

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Why It Is Still Sold OTC

• The package insert warns: "Do not use if you have glaucoma"
• Ophthalmologists always warn patients with narrow angles or PACG to avoid all decongestant/whitening eye drops
• Any patient with a shallow anterior chamber (Van Herick grade 1-2) should be warned

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Summary