Glaucoma: Basic to Clinics

1. Definition and Epidemiology

• Affects 2-3% of people over age 40; up to 50% may be undiagnosed
• Second leading cause of blindness worldwide
• Primary open-angle glaucoma (POAG) is the most common form in White, Hispanic/Latino, and African populations
• Risk factors: elevated IOP, older age, African ancestry, positive family history, myopia, low blood pressure, disc hemorrhages, thin central corneal thickness (CCT)

2. Aqueous Humor Dynamics - The Core Pathophysiology

1. Trabecular (conventional) pathway (~70-90%): through the trabecular meshwork → Schlemm's canal → episcleral veins. This is the pressure-sensitive pathway.
2. Uveoscleral (unconventional) pathway (~10-30%): across the ciliary body face into the supraciliary and suprachoroidal spaces

3. Classification

GLAUCOMA
├── PRIMARY
│   ├── Primary Open-Angle Glaucoma (POAG) — most common
│   ├── Primary Angle-Closure Glaucoma (PACG)
│   └── Normal-Tension Glaucoma (NTG)
├── SECONDARY
│   ├── Secondary Open-Angle (pseudoexfoliation, pigmentary, steroid-induced,
│   │   neovascular after retinal ischemia, traumatic)
│   └── Secondary Angle-Closure (neovascular, inflammatory, phacomorphic,
│       phacolytic, malignant glaucoma)
└── CONGENITAL / DEVELOPMENTAL
    ├── Primary congenital (buphthalmos)
    └── Associated (Sturge-Weber, NF1, aniridia)

4. Pathogenesis of Optic Nerve Damage

1. Direct mechanical damage - elevated IOP compresses axons passing through the lamina cribrosa, causing physical deformation of the laminar plates and impeding axoplasmic flow
2. Ischemic damage - compression of blood vessels supplying the optic nerve head reduces perfusion (ocular perfusion pressure = mean arterial pressure - IOP)

• Retinal ganglion cell (RGC) death occurs via apoptosis (programmed cell death), not necrosis
• The triggering event involves calcium ion influx into the cell body and increased intracellular nitric oxide
• Glutamine metabolism is intrinsically involved
• A secondary cascade follows: astrocyte and glial cell proliferation, extracellular matrix alterations at the lamina cribrosa, and optic nerve head remodelling
• Loss of axons leads to enlargement of the optic cup - recorded clinically as an increased cup-to-disc (C:D) ratio

5. Primary Open-Angle Glaucoma (POAG)

Clinical features

• Asymptomatic until late - peripheral visual fields may be reduced considerably before the patient notes any functional loss
• First symptoms: difficulty reading, reduced contrast sensitivity, or glare
• Most cases detected during routine eye examination - elevated IOP or high C:D ratio

Diagnosis requires all of:

• Elevated IOP (or progressive nerve damage despite normal IOP in NTG)
• Characteristic optic disc changes (see below)
• Visual field defects on automated perimetry
• Open angle on gonioscopy

Optic disc changes in glaucoma

• Disc haemorrhages (splinter haemorrhages extending from the NRR onto the retina, most commonly inferotemporally) - these are a risk factor for progression
• RNFL defects (wedge-shaped defects on red-free photography) - these precede optic disc and visual field changes

Visual field defects (automated perimetry)

• Test area most commonly used: 24-2 or 30-2 pattern (30° radius from fixation)
• 10-2 for central field monitoring in advanced disease
• Classic patterns: nasal step, arcuate (Bjerrum) scotoma, paracentral scotoma, and ultimately tunnel vision

Genetics

• Mutations in MYOCILIN (MYOC) - most common, accounts for ~4% of POAG
• Other genes: OPTN (optineurin), NTF4, WDR36
• If a single family member develops glaucoma before age 35, the chances of a MYOC mutation may be as high as 33%
• Polygenic risk scores (PRS) are now being developed to predict susceptibility

6. Primary Angle-Closure Glaucoma (PACG)

Mechanism (pupillary block)

• Hyperopia - shortened anterior-posterior axis, shallow anterior chamber
• As the crystalline lens enlarges with age, the iris is displaced anteriorly
• Posterior iris surface comes in tight contact with the anterior lens surface
• Aqueous accumulates in the posterior chamber → iris bombé (forward bowing of peripheral iris)
• Peripheral iris occludes the trabecular meshwork → sudden IOP rise

Acute angle-closure attack

• Severe eye pain (may radiate and be poorly localized), headache, nausea/vomiting (can mimic acute abdomen)
• Blurred vision with halos around lights
• Red eye with mid-dilated, non-reactive pupil, corneal oedema (cloudy cornea), shallow anterior chamber

1. Topical IOP-lowering drops: beta-blocker (timolol 0.5%), alpha-agonist (apraclonidine), pilocarpine
2. Systemic: acetazolamide 250-500 mg IV (or oral if IV unavailable)
3. Hyperosmotic agents (mannitol IV) in severe cases
4. Laser peripheral iridotomy (LPI) - definitive treatment; creates a fistula bypassing pupillary block
5. Prophylactic LPI to the fellow eye (high risk of attack)
6. Lens extraction is an additional option (age-related lens growth contributes to angle closure)

7. Normal-Tension Glaucoma (NTG)

• Progressive glaucomatous optic neuropathy with IOP consistently ≤21 mmHg
• Mechanism: vascular insufficiency, increased susceptibility of the optic nerve to ischemia, autoimmune processes
• More common in Japanese patients and in women
• Associated with vasospastic conditions (Raynaud's, migraine), systemic hypotension
• Management: IOP reduction (prostaglandins preferred) and addressing vascular risk factors

8. Secondary Glaucomas

Pseudoexfoliation Glaucoma

• Most common form of secondary open-angle glaucoma globally
• Fibrillin gene mutation → abnormal fibrillogranular material deposits on the lens capsule, iris, trabecular meshwork
• Especially prominent in Scandinavians and Arabs
• Higher IOP spikes, more difficult to control
• Treatment as for POAG but often requires surgery sooner

Pigmentary Glaucoma

• Pigment granules from the iris pigment epithelium deposit in the trabecular meshwork
• Young myopic males; Krukenberg spindle on corneal endothelium
• Scheie line on trabecular meshwork; iris transillumination defects

Neovascular Glaucoma

• New vessels (driven by VEGF upregulation from chronic retinal ischemia, e.g., PDR, CRVO) grow over the iris surface and angle
• Myofibroblasts in the neovascular membrane contract, creating peripheral anterior synechiae (PAS), obliterating the angle
• Causes: diabetic retinopathy, central retinal vein occlusion, ocular ischemic syndrome
• Very difficult to manage; anti-VEGF injections + aggressive IOP lowering

Steroid-Induced Glaucoma

• Secondary open-angle glaucoma from topical, periocular, inhaled, or systemic glucocorticoids
• Without a family history of glaucoma: ~5% of normal individuals show marked IOP rise
• With a positive family history: up to 90% may develop moderate-to-marked IOP elevation
• Risk is reduced but not eliminated with loteprednol (a soft steroid)

9. Gonioscopy and Angle Assessment

10. Investigations

11. Medical Treatment

Drug Classes and Mechanisms

Recent evidence (2025): A network meta-analysis (PMID 40701331, Ophthalmology 2025) found prostaglandin analogues remain the most effective single agents, with combination therapy providing additive reduction.

12. Laser Treatment

Selective Laser Trabeculoplasty (SLT)

• Uses 532 nm Nd:YAG laser, selectively targets pigmented trabecular meshwork cells
• Increases trabecular outflow via macrophage and cytokine-mediated remodelling
• Can be considered first-line therapy - repeatable, no medication side effects
• Recent meta-analysis (PMID 39018052, J Glaucoma 2024) confirms SLT is equivalent to medical therapy in reducing IOP at 36 months

Argon Laser Trabeculoplasty (ALT)

• Older technique; creates thermal burns on trabecular meshwork; limited repeatability

Laser Peripheral Iridotomy (LPI)

• Nd:YAG laser creates a hole in peripheral iris
• Definitive treatment for angle-closure; prophylactic in the fellow eye

Diode Laser Cyclodestruction (cycloablation)

• Reduces aqueous production by ablating ciliary body
• Reserved for refractory glaucoma or eyes with poor visual potential

13. Surgical Treatment

Trabeculectomy

• Gold standard filtering surgery
• Creates a fistula (bleb) from anterior chamber to subconjunctival space
• Augmented with mitomycin C (MMC) or 5-fluorouracil (5-FU) to reduce bleb scarring
• Complications: hypotony, bleb leak, endophthalmitis, cataract

Glaucoma Drainage Devices (Tube-Shunts)

• Ahmed, Baerveldt, Molteno implants
• Tube drains aqueous to an equatorial reservoir
• Used in failed trabeculectomy, neovascular glaucoma, uveitic glaucoma
• A 2025 meta-analysis (PMID 39394492) found the PreserFlo MicroShunt has comparable IOP reduction to trabeculectomy with fewer early hypotony complications

Minimally Invasive Glaucoma Surgery (MIGS)

• iStent, Hydrus, KDB goniotomy, OMNI, XEN gel stent
• Lower risk profile; suitable for mild-to-moderate glaucoma combined with cataract surgery
• Less IOP reduction than trabeculectomy but better safety

14. Monitoring and Progression

• Baseline IOP, extent of damage, age, life expectancy
• A 20-30% reduction from baseline is typically the starting target
• May need to be lowered further if progression continues

• Visual field: Event-based (comparing to baseline) or trend-based analysis
• RNFL OCT: Objective, detects change before field loss
• Disc photography: Document structural changes

15. Special Situations

Congenital/Developmental Glaucoma

• Primary congenital: Trabeculodysgenesis; presents at birth or within first year; buphthalmos (ox eye), Haab's striae, photophobia, epiphora
• Surgery (goniotomy or trabeculotomy) is first-line, not medical treatment
• Sturge-Weber syndrome: Glaucoma in ~30% ipsilateral to facial haemangioma; glaucoma drainage devices offer best IOP control
• Aniridia (PAX6 gene): Glaucoma drainage devices are treatment of choice

Glaucoma in Pregnancy

• Beta-blockers: may cross placenta; neonatal bradycardia
• Brimonidine: avoid (crosses blood-brain barrier, causes neonatal apnoea)
• Carbonic anhydrase inhibitors: teratogenic (avoid in first trimester)
• Prostaglandins: avoid (uterotonic)
• Safest option: topical beta-blocker (with nasolacrimal occlusion) under specialist supervision; surgery preferred over systemic CAIs

Normal-Tension vs. High-Tension POAG

• Both treated by IOP reduction - IOP lowering is beneficial even in NTG
• In NTG, prostaglandins + addressing vascular risk factors (nocturnal hypotension, vasospasm)

Summary: The Glaucoma "Big Picture"

Impaired aqueous outflow (or ↑ production)
              ↓
        Elevated IOP
              ↓
    Mechanical + ischemic injury at lamina cribrosa
              ↓
    Retinal ganglion cell apoptosis
              ↓
   RNFL thinning → optic disc cupping → visual field loss
              ↓
            Blindness (if untreated)

GOAL: Lower IOP to a target that halts or slows progression
      throughout the patient's lifetime

• Kanski's Clinical Ophthalmology: A Systematic Approach, 10th ed. (Chapters 11 and related)
• Robbins & Kumar Basic Pathology, p. 868-870
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 74
• Goldman-Cecil Medicine, Chapter 391
• PMID 39018052 - SLT vs. Medical Therapy meta-analysis (J Glaucoma, 2024)
• PMID 39394492 - PreserFlo vs. Trabeculectomy meta-analysis (2025)
• PMID 40701331 - Glaucoma medication network meta-analysis (Ophthalmology, 2025)