Glaucoma - A Comprehensive Review

Definition

The goal of glaucoma treatment is to slow the rate of progression throughout a patient's lifetime to maintain visual function and quality of life, at a sustainable cost.

• Kanski's Clinical Ophthalmology, 10th ed.

Aqueous Humor Dynamics - The Foundation

• Posterior chamber → through the pupil → anterior chamber
• Primary outflow (80-90%): Trabecular meshwork → Schlemm's canal → episcleral veins (conventional/pressure-sensitive)
• Secondary outflow (10-20%): Uveoscleral pathway (pressure-independent)

Classification

1. By Mechanism

Primary Open-Angle Glaucoma (POAG)

Epidemiology

• Most common form worldwide; affects ~3.5% of the global population >40 years
• Leading cause of irreversible blindness globally
• Risk factors: elevated IOP, positive family history, African/African-Caribbean ancestry, increasing age, myopia, thin corneal thickness (CCT), diabetes, systemic hypertension
• GWAS has identified >40 gene loci associated with POAG

Pathogenesis

• Dysfunction of trabecular meshwork cells (decreased phagocytic activity, accumulation of extracellular debris)
• Loss of cellularity with aging
• Increased deposition of fibronectin, laminin, and other extracellular matrix proteins
• Genetic factors (MYOC, OPTN, TBK1 mutations)

Clinical Features

IOP Assessment

• Measured by Goldmann applanation tonometry (gold standard)
• Corrected for central corneal thickness (CCT): Thin corneas give falsely low readings; thick corneas give falsely high readings
• Normal CCT: 540-560 μm; CCT < 500 μm is an independent risk factor for POAG
• Diurnal variation of IOP (up to 5 mmHg over 24 hours) is relevant - IOP peaks in early morning

Optic Disc and RNFL Changes in Glaucoma

1. Optic Nerve Head (ONH)

• Pathological cupping: Irreversible loss of nerve fibers, glia, and blood vessels → increased cup-to-disc ratio (CDR)
• Normal CDR: up to 0.5 (though this varies with disc size - large discs have larger physiological cups)
• Neuroretinal rim (NRR) thinning - typically follows the ISNT rule (Inferior > Superior > Nasal > Temporal in health). Glaucoma preferentially attacks inferior and superior poles first.
• NRR notching (focal loss) is the most specific sign

2. Disc Haemorrhages

• Small, flame-shaped haemorrhages at the NRR margin (most commonly inferotemporal)
• Highly significant - indicate active damage and predict progression
• More common in normal-tension glaucoma (NTG)

3. Four Morphological Glaucomatous Disc Patterns (Kanski):

• Focal ischaemic: Localized superior/inferior notching; arcuate field defects threatening fixation early
• Myopic disc with glaucoma: Tilted, obliquely inserted disc; temporal crescent; dense superior/inferior scotomas; younger males
• Sclerotic: Shallow saucerized cup; gently sloping NRR; associated with systemic vascular disease; older patients
• Concentrically enlarging: Uniform NRR thinning; diffuse visual field loss; significantly elevated IOP at presentation

4. RNFL Changes

• Detectable before visual field loss by approximately 5 years
• Localized wedge-shaped RNFL defects on red-free fundus photography
• Measured quantitatively by OCT (Optical Coherence Tomography) - now the standard imaging tool

Imaging in Glaucoma

Optical Coherence Tomography (OCT)

• Peripapillary RNFL thickness (circumpapillary scan)
• Macular ganglion cell complex (GCC) thickness
• ONH parameters (rim area, CDR, disc area)
• Allows detection of pre-perimetric glaucoma (structural damage without field loss)
• Serial OCT enables detection of progression before functional testing

Visual Field Testing (Perimetry)

• Standard automated perimetry (SAP) using Humphrey Field Analyzer (HFA)
• 24-2 pattern - standard for glaucoma monitoring (tests within 24° temporally, 30° nasally)
• 10-2 pattern - detects central defects; used in advanced glaucoma with split fixation
• 30-2 pattern - alternative to 24-2
• Characteristic field defects:
  • Nasal step (respects horizontal midline)
  • Arcuate (Bjerrum) scotoma (arches from blind spot to nasal midline)
  • Paracentral scotoma
  • Altitudinal defect (superior > inferior)
  • Tubular/central island (late stage)

Other Imaging

• Gonioscopy - direct visualization of the anterior chamber angle; essential to classify open vs. closed angle
• Ultrasound biomicroscopy (UBM) - images structures behind the iris (ciliary body); particularly useful for angle-closure glaucoma
• Anterior segment OCT - evaluates angle anatomy; useful for angle-closure subtypes; non-contact
• Stereo disc photography - historical gold standard; still valuable for qualitative documentation

Normal-Tension Glaucoma (NTG)

Definition

Pathogenesis

• IOP-independent vascular and mechanical factors are more prominent
• Proposed mechanisms: anomalies of local/systemic vascular regulation, structural optic nerve vulnerability, autoimmune processes
• Thin CCT accounts for a proportion of cases (falsely low tonometry)

Risk Factors

• Older age (tends to present later than POAG)
• Female sex
• Japanese ethnicity (more prevalent)
• Family history
• Nocturnal systemic hypotension (>20% BP dip) - especially in patients on antihypertensives
• Migraine, Raynaud phenomenon (vascular dysregulation)
• Obstructive sleep apnoea
• Low serum retinol
• OPTN gene mutations (optineurin)

Management

• IOP reduction remains the mainstay even in NTG (lowers risk of progression)
• Target IOP typically set 20-30% below baseline
• Consider systemic vascular risk factor management
• Calcium channel blockers (e.g., nifedipine) may have a neuroprotective role in NTG with vascular dysregulation

Primary Angle-Closure Glaucoma (PACG)

Epidemiology

Anatomy

Mechanism (see diagram above)

1. Iris apposition to the lens at the pupil margin blocks aqueous flow from posterior to anterior chamber
2. Pressure builds in the posterior chamber → iris bows forward (iris bombé)
3. Peripheral iris occludes the trabecular meshwork
4. IOP rises dramatically → acute angle-closure crisis

Acute Angle-Closure Crisis (AACC)

• Sudden onset of severe ocular pain (periorbital), headache, nausea/vomiting
• Blurred vision with coloured halos around lights
• Red eye
• Markedly elevated IOP (often 40-70 mmHg)
• Corneal oedema (hazy, steamy cornea)
• Fixed, mid-dilated (4-6 mm), oval pupil
• Shallow anterior chamber
• Ciliary injection

1. Immediate IOP reduction: acetazolamide 500 mg IV/oral + topical beta-blocker + topical steroid
2. Pilocarpine 2-4% (once IOP < 40 mmHg, as ischaemic iris is unresponsive at higher pressures)
3. Laser peripheral iridotomy (LPI) - definitive treatment; creates a hole in the peripheral iris to bypass pupillary block; also performed prophylactically in the fellow eye
4. Systemic hyperosmotic agents if needed (glycerol, mannitol)

Chronic Angle-Closure Glaucoma

Secondary Glaucomas

Pseudoexfoliation Glaucoma (PXG)

• Most common identifiable cause of secondary open-angle glaucoma worldwide
• White fibrillar material (pseudoexfoliative material) deposits on the lens capsule, zonules, corneal endothelium, and trabecular meshwork
• Associated with fibrillin gene (FBN1) and LOXL1 mutations
• Significantly higher IOP, more asymmetric, worse prognosis than POAG
• Higher rate of vitreous loss during cataract surgery (zonular weakness)

Pigmentary Glaucoma

• Predominantly young myopic males
• Iris transillumination defects (radial spoke-like pattern at mid-peripheral iris)
• Pigment deposits on corneal endothelium (Krukenberg spindle) and trabecular meshwork
• IOP rises after exercise or pupillary dilation (pigment release)
• May "burn out" with age as iris pigment is exhausted

Steroid-Induced Glaucoma

• Topical, periocular, systemic, or intravitreal steroids
• Mechanism: steroids increase glycosaminoglycan deposition in the trabecular meshwork → reduced outflow
• ~35% of the general population are "steroid responders"
• IOP typically normalizes after discontinuing steroids

Neovascular Glaucoma (NVG)

• New abnormal blood vessels (rubeosis iridis) grow over the trabecular meshwork
• Common causes: diabetic retinopathy, central retinal vein occlusion, ocular ischaemic syndrome
• Fibrovascular membrane contracts → peripheral anterior synechiae → completely closed angle
• Treatment: anti-VEGF + panretinal photocoagulation (PRP) to address the ischaemic stimulus + glaucoma surgery

Inflammatory (Uveitic) Glaucoma

• Trabeculitis, trabecular meshwork blockage by inflammatory cells/debris
• Posterior synechiae → pupillary block → "seclusio pupillae" → iris bombé
• Secondary angle closure from extensive PAS
• Treatment: treat underlying uveitis + IOP lowering (avoid prostaglandins in active inflammation; avoid miotics if posterior synechiae)

Traumatic Glaucoma

• Angle recession glaucoma: Tear between the circular and longitudinal ciliary muscle fibres after blunt trauma. Long-latent (years). Requires lifelong monitoring.
• Ghost cell glaucoma: Red blood cell ghosts (degenerated RBCs) clog trabecular meshwork after vitreous haemorrhage
• Lens-related: Phacolytic (lens proteins leak from hypermature cataract), phacomorphic (intumescent lens causes angle closure)

Developmental (Congenital) Glaucoma

Primary Congenital Glaucoma

• Trabeculodysgenesis (Barkan's membrane or abnormal trabecular development)
• Presents at birth to age 3 years
• Classic triad: Epiphora, photophobia, blepharospasm
• Buphthalmos (enlarged globe) - corneal diameter >13 mm; Haab's striae (horizontal breaks in Descemet's membrane)
• Treatment: goniotomy or trabeculotomy (primary surgical; medical treatment only temporizing)
• AR inheritance in ~10%; CYP1B1 gene mutations are most common

Glaucoma in Phacomatoses

• Sturge-Weber syndrome: Glaucoma in ~30% of cases ipsilateral to facial haemangioma. Infants may develop buphthalmos (trabeculodysgenesis). Older patients: elevated episcleral venous pressure from episcleral haemangioma. Medical or surgical (combined trabeculotomy-trabeculectomy) treatment; risk of choroidal effusion.
• Neurofibromatosis type 1: Rare unilateral congenital glaucoma; ~50% have plexiform neurofibroma of the upper eyelid on the same side.

Pharmacological Treatment

Step 1 (First-line): Prostaglandin Analogues (PGAs)

• Irreversible darkening of iris (brown pigmentation)
• Hypertrichosis (increased eyelash length/pigmentation)
• Periorbital fat atrophy (deepened upper lid sulcus)
• Conjunctival hyperaemia
• Cystoid macular oedema (rare; use with caution in aphakia/pseudophakia)
• Reactivation of uveitis/herpes - use cautiously

Step 2: Beta-Adrenergic Antagonists (Beta-Blockers)

• Bradycardia, heart block
• Bronchoconstriction (avoid in asthma/COPD)
• Masking of hypoglycaemia symptoms
• CNS effects (depression, fatigue)
• Betaxolol (β₁-selective) is safer in respiratory disease but less efficacious

Step 3: Alpha-2 Adrenergic Agonists

Step 4: Carbonic Anhydrase Inhibitors (CAIs)

Step 5: Rho-Kinase (ROCK) Inhibitors (Newer Class)

Miotics (Cholinergic Agents)

Fixed Combination Drops

• Latanoprost/timolol (Xalacom)
• Dorzolamide/timolol (Cosopt)
• Brimonidine/timolol (Combigan)
• Bimatoprost/timolol (Ganfort)
• Netarsudil/latanoprost (Rocklatan)

Surgical and Laser Treatment

Laser

• Laser Peripheral Iridotomy (LPI): Definitive treatment for angle-closure (pupillary block); creates an aqueous bypass channel through the peripheral iris using Nd:YAG laser
• Selective Laser Trabeculoplasty (SLT): Applies 532 nm laser to trabecular meshwork; stimulates macrophage-mediated trabecular remodelling; IOP reduction ~25%; repeatable; now considered a first-line option (equal to medical therapy in the LiGHT trial); no thermal damage to meshwork
• Argon Laser Trabeculoplasty (ALT): Older; causes coagulative damage to meshwork; less favoured than SLT
• Diode laser cyclodestruction (cycloablation): Destroys ciliary body epithelium; used in refractory cases or poor surgical candidates

Filtration Surgery

• Trabeculectomy: Gold standard incisional surgery; creates a guarded fistula (bleb) allowing aqueous to drain under the conjunctiva; antimetabolites (Mitomycin-C, 5-Fluorouracil) enhance bleb survival by reducing fibrosis
  • Complications: Bleb failure, bleb-related endophthalmitis, hypotony maculopathy, cataract, malignant glaucoma
• Combined trabeculectomy-trabeculotomy: Used in developmental glaucoma

Glaucoma Drainage Devices (Tubes)

• Baerveldt, Ahmed, Molteno implants
• Route aqueous to a posterior equatorial plate via a tube in the anterior chamber
• Used in refractory cases, uveitic glaucoma (better success than trabeculectomy per recent meta-analysis), previous failed trabeculectomy, aniridia
• A 2024 systematic review (PMID 39293570) comparing trabeculectomy vs. tube shunts in uveitic glaucoma found comparable IOP control but different complication profiles

Minimally Invasive Glaucoma Surgery (MIGS)

• Performed at the time of cataract surgery or as standalone
• Targets include: Schlemm's canal (iStent inject, Hydrus microstent), suprachoroidal space (CyPass, iStent Supra), subconjunctival space (XEN gel stent)
• Lower risk profile than trabeculectomy but moderate IOP reduction (~20-30%)
• Best suited for mild-moderate glaucoma

Optic Nerve Neuroprotection

1. Mechanical: Direct compression of axons and vessels at the lamina cribrosa by elevated IOP
2. Vascular: Impaired ocular blood flow, reduced perfusion, ischaemia of the optic nerve head

• NMDA receptor antagonists (memantine - failed in phase III trial)
• Neurotrophic factors (BDNF, CNTF)
• Mitochondrial protection
• Stem cell therapy

Monitoring and Targets

• Baseline IOP and level of damage
• Rate of progression
• Patient age and life expectancy
• As a general rule: 30% reduction from baseline for POAG; lower targets (8-12 mmHg) for NTG or advanced damage

Malignant Glaucoma (Aqueous Misdirection)

Key Summary Table

• Kanski's Clinical Ophthalmology: A Systematic Approach, 10th ed. - Primary reference throughout
• Robbins & Kumar Basic Pathology and Robbins, Cotran & Kumar Pathologic Basis of Disease - Pathogenesis and morphology
• Goodman & Gilman's The Pharmacological Basis of Therapeutics - Drug mechanisms
• Katzung's Basic and Clinical Pharmacology, 16th ed. - Prostaglandin analogues and beta-blockers
• Recent evidence: Trabeculectomy vs. tube shunts in uveitic glaucoma (2024, PMID 39293570)