Glaucoma: From Basic Science to Clinical Practice

Fig. A) Normal eye anatomy. B) Normal aqueous outflow via trabecular meshwork to Schlemm's canal. C) Primary angle-closure with iris bombé and pupillary block. D) Neovascular glaucoma with peripheral anterior synechiae. - Robbins & Kumar Basic Pathology

1. Definition

• Goldman-Cecil Medicine, p. 4131 - Ganong's Review of Medical Physiology, p. 199

2. Basic Science: Aqueous Humor Dynamics

Production

Drainage - Two Pathways

• Mechanical compression of RGC axons at lamina cribrosa
• Impaired axoplasmic transport
• Ischemia of the optic nerve head
• Progressive RGC apoptosis
• Goldman-Cecil Medicine, p. 4131 - Ganong's Review of Medical Physiology, p. 199

3. Classification

GLAUCOMA
├── PRIMARY
│   ├── Primary Open-Angle Glaucoma (POAG)  ← most common worldwide
│   ├── Primary Angle-Closure Glaucoma (PACG) ← most common in Asia
│   └── Normal-Tension Glaucoma (NTG)
└── SECONDARY
    ├── Open-angle: pseudoexfoliation, pigmentary, steroid-induced, trauma
    └── Angle-closure: neovascular, phacomorphic, plateau iris

4. Primary Open-Angle Glaucoma (POAG)

Epidemiology & Risk Factors

• Most prevalent type in people of European and African descent
• Prevalence in >70 year-olds: ~6% (White), ~16% (Black), ~3% (Asian)
• Affects both genders equally

• Elevated IOP - the higher, the greater the risk; asymmetry ≥4 mmHg is significant
• Age - older individuals at higher risk
• Race - Black patients develop POAG up to 4x more often, earlier, and more severely
• Family history - first-degree relatives: siblings ×4 risk, offspring ×2 risk
• Myopia - associated with increased incidence and susceptibility
• Large optic disc - more vulnerable to IOP-induced laminar deformation
• Low ocular perfusion pressure - vascular risk
• Anti-VEGF therapy - repeated injections (especially bevacizumab) can cause sustained IOP rise
• MYOC gene mutations - myocilin protein in trabecular meshwork; OPTN gene (optineurin) also implicated; >127 GWAS loci identified

Pathophysiology

Optic Disc Changes (Clinical Signs)

• Neuroretinal rim (NRR) thinning - normally follows the ISNT rule (Inferior > Superior > Nasal > Temporal). Violation of this rule is suspicious.
• Cup-to-disc (C/D) ratio increase - vertical C/D >0.7 in only 2% of normal population; asymmetry ≥0.2 between eyes is suspicious
• Notching of the neuroretinal rim (especially inferotemporal or superotemporal)
• RNFL defects - wedge-shaped, best seen with red-free light
• Disc hemorrhages (splinter/Drance hemorrhages) - indicator of progression
• Peripapillary atrophy (beta-zone PPA)

Visual Field Defects (progression pattern)

1. Early: Small paracentral depressions (superonasally), increased variability
2. Moderate: Arcuate (Bjerrum) scotoma, nasal step (Rönne step)
3. Advanced: Ring scotoma, tunnel vision, central island
4. End-stage: Complete loss of central and peripheral vision

Diagnosis

• Tonometry (Goldman applanation) - note: corneal thickness (pachymetry) affects accuracy
• Gonioscopy - open angle confirmed
• Optic disc exam - dilated fundoscopy + OCT of RNFL
• Automated perimetry (Humphrey 24-2 or 30-2) - SAP; 10-2 for advanced
• OCT (optical coherence tomography) - RNFL thickness measurement is now standard

5. Primary Angle-Closure Glaucoma (PACG)

Mechanism

Acute Angle-Closure Crisis - Clinical Presentation

Gonioscopy Grading (Shaffer System)

• Grade 4 (35-45°): Wide open - ciliary body visible
• Grade 3 (25-35°): Open - scleral spur visible
• Grade 2 (20°): Trabeculum visible but not scleral spur - risk of closure
• Grade 1 (10°): Very narrow - only Schwalbe line visible
• Grade 0: Closed (iridocorneal contact)

6. Secondary Glaucomas

7. Normal-Tension Glaucoma (NTG)

8. Pharmacology - Drug Classes for Glaucoma

A) Prostaglandin Analogues (First-line)

• Mechanism: FP receptor agonists → increase uveoscleral outflow
• Dosing: Once daily (evening preferred)
• IOP reduction: 25-35% (most potent single agents)
• Side effects: Increased iris/periorbital pigmentation, eyelash growth (hypertrichosis), conjunctival hyperemia, macular edema (in aphakic/pseudophakic patients)
• Contraindicated/caution: Uveitis, cystoid macular edema

B) Beta-Adrenergic Antagonists (Beta-Blockers)

• Mechanism: Block beta-2 receptors on ciliary epithelium → decrease aqueous production (~50% reduction in production)
• Dosing: Timolol 0.5% BID (most commonly used)
• IOP reduction: 20-25%
• Systemic side effects: Bradycardia, bronchospasm (contraindicated in asthma/COPD), fatigue, depression, sexual dysfunction, masking of hypoglycemia
• Local side effects: Corneal anesthesia (non-selective agents)

C) Carbonic Anhydrase Inhibitors (CAIs)

• Mechanism: Inhibit carbonic anhydrase II in ciliary epithelium → reduce aqueous secretion (~15-20%)
• Use: Topical as second/third-line; systemic acetazolamide for acute angle-closure emergency
• Side effects - topical: Local stinging, bitter taste, corneal edema (in endothelial disease)
• Side effects - systemic (acetazolamide): Paresthesias (very common), metabolic acidosis, hypokalemia, renal stones, aplastic anemia (rare), sulfonamide cross-reactivity - contraindicated in sulfa allergy

D) Alpha-2 Adrenergic Agonists

• Mechanism: Alpha-2 stimulation → decrease aqueous production + increase uveoscleral outflow
• Dosing: Brimonidine TID
• IOP reduction: ~20-25%
• Side effects: Allergic conjunctivitis (up to 10-15%), drowsiness (crosses BBB), dry mouth
• Contraindicated: Neonates/infants (CNS depression - apnea risk), MAO inhibitor users

E) Rho-Kinase (ROCK) Inhibitors (Newest Class)

• Mechanism: Inhibit ROCK → relax trabecular meshwork cells → increase conventional (trabecular) outflow + reduce episcleral venous pressure
• IOP reduction: ~20%
• Side effects: Conjunctival hyperemia, corneal verticillata (whorl-like deposits), subconjunctival hemorrhage
• Note: First drug class to directly target trabecular meshwork outflow

F) Cholinergic Agonists (Miotics) - Largely Historical

• Mechanism: M3 receptor → ciliary muscle contraction → opens trabecular meshwork → increases conventional outflow; also causes pupillary constriction (helpful in angle closure)
• Side effects: Miosis (reduced vision in dim light, especially with posterior subcapsular cataract), brow ache, induced myopia, risk of retinal detachment
• Current use: Pilocarpine still used in acute angle-closure to break the attack (miosis pulls iris away from angle)

G) Combination Products

• Timolol + Dorzolamide (Cosopt)
• Timolol + Brimonidine (Combigan)
• Timolol + Latanoprost (Xalacom)
• Reduces drop burden and improves adherence

9. Non-Pharmacological Treatment

Laser Therapy

• Applies energy to trabecular meshwork → macrophage-mediated remodeling → improved outflow
• Can be considered first-line for POAG (as effective as medications in many patients per the LiGHT trial)
• Repeatable; takes ~4-6 weeks for full effect
• A 2024 systematic review and meta-analysis (PMID 39018052) confirmed SLT is non-inferior to medical therapy for open-angle glaucoma/ocular hypertension

• Creates a small hole in peripheral iris → bypasses pupillary block → equalizes pressure between chambers
• Definitive treatment for acute angle-closure crisis and prophylaxis for fellow eye
• Nd:YAG laser most commonly used

• Used for plateau iris syndrome (not corrected by LPI alone)

Surgical Treatment

• Gold-standard surgical procedure
• Creates a fistula from anterior chamber to subconjunctival space (bleb)
• Antimetabolites (Mitomycin C, 5-FU) applied intraoperatively to prevent scarring and bleb failure
• Risk of hypotony, bleb-related infection (blebitis, endophthalmitis)

• Ahmed, Baerveldt, Molteno valves
• Tube from anterior chamber to an episcleral reservoir plate
• Used in refractory cases, neovascular glaucoma, failed trabeculectomy
• A 2025 meta-analysis (PMID 39394492) compared PreserFlo MicroShunt vs trabeculectomy - similar IOP control with a favorable safety profile for MicroShunt

• iStent, Hydrus microstent, goniotomy, trabectome
• Lower efficacy than trabeculectomy but much safer - suited for mild-moderate POAG often combined with cataract surgery

• Diode laser cyclophotocoagulation/cycloablation
• Destroys ciliary body to reduce aqueous production
• Reserved for refractory/end-stage cases or blind painful eyes

10. Acute Angle-Closure - Emergency Management

1. Immediate IOP-lowering:
   • Acetazolamide 500 mg IV (or 2 × 250 mg oral if IV unavailable)
   • Topical timolol 0.5% - one drop
   • Topical alpha-agonist (apraclonidine or brimonidine)
   • IV mannitol 1-2 g/kg if IOP remains very high (osmotic agent)
2. Pupillary constriction:
   • Pilocarpine 2-4% - once IOP begins to fall below ~40 mmHg (at very high IOP, sphincter is ischemic and pilocarpine is ineffective)
3. Definitive treatment:
   • Nd:YAG laser iridotomy as soon as cornea clears
   • Fellow eye treated prophylactically
   • Lens extraction may be preferred in patients with significant cataract (lens contributes to angle crowding)

11. Monitoring and Target IOP

• Severity of existing damage (C/D ratio, mean deviation)
• Baseline IOP
• Central corneal thickness (CCT) - thin cornea falsely underestimates true IOP
• Rate of progression
• Patient age and life expectancy

12. Key Clinical Pearls

• Kanski's Clinical Ophthalmology: A Systematic Approach, 10th Ed.
• Goldman-Cecil Medicine International Edition (2025)
• Robbins & Kumar Basic Pathology
• Goodman & Gilman's The Pharmacological Basis of Therapeutics
• Ganong's Review of Medical Physiology, 26th Ed.
• Tintinalli's Emergency Medicine: A Comprehensive Study
• Recent evidence: SLT vs medical therapy meta-analysis [PMID 39018052]; PreserFlo vs trabeculectomy meta-analysis [PMID 39394492]; glaucoma drug network meta-analysis [PMID 40701331]