What is the pathophysiology of glaucoma?

Pathophysiology of Glaucoma

Glaucoma is fundamentally a progressive optic neuropathy characterized by retinal ganglion cell death and axonal degeneration in the optic nerve, driven primarily by elevated intraocular pressure (IOP) that disrupts the balance between aqueous humor production and drainage, though vascular insufficiency and biomechanical stress at the optic nerve head also contribute significantly to disease progression. 1, 2

Primary Mechanism: Aqueous Humor Dynamics and IOP Elevation

The core pathophysiologic disturbance in glaucoma centers on disrupted aqueous humor dynamics 3, 4:

• Aqueous humor is produced by the ciliary processes and normally drains through two pathways: the conventional (trabecular meshwork) outflow pathway and the unconventional (uveoscleral) outflow pathway 3, 4
• Compromised drainage through the trabecular meshwork is the primary contributor to pathologic IOP elevations, creating an imbalance between production and outflow 4
• Elevated IOP is the major modifiable risk factor for glaucomatous optic nerve damage and visual field loss, with higher pressures conferring greater risk of progression 5, 3

Critical caveat: Approximately 50% of patients with primary open-angle glaucoma have IOP consistently within the normal range (normal-tension glaucoma), yet still experience progressive optic nerve damage 1. This indicates that IOP elevation alone does not fully explain the pathophysiology.

Retinal Ganglion Cell Degeneration

The ultimate pathologic endpoint is progressive death of retinal ganglion cells (RGCs) and loss of their axons in the optic nerve 2:

• RGC loss produces characteristic excavation and cupping of the optic nerve head, particularly affecting the inferior and superior poles 1
• Axonal degeneration manifests as diffuse or localized thinning of the retinal nerve fiber layer (RNFL) 1
• This neurodegeneration results in irreversible peripheral visual field defects that progress centrally if untreated 1

Vascular and Perfusion Mechanisms

Beyond mechanical pressure effects, compromised optic nerve perfusion plays a substantial pathophysiologic role 1:

Systemic Hypertension Paradox

• Systemic hypertension increases glaucoma risk through multiple mechanisms: increased ciliary body perfusion leading to higher aqueous production, decreased optic disc perfusion from sclerotic arterioles, or paradoxically through antihypertensive treatment causing systemic hypotension and reduced optic nerve perfusion 1
• Low diastolic perfusion pressure specifically increases glaucoma risk in patients receiving antihypertensive treatment 1

Vasospastic Disorders

• Migraine headache and peripheral vasospasm (Raynaud's syndrome) decrease autoregulation of optic disc blood flow, increasing susceptibility to glaucomatous damage 1, 6
• The optic nerve has less effective autoregulation compared to brain tissue, making it more vulnerable to hypoperfusion 7

Biomechanical Stress Mechanisms

Translaminar Pressure Gradient

• The pressure difference between IOP and intracranial pressure (translaminar gradient) may contribute to optic nerve damage 1
• Patients with glaucoma demonstrate lower intracranial pressure compared to controls, with normal-tension glaucoma patients showing even lower levels 1
• Conversely, ocular hypertension patients without glaucoma have higher intracranial pressure, suggesting this gradient may be protective 1

Structural Vulnerability

• Axial myopia creates weaker scleral support at the optic nerve head, increasing susceptibility to pressure-related damage 1
• This explains why myopia is an independent risk factor for glaucoma across multiple ethnic populations 1

Metabolic and Cellular Mechanisms

Several systemic conditions alter cellular metabolism and tissue properties 1:

• Diabetes mellitus increases glaucoma risk through microvascular changes in the optic nerve and potentially through altered corneal biomechanics 1
• Hypothyroidism may contribute via decreased cellular metabolism (increasing RGC susceptibility to injury) and altered mucopolysaccharides in the trabecular meshwork (increasing IOP) 1

Genetic Architecture

Complex genetic factors influence susceptibility to glaucomatous optic neuropathy, affecting aqueous humor dynamics, IOP regulation, central corneal thickness, and optic disc parameters 1. The genetic architecture is multifactorial rather than following simple Mendelian inheritance patterns 1.

Clinical Implications for Understanding Disease Progression

The pathophysiology explains why IOP reduction remains the only proven treatment strategy despite not being the sole mechanism 5, 2:

• Lowering IOP reduces the mechanical stress on RGC axons at the lamina cribrosa 5
• Even in normal-tension glaucoma, IOP reduction is beneficial because it favorably alters the stress gradient across the optic nerve head 1
• Current pharmacologic agents target aqueous dynamics by either reducing production (beta-blockers, carbonic anhydrase inhibitors) or increasing outflow (prostaglandin analogs, cholinergic agonists) 5, 8

Important limitation: IOP reduction only partially addresses the underlying RGC susceptibility to degeneration, which is why research focuses on neuroprotection, neuroregeneration, and neuroenhancement strategies 2.