Pathophysiology of Glaucoma

Primary Mechanism: Aqueous Humor Dynamics and IOP Elevation

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
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 2, 1

Progressive death of retinal ganglion cells (RGCs) and loss of their axons in the optic nerve 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

Compromised optic nerve perfusion plays a substantial pathophysiologic role 3, 2, 4
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 3, 4, 5
Low diastolic perfusion pressure specifically increases glaucoma risk in patients receiving antihypertensive treatment 2, 4
Migraine headache and peripheral vasospasm (Raynaud's syndrome) decrease autoregulation of optic disc blood flow, increasing susceptibility to glaucomatous damage 6, 7, 8, 9

The pressure difference between IOP and intracranial pressure (translaminar gradient) may contribute to optic nerve damage 3, 2, 4
Patients with glaucoma demonstrate lower intracranial pressure compared to controls, with normal-tension glaucoma patients showing even lower levels 2, 4, 6
Axial myopia creates weaker scleral support at the optic nerve head, increasing susceptibility to pressure-related damage 6, 7, 8

Diabetes mellitus increases glaucoma risk through microvascular changes in the optic nerve and potentially through altered corneal biomechanics 6, 8
Hypothyroidism may contribute via decreased cellular metabolism (increasing RGC susceptibility to injury) and altered mucopolysaccharides in the trabecular meshwork (increasing IOP) 3, 2, 8

Complex genetic factors influence susceptibility to glaucomatous optic neuropathy, affecting aqueous humor dynamics, IOP regulation, central corneal thickness, and optic disc parameters 5, 6

IOP reduction remains the only proven treatment strategy despite not being the sole mechanism, and lowering IOP reduces the mechanical stress on RGC axons at the lamina cribrosa, and even in normal-tension glaucoma, IOP reduction is beneficial because it favorably alters the stress gradient across the optic nerve head 1

Systemic hypertension is modestly but significantly associated with a higher incidence of primary open‑angle glaucoma (POAG), with risk increases reported between 17 % and 56 % in large population‑based studies【10】【11】.
After adjusting for diabetes and hyperlipidaemia, individuals with hypertension (without those comorbidities) have a 17 % greater risk of developing POAG (P < 0.001)【10】【11】.

Increased aqueous‑humour production – Elevated perfusion of the ciliary body in hypertension may raise aqueous‑humour formation, contributing to higher intra‑ocular pressure【10】【11】.
Direct vascular injury – Hypertensive arteriolosclerosis can diminish optic‑disc perfusion, promoting glaucomatous damage【10】【11】.
Paradoxical iatrogenic hypotension – Antihypertensive therapy may induce systemic hypotension, reducing optic‑nerve perfusion and potentially accelerating glaucoma progression【10】【11】.

A diastolic ocular perfusion pressure < 50 mmHg is a notable risk factor for POAG, particularly among patients receiving antihypertensive medication【10】【11】.
The association between low diastolic ocular perfusion pressure and increased glaucoma risk is observed only in those treated with antihypertensives【10】【11】.

Clinicians should exercise caution when managing hypertensive patients who develop normal‑tension glaucoma, as aggressive blood‑pressure lowering may paradoxically worsen glaucomatous injury【10】【11】.
Hypertensive individuals who also have diabetes exhibit a 48 % higher risk of glaucoma (P < 0.001)【10】【11】.
Co‑existing migraine or peripheral vasospasm (Raynaud’s phenomenon) in hypertensive patients adds further risk by impairing optic‑disc autoregulation【10】【11】.
Coordination with primary‑care physicians is recommended to avoid excessive nocturnal hypotension in glaucoma patients, thereby protecting optic‑nerve perfusion【10】【11】.