What causes glaucoma?

Causes of Glaucoma

Glaucoma is fundamentally caused by progressive retinal ganglion cell death and optic nerve axonal degeneration, driven by a combination of elevated intraocular pressure (IOP), vascular insufficiency, and biomechanical stress at the optic nerve head, though approximately 50% of patients develop optic nerve damage despite normal IOP levels. 1

Primary Pathophysiologic Mechanisms

Elevated Intraocular Pressure

• IOP elevation disrupts the balance between aqueous humor production and drainage, creating mechanical stress on retinal ganglion cell axons at the lamina cribrosa. 1
• Elevated IOP (>21 mmHg) remains the major modifiable risk factor, though nearly 40% of primary open-angle glaucoma patients never demonstrate elevated IOP during office measurements. 2
• The higher the IOP level, the greater the likelihood of glaucomatous optic nerve damage and visual field loss. 3

Vascular and Perfusion Abnormalities

• Compromised optic nerve perfusion plays a substantial pathophysiologic role independent of IOP. 1
• Migraine headaches and peripheral vasospasm (Raynaud's syndrome) decrease autoregulation of optic disc blood flow, increasing susceptibility to glaucomatous damage. 4, 1
• Low diastolic perfusion pressure specifically increases glaucoma risk, but only in patients receiving antihypertensive treatment. 4, 1

Biomechanical Stress

• The translaminar pressure gradient (difference between IOP and intracranial pressure) contributes to optic nerve damage. 4, 1
• Patients with glaucoma demonstrate lower intracranial pressure compared to controls, with normal-tension glaucoma patients showing even lower levels. 4, 1

Major Risk Factors That Increase Susceptibility

Structural and Anatomic Factors

• Axial myopia creates weaker scleral support at the optic nerve head, increasing susceptibility to pressure-related damage. 4, 1
• Thin central corneal thickness (<555 μm) increases the risk of developing primary open-angle glaucoma. 2

Systemic Medical Conditions

• Type 2 diabetes mellitus increases glaucoma risk by 40-100% through microvascular changes in the optic nerve that increase susceptibility to damage. 4
• Patients with concomitant systemic hypertension and diabetes have a 48% increased risk of glaucoma (P<0.001). 4
• Hypothyroidism may contribute via decreased cellular metabolism (increasing retinal ganglion cell susceptibility to injury) and altered mucopolysaccharides in the trabecular meshwork (increasing IOP). 4, 1

Systemic Hypertension (Controversial Association)

• The relationship between systemic hypertension and glaucoma remains controversial, with conflicting evidence. 4
• After adjusting for diabetes and hyperlipidemia, patients with systemic hypertension alone have a 17% increased risk of developing open-angle glaucoma (P<0.001). 4
• Three potential mechanisms explain how hypertension may cause glaucoma: 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. 4, 1

Demographic Risk Factors

• Older age is a major demographic risk factor. 2
• African race or Latino/Hispanic ethnicity carry increased risk. 2
• Family history of glaucoma substantially increases risk. 2
• Male sex is associated with higher glaucoma risk, possibly due to protective effects of female hormones on ganglion cell loss. 4

Genetic Architecture

• Complex genetic factors influence susceptibility to glaucomatous optic neuropathy, affecting aqueous humor dynamics, IOP regulation, central corneal thickness, and optic disc parameters. 4, 1
• Traditional linkage methods have identified genes for heritable forms of glaucoma, while genome-wide studies continue to identify common and rare genetic variants associated with open-angle glaucoma. 4

Clinical Pitfalls and Caveats

Normal-Tension Glaucoma

• Approximately 50% of primary open-angle glaucoma patients have consistently normal IOP yet still experience progressive optic nerve damage, indicating that IOP is not the sole causative mechanism. 1
• This underscores the importance of vascular, biomechanical, and metabolic factors in disease pathogenesis. 1

Medication-Induced Risk

• Corticosteroids, anticholinergics, certain antidepressants, and topiramate may predispose patients to glaucoma. 5
• Anticholinergics should be used with caution in narrow-angle glaucoma but are less problematic in open-angle glaucoma. 6

Treatment Implications

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

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