Glaucoma

Primary open-angle glaucoma (POAG) — outflow resistance at a microscopically open angle

• Trabecular meshwork sclerosis: extracellular matrix deposition and loss of trabecular cellularity raise conventional outflow resistance without any visible angle obstruction on gonioscopy.
• Non-modifiable risk factors: older age, African or Afro-Caribbean ancestry (earlier onset, more aggressive course), first-degree family history, and thin central corneal thickness — the last identified as an independent predictor of conversion from ocular hypertension to glaucoma in the Ocular Hypertension Treatment Study and incorporated into the American Academy of Ophthalmology (AAO) Preferred Practice Pattern risk assessment. Thin corneas also cause applanation tonometry to underestimate true IOP.
• Modifiable/treatable factors: elevated IOP is the only proven modifiable factor. High myopia and low ocular perfusion pressure also contribute.

Secondary open-angle mechanisms (material clogging the meshwork)

• Pseudoexfoliation syndrome: fibrillar white material on the anterior lens capsule and pupillary margin; associated with LOXL1 variants and with zonular weakness at cataract surgery.
• Pigment dispersion: iris chafing against zonules in young myopic men; Krukenberg spindle and radial iris transillumination defects, worse after exercise.
• Steroid-induced glaucoma: topical, periocular, inhaled, or systemic corticosteroids raise IOP in genetically susceptible steroid responders over weeks — an important iatrogenic, modifiable cause.
• Neovascular glaucoma: VEGF-driven fibrovascular membrane over the angle from proliferative diabetic retinopathy, central retinal vein occlusion, or ocular ischemic syndrome.
• Traumatic (angle-recession), uveitic, and lens-particle/phacolytic glaucoma.

Angle-closure mechanisms

• Pupillary block: hyperopia (short axial length), shallow anterior chamber, advancing age with lens thickening, East Asian ancestry, and female sex.
• Pharmacologic triggers: anticholinergics, sympathomimetics, and topiramate (ciliochoroidal effusion causing bilateral, non-pupillary-block closure). Dim light and mydriatic drops precipitate attacks.

• Elevated intraocular pressure (IOP): IOP is maintained by the balance between aqueous humor production (by the ciliary body epithelium) and outflow through the trabecular meshwork (conventional pathway, ~90%) and uveoscleral route (unconventional pathway, ~10%). Impaired outflow or excessive production increases IOP, which transmits pressure to the optic nerve head.

• Mechanical compression of axons: Elevated IOP compresses axons of retinal ganglion cells at the optic disc, impairing axonal transport and leading to ischemia and eventual death of these neurons. The lamina cribrosa, a connective tissue structure at the optic nerve head, becomes a site of mechanical stress.

• Ischemic injury and vascular insufficiency: Chronic elevated IOP compromises blood perfusion to the optic nerve head by exceeding the autoregulatory capacity of ophthalmic vessels. This results in relative hypoxia of ganglion cells and supporting glial cells, triggering apoptosis.

• Excitotoxicity from glutamate: Ischemic stress triggers release of excess glutamate from retinal neurons, causing overstimulation of N-methyl-D-aspartate (NMDA) receptors and Ca²⁺ influx in ganglion cells, leading to apoptotic cascades.

• Oxidative stress and inflammation: Mitochondrial dysfunction and reduced antioxidant defenses in glaucomatous eyes generate reactive oxygen species (ROS), activating inflammatory pathways and promoting neuronal apoptosis through cytochrome c release.

• Genetic susceptibility and risk factors: Open-angle glaucoma has polygenic inheritance; elevated IOP alone does not guarantee glaucoma (some patients have normal-tension glaucoma with IOP <21 mmHg). Risk factors include African ancestry, older age, myopia, family history, and elevated IOP.

• Asymptomatic in early disease: Most patients with open-angle glaucoma have no symptoms until significant optic nerve damage has occurred; this is the classic "silent thief of sight." Screening and early detection are essential.

• Progressive visual field loss: Loss begins peripherally (arcuate scotomas respecting the horizontal meridian, Bjerrum scotomas) and progresses centrally. Patients may compensate with the contralateral eye, delaying recognition of monocular field loss. Nasal step defects are characteristic.

• Optic disc changes: Increased cup-to-disc ratio (C/D) with vertical elongation, notching of the rim (especially inferiorly and superiorly), laminar dot signs, and possible optic nerve head hemorrhages (Drance hemorrhages, a sign of active glaucomatous damage). C/D >0.5 is concerning; asymmetry between eyes warrants investigation.

• Acute angle-closure glaucoma (ophthalmologic emergency): Sudden severe eye pain, blurred vision with halos around lights, headache, nausea/vomiting, red eye with corneal edema ("steamy cornea"), fixed mid-dilated pupil, and markedly elevated IOP (often >40 mmHg). Angle closure occurs when peripheral iris is pushed forward, obstructing trabecular meshwork outflow. Risk factors include hyperopia (short axial length), narrow angles (gonioscopically), and pupillary dilation.

• Normal-tension glaucoma (NTG): Progressive ganglion cell loss despite IOP consistently <21 mmHg; may represent increased susceptibility to ischemic injury or vascular insufficiency. More common in Japanese and East Asian populations; requires aggressive IOP lowering even at normal pressures.

• Tonometry to measure IOP: Goldman applanation tonometry is the gold standard, measuring the force required to flatten a 3.06 mm area of cornea. Normal IOP is 10–21 mmHg; values >21 mmHg are considered elevated but do not diagnose glaucoma alone. Portable methods (Tono-Pen, non-contact tonometry) useful for screening.

• Ophthalmoscopy and optic disc assessment: Direct and indirect funduscopy evaluate cup-to-disc ratio, rim notching, disc hemorrhages, and pallor. Increased C/D, especially asymmetric or >0.6, warrants further workup. Serial photographs document progression.

• Perimetry (visual field testing): Standard automated perimetry (SAP) or Humphrey visual field testing detects and monitors glaucomatous field defects. Glaucoma Hemifield Test (GHT) and Pattern Standard Deviation (PSD) help identify early glaucomatous changes. Reliable fields require good patient cooperation; false positives/negatives are common and require repeat testing.

• Optical coherence tomography (OCT) of the optic nerve and retinal nerve fiber layer (RNFL): Spectral-domain OCT directly images the optic nerve head and peripapillary RNFL, showing thinning in glaucoma. RNFL thinning may precede visual field defects, making OCT valuable for early detection and monitoring. High sensitivity and specificity.

• Gonioscopy: Essential examination classifying glaucoma as open-angle vs. angle-closure by directly visualizing the angle structures and trabecular meshwork. Uses a specialized lens to overcome corneal refraction. Determines whether angles are open (trabecular meshwork visible) or closed (iris obstructs meshwork).

• Diagnostic criteria: Glaucoma is diagnosed by combination of findings: elevated IOP, characteristic optic nerve changes (increased C/D, rim thinning), and/or reproducible visual field defects consistent with glaucomatous loss. Ocular Hypertension (IOP >21 mmHg without optic nerve or field changes) is a risk state requiring monitoring.

• First-line pharmacotherapy—prostaglandin analogs: Latanoprost, travoprost, or bimatoprost (dosed once daily, usually PM) reduce IOP by 25–35% by increasing uveoscleral outflow. These are preferred initial agents given efficacy, once-daily dosing, and minimal systemic side effects. Side effects include iris/conjunctival pigmentation, eyelash growth (hypertrichosis), and occasional local irritation. Pregnancy category C; avoid in active uveitis or herpetic keratitis.

• Beta-blockers (second-line): Timolol 0.5% twice daily is most commonly used, reducing IOP by 20–25% by decreasing aqueous humor production. Non-selective agents have systemic absorption risk (bronchospasm, bradycardia, decreased cardiac output, fatigue, depression). Use cautiously in asthma, COPD, bradycardia, heart block, or diabetes (masking hypoglycemia). Once-daily formulations and selective agents (betaxolol) available. Apply pressure to lacrimal canaliculus to reduce systemic absorption.

• Topical alpha-2 agonists: Brimonidine 0.2% two to three times daily decreases IOP by 15–20% through both decreased aqueous production and increased uveoscleral outflow. Side effects include dry mouth, drowsiness, conjunctival blanching, and rare allergic reactions. Used as adjunctive or monotherapy. Apraclonidine used acutely (laser prophylaxis).

• Carbonic anhydrase inhibitors (CAI): Topical agents (dorzolamide, brinzolamide three times daily) reduce IOP ~15–20% by inhibiting aqueous humor secretion. Useful as adjuncts. Systemic acetazolamide (PO or IV) achieves greater IOP reduction (25–30%) but causes metabolic acidosis, paresthesias, hypokalemia

Disease-related

• Irreversible blindness: retinal ganglion cell axons do not regenerate, so any field already lost is permanent; therapy only slows further loss. Signaled by progressive rim notching, enlarging arcuate defects, and eventual tunnel vision with a spared central island.
• Acute angle-closure crisis — EMERGENCY: sustained IOP above perfusion pressure produces ischemic iris sphincter palsy (fixed mid-dilated pupil), corneal endothelial pump failure (steamy cornea), and optic nerve infarction within hours. Untreated attacks leave glaukomflecken (anterior subcapsular lens opacities), iris atrophy, and permanent peripheral anterior synechiae.
• Central retinal artery/vein occlusion may be precipitated when IOP exceeds arterial perfusion pressure.

Treatment-related

• Beta blockers (timolol): nasolacrimal absorption bypasses first-pass metabolism — bronchospasm in asthma/COPD, bradycardia, heart block, fatigue, and masking of hypoglycemic warning signs. Punctal occlusion reduces systemic delivery.
• Brimonidine: alpha-2–mediated CNS depression, apnea, and hypotension in infants; contraindicated in children under 2 years.
• Acetazolamide: metabolic acidosis with paresthesias, hypokalemia, nephrolithiasis, and rare aplastic anemia/Stevens–Johnson in sulfonamide-sensitive patients.
• Prostaglandin analogs: irreversible iris hyperpigmentation and heterochromia, hypertrichosis, periorbital fat atrophy, and cystoid macular edema in pseudophakic or uveitic eyes.
• Pilocarpine: brow ache from ciliary spasm, fixed miosis with dim vision, and rhegmatogenous retinal detachment risk.
• Laser peripheral iridotomy: transient IOP spike, dysphotopsia (linear glare).
• Trabeculectomy (especially with mitomycin C): hypotony with maculopathy and choroidal effusion, bleb leak, cataract, and bleb-related endophthalmitis — an EMERGENCY presenting as pain, hypopyon, and vision loss even years later, requiring urgent tap-and-inject.
• **Aqueous misdirection (malignant glaucoma)**: shallow chamber with high IOP after filtering surgery despite a patent iridotomy.

• The acute angle-closure stem: an older hyperopic patient in a dark movie theater or after an anticholinergic develops a severe unilateral headache, nausea and vomiting, halos around lights, a red eye, a steamy cornea, and a fixed mid-dilated pupil. The single best next step is tonometry, not CT head — the vomiting is a vagal reflex, not gastroenteritis or migraine.
• Definitive therapy is anatomic, not medical: per the AAO Preferred Practice Pattern, medical therapy (topical beta blocker, alpha-2 agonist, carbonic anhydrase inhibitor, plus systemic acetazolamide ± osmotic agent) buys time, and laser peripheral iridotomy is curative — performed bilaterally, because the fellow eye shares the occludable anatomy.
• Common distractor: pilocarpine given first. At very high IOP the iris sphincter is ischemic and unresponsive; miotics are added after pressure falls. A second distractor is atropine/mydriatics, which worsen block.
• Anticholinergics are only dangerous in narrow angles. Withholding an antihistamine, TCA, or scopolamine from a patient with treated open-angle glaucoma is the wrong answer.
• Open-angle glaucoma is painless and asymptomatic; peripheral arcuate/nasal-step loss precedes central acuity change, so 20/20 vision does not exclude glaucoma. USPSTF concluded evidence is insufficient (I statement) to recommend for or against screening asymptomatic adults for primary open-angle glaucoma.
• The association examiners love: pseudoexfoliation (white flaky material on the lens capsule and pupil margin) and pigment dispersion (Krukenberg spindle, iris transillumination defects in a young myope) as secondary open-angle causes; also corticosteroids in any form as an iatrogenic cause.
• Buphthalmos, epiphora, photophobia, and blepharospasm in an infant means congenital glaucoma — the immature sclera stretches rather than cups, and management is surgical (goniotomy/trabeculotomy).
• Normal-tension glaucoma still requires IOP lowering; a "normal" pressure never rules glaucoma out, and thin corneas make measured IOP read falsely low.