Primary Open-Angle Glaucoma (POAG)

Signs and Symptoms: Although early and moderate POAG patients are virtually asymptomatic, there are definitive signs: progressive enlargement of the optic cup at the expense of the neuroretinal rim (either diffusely or focally) and repeatable visual field loss. Other glaucomatous signs include elevated intraocular pressure in many cases, nerve fiber layer (NFL) loss, notching of the neuroretinal rim at the inferior or superior poles, advancing peripapillary atrophy and NFL hemorrhages emanating from the optic disc.

Pathophysiology: Even today, much remains unknown about this disease. Elevated IOP almost certainly plays a significant role, but the process is poorly understood. According to the mechanical theory of POAG, chronically elevated IOP distorts the lamina cribrosa, crimping the axons of retinal ganglion cells as they pass through the lamina cribrosa and eventually killing the cells. The vascular theory suggests that with elevated IOP, reduced blood flow to the optic nerve starves the cells of oxygen and nutrients.

Advanced cupping and nerve fiber layer defect in primary open angle glaucoma.

More recent research suggests another mechanism of ganglion cell death. Some glaucoma patients exhibit elevated levels of the neurotransmitter glutamate within the vitreous. Ganglion cells contain protein receptors that, when activated by glutamate, increase intr acellular calcium to toxic levels, forming destructive free radicals that kill the cells. This plays into the apoptotic theory of glaucoma--a neurocellular process in which a retinal ganglion cell will commit "suicide." Apoptosis is a normal cellular event designed to ensure a healthy neurological system where non-viable cells are removed. Glaucoma is an abnormal expression of this normal process.

Excess glutamate accumulation--which may result from ischemia--may trigger apoptosis. Another possible inciting event: the deprivation of vital neurotrophic nutrients for the retinal ganglion cells from the lateral geniculate nucleus. The vital nutrient--brain derived neurotrophic factor (BDNF)--reaches the retinal ganglion cells from the lateral geniculate nucleus via axoplasmic transport. Elevated IOP and ischemia disrupt axoplasmic transport and deprive the retinal ganglion cells of this vital nutrient.

Management: Significant advances have been made in recent years in diagnostic devices for glaucoma. A scanning laser ophthalmoscope (Heidelberg Retinal Tomograph II) can identify abnormalities in optic disc morphology and compare them against a normative database, documenting changes to the optic disc topography over time. A scanning laser polarimeter (GDx Nerve Fiber Analyzer by Laser Diagnostic Technologies) can accurately identify changes in the retinal nerve fiber layer. Here again, a normative database assigns statistical significance and can identify abnormalities in the nerve fibers. Genetic testing (Ocugene) can identify patients with genetic characteristics of glaucoma and possibly predict the course of the disease.

Despite advances in diagnostic technology and new research into neuroprotection, the mainstay of glaucoma treatment remains IOP reduction. Beta-blockers are still very popular medications and used in many cases of POAG. Timoptic (timolol maleate, Merck) is the most commonly prescribed beta-blocker, but others are also noteworthy.

Endstage primary open-angle glaucoma.

Betoptic S (betaxolol 0.25% suspension, Alcon) selectively blocks beta-1 receptors, largely sparing beta-2 receptors in the lungs (making it a safer option for patients with certain pulmonary conditions, though other classes of medication may ultimately be safer for these patients). Other unique beta-blockers include Ocupress (carteolol, Novartis)--which has less propensity than other beta-blockers to elevate total cholesterol levels and reduce HDL cholesterol levels--and Timoptic-XE (timolol maleate, Merck), which allows for once-a-day therapy.

Alpha-adrenergic medications advanced with the development of Alphagan (brimonidine 0.2%, Allergan), a selective alpha-2 adrenergic agonist. This medication has an excellent safety profile and IOP-lowering potential similar to beta-blockers. While clinicians have frequently prescribed Alphagan bid, clinical studies show that it should be prescribed tid, especially when used as monotherapy. Otherwise, IOP control could be lost at times throughout the day. The most common adverse effect has been allergic reactions. A new formulation, Alphagan P (brimonidine 0.15% in Purite), has reduced the incidence of local allergic reactions by 41%.¹

Topical carbonic anhydrase inhibitors such as Trusopt (dorzolamide, Merck) and Azopt (brinzolamide, Alcon) have been successful in lowering the IOP in many patients. However, few clinicians use these medications as first-line therapy. Cosopt (Merck), which combines timolol 0.5% with dorzolamide, can be effective when a single agent fails to control IOP.

IOP control was revolutionized with the development of prostaglandin analogs and prostaglandin-like medications. Xalatan (latanoprost, Pharmacia) has enjoyed considerable success, offering outstanding IOP lowering, long-term control, and minimal local and systemic effects. Rescula (unoprostone, Novartis), actually a docosanoid, has a similar safety profile to Xalatan, though its IOP-lowering is not as great and it requires bid dosing.

More recently developed is Lumigan (bimatoprost, Allergan). Like Xalatan, this medication increases uveoscleral outflow of aqueous and has outstanding IOP-lowering ability. The medication is well tolerated systemically, hyperemia being the main adverse effect.

Another new prostaglandin analog, Travatan (travoprost, Alcon) apparently has a greater IOP-lowering potential in patients of African descent. It, too, is well tolerated systemically and ocularly. Travatan has been shown to be more effective than Timoptic in IOP reduction.^2-3

Clinical Pearls:

• Glaucoma is a long-term disease. Accumulate the necessary information so that you can diagnose with confidence. Do not to rush to a diagnosis. It typically is not necessary to diagnose the disease and start treatment at the patient's initial presentation.
• A single IOP measurement does not accurately represent the patient's true status, but is merely a snapshot pressure at that moment. Before making a diagnosis or initiating treatment, take repeated IOP measurements at different times on different days so that you have a more accurate picture of the patient's IOP "baseline range."
• While scanning lasers have not supplanted visual fields in the diagnosis and management of glaucoma, they provide useful information on optic nerve head and nerve fiber layer structure.
• Prostaglandins and prostaglandin-like medications are not FDA-approved as first-line therapy due to the possibility of inducing ocular inflammation and iris color changes. Yet many clinicians use them as first-line therapy.

1. Katz LJ. Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma 2002 Apr;11(2):119-26.
2. Fellman RL, Sullivan EK, Ratliff M, et al. Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: a 6-month, masked, multicenter trial. Ophthalmology 2002 May;109(5):998-1008.
3. Goldberg I, Cunha-Vaz J, Jakobsen JE, et al. Comparison of topical travoprost eye drops given once daily and timolol 0.5% given twice daily in patients with open-angle glaucoma or ocular hypertension. J Glaucoma 2001 Oct;10(5):414-22.

Other reports in this section

• Crystalline Lens Subluxation
• Ciliary-Block Glaucoma
• Primary Open-Angle Glaucoma
• Pigment Dispersion Syndrome and Pigmentary Glaucoma
• Pseudoexfoliation Syndrom and Pseudoexfoliative Glaucoma
• Anterior Uveitis