Low-pressure (normal tension) glaucoma is a type of open-angle glaucoma resulting in damage to the optic nerve and abnormalities of the visual field. Eye (intraocular) pressure in this type of glaucoma is not higher than that usually considered to be normal (less than 21 mmHg) for the eye. The present treatment of low-pressure glaucoma is also directed to lowering the "normal" eye pressure. Both medications in this study, brimonidine and timolol, lower eye pressure.

Laboratory research over the past decade indicates the potential to treat glaucoma not only by lowering eye pressure, but with treatments aimed at the damage occurring at the optic nerve. One group of drugs, selective alpha2-adrenergic agonists, have been shown in laboratory animals to protect against the effects of nerve damage following local stroke. Brimonidine, one of the medications in the current study, is a selective alpha2-adrenergic agonist which protects against damage to optic nerve in animal models of glaucoma..

The hypothesis of the present study is that brimonidine eye drops provide protection to the damaged optic nerve independent of lowering eye pressure in patients with low-pressure glaucoma. This will be determined by (1) measuring eye pressure, (2) performing visual field examinations, and (3) examination of the optic nerve.

The term glaucoma describes a specific pattern of optic nerve head and visual field damage caused by a number of different diseases of the eye, most (but not all) of which are associated with an elevated eye pressure. Glaucoma is currently considered to be a progressive neurodegenerative disorder. Low-pressure glaucoma (LPG) is a type of open-angle glaucoma (OAG) with progressive visual field and optic nerve damage despite an untreated eye pressure in the statistically normal (mean 15.9, SD 2.9 mmHg) range, usually less than 21 mmHg. Therefore, in this condition, pressure-independent mechanisms (e.g., vascular or structural defects of the optic nerve) may be the main, if not the sole, cause of the optic neuropathy. LPG represents 6.7% to 68.3% of all OAGs.

Current glaucoma treatment is directed to lowering eye pressure using medical therapy (eye drops), laser treatment, and/or surgery, to a level that stops progressive optic nerve damage. The efficacy of lowering eye pressure in LPG has been reported. Both protocol medical treatments, brimonidine and timolol, show similar efficacy to lower eye pressure.

Laboratory research over the past decade indicates the potential to manage glaucoma not only by lowering eye pressure, but with treatment modalities aimed at the damage occurring at the optic nerve. Possible therapies may include agents effective as neuronal protectants to increase or prolong the survival rate of injured retinal ganglion cells. Treatments could also be directed to the rescue of nerve fibers from secondary degeneration, as stimulants to expand dendritic fields, and to promote nerve regeneration or neural transplantation.

Selective α2-adrenergic agonists have been shown to have a neuroprotective effect in animal models of focal cerebral ischemia. Brimonidine is reported to protect the optic nerve and retinal ganglion cells from secondary degeneration following a partial crush lesion to the adult rat optic nerve. One molecular mechanism for this neuroprotection may relate to up-regulation of neuronal survival factors. In rats, systemic α2-adrenergic agonists induce basic fibroblast growth factor mRNA in the retina. Treatment with α2-agonists before and during constant light exposure reduces retinal photoreceptor degeneration in albino rats. Animal studies demonstrate that topical administration of brimonidine results in pharmacologic concentrations of drug in the vitreous (100-170 nM). Therefore, ocular dosing with brimonidine provides a route for drug delivery to the retina in amounts sufficient to bind and activate the α2-adrenoceptor and provide a neuroprotective effect.

The study hypothesis is to evaluate the ability of topical treatment with 0.2% brimonidine, a highly selective α2-adrenergic agonist, to impart neuroprotection to the damaged optic nerve in patients with LPG. Comparison is made to 0.5% timolol, a nonselective β-adrenergic antagonist, without reported neuroprotective properties. Patients will be randomly assigned to twice daily double-masked treatment with one of these drugs. Neuroprotection will be assessed by evaluation of automated static visual fields performed at 4 month intervals for 4 years of treatment.

Inclusion Criteria:

• Age: 30 years or older.
• Low-pressure glaucoma in at least one eye: untreated IOP < 21 mmHg, glaucomatous field loss on Humphrey 24-2 perimetry, and optic disc cupping.
• Best corrected visual acuity at least 20/40 in at least one eye.
• At least two visual fields within the 6 months prior to enrollment.
• Phakic or pseudophakic (cataract surgery > one year to enrollment) eye.

Exclusion Criteria:

Either eye patient exclusion:

• Past history of confirmed treated or untreated applanation IOP > 21 mmHg.
• Untreated IOP of > 21 mmHg on diurnal curve on Study Day 0.
• Untreated IOP > 4 mmHg difference between the two eyes.
• Extensive field damage: MD > 15 dB or threat fixation in both hemi fields.
• Evidence of exfoliation or pigment dispersion.
• History of angle-closure or occludable gonioscopic anterior chamber angle.
• Prior filtration surgery.
• Prior laser iridotomy.
• Laser trabeculoplasty < 6 months prior enrollment or for an IOP > 21 mmHg.
• History of chronic inflammatory eye diseases (e.g., scleritis, uveitis).
• History or signs of intraocular trauma.
• Severe or potentially progressive retinal disease.
• Any abnormality preventing reliable applanation tonometry.
• History of hypersensitivity to study medications or their components.
• Current use of any ophthalmic, dermatologic or systemic steroid preparation.
• Therapy with another investigational agent within the past 30 days.

Single eye exclusion:

• Cataract surgery within the past year.
• Aphakia.
• Only sighted eye.

Concomitant conditions:

• Resting pulse < 50 beats per minute.
• Unstable or uncontrolled cardiovascular, renal, or pulmonary disease.
• Recent heart attack or stroke.
• Women contemplating pregnancy, who are pregnant or are a nursing mother.