Early detection and therapy for prevention of vision loss

Glaucoma: early detection and therapy for prevention of vision loss

Lisa F. Rosenberg

Glaucoma is second only to macular degeneration of aging as a cause of irreversible blindness in the United States.[1] Glaucoma is the most common cause of blindness among blacks, who tend to have severe optic nerve damage at an earlier age than whites.[2] Data from population-based studies.[2,3] vary widely but suggest that between 80,000 and 150,000 Americans are blind as a result of glaucoma. An estimated 2.5 million persons in the United States have glaucoma and, unless early ophthalmologic care is obtained, most persons remain unaware of the condition until late in the disease process, when the optic nerve is so severely damaged that central vision is impaired.

Definition and Diagnosis


Primary open-angle glaucoma is a bilateral disease initially characterized by damage to the optic nerve, resulting in loss of peripheral vision. Eventually, central vision becomes impaired as well. Optic disc findings include progressive changes in the appearance of the optic nerve head. These changes lead to enlargement of the central cup, thinning of the neuroretinal rim and focal abnormalities of the disc rim, such as hemorrhage or notching (Figures 1 and 2). Computerized and manual perimetry are used to measure visual field function (Figures 3 and 4).

While one-half of patients with glaucoma have an intraocular pressure greater than 21 mm Hg when glaucoma is detected, elevated intraocular pressure is not essential to make the diagnosis. Elevated intraocular pressure is a result of improper function of the trabecular meshwork drain of the eye, located within the anterior chamber angle (Figure 5, left).


Primary angle-closure glaucoma is far less common than primary open-angle glaucoma and results from obstruction of the drain of the eye by the iris. Increased surface apposition of the lens to the iris causes an increased resistance to the normal flow of aqueous humor from the posterior chamber through the pupil to the anterior chamber (pupillary-block mechanism). The resultant pressure gradient between the posterior and anterior chambers causes the iris to bow forward and obstruct the trabecular meshwork, leading to elevation of intraocular pressure (Figure 5, right).

Angle-closure glaucoma generally is bilateral and has a predilection for far-sighted women in their 50s. Surgical treatment with laser iridotomy or incisional iridectomy allows aqueous humor to bypass the pupillary block and eliminates the pressure gradient between the anterior and posterior chambers. Timely treatment may also prevent permanent damage to the trabecular meshwork and other ocular structures, and most importantly, the optic nerve. Residual elevation of intraocular pressure after an iridotomy signifies permanent outflow impediment resulting from adhesions between the iris and the trabecular meshwork. Subsequent treatment is directed at preventing optic nerve damage and is the same as treatment for open-angle glaucoma, which is the focus of this article.

When undetected or inadequately treated, glaucoma is a relentlessly progressive, potentially blinding disorder. The speed at which optic nerve damage develops is influenced by various risk factors discussed below. While glaucoma is not curable, it is treatable.

Risk Factors


Elevated intraocular pressure is the most consistent risk factor for the development of progressive optic nerve damage. When intraocular pressure is higher than the statistically normal level (21 mm Hg), loss of visual field develops at a rate of about 1 percent per year.[4,5] However, there is no level of intraocular pressure below which persons are free of risk for glaucomatous optic nerve damage; likewise, there is no intraocular pressure above which damage always occurs. Therefore, optimal intraocular pressure for the maintenance of good ocular health must be determined individually and reassessed regularly for every patient.

While elevated intraocular pressure correlates with progressive optic nerve damage, its sensitivity, specificity and positive predictive value for the presence of glaucoma is poor. In one-half of all persons with glaucoma, intraocular pressure is below 22 mm Hg at the time of screening.” Screening is most effective when measurements of intraocular pressure are considered in combination with visual assessment of the optic nerve and evaluation of historical risk factors.


A large optic cup suggests glaucomatous damage.[9,10] The normal optic disc consists of fenestrated connective tissue, called the lamina cribrosa, through which approximately 1 million axons exit to the brain. In many eyes, a physiologic depression, called the cup, is present in the lamina cribrosa. The average cup-to-disc ratio is 0.3 and appears symmetric between the two eyes. In glaucoma, the neuroretinal rim becomes thin, and the cup becomes enlaged as nerve fibers atrophy. Often, glaucoma affects the eyes asymmetrically, so that one cup appears larger than the other. When a cup-to-disc ratio of 0.6 or greater is observed ophthalmoscopically, or when asymmetry is evident between the two eyes, glaucoma should be suspected. Ophthalmoscopy is the single most valuable and sensitive examination the family physician can perform to screen for glaucoma.


The risk of glaucoma increases substantially with age.[1,11] The prevalence of elevated intraocular pressure rises from approximately 2 per-cent in patients under 40 years of age to approximately 9 percent in patients over 70 years of age. Therefore, the proportion of patients with optic disc damage and vision loss rises from 1 percent in persons 40 to 49 years of age to at least 20 to 30 percent in those over the age of 70.[1,11,12]


Blacks tend to have a more aggressive form of open-angle glaucoma.[2,3,13] Optic nerve damage tends to occur at least one decade earlier in this group than in other populations. It is also more severe at the time of diagnosis and is more refractory to treatment in blacks.


Glaucoma exhibits a hereditary tendendency.[9,10,14] The genetic basis of glaucoma is being actively sought, but it is not yet well understood. A gene for one type of juvenile glaucoma has been localized to chromosome 1q21-q31.[15]


Abnormalities in vascular function, such as arterial hypertension,[16,17] diabetes mellitus[18] and migraine,[19] have been associated with glaucoma, although the relationships are not well understood. The incidence of elevated intraocular pressure increases with age, as does the incidence of diabetes and arterial hypertension, yet the latter two conditions are not necessarily causally related.

Medication taken to regulate blood pressure may reduce intraocular pressure. Moreover, systemic antihypertensive medication taken before bedtime may cause blood pressure to decrease to very low levels during sleep. When this drop occurs, blood flow to the optic nerve may be diminished. Reduced ocular blood flow may actually lead to further optic nerve damage and visual loss, particularly in patients whose baseline intraocular pressure tends to be low.


Myopia, or nearsightedness, seems to be another risk factor for the development of optic nerve damage.[20,21] The thinner eye wall and larger eye in myopic patients may predispose the eye to stretching and damage when subjected to elevated intraocular pressure.


Use of corticosteroids, especially the systemic types, may cause elevation of intraocular pressure. With chronic use of corticosteroids, cataracts may also develop. Yearly eye examination should be performed in patients using any form of corticosteroids for intervals longer than four weeks (such as persons with obstructive lung disease or transplant recipients).

Clinical Assessment

Up to 50 percent of patients with glaucomatous optic nerve damage have an intraocular pressure below 22 mm Hg.[1,22] Whenever possible, measurement of intraocular pressure should be made by applanation tonometry because it is more accurate than Schiotz tonometry, which tends to underestimate intraocular pressure and is somewhat cumbersome. Newer, portable hand-held tonometers – while expensive – provide an alternate means of safely measuring intraocular pressure. However, intraocular pressure cannot be relied on as the sole means of diagnosing glaucoma.

Optic nerve appearance and visual field status provide crucial complementary information. Unfortunately, measurement of the visual fields is usually impractical as a screening tool because it requires specialized instrumentation, trained personnel and an examination period of 10 to 20 minutes for each eye. Moreover, significant optic nerve changes are apparent on ophthalmoscopic examination before abnormalities in the visual field are detected. Therefore, ophthalmoscopic examination of the optic nerve head for damage is the most sensitive and cost-effective, but underused, method of screening for glaucoma in the primary care setting.[23] It is especially efficient for screening high-risk populations that underutilize preventive health measures, such as blacks and elderly persons.

Pharmacologic dilation of the pupils, such as with 0.5 percent tropicamide, aids examination of the ocular fundus. The clinical information elicited during pupil dilation outweighs the accompanying low risk of precipitating acute angle-closure glaucoma. If the optic nerve appears to have a large cup-to-disc ratio, asymmetry of cupping, narrowed disc rim or disc hemorrhage (Figure 2), glaucoma should be suspected and the patient should be referred to an ophthalmologist for comprehensive evaluation. Glaucoma screening (assessment of risk factors and ophthalmoscopy) can be carried out by the family physician during periodic health screening examinations beginning at 35 years of age.



Americans, especially those in high-risk groups, are largely unaware of the risk factors for glaucoma and of the importance of periodic ophthalmic examinations in reducing, delaying or preventing loss of sight. Glaucoma 2001, a public service project, is committed to reducing the incidence of blindness from undetected and untreated glaucoma by the year 2001. Sponsored by the Foundation of the American Academy of Ophthalmology, the program will be available to family physicians in all states in January 1996. Glaucoma 2001 aims to enhance physician and public awareness of glaucoma risk factors (age, race, family history, last complete eye examination). The project emphasizes evaluation of risk factors, in conjunction with ophthalmoscopy, as the best way for family physicians to identify patients who are in need of more extensive testing (Table 1). Each risk factor is assigned a relative weight. The risk of glaucoma is determined by combining risk factors to determine a total score; a patient with a score of 4 or greater is considered to be at high risk for glaucoma.


Analysis of Risk Factors for Glaucoma

Variable* Weight Age

Less than 50 years 0

50 to 64 years 1

65 to 74 years 2

More than 75 years 3 Race

White/other 0

African American 2 Family history of glaucoma

None or only in non-first-degree 0


Positive in parents 1

Positive in siblings 2 Last complete eye examination

Within past two years 0

Within past two to five years 1

More than five years ago 2 Total

NOTE: A patient is considered to be at high risk for glaucoma if the cumulative score is 4 or greater; moderate risk if score is 3; low risk if score is 2 or less.

* – Other historical variables, such as high myopia or hyperopia, systemic hypertension, steroid use and, perhaps, diabetes, are not strong enough to be assigned a weght but may be considered in the overall assessment of glaucoma risk.

From American Academy of Ophthalmology. Glaucoma 2001 Project Risk Factor Analysis card, copyright 1994: American Academy of Ophthalmology. Used with permission.

Ophthalmologists participating in Glaucoma 2001 will provide a medical eye examination, at no out-of-pocket expense to the patient, to all referred persons who have been determined to be at risk for glaucoma. More information about the Glaucoma 2001 project can be obtained by telephone: 800-391-EYES.


Glaucomatous change develops rapidly in a relatively small number of persons with glaucoma. Thus, the decision to treat involves assessment of historical and objective risk factors. Patients who are at high risk for glaucomatous optic neuropathy or already exhibit signs of the disease are usually candidates for treatment. The goal of treatment is to lower intraocular pressure (the only risk factor amenable to treatment) to such a level that further optic nerve damage is unlikely. This “target” pressure may vary during the course of the disease. The chosen target pressure takes into account the severity of optic nerve damage, the absolute level of intraocular pressure and, if known, the rapidity with which damage has occurred. In general, the more advanced the damage to the optic nerve, the lower the target pressure. However, since the protective effect of lowered intraocular pressure is not absolute, relentless deterioration may continue in some patients despite seemingly normal intraocular pressure. Other factors, in addition to intraocular pressure, appear to play an important role in the disease process.

Intraocular pressure is lowered by any combination of three treatment modalities: medication (topical and systemic), laser surgery and filtration surgery. Glaucoma is particularly challenging to manage because it is chronic, often asymptomatic and requires multiple, expensive medications that must be used frequently and often cause untoward side effects. A high level of compliance is required, because treatment for glaucoma is lifelong. The patient’s physical condition and social situation profoundly affect his or her ability to comply with treatment and, thus, must always be taken into account. Treatment, therefore, will vary from patient to patient but have the universal goal of conferring the greatest benefit at the lowest risk, cost and inconvenience to the patient.


Antiglaucoma drugs (Table 2) exert their pharmacologic effect by acting on the cholinergic and adrenergic branches of the autonomic nervous system within the eye. Acetylcholine is the postganglionic mediator of the cholinergic nervous system. It is inactivated by acetylcholinesterase. Stimulation of the cholinergic receptor increases aqueous humor outflow following contraction of the ciliary muscle, which is located at the base of the drain of the eye. Both alpha- and beta-adrenergic receptors appear to influence aqueous humor dynamics, and the interactive mechanisms are complex. In general, stimulation of the beta receptors increases aqueous humor outflow, while inhibition reduces aqueous humor production.


Commonly Prescribed Antiglaucoma Medications and Adverse Effects

Drug Adverse effects Beta blockers Bronchospasm,

exacerbation of Timolol (Timoptic) congestive heart failure,


Levobunolol (Betagan Liquifilm, conduction disturbances,

depression, AK Beta) confusion, impotence,

worsening of Metipranolol (Optipranolol) myasthenia gravis,

elevated serum Carteolol (Ocupress) lipid levels Betaxolol (Betoptic) Adrenergics Tachycardia, hypertension,

tremor, Apraclonidine (Iopidine) anxiety Epinephrine (Epifrin, Glaucon) Dipivefrin (Propine) Miotics Exacerbation of congestive

heart failure, Pilocarpine hydrochloride gastrointestinal upset,


(Adsorbocarpine, Akarpine, dysrhythmias

Isopto Carpine, etc.) Pilocarpine nitrate (Piloptic,

Pilagan) Carbachol (Isopto Carbachol) Physostigmine sulfate (Eserine

Sulfate) Physostigmine salicylate

(Isopto Eserine) Echothiophate (Phosopholine) Isoflurophate (Floropryl) Carbonic anhydrase inhibitors Lethargy, paresthesias,

depression, Acetazolamide (Diamox) gastrointestinal upset,

nephrolithiasis, Dorzolamide (Trusopt)* rash, impotence, blood

dyscrasias Methazolamide (Neptazane) (aplastic anemia)

* – Topical formulation recently released june 1995); no adverse effects have been

Systemic effects from topical medications occur when the drug is absorbed by the nasal mucosa. Closing the eyelids gently for three to five minutes or applying pressure across the upper and lower eyelids with the thumb and index finger helps to reduce nasolacrimal drainage of the drug into tears by eliminating blinking movements. Newer antiglaucoma drugs have improved compliance and reduced ocular side effects in many patients.


In most instances, treatrment begins with a beta-adrenergic blocker. Pharmacologic treatment is dominated by two classes of topical beta-adrenergic antagonists: nonselective beta,- and [beta.sub.2]-receptor blockers (timolol [Timoptic], levobunolol [Betagan Liquifilm, AK Beta], metipranolol [Opti-Pranolol], carteolol [Ocupress]), and a selective [beta.sup.1]-receptor blocker (betaxolol [Betoptic]). Beta blockers are the drugs most commonly used in the treatment of glaucoma because of their effectiveness, low incidence of side effects, and once- or twice-daily dosing. The mechanism of action of beta blockers is to reduce aqueous humor formation.

While numerous potential side effects arise from beta-blocker therapy, the most important are cardiac and pulmonary complications (Table 2). Because of the effect of beta, blockers on cardiac contractility and the effect of [beta.sub.2] blockers on the pulmonary system, beta blockers may worsen congestive heart failure, induce or exacerbate bradycardia and incite bronchospasm. Betaxolol, the only selective [beta.subs.1] blocker available, has less systemic absorption and is associated with a lower incidence of pulmonary and cardiovascular side effects than other nonselective beta-receptor antagonists. However, it also has less of an ocular hypotensive effect.

Other adverse effects of beta blockers include central nervous system effects, such as confusion and depression, especially in elderly patients. Impotence and worsening of myasthenia gravis may also occur. Beta blockers also produce small adverse alterations in serum lipid profiles, specifically with respect to the ratio of total cholesterol to high-density lipoprotein cholesterol.24


Epinephrine derivatives are second-line drugs and require only twice-daily dosing but are not nearly as effective as beta blockers. Adrenergics are direct alpha and beta stimulators, and lower intraocular pressure by increasing aqueous humor outflow. Use of these compounds is often limited by the frequent occurrence of ocular allergy. Elevated blood pressure, tachyarrhythmias anxiety have been associated with use of these agents. Dipivefrin (Propine) is a prodrug that is converted to epinephrine within the eye and rarely causes systemic side effects.

Apraclonidine (Iopidine), a derivative of clonidine, is a new [alpha.sub.2]-agonist that reduces intraocular pressure by decreasing aqueous humor production. Secondary effects on anterior ocular circulation may also contribute to a reduction in intraocular pressure. Because apraclonidine is unable to cross the blood-brain barrier, alterations in cardiovascular parameters are rare.


The most commonly used miotic agent is pilocarpine, which stimulates muscarinic binding of acetyldiohne within the neuro-muscular junction of the iris, thereby lowering intraocular pressure by enhancing aqueous humor outflow. This drug is the most challenging to patient compliance because it requires four-times daily dosing and causes blurred vision. Systemic complications from cholinergic stimulation (increased bronchial secretions, nausea, vomiting and diarrhea) are exceedingly rare and occur only when large doses are administered for an acute attack of angle-closure glaucoma. Echothiophate (Phosopholine), another miotic drug, acts indirectly by preventing acetylcholinesterase from hydrolyzing acetylcholine. Effects of echothiophate may prolong respiratory paralysis in patients receiving succinylcholine during general anesthesia.

The Author

LISA F. ROSENBERG, M.D. is assistant professor of ophthalmology at Northwestern University Medical School, Chicago. Dr. Rosenberg graduated from Rush Medical College in Chicago, and completed a residency in ophthalmology at Washington University School of Medicine in St. Louis. She subspecializes in glaucoma at Northwestern University, where she also completed a fellowship in glaucoma.

Address correspondence to Lisa F. Rosenberg, M.D., Department of Ophthalmology, Northwestern University Medical School, 300 East Superior Ave. (Tarry 5-715),


The oral carbonic anhydrase inhibitors, such as methazolamide (Neptazane) and acetazolamide (Diamox), lower intraocular pressure by decreasing production of aqueous humor through inhibition of the enzyme carbonic anhydrase, which is involved in the formation of aqueous humor. Systemic side effects are common and include malaise, anorexia, depression and paresthesias. The carbonic anhydrase inhibitors, particularly acetazolamide, may alter serum electrolytes and cause mild systemic metabolic acidosis. These changes are usually not clinicaly significant unless the patient is using another systemic diuretic. Carbonic anhydrase inhibitors alter urinary Citrate excretion and may induce renal calculi. Idiosyncratic blood dyscrasias, such as aplastic anemia, have also been linked to use of carbonic anhydrase inhibitors.

A topical formulation of a carbonic anhydrase inhibitor, dorzolamide (Trusopt), has recently become available for the treatment of glaucoma. This drug lowers intraocular pressure by inhibiting carbonic anhydrase in the ciliary body and, therefore, has none of the side effects associated with systemic carbonic anhydrase inhibitors.


If optimal intraocular pressure has not been achieved with medication, if intolerable side effects arise or if patient noncompliance is a problem, surgical intervention is recommended. The argon laser produces a high-energy light beam that is converted to heat when it is applied to the trabecular meshwork of the eye. The mechanism of action is unknown, but laser therapy improves aqueous outflow, perhaps by opening intratrabecular spaces or by stimulating the release of factors that regulate cell function in the trabecular meshwork.

Argon laser trabeculoplasty is an outpatient procedure that can be performed under topical anesthesia in the office or at tions rarely occur and include transient ocular irritation, inflammation and worsening of glaucoma. In some cases, the dose of antiglaucoma medication may be reduced after trabeculoplasty, while still maintaining an acceptable intraocular pressure. The effect of laser surgery may be only temporary, with failure to maintain lower pressures for five years occurring in one-half of treated eyes.


Glaucoma filtration surgery bypasses normal trabecular outflow and provides an alternate exit for aqueous humor. An opening into the eye is made at the junction of the cornea and sclera, usually under a flap constructed in the sclera. The flap is reapproximated by fine sutures, the tension of which determines the amount of aqueous humor outflow. Filtration surgery is reserved for patients in whom a satisfactory intraocular pressure cannot be maintained with medication or with laser surgery. Most surgeries are done on an outpatient basis, but frequent postoperative visits are required to monitor filtration function. While long-term control of intraocular pressure is often achieved, many patients may also require the addition of antiglaucoma medication. Recent developments in the use of postoperative fluorouracil(25) and intraoperative mitomycin-C (26) have increased the success of filtration surgery. These agents are potent inhibitors of wound healing, which is the most common reason filtration surgery fails to control intraocular pressure.

Additional surgical interventions for glaucoma, such as implanted plastic shunts and selective destruction of the ciliary body, may also be performed. These techniques are reserved for patients whose glaucoma is refractory to other treatment methods. The most important surgical complications are those that threaten vision. Massive bleeding and infection, while very rare, are the most feared complications since their occurrence often portends a disastrous ocular outcome. Other important complications include cataract formation an development of a wound leak.

Follow-up Evaluation

The purpose of the follow-up evaluation is to assess response to therapy and to alter or adjust treatment. Intraocular pressure is measured during every examination, and the appearance and functional status of the optic nerve are monitored periodically via visual field testing). The frequency of follow-up depends on the seventy of the disease. During initiation or adjustment of therapy, it may be necessary to examine the patient relatively often (e.g., weekly or monthly) until intraocular pressure is stabilized. Therapeutic compliance is continually assessed and close attention is paid to the management of side effects. It is important for the patient to understand that eye medications can manifest important systemic effects. The ophthalmologist is responsible for communicating the patient’s ocular regimen to his or her family physician. The patient should also be instructed to report all changes in medication to both the ophthalmologist and the family physician.

Future of Glaucoma Screening

and Management

Advances aided by computerized technology are being made in the detection and quantification of glaucomatous ocular abnormalities. Ongoing investigations are exploring new psychophysical tests of vision, including color vision analysis, blue-on-yellow visual field testing and testing of contrast sensitivity, dark adaptation and other measures of retinal function (such as the pattern electroretinogram). These types of testing offer the possibility of increased sensitivity for detection of visual defects currently not detected by standard visual field assessments. New computerized image-analysis systems for the measurement of optic nerve architecture aim to replace the subjective interpretation of optic nerve appearance with objective measurements.

New classes of therapeutic medications are being tested for efficacy in reducing intraocular pressure. Topical prostaglandin analogs have been shown to reduce intraocular pressure by a magnitude similar to that of the beta blockers and are well tolerated both systemically and ocularly. Ethacrynic acid, injected into the anterior chamber, is being studied as a possible long-acting (e.g., months) agent to reduce intraocular pressure by its effect on the microstructure within the outflow pathway. Although these new developments hold promise for earlier diagnosis and improved control of glaucoma, the screening and treatment partnership of family physicians and ophthalmologists remains important in the detection and management of this disease.

Figure 5 is adapted from Trobe ID. The physician’s guide to eyecare. American Academy of Ophthalmology, 1993. Used with permission. Supported by a grant to the Department Of Ophthalmology, Northwestern University Medical School, Chicago, by Research to Prevent Blindness, New York, N.Y.


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