David S. Friedman
Glaucoma is a progressive disease of the optic nerve head with a characteristic appearance (and cupping). Although many persons with glaucoma have elevated intraocular pressure (IOP), virtually all population-based studies of glaucoma have found that at the initial screening half of those with glaucoma have IOPs that are less than 21 mm Hg are not considered “normal.” In developed countries fewer than half of those with glaucoma know they have the disease, and in the developing world it is uncommon for persons with glaucoma to be diagnosed. Glaucoma is the second leading case of blindness in the United States, with over 2 million Americans affected. As with all chronic diseases associated with older age, glaucoma prevalence will increase in the coming decades to an estimated 3.2 million affected individuals, because of the aging of the U.S. population (1). Many more will require treatment and monitoring of high IOP.
The glaucomas are classified into primary and secondary groups (Table 108.1). Among African Americans, whites, and Hispanics, primary open-angle glaucoma accounts for 95% of all patients with glaucoma, but among other populations (e.g., Chinese and those from south India), angle-closure glaucoma accounts for almost half the cases (2, 3, 4). Secondary glaucomas occur when IOP is elevated because of a known cause such as trauma or intraocular inflammation and is far less common than primary open-angle and primary angle-closure glaucoma.
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TABLE 108.1 Types of Glaucoma |
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Anatomy and Physiology
The eye continuously circulates aqueous humor that maintains the shape of the eye and provides nutrition to avascular intraocular structures such as the lens (Fig. 108.1). IOP is maintained in a steady state by ongoing production and removal of aqueous humor. Elevated eye pressure is in part caused by obstruction to the outflow of aqueous humor at the level of the trabecular meshwork. The aqueous humor is a clear ultrafiltrate of the blood and occupies part of the posterior and anterior chambers of the eye. It is produced both by secretion and ultrafiltration at the level of the epithelium of the ciliary body. At least two enzymes have been implicated in aqueous formation: sodium/potassium-activated adenosine triphosphatase (ATPase) and carbonic anhydrase. Antagonists of these enzymes appear to reduce the rate of aqueous formation and thereby lower IOP. Once produced, the aqueous humor circulates from the posterior chamber into the anterior chamber of the eye. The trabecular meshwork, an intricate system of connective tissue fibers, is located in the periphery of the anterior chamber. The aqueous humor percolates through this meshwork to be reunited with the venous blood via the canal of Schlemm.
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FIGURE 108.1. Anatomy of the eye: cross-section of the cornea. (Modified from Basmajian JV. Grant's method of anatomy. 8th ed. Baltimore: Williams & Wilkins, 1971:543. ) |
Types of Glaucoma
Table 108.1 outlines the major types and causes of glaucoma. However, only primary open-angle glaucoma and primary angle-closure glaucoma are discussed in this chapter because they are the types likely to be seen regularly. Open-angle glaucoma takes its name from the normal-appearing anterior chamber angle, a contrast to the narrow angle of angle-closure glaucoma, as shown in Fig. 108.2. Individuals with normal-tension glaucoma behave similarly to those with higher pressure open-angle glaucoma, and research has shown that IOP-lowering therapy can prevent progression of the disease in these individuals (5).
Primary Open-Angle Glaucoma
Prevalence and Risk Factors
Primary open-angle glaucoma is by far the most common cause of glaucoma in the United States; the prevalence for
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persons of European descent older than the age of 40 is around 2%, while nearly 6% of African Americans in this age range are affected (6,7, 8, 9).
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FIGURE 108.2. Illustration showing a shadow cast on the na-sal side of the iris resultant from the bowed iris in angle-closure glaucoma (right). In open-angle glaucoma, the iris is not bowed, so the shadow is not cast (left). |
Prevalence increases substantially with age, approaching 10% for whites older than 75 years of age and 20% for blacks (2). Hispanics appear to have rates intermediate between whites and blacks. Indeed, because open-angle glaucoma is so prevalent, is asymptomatic, and is treatable, open-angle glaucoma is the primary reason behind the recommendation for annual eye examination for people 65 years and older. Primary open-angle glaucoma causes 15% to 20% of all blindness in this country (10). Men and women are affected equally, but African Americans are affected at a higher frequency and at an earlier age, and open-angle glaucoma is the leading cause of blindness in African Americans. Recent research in Hispanics in Arizona and Los Angeles indicates that Hispanics have rates similar to whites until their sixties, when rates increase dramatically and are closer to those of blacks (11, 12).
Open-angle glaucoma is familiar, but the pattern of inheritance is not yet known. Siblings of affected individuals are at 10 times the risk of having open-angle glaucoma (13). An association between open-angle glaucoma and both diabetes mellitus (DM) and elevated blood pressure has been proposed, but these hypotheses are uncertain and more research is necessary to define such relationships. Patients who have high degrees of myopia (near vision) likely are at higher risk of open-angle glaucoma, but this hypothesis is uncertain as well (14). Glaucoma risk may also be increased with prolonged use of oral and nasal glucocorticoid inhalers, especially in individuals with a family history of glaucoma (15,16).
Manifestations and Physical Examination
Open-angle glaucoma is typically asymptomatic until its latest stages. When symptoms do occur, damage to the optic nerve is present and may be substantial. Central vision and the ability to recognize forms on a vision test chart are preserved until very late. For this reason, testing of visual acuity is not a reliable method to screen for glaucoma. Occasionally, a patient with open-angle glaucoma may notice halos around lights and blurring of vision if there is a sudden rise in IOP. Patients with this history should be referred urgently to an ophthalmologist. Patients with open-angle glaucoma rarely complain of headache that can be attributed to increased IOP.
The ocular pressure may be elevated for years before any change in the optic disk is noted. The change in the optic disk is revealed by increasing excavation of the central physiologic disk cup, visible on funduscopic examination (Fig. 108.3). This is most easily seen by use of the direct ophthalmoscope, and by the ophthalmologist using a slit lamp and a handheld lens (which allows for stereoscopic viewing). Over years the pink color of the disk fades and becomes pale, and vessels coursing over the disk show a sharp bend at the rim. Patients thought to have an enlarged optic cup (cup-to-disk ratio ≥0.7) should be referred to an ophthalmologist within a month.
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FIGURE 108.3. Changes in the optic disk with increasing intraocular pressure showing on both the frontal and coronal views: (A)normal, (B) early change, and series (C) late change. |
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One should assume that open-angle glaucoma has no symptoms until the patient is on the verge of blindness. Detection must be accomplished based on knowledge of risk factors (age, race, and family history) and examination findings. The diagnosis is then confirmed after referral to an ophthalmologist.
In evaluating the patient with suspicion for glaucoma, the ophthalmologist typically measures the eye pressure, visualizes the angle of the anterior chamber and the fundus, and assesses the visual fields.
Screening for Open-Angle Glaucoma
The ideal method for screening for primary open-angle glaucoma is controversial, and false positive and false negative detection rates are high. Population-based screening for glaucoma remains difficult because of the lack of an ideal screening device, the relatively high cost of screening and referral, and the limited data on treatment efficacy. However, recent developments have increased the evidence in support of wider screening, and the Center for Medicare and Medical Services recently added a benefit for glaucoma screening to Medicare beneficiaries with known risk factors. A new screening device, the frequency doubling technology perimeter, has demonstrated sensitivity and specificity over 90% in several reports, but widespread effectiveness has not been tested (17,18). Additionally, two large clinical trials indicate that lowering eye pressure is associated with slower progression of glaucoma (5,19), and one multi-center study demonstrated that lowering IOP decreases the likelihood of developing glaucoma in individuals with elevated IOP who do not have optic nerve damage (20).
Screening for glaucoma involves one of three different approaches: tonometry, funduscopic assessment or imaging of the optic cup and nerve fiber layer, and visual field assessment. For years it was recommended that primary care clinicians screen high-risk patients for glaucoma by measuring eye pressure directly with a Schiotz tonometer. This approach is too insensitive and nonspecific to be of value. IOP screening, even with ideal instruments, has poor screening characteristics, because half of all individuals with glaucoma will have eye pressures in the normal range on a single IOP screen. New digital imaging devices show promise for detecting glaucoma by assessing the optic nerve head appearance. These instruments can collect data through an undilated pupil in under 1 minute and may be more widely used in the future (21). Finally, functional tests such as the perimeter described above show promise as screening devices. They obtain results in under 2 minutes per eye, are portable and inexpensive, and could conceivably be used in public settings such as departments of motor vehicles. Others have adapted this approach to the Internet so that individuals can test themselves. More research is needed, however, to study the performance of each of these devices in community-based populations. Because ophthalmologists generally do all three evaluations, the ideal screening approach at present is a complete eye examination. Primary care clinicians are encouraged to advise white and Hispanic patients age 65 and older (those at higher risk) to be referred to an eye specialist every 1 or 2 years glaucoma screening, whereas African Americans should be referred at an earlier age, perhaps even age 50.
Patients referred to an ophthalmologist generally have an evaluation consisting of several observations: determination of the IOP by applanation tonometry; funduscopic assessment of the optic disk and retina through the dilated pupil; visual field assessment, usually with a computerized perimeter; and gonioscopic examination, which permits the ophthalmologist to visualize the angle of the anterior chamber by using an instrument containing a contact lens and mirror. The patient usually experiences minimal or no discomfort during these procedures.
Approximately one fifth of patients found to have asymptomatic increased IOP on preliminary screening are shown to have glaucoma after thorough evaluation. Approximately 30% may be found not to have elevated pressures on reassessment, and about 50% have “ocular hypertension” without glaucoma. A large National Institutes of Health (NIH)-funded trial recently documented that individuals with elevated IOP have about a 10% risk of developing early glaucoma over 5 years of followup, and this risk can be reduced by half with lowering of IOP (20). Furthermore, important risk factors were identified in that trial to help determine which individuals with elevated IOP require treatment (22). Important risk factors included higher IOP, larger cup-to-disc ratio, and a thin central cornea. Individuals with certain combinations of these characteristics had over a 30% risk of developing glaucoma over 5 years, while those in the lower risk groups had about a 2% risk. Risk assessment is therefore an important aspect of the management of ocular hypertension.
Treatment
When the ophthalmologist establishes the diagnosis of open-angle glaucoma, treatment is prescribed based on the level of IOP, the degree of visual field loss, and the amount of optic nerve damage. As stated above, lowering IOP in individuals with open-angle glaucoma has recently been proven to slow the rate of progression of the disease. IOP lowering can be achieved by three different approaches: medical therapy, laser treatment, and surgical proce-dures.
Most ophthalmologists initially treat open-angle glaucoma with medicines, although the American Academy of Ophthalmology Preferred Practice Pattern recommends that all three approaches be discussed and considered as potential primary treatments. While a recent NIH-sponsored multicenter clinical trial comparing surgery to medications as first-line therapy showed no difference in outcomes at 5 years, most ophthalmologists do not recommend surgery until later in the disease course given the potential for poor outcomes that exists.
The options for medical treatments have increased over the last decade with the addition of topical prostaglandins, α-agonists, and carbonic anhydrase inhibitors (CAIs). IOP-lowering drugs work by one of three mechanisms: they decrease aqueous production (β-blockers, α-agonists, and CAIs), increase outflow through the trabecular meshwork (miotics, prostaglandins, and α-agonists), or increase outflow through alternative pathways (uveoscleral outflow, prostaglandins).
The aim of therapy is to maintain the IOP at a level that does not lead to further optic nerve damage. Target pressures are chosen based on the IOP at which the patient sustained damage and the severity of the glaucoma. For example, an individual who presents with severe damage at a pressure of 20 mm Hg likely needs a pressure around 14 mm Hg to be safe, whereas an individual with mild disease and a pressure of 30 mm Hg might be followed at an IOP of 24 mm Hg. The relatively low rate of side effects and effective IOP-lowering with prostaglandins has led to wide use of these compounds, and they are now the most frequently prescribed first-line therapy for glaucoma. Furthermore, prostaglandins are used once a day, resulting in greater patient compliance. No definite systemic side effects have been shown to be caused by prostaglandins. Ocular side effects include changing blue or hazel eyes to brown in a significant proportion of individuals. These agents also increase eyelashes in number and length. β-Blockers are still frequently prescribed for glaucoma either as primary or secondary therapy. α-Agonists and topical CAIs are less frequently prescribed, and appear slightly less effective than prostaglandins and β-blockers. Combination drops are also available, with a combination β-blocker and topical CAI widely used. Miotics, which were the mainstay of therapy for many years, are now rarely used because they cause miosis and dim vision. Eye drops enter the bloodstream directly through the nasal mucosa without any first pass through the liver, resulting in relatively high drug levels in the blood. β-Blocking agents can exacerbate congestive heart failure, can cause shortness of breath in otherwise healthy elderly individuals (23), lead to depression, and raise low-density lipoprotein (LDL) cholesterol. α-Agonists can cause dry mouth and, in up to 10% of patients, significant lethargy. All individuals on these agents should be questioned about this side effect, because many may not identify the association with the eye drops they are taking. α-Agonists can also lead to systemic hypotension. Topical CAIs are usually well tolerated with no reports of aplastic anemia or kidney stones caused
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by these agents since they were released nearly 10 years ago.
Oral CAIs are now rarely prescribed for glaucoma. Topical CAIs are used first, but in rare patients, oral CAIs can significantly drop the eye pressure when topical therapy is inadequate. Oral CAIs have myriad side effects (Table 108.2) and are therefore only used as a last resort.
Topical agents for glaucoma are usually tested in a one-eyed trial to see if they are effective for the patient. Once effectiveness and tolerability is determined, the agents are typically used bilaterally unless there is no evidence of disease in the contralateral eye. Once the target IOP has been attained, the ophthalmologist usually examines the patient two to four times per year for assessment of visual fields, measurement of IOP, funduscopic examination, and gonioscopy.
Argon laser trabeculoplasty is an alternative approach to lowering IOP for individuals with glaucoma and ocular hypertension and is considered a reasonable first-line therapy. This office procedure requires only topical anesthesia and can result in a significant reduction in ocular pressure in close to 90% of patients. However, this effect is frequently transient, with about 50% of treatments still effective 5 years after initial treatment (24). The safety of this treatment is well documented in two large NIH-sponsored clinical trials (24,25). The mechanism by which laser trabeculoplasty exerts its beneficial effects is uncertain but is most likely due to the release of chemical mediators in the trabecular meshwork at the time treatment. A modification of this procedure using a different laser may allow for more repeat laser treatments than is currently possible using the argon laser, but data remain limited as to whether or not multiple treatments are effective.
Surgery in primary open-angle glaucoma is designed to construct outflow channels for the aqueous humor or, in the some severe cases, to destroy the ciliary body in order to decrease aqueous production. Surgery lowers pressure more than medicines or lasers but has more potential adverse consequences. In the last few years, tremendous advances have been made in glaucoma filtering surgery. The major problem with the procedure, which makes a hole in the eye to allow aqueous drainage into the subconjunctival space, is the tendency for healing, which closes the hole and results in failure to control IOP. Topical antimetabolites used at the time of surgery are associated with a substantial increase in the success rate by preventing scarring of the new channel. There is concern about late infections in all patients who have had glaucoma filtering surgery, and late infections may be more common in these antimetabolite procedures. Currently, unless results from new trials recommend otherwise, surgical procedures are reserved for patients in whom medical management fails. Medications may still be required after surgery. New nonpenetrating procedures, in which the aqueous fluid percolates through a very thin membrane of tissue that is left at the time of surgery, are under investigation and show promise. These appear to have a safer profile than standard filtration procedures, but do not lower IOP as much as the more standard glaucoma procedure (“trabeculectomy”). Another significant improvement on the horizon is the use of more specific agents to modulate wound healing. These drugs may lead to more healthy tissue after surgery and may reduce the likelihood of eye infections in operated eyes.
Monitoring
The patient with open-angle glaucoma must receive regular ophthalmologic followup, but claims data indicate that a substantial proportion drop out from care. The generalist can remind patients of the need for regular examinations if they carry a glaucoma diagnosis. In addition, the primary care clinician should be alert to any side effects from the drugs prescribed by the ophthalmologist (Table 108.2).
There has been concern about the impact of systemic medications on glaucoma, particularly anticholinergics, adrenergics, hypnotics, and corticosteroids. Except for corticosteroids, none of these drugs is contraindicated in open-angle glaucoma. The concern raised by these
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medications is that they can cause acute angle-closure glaucoma in susceptible individuals, but angle-closure glaucoma is relatively rare among most U.S. populations, and individuals with angle-closure who are diagnosed are routinely treated with iridotomy which removes the risk from most of these medications. Systemic corticosteroids (including inhaled steroids) and, in particular, corticosteroids applied to the eye may raise IOP and are relatively contraindicated in open-angle glaucoma.
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TABLE 108.2 Systemic Effects of Medications Used to Treat Glaucoma |
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Primary Angle-Closure Glaucoma
The basic defect in primary angle-closure glaucoma is the inability of aqueous humor to reach the filtration apparatus. When the pupil is in a mid-dilated position, the iris is bowed forward and blocks the outflow of aqueous humor (Fig. 108.2). The primary site of aqueous blockage is at the iris–lens interface. The iris moves forward as the pressure rises behind it, and physically blocks the trabecular meshwork. Chronic forms of angle closure also exist.
Although angle-closure glaucoma is far less common than open-angle glaucoma in the United States, one must be aware of the possibility of acute angle-closure attacks. These can occur spontaneously, or they may be precipitated by the use of mydriatics, sympathomimetics, hypnotics, and in several instances, topiramate (an antiseizure medicine); if this occurs, urgent recognition and treatment are mandatory to prevent damage to the eye. Additionally, cases of angle-closure glaucoma can be misdiagnosed as possible neurosurgical or gastrointestinal conditions (because of symptoms such as headaches and nausea and vomiting), so recognition of the condition is important. Patients may have a positive family history, women are affected more than men, and the condition is far more common among Asians and those from the Indian subcontinent than among whites, African Americans, and Hispanics.
Patients who have smaller eyes with shallow anterior chambers are predisposed to primary angle-closure glaucoma. Patients with these predispositions can develop either acute attacks of angle-closure glaucoma, with extremely elevated eye pressure and pain, or can develop a silent form of the disease known as chronic angle-closure glaucoma. The probability of inducing acute angle-closure glaucoma through dilation of the pupils in older blacks and whites is less than 1 in 3,000, so one should use mydriatic eyedrops for individuals in need of a detailed examination of the eye whenever medically necessary. If an acute attack develops in such a circumstance, it can often be treated rapidly with minimal adverse sequelae.
Diagnosis
Early diagnosis of an acute angle closure crisis is critical because blindness may ensue and virtually every case is surgically curable if diagnosed early. Cure is increasingly less likely if repeated attacks have occurred and have resulted in scarring of the trabecular meshwork. Although many acute attacks occur without any prodromal symptoms, some may experience episodes of ocular pain (usually located in the periocular or supraocular region), episodes of blurred vision, and seeing halos around lights at night before the initial attack. These symptoms occur because of corneal epithelial edema that has developed as a result of the increased IOP. Often patients find relief in well-lighted rooms or outdoors, where daylight causes constriction of the pupil and opening of the anterior chamber angle.
Examination during an acute attack usually reveals marked elevation of IOP, from 25 to as high as 90 mm Hg. The eye is red and painful, although rarely the patient complains of abdominal pain or headache only. Frequently there is tearing and photophobia. Corneal edema is present during an acute attack, and the anterior chamber may appear cloudy because of inflammation.
In patients predisposed to angle-closure glaucoma, the anterior chamber is shallow. This may be seen by illuminating the eye with a flashlight from the side and showing a shadow resulting from the bowed iris over the nasal portion of the eye (Fig. 108.2). This penlight test does not appear to separate well individuals with occludable angles from those with open angles, and is of questionable value in a general practitioner's office. Examination of the anterior chamber angle with a gonioscopic lens may reveal scarring of the trabecular meshwork and peripheral anterior synechiae.
Differential Diagnosis
The patient who has acute angle-closure glaucoma may present with an acute red eye. Initially, angle-closure glaucoma should be differentiated from acute iritis, acute conjunctivitis, and iridocyclitis. Chapter 109 discusses this differential diagnosis.
Treatment
Severe attacks of angle-closure glaucoma may cause blindness in 2 to 3 days or less depending on the level of IOP and the sensitivity of the optic nerve to ischemia. In some instances, ciliary ischemia stops aqueous production before blindness occurs. However, untreated acute attacks typically result in severe blinding glaucoma.
If the diagnosis of acute angle-closure glaucoma is suspected, an urgent referral to an ophthalmologist is indicated. The ophthalmologist probably will initiate treatment with immediate administration of acetazolamide (Diamox) 500 mg orally and instillation of pressure-lowering eye drops. If it will take hours to reach an ophthalmologist, therapy should be initiated in advance. In severe
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cases, the ingestion of hyperosmotic glycerol—1 mL/kg mixed as a 50% solution with chilled juice—almost always interrupts an acute attack. Hyperosmotic agents such as glycerol or intravenous mannitol dehydrate the vitreous and lower eye pressure. Practitioners who use mydriatics for funduscopic examination or who have patients with narrow anterior ocular chambers may want to have an angle-closure kit consisting of glycerol (glycerin, available as generic), acetazolamide (Diamox), and a β-blocker eye drop for use if an acute attack develops. Other possible treatments for an acute angle-closure crisis include laser iridoplasty and paracentesis, but these are generally carried out by an ophthalmologist.
Patients found to have a shallow anterior chamber even if they have not had a symptomatic attack of glaucoma should be referred to an ophthalmologist for evaluation, for education regarding specific manifestations of an acute attack, and for their initial treatment, usually prophylactic argon laser iridotomy.
The definitive treatment of acute primary angle-closure glaucoma is essentially surgical. If the diagnosis is made early enough in the course of the disease, a peripheral iridotomy can be done to relieve the pupillary block and allow the IOP to return to normal. In some acute cases, the trabecular meshwork remains permanently damaged or the filtering angle is scarred closed. Chronic medical therapy or even surgery may be required to prevent progressive optic nerve damage in these cases. Laser peripheral iridotomy under topical anesthesia has little risk and results in cure in most cases. Surgical iridectomy may also be performed. The laser iridotomy in the attack eye is performed as soon as the view is clear enough to do so. Generally, the laser iridotomy in the contralateral eye is performed soon after the attack, within 1 or 2 days. Followup care by the ophthalmologist after laser iridotomy is necessary to confirm that IOP control has been achieved.
When a patient has a shallow anterior chamber or is under treatment for angle-closure glaucoma, there should be concern about the use of certain medications. Systemic anticholinergics and adrenergic drugs may rarely precipitate an acute attack by causing dilation of the pupils. Hypnotics have also been implicated in causing acute attacks. Corticosteroids or vasodilating drugs are not contraindicated in patients with angle-closure glaucoma.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.