FREQUENTLY ASKED QUESTIONS: GLAUCOMA

Copyright, Robert Ritch, MD (ritch@inx.net)

Professor and Chief, Glaucoma Service

the New York Eye and Ear Infirmary

310 East 14th Street, New York, NY 10003

and

Jeffrey Liebmann, MD (liebmann@inx.net)

Clinical Associate Professor of Ophthalmology

Associate Director, Glaucoma Services

The New York Eye and Ear Infirmary

This is the SIXTH posting of this FAQ sheet.

Permission to copy all or part of this work and post to other Web sites is granted provided that the copies are not made or distributed for resale, and provided that the AUTHOR, COPYRIGHT and NO WARRANTY sections are retained verbatim and displayed as is.

THE AUTHORS PROVIDE NO WARRANTY. THE INFORMATION IS PROVIDED TO ASSIST UNDERSTANDING OF GLAUCOMA. IT DOES NOT REPLACE AN EYE EXAMINATION AND IS NOT MEANT AS A GUIDELINE FOR TREATMENT OF ANY INDIVIDUAL PERSON SUFFERING FROM GLAUCOMA.

For additional information about glaucoma, see http://www.glaucoma.net and http://www.nyee.edu.

Your feedback is welcome.

OUTLINE

I. WHAT IS GLAUCOMA?

A. What glaucoma is not

B. What glaucoma is

C. The problem with terminology

II. THE EYE AS A CAMERA

III. HOW GLAUCOMA DEVELOPS

1. Intraocular pressure
2. IOP versus other risk factors

IV. CLASSIFICATION OF THE GLAUCOMAS

V. THE OPEN-ANGLE GLAUCOMAS

4. A. Primary open-angle glaucoma

B. Pigment dispersion syndrome / Pigmentary glaucoma

C. Exfoliation Syndrome

D. Normal-Tension Glaucoma

E. A diagrammatic overview

VI. ANGLE-CLOSURE GLAUCOMA

A. Acute angle-closure glaucoma

B. Chronic angle-closure glaucoma

VII. GLAUCOMA IN CHILDREN

A. Congenital glaucoma

C. Juvenile primary open-angle glaucoma

D. Sturge-Weber syndrome

E. Aniridia

F. Glaucoma associated with uveitis

VIII. WHO IS AT RISK FOR GLAUCOMA?

IX. DIAGNOSING GLAUCOMA

1. Tonometry
2. Perimetry
3. Ophthalmoscopy
4. Gonioscopy

X. TREATMENT OF GLAUCOMA

A. Eye drops

B. Laser Surgery

1. Open-angle glaucoma

a. Laser trabeculoplasty

2. Angle-closure glaucoma

a. Laser iridotomy

b. Argon laser peripheral iridoplasty

C. Operative Surgery

1. Filtering surgery

2. Glaucoma implants

3. Combined cataract and glaucoma surgery

4. Cyclophotocoagulation

5, Setons

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Glaucoma is not a single entity. Rather, there are specific conditions that lead to glaucoma. A specific condition has a defined cause, mode of onset, pathophysiology, and course. Intervention can potentially occur at a number of different stages, from prevention, to treatment, to cure, and to reversal of damage caused by the disease.

Over the last 50 years, what we could call the CENTRAL DOGMA has held sway. This dogma goes as follows:

1. Glaucoma is a disease caused by elevated intraocular pressure (IOP). The elevated IOP damages and destroys the axons of the optic nerve, leading to progressive blindness.

2. Glaucoma can be divided into two broad types - OPEN-ANGLE and ANGLE-CLOSURE. Each of these, in turn, can be divided into primary and secondary forms.

This dogma has played a major role in retarding thinking and inhibiting new approaches to understanding and therapy of glaucoma, and it should be discarded.

Other risk factors for glaucomatous damage besides elevated IOP have really only begun to be explored in the past decade. Much remains to be discovered, so that new approaches to treatment can be devised. We can refer to these other risk factors as non-pressure-dependent risk factors, and the damage they cause as non-IOP-dependent damage. This will described in more detail in Section III.

The most intensively investigated cause of non-pressure-dependent glaucomatous damage is the possibility of an insufficient blood supply to the optic nerve head and adjacent retina. This is presently believed to be a major risk factor for glaucomatous damage. However, other hemorheologic (flow properties of blood) abnormalities, such as increased erythrocyte agglutinability (tendency for red blood cells to stick to each other), decreased erythrocyte deformability (ability of the red blood cells to change shape so that they can squeeze into capillaries), increased serum viscosity, or increased platelet aggregability may also play a role, as may certain cardiovascular conditions, such as atrial fibrillation.

Other possible risk factors, most of which have been as yet little explored, include low blood pressure, abnormally low intracranial pressure, autoimmune phenomena, sleep apnea, sleeping with the pillow or one’s knuckles pressed against the eye, an abnormally hard or soft lamina cribrosa (the stack of platelike "perforated wafers" through which the optic nerve cells pass through the eye), inherited or acquired abnormalities of the connective tissue of the lamina cribrosa, primary ganglion cell degeneration, and other as yet unconsidered possibilities.

The attempt to fit modern concepts into century-old terminology creates confusion in the minds of physicians and patients alike. Ask 5 glaucoma specialists just what exactly is primary open-angle glaucoma (POAG) and you may get 5 different answers. For instance, we use the term POAG to refer to a patient with elevated IOP and visual field and/or optic nerve damage, while reserving the term "ocular hypertension" for persons with elevated IOP but no detectable disc or visual field damage. A better term for the latter group is "glaucoma suspect," which includes both ocular hypertensives and persons with large cup/disc ratios who may have early normal-tension glaucoma but still have normal visual fields. Open-angle glaucoma implies visual field damage, but angle-closure glaucoma does not. Someone with a closed angle and markedly elevated IOP is deemed to have acute closed-angle (angle-closure) glaucoma, and one with a mostly closed angle, a normal disc, a normal visual field, and scar tissue in the angle is called "chronic angle-closure glaucoma." In some instances we use the term to describe the disc and field damage, in others the angle damage, and in still others the pressure alone. It is therefore best to understand the mechanisms of the various entities which lead to glaucoma and not become bogged down in definitions.

The eye captures information about shape, color, and movement and relays it in the form of nerve impulses to the brain. The brain processes this information into the "pictures" we see.

The outer, white layer of the eyeball is the sclera, a tough, leathery protective shell. The front, transparent portion of the shell is the cornea, through which light enters the eye. The cornea is much like the lens of a camera, providing the eye with much of its focusing power.

The colored portion of the eye is the iris, which functions like the diaphragm of a camera. The iris contains muscles which control the size of the pupil, regulating the amount of light entering the eye. The pupil constricts in bright light and dilates in dim light, adjusting the amount of light which passes through the pupil to the retina, which is analogous to the camera's film. The two layers of cells on the back of the iris are so filled with melanin pigment that they are black, and are known as the iris pigment epithelium. They prevent light from passing through the iris anywhere but through the pupil. The difference between blue and brown irises is the amount of pigment in the front portion of the iris.

The lens behind the iris is also transparent, and adjusts its shape and thickness to fine focus the image onto the retina. When we read, the eye accommodates to refocus a near image. The lens enlarges throughout life as it produces new cells. The ability to accommodate decreases steadily throughout life. Presbyopia occurs when there is not enough accommodative power remaining to read without glasses, usually in the early 40s. A cataract is an opacification of the lens, so that vision decreases and cannot be corrected by changing the power of one’s eyeglasses. When the cataract is sufficiently dense to interfere with one’s activities, surgery becomes necessary.

The lens is held in place by the zonules, which are analogous to the ropes holding the mat of a trampoline in place. When the eye accommodates, the muscle holding the zonules against the wall of the eye tightens, loosening the hold of the zonules on the lens and allowing it to move slightly forward and increase in thickness to refocus the image of the close object being looked at on the retina. The iris, lens, and zonules play an important role in three common conditions which lead to glaucoma – pigment dispersion syndrome, exfoliation syndrome, and angle-closure.

After passing through the lens, the light enters the vitreous, a gel-like substance which serves as the shock absorber for the eye, and then reaches the retina. The retina then delivers the image to the brain via nerve signals which are sent through the optic nerve to the brain, which processes these signals into a "picture", or visual image.

The anterior chamber, or front compartment of the eye, is bounded by the cornea, iris, pupil, and lens (Figure 2). It is filled with a watery fluid called aqueous humor, which provides the cornea and the lens with oxygen and vital nutrients. The aqueous humor also provides the necessary pressure (IOP) to maintain the shape of the eye. It is secreted into the posterior chamber (the fluid compartment behind the iris) by the ciliary body, a tiny gland which runs circumferentially behind the iris, passes between the iris and the lens into the anterior chamber, and then flows out through the trabecular meshwork, a tiny sponge-like tissue which runs circumferentially at the corneal periphery just anterior to the iris. After passing through the trabecular meshwork, the aqueous humor enters a tiny circumferential capillary called Schlemm's canal.

In order to comprehend the effect of increased IOP, think of the eye as a balloon. When too much air is blown into a balloon, pressure causes it to pop. But the eye is too strong to pop. Instead, it gives at the weakest point, which is the site in the sclera at which the optic nerve leaves the eye. The optic nerve, which carries visual information to the brain, is made up of over one million nerve cells, and while each cell is several inches long, it is extremely thin - about one twenty-thousandth of an inch in diameter. Simplistically, elevated IOP compresses the axons of the nerve cells, causing them to become damaged and eventually die, resulting in permanent visual loss. Early diagnosis and treatment can help prevent this from happening.

As a general rule, in the open-angle glaucomas, the eye is anatomically normal, but blockage or malfunction of the drain of the eye (the trabecular meshwork) leads to elevated IOP. In normal-tension glaucoma, the major risk factors causing the glaucoma are not in the trabecular meshwork, but act at the level of the optic disc. In angle-closure glaucoma, the trabecular meshwork is normal, but the iris is pushed against it, blocking the flow of fluid (aqueous humor) from the eye.

The analogy to a sink is a useful one. In a normal eye, the faucet is always on and the drain is always open. In open-angle glaucoma, the drain gets clogged. When this happens, aqueous can not leave the eye as fast as it produced, causing the fluid to back up. Since the eye is a closed compartment, the "sink" can't overflow. Instead, the backed up fluid causes increased pressure to build up within the eye. We need to use chemical drain-cleaner (eye drops) to open the drain or turn down the faucet. If this is insufficient, we can snake the train (laser trabeculoplasty), and if that doesn't work, we need to put in new plumbing (surgery).

In angle-closure glaucoma, the drain is normal, but it's covered by a stopper. We need to remove the stopper (laser iridotomy or laser iridoplasty) rather than treat with medications. Open-angle and angle-closure glaucomas are about as alike as a heart attack and a bullet wound to the heart. The disease mechanisms, the basic approach to treatment, and the prognosis all differ. And that is why the terminology is confusing.

A. Intraocular Pressure

Glaucoma has been so intimately connected with the concept of elevated IOP that a detailed explanation of how these concepts arose, how they have been used in the management of the disease, and our present concepts of the origin of glaucomatous damage, which are presently in an active stage of evolution, is warranted.

The average IOP ranges between 14 and 20 millimeters of mercury (mmHg). A pressure of 22 is considered to be suspicious and possibly abnormal. However, not all patients with elevated IOP develop glaucoma-related eye damage. The choice of 22 mmHg as the dividing line between normal and abnormal was based solely on statistics. Population studies in the 1950s found an average IOP of about 15.5 mmHg. Two standard deviations from the mean above this was taken as the upper limit of normal, so that about 2.5% of the population fell above this line. However, as often happens, what was a conceptual demarcation became established over a few years into a normal versus disease situation, and It became common to treat anyone with an IOP of 22 mmHg or more to lower the pressure. By the late 1960s and early 1970s, it had become evident that only about 10% of people with an IOP of 22 mmHg or more would develop glaucomatous damage. The higher the IOP, the greater the chances of developing damage.

People with an IOP of 22 mmHg or more came to be termed ocular hypertensives. Again, this was a working definition, but later became treated as if it were a separate disease. Ocular hypertension merely means that a person has an elevated IOP of 22 mmHg or more but no detectable damage on optic nerve or visual field examination. If a person with ocular hypertension develops damage, he or she then becomes diagnosed as having glaucoma. For reasons stated earlier, "glaucoma suspect" is a better term, and "ocular hypertension" should be reserved just for dividing patients into different categories for clinical studies.

Once a sufficient number of nerve cells are destroyed, "blind spots", or scotomas, begin to form in the field of vision. These scotomas usually develop first in the peripheral field. Later, the central vision, which we experience as "seeing", is affected. Once visual loss occurs, it is irreversible because once the nerve cells are dead, nothing can restore them at the present time.

The relationship between IOP as a risk factor and non-pressure-dependent risk factors in the causation of glaucomatous damage is depicted in Figure 3. The higher the IOP at which damage develops, the greater the component of pressure-dependent damage. The lower the IOP at which damage progresses, the greater the contribution of non-pressure-dependent factors. There is no magic number separating those with primarily pressure-dependent damage (so-called high-tension glaucoma) from those with primarily non-pressure-dependent damage (so-called normal-tension glaucoma). Moreover, the particular IOP at which 50% of damage is due to each of the risk factor categories can vary from individual to individual or even in an individual over time.

These non-pressure-dependent factors have been primarily conceived of as causes of normal-tension (low-tension) glaucoma. However, they are likely to play a role in high-tension glaucoma as well. Underlying pressure-dependent or non-pressure-dependent mechanisms of damage may be construed as comprising a spectrum. The higher the IOP at which damage develops, the greater the component of pressure-dependent damage. Angle-closure glaucoma, juvenile open-angle glaucoma, and exfoliative glaucoma fall into this category. The lower the IOP at which damage continues to progress, the greater the contribution of non-pressure-dependent factors. A patient who develops glaucomatous damage at an IOP of 14 mmHg most certainly has a preponderance of non-pressure-dependent factors.

Looking at glaucomatous damage in this manner enables us to focus on attempting to ascertain the relative contribution of pressure-dependent and non-pressure-dependent factors. A patient presenting with IOP of 40 mmHg obviously needs immediate treatment to lower the IOP. A patient presenting with maximum IOP of 18 mmHg and glaucoma (i.e., "normal-tension" glaucoma by definition) may benefit from lowering IOP, but this is done primarily because we have little other choice of therapy. In the future, this will change. It is the patient presenting with visual field loss at IOP in the mid-20’s that most likely has a multi-mechanism cause of damage. Therefore, whereas lowering IOP to 20 mmHg (i.e., "normal") will ordinarily suffice for the patient presenting with IOP of 40 mmHg, at least if the patient does not have extensive damage), whereas lowering it to 20 mmHg in a patient with multi-mechanism disease may not be sufficient.

This concept also makes it easier to see how susceptibility to glaucomatous damage can change over time. Many studies have shown that "ocular hypertensives" convert to glaucoma at a rate of about 1% per year. But why do they convert? Glaucomatologists have long held that damage builds up slowly until it finally reaches a great enough extent to be detectable on ophthalmoscopic or perimetric examination. There is another possibility, just as likely, that other risk factors for glaucomatous damage may develop even though IOP remains constant. A patient who is 40 years old and in good physical condition may be expected to withstand an IOP of 26 mmHg for a long time. However, as that patient ages, and cardiovascular disease develops, the eye may not be sufficiently perfused so that it can no longer withstand that IOP of 26 mmHg. Similarly, changes in the lamina cribrosa, supporting nerve cells (e.g., astrocytes), systemic blood pressure abnormalities, development of diabetes, etc., may compromise the status of the optic nerve.

Epidemiologically, glaucoma affects people of all ages in every population in the world, so that an estimated 65 million people worldwide have it. In dividing up glaucoma, there are 5 common entities which comprise the greatest proportion of the affected populations. Each of these is more or less common among certain populations. Each of these is described in more detail below. In addition, there are many other conditions which can lead to glaucoma, some of which are hereditary, and others acquired.

POAG has been called the most common "form" of glaucoma. It is a diagnosis of exclusion, in that the diagnosis is made when nothing else is visible, such as pigment, exfoliation, or inflammation, to which to attribute the glaucoma. It is the most common because patients with elevated IOP but no visible damage (glaucoma suspects, ocular hypertension) are included in the category. POAG is most common among persons of African descent, who are affected about 4-5 times as commonly as Caucasians. Myopes are also more commonly affected.

Normal-tension glaucoma, until recently called low-tension glaucoma and thought to be rare, is now realized to be quite common. In Japan, it is more common than high-tension glaucoma.

Pigment dispersion syndrome (pigmentary glaucoma) is an autosomal dominant condition which may affect about 2.5% of the Caucasian population. It is rare in other populations. This is about 20-30 times as common as previously believed, the reason being that many people with mild involvement never have eye examinations or are not diagnosed. It typically appears in the 20s and 30s, ages not usually thought of as being susceptible to glaucoma.

Exfoliation syndrome occurs worldwide and increases in prevalence with age (incidence is the number of new cases appearing in a given amount of time; prevalence is the percentage of cases existing in an examined population). It occurs in about 10% of the population over age 50 and its frequency varies from one population to another. People with exfoliation syndrome have about 6 times the chance of developing glaucoma compared to those who do not.

Angle-closure glaucoma also occurs worldwide but is most common in Orientals. The highest rate in the world occurs in Eskimos. Farsighted people are more likely to develop angle-closure. This is really a different category of disease from the other four entities above.

One way to think of the glaucomas is in five stages: 1) an initial sequence of events, which cause 2) alterations in the aqueous outflow system, which result in 3) elevated IOP, which leads to 4) atrophy of the optic nerve and 5) progressive loss of the visual field. This scheme, however, implies that elevated IOP is the only contributing factor, which we know is not true. To be complete, we should include IOP-independent causative factors, such as vascular and structural alterations of the optic nerve head, which may also contribute in some cases to the mechanism of glaucomatous optic neuropathy. In normal-tension glaucoma, for example, pressure-independent mechanisms may be the main, if not sole, cause of the optic nerve damage.

The fact is, however, that an IOP which is too high for the eye in question is the principal causative factor in the vast majority of the glaucomas. Furthermore, it is the only factor for which we currently have effective treatment measures. For these reasons, we will focus primarily on the pressure-related portion of the five-part pathway as we consider new classifications for the glaucomas. However, as continued studies lead to a better understanding of the pressure-independent mechanisms of glaucomatous optic atrophy, this knowledge will influence not only the classification of the glaucomas, but also our approach to managing many of the conditions.

Stage 1 includes the series of events that initiate pathologic alterations in a previously normal aqueous outflow system. Stage 2 begins with the first detectable change in the system, which eventually leads to aqueous outflow obstruction and elevated IOP. These two stages distinguish the various clinical forms of glaucoma and, therefore, provide the most logical basis for classifying the glaucomas. The last three stages represent a more or less common pathway, although variations may be seen within the clinical forms of glaucoma. Stage 3 (elevated IOP) differs somewhat among the glaucomas according to the rate of onset, magnitude, and chronicity of the pressure elevation. These clinical variations in the IOP may influence the variable nature of the of optic neuropathy (Stage 4) and the subsequent visual field loss (Stage 5), although variations in the latter two stages are also most likely a result of the pressure-independent mechanisms of glaucomatous optic atrophy.

The fundamental question of how we define glaucoma must be addressed. One school of thought is that the diagnosis should be reserved for those patients with documented visual field and/or optic nerve loss, since all individuals with elevated IOP do not develop damage. If we were to carry this thought to its extremes, what diagnosis would we someday give to a person who has only a defective gene (i.e., Stage 1) that is known to be associated with a certain form of glaucoma? Although we lack the information at the present time to answer that question, it is most likely that, for any glaucoma, only a certain percentage of patients with Stages 1, 2 or 3 will develop glaucomatous optic neuropathy (Stage 4). For each form of glaucoma, therefore, we will have to consider the potential risk for progression from one stage to the next, and the risk/benefit ratio of a specific treatment, before deciding whether to intervene at a particular stage.

Possibly the most important of the recent advances in glaucoma research have come in our understanding of the series of events that start the five-stage process toward eventual blindness. These observations provide the potential for early diagnosis and treatment of the initial events before they lead to outflow obstruction. Appropriate treatment at this stage would not only reduce the risk of eventual IOP elevation and subsequent visual loss, but would also spare our patients the side effects and complications that are currently associated with the medical and surgical management of elevated IOP.

This treatment concept, has been referred to as "early glaucoma intervention," is already possible for some forms of glaucoma. One example is neovascular glaucoma, in which at least part of the initial series of events (Stage 1) typically include a retinal vascular disorder, decreased oxygen supply to the retina, stimulation of new blood vessel formation, and new blood vessels on the iris. The mechanism of aqueous outflow obstruction (Stage 2) begins with neovascular changes in the anterior chamber angle and progresses through formation of a fibrovascular membrane which obstructs aqueous outflow and eventually contracts to close the angle, causing further outflow obstruction.

Another glaucoma in which we are very close to applying the concept of early glaucoma intervention is pigmentary glaucoma. We have learned that the initial events (Stage 1) in this condition include a specific configuration of the anterior ocular segment, posterior bowing of the peripheral iris, and rubbing of iris pigment epithelium against packets of lens zonules with the subsequent release and dispersion of pigment granules. We have also learned that the mechanism (Stage 2) by which these initial events lead to outflow obstruction includes clogging of the intertrabecular spaces with the pigment granules and eventual loss of trabecular endothelial cells with collapse of the trabecular collagen beams. More recently we have learned that a pressure differential between the anterior and posterior chambers is responsible for the posterior iris bowing in many eyes with pigment dispersion and that this can be relieved by a laser iridotomy. Therefore, if we were able to identify patients with the pigment dispersion syndrome before the development of irreversible outflow obstruction, we might be able to prevent IOP elevation with a prophylactic iridotomy. Before this treatment strategy can be recommended, however, we need diagnostic measures to predict which patients with the pigment dispersion syndrome have a sufficient risk of developing IOP elevation to justify the prophylactic iridotomy, and we need long-term trials to prove that the iridotomy will prevent the eventual IOP elevation.

The two glaucomas cited above have traditionally been classified as secondary glaucomas. One example of how arbitrary our division of primary and secondary glaucomas has been occurs with the pupillary block form of "primary" angle-closure glaucoma. In this condition we have a reasonable understanding of the initial events (Stage 1) which include a specific configuration of the anterior ocular segment, mid-dilation of the pupil, functional pupillary block, and a pressure differential between the anterior and posterior chambers. The mechanism of outflow obstruction (Stage 2) is also known to involve closure of the anterior chamber angle due to forward bowing of the peripheral iris. In addition we have an excellent treatment in the laser iridotomy. All we lack before the concept of early glaucoma intervention can be applied to this glaucoma is a test that will predict which patients in the high risk population have a high enough chance of developing angle closure to justify a prophylactic iridotomy.

These three examples of how the concept of early glaucoma intervention will someday be applied to both "primary and secondary" glaucomas are provided to emphasize the importance of understanding the initial events of all the glaucomas. It follows, therefore, that the ideal classification scheme for the glaucomas should be based on these initial events. At the present time, however, it is not possible to fully develop such a classification, due to our incomplete understanding of the initial events for all the glaucomas. The largest gap in our knowledge has to do with that group of glaucomas that we have called POAG. Despite the fact that more research has been focused on these conditions than any other group of glaucomas, our understanding of both the initial events and the mechanisms of aqueous outflow obstruction remains remarkably limited. We are beginning, however, to see glimpses of what the future may hold through continued research in cellular and molecular biology, and some day we will have an understanding of genetic defects for many of the glaucomas. This knowledge will not only provide a means of early diagnosis of the initial events, but also a rationale for treatment before these events lead to outflow obstruction.

Gene linkage studies are progressing at a rapid pace. We have already obtained significant information regarding the genetic defects in autosomal dominant juvenile open-angle glaucoma, primary congenital glaucoma, pigment dispersion syndrome, Axenfeld-Rieger syndrome some rare diseases which cause glaucoma in infants and children. As knowledge of the initial events becomes available for an ever increasing number of the glaucomas, we may eventually be able to develop a complete classification scheme, based on these initial events. Until continued research provides the answers to these gaps in our knowledge, however, we can only partially develop this classification.

This is the most "common" glaucoma affecting Caucasians and persons of African ancestry. Its incidence increases with age. POAG has no symptoms - IOP slowly rises and the disease often goes undetected - for which reason it has been termed the "sneak thief of sight". It is painless and the patient often does not realize that he or she is slowly losing vision until the later stages of the disease. However, by the time the vision is impaired, the damage is irreversible.

The term "primary open-angle glaucoma" is a misnomer. It implies that there is a single disease with a specific abnormality causing the disease (an abnormality which has yet to be discovered). In actuality, a patient is diagnosed as having POAG when we can’t see anything on slit-lamp examination which would lead to its being called something else. In other words, it is a diagnosis of exclusion (in medical terms, a "wastebasket" diagnosis is a group of disorders which we have not figured out how to identify and separate). A better term would be "idiopathic" open-angle glaucoma, indicating that we don’t know what causes it. However, the term POAG has been in use for so long, we will continue to use it here for now.

In POAG, there is no visible abnormality of the trabecular meshwork. It is believed that something is wrong with the ability of the cells in the trabecular meshwork to carry out their normal function, or there may be fewer cells present, as a natural result of aging. POAG is a chronic disease which is presently incurable. However, it can be slowed or arrested by treatment. Since there are no symptoms, many patients find it difficult to understand why lifelong treatment with expensive drugs is necessary, especially when these drugs are often bothersome to take and have a variety of side effects.

Pigment dispersion syndrome (PDS) is a hereditary condition (autosomal dominant - so that 50% of children and siblings and one parent have the disease) affecting primarily Caucasians (95%). We have seen it in patients from as far east as India and as far south as Ethiopia. The prevalence of PDS has been greatly underestimated and it is often not diagnosed on eye examination because of a low index of suspicion. The gene may be present in over 2% of the Caucasian population. Not everyone with the gene appears to develop the syndrome. It is most common in myopes (nearsighted persons) and quite rare in hyperopes (farsighted persons).

About 10% of people carrying the gene develop glaucoma, which usually develops between ages 20 and 40. Pigmentary glaucoma is the most common glaucoma in persons under age 40. The more nearsighted one is, the earlier the glaucoma develops. For unknown reasons, men develop glaucoma 2-3 times as often as women (perhaps a protective effect of progesterone?). It most often begins in the 20s and 30s, which makes it particularly threatening to a lifetime of normal vision. Because most people with PDS are younger, they don't get checked for glaucoma routinely, and it is all too common for the diagnosis to be made after one eye has become blind or lost significant vision. Younger people with glaucoma may complain of blurred vision and worsening vision and still not have their pressures checked or visual fields performed because they are told they are too young to have glaucoma.

The anatomy of the eye plays a key role in the development of pigmentary glaucoma. The normal iris is flat, like a frisbee. In PDS, the iris drops downward before angling centrally, so that it looks like a pie pan. This causes the pigment layer of the iris to rub against the zonules when the pupil constricts and dilates during focusing. This rubbing action ruptures the cells of the iris pigment epithelium, releasing pigment particles into the aqueous humor. The pigment is deposited throughout the anterior segment, including the trabecular meshwork, which becomes densely clogged with pigment, visible on examination.

Sudden pigment release at the time of pupillary dilation or after bouncing-type exercise, such as jogging or basketball, may produce sudden and marked rises in IOP by overloading the trabecular meshwork. Exercise-induced pigment liberation may be prevented by pretreatment with pilocarpine.

Pigment release tapers off after age 40. We think this is due to the development of relative pupillary block secondary to gradual lens enlargement, eliminating the contact between the iris and the zonules, and also to presbyopia. The ideal primary treatment for pigmentary glaucoma would be not to just lower IOP, but to eliminate contact between the iris and zonules, preventing further pigment release.

Miotic (cholinergic) drugs, such as pilocarpine, produce both pupillary constriction and an increase in aqueous outflow and should be in principle the drug of choice with which to initiate therapy. However, their side effects are most prominent in younger patients, who are the ones who have pigmentary glaucoma. These include accommodative spasm, induced myopia, and difficulty with functioning both in work-related situations and activities such as sports and driving, particularly at night. Fortunately, a slow-release form, pilocarpine Ocuserts, are well tolerated by younger individuals.

We have had great success with pilocarpine Ocuserts in patients with pigmentary glaucoma. They immobilize the pupil without causing extreme miosis. In most cases, the pupil is about 3 mm in diameter, allowing more normal functioning. The IOP-lowering effect is irregular on the 6th and 7th days, and we have patients change them every 5 days. Unless patients are already taking 4% pilocarpine, we initiate treatment with P-20 Ocuserts (2% equivalent) and suggest that the patient begin it in one eye only for 2 weeks until getting used to it and becoming comfortable. Patients are shown an instructional video and then further instructed on insertion and removal by a technician. They are also told to expect to have it fall out during sleep or in the shower for a while, but that eventually it will remain in place. With this encouragement, acceptance and success have been high.

Because of the association of retinal detachment with PDS (about 6-7% lifetime chance), a thorough peripheral retinal evaluation should be performed before starting treatment with miotics. Lattice degeneration, a peripheral retinal thinning, which predisposes to retinal detachment, is more common in patients with PDS than in normals with similar refractive errors.

The success of laser iridotomy in eliminating contact between the iris and zonules offers new possibilities, both in treatment and in our understanding of the mechanism. In pigment dispersion syndrome, the area of contact between the iris and lens is greater than normal, so that the iris drapes over the lens, preventing aqueous humor from equilibrating between the posterior and anterior chambers. Aqueous humor produced in the posterior chamber flows normally to the anterior chamber, but cannot flow back, resulting in a higher pressure in the anterior chamber than in the posterior chamber, and pushing the iris against the zonules. This has been termed "reverse pupillary block", to distinguish it from the analogous situation, pupillary block, which occurs in angle-closure glaucoma. Iridotomy creates an additional pathway, just as in angle-closure glaucoma, allowing for aqueous equilibration and flattening the contour of the iris.

Who should undergo laser iridotomy? Ostensibly, by preventing pigment liberation from the iris, the trabecular meshwork would have time to clear itself of pigment already deposited and reduce or eliminate further deposition. Therefore, patients should still be in the pigment liberation stage, which is suggested by the liberation of visible pigment into the anterior chamber after dilation of the pupil with special eye drops. Patients who have uncontrolled glaucoma and are facing surgery are also poor candidates for laser iridotomy, since perhaps years are required to achieve functional reconstitution of the trabecular meshwork.

We have restricted iridotomy to patients under age 45 who have elevated IOP with no damage or early glaucomatous damage. Clinical trials are needed to determine whether Ocuserts or iridotomy can normalize IOP in eyes with glaucomatous damage, prevent glaucomatous damage in eyes with elevated IOP, and prevent elevated IOP in normotensive eyes. Since perhaps as few as 10% of people with PDS go on to develop glaucoma, and since laser iridotomy itself destroys iris cells and releases a large amount of pigment and debris, which can further compromise the trabecular meshwork, we do not presently advocate treating eyes of people with PDS and normal IOP.

Exfoliation syndrome (XFS) is the most common identifiable cause of glaucoma worldwide. We estimate that it accounts for about 25% of all glaucoma, or about 16 million affected people. About 25% of people with XFS have elevated IOP or glaucoma, so that perhaps 60 million people worldwide have XFS. The diagnosis is very often missed, and the patients considered to have POAG. XFS is found in every race and ethnic group in the world. The reported prevalence (how common it is) rates have varied widely, reflecting a combination of true differences due to racial, ethnic, or other yet-to-be-defined reasons, age of the population group examined, the clinical criteria for making the diagnosis, the ability of the examiner to detect earlier stages of the disease, and the thoroughness of examination. In particular, many cases of XFS go undetected because of failure to dilate the pupil or to examine the lens by the slit-lamp after dilation, and because of a low index of suspicion on the part of the examiner.

Glaucoma resulting from XFS, or exfoliative glaucoma, has a worse prognosis than POAG, and the clinical course is more severe. The average IOP is higher at the time of detection of exfoliative glaucoma than it is in POAG, while optic nerve and visual field defects are more severe at the time of presentation and progress more rapidly. It responds less well to medical therapy than does POAG and treatment failure occurs more commonly. The proportion of patients with XFS shows a steady increase when measured in groups of patients with open-angle glaucoma without optic nerve damage, in those with damage, in those undergoing surgery, and in those with end-stage glaucoma.

XFS is characterized by the buildup of white material on the anterior lens surface in three distinct zones. There is a thin central disc of material deposited on the lens surface, a peripheral granular zone, which may consist of more than one layer, and a clear zone separating these two areas. The appearance is reminiscent of sugar-coated cereal. The material is rubbed off the lens by movement of the iris and at the same time, pigment is rubbed off the iris. Both pigment and exfoliation material clog the trabecular meshwork, leading to elevated IOP, sometimes to very high levels (e.g., over 50 mmHg).

American ophthalmologists have traditionally put little emphasis on making a diagnosis of XFS, since treatment was regarded as the same as that for POAG. Developments in recent years make it much more important to make a correct diagnosis. XFS is now known to be an ocular manifestation of a systemic condition, seen physically only in the eye because of its easy visibility and the fact that it causes glaucoma. Differences in the approach and response to various treatments are beginning to be recognized. Finally, XFS develops prior to its clinically visible appearance on the lens surface, and other signs can serve as a tip-off to diagnosis. Recently, XFS has been associated with stroke, angina, and myocardial infarction. It is only a lack of attention that is holding back major strides in the elucidation of the fundamental nature of this condition.

XFS can cause both open-angle glaucoma and angle-closure glaucoma, often producing both in the same person. The chance of developing glaucoma is about six times as high in people with XFS compared to the general population. It often appears in one eye long before the other, for unknown reasons. In anyone over age 50 with unilateral glaucoma, XFS should be the presumptive diagnosis in the absence of another obvious cause. XFS can be detected before glaucoma develops, and people with it should be observed regularly for the onset of elevated IOP or narrowing of the angle.

It is theoretically logical that miotics (e.g., pilocarpine) could be the drug of choice in XFS with glaucoma. Beta-adrenergic blocking agents, although reducing aqueous secretion, decrease the amount of aqueous flow through the meshwork, which could be detrimental to clearing of pigment, and could decrease the volume of the posterior chamber, perhaps increasing the degree of contact between the iris and the lens, and the amount of pigment rubbed off the iris. Miotics, in addition to increasing aqueous outflow, could help to prevent the progression of the disease by reducing pupillary movement.

Argon laser trabeculoplasty is initially highly successful, producing a greater average drop in IOP in eyes with XFS than in eyes with POAG. In XFS, however, sudden late rises in IOP may occur after a year or more of good control. Presumably, this is due to continued liberation of iris pigment causing further blockage of the trabecular meshwork. Continued use of pilocarpine after ALT may theoretically prevent this. Retreatment may be successful in some eyes.

The results of trabeculectomy are comparable to those in POAG. There do not appear to be any unusual complications. Complications of cataract surgery, however, are 6 to 10 times more common in patients with XFS. These include poor dilation of the pupil at the time of surgery, rupture of the lens capsule, tearing of the zonules, and loss of vitreous fluid during the operation. Eyes with XFS also have more postoperative inflammation and more problems with shifting of the position of intraocular lenses as time goes by.

Normal-tension glaucoma has been defined as open-angle glaucoma in a person in whom the IOP never goes above 22 mmHg. For a long time, this was thought to be a rare disease. It is now being realized that the number of persons with normal-tension glaucoma has been vastly underestimated. In Japan, for instance, twice as many people have normal-tension glaucoma as high-tension glaucoma.

Paramount in the clinical evaluation of individuals with normal-tension glaucoma is a careful history with attention to the presence of a family history of glaucoma, vasospastic symptoms such as Raynaud's phenomenon or migraine headache, or history of hypotension or significant blood loss. The chronicity and pattern of visual loss (e.g., darkening or blurring of acuity) is critical. Patients with non-glaucomatous cupping may report a history of ocular trauma, ocular pain (particularly associated with eye movements) or prior episodes of visual loss, concurrent neurologic symptoms (such as headache or cranial arteritis symptomatology), or history of syphilis. In addition, it is important to inquire about a history of prior corticosteroid use which may suggest previous intraocular pressure elevation.

The terms high-tension and normal-tension glaucoma are misleading. The problem has resulted from artificial definitions, such as 22 mmHg as a cutoff. There is no real cutoff point. People can have a pressure component to their damage and they can have non-pressure-dependent mechanisms of damage. The proportion of sensitivity to each may vary from individual to individual. Both IOP and other mechanisms of damage are "risk factors" for glaucomatous damage. The higher the IOP, the greater the risk of pressure-induced damage. The worse the vascular supply to the optic nerve, the greater the risk of damage on this basis. When more than one risk factor is present, they are presumably additive. People with no other risk factors and a pressure of 25 mmHg may never develop damage. People with IOP of 25 mmHg and several other risk factors may be easily susceptible to damage. There is no hard and fast rule.

In figure 5, glaucoma represents the state of optic nerve damage, whether mild or extensive. Increased IOP is merely a proximate step leading to the damage. But that elevated IOP is caused by dysfunction of the trabecular meshwork, which in turn has specific causes (X, Y, Z) representing different diseases which act by specific mechanisms. For example, X could be autosomal dominant juvenile open-angle glaucoma (JOAG), for which the gene has recently been identified as producing a protein which affects the "stickiness" of the fluid pathways in the trabecular meshwork. Y could be pigment dispersion syndrome, in which the iris rubs against the zonules which hold the lens in place, causing disruption of the pigmented cells in the back of the iris and releasing pigment which clogs the trabecular meshwork. C could represent uveitis, in which inflammation gradually kills off the cells of the trabecular meshwork.

It is easy to see that waiting until damage has occurred to start treating IOP is like locking the barn door after 3/4 of the horse is out. The only approach to glaucoma has been to lower IOP. Common sense suggests that if we can treat PRIOR to elevation of IOP, we can prevent the damage to the meshwork which causes the elevated IOP which causes the damage (sort of like "The House That Jack Built". Nevertheless, relatively little attention has been paid to preventing elevated IOP. At the present time, we can’t replace the gene or modulate TIGR protein activity for JOAG, but that will come. We can’t replace the gene for pigment dispersion, but we can prevent pupillary movement, leading to reversal of the disease. Increasing discoveries regarding inflammation and the immune system will lead to improved treatments of uveitis. What is important now is to try to prevent the development of glaucoma in newer ways than just lowering IOP.

Angle-closure glaucoma affects nearly half a million people in the United States. In China and surrounding countries, it is more common than open-angle glaucoma. There is a tendency for this disease to be inherited. It is more common in hyperopes (far-sighted people). Within the category of angle-closure, the terminology is inconsistently used. Some use "angle-closure," others "closed-angle," and still others "narrow angle." The latter is particularly misleading, since it can describe a patient with POAG and narrow angles or one with actual angle-closure.

In people with a tendency to angle-closure glaucoma, the anterior chamber is smaller than average. As mentioned earlier, the trabecular meshwork is situated in the angle formed where the cornea and the iris meet. In most people, this angle is about 45 degrees. The narrower the angle, the closer the iris is to the trabecular meshwork. As we age, the lens routinely grows larger. The ability of aqueous humor to pass between the iris and lens on its way to the anterior chamber becomes decreased, causing fluid pressure to build up behind the iris, further narrowing the angle. If the pressure becomes sufficiently high, the iris is forced against the trabecular meshwork, blocking drainage, similar to putting a stopper over the drain of a sink. When this space becomes completely blocked, an angle-closure glaucoma attack (acute glaucoma) results.

Unlike POAG, in which IOP increases slowly, in acute angle-closure, it increases suddenly. This sudden rise in pressure can occur within a matter of hours and become very painful. If the pressure rises high enough, the pain may become so intense that it can cause nausea and vomiting. The eye becomes red, the cornea swells and clouds, and the patient may see haloes around lights and experience blurred vision.

If the attack goes untreated, scarring of the trabecular meshwork may occur and result in permanent glaucoma, which is much more difficult to control. Cataracts may also develop. Damage to the optic nerve may occur quickly and cause permanently impaired vision.

Many of these sudden "attacks" occur in darkened rooms, such as movie theaters, which cause the pupil to dilate. Acute stress is another predisposing condition. When the pupil dilates, the contact between the lens and the iris is maximized. This further narrows the angle and may trigger an attack. A variety of drugs can also cause dilation of the pupil and lead to an attack of glaucoma. These include anti-depressants, cold medications, antihistamines, and some medications to treat nausea.

Acute glaucoma attacks are not always full blown. Sometimes a patient may have a series of minor attacks. A slight blurring of vision and haloes (rainbow-colored rings around lights) may be experienced, but without pain or redness. These attacks may end when the patient enters a well lit room or goes to sleep-two situations which naturally cause the pupil to constrict, thereby allowing the angle to open spontaneously.

An acute attack is an emergency condition. If the pressure is not relieved within a few hours, vision can be permanently lost. An acute attack may be stopped with a combination of drops which constrict the pupil, and drugs that help reduce aqueous production. When IOP has dropped to a safe level, laser iridotomy is the treatment of choice. This is an outpatient procedure in which a laser beam is used to make a small opening in the iris, allowing aqueous to pass directly from the posterior chamber to the anterior chamber. Since it is common for the other eye also to have a narrow angle, laser iridotomy on the unaffected eye is done as a preventative measure.

Routine examination using a technique called gonioscopy can predict one's chances of developing angle-closure. A special lens which contains a mirror is placed lightly on the front of the eye and the width of the angle examined visually. Patients with narrow angles can be warned of early symptoms, so that they can seek immediate treatment.

Not all people with angle-closure experience an acute attack. Many develop what is called chronic angle-closure glaucoma. In this case, the iris gradually closes over the drain, causing no overt symptoms. When this occurs, scars slowly form between the iris and the drain and the IOP will not rise until there is a significant amount of scar tissue formed-enough to cover the drainage area. If the patient is treated with medication, such as pilocarpine, an acute attack may be prevented, but the chronic form of the disease may still develop.

The number of younger people with glaucoma has been vastly underestimated in the past. In fact, it was more common than not a generation ago not to bother checking IOP in people under the age of 35 because it was thought glaucoma was exceedingly rare in this age group. We know now that it is not, and we know that glaucomatous damage ordinarily takes a long time to develop. Someone with symptomatic damage detected at age 45 might have had elevated IOP for 20 years. Glaucoma does increase in frequency with age. Those glaucomas that increase in frequency with age are primarily POAG, exfoliation syndrome, non-pressure-dependent mechanisms of damage, and angle-closure. Pigmentary glaucoma, as mentioned, develops in the 20s and 30s. Juvenile open-angle glaucoma, often hereditary, is probably second in frequency to pigmentary glaucoma. Glaucoma in childhood (under age 18) is much less common and is often associated with specific syndromes. We will describe the more common of these here.

Congenital, or infantile, glaucoma, occurs in about 1 in 10,000 births. It is defined as glaucoma appearing between birth and ages 3 to 4. Up to this age, the eye wall is distensible, so that the eye can noticeably and progressively enlarge when IOP is elevated. It may occur without other findings (primary congenital glaucoma), associated with other syndromes, or after injury, congenital cataract extraction, or inflammation. Primary congenital glaucoma is due to failure of development or abnormal development of the trabecular meshwork. Most cases of primary congenital glaucoma are sporadic in occurrence. In the approximately 10% in which a hereditary pattern is evident, it is believed to be usually autosomal recessive.

Congenital glaucoma is usually detected by the parents when the eye is noted to enlarge or the cornea becomes hazy. When the cornea stretches, breaks occur in the inner corneal lining, or endothelium, which pumps water out of the cornea to maintain its transparency. When breaks occur, aqueous humor enters the cornea, causing it to swell, a hazy, frosted glass appearance. The baby is sensitive to light and tearing may be present. As the cornea stretches, ruptures allow more aqueous into the corneal stroma and epithelium, causing a sudden increase in edema and haze and an increase of tearing and avoidance of bright light. The infant may become irritable to the point of burying its head in a pillow to avoid lights.

Treatment is surgical and often successful, although more than one operation may be necessary. Goniotomy and trabeculotomy are operations designed to incise the trabecular meshwork to help it to function. If these are unsuccessful, then filtering surgery as performed in adults becomes necessary. The prognosis is worse if the glaucoma is present at birth.

Advances in our understanding of the genetics of glaucoma are progressing at a rapid pace. There are at least 3 different chromosomes which can contain abnormal genes causing congenital glaucoma. The one best characterized to date is a gene on chromosome 2 which codes for a protein called cytochrome P4501B1, one of a series of enzymes involved in oxygen metabolism (mono-oxygenases).

By definition, glaucoma developing between ages 4 and 10 are called late congenital glaucoma, or developmental glaucoma. Primary open-angle glaucoma, because thought rare in younger patients, was considered a disease affecting people from age 35 on. Thus, POAG developing the span between ages 10 and 35 came to be termed, by convention, juvenile primary open-angle glaucoma. About 35% of people with this disease are high myopes (very nearsighted), and 85% total are nearsighted.

Juvenile POAG is strongly hereditary and often autosomal dominant, meaning that only a single copy of the gene from one parent can cause disease, so that 50% of the offspring of an affected parent are affected. The first glaucoma gene characterized, in 1996, was one responsible for autosomal dominant juvenile POAG, and since that time, numerous mutations in this gene have been found in several large families with hereditary glaucoma. This gene produces a "sticky" protein, TIGR, or myocilin, which makes the trabecular meshwork less permeable to aqueous humor leaving the eye. Its concentration may increase in susceptible individuals when they are treated with steroids. Mutations in this gene are also responsible for about 3% of POAG in older age groups. Several other genes on other chromosomes are under active investigation for their ability to cause either juvenile or adult-onset POAG or both.

C. Sturge-Weber syndrome (Figure 6)

Sturge-Weber syndrome is relatively common and everyone has known someone at one time or another with a port-wine stain on the face. When the port-wine stain affects the forehead and upper lid, glaucoma occurs about 2/3 of the time. It can occur at birth or infancy, but more commonly develops between ages 9 and 16. For some reason, this has not been well known, and many children are only detected after they have suffered severe damage. Sturge-Weber Syndrome is a common cause of blindness from glaucoma in childhood. Most of this blindness could be prevented through timely diagnosis and appropriate treatment.

Ocular manifestations of Sturge-Weber syndrome occur in infancy and early childhood. The hallmark of the condition is a facial birthmark (port wine stain), which is unilateral in 90% of affected children, and involves the region of distribution of the first and second divisions of the trigeminal (fifth) nerve. The first division corresponds to the forehead and upper eyelid. The second division corresponds to the cheek and lower eyelid. The third division corresponds to the jaw.

Vascular malformations may affect the eyelids, sclera, conjunctiva, and iris. When the upper lid is involved, the eye is also usually involved. The iris may appear darker than that in the opposite eye. Vascular malformations of the choroid, the spongy vascular tissue which lies between the retina and the sclera, in about 40% of affected eyes. They are easily overlooked in younger patients and grows slowly.

One third of patients with Sturge-Weber syndrome have increased IOP. This is characteristically on the same side as the vascular malformation, although glaucoma can sometimes occur bilaterally. Glaucoma can occur at various stages in life, but most commonly occurs in infancy and childhood.

Glaucoma may be present at birth or develop in the first few years of life. This is called congenital glaucoma. Congenital glaucoma results from developmental abnormalities that result in malfunction of the tissue which drains fluid from the eye. It is usually detected by the parents. The most characteristic signs of congenital glaucoma are enlargement of the eye, a hazy cornea, tearing, and photophobia (the baby tries to hide its head from bright light). All babies with Sturge-Weber syndrome should have IOP measured in infancy and, if normal, once a year thereafter. After the age of three or four, the eye wall becomes thicker and does not enlarge when the IOP rises, and it is necessary to measure IOP in order to determine the presence or absence of glaucoma.

The development of glaucoma during childhood and adolescence is also common. These children usually have a vascular malformation of the sclera, which causes elevated pressure in the veins which drain the eye. This, in turn, causes IOP to rise, with subsequent damage to the drainage system of the eye. Medical treatment (eye drops) may control this type of glaucoma. If medical treatment fails, surgical intervention becomes necessary. Laser treatment for the glaucoma is ineffective. With early diagnosis, and appropriate treatment geared to the type of glaucoma and the findings from examination of the eye, the glaucoma can often be controlled and vision preserved.

Aniridia is a hereditary condition uniformly associated with iris abnormalities. This development condition is rare, occurring in approximately 1 in 50,000 live births. Typically, the iris appears as a small rudimentary stump associated with a large pupil. Aniridia may be associated with congenital glaucoma, but glaucoma most commonly develops in childhood or adolescence. Other abnormalities include cataract, failure of the macula (the area of the retina responsible for sharp central vision) to develop, nystagmus (uncontrolled movements of the eyeball), and corneal vascularization.

Three genetic types of aniridia have been recognized. About 85% of patients have isolated, autosomal dominant aniridia (not associated with other systemic manifestations). About 13% have autosomal dominant aniridia associated with Wilms' tumor, genitourinary anomalies, and mental retardation (WAGR), while 2% have autosomal recessive aniridia associated with cerebellar ataxia and mental retardation. The aniridia gene, now called the PAX6 gene, has been established as the only genetic locus for aniridia and is located on chromosome number 11.

Treatment of congenital glaucoma is the same as for primary congenital glaucoma. Long-term treatment of childhood glaucoma is difficult, complicated, and often frustrating, but is constantly improving.

Uveitis is a nonspecific term referring to inflammation of the choroid, ciliary body, and or iris. It may be due to local, systemic, exogenous or endogenous causes. Although some forms of uveitis may be classified into clinical entities, most are nonspecific and can be broadly described as being only anterior or posterior, granulomatous or nongranulomatous. Anterior uveitis is also termed iritis or iridocyclitis. Glaucoma is a frequent complication of uveitis.

IOP may be low in eyes with anterior uveitis because of a decrease in aqueous humor formation ("secretory hypotony"). However, uveitis may also lead to acute or chronic, open-angle or angle-closure glaucoma. Elevated IOP may be caused by active inflammation, insufficient antiinflammatory therapy, excessive corticosteroid use, or insufficient glaucoma therapy. The chronic and recurrent nature of the inflammation may lead to death of the trabecular cells which control the exit of aqueous humor, and which do not replenish themselves.

Medical treatment of glaucoma associated with active uveitis is directed toward controlling inflammation and preventing its damaging effects on outflow pathways, as well as controlling IOP. Dilating the pupil and decreasing the inflammation help to minimize damage and scarring of intraocular tissues and visual loss. If medical therapy fails, surgery may become necessary. When angle-closure occurs, laser iridotomy is indicated. Argon laser trabeculoplasty is contraindicated in open-angle glaucoma associated with uveitis because it fails in virtually all cases, causes increased inflammation, and destroys a certain percentage of the remaining viable trabecular cells. Filtration surgery in eyes with uveitis has a lower success rate and higher complication rate than in eyes without uveitis.

Since glaucoma is produced by many different conditions, it occurs at all ages and in all races. However, some people are at greater risk than others.

A. People over age 45. While glaucoma can develop in younger patients, it occurs more frequently with age.

B. People with a family history of glaucoma. This applies particularly to people with pigmentary glaucoma, which is strongly inherited. Juvenile POAG is also commonly inherited. A number of rare types are genetic. Adult onset POAG and exfoliation syndrome may have some hereditary tendency, but data is tenuous.

C. Myopes are more prone to develop open-angle glaucoma. Hyperopes are more prone to develop angle-closure glaucoma.

D. There is no glaucoma exclusive to any race or ethnic group. However, there are some rough epidemiological rules. Persons of African descent are more prone to develop POAG, by a ratio to about 4:1 compared to Caucasians. Pigmentary glaucoma occurs almost exclusively in Caucasians. Angle-closure is more common than open-angle glaucoma in Asians. Everyone can develop exfoliation syndrome, but it appears to be most common in those of European descent.

A variety of diagnostic tools aid in determining the presence, absence, or predisposition to glaucoma.

A. Tonometry.

From a practical standpoint, a "normal" IOP is one that does not result in glaucomatous optic nerve head damage. Because not all eyes respond similarly to a particular IOP level, a normal pressure cannot be represented as a specific measurement. Therefore, the most that we can expect is to determine their relative chance of developing glaucoma at different pressure levels given the knowledge of the distribution of IOP in general populations and in populations of individuals with glaucomatous damage

The tonometer measures IOP. In applanation tonometry, the eye is anesthetized with drops and, at the slit lamp, a plastic prism is lightly placed on the cornea. A strain gauge determines IOP. In air tonometry, which is less accurate, a puff of air is sent onto the cornea to take the measurement. Since this instrument does not come in direct contact with the cornea, no anesthetic eye drops are required.

Testing the visual field is the best way of determining if vision is being lost due to glaucoma. At the present time, almost all visual field testing is done using computerized automated perimetry. The patient sits facing a computerized screen and asked to press a button whenever a flash of light appears. If the flash of light falls into a scotoma, it is not seen, and this registers on the printout as a blind spot. Sequential visual fields in a glaucoma patient can be used to determine whether the disease is stable or progressing

The optic nerve can be seen directly by the examiner using an instrument called an ophthalmoscope. The color and appearance of the disc can indicate whether or not damage from glaucoma is present and how extensive it is.

In this test, a mirrored lens is placed on the cornea, allowing the examiner to view the angle directly. Narrow angles and angle-closure can be detected. This test should be performed routinely on any initial complete eye examination and patients with narrow angles should be gonioscoped at routine intervals to inspect for further narrowing or capability of closure.

Glaucoma can be treated with eye drops, pills, laser surgery, eye operations, or a combination of methods. The whole purpose of treatment is to prevent further loss of vision. LOSS OF VISION IN GLAUCOMA IS IRREVERSIBLE. Bringing the pressure under control will not restore lost vision, but only prevent further vision from being lost. Keeping the IOP under control is the key to preventing loss of vision from glaucoma. New approaches are being developed for the treatment of normal-tension glaucoma [section under development].

In order to prevent further visual loss from glaucoma, the IOP must be constantly controlled. This requires taking medications chronically. If a drop is given four times a day, it is because the effect of the drop only lasts about 6 hours. Drops given twice a day have a "duration of action" of about 12 hours. Proper taking of drops and use of punctal occlusion will result in more of the drop getting into the eye and less into the blood stream, resulting in more effective treatment. Punctal occlusion and proper drop instillation are very important.

One of the most difficult problems faced by glaucoma patients is that of having to take medications which may have both ocular and systemic side effects to control a disease which is usually painless and has no symptoms. Understanding the necessity for the medication often helps to reduce the severity of a side effect, since it is often magnified by anxiety.

A side effect is any action produced by a drug beyond the intended one of lowering IOP. Some patients have no side effects whatsoever, while others find them too severe to tolerate. Why a drug causes side effects in some persons and not others or why the same side effect of the same drug is severe in one person and mild in another are poorly understood.

Quality of life is important. We sometimes have to make the decision to perform laser or surgery, even if the pressure can be controlled, if the side effects of the medications necessary for control are intolerable. It is up to the patient to participate in and ultimately make the decision in such a situation. What one should not do is skip taking the medications and lose vision because of side effects. One should also not be afraid to mention any side effects one might have or attribute to the drugs, since it is not one's fault that the drugs cause them.

All drops may cause some burning or stinging when instilled. Often, this effect is due not to the drug but to the antibacterial preservatives in the solution. It is rarely intolerable and can be used to advantage, since it lets the patient know that the drop got into the eye. Many patients don't think a drop is really medicine if it doesn't cause a little irritation.

Miotics (cholinergic agents) are drops which help to open the spaces in the trabecular meshwork and increase the rate of fluid flow out of the eye. The most common is pilocarpine. Carbachol is somewhat stronger and echothiophate (Phospholine®) is stronger still but has a tendency to cause cataracts and is only used in patients who have already had cataracts removed.

Epinephrine also lowers intraocular pressure by increasing the rate of fluid flow out of the eye. Dipivefrin (Propine®) is converted to epinephrine once inside the eye.

Beta-adrenergic blocking agents, or beta-blockers, decrease the rate at which fluid flows into the eye. Timolol (Timoptic®) and levobunolol (Betagan®) appear to have a slightly greater pressure-lowering effect than betaxolol (Betoptic®), but the latter is safer in patients with pulmonary disease, such as asthma or emphysema, and may have less of an effect on blood pressure. Oral beta-blockers are commonly used for hypertension and angina and in these situations, also lower IOP.

Carbonic anhydrase inhibitors (CAI) reduce fluid flow into the eye by inhibiting the enzyme which interconverts water and carbon dioxide to hydrogen and bicarbonate ions. For over 40 years, only pills were available. These consisted of acetazolamide (Diamox®), methazolamide (Neptazane®) and chlorpropamide (Daranide®). Although well tolerated by many patients, they were also associated with many serious side effects (see below), including fatalities. In 1995, the first CAI eye drop, dorzolamide (Trusopt®) became available. Brinzolamide (Azopt) was released in 1998. Although side effects may still occur in some patients, they have been greatly reduced overall.

Alpha agonists reduce aqueous humor production and increase aqueous outflow. Uveoscleral outflow normally accounts for about 10% of the outflow from the eye. The rest is handled by the trabecular meshwork. However, when the meshwork is damaged by glaucoma, uveoscleral outflow becomes more important. Apraclonidine (Iopidine®) and brimonidine (Alphagan®) are presently marketed. Brimonidine has a significantly higher relative selectivity for the alpha-2 receptors, while apraclonidine has mixed alpha-1 and alpha-2 stimulatory activity.

Prostaglandins act to increase the rate of outflow of aqueous humor not through the trabecular meshwork, but by another pathway called uveoscleral outflow. Latanoprost (Xalatan®), the agent most recently brought to market in the U.S., represents a new class of compounds which should prove additive with all other antiglaucoma drugs.

One should not become neurotic when reading a list of possible side effects of a drug, such as the package insert. You may not get any side effects at all. If you do, it may only be a minor bother. Serious side effects are rare. If they weren't, we wouldn't be using the drugs in the first place. Sometimes, the only way to prove a side effect, particularly subjective ones such as anxiety, depression, or vivid dreams, is due to the medication is to stop using it, wait for the reaction to go away, and try it again. This is known as retesting. If you think you have an unusual reaction to a drug, mention it to your physician or post it on the Internet. A good place for this is alt.support.glaucoma. If you retest yourself twice and prove the side effect related to the drug and it is an unusual one, contact us by e-mail. We can then forward it to the National Registry of Ocular Drug-Induced Side Effects. Remember that all drops may cause burning and stinging and that any drug may produce a rash. If you have a definite allergic reaction to a drug, you should stop using it.

Miotics may cause periorbital pain, browache, and pain inside the eye. This often disappears after a few days of taking the drop. Blurred vision and extreme nearsightedness are most common in younger patients, who often cannot tolerate these drops. Because miotics reduce the size of the pupil and prevent it from dilating normally in the dark, many patients complain of dim vision, particularly at night or when going into a dark room. Systemic side effects are rare with pilocarpine, more common with carbachol, and not unusual with echothiophate. These include stuffy nose, sweating, increased salivation, and occasional gastrointestinal problems. Rare side effects include retinal detachment, mostly on circumstantial evidence. Patients with high myopia and pigment dispersion are more prone to both retinal detachment and glaucoma. PILOCARPINE GEL is applied at bedtime and may be substituted for drops in many patients. In addition to the convenience of not having to use drops four times a day, the effect on the pupil is often less. Ocuserts are pilocarpine membranes worn under the lids and changed every 5 days. These cause less blurring of vision and are especially useful in younger patients.

Epinephrine and dipivefrin frequently cause burning on instillation. A red eye is common and is an effect not of the drop initially, which whitens the eye by constricting blood vessels, but of the rebound effect when it wears off. The most common problem is development of an allergic reaction, which may occur after years of use. Epinephrine may cause palpitations, elevated blood pressure, tremor, headache, and anxiety. Dipivefrin has a much lower rate of systemic side effects.

Beta-blockers cause few ocular side effects. A few patients have complained of blurring of vision. This is more common when beta-blockers and epinephrine are used together, because this combination dilates the pupil. The most common systemic side effects include exacerbation of pulmonary disease, difficulty breathing, slowing of the pulse, and decreased blood pressure. More recently, central nervous system side effects have been reported. these include memory loss, dizziness, fatigue, weakness, decreased exercise tolerance, anxiety, hallucinations, insomnia, and impotence.

Carbonic anhydrase inhibitors commonly cause side effects. The most common are urinary frequency and tingling in the fingers and toes. These are often transient and disappear after a few days. Kidney stones may occur, but are also common without their use. Most glaucoma specialists use them unless a patient has had or develops a kidney stone or only has one kidney. A rare but serious side effect is aplastic anemia. Rashes are not uncommon. Potassium loss may occur when these drugs are taken simultaneously with digitalis, steroids, or chlorothiazide diuretics.

Depression, fatigue, and lethargy are common side effects and are often not realized by the patient or by close family. These side effects may not appear immediately but develop gradually. Since many patients with glaucoma are elderly, these side effects are attributed to getting older. Patients and their families should be on the alert for these side effects and, when suspected, the drug can be stopped for a short time for verification. Other common side effects are gastrointestinal upset, metallic taste to carbonated beverages, impotence, and weight loss. Sequels cause less side effects than tablets.

The use of topical CAIs has markedly reduced the frequency and severity of these side effects. With chronic use, some 20% of patients develop a topical allergy, with conjunctival redness and itching, redness, and scaling of the lower eyelids.

Alpha-agonists are chemically related to systemic medications for the treatment of hypertension, and systemic side effects of these medications are unusual. Ocular allergy develops in a high percentage of patients using apraclonidine on a prolonged basis; allergic reactions appear to be less with brimonidine. Patients who develop an allergy to apraclonidine can be switched to brimonidine. The most common side effects are slight elevation of the upper lid, dry mouth, dry nose, and mild sedation. Some patients may develop dizziness.

Prostaglandin analogues stimulate the uveoscleral pathway for aqueous

outflow, and can be potent pressure-reduction medications. Although

ocular injection and irritation may occur, these drugs are extremely

well-tolerated and require only once daily dosing. A darkening of iris

color occurs in approximately 5% of eyes with use of latanoprost for several months or more due to an increase in the production of melanin in the melanocytes of the iris. Pure brown eyes and pure blue eyes are not effected. Hazel, green, and golden-brown eyes are. Increased eyelash growth is not uncommon (and a patent for hair growth has been granted). Since the drug is new, other side effects are only beginning to be reported and have not been proven yet. Conjunctival redness is common. Flareups of uveitis and macular edema, facial burning or rash, and uterine bleeding in postmenopausal women are possibilities.

Laser surgery is been used as treatment for a wide variety of glaucomas. The ability of light to penetrate the transparent structures of the eye (cornea and lens) allows it to have its desired affect on the targeted tissue. This is different from most other sites in the body, where penetration of light is blocked by the skin or thick outer tissues. Numerous different types of lasers are used in eye surgery for various purposes. These include argon, krypton, neodymium-YAG, diode, and excimer lasers.

1. OPEN-ANGLE GLAUCOMA.

a. Laser Trabeculoplasty

In eyes with open-angle glaucoma, the laser energy is applied directly to the damaged drain, or trabecular meshwork. Argon laser trabeculoplasty (ALT) was first used as an intermediate step between drugs and surgery, but is now being used earlier in the disease process. ALT is most successful in eyes which do not have active inflammation. Its success increases with the age of the patient (except in pigmentary glaucoma) and the amount of pigment on the trabecular meshwork. Of the three most common forms of open-angle glaucoma, primary or chronic open-angle glaucoma, pigmentary glaucoma, and exfoliative glaucoma, the effect of ALT is greatest in the latter. In general, ALT is more effective in older individuals, except in pigmentary glaucoma, where younger patients tend to have a better pressure-lowering response. ALT works less well in eyes with a history of prior surgery, such as cataract or angle-closure glaucoma following laser iridotomy (see below). It may be useful in normal-tension glaucoma. ALT produces borderline or poor results in most other open-angle glaucomas. Aside from pigmentary glaucoma or other glaucomas with pigmentation of the trabecular meshwork, we do not feel that it should be performed in patients under age 40, as it is usually ineffective and may worsen the condition. It should also not be performed in eyes with active uveitis, neovascular glaucoma, iridocorneal endothelial syndrome, aniridia, or other childhood glaucomas.

The entire procedure takes less than ten minutes, is painless, and is performed on an outpatient basis. A single drop of anesthetic is administered beforehand. Most doctors also pretreat with a drop of apraclonidine (Iopidine), which decreases the likelihood of a postoperative rise in pressure. The laser beam is focused on the trabecular meshwork and 50 to 100 burns over 180° to 360° placed on the meshwork. Many surgeons divide the treatment into two sessions of 180° treatment each, in order to gauge its effectiveness and limit complications. If IOP comes under control after the first treatment, the second may be postponed until the effect of the first treatment wears off. One to three hours after the surgery the pressure in the eye is rechecked. Follow-up varies from 1 day to 1 week, and depends upon the type and status of the glaucoma. The final effect is often not attained for 4-6 weeks. Complications are infrequent and usually transient and include of pressure and mild inflammation.

Contrary to what some people think, the laser does not burn a hole through the eye. Instead, the heat causes some areas of the trabecular meshwork to shrink, theoretically resulting in adjacent areas stretching open and permitting aqueous humor to drain more easily. It is also possible that the laser stimulates DNA synthesis, promoting regrowth of trabecular cells.

The timing of laser trabeculoplasty remains controversial. In the 1980s, it was first used as an intermediate step between drugs and surgery, but is now being used earlier in the disease process. A long-term study performed by the National Eye Institute/National Institutes of Health (USA) has confirmed the clinical impression that, at the very least, laser trabeculoplasty is a safe and effective method of lowering IOP.

The effectiveness of laser trabeculoplasty varies from individual to individual and usually cannot be predicted. The average reduction in eye pressure is approximately 11 mmHg in exfoliative glaucoma and 7 mmHg in POAG and younger patients with pigmentary glaucoma. On the other hand, if the target pressure is 16 mm Hg, and the starting pressure is 35 mm Hg, the likelihood of achieving the target pressure with ALT is low. Unfortunately, virtually all patients who undergo ALT will either need to continue their eye drops or require them later on. The duration of the effect is also variable. Some individuals appear to respond only transiently, while others can maintain good control for years.

2. ANGLE-CLOSURE GLAUCOMA.

Blockage of aqueous flow between the posterior and anterior chambers in relative pupillary block (the most common cause of angle-closure glaucoma) can be relieved with a procedure called laser iridotomy. This surgery, which can be performed with the argon or Nd-YAG lasers, creates a hole in the iris to allow free passage of aqueous. In angle-closure glaucoma, the blockage of fluid flow may cause an acute attack of glaucoma and very high IOP, pain, and loss of vision. Laser iridotomy can successfully eliminate the chance of acute or chronic angle-closure glaucoma in most eyes. A series of high quality images of the living eye depicting the anatomy before and after laser iridotomy can be found at the Ocular Imaging Center, information for patients. This link can be accessed through The Glaucoma Home Page at www.web-xpress.com/gany.

Laser iridotomy is also being evaluated as a possible therapy for reverse pupillary block in pigment dispersion syndrome and pigmentary glaucoma, although this remains under investigation. The procedure for laser iridotomy and potential for complications are described above. The procedure is ambulatory, generally pain-free, and takes approximately 10 minutes to perform.

Under certain circumstances, laser iridotomy may fail to open a closed angle. If the angle is not permanently closed with scar tissue, ALPI may help to open the angle. This is particularly useful in less common forms of angle-closure, such as plateau iris syndrome or lens-related angle-closure. The procedure consist of applying the laser to contract and mechanically pull the iris out of the drain. Other uses include acute attacks of angle-closure in which laser iridotomy cannot be performed or is ineffective or continued angle-closure despite a patent laser iridotomy is present.

Operative surgery for glaucoma falls into 2 general categories reflecting the mechanism by which the surgery lowers the pressure. Since the problem in most glaucomas is that the drain does not function properly, the most commonly performed type of surgery involves creation of a new drainage structure for aqueous to leave the eye. The most common operation of this type is called trabeculectomy. In trabeculectomy, the surgeon fashions a new drain in the region of the trabecular meshwork (the damaged drain) and the sclera (which is the white covering of the eye). Fluid production within the eye is allowed to continue normally, and pressure reduction is achieved by allowing the fluid to exit the eye through the new drain. With the advent of microsurgery and the use of the antiscarring drugs 5-fluorouracil (also known as 5-FU) and mitomycin C, these procedure have become much more effective at lowering pressure, preserving vision, and preventing complications. Techniques such as releasable sutures and laser suture lysis allow for a more gradual reduction of IOP after surgery and often avoid periods of prolonged low pressure, which can be a major source of complications during the first few weeks after surgery. Long term complication of this type of surgery include the possibility that cataract formation might accelerate and failure of the filtering operation months or years later.

Since this procedure is performed in an operating room, it typically takes longer (about 30-45 minutes) and involves more frequent follow-up care by the surgeon. Most patients are seen frequently (once or twice per week) for the first 4-6 weeks following the surgery, during which time the pressure is monitored and the healing process monitored. Postoperative drops can often be eliminated during this time.

Upon occasion, because of abnormal eye anatomy or history of previous eye surgery, it is not possible for the surgeon to build a new drain from the tissue present within the eye. Under these circumstances, an artificial drainage tube, made of plastic, may be inserted into the eye to act as a new drain. Although the modern form of glaucoma drainage tube implant surgery was first developed in the 1960s, advances in implant design during the 1980s and 1990s have made this procedure safer.

Since glaucoma often occurs in older individuals, the presence of a hazy lens, or cataract, is common during the preoperative examination. Although the correction of vision loss due to cataract requires surgery, the good news is that cataract surgery can successfully reverse the vision loss associated with the cataract, although the glaucoma damage will still be present. In this situation, the presence of coexisting cataract and glaucoma can be addressed by combined cataract surgery and glaucoma filtering surgery, most often with good results for both. The success of the glaucoma surgery in this instance is aided by the use of the antiscarring medication mitomycin C, which has been a huge advance for glaucoma surgeons and their patients requiring combined cataract and glaucoma surgery.

As mentioned earlier, in the above forms of glaucoma surgery the surgeon creates or implants a new drain for fluid to exit the eye and fluid production is allowed to continue. In cyclodestruction, the gland that produces the fluid, the ciliary body, is partially destroyed to decrease the amount of fluid produced in the eye. This is analogous to turning down the faucet in an overflowing sink. Unfortunately, the functioning of the eye depends upon the production of fluid, and cyclodestruction can cause a change in the composition of the fluid. Fortunately, the development of new laser technologies have made his procedure safer and less uncomfortable than in the past. Most physicians, however, reserve this surgery for eyes which have failed filtering surgery or those which are so badly damaged that the prognosis for the retention of vision is grim.

Figure 1 – schematic of eye

Figure 2 – anterior segment

Figure 3 – Graph

Figure 4 – XFS

Figure 5 – diagram

Figure 6 – SWS

Figure 7 - aniridia