Primary open-angle glaucoma (POAG) can be considered a chronic, progressive, anterior optic neuropathy that is accompanied by a characteristic cupping and atrophy of the optic disc, visual field loss, open angles, and no obvious causative ocular or systemic conditions. In the majority, but by no means all, cases the intraocular pressure (IOP) is elevated above the statistically ‘normal’ range, reflecting a reduced aqueous humor outflow facility. Although elevated IOP is not the cause of all damage in POAG, it is the major risk factor. The issue of IOP has been complicated by the rediscovery of the importance of corneal thickness as both a parameter that may cause inaccurate readings with applanation tonometry and an independent factor that may change the risk of developing open angle glaucoma. The mechanism by which elevated IOP damages the optic nerve is not clear, but ischemia of the optic disc or nerve fiber layer, direct mechanical compression of axons, local toxicity, or some combination of these has been implicated.
Primary open-angle glaucoma may be more than one disease with a final common pathway of damage to the ganglion cells and optic nerve; at present, we are unable to clearly distinguish any subclassification, although attempts have been made to divide POAG into ‘IOP sensitive’ and ‘IOP insensitive’ forms. Given our lack of knowledge on this subject, we will continue to discuss POAG as if it were a single disease. Primary open-angle glaucoma is referred to by a variety of other names, including open-angle glaucoma, chronic open-angle glaucoma, chronic simple glaucoma, and open-angle glaucoma with damage.
Primary open-angle glaucoma is the most common form of glaucoma in many countries and accounts for 60–70% of the cases seen in the United States. By the year 2000, it was estimated that there were approximately 2.5 million cases of POAG in the United States (about 1.9 million white Americans and 0.6 million black Americans). The Dana Center in Baltimore estimates that 45 million people worldwide will have open-angle glaucoma by the year 2010, of which 4.5 million will be bilaterally blind. This disease has a hereditary component and becomes more prevalent with age. Because POAG is very slowly progressive, it is usually asymptomatic until late in its course; affected individuals can develop severe damage before they seek professional help. Most cases of POAG are discovered through screening programs or on routine ocular examinations. Population-based screening programs may have a small yield and may not be cost effective; however, screening programs directed towards those at higher risk (e.g. the elderly, people of African descent) may be more productive.
In a minority of white patients but a majority of Japanese patients, optic nerve cupping and visual field loss develop without recorded IOPs above the statistical norm. This condition is called normal-tension glaucoma (normal-pressure glaucoma, low-tension glaucoma, or low-pressure glaucoma). Many individuals have IOPs above the statistically ‘normal’ range (>2 standard deviations from the mean, or 21 mmHg), but only a very small percentage of these ever develop optic nerve damage. Those individuals with ‘elevated’ IOPs who also have normal optic nerves, normal visual fields, and no known ocular or systemic condition accounting for the increased pressure are said to have ocular hypertension . These individuals are at increased risk (compared with those with ‘normal’ IOP) of developing true glaucoma. The Ocular Hypertension Treatment Study (OHTS) showed that many of those with above ‘normal’ IOP have thick corneas and are at low risk for development of actual glaucoma.
The existence of normal-tension glaucoma and ocular hypertension implies that some optic nerves are quite sensitive to the effects of IOP, whereas others are quite resistant. As noted previously, ischemia, mechanical factors, and neurotoxic agents have been cited, but, unfortunately, we are unable to formally identify those clinical factors leading to optic nerve damage. Although we know about some risk factors, it is impossible to determine with any degree of confidence which of those individuals with ‘elevated’ IOPs will ultimately develop actual optic nerve damage (although we can estimate risk). Nor can we determine the ‘safe’ level of IOP for any given individual.
The study of epidemiology (the distribution of a disease in a population, and the identifiable conditions that are associated with it) helps us understand some of the factors that alter the risk of glaucoma, its progression, and its sequelae. The understanding of POAG has been significantly improved in recent years by the application of epidemiologic principles. From reviews of various sources of data, it can be estimated that 2.25 million Americans 40 years of age and older have POAG. In Australia, the prevalence of definite glaucoma ranges from 2.1 to 2.5% of those over 50 years old and the number of people with glaucoma is expected to double by the year 2030. Worldwide, over 2 million people develop this condition every year. Between 84000 and 116000 persons are estimated to be bilaterally blind (visual acuity <20/200) in the United States. Worldwide, more than 3 million people are bilaterally blind because of POAG.
In most studies performed in western Europe and in the United States, the prevalence of POAG is 0.5–1% of the population above age 40 ( Table 17-1 ). Various studies have reported different prevalences depending on the population sampled, the ages of the individuals studied, the techniques of examination, and the definitions of glaucoma used. The most recent US study using rigorous definitions estimated the overall prevalence of open-angle glaucoma at about 1.9% of those over 40, with blacks having three times the prevalence of whites. A similar overall prevalence was found for definite POAG in those over age 40 in Spain. Many previous studies found higher prevalence rates because the investigators diagnosed glaucoma by elevated IOP or abnormal aqueous humor dynamics instead of visual field loss and optic disc cupping.
|Investigator||Site||Ages (years)||No. examined||Diagnostic criteria||Prevalence (%)|
|Stromberg||Skovde, Sweden||>40||7275||Disc and field changes||0.41|
|Hollows & Graham||Wales||40–74||4231||Disc and field changes||0.47|
|Bankes et al||England||>40||5941||Disc and field changes||0.76|
|Kahn & Milton||Framingham, Mass||52–85||2433||Visual field changes||1.43|
|Bengtsson||Dalby, Sweden||55–70||1511||Disc and field changes||0.86|
|Mason et al||St Lucia, West Indies||30–86||1679||Disc and field changes||8.8|
|Tielsch et al||Baltimore, Maryland (white)||>40||2913||Disc and field changes||1.29|
|Tielsch et al||Baltimore, Maryland (black)||>40||2395||Disc and field changes (black)||4.74|
|Shiose et al||Japan||≥40||8126||Disc and field changes||2.6|
|Klein et al||Beaver Dam, Wisc||43–84||4926||Disc and field changes||2.1|
|Coffey et al||Ireland||≥50||2186||Disc and field changes||1.9|
|Leske et al||Barbados, West Indies||40–84||4709||Disc and field changes||6.6|
|Dielmans et al||Rotterdam, Netherlands||≥55||3062||Disc and field changes||1.1|
|Mitchell et al||Blue Mountain, Australia||≥49||3654||Disc and field changes||3.1|
|Friedman et al||Estimate US||>40||Meta-analysis||Disc and field changes||1.9|
However, even more recent studies, using strict criteria for optic nerve damage, have shown a surprisingly high prevalence, especially among those of black African ancestry and among those over 70 years of age (see Ch. 1 ). Recent studies have emphasized the differences among various racial and ethnic groups vis-à-vis the prevalence of glaucoma. For example, in southern India, the prevalence of open-angle glaucoma is 1.6% of the population with greater than 98% unaware that they have the disease. In Japan, glaucoma is quite common compared to other Asian and Caucasian societies. In the Tajima study, 3.9% of those over 40 years old had POAG and the vast majority had IOPs below 21 mmHg. Among Singapore Chinese, the prevalence of POAG in those over 40 years of age is about 1.6%. The prevalence of open-angle glaucoma also appears to be relatively high in a population study in Bangladesh (about 2% in people over 40). However, the highest prevalence is still in those of west African origin; for example, in Ghana, the prevalence of open-angle glaucoma is over 8% in those over 40. In South Africa, the prevalence of glaucoma in general was almost 3% among black South Africans over 40; surprisingly, 16% of these had exfoliative glaucoma. However, even some Caucasian populations may have a high prevalence of glaucoma; for example, in Iceland, the prevalence of glaucoma (including exfoliative) in those over 50 is 4%. In another example, Greeks seem to have an unusually high prevalence: >4% compared to other European groups. Australians also have a relatively high prevalence of glaucoma (3%), with women having a higher prevalence than men and the prevalence increasing ‘exponentially’ with age.
Few studies determining the true incidence of POAG in the general population have been undertaken. A study of this type requires a large population-based sample with long-term follow-up. Such a study has been performed in Barbados over 4 years. In this population of largely black African ancestry, the 4-year incidence of glaucoma over 40 years of age is 2.2%, with higher rates for males, those of African ancestry, those with high IOPs, and those with suspicious discs at enrollment. Incident rates increased from 1.2% in the 40–49 age group to 4.2% in those over 70. Using data from theFramingham study, Podgor and co-workers have estimated that the incidence of POAG rises from 0.2% at age 55 to 1.1% at age 70; that is, the incidence of POAG is 2 cases per 1000 people per year from age 55 to 60 years, and 11 cases per 1000 people per year from age 70 to 75 years. The Rotterdam study showed that the incidence of glaucoma over 6.5 years in those over 55 years of age was 1.2% for probable open-angle glaucoma and 0.6% for definite open-angle glaucoma. The incidence increased with age so that at age 60, the incidence was about 1% and it rose to 3% at age 80. As in most other studies, most of the patients with incident glaucoma were unaware of their disease. In Australia, the overall 5-year incidence of definite glaucoma in those over 40 was 0.5% and of definite and probable glaucoma 1.1%; the incidence ranges from near 0 at 40 to over 4% at age 80. A similar increase in incidence has been found in Minnesota.
There is general agreement that IOP is the most important known risk factor for open-angle glaucoma development. Evidence clearly indicates that elevated IOP can cause glaucomatous optic nerve changes in experimental animals. Even in normal-pressure glaucoma, asymmetric IOP has been noted to correlate with asymmetric cupping and field loss, with the greater damage most often occurring on the side with higher pressure. Population surveys also support the increase in prevalence of open-angle glaucoma with increasing IOP. Among those with elevated IOP without evidence of glaucomatous damage (ocular hypertensives), the OHTS study shows that the higher the IOP, the more likely that glaucomatous damage will develop. Because many individuals with ‘elevated’ IOP never develop glaucoma, and because many people with glaucoma have ‘normal’ IOPs, IOP obviously cannot be the only risk factor.
The prevalence of POAG increases with age ( Table 17-2 ). However, one should not infer from this statement that the disease is limited to middle-aged and older individuals; it occurs in children and young adults as well. The effect of age on the prevalence of POAG holds true even after compensating for the relationship between increasing age and increasing IOP. Even in Japan where IOP does not increase with age, open-angle glaucoma does increase in prevalence with age. Age is also a risk factor for the conversion from ocular hypertension to open-angle glaucoma.
|Age (years)||Wales (Hollows and Graham)||Framingham, Mass. (Liebowitz and Co-workers)||Baltimore White (Tielsch and Co-workers) *||Baltimore Black (Tielsch and Co-workers) *|
Conflicting information exists about the effect of gender on the prevalence of POAG. In several studies, males had a higher prevalence of glaucoma. In the Barbados study, POAG was associated with older men, high IOP, positive family history, lean body mass, and low blood pressure to IOP ratio.
As noted above, POAG is more prevalent in blacks than in whites. Furthermore, the disease seems to develop at an earlier age and has a more rapid progression in black patients. It is estimated that the incidence and the prevalence of blindness from glaucoma are 8–10 times higher in black patients than in white patients in the United States. The OHTS study showed black race to be a risk factor for the development of open-angle glaucoma from ocular hypertension using univariate analysis; however, race drops out of the risk factors in the multivariate analysis because blacks have significantly thinner corneas than other racial groups and the thin corneas become the predominant risk factor. Some have proposed that optic nerve ischemia from sickle cell anemia contributes to the high prevalence of POAG in blacks. However, this theory was not supported by one study, which found that only 2 of 40 black patients requiring filtering surgery had a positive test for sickle cell trait. Black patients seem to respond to some treatment modes less favorably than do whites; whether this explains the more virulent course has not been answered. Furthermore, some black patients may not have access to the same quality of treatment as white patients have. When compared with whites, blacks have higher levels of IOP and larger cup-to-disc diameter ratios. In the USA, in those of Hispanic (admittedly a very mixed group) background, the prevalence of open-angle glaucoma is midway between that of blacks and whites with a more rapid rise in prevalence as the population ages. Latinos of Mexican background living in Los Angeles also have a higher prevalence of open-angle glaucoma that is nearly 5% in those over 40; the prevalence is therefore somewhere between those of European ancestry and those of African ancestry.
Data on the prevalence of POAG in other ethnic and racial groups are less complete. It is stated that POAG is rare in Pacific Islanders, some Asians, and certain Native American tribes. In Mongolia, the prevalence of open-angle glaucoma was found to be quite low (0.5%) with angle-closure glaucoma having a prevalence of 1.4%. In Japan, the prevalence of POAG is 0.58%, with normal-pressure glaucoma having a prevalence of 2.04%. In an English study, the prevalence of open-angle glaucoma was found to be similar in those of European descent and in those of Asian descent. However, it is unlikely that this population living in England is representative of all Asian groups. In Tunis, the overall prevalence of open-angle glaucoma in a population over 40 years of age was 2.7%. This is similar to that found in Europeans but lower than that found in those of black African descent. In southern India (mostly Tamil), as noted above, the prevalence of open-angle glaucoma is 1.6% in those over 40. Further surveys using standardized techniques and definitions are needed in many population groups.
Very few studies have been performed on the relationship between socioeconomic variables and the prevalence of POAG. In different reports, manual laborers have an increased and a decreased prevalence of POAG. The Baltimore Eye Study suggested that socioeconomic factors played some role in the increased prevalence and severity of open-angle glaucoma in those of black African descent, but only a small part compared with racial factors. A retrospective study from England looking for parameters contributing to blindness from glaucoma found that lower socioeconomic status was indeed one of the risk factors despite universal health care in that country.
Little is known about the effect of lifestyle, vocation, geography, diet, and nutrition on glaucoma. Moderate exercise has been shown to decrease IOP in both normal volunteers and in patients with POAG. Furthermore, moderate exercise has been shown to increase choroidal blood flow, although with some limits. However, whether regular exercise results in better long-term IOP control or improved ganglion cell survival has not been demonstrated. One study showed little effect of caffeine on IOP but a more recent study did implicate caffeine use as being related to increased IOP and to having glaucoma. It may be difficult in these kind of studies to separate out the effects of a substance like caffeine and the effects of the total fluid volume associated with the intake.
Myopia has been associated with POAG in many studies. It is not clear whether myopia has a direct influence on the prevalence of the disease or whether it acts through its known associations with increased IOP and larger cup-to-disc ratios. It is often difficult to diagnose glaucoma in myopic individuals because they have (1) broad, shallow optic cups with less distinct margins; (2) baring of the blind spot or other refractive scotomata on visual field testing; (3) low ocular rigidity, which makes Schiøtz tonometer readings inaccurate, and (4) thin corneas and sclera which may give falsely low readings on Goldmann tonometry.
As noted previously, a thin cornea is a risk factor for conversion from ocular hypertension to open-angle glaucoma. Race as a risk factor in itself disappeared when corneal thickness was taken into account; that is, those of African ancestry had thinner corneas and this accounted for all of the increased risk for conversion to open-angle glaucoma among blacks with ocular hypertension. A thin cornea also seems to be a marker and possible risk factor for advanced glaucoma on diagnosis. A thin cornea will cause Goldmann tonometry to underestimate the IOP. In the OHTS study cited above, the increased risk related to thin corneas could not be explained solely by the underestimation of IOP. Therefore, thin corneas may be a marker for increased susceptibility of the optic nerve. Perhaps, people with thin corneas have less support tissue in the optic nerve making it more liable to pressure-induced and/or vascular damage.
Primary open-angle glaucoma appears to have a genetic or familial component. Over the years, autosomal dominant, autosomal recessive, and sex-linked inheritance patterns have been reported. Currently, most authorities believe that the genetic influence occurs through polygenic or multifactorial transmission. It is reported that 5–50% of cases of POAG are hereditary, with the best estimate being 20–25%. The risk of developing POAG in first-degree relatives is 4–16%. The Rotterdam study found that relatives of patients with POAG were 10 times more likely to have or develop glaucoma than relatives of those without glaucoma. In Australia, the odds ratio for first-degree relatives is 3.1 and a positive family history was the strongest risk factor for development of glaucoma. A monozygotic and dizygotic twin study estimated the inheritability to be 13%. In a carefully done study of laboratory-confirmed monozygotic twins and their spouses in Iceland, the concordance for open-angle glaucoma in the twins was 98%, much higher than in the spouse pairs. In one study, the association was higher with a sibling affected than with a parent or child. In the Barbados study, 25% of the siblings of patients with POAG had either POAG or were suspect for POAG. Siblings of those individuals with glaucoma are more likely to have a higher IOP and a larger cup-to-disc ratio than siblings of those without glaucoma. Two longitudinal studies – one population-based and the other over 18 years in length – demonstrated a strong association between the development of glaucoma and positive family history.
Recently, studies have identified one gene (GLC1A) that is associated with juvenile-onset open-angle glaucoma and some (about 3–4%) cases of POAG in adults. This gene is located on chromosome 1 in the q23–25 region. Three different mutations of this gene have been identified in about 4% of patients with POAG. One particular mutation seems to account for most of the abnormal genes found in a population of glaucoma patients in India. This mutation was only present in about 5% of the total glaucoma population. Yet another mutation has been identified in a Chinese family with juvenile-onset open-angle glaucoma. Another gene that has been associated with adult-onset open-angle glaucoma is located on chromosome 2 (GLC1B). Both of these genes associated with POAG in adults seem to be related to an early-onset type. Some well-established pedigrees have had abnormalities in neither of these genes (see Ch. 20 ). Allingham and co-workers have identified a mutation on chromosome 15 that accounts for a relatively large subset (17%) of early, but not childhood-onset, glaucoma. Junemann and co-workers found a relatively high prevalence of polymorphisms in the methylenetetrahydrofolate reductase gene in POAG patients but not in exfoliative glaucoma patients in Germany. A group from Australia identified a novel gene abnormality on chromosome 3 which occurs in a large Tasmanian family with early-onset open-angle glaucoma, one-third of whom have mutations in the myocilin gene and others with glaucoma show mutations on chromosome 3. Another study found an association between an endothelial nitric oxide synthase gene and open-angle glaucoma accompanied by migraine.
All these studies open an exciting frontier and suggest that open-angle glaucoma may be associated with several different genes, each of which may produce a different time of onset and, perhaps, clinical course; furthermore, similar phenotypes can be seen with different mutations of different chromosomes even within the same family. The next few years should see some clarity in this area.
Several ocular factors associated with POAG – including IOP, outflow facility, and cup-to-disc ratio – appear to be genetically determined. For example, children and siblings of glaucoma patients are far more likely to have abnormal aqueous humor dynamics than are first-degree relatives of normal individuals. Thus some of the polygenic inheritance of POAG may occur indirectly through these associated factors rather than directly through the disease itself.
Primary open-angle glaucoma has been linked to a variety of endocrine and vascular disorders. Several studies have shown a high prevalence of diabetes mellitus in patients with POAG, as well as a high prevalence of POAG in patients with diabetes. Although neither the Baltimore Eye Study nor the Diabetes Audit and Research in Tayside Study (DARTS) in the United Kingdom were able to find an association of open-angle glaucoma with diabetes mellitus, but the most recent population studies strongly support an association with diabetes mellitus. These include the Blue Mountains Eye Study in Australia, the Rotterdam Study, and the Beaver Dam Eye Study in Wisconsin. The explanation for this relationship remains obscure, but some investigators have proposed that diabetes affects the small blood vessels supplying the optic nerve, thereby rendering it more susceptible to glaucomatous damage.
Other investigators have proposed a relationship between POAG and thyroid disease. In one study, open-angle glaucoma was associated with chronic thyroid orbitopathy. A more recent study confirmed the association of Graves’ disease with not only open-angle glaucoma but also normal-tension glaucoma and ocular hypertension (not surprising as the IOP can be raised with restrictive muscle conditions). However, not all studies have shown this association. In the Veteran’s Hospital in Birmingham, Alabama, an association was found between males with open-angle glaucoma and hypothyroidism.
Corticosteroid function and systemic vascular disease, and their relationships to POAG, are discussed in greater detail later in this chapter. Having open-angle glaucoma does not seem to influence mortality; this is an important observation since decisions about the intensity of treatment can be made against the background of typical life expectancy for age.
Vascular disease has long been suspected of contributing to glaucomatous damage. In the Barabados study, baseline systemic hypertension seemed actually to reduce the risk of incident open-angle glaucoma while low blood pressure (or more accurately, low perfusion pressure) seemed to increase the risk. Studies of blood flow in and around the eye in the laboratory strongly suggest that blood flow is reduced or disordered in glaucoma. However, whether this abnormal blood flow is a primary causal phenomenon or secondary to the optic atrophy has not been shown. One study of American veterans suggests that long-term oral statin or other anticholesterol use is associated with a lower risk of open-angle glaucoma. A subsequent study in a broader population has confirmed this observation. The Blue Mountains Eye Study suggests an association between open-angle glaucoma and migraine.
A few studies have linked primary open-angle glaucoma with sleep apnea. The mechanism of this is not clear but may relate to the respiratory disturbance leading to transient nocturnal episodes of hypoxia, which may increase the propensity of the optic nerve to damage. However, not all studies have been able to confirm this association.
The Rotterdam study produced an unexpected and as yet unexplained association between early menopause and glaucoma.
A detailed discussion of POAG must address two fundamental issues: (1) the mechanism(s) of IOP elevation, and (2) the mechanism(s) of progressive optic nerve cupping and atrophy.
DIMINISHED AQUEOUS HUMOR OUTFLOW FACILITY
It is generally accepted that the increased IOP seen in most cases of POAG is caused by a decreased facility of aqueous humor outflow. Although there have been a few reports of patients with hypersecretion of aqueous humor, these reports were based on tonographic estimates of aqueous humor production rather than on direct measurements such as fluorophotometry. If the entity of hypersecretion exists, it must be exceedingly rare and therefore will not be discussed further here.
In enucleated normal human eyes, Grant demonstrated that incising the entire trabecular meshwork reduced the resistance to outflow by 75%. This finding was confirmed by Peterson and co-workers. From this observation, most investigators inferred that the increased resistance to outflow seen in glaucoma must also lie between the anterior chamber and the lumen of Schlemm’s canal. The main site of resistance to outflow is probably in juxta-canalicular tissue, where the greatest concentration of mucopolysaccharides and the greatest phagocytic activity reside. This was further confirmed by careful microcannulation and pressure measurements at various locations within the trabecular meshwork area; the resistance was found in a region 7–14 mm internal to the inner wall of Schlemm’s canal.
It should be emphasized that not all authorities accept this hypothesis. Others have also proposed that outflow facility is reduced because the trabecular meshwork prolapses into Schlemm’s canal, thus occluding the lumen and preventing circumferential flow of aqueous humor to the collector channels. The argument against this theory is that Schlemm’s canal only collapses at very high levels of IOP. No evidence exists to show that the canal is occluded when IOP is in the range of 25–35 mmHg, which is the situation in most eyes with POAG.
The decreased outflow facility in glaucoma has also been ascribed to an obstruction of the intrascleral collector channels. This obstruction could be caused by an accumulation of glycos-aminoglycans in the adjacent sclera. Krasnov has proposed that POAG is really several different diseases with different sites of resistance. He believes that obstruction in the collector channels accounts for approximately 50% of the cases of POAG. This theory was partially refuted by experiments that demonstrated that unroofing Schlemm’s canal did not reduce resistance to outflow in glaucomatous eyes until the canal was entered; that is, no scleral blockage was noted.
If the hypothesis is accepted that the trabecular meshwork or the endothelium of Schlemm’s canal is the site of the increased resistance to outflow in POAG, the question of what process interferes with normal aqueous elimination must be asked. Several theories have been proposed to explain this phenomenon, including those that follow:
An obstruction of the trabecular meshwork by foreign material. Several investigators have noted the accumulation of foreign material in the trabecular meshwork and juxtacanalicular tissue, including pigment, red blood cells, glycosaminoglycans, amorphous material, extracellular lysosomes, plaquelike material, and protein. Lütjen-Drecol and Rohen have postulated that the electron-dense material consists of collagen and elastin and that these materials are responsible for the increased resistance to aqueous outflow. It is also possible that a normal constituent that is catabolized insufficiently or synthesized excessively obstructs the meshwork.
A loss of trabecular endothelial cells. Glaucomatous eyes have fewer endothelial cells than normal eyes, although the rate of decline in the two is similar. This suggests a premature aging process in glaucomatous eyes. A loss of endothelial cells would interfere with various important trabecular functions, including phagocytosis and synthesis and degradation of macromolecules. The lack of a complete endothelial covering could allow the trabecular beams to fuse.
A reduction in pore density and size in the inner wall endothelium of Schlemm’s canal. The endothelium lining the inner wall of Schlemm’s canal accounts for 10–20% of the total resistance. Ultramicroscopic pores can be found in the endothelium of the inner wall of Schlemm’s canal, and they seem to be reduced in both size and density in open-angle glaucoma.
A loss of giant vacuoles in the inner wall endothelium of Schlemm’s canal. Giant vacuoles may play a crucial role in moving fluid from the meshwork into the lumen of Schlemm’s canal. A reduction in the number and size of these microstructures is seen in glaucoma. Alvarado and Murphy found a reduction in the area of ‘cul-de-sacs’ in the juxtacanalicular tissue in glaucomatous eyes; this reduction could account for the increased resistance to outflow.
A loss of normal phagocytic activity. Phagocytosis occurs in the trabecular meshwork continuously and represents the self-cleaning filter of the meshwork. It has been postulated that the trabecular endothelial cells lose their normal phagocytic activity or are overwhelmed by foreign material, which leads to cell death or migration from the beams.
Disturbance of neurologic feedback mechanisms. Nerves, whose function is unknown, have been found in the trabecular meshwork. Nerve endings, some of which could be mechanoreceptors, have been located in the scleral spur of humans. It has been speculated that these nerves could function to slow down aqueous formation or speed outflow when IOP is elevated. Theoretically, some interference with this feedback mechanism could lead to unchecked elevation of IOP.
Histopathologic study of the conventional aqueous drainage system from patients with POAG reveals a number of abnormalities, including those that follow ( Fig. 17-1 ):
Alterations in the trabecular beams, including fragmentation of collagen, increased curly and long-spacing collagen, and coiling of fiber bundles
Thickened basement membranes
Narrowed intertrabecular spaces
Fused trabecular beams
Decreased number of trabecular endothelial cells
Reduced actin filaments
Accumulation of foreign material
Decreased number of giant vacuoles
Narrowing of collector channels
Closure of Schlemm’s canal
Thickened scleral spur.
However, these histopathologic changes must be interpreted with caution. Most of the glaucoma specimens are obtained at surgery; thus artifacts are common, and it is impossible to fix the tissues at their normal IOP levels. In addition, the specimens generally come from eyes with advanced damage. Furthermore, it is difficult to know whether the changes seen are primary phenomena or secondary to the effects of increased IOP or medical and surgical treatment. Finally many of the histopathologic alterations are also seen in older, normal eyes. In fact, some researchers have proposed that the outflow changes of POAG could be an acceleration of the normal aging process.
Although it is impossible to be sure of the fundamental defect of aqueous humor outflow in POAG, the balance of the evidence favors the trabecular meshwork or the endothelium of Schlemm’s canal as the site of the increased resistance. If we accept this hypothesis, we must still ask why outflow facility is reduced in POAG. Various investigators have linked the increased resistance to outflow with altered corticosteroid metabolism, dysfunctional adrenergic control, abnormal immunologic processes, and oxidative damage.
Altered corticosteroid metabolism
Soon after the early descriptions of corticosteroid-induced IOP elevations, Armaly and Becker and Hahn noted that patients with POAG were quite responsive to topical glucocorticoids. These researchers proposed that the IOP response to topical corticosteroids was inherited and that this inheritance was either the same as, or closely linked to, the inheritance of POAG. The corticosteroid hypothesis was then extended to include a generalized sensitivity to the effects of glucocorticoids in patients with POAG. Various investigators noted patients with POAG had (1) increased plasma levels of cortisol; (2) increased suppression of plasma cortisol with different doses of exogenous dexamethasone; (3) continued suppression of plasma cortisol by dexamethasone despite concomitant administration of diphenylhydantoin (phenytoin); (4) disturbed pituitary adrenal axis function, and (5) increased inhibition of mitogen-stimulated lymphocyte transformation by glucocorticoids. Researchers postulated that endogenous corticosteroids affected trabecular function by altering prostaglandin metabolism, glycosaminoglycan catabolism, release of lysosomal enzymes, synthesis of cyclic adenosine monophosphate, or inhibition of phagocytosis.
The corticosteroid hypothesis came under attack as subsequent studies in glaucomatous patients failed to confirm the increased sensitivity of non-ocular tissues to the effects of glucocorticoids. In addition, the IOP response to topical corticosteroids was shown to lack reproducibility and to be less controlled by inheritance than previously thought.
Recent data have re-opened the corticosteroid issue. Trabecular endothelial cells from patients with POAG have an abnormal metabolism of glucocorticoids, with increased levels of delta-4 reductase and reduced levels of 3-oxidoreductase. The importance of this observation, and whether it represents a primary or a secondary change in the tissue, is unclear at present. Most recently, a gene mutation (GLC1A) has been associated with juvenile-onset glaucoma and a small fraction of adult-onset POAG. Mutations of this gene (trabecular meshwork-inducible glucocorticoid response (TIGR)) are associated with the production of an abnormal glucocorticoid-inducible stress-response protein (myocilin) in the trabecular meshwork that may affect glycosaminoglycan and other glycoprotein metabolism, as well as cell-surface properties. In addition to giving a genetic basis for some types of glaucoma, the TIGR gene could tie in a possible role for corticosteroids in the glaucomatous process. Furthermore, patients who respond to topical steroids with a very high IOP are more likely to develop visual field loss than moderate responders. In this study, none of those who were low responders developed visual field loss.
Dysfunctional adrenergic control
In analogous fashion to the corticosteroid theory, others have proposed that the diminished outflow facility in patients with POAG could be explained by an increased sensitivity to adrenergic agonists. Various reports indicated that patients with POAG had (1) a greater IOP reduction after the administration of topical adrenaline (epinephrine); (2) a greater response to adrenaline (epinephrine) or theophylline in inhibiting mitogen-stimulated lymphocyte transformation, and (3) more frequent premature ventricular contractions after topical administration of adrenaline (epinephrine). Furthermore, ocular hypertensive subjects who demonstrated a fall in IOP greater than 5 mmHg after topical adrenaline (epinephrine) administration had a higher rate of developing visual field loss. However, additional studies have generally failed to confirm an increased sensitivity to adrenergic agonists in patients with POAG.
Abnormal immunologic processes
Other investigators have explained the diminished aqueous humor outflow in POAG by abnormal immune responses. Increased levels of γ-globulin and plasma cells have been detected in the trabecular meshwork of patients with POAG. Furthermore, glaucoma patients were noted to have a high prevalence of antinuclear antibodies. However, subsequent, more detailed studies have failed to confirm these findings. An association between POAG and certain human lymphocyte antigens was reported and then refuted by multiple studies. Endothelin-like immunoreactivity has been noted to be increased in the aqueous of glaucoma patients, suggesting a role for this molecule in IOP regulation. Antibodies to heat shock protein, an indicator of cell stress, have been noted to be increased in the serum of glaucoma patients. Evidence for immunologic factors in open-angle glaucoma, especially in the retinal ganglion cell layer, have led some to propose vaccination as a potential neuroprotecting treatment in glaucoma.
Interest has developed in the question of whether the trabecular meshwork could be damaged by oxidative insult. The meshwork contains glutathione, which may protect the endothelial cells from the effects of hydrogen peroxide (H 2 O 2 ) and other oxidants. This interesting hypothesis is still the subject of active research.
Other toxic influences
Lütjen-Drecoll has postulated that transforming growth factor (TGF) beta2 may be involved in the pathogenesis of open-angle glaucoma. Dan and co-workers have shown that there is a three-fold increase in the levels of plasminogen activator inhibitor in the aqueous humor of glaucoma patients compared to cataract patients without glaucoma. These findings suggest that this protein may play some role in the pathogenesis of increased IOP.
In summary, the cause of the trabecular dysfunction in POAG is unclear at present. To date, no single theory explains the pathophysiology.
OPTIC NERVE CUPPING AND ATROPHY
The second major issue to be addressed in the pathogenesis of POAG is the cause of the optic disc cupping and atrophy. This topic is dealt with in detail in Chapter 12 . Cupping consists of backward bowing of the lamina cribrosa, elongation of the laminar beams, and loss of the ganglion cell axons in the rim of neural tissue. Cupping is the hallmark of glaucomatous damage, although it is seen occasionally in ischemic states and compressive lesions in the posterior optic nerve and chiasm. Histologic studies indicate that optic nerve cupping includes the loss of all three elements of the disc – axons, blood vessels, and glial cells. Glial cells appear to atrophy as a secondary phenomenon, and some glial cells are present even in advanced stages of glaucomatous optic atrophy. Other investigators have reported selective loss of capillaries in the disc substance or in the peripapillary retina. These findings have not been confirmed, however and blood vessels actually seem to be lost in proportion to the loss of axons. A recent study of the submicroscopic histopathology and immunohistochemistryof the optic nerve showed fibrosis, arterioscerotic changes and loss of capillaries in glaucomatous optic nerves compared to non-glaucomatous ones. These changes were not present in the higher IOP eyes with pseudoexfoliative glaucoma.
Most authorities believe that the lamina cribrosa is the site of glaucomatous optic nerve damage. The lamina is a relatively rigid structure that surrounds the densely packed axons. Furthermore, the lamina is the tissue that divides the higher IOP space from the lower subarachnoid pressure space. Early in glaucoma, the lamina is compressed. In the later stages of the disease, the laminar sheets become fused, and the entire lamina bows backward.
It is commonly accepted that increased IOP either directly or indirectly causes optic nerve cupping. The evidence for this can be summarized as follows:
Most patients with POAG have increased IOP, which generally predates by years the development of cupping and visual field loss.
Elevated IOP is a major risk factor for the development of POAG in glaucoma suspects.
Elevated IOP is the only known common element to a wide variety of secondary glaucomas.
In all animal models of glaucoma, elevated IOP precedes optic nerve damage and visual loss.
Even in normal-pressure glaucoma, in which IOPs do not exceed the statistically ‘normal’ range, the degree of cupping is related to the level of IOP.
Mechanical changes in the topography of the optic nerve and in the lamina cribrosa are seen early in experimental glaucoma with elevated IOP in monkeys and are not seen in other forms of optic nerve damage.
Although IOP is certainly one risk factor, most investigators point to other factors that also affect glaucomatous cupping. They point to the observations that (1) a significant per cent of patients develop optic nerve cupping and visual field loss at normal levels of IOP; (2) some patients maintain normal optic nerves and visual function despite elevated IOP, and (3) the level of IOP does not correlate well with the progression of established POAG. However, these observations do not refute a linkage between IOP and optic nerve damage; rather they imply variable resistance of the optic nerve to pressure-induced damage. That is, some nerves are more sensitive to pressure than are others.
More than 130 years ago, Mueller proposed that elevated IOP led to direct compression and death of axons, whereas von Jaeger stated that ischemia was the cause of progressive glaucomatous cupping. Yamazaki and Drance reported abnormal retrobulbar circulation by color Doppler imaging in eyes with progressively worsening normal-tension glaucoma compared to those with stable glaucoma. Other studies have supported some abnormality in ocular circulation in patients with primary open-angle glaucoma and normal-tension glaucoma compared to secondary glaucomas. Although the debate over the role of mechanical versus circulatory factors continues to the present, most would agree that no one theory explains all of the observed phenomena and that each plays some role in at least some patients. The optic nerve damage from glaucoma is multifactorial and, at different times and in different eyes, may involve genetic susceptibility factors, mechanical forces, ischemia, loss of neurotrophic factors, and neurotoxicity. It also may be that actual ganglion cell death depends on the inability of astroglial cells to prevent or repair injury to the cell or its extracellular matrix regardless of the source of the initial trauma.
Primary open-angle glaucoma is usually described as an insidious, slowly progressive, bilateral condition. The adjective ‘insidious’ is appropriate because most patients are asymptomatic until the late stages of the disease. The few exceptions to this rule include the occasional patient who notices a scotoma when performing a monocular visual task and the young patient who has sudden, severe elevations in IOP that cause corneal edema, halo vision, and discomfort. If patients are not diagnosed until they develop extensive glaucomatous damage, they become symptomatic from loss of fixation in one or both eyes or from loss of peripheral vision, which interferes with activities such as driving. The early stages of POAG usually develop slowly over months to years. As glaucoma advances, however, the pace accelerates. In a recent study from Melbourne, Australia, the prevalence of glaucoma increased from 0.1% in the 40- to 49-year-old age group to 9.7% in the 80- to 89-year-old age group; 50% of those found to have glaucoma were previously undiagnosed. Untreated open-angle glaucoma can and does lead to significant vision loss and blindness. The 10-year incidence, in an untreated Afro-Caribbean population, of unilateral blindness was 16% and of bilateral blindness was 11%. In another study of a treated Afro-Caribbean population, open-angle glaucoma was responsible for approximately one-fifth of the prevalent blindness.
Quality of life is generally not affected early in glaucoma, but as the disease progresses or as treatment becomes more aggressive, quality of life may be impacted. In fact, patients with glaucoma also tend to have other medical conditions which directly or indirectly through the required treatment may affect quality of life and even the ability to apply glaucoma medications; this situation should be kept in mind when prescribing additional glaucoma medications.
Primary open-angle glaucoma is generally a bilateral disease of adult onset; however, a juvenile-onset type is seen that is indistinguishable from the adult-onset variety except for a stronger genetic factor and a more aggressive course. At least one eye should have either characteristic damage to the optic nerve or retinal nerve fiber layer or characteristic visual field changes, open angles with no obvious abnormality, and absence of any other condition known to cause glaucoma. Primary open-angle glaucoma often is asymmetric on presentation, however, so that one eye may have moderate or advanced damage, whereas the fellow eye may have minimal or no detectable damage. In this situation, the clinician must not be fooled and mistakenly conclude that the patient has a unilateral secondary glaucoma.
Most patients of European or African ancestry with POAG have elevated IOPs in the range of 22–40 mmHg. A few patients may have much higher pressures, which occasionally reach levels of 60 or even 80 mmHg. Some patients will never have IOPs over 18 mmHg. These patients are said to have normal-tension glaucoma (low-tension glaucoma). It is important to remember that IOP fluctuates throughout the day and that patients with glaucoma undergo wider fluctuations than do normal individuals. Although most people reach their highest IOPs in the morning, others may reach their peaks in the afternoon or evening or follow no consistent pattern. Diurnal IOP measurements may be useful in some situations, including diagnosing POAG, explaining progressive damage despite apparent good pressure control, evaluating the efficacy of therapy, and distinguishing normal-tension glaucoma from POAG.
Most individuals have fairly symmetric IOP readings although asymmetric POAG does occur reasonably frequently. When pressure is higher in one eye, that eye usually has a larger cup and a more damaged visual field than the fellow eye. Marked differences in IOPs between the two eyes should raise suspicion of exfoliative syndrome or another form of secondary glaucoma.
A reduced outflow facility is the fundamental abnormality of aqueous humor dynamics in POAG. As glaucoma progresses, outflow facility declines progressively. Measurements of outflow facility by tonography are not part of the routine clinical assessment of glaucoma today. Single measurements of outflow facility do not help much in the diagnosis of POAG or in the assessment of the efficacy of treatment.
An afferent pupillary defect can be seen in patients with asymmetric or unilateral glaucoma. This finding, which is also referred to as Marcus Gunn’s sign , is elicited by the swinging flashlight test. It has even been noted in patients with asymmetric cupping and normal kinetic visual fields.
The angles are open in patients with POAG. The angles can be narrow, but there can be no peripheral anterior synechiae (unless caused by prior laser treatment or surgery), no apposition between the iris and the trabecular meshwork, and no developmental abnormalities of the angle. Moderate pigmentation of the meshwork is often present in proportion to the patient’s age and race. Heavy pigmentation is suggestive of other disorders, including pigmentary glaucoma, exfoliative syndrome, trauma, and uveitis.
The crucial clinical findings in POAG are those that occur in the optic disc and visual field. Defects in the nerve fiber layer are also seen in most patients. These matters are presented in detail in Chapter 10 , Chapter 13 and are not discussed further here. Other findings include impairment of contrast sensitivity, temporal contrast sensitivity, loss of color perception, and other psychophysical impairments as outlined in Chapter 11 .
The differential diagnosis of POAG includes conditions that can mimic any of the cardinal features of the disease, such as elevated IOP, cupping and atrophy of the optic disc, and visual field loss. Primary open-angle glaucoma must be distinguished from a variety of secondary and developmental glaucomas. These include exfoliative syndrome, pigmentary dispersion, trauma, anterior segment inflammation, subacute or chronic angle closure, elevated episcleral venous pressure, Axenfeld’s and Rieger’s syndromes, and corticosteroid administration. These conditions are usually distinguished from POAG by a careful history and clinical examination.
Optic disc cupping is typical but not pathognomonic of glaucoma. Cupping has been reported in association with arteritic and non-arteritic anterior ischemic optic neuropathy, as well as withcompressive optic nerve lesions. At times, pits or colobomas of the optic nerve can be mistaken for enlarged cups, although the glaucomatous process can produce a pit-like appearance of the optic nerve. As a general rule, glaucoma causes more optic disc cupping than pallor, whereas the opposite occurs for most neurologic or ischemic diseases.
Many conditions can cause visual field loss that has an arcuate or nerve fiber bundle appearance. Box 17-1 lists some of these conditions.
Atypical retinitis pigmentosa
Branch vein occlusion
Branch artery occlusion
Optic disc lesions
Optic nerve lesions
Arteritic and non-arteritic ischemic optic neuropathy
Generally the ophthalmologist institutes treatment when the patient either has the classic glaucoma triad of visual field loss, optic nerve cupping, and elevated IOP, or is at high risk of developing them. Other indications for treatment include progressive cupping without detectable visual field loss, the development of visual field loss, episodes of corneal edema caused by elevated IOP, and a vascular occlusion associated with increased IOP. In patients with asymmetric POAG (i.e., bilateral elevated IOP with unilateral optic nerve cupping and unilateral visual field loss), the other eye usually is treated aggressively because it has at least a 40% chance of developing visual field loss over a 5-year period.
The major goal of glaucoma treatment is to preserve good visual function for the patient’s lifetime and prevent interference, in so far as is possible, with the quality of life. This is accomplished by lowering the IOP (until a better treatment comes along) to a level that will stop, or at least slow, the progression of optic nerve damage and its consequent vision loss. The treatment should maximize good visual function and comfort, as well as preserve a reasonable quality of life for the patient by minimizing the side effects from the treatment itself, the risk of vision loss and, in many cases, the costs associated with treatment.
For some years, doubt existed regarding the efficacy of pressure lowering for glaucoma. However, a spate of randomized, prospective clinical trials over the past decade have left no doubt that pressure lowering is effective both in slowing or stopping the progression of actual glaucoma and in reducing the risk of conversion from ocular hypertension to frank glaucoma. While at this point in history, we have many choices of pressure-lowering therapy, including medications, laser surgery and incisional surgery, no curative therapy exists for POAG, so one can only aim at controlling the disease. We can lower the IOP but as yet cannot directly protect the optic nerve or enable regeneration of damaged or dead ganglion cells. Although some improvement in optic nerve parameters can be expected in a minority of patients treated for glaucoma, it is rare that substantive anatomic or functional improvement occurs after satisfactory pressure lowering. Medications that may stabilize or slow the progression of glaucomatous damage independent of pressure lowering are currently being developed but are not yet available for clinical use. Some medications may have neuroprotective properties in the laboratory but none has been absolutely proven clinically. Perhaps, by the time the next edition of this book is published, neuroprotective agents will have been shown effective and will be available for clinical use.
It is impossible to determine a priori what level of IOP is necessary to stabilize the patient’s disease. Some patients suffer progressive damage at 16 mmHg, whereas others tolerate IOPs of 40 mmHg for long periods. A general rule is, however, that the higher the IOP, the greater the likelihood of progressive damage. The Advanced Glaucoma Intervention Study (AGIS) strongly suggested that patients with open-angle glaucoma need pressure lowering both in amount and consistently over time. Progressive damage is an indication that more aggressive therapy is needed to lower IOP. The decision to pursue more aggressive therapy is complicated because it must reflect not only the rate of progression and the state of the disease but also the patient’s beliefs, preferences, age, general health, and life expectancy. Costs also need to be considered in many cases.
The current practice is to estimate the pressure level (range) below which further damage to the optic nerve is unlikely to occur (target pressure) and then aim to keep the IOPs consistently below this level or, at least, within the estimated range. The target pressure is estimated by noting the untreated level of IOP; the degree of optic nerve cupping and visual field loss; the family history of glaucoma; the presence of any other aggravating conditions such as diabetes mellitus or arteriosclerotic vascular disease, and the rate of progression if known. In the average patient, the clinician should aim for a pressure 20–30% below the initial untreated pressure. With greater optic nerve damage (e.g., 0.8 disc diameter cupping or more), increasing age, and more risk factors, the target pressure should be lowered. The target pressure should be reassessed periodically and lowered if progression, optic nerve hemorrhage, or increase in risk factors occurs (see Chapter 22 ). One should also keep in mind that in the AGIS, not only was lack of progression associated with a low average IOP but also with no IOPs exceeding 18 mmHg during the entire 6 years of the study. So, maintaining the IOP consistently below 18 mmHg in the average glaucoma patient and lower yet in the patient with advanced disease seems like a reasonable goal. While lowering pressure definitely slows or stops progression in most patients, it does not do so in all patients and it is difficult to identify those who will progress or reliably determine target pressure from any baseline characteristics.
TYPES OF TREATMENT
The usual progression of treatment in POAG is medical therapy, followed by laser trabeculoplasty, then filtering surgery. Several large, prospective controlled trials of glaucoma treatment have been completed ( Table 17-3 ). In general, the studies show that lower IOPs tend to preserve vision better, and filtering surgery seems to achieve that best of the three modalities. Laser trabeculoplasty seems to be as effective as timolol for initial treatment of glaucoma. A few studies have been done comparing medical therapy and filtering surgery. Generally these trials have shown that filtering surgery is more effective than medical therapy in preserving visual field but is associated with a greater loss of visual acuity and a higher incidence of cataract, although glaucoma itself as well as topical medical treatment are risk factors for cataract formation.
|Study||Target group||Purpose||Patients ( n )||Follow-up (years)||Findings|
|Scottish Glaucoma Trial||Newly diagnosed primary open-angle glaucoma (POAG)||Medication vs. trabeculectomy||99||3.5||Trabeculectomy lowered IOP more than medication and protected better against further visual field loss|
|Moorfields Primary Treatment Trial||Newly diagnosed POAG||Medication vs. laser trabeculoplasty vs. trabeculectomy||168||5+||Trabeculectomy lowered IOP the most, laser trabeculoplasty (ALT) next and medication least. Medical treatment and ALT groups showed more visual field loss than trabeculectomy|
|Glaucoma Laser Trial (GLT)||Newly diagnosed POAG||Medication versus ALT||271||2.5–5.5||Initial ALT at least as effective as timolol in reducing IOP and preserving vision|
|Glaucoma Laser Follow-up Study||Newly diagnosed POAG||Medication versus ALT (long-term follow-up)||203||6–9||Initial ALT at least as effective as timolol in reducing IOP and preserving vision over 6–9 years|
|Early Manifest Glaucoma Trial (EMGT)||Newly diagnosed POAG||ALT plus medication vs. observation||255||6||Treatment halved the rate of progression (53% vs. 26%). Lower IOP associated with less progression|
|Collaborative Initial Glaucoma Treatment Study (CGITS)||Newly diagnosed POAG||Medication versus trabeculectomy||607||5||Both medication and surgery had same visual field results at 5 years. Visual acuity worse early in study for trabeculectomy but same at 5 years|
Despite the findings of these controlled clinical trials, most experts, at least in the United States, continue to use medical therapy as the first-line approach in POAG (see Chapter 21 , Chapter 22 , Chapter 23 , Chapter 24 , Chapter 25 , Chapter 26 , Chapter 27 , Chapter 28 ). The reasons for this approach include the relatively short effectiveness of laser treatment and even surgery as measured against the lifetime needs of the glaucoma patient and the relative safety of medical treatment. Trabeculectomy has the risk of profound visual loss or other significant complications. Although the side effects of medical therapy can be protean, they are rarely permanent and usually disappear after cessation of the particular offending treatment. In Europe, with the advent of the more potent antiglaucoma drugs, glaucoma surgery as primary treatment has declined. In general, the clinician should prescribe the safest drug or drugs for the patient in the lowest doses necessary to control the IOP at the desired level. It is important to measure IOP at different times of the day and at different intervals after drug administration to determine the response to therapy. The failure of medical treatment is usually judged by inadequate control of IOP, progressive visual field loss or optic nerve cupping, the appearance of an optic nerve hemorrhage, intolerable side effects of medication, or demonstrated (or admitted) poor compliance with therapy.
The clinician should use the patient’s previous course in both eyes as a guide for judging the adequacy of therapy. For example, if an individual has progressive damage in either eye when IOP was in the range of 20 mmHg, and the pressure is at that level again, more aggressive treatment is probably indicated rather than waiting for further damage. Studies have shown that from a societal point of view (as well as the patient’s), treating the disease adequately to prevent progression is more cost effective than trying to manage more advanced disease.
In developed countries like the US and western Europe, the prostaglandin analogues are the usual first medications to try since their once a day regimen makes compliance easier and their side effects are relatively benign. The non-selective β-blockers are also popular because they can be given once or twice a day and have infrequent ocular side effects, although significant systemic side effects often occur after months of treatment. These two classes of medications represent the most effective for monotherapy. Wide variations occur in treatment patterns in the US and women are often treated less aggressively than men. When one medication lowers the IOP but not enough, a second medication can be added. However, if the first fails to lower the IOP a significant amount, then substitution is preferable. When a second or third medication becomes necessary, the use of combination drops may help compliance. Studies on compliance and persistence suggest that neither are achieved anywhere near the rate that doctors think. Nevertheless, over 90% of patients can be expected to be controlled with medications over their lifetime. For the typical glaucoma patient, two or three medications would be the maximum suggested before resorting to laser or incisional surgery. At present, maximum medical therapy consists of a prostaglandin-like agent, a β-adrenergic antagonist, a topical carbonic anhydrase inhibitor, and an α-agonist. Most ophthalmologists recommend laser trabeculoplasty before resorting to miotics (except in aphakic or pseudophakic eyes), although these agents should not be forgotten as potential therapy. Systemic carbonic anhydrase inhibitors are rarely used unless surgery is not feasible or has failed.
When medical treatment fails or when at least two topical agents have been found wanting, argon or selective laser trabeculoplasty is the next therapeutic option for most individuals with POAG, as well as being the primary treatment for those unable or unlikely to use medical therapy (see Ch. 32 ). This technique reduces IOP substantially in 70–80% of patients. Most individuals continue to require at least some medical therapy after laser trabeculoplasty, although it is possible to reduce the number of medications in a significant percentage of patients. Unfortunately, in many patients, IOP rises again months to years after laser treatment. There seems little difference in the long-term outcome between argon and selective laser trabeculoplasty.
If medical treatment and laser surgery are inadequate to control POAG, filtering surgery is the next appropriate step. Filtering surgery controls IOP in approximately 80–90% of patients with POAG. Approximately one-third of Caucasian patients with POAG go on to filtration surgery according to one retrospective study in Minnesota. Racial differences exist in the response to laser surgery and filtering surgery; for example, the AGIS showed that whites responded better to filtering surgery first compared to blacks who responded better to argon laser trabeculoplasty first. Economics and the results of the Collaborative Initial Glaucoma Treatment Study (CIGTS), where surgical and medical therapy in newly diagnosed glaucoma patients were found to be equally effective at long-term pressure control, probably justify filtering surgery as the primary treatment in developing countries.
If one drainage procedure fails to control IOP or if the risk factors for failure are high (e.g., black African ancestry, youth, secondary glaucoma), many ophthalmologists repeat filtering surgery with an inhibitor of wound healing, such as 5-fluorouracil or mitomycin C. On the other hand, many use topical application or injection of these agents even in primary filtering operations. If two or more filtering surgeries have failed despite antifibrosis agents or there is a high likelihood of failure after a single filtering operation fails, a tube-shunt (glaucoma drainage) device such as a Molteno, Baerveldt, or Ahmed implant can be used. A recently concluded randomized controlled trial suggests that non-valved implants such as the Molteno or Baerveldt are as good if not somewhat better at controlling IOP at 1 year than a trabeculectomy in a previously operated eye. So, some would consider a tube-shunt procedure after the first trabeculectomy (or similar) fails. It is also possible to reduce aqueous humor formation by treating the ciliary body with trans-scleral cyclophotocoagulation or endocyclophotocoagulation, although these are usually reserved for end-stage cases.
The prognosis in POAG is determined by (1) the degree of optic nerve damage; (2) the height of the IOP; (3) the vulnerability of the disc tissue; (4) the presence of systemic vascular disease; (5) the compliance with treatment, and (6) the timeliness and appropriateness of treatment. Age is also a factor, as the older one gets the more likely the disease is to progress. Few prospective studies exist on the prognosis of untreated open-angle glaucoma. One such study, done on the island of St Lucia in the Caribbean, noted progression to end-stage disease over a 10-year period in about 35% of untreated eyes, with about 55% of eyes progressing. Generally, treated open-angle glaucoma progresses relatively slowly. In one study, approximately one-third of patients with open-angle glaucoma became worse over 9 years. In another retrospective study done in Iowa on mostly Caucasian patients, 68% of patients progressed over at least 8-years follow-up, as detected by visual field tests, with an average loss of about 1.5% per year. Progression of optic cupping in treated patients as measured by stereo photography was about 0.0068 linear cup-to-disk ratio units per year; higher treated IOP were associated with more rapid progression. In Olmsted County, Minnesota, a retrospective study of all newly diagnosed glaucoma patients (mostly white) found the risk of less than 20/200 vision or less than 20° of visual field in one eye to be 27% over 20 years, and in both eyes, 9%. In another study with about 20 years of follow-up, only 20% remained stable and 80% progressed with about 17% becoming legally blind; about 40% of the blindness was caused by glaucoma. These two studies seem to have found about the same rates of blindness. In a retrospective study like this, many patients could have remained stable but died and therefore were not counted. On the other hand, bilateral blindness is uncommon in treated open-angle glaucoma and many of the unilaterally blind are blind at diagnosis. In the Barbados Eye Studies, the incidence of progression due to glaucoma alone over 4 years in treated eyes was about 1% to low vision (20/40–20/100) and 0.3% to blindness (20/200 or less). In this same group, those over 70 at the initial visit had a 22% chance of reaching 20/40 or less and a 7% chance of becoming blind; about one-fifth of these were due to glaucoma alone. These figures probably accurately represent the incidence of significant visual loss in an Afro-Caribbean population whose glaucoma is likely to be more severe at diagnosis and more progressive than that in patients of European descent.
In the Early Manifest Glaucoma Trial study where patients with early glaucoma were randomly assigned to treatment or no treatment, over 53% progressed during the 6 years of the study. Treatment halved the rate of progression and a 10% reduction in the rate of progression was manifest for each mmHg lowering of IOP achieved. As a general rule, the two eyes tend to react similarly so progression in one eye of someone with symmetrical glaucoma suggests that treatment should be more aggressive in both eyes. The greater the degree of visual field loss, the more progression is likely to occur.
Several clinicians have noted that patients with advanced optic nerve cupping generally have a worse prognosis. Some authorities have explained this observation by stating that a damaged disc is more susceptible to further damage. An alternative explanation is that a disc with advanced damage has very few remaining axons, so that each nerve fiber lost is of greater importance. Some authorities propose that eyes with advanced damage require low-normal or even subnormal levels of IOP to stabilize the disease. One retrospective study demonstrated that patients having trabeculectomy in advanced medically uncontrolled glaucoma had about a 45% chance of becoming legally blind over 10 years, which means that over 50% were prevented from becoming blind by this treatment. Once again, as in previous studies, the more advanced the disease, the more likely the patient was to progress to legal blindness despite surgery.
In a recent 4-year prospective study of relatively large numbers (total >500) of patients with open-angle glaucoma – most with high pressures, some with low pressures, and some with secondary glaucoma – the risk factors for progression in those with high pressures were older age, advanced perimetric damage, smaller neuroretinal rim, and larger zone beta of parapapillary atrophy. Those with low IOPs showed only presence of disk hemorrhages at baseline as a risk factor. There were no differences between those with primary glaucoma and those with secondary glaucoma in the risk factors for progression.
As mentioned previously, some eyes can tolerate elevated IOPs for long periods, whereas others suffer progressive damage at apparently normal levels of pressure. This phenomenon is usually explained by variable resistance of the optic disc to pressure-induced damage. Other factors that may be important include variable vascular perfusion to the optic nerve and differing compliance with treatment. Correlation between low blood flow velocity in the retinal artery circulation and progression has been noted. Although a very few clinicians believe that the natural history of POAG is not altered by treatment, the vast majority believe – based on several controlled studies – that control of IOP stabilizes the disease or slows its course in most patients.
One should not infer from this statement, however, that successful reduction of IOP can be equated with stabilization of the disease. Some patients have progressive visual field loss despite marked reductions of IOP by medical therapy, argon laser trabeculoplasty, or filtering surgery. However, the overwhelming preponderance of evidence favors lowering IOP as the best current treatment that provides for both stabilization of the disease and the most cost-effective approach. It is important that patients realize the need for periodic follow-up for the remainder of their lives, even after treatment has reduced IOP. Clinicians must distinguish progressive glaucomatous damage from short- and long-term fluctuations in visual function, as well as from the slow decline in visual function that occurs with age.
Other prognostic factors stated to be important in POAG include the presence of an optic disc hemorrhage and a family history of glaucoma. Aung and co-workers noted that normal-tension glaucoma patients with the E50K mutation in the optineurin gene were three times as likely to progress as those without the mutation. Several studies have noted nocturnal drops in arterial blood pressure to be associated with progressive optic nerve damage. Patients with a poor life expectancy also are more likely to progress. Myopia was found to be associated with a better prognosis in one study.
THE GLAUCOMA SUSPECT AND OCULAR HYPERTENSION
A patient may be considered a POAG suspect (i.e., more likely to develop glaucoma than the average person) on the basis of family history of the disease, a suspicious-appearing optic disc, or an elevated IOP. An individual who has a first-degree relative with POAG has approximately an eight-fold greater risk of developing the disease. Not all studies have confirmed this strong a relationship to family history. However, prudence dictates that anyone with a first-degree relative (parent, sibling, or child) with POAG should have regular ocular examinations, including tonometry and ophthalmoscopy, every 1 or 2 years up to age 60, with increasing frequency over age 60. If additional risk factors exist, such as elevated IOP, thin corneas and/or black African ancestry, then more frequent examinations are in order. An individual with a suspicious-appearing optic disc (e.g., a large cup-to-disc ratio, slight asymmetry of the cups, slight irregularity of the rim, questionable nerve fiber layer dropout) requires a careful examination that includes tonometry, perimetry, and some method of recording the appearance of the optic nerve and nerve fiber layer such as photography or other imaging. Gonioscopy is also in order. The frequency of follow-up for such a person depends on the clinician’s level of suspicion. The most common reason to consider a patient a glaucoma suspect is because of elevated IOP on routine examination or screening. This subject is discussed in the next section.
EPIDEMIOLOGY OF OCULAR HYPERTENSION
Individuals with IOPs of 21 mmHg (the statistical upper end of the ‘normal’ range) or greater, normal visual fields, normal optic discs, open angles, and absence of any ocular or systemic disorders contributing to the elevated IOPs are referred to as having ocular hypertension . Some clinicians prefer other names for this group, including glaucoma suspect, open-angle glaucoma without damage, and early glaucoma. The term used is not important as long as clinicians realize that they are dealing with individuals who are at greater risk of developing POAG but have not yet shown definitive evidence of the disease.
The concept of ocular hypertension is important because this set of findings occurs in 4–10% of the population over age 40. Ocular hypertension is present in up to 18.4% of people over 40 years old of black African descent compared with 13.6% of those of mixed race and only 4.6% of whites in the same age groups. In both Australia and Pakistan, IOPs over 21 mmHg occur in about 3.5% of the population. Ocular hypertension is clearly far more prevalent than POAG ( Table 17-4 ). In the past, it was common to equate elevated IOP with POAG; that is, individuals with increased IOP would develop glaucoma if they lived long enough. It is now clear that only about 0.5–1% of ocular hypertensive patients per year develop visual field loss as detected by kinetic perimetry ( Table 17-5 ). Although threshold perimetry may be more sensitive than kinetic, it is unlikely that the number of ocular hypertensive patients converting to open-angle glaucoma would exceed 2% per year.
|Population||Prevalence of abnormal intraocular pressure (%)||Prevalence of open-angle glaucoma with visual field loss (%)|
|Des Moines, Iowa||12.7||1.3|
|Blue Mountain, Australia||3.7||3.0 *|
|Barbados, West Indies (black population)||18.4||7.0|
|Barbados, West Indies (white population)||4.6||0.8|
|Reference||Intraocular pressure||Follow-up (years)||Patients ( n )||Per cent developing open-angle glaucoma|
|Linner & Stromberg||22–26||5||152||2.0|
|Hovding & Aasved||>21||20||29||27.6|
The Ocular Hypertension Treatment Study (OHTS), which randomly assigned 1600+ patients with IOPs between 24 and 32 mmHg and without visual field defects to observation or medical treatment that lowered IOP at least 20%, found that, at the end of 5 years, 9.5% of the observation group developed a glaucoma ‘end point’ whereas only 4.4% of the treated group did. The numbers were almost double when the African-Americans were considered separately, with 16% developing a glaucoma end point in the observation group and 8.4% in the treated group. This creates a dilemma about what to do with these individuals who are at increased risk for developing POAG. On the one hand, ophthalmologists want to intervene as early as possible to prevent optic nerve cupping and visual field loss. On the other hand, most ocular hypertensive individuals will complete their lives without developing substantial visual loss.
Thus, instituting treatment in all patients does not seem reasonable, taking into consideration the low incidence of conversion from ocular hypertension to frank open-angle glaucoma, as well as the cost, inconvenience, side effects, and frequent non-compliance. Note that even 4% of the total and 8.4% of the African-American treated patients in the OHTS study went on to develop progressive optic nerve change or visual field damage. This debate has been sharpened by recent studies showing that ocular hypertensive patients can lose as many as 40% or even 50% of their optic nerve axons despite having normal kinetic visual fields, or as many as 35% of their ganglion cells despite normal automated threshold perimetry. Despite this finding, the current recommendation is that most ocular hypertensive individuals do not require medical therapy. Treatment should be reserved for those patients who demonstrate early damage and for those who are thought to be at high risk for developing glaucoma (see below). Newer modalities such as short-wavelength automated perimetry, frequency-doubling perimetry, and confocal laser ophthalmoscopy appear to be able to detect optic nerve functional damage and anatomic damage before they are seen with clinical examination or with standard threshold static perimetry. The question of what constitutes early optic disc and visual field changes is addressed in detail in Chapter 10 , Chapter 13 .
RISK FACTORS FOR DEVELOPMENT OF OPEN-ANGLE GLAUCOMA
The OHTS, which may be our best modern study of the fate of treated versus untreated ocular hypertensives, showed that 9.5% of untreated ocular hypertensives will go on to develop open-angle glaucoma as manifest by optic nerve changes or visual field changes in 5 years. Rougly 10% of ocular hypertensive eyes will develop evidence of visual field loss as measured by threshold perimetry over a 9–10-year period. Another study in Sweden followed ocular hypertensives for a mean of almost 9 years and found a conversion rate for those without (pseudo)exfoliation of 27% based only on visual field measurements. Many parameters have been stated to be risk factors for the development of POAG ( Box 17-2 ). Unfortunately, no parameter taken alone has proven to be a useful risk factor because of the following reasons:
Most of the studies on risk factors dealt with one parameter in isolation. This type of univariate analysis is unlikely to shed light on a disease as complex as POAG.
In many studies, the investigators assumed that parameters that separated a group of glaucomatous eyes from a group of normal eyes were risk factors. Retrospective separation of groups is very different from prospective predictions.
Many putative risk factors were identified in retrospective or cross-sectional studies rather than in prospective studies. This makes it difficult to distinguish factors that have prognostic value (because they occur early in the disease process) from factors that are not helpful (because they occur late in the disease course).
Different studies used different populations, definitions, and examination techniques.
Prospectively proven risk factors
Thin corneas (<535 microns)
Elevated intraocular pressures
Vertical cupping of the optic nerve (>0.6)
Increased pattern standard deviation on threshold perimetry
Abnormalities in the optic nerve with the scanning laser ophthalmoscope
Putative risk factors
Race (blacks and Hispanics)
First-degree relative with open-angle glaucoma
General medical status
Coronary artery disease
Peripheral vascular disease
Abnormal cold pressor test
Aggressive antihypertensive therapy
Diabetes (some studies say a risk, others a protective)
Aqueous humor dynamics
Large diurnal variation in IOP
Rising IOP with time
Increased IOP in supine position
Large cup-to-disc diameter ratio
Optic disc hemorrhage
Filling defects on fluorescein angiography
Miscellaneous ocular findings
Central retinal vein occlusion
Intraocular pressure is the most obvious example of a single risk factor that fails to predict the development of POAG. Most ophthalmologists accept the link between elevated IOP and POAG. However, only 10% or so of the patients with elevated IOP have glaucomatous visual field loss. In addition, one-third of the persons detected with glaucomatous visual field loss have normal IOPs during their initial screening examination. Finally, many individuals can maintain normal visual function for long periods despite elevated IOP. Thus, although elevated IOP is associated with POAG, it is neither necessary nor sufficient for development of the disease.
Some investigators ( Table 17-6 ) have carried out a more detailed multivariate analysis of risk factors. These researchers have identified elevated IOP, optic disc abnormalities, increasing age, family history of glaucoma, decreased outflow facility, and systemic vascular disease as the factors that best predict the development of POAG. In a retrospective study, Hart and co-workers identified 96% of the eyes that developed POAG and 79% of the eyes that did not. In a prospective study, Drance and co-workers predicted 79% of the eyes that developed POAG and 74% of the eyes that did not. Once again, the OHTS study has come to the rescue. Using multivariate analysis, the OHTS team found that the risk factors for conversion from ocular hypertension to manifest glaucoma are thin corneas, older age, larger vertical and horizontal cup-to-disc ratio, larger pattern standard deviation, and higher IOP. Of all the risk factors, thin central corneal thickness was the most powerful. Note that when thin corneas are taken into account, being of African descent drops out as a risk factor. A second retrospective study has confirmed the importance of thin corneas as an important risk factor. The Swedish long-term study noted above randomized ocular hypertensives to either treatment with timolol or placebo for up to 10 years and found risk factors that were similar to the OHTS study (although they did not measure corneal thickness); the risk factors for conversion to open-angle glaucoma in this study were suspicious disk, older age, and higher IOP.