Primary open angle glaucoma

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.1 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 openangle 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).2 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.3 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.4,5Population-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.6

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 normaltension 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.7

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.

Epidemiology

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.8 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 2030.9 Worldwide, over 2 million people develop this condition every year. Between 84 000 and 116 000 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.10

Prevalence

In most studies performed in western Europe and in the United States, the prevalence of POAG11 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.27 A similar overall prevalence was found for definite POAG in those over age 40 in Spain.28 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.

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 openangle glaucoma is 1.6% of the population with greater than 98% unaware that they have the disease.29 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.30 Among Singapore Chinese, the prevalence of POAG in those over 40 years of age is about 1.6%.31 The prevalence of open-angle glaucoma also appears to be relatively high in a population study in Bangladesh (about 2% in people over 40).32 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 40.33 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.34 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%.35 In another example, Greeks seem to have an unusually high prevalence: 4% compared to other European groups.36 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.37

Incidence

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.38 Incident rates increased from 1.2% in the 40–49 age group to 4.2% in those over 70.39 Using data from the Framingham study, Podgor and co-workers40 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.41 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 80.42 A similar increase in incidence has been found in Minnesota.43

Intraocular pressure

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.44,45 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.46,47 Population surveys also support the increase in prevalence of open-angle glaucoma with

increasing IOP.13,48,49 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.50 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.

Age

The prevalence of POAG increases with age (Table 17-2).13,20,22,48,51 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.52–54 The effect of age on the prevalence

of POAG holds true even after compensating for the relationship between increasing age and increasing IOP.55 Even in Japan where IOP does not increase with age, open-angle glaucoma does increase in prevalence with age.30 Age is also a risk factor for the conversion from ocular hypertension to open-angle glaucoma.50

Gender

Conflicting information exists about the effect of gender on the

prevalence of POAG. In several studies, males had a higher prevalence of glaucoma.16,24,25,56 In the Barbados study, POAG was asso-

ciated with older men, high IOP, positive family history, lean body mass, and low blood pressure to IOP ratio.57

Race

As noted above, POAG is more prevalent in blacks than in

whites.20,58 Furthermore, the disease seems to develop at an earlier age and has a more rapid progression in black patients.40,59–62 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.20,63 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.50 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.64 Black patients seem to respond to some treatment modes less favorably than do whites;65–68 whether this explains the more viru-

lent 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 IOP69–71 and larger cup-to-disc diameter ratios.72 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.73 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.74

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,75 some Asians,76–78 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%.79 In Japan, the prevalence of POAG is 0.58%, with normalpressure glaucoma having a prevalence of 2.04%.21 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.80 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.81 In southern India (mostly Tamil), as noted above, the prevalence of open-angle glaucoma is 1.6% in those over 40.29 Further surveys using standardized techniques and definitions are needed in many population groups.

Socioeconomic factors

Very few studies have been performed on the relationship between socioeconomic variables and the prevalence of POAG. In different reports, manual laborers have an increased82 and a decreased83 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.20A 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.84 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.85,86 Furthermore, moderate exercise has been shown to

increase choroidal blood flow, although with some limits.87 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.88,89 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.

Refractive error

Myopia has been associated with POAG in many studies.90–94 It is not clear whether myopia has a direct influence on the preva-

lence of the disease or whether it acts through its known associations with increased IOP and larger cup-to-disc ratios.95,96 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.

Corneal thickness

As noted previously, a thin cornea is a risk factor for conversion from ocular hypertension to open-angle glaucoma.1 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.97 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.

Heredity

Primary open-angle glaucoma appears to have a genetic or famil-

ial component. Over the years, autosomal dominant,52,98 autosomal recessive,99,100 and sex-linked101 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%.102 The risk of developing POAG in firstdegree relatives is 4–16%.102–107 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.108 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.109 A monozygotic and dizygotic twin study estimated the inheritability to be 13%.110 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.111 In one study, the association was higher with a sibling affected than with a parent or child.112 In the Barbados study, 25% of the siblings of patients with POAG had either POAG or were suspect for POAG.111 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.113,114 Two longitudinal studies – one population-based

and the other over 18 years in length – demonstrated a strong asso-

ciation between the development of glaucoma and positive family history.58,115

Recently, studies have identified one gene (GLC1A) that is asso-

ciated with juvenile-onset open-angle glaucoma and some (about 3–4%) cases of POAG in adults.116,117 This gene is located on chro-

mosome 1 in the q23–25 region.118 Three different mutations of this gene have been identified in about 4% of patients with POAG.119 One particular mutation seems to account for most of the abnormal genes found in a population of glaucoma patients in India.120 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.121 Another gene that has been associated with adult-onset open-angle glaucoma is located on chromosome 2 (GLC1B).122 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.123 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.124 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 3.125 Another study found an association between an endothelial nitric oxide synthase gene and open-angle glaucoma accompanied by migraine.126

All these studies open an exciting frontier and suggest that openangle 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, out-

flow facility, and cup-to-disc ratio – appear to be genetically determined.127,128 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.129 Thus some of the polygenic inheritance of POAG may occur indirectly through these associated factors rather than directly through the disease itself.

Systemic factors

Primary open-angle glaucoma has been linked to a variety of endocrine and vascular disorders. Several studies have shown a high prev-

alence of diabetes mellitus in patients with POAG, as well as a high prevalence of POAG in patients with diabetes.130–134 Although nei-

ther the Baltimore Eye Study nor the Diabetes Audit and Research in Tayside Study (DARTS) in the United Kingdom were able to find