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.332 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.333 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 20º of visual field in one eye to be 27% over 20 years, and in both eyes, 9%.334 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.335 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.336 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).337 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.338 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.339 The greater the degree of visual field loss, the more progression is likely to occur.340

Several clinicians have noted that patients with advanced optic nerve cupping generally have a worse prognosis.317–320,341,342

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.319,343,344 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.345 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.346 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 pressureinduced 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.347 Although a very few clinicians believe that the natural history of POAG is not altered by treatment,263 the vast majority believe –

based on several controlled studies – that control of IOP stabilizes the disease or slows its course in most patients.299,300,321,325,348,349

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 reduc-

tions of IOP by medical therapy, argon laser trabeculoplasty, or filtering surgery.320,350–352 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.353 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 shortand 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.322,354 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.355 Several studies have noted nocturnal drops in arterial

blood pressure to be associated with progressive optic nerve damage.356,357 Patients with a poor life expectancy also are more likely

to progress.358 Myopia was found to be associated with a better prognosis in one study.359

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.360,361 Not all studies have confirmed this strong a

relationship to family history.112 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 40.13,14,51,362

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.363

In both Australia and Pakistan, IOPs over 21 mmHg occur in about 3.5% of the population.364,365 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

Table 17-4  Prevalence of abnormal intraocular pressure and glaucoma

Modified from Anderson DR: Surv Ophthalmol 212:479, 1977. *Includes normal-pressure glaucoma.

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).367,369,370,372,376,377 Although threshold perimetry may

be more sensitive than kinetic,378 it is unlikely that the number of ocular hypertensive patients converting to open-angle glaucoma would exceed 2% per year.

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.379 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.380 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.379,380 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,344 or as many as 35% of their ganglion cells despite normal automated threshold perimetry.381 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

Box 17-2  Risk factors in ocular hypertension

Prospectively proven risk factors

Thin corneas ( 535 microns) Elevated intraocular pressures Increasing age

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 Pseudoexfoliation

Putative risk factors

I.Sociodemographic factors

a.Gender (women)

b.Race (blacks and Hispanics)

II.First-degree relative with open-angle glaucoma

III.General medical status

a.Cardiovascular disease

i.Coronary artery disease

ii.Atherosclerosis

iii.Cerebrovascular disease

iv.Peripheral vascular disease

v.Abnormal cold pressor test

vi.Hypertension

vii.Aggressive antihypertensive therapy

viii.Hypotension

ix.Hemodynamic crisis

b.Endocrine disease

i.Thyroid disease

ii.Diabetes (some studies say a risk, others a protective factor)

iii.Acromegaly

iv.Cushing disease

IV. Aqueous humor dynamics

a.Large diurnal variation in IOP

b.Rising IOP with time

c.Increased IOP in supine position V. Optic disc

a.Large cup-to-disc diameter ratio

b.Optic disc hemorrhage

c.Filling defects on fluorescein angiography

d.Parapapillary atrophy

VI. Miscellaneous ocular findings

a.Myopia

b.Pigment dispersion

c.Central retinal vein occlusion

perimetry.382–385 The question of what constitutes early optic disc and visual field changes is addressed in detail in Chapters 10 and 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.7,50 Rougly 10% of ocular hypertensive eyes will develop evidence of visual field loss as measured by threshold perimetry over a 9–10-year period.331Another 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.386 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:

1.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.

2.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.

3.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).

4.Different studies used different populations, definitions, and examination techniques.

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.12–15,387 In addition, one-third of

the persons detected with glaucomatous visual field loss have normal IOPs during their initial screening examination.12,14,15 Finally,

many individuals can maintain normal visual function for long periods despite elevated IOP.115,366–372,388 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-workers392 identified 96% of the eyes that developed POAG and 79% of the eyes that did not. In a prospective study, Drance and co-workers390 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 devi-

ation, and higher IOP.375 Of all the risk factors, thin central corneal thickness was the most powerful.7,50 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.394 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.389

Nerve fiber layer defects have been shown to precede visual field

defects in ocular hypertensive eyes converting to open-angle glaucoma by as much as 4–5 years.395,396 Fluorescein angiographic fill-

ing defects in the optic nerve may precede development of visual field loss in ocular hypertensive patients.397 Other tests that have shown in longitudinal studies to predict those who have already

developed early glaucoma or who will develop it in the future include blue-yellow perimetry,383,398 motion detection perimetry,399,400 pattern electroretinogram,401 and optic nerve changes by

scanning laser ophthalmoscopy.402 Nerve fiber layer assessment by

scanning laser polarimetry shows reduced nerve fiber layer levels in ocular hypertensive patients compared with normals;403 some think this may indicate very early neural damage.Tezel and co-workers404 retrospectively evaluated 175 ocular hypertensive patients over 10 years. Ninety eight of 350 eyes developed actual glaucoma over a 10-year follow-up period as measured by visual field changes, optic nerve damage, or both. Parapapillary atrophy, as well as larger vertical cup-to-disc ratio, and small neural retinal rim area-to-disc area ratio were associated with progression. Age, positive family history, and elevated IOPs were also correlated with progression. An enlarging area of parapapillary atrophy was also correlated with development of glaucoma.405 In a small subset of the OHTS patients who had scanning laser ophthalmoscopy during their

follow-up, abnormalities in some of the parameters as well as in the overall classification and the Moorfields’ regression classification were identified as risk factors for progression to glaucoma.406 The cardiologists have been well ahead of the ophthalmologists in being able to assess risks of disease development. Fortunately, ophthalmology is catching up. Using the OHTS results, Medeiros and colleagues have developed a risk calculator for ocular hypertensives that can be helpful in predicting the relative risk for actual glaucoma development.407 They have validated this model in a prospective study independent of the OHTS group of patients. A scoring tool based on this model has been published by Pfizer Corporation (STARRII Risk Calculator) and, as of this writing, has been pro-

vided to ophthalmologists and others free of charge (Fig. 17-2).