Chapter 231 – When to Treat Glaucoma
REBECCA S. WALKER
JODY R. PILTZ–SEYMOUR
The decision to initiate therapy to lower eye pressure is a very serious one that has far-reaching consequences. Once started, therapy generally is continued for the rest of the patient’s life. Patients may be subjected to untoward side effects, significant costs, and altered quality of life from the use of glaucoma medications. In addition, the public health impact of treatment is enormous; therapy is expensive and requires regular medical attention.
Determining when to start treatment requires a complex decision-making process, which must be individualized for each patient. Any decision to initiate therapy must weigh the patient’s risk factors for the development or progression of glaucoma against the risk of side effects, complications, and inconveniences of treatment. The main goals of glaucoma therapy are to preserve functional vision and quality of life.
ANALYSIS OF RISK FACTORS
The most important indications of the future risk for glaucomatous damage are the extent of damage already present and the current rate of progression of the disease.  The extent of damage may be assessed by evaluation of the status of the optic nerve and visual field. Stereoscopic evaluation of the optic discs is carried out to search for signs of glaucomatous damage, which include thinning of the neuroretinal rim (particularly at the superior and inferior poles), notching of the rim, splinter hemorrhages, asymmetry between the appearance of the optic nerves, or peripapillary atrophy. Evaluation of the nerve fiber layer with red-free illumination or special photographic techniques may help the detection of widespread loss or focal, wedge-shaped defects. Visual fields are best evaluated using threshold techniques of the central 24–30°. Eyes affected by glaucoma exhibit characteristic nerve fiber bundle pattern defects with or without generalized depression (see Chapter 214 ).
Documentation of progressive change of the optic disc or visual field is the hallmark of the diagnosis of glaucoma, but generally is not possible on initial patient encounters. The rate of progression can be determined only by serial examinations over time. Typically, standard threshold perimetry is performed one to four times per year. Stereoscopic nerve head evaluation is also performed at regular intervals, ideally with baseline and possibly interval stereophotographic documentation. Other psychophysical tests (which include short-wavelength and frequency-doubling perimetry), or other methods of optic nerve or nerve fiber layer analysis (such as scanning laser topography of the optic disc or polarimetry of the nerve fiber layer) may play a role in the assessment of the rate of progression over time. Detection of change is critical, since it is believed that the risk of further injury with sustained high IOP accelerates as the disc injury progresses. Studies have shown that treatment initiated at an early stage of glaucoma is more effective in the prevention of glaucoma damage than treatment started in more advanced stages.
Other critical risk factors that must be considered in the decision to initiate therapy include the level of intraocular pressure (IOP), central corneal thickness (CCT), age, race, and family history of glaucoma. Other probable risk factors include myopia, systemic hypertension, systemic hypotension, nocturnal hypotension, vasospasm (associated with cold extremities, migraine headaches, Raynaud’s disease), sleep apnea and diabetes mellitus. Any decision to treat must also take into account psychosocial issues such as the patient’s overall health and predicted life expectancy, current systemic medications, risk of medication side effects, degree of understanding of the disease and treatments, level of compliance, and financial impact of treatment.
IOP is the leading causal risk factor for glaucoma, and at present, the only risk factor for which clinically proven treatment options exist. Both the incidence and prevalence of glaucoma increase with increasing IOP ( Fig. 231-1 ). Compared to an IOP of 15?mmHg (2.0?kPa) or lower, the relative risk of glaucomatous optic nerve damage increases 13-fold for an IOP of 22–29?mmHg (2.9–3.9?kPa), and 40-fold for an IOP >30?mmHg (>4.0?kPa). Asymmetrical or unilateral glaucoma, including secondary glaucoma or angle-closure glaucoma, typically results in worse damage in the eye affected by the higher IOP. Numerous animal models of glaucoma have shown that chronically raised IOP induces glaucomatous optic neuropathy in both primate and nonprimate species.
Multicentered clinical trials have definitively proven that lowering IOP is beneficial in preventing ongoing glaucoma progression in eyes with manifest glaucoma damage. In the Advanced Glaucoma Intervention Study (AGIS), when IOP was below 18?mmHg on all visits over 6 years (average IOP of 12?mmHg), almost no visual field progression ensued; for eyes with IOP <18?mmHg on fewer than 50% of visits (average IOP of
Figure 231-1 Prevalence of primary open-angle glaucoma in relation to screening intraocular pressure. The curves are smoothed using a running mean with window width of 7?mmHg. For Caucasian–American subjects, n = 5604 eyes, and for African–American subjects, n = 4464 eyes. (Data from Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA. 1991;266:369–74.)
20?mmHg), visual field defect scores worsened by 0.63 units (p = .083). The Collaborative Normal-Tension Glaucoma Study (CNTGS) demonstrated less visual field progression in patients with normal-tension glaucoma in whom treatment successfully reduced the IOP by 30% or more to an average of 11?mgHg.
The Early Manifest Glaucoma Trial randomized patients with early to moderate glaucomatous damage to treatment with laser trabeculoplasty and betaxolol or observation. Patients were followed every 3 months with Humphrey visual fields and IOP measurements and optic disc photography every 6 months. Treatment reduced IOP on average by 25%, and average follow-up was 6 years. Progression occurred later and less frequently in the treated group than in controls (p = .007). In a multivariate analysis, progression risk was halved by treatment (hazards ratio = 0.50; 95% CI, 0.35–0.71). The risk of progression decreased by about 10% with each millimeter of mercury that IOP was reduced from baseline to the first follow-up visit (hazards ratio = 0.90 per millimeter of mercury decrease; 95% CI, 0.86–0.94). 
Great variability occurs among individuals in the susceptibility of the optic nerve to damage from IOP. No IOP exists below which glaucoma never occurs or above which glaucoma always occurs. Of patients who suffer glaucoma, 50% have screening IOPs of <21?mmHg (<2.8?kPa) and approximately one in six do not have IOP >21?mmHg (>2.8?kPa) on repeated testing.   Though the relative risk of glaucoma is low when IOP is <20?mmHg (<2.7?kPa), damage may still occur. Even when IOP remains within the normal range, the risk of visual field loss is greater in the eye with the higher IOP.
Ocular hypertension (OHT) is a common disorder that affects 3–6 million people in the United States. In a population over 70 years of age, 10% of people suffer OHT, whereas only 2% have primary open-angle glaucoma. Numerous small studies have tried to evaluate the rate of glaucoma development in untreated ocular hypertensives and whether treatment prevents or delays the development of glaucoma. These studies suggest that 0.5–4.0% of OHT subjects develop primary open-angle glaucoma each year, and roughly half of these small studies favored medical treatment, while half favored observation.   Since only a minority of people with OHT develop glaucoma, it is not reasonable to treat all patients who have OHT. Currently, approximately 1.5 million glaucoma suspects in the United States are treated, which translates into a $300 million per year public health burden.
Fortunately, the Ocular Hypertension Treatment Study (OHTS)—a long-term, multicenter clinical trial sponsored by the National Eye Institute—recently reported its 5-year results.  OHTS was designed to determine whether medical reduction of IOP prevents or delays the onset of glaucomatous damage in OHT subjects. It also sought to determine the risk factors involved in the glaucomatous process. More than 1500 subjects were enrolled and followed for more than 5 years.
Patients were randomized to medical treatment (using any of the topical medications approved by the U.S. Food and Drug Administration) or observation. Goal IOP for subjects in the treatment group was a 20% reduction of IOP and an IOP <24?mmHg (<3.2?kPa). Patients were followed using Humphrey visual fields (program 30-2) and stereoscopic optic disc photographs.
The risk of developing glaucomatous optic disc and/or visual field loss was significantly reduced in the treated group; 9.5% of patients in the observation group developed glaucoma compared with 4.4% of those in the medically treated group. In addition to the level of IOP, the following were identified as the principal risk factors for the progression of OHT to glaucoma: CCT, age, and cup-to-disc ratio. African-Americans had a higher incidence of glaucoma than other study participants, but this higher incidence was accounted for by thinner corneas and larger cup-to-disc ratios at baseline. Results from ancillary studies evaluating short-wavelength perimetry and scanning laser optic-nerve head topography are pending.
CENTRAL CORNEAL THICKNESS.
One of the most surprising findings of the OHTS was the impact of CCT on the development of glaucoma in the OHTS. Pachymetry measurements were not part of the initial protocol, but were added on when their potential significance became apparent. Overall, participants in OHTS had thicker corneas than the average population with an average corneal thickness of 573.0 ± 39.0?µm, and a quarter of the OHTS subjects had CCT >600?µm. African-Americans had thinner corneas than white subjects (555.7 ± 40.0?µm vs. 579.0 ± 37.0?µm; p <.0001). Eyes with thinner corneas had increased risk of developing glaucoma compared with eyes with thick corneas. For example, for eyes with IOP of >25.75, the risk of developing glaucoma was 6% for subjects with CCT >588?µm, but 36% for those with CCT<555?µm. Overall, CCT was found to be a potent risk factor for the development of POAG.
Age is another important risk factor for primary open-angle glaucoma. The prevalence of glaucoma increases from 0.2% in individuals 50–54 years of age to 2% of the population 70–74 years of age ( Table 231-1 ). The incidence rates for the development of glaucoma over a 4-year period also increased with age; the Barbados Eye Studies demonstrated a rate of 1.2% in patients 40–49 years of age and 4.2% in those aged 70 years or older. This increased prevalence of glaucoma with increasing age may relate to the longer exposure to elevated IOP and/or a greater susceptibility of optic nerves in older people to sustain damage from elevated IOP. The prevalence of OHT also increases with age; OHT occurs in 1.3% of subjects 30–39 years of age versus 10.5% of those 70–79 years of age.
Race is also an important risk factor for primary open-angle glaucoma. The Baltimore Eye Survey shows that the prevalence of primary open-angle glaucoma is 4.3 times greater in African–Americans than in other races and that African–Americans
TABLE 231-1 — PREVALENCE OF DEFINITE PRIMARY OPEN-ANGLE GLAUCOMA BY AGE AND RACE*
Screening Examination (Number)
Adjusted Rate/100 (95% Confidence Interval)
Adapted with permission from Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA.1991;266:369–74.
* Adjusted rate is modified for nonresponse to definitive ophthalmologic examination. Difference (African-American – Caucasian-American) 5.10 – 1.19 3.91% (95% confidence interval, range 3.45–4.37%).
are four to eight times more likely to go blind from glaucoma than Caucasian–Americans. In this series the prevalence of glaucoma was 1.2% among African–Americans 40–49 years of age, and 11.3% in African–Americans 80+ years of age (see Table 231-1 ). 
The Barbados Eye Study found a similar prevalence of primary open-angle glaucoma in the African–Caribbean inhabitants of Barbados as was found in African–Americans in Baltimore—7% of African–Caribbean adults versus 0.8% of Caucasian–Caribbeans.   The Rotterdam study based on the Caucasian population of the Netherlands showed a prevalence of primary open-angle glaucoma of approximately 1%, similar to the prevalence found in the Baltimore Eye Survey among Caucasian–Americans. It is not known why primary open-angle glaucoma is more common in individuals of African descent. It appears that an inherent predisposition may exist for the disease, which is present at an earlier age.
Family history is a well-described risk factor for glaucoma. The Baltimore Eye Survey noted a 3.7-fold increased risk of primary open-angle glaucoma in individuals who had a sibling affected by primary open-angle glaucoma and a 2.2-fold increased risk if a parent was affected ( Table 231-2 ).
PRINCIPLES OF INITIATION OF THERAPY
Prior to the initiation of therapy in any patient, it is important to establish a baseline for future comparisons. The IOP of most people who do not have glaucoma varies by <4?mmHg (<0.5?kPa) over a 24-hour period. Glaucoma patients have large diurnal variations of IOP, which may change by >10?mmHg (>1.3?kPa). Many patients have a regular diurnal pattern, most typically with a high IOP upon awakening, but other patterns also occur.
Unless IOP is dangerously high for a patient or a return visit is too inconvenient (distance to doctor, work schedule, etc.), it is wise not to start therapy at the first patient encounter. It is important to measure IOP on more than one occasion and preferably several times a day to characterize the patient’s diurnal variation. It is also important to obtain baseline documentation of optic disc appearance and visual field performance. Discs can be drawn, but stereophotographs provide a more accurate record. Computerized tomographic imaging with instruments such as the Heidleberg Retinal Tomograph, Heidleberg Engineering, Inc (Carlsbad, CA) may also enable detailed, precise measurements of the morphology of the optic nerve head. The role of other fundus imaging systems, such as nerve fiber layer polarimetry and optical coherence tomography, are still in evolution. Since a steep learning curve occurs, automated fields are performed at least twice at baseline if the patient is inexperienced at perimetry.
It is crucial to involve patients in the decision to start therapy and in the choice of the appropriate treatment plan. Most patients in the United States are started on topical medicines.
TABLE 231-2 — BALTIMORE EYE SURVEY: ASSOCIATION OF PRIMARY OPEN-ANGLE GLAUCOMA WITH A FAMILY HISTORY OF GLAUCOMA
Odds Ratio (95% Confidence Interval)
Age–Race Adjusted Odds Ratio* (95% Confidence Interval)
Any first-degree relatives
* Age–race adjustment conducted using logistics regression analysis.
Patients are offered the least amount of medication needed to achieve their goal. Patients need to be informed and questioned about side effects, costs, and how their overall therapy and disease process influences their everyday life. Compliance with treatment improves with enhanced patient education.
In the United States, laser and surgical intervention are typically performed in cases of medication failure or intolerance. The Glaucoma Laser Trial sponsored by the National Eye Institute, however, has shown that argon laser trabeculoplasty may be a viable first therapy for glaucoma. Recently introduced selective laser trabeculoplasty (SLT) has similar efficacy as argon laser trabeculoplasty without causing thermal changes. It is postulated that SLT treatment can be repeated at regular intervals. Its role in the glaucoma armamentarium is still evolving. Although the Glasgow Glaucoma Trial and the Moorfields Primary Treatment Trial demonstrated better IOP control with initial surgical intervention, the Collaborative Initial Glaucoma Treatment Trial, sponsored by the National Eye Institute, found the same rate of visual field loss when initial treatment of glaucoma was either medical or surgical. In addition, visual acuity loss was greater in the surgery group compared with the medical group in the early follow-up period.
INITIATION OF THERAPY IN THE GLAUCOMA PATIENT
Most patients who have moderate-to-severe glaucoma are started on therapy to lower IOP. These patients have developed optic disc damage at their baseline, untreated IOP and are very likely to have continued progressive damage over time if the condition is left untreated. In most of these patients, the benefit of treatment far outweighs the risk of complications.
Not every case of primary open-angle glaucoma, however, requires treatment. The true goal of glaucoma therapy is not to lower IOP or to prevent progressive disc damage or visual field loss. The primary goal of glaucoma treatment is to preserve a patient’s quality of life by preventing the development of functional visual impairment during the patient’s lifetime, while minimizing any adverse effects of glaucoma treatment. Unfortunately, few studies have been carried out to evaluate real-life functional deficits in glaucoma. Most patients are not bothered by early or even moderate amounts of glaucoma damage. Cases of early glaucoma in an elderly person may be treated best by observation, because even progressive changes may go undetected by the patient, and these patients are at significant risk of side effects from medication. Similarly, glaucoma therapy should be administered less aggressively in any patient who has a limited life expectancy.
Primary open-angle glaucoma is a bilateral disease, although it is often strikingly asymmetrical. If damage is present in only
one eye, it is important to first rule out secondary causes of unilateral open-angle glaucoma, which most commonly include pseudoexfoliation, traumatic angle-recession, and corticosteroid-induced glaucoma. If secondary causes of glaucoma are excluded, the damage in one eye is predictive of damage in the other eye and treatment often is initiated in both eyes.
INITIATION OF THERAPY IN THE GLAUCOMA SUSPECT
The decision to initiate therapy is much more controversial in the patient who is suspected of having glaucoma. It is particularly important for glaucoma suspects to be involved in the decision process. There are two main types of glaucoma suspects:
• Those subject to significant risk factors for the future development of glaucoma—most importantly, high IOP (OHT is discussed separately below)
• Those who suffer very early glaucoma damage that cannot definitely be differentiated from normal (i.e., optic discs of suspicious appearance).
Determination of whether an optic nerve of suspicious appearance is glaucomatous is difficult. Great overlap exists between normal and diseased optic nerves. The average optic disc has a cup-to-disc ratio of 0.3–0.4, but a wide variation of normal occurs. The significance of the size of the cup depends on the size of the disc. It is difficult to determine whether the large disc with a high cup-to-disc ratio is pathological or physiological. Progressive disc changes may develop while visual field tests remain normal, and substantial axonal loss may develop before defects occur on kinetic perimetry. Therefore, a normal visual field test does not rule out glaucoma. Evaluation of the nerve fiber layer may be particularly important in these cases.
Treatment is considered the more suspicious the nerve appears, if nerve fiber layer loss is detected, or if other significant risk factors exist for glaucoma. As discussed, in patients who have early glaucoma, treatment may be deferred in those with limited life expectancy. On the other hand, treatment may be initiated at an earlier stage in subjects in whom it is difficult to detect change in the optic nerve status over time. This includes patients who have anomalous discs, disc drusen, high myopia, and tilted discs, and patients in whom an adequate fundus examination cannot be performed. Similarly, treatment may be begun at a lower threshold in patients who are unable to perform visual field testing or in patients who suffer nonglaucomatous causes of visual field loss.
The initiation of therapy is most controversial in patients who have elevated IOP and normal optic nerves and visual fields. Although the OHTS showed a significant reduction in the development of glaucoma with treatment, approximately 90% of patients in the observation group did not develop glaucoma during the first 5 years of the study. OHTS II will evaluate if there is any difference if treatment of OHT is delayed. Until those data are available, it is recommended that treatment be considered in high-risk OHT subjects (i.e., those with high IOP, thin corneas, and large cup-to-disc ratios) while taking into account medical status, life expectancy, financial, and other psychosocial issues.
The decision of when to treat a patient to prevent glaucomatous damage cannot be simplified into a straightforward algorithm. A myriad of factors, both objective (e.g., optic nerve status, level of IOP, visual field defects) and subjective (e.g., patient lifestyle, compliance), must be taken into account. These factors must be tempered by the current knowledge of how and why glaucoma develops and whether treatment is efficacious. Fortunately, a great deal of active investigation has facilitated our decision-making process over the last decade, permitting treatment decisions based on sound data from large-scale, prospective, randomized clinical trials.
1. Anderson DR. Glaucoma: the damage caused by pressure. XLVI Edward Jackson Memorial Lecture. Am J Ophthalmol. 1989;108:485–95.
2. Grant WM, Burke JF Jr. Why do some people go blind from glaucoma? Ophthalmology. 1982;89:991–8.
3. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109:1090–5.
4. The advanced glaucoma intervention study (AGIS):7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 1000;130:429–40.
5. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126:487–97.
6. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002 Oct;120(10):1268–79.
7. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003 Jan;121(1):48–56.
8. Kahn HA, Milton RC. Alternative definitions of open-angle glaucoma. Arch Ophthalmol. 1980;98:2172–7.
9. Cartwright MJ, Anderson DR. Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low tension glaucoma). Arch Ophthalmol. 1988;106:898–900.
10. Kitazawa Y, Horie T, Aoki S, et al. Untreated ocular hypertension: a long-term prospective study. Arch Ophthalmol. 1977;95:1180–4.
11. Lundberg L, Wettrell K, Linner E. Ocular hypertension: a prospective twenty-year follow-up study. Acta Ophthalmol (Copenh). 1987;65:705–8.
12. Schulzer M, Drance SM, Douglas GR. A comparison of treated and untreated glaucoma suspects. Ophthalmology. 1991;98:301–7.
13. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002 Jun;120(6):701–13.
14. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002 Jun;120(6):714–20.
15. Brandt JD, Beiser JA, Kass MA, Gordon MO. Central corneal thickness in the Ocular Hypertension Treatment Study (OHTS). Ophthalmology. 2001 Oct;108(10):1779–88.
16. Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA. 1991;266:369–74.
17. Leske MC, Connell AM, Wu S. Incidence of open-angle glaucoma. The Barbados Eye Studies. Arch Ophthalmol. 2001;119:89–95.
18. Armaly MF. On the distribution of applanation pressure. I. Statistical features and the effect of age, sex, and family history of glaucoma. Arch Ophthalmol. 1965;83:11–8.
19. Leske MC, Connell AM, Schachat AP, et al. The Barbados Eye Study. Prevalence of open angle glaucoma. Arch Ophthalmol. 1994;112:821–9.
20. Tielsch JM, Katz J, Sommer A. Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey. Arch Ophthalmol. 1994;112:69–73.
21. Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the collaborative initial glaucoma treatment study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108:1943–53.
22. Britton RJ, Drance SM, Schulzer M, et al. The area of the neuroretinal rim of the optic nerve in normal eyes. Am J Ophthalmol. 1987;103:497–504.
23. Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema and toxic neuropathy. Arch Ophthalmol. 1982;100:135–46.