Chapter 211 – Screening for Glaucoma
PAUL P. LEE
AERLYN G. DAWN
• Ideal screening identifies all individuals who have a disease (sensitivity) and eliminates those without the disease (specificity).
• Screening for the earliest stage of a disease assumes that patients will suffer progressive loss, which has a measurable effect on patients’ lives, and that interventions can retard, stop, or reverse such loss.
• Acceptable screening performance for open-angle glaucoma is 85% sensitivity for glaucomas and other optic neuropathies with visual field defects and specificity of at least 95% (preferably 98%).
• The current definition of glaucoma as a group of optic neuropathies may simplify future identification by screening of characteristic optic nerve and nerve fiber abnormalities.
• New technology may offer enhanced performance.
The glaucomas are a diverse group of eye conditions that share either the common feature of progressive optic neuropathy (the open-angle variants)  or the common feature of occludable drainage angles in the anterior chamber (the closed-angle variants). Because these represent two distinct groups of entities at two distinct anatomic areas, screening for both requires two distinct approaches. For the purposes of this chapter, a general approach to the understanding of screening programs is described that can be applied to both. However, specific comments and a review of screening studies are limited to the more common open-angle forms (the reader is referred to a published review by Congdon et al. for such aspects of closed-angle screening).
From a societal perspective, screening should ideally identify every patient who has a disease (100% sensitivity) while clearing every individual who does not (100% specificity). In reality, no test has these technical performance characteristics. Instead, a reasonable balance is sought between sensitivity and specificity. Definition of the reasonable balance may be arbitrary—achieved through consensus over time—or based on empirical analyses of test performance (e.g., receiver operating characteristic curves) and associated costs of screening and cost per true case identified. To be a practical reality, screening tests must be simple to perform, need the assistance of lay people or less costly midlevel or technician-level providers (or none at all), and be quick enough to be done on otherwise asymptomatic people in the community setting (i.e., on a population basis).  
Prior Glaucoma Screening Efforts
In the past, glaucoma screening has relied upon intraocular pressure (IOP) measurements, based on a case definition of glaucoma that required the presence of visual field defects, optic nerve or nerve fiber layer defects, and elevated IOP (except in the “normal tension” variant, in which elevated IOP was not required). Performance of IOP measurements alone has been unacceptably poor in screening for glaucomas defined in this manner.  Indeed, in a population-based analysis (which minimizes elements of selection bias) from the Baltimore Eye Survey in which elevated IOP was not required for a case definition of glaucoma, IOP levels had a maximum sensitivity of 93% among Caucasians and those who had a family history of glaucoma at an IOP of >16?mmHg (2.1?kPa) but with accompanying specificities of only 36% and 39%, respectively.  At the traditional cutoff of IOP >21?mmHg (2.8?kPa), sensitivities across various risk factors were only about 48%.
Numerous studies have evaluated the use of other screening parameters, such as various automated visual field screening and suprathreshold strategies, optic nerve head cup-to-disc ratios, optic nerve neuroretinal rim indicators, risk factor analyses (such as age, sex, race, and ocular and medical history), and combinations thereof.  These studies have found all such indicators inadequate for use as screening tools. Thus, significant interest remains in finding a method to screen for glaucoma, given the large numbers of patients who have glaucoma and that at least half of those who have glaucoma (defined as having both field and disc defects) do not know that they have the disorder.
Current Glaucoma (Open-Angle) Definition
The results of prior studies need to be read cautiously in light of the current definition of primary open-angle glaucoma, first promulgated by the American Academy of Ophthalmology in 1996 : “a multifactorial optic neuropathy in which there is a characteristic acquired loss of optic nerve fibers.” The current definition further states that the definitive characteristics of glaucoma are based on either visual field loss or “appearance of the disc or retinal nerve fiber layer.” Early or mild glaucoma is defined as having characteristic optic nerve abnormalities with normal visual fields. Thus, visual field defects are no longer part of the case definition of glaucoma. The American Academy of Ophthalmology (AAO) defines moderate glaucoma as having visual field abnormalities in one hemifield, not within 5° of fixation. Severe glaucoma is defined as visual field abnormalities in both hemifields or loss within 5° of fixation. The effect of this definition is to expand the number of people in the United States who could have glaucoma to over 15 million instead of the 2.2 million people currently estimated by Prevent Blindness America. Thus, the performance of screening tests has to be reevaluated.
PURPOSE OF THE TEST
A screening test for glaucoma detects glaucoma before it causes significant loss of function for the individual. The current definition raises at least three questions: (1) What are the likelihood and rate of progressive loss from early glaucoma, in which there is only optic nerve or retinal nerve fiber layer loss? (2) Do available treatments slow, stop, or reverse loss of nerve fibers and the consequent visual functioning, and does the success of such treatment vary if treatment is delayed until later in the course? (3) At what point does loss of nerve fibers cause functional loss of significance to patients, and what degree of visual field loss (or any other physiological or psychometric measure), if any, is required before patients notice a decrease in their visual functioning or their general quality of life? The answers are essential because they address key concepts that were presupposed in prior screening efforts—that even early loss adversely affects patients (or that later loss is harder to control), that treatment is effective in at least slowing down the rate of both anatomic and functional loss, and that a sufficiently high number of patients progress without treatment to make it worthwhile to screen for even early stages prior to any functional or field loss.
Estimates of the likelihood of progression from early optic nerve loss to subsequent additional loss run from 9% to as high as 63% over a 5-year period,   which suggests that additional
optic nerve fiber loss is significant. Recent data from the Ocular Hypertension Treatment Study (OHTS) show that the risk of developing initial field loss or progressive optic nerve damage among those with no visual field loss but elevated eye pressures was 9.5% over 5 years. Among the risk factors for progression are a larger cup-to-disc ratio, indicating the possibility of subtle prior glaucomatous damage (early glaucoma by definition). Of note, the risk of progressive disease among subpopulations in the study ranged to over 35% depending on the presence of identified risk factors, for progression. 
The Early Manifest Glaucoma Trial (EMGT) results provide gold-standard evidence of the rates of progression among those who have visual field loss and no treatment, compared with those with treatment. The EMGT was designed to determine whether treatment retards vision loss in those who already have relatively mild visual field loss (moderate glaucoma) at presentation. Patients in the control arm without treatment had a 62% rate of progression based on visual field or optic nerve head criteria (overall, the study had a 53% rate of progression) over 6 years. Thus, based on the results of these two trials, there is now solid evidence of the rates of progression of glaucoma among those without treatment. Further, in both studies, data identify the various risk factors for progression, so that subpopulations of patients at greater (or lower) risk can be identified. Of note, there is a large difference in progression rates between those with no visual field loss (9.5%) and those with reliable mild visual field loss (62%).
The second issue, the medical profession’s ability to retard or arrest loss of optic nerve fibers or deterioration of the visual field, is being addressed in several large, randomized controlled clinical trials sponsored by the National Eye Institute. These include trials with a no-treatment arm (EMGT and the Ocular Hypertension Treatment Study ) and studies to evaluate the effectiveness of various treatment modalities (Advanced Glaucoma Intervention Study [AGIS] and the Collaborative Initial Glaucoma Treatment Study ). Both the OHTS and EMGT clearly demonstrate that lowering intraocular pressure significantly reduces the rate of progression of disease compared with no treatment.  In the OHTS results, treatment to lower IOP halved the rate of progression from 9.5% to 4.4% over 5 years. In the EMGT, only 45% of those who had pressure lowering (averaging 25% reduction) progressed (vs. 62% in the untreated control group) and did so later in the course of follow-up. Both studies also provide important information on the risk factors for progression. Further, results from the AGIS show that low IOP is associated with a reduction in the progression of visual field defects. Evidence from the Collaborative Normal Tension Glaucoma Study Group shows that IOP plays a role in the pathogenesis of normal-tension glaucoma as well. Although more complete answers to the questions addressed in these studies are expected in the next few years, the evidence now available strongly supports the notion that treatment can retard the rate of vision loss due to glaucoma. Thus, effective treatment is indeed available.
Finally, our ability to understand the effect of less than optimal vision on patients’ function has increased considerably in the past few years. For patients who have blurred vision or trouble seeing, the impact on their general quality of life is commensurate with that of several major systemic illnesses.  Yet glaucoma patients traditionally have been thought not to have noticeable problems with their vision until relatively late in the disease. Evidence from a prospective case-control study showed that patients with glaucoma had significantly less general functional status than those without glaucoma, although this finding is contradicted in other studies.  Notably, visual field loss has been shown to be correlated with reduction in glaucoma patients’ activities of daily vision. Studies show that visual field loss is related to a higher rate of automobile accidents and that visual field loss has a measurable impact on vision-related quality of life (i.e., the ability to perform important visual tasks, such as reading or driving, and the individual’s satisfaction with lifestyle).  However, the issue of when glaucoma-related vision loss becomes significant currently can be answered only indirectly, by a comparison of the performance of normal patients who do not have glaucoma with that of patients who have early field loss. Using a moderate effect size of 0.5 standard deviations, AGIS field loss defects would have to increase between 3 and 10 points (on a 20-point scale) before a functionally significant field loss is described.
Thus, in assessing the state of our knowledge, sufficient data exist to answer the first two of these three key questions. Rates of progression without treatment are known, as are the benefits of treatment in reducing the rate of progression of even visual field loss. Data also exist to begin to answer the third question; they suggest that individuals who have significant visual field loss do have important decrements in vision-related quality of life and in important activities of modern life. Thus, screening for those with visual field loss is something that, in principle, is desirable. However, without a definable and measurable benefit from the identification of early cases of glaucoma (no visual field loss), it is less certain that screening for glaucoma to identify all such individual with early glaucoma is as strongly indicated. As additional information is developed about the rates of progression over even longer time frames, particularly the overall proportion of patients that eventually do progress to visual field loss and then have additional progressive field loss, screening for early glaucoma on a generalized basis may become more desirable.
USE OF THE TEST AND INTERPRETATION
The Glaucoma Advisory Committee of Prevent Blindness America has promulgated criteria for minimum performance characteristics for adjunctive devices used in screening for glaucoma, which include 95% specificity (98% preferable) and at least 85% sensitivity for moderate to severe visual field defects. The desirability of these or any other criteria for specificity or sensitivity must be evaluated in light of the effect of such performance on the probability that someone be correctly identified as having glaucoma after a positive test result, through application of Bayes’ theorem ( Table 211-1 ). Such a screening test performance, given the low prior probability of glaucoma in the general population above 40 years of age (using the old case definition), still results in three false positives for every true positive. However, if the prior probability could be raised to, for example, 8–10% (as with testing family members only or using the current definition of glaucoma with only optic nerve head findings required), test performance at these criteria would be enhanced significantly and result in two true cases for every false positive identified.
Use of a screening test with 100% sensitivity has little effect on the posterior probability that a positive test correctly identifies a patient as having glaucoma ( Table 211-2 ). Thus, changing the sensitivity of the test beyond 85% has much less effect than the application of methods to alter the prior probability of
TABLE 211-1 — APPLICATION OF BAYES’ THEOREM TO SCREENING TEST PERFORMANCE
General Population Over 40 Years of Age
Family Members/Nerve Head Only
Positive test (%)
TABLE 211-2 — APPLICATION OF BAYES’ THEOREM TO ENHANCED SCREENING TEST PERFORMANCE
General Population Over 40 Years of Age
Family Members/Nerve Head Only
Positive test (%)
Positive test (%)
having glaucoma in the populations being screened. However, an increase in the specificity of the test to the 0.98 level, suggested by Prevent Blindness America (but not required), results in the best improvement in test performance. Thus, methods that increase the prior probability of having glaucoma and tests with better specificity may be efficient means of screening for glaucoma, provided adequate sensitivity exists. 
Additional statistical methods exist to help assess the use of different tests for the detection of glaucoma and are likely to become more widely used. The likelihood ratio (LR) expresses the relative rate of a positive test among those with glaucoma compared with those without. Thus, it is an indicator of how much more (or less) likely a given test result is obtained among diseased versus non-diseased individuals. The LR can be calculated as sensitivity / (1 – specificity) for a positive test and (1 – sensitivity) / specificity for a negative test. In the case of the Prevent Blindness America recommendations, the calculated LR of a desirable test for detecting glaucoma would be 17. When combined with a prior probability of disease, the LR can be used (with published algorithm scales) to provide a post-test probability, similar to the results of using Bayes’ Theorem.
Incorporation of LR assessments offers several advantages. First, they are less likely to change with the prevalence of a disease. Second, they can be used to combine the results of multiple tests. Third, they can be used when screening test results are ordinal or continuous in nature, rather than categorical. This feature allows for potentially greater insights into analyzing test results, especially in comparing among different tests.
Receiver operating characteristic (ROC) curves share in common with the LR the ability to take advantage of ordinal or continuous test results. Both approaches allow for the comparison of various screening tests. However, additional statistical issues exist with the use of ROC curves: nonparametric vs. parametric (or semiparametric) tests, the impact of having multiple applications of the same test on a single patient (longitudinally and cross-sectionally), and multiple evaluators assessing a single test result.
Direct Indicators of Glaucomatous Optic Nerve Damage
With the current case definition of glaucoma as an optic neuropathy and the demonstration that optic nerve fiber loss may be identified prior to the onset of visual field loss,  screening for glaucoma can be simplified to evaluation of the results of various methods of assessment used to evaluate the optic nerve. With the definition of what optic nerve fiber findings constitute “characteristic” loss, the AAO Preferred Practice Pattern has one possible set of indicators for screening: thinning or notching of the rim, progressive change (cupping), or nerve fiber layer defects.  Screening programs that determine that one or more of these findings exist have screened appropriately for glaucoma.
Imaging of the optic nerve and retinal nerve fiber layers is used to determine structural loss. New imaging techniques, including confocal scanning laser tomography (CSLT), scanning laser polarimetry (SLP), optical coherence tomography (OCT), and retinal thickness analysis (RTA), have shown promise for glaucoma screening. A longitudinal prospective study found that glaucomatous disc changes determined with CSLT occur more frequently than visual field changes and that less than half of glaucoma patients with disc changes also showed visual field changes. Using the current preperimetric definition of early glaucoma, Heidelberg Retinal Tomography (HRT), a form of CSLT, has sensitivities of <30% at a specificity of 95%. Sensitivity and specificity rise to 84% and 90% to 96%, respectively, for moderate glaucoma.  SLP, using the GDx device, has a sensitivity of 58% at a given specificity of 80% for preperimetric RNF defects and sensitivity and specificity of 89% and 87% for moderate glaucoma.  OCT has been shown to have sensitivity and specificity of 82% and 84%, respectively, for moderate glaucoma. Although RTA has generated interest as a potential tool for diagnosing glaucoma, few data exist related to the use of this technology.
A comparative study concluded that when used alone, HRT, SLP, and OCT summary reports “did not provide sensitivities and specificities that justify implementing them as primary population screening tools for early to moderate glaucoma.” Also, one of the major disadvantages of these technologies is the need for a skilled operator. A review by Michelson and Groh summarizes the specific advantages and disadvantages of these technologies. Conventional photographic imaging of the optic disc by an experienced examiner remains the most sensitive method of detecting early glaucoma ; however, these new imaging technologies hold potential for glaucoma screening, particularly in combination with functional testing such as frequency-doubling technology. One of the major difficulties of assessing these new imaging technologies is the fact that the accuracy of the test can be determined only by comparing it with a “gold standard” reference test, yet no single test can provide a definitive diagnosis of glaucoma. Several long-term prospective studies that will help determine the roles of these new technologies in glaucoma screening are in progress.
In evaluating the optic nerve, uncertainty and inaccuracy related to screening arise from the inherent variability between observers in the assessment of the same clinical situation (interobserver variability), with the same observer at different points in time (intraobserver variability), and with the accuracy of the method used to measure the optic nerve head or nerve fiber layer. Some studies have found that experts have relatively high levels of interobserver and intraobserver consistency for certain indicators; others suggest that significant variation exists or that the levels of agreement fall with less experienced observers and with the method used.   Recent data from the OHTS using a rigorous quality assurance protocol show that trained technicians achieved high reproducibility between repeated gradings of the baseline horizontal cup/disc ratio from optic disc stereophotographs. The percentage of regradings differing by =0.2 disc diameters from the baseline estimate of horizontal cup/disc ratio ranged from 4 to 7, and intraclass correlation coefficients ranged from 0.92 to 0.93. However, the authors point out that these findings cannot be generalized to routine clinical practice. If agreement rates for the presence or absence of glaucoma are substituted as equivalents for sensitivity and specificity, likely posterior probabilities can be generated for an accurate screening result for glaucoma status using these techniques.
The risks associated with screening for glaucoma fall into two categories. (1) The risk of false identification of the true ocular status—either false reassurance that a person is free of a disease or false identification that the person has a disease. The complications associated with this are an increased risk of undergoing subsequent, undetected visual loss in the former and the concomitant anxiety and expense of clarification of the true situation in the latter. (2) Because the optic nerve and its functioning are likely to be the focus of future screening efforts (assuming that screening is desirable), the most common risk is likely to be the precipitation of an angle-closure attack for tests that require dilation of the pupils for an accurate assessment of the optic nerve or retinal nerve fiber layer. The risk of this occurrence on a population basis has been estimated to be, at most, 1 in 333 subjects.
New Automated Perimetry Tests
Prior to the current definition of glaucoma, investigators reported several promising methods for the detection of individuals who have visual field loss on standard suprathreshold static perimetry or kinetic perimetry (Goldmann), including scotopic sensitivity testing, Henson visual field analysis and Damato campimetry (and oculokinetic perimetry),   peripheral color contrast, and simultaneous interocular brightness sense testing. All of these techniques are designed to screen for moderate glaucoma in which visual field loss is already present.
Investigators have also reported several newer techniques that may offer the possibility of detecting earlier visual field defects and progression of glaucomatous visual field loss. Computer-assisted visual fields are widely used to determine functional loss of vision. Techniques introduced in recent years include frequency-doubling technology (FDT) perimetry, short wavelength automated perimetry (SWAP), high-pass resolution perimetry (HPRP), motion automated perimetry (MAP), the multifocal electroretinogram (mERG), and the multifocal visual evoked potential (mVEP). In addition, the application of the Swedish interactive threshold algorithm (SITA) to conventional full threshold perimetry appears to increase sensitivity and reproducibility and to reduce testing times and intertest variability. 
Of these techniques, FDT has shown the greatest promise as a practical means of glaucoma screening. A prospective study found that FDT showed sensitivity of 85% and specificity of 90% for early glaucomatous visual field loss (moderate glaucoma by the current AAO definition). Moreover, Cello et al. showed that FDT had 96% sensitivity and 96% specificity for detecting moderate glaucomatous visual field loss. These data suggest that FDT would meet the minimum performance characteristics for glaucoma screening recommended by Prevent Blindness America. Studies have found that screening FDT appears to be effective as a screening tool to detect moderate glaucomatous damage.  FDT is significantly more rapid than standard automated perimetry, SWAP, HPRP, or MAP, making it well suited for screening. Studies using the FDT screening mode found that the average testing time was <2 minutes per eye (instrument time) for glaucoma patients and less than 30 seconds per eye for nonglaucoma controls.  In addition, FDT perimetry is relatively inexpensive, portable, and does not require special training for the examiner or patient. Furthermore, FDT may have less intertest and intratest variability than conventional perimetry.
Other perimetric techniques also show promise but have disadvantages that make them impractical for screening in their current forms. SWAP, or blue-yellow perimetry, may detect field defects earlier than white-on-white standard threshold automated perimetry. However, SWAP also requires more time than standard threshold automated perimetry, making it impractical for screening. Investigators are researching the possibility of a SITA version of SWAP, which may reduce SWAP testing times. A prospective longitudinal cohort study found that HPRP, which is designed to test selectively the parvocellular system, can be more effective than standard threshold automated perimetry at detecting progressive glaucomatous visual field loss. However, HPRP can be sensitive to blur and media opacities, which may limit its effectiveness. MAP relies on the observation that glaucoma patients show defects in motion perception. A 5-year prospective cohort study showed that MAP can be useful for detecting early glaucomatous visual loss and can be a strong predictor of standard white-on-white visual field loss. However, as with SWAP, the length of MAP testing (approximately 15 minutes) makes it impractical for screening.
The mERG measures the local electrical responses of the retina throughout the central visual field and does not rely on subjective patient responses. mERG has been shown to provide objective measurement of visual function from localized regions. A pilot study suggested that mERG might play an important role in detecting early glaucomatous changes and recommended the use of mERG as a supplementary test for glaucoma suspects. However, data suggest that the sensitivity of the test is limited and that mERG findings in most glaucoma patients do not correlate well with visual field defects present on standard automated perimetry.  Thus, additional work is needed to understand the nature and etiology of these differences.
Because of these limitations of mERG, some researchers have expressed increasing interest in the mVEP, which shows stronger correlation with standard automated perimetry.  mVEP measures the localized electrical responses from the occipital cortex for the central visual field, and, like mERG, mVEP can objectively detect glaucomatous visual field defects. However, significant interindividual variability in mVEP responses has limited the application of mVEP perimetry to glaucoma screening. 
If screening for the earliest stage of glaucoma, that of optic nerve fiber loss alone, is desired, these methods will need to be evaluated in light of the current definition of glaucoma (see prior section). However, if screening is found to be efficient only for those who have visual field loss, methods predicated on field loss should receive further attention and evaluation as potential screening techniques. Given that patients most likely do not experience any impairment of quality of life until some visual field loss has already occurred, screening at the level of early visual field loss (moderate glaucoma) may be an effective strategy.
Genetic Testing for Glaucoma
Finally, in the past decade, genetic analysis of families with primary open-angle glaucoma has identified at least six different genetic loci that may be involved in the pathogenesis of the disease.      The identification of the TIGR/myocillin gene has led to the introduction of a genetic test called OcuGene. Although the usefulness of the test is limited because the test detects <5% of people who will later develop open-angle glaucoma as adults,  genetic testing for glaucoma is becoming a reality. Moreover, at the 2002 ARVO meeting, Li et al., showed that patients expressed relatively positive attitudes toward hypothetical genetic testing for glaucoma. Thus, genetic linkage analysis offers the promise that someday patients will be screened for glaucoma on a genetic basis through peripheral blood or other specimens. Again, however, the performance of these techniques may vary depending on the case definition of glaucoma used. Similarly, the utility of such screening also presupposes that effective treatments exist and that the cost-benefit ratio of such screening, based in large part on the test’s performance characteristics (see earlier), justifies screening a given population.
Comparison of Techniques to Screen for Glaucoma
Because the comparison of tests with different sensitivities and specificities at different cutoff or threshold levels is difficult to evaluate fully, the use of receiver operating characteristic curves and likelihood ratios to supplement our understanding of the relative value of tests will become essential for the comparison of the test performances of different means of screening for glaucoma.  Comparison of the areas under the ROC curves, as well as of the graphical displays of such curves, readily identifies the tests or methods that are superior to others. Use of LR results will potentially provide even more detailed insights into which tests will be most helpful.
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