Psychophysics

Update on psychophysical tests for glaucoma

Joseph Caprioli

Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA, USA

As far back as the 1800s, psychophysics was defined as measuring the responses of the mind. We tend to equate what comes out on the Humphrey visual field print-out with what is going on in the eye. It is not just the eye, of course. It is the eye, it is the brain, it is all those connections that end up triggering the thumb to press that button, and so it is really what is going on in the mind and not just in the eye.

What are some of the drawbacks of standard perimetry? It is well established that standard automated perimetry (SAP) is relatively insensitive to the earliest loss of retinal ganglion cells. If you believe that early detection of glaucomatous damage is important, then standard white-on-white perimetry is not going to provide you with that information. Automated perimetry and other visual psychophysical techniques are susceptible to many artifacts, ocular media being one of the important ones. In addition, the greatest problem that faces us when following patients over time, is the magnitude of long-term fluctuation or variability of the measurement over time. Long-term fluctuation is the largest confounding variable in the detection of the occurrence of glaucomatous progression.

How can we deal with some of these problems? Figure 1 shows a 56-year-old male with ocular hypertension and a glaucomatous disc. SAP demonstrates a few isolated defects in the superior field. This is not a very robust measure of damage. However, as an alternative, if we measure motion sensitivity in the part of the retina that is involved with this defect, we get a very abnormal result (Fig. 2). In the adjacent retina, in an area served by the relatively normal nerve fiber layer and optic nerve, it can be seen that motion sensitivity is normal.

Part of the problem with glaucoma detection is the compromise we make in terms of visual field testing grid density. We currently use a grid which has 6° spacing, at least with the Humphrey. The Octopus fields had program G1 with variable spacing, depending on field location, and slightly higher resolution in the central part of the field where we were looking for early glaucomatous defects. One approach would be to increase the resolution of our test. This costs time and the 6° grid is a compromise. With some of the new algorithms, particularly the SITA algorithm which shortens test time, it may now be reasonable to increase test

Address for correspondence: Joseph Caprioli, MD, Jules Stein Eye Institute, UCLA School of Medicine, 100 Stein Plaza, Suite 2-118, Los Angeles, CA 90095, USA. e-mail: caprioli@ucla.edu

Glaucoma in the New Millennium, pp. 151–164

Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001

edited by Jonathan Nussdorf

© 2003 Kugler Publications, The Hague, The Netherlands

Fig. 1.

grid density. The Humphrey perimeter can be used to merge two 10° fields to obtain 1° resolution. This is not a practical thing to do in all patients, but it might be worthwhile in some cases when applied with some thought. As an example, the detection performance of a low resolution SAP 24-2 pattern can be improved by increasing the density of the test grid (Fig. 3). What are some of the advantages of this type of high resolution approach? It can be applied to specific areas of the field of concern. If we are relatively selective about applying this technique with the newer testing algorithms, then the increase in test time is relatively modest. Finally, it may improve our understanding of how scotomas enlarge and deepen in glaucoma. Useful sites might be in suspicious areas of the original field, along the nasal step area, or after structural evaluation has suggested suspicious locations.

Fig. 2.

If the standard field does not come up with anything, you could tune that field slightly to the area of suspicion, which would correspond with the area of the structural defect (Fig. 4).

What other future developments in glaucoma psychophysics are there? One is the departure from the fixed grid to the development of adaptive testing strategies individualized for a particular patient, so that areas of scotomas or around edges of scotomas will be tested with higher resolution.

We know that clinically detectable structural damage can occur before functional loss. Quigley’s histological studies have shown us that areas with a 40% loss of ganglion cells correspond to about one logarithmic unit of decrease in visual sensitivity, or a 10-dB loss with SAP. Twenty percent ganglion cell loss corresponds to about 5 dB, and so forth. We have psychophysical tests that detect glaucomatous loss with greater sensitivity than SAP. For example, motion perimetry and short wavelength automated perimetry (SWAP), and frequency doubling perimetry (FDP). The rationale for using some of these other tests depends upon the selective stimulation of retinal ganglion cell (RGC) subclasses. These RGC subclasses differ in size, shape, distribution, connectivity, and information processing capabilities. In the simplest terms, we can divide the majority of RGCs into magnocellular and parvocellular subclasses (Fig. 5). Magnocellular RGCs project to the magnocellular layer of the lateral geniculate nucleus and tend to transmit achromatic luminance information, and exhibit greater sensitivity to lower spatial and higher temporal frequencies, i.e., they are more sensitive to motion. Parvocellular RGCs project to the parvocellular layer of the lateral geniculate nucleus and exhibit higher sensitivity to higher spatial frequency and lower temporal frequency tasks and color vision. Relative to the distribution of magnocellular RGCs, parvocellular RGCs are more highly concentrated in the macular region. Parvocellular RGCs are more tuned to central vision (Fig. 6).

Quigley’s work suggested that magnocellular RGCs could be preferentially affected and damaged early on in glaucoma. Thus, psychophysical tests designed

Fig. 3.

to stimulate and stress the magnocellular pathway could demonstrate greater sensitivity in detecting early glaucoma. In addition, Johnson has developed an alternative hypothesis called the ‘reduced redundancy theory’ (Fig. 7). If we select a relatively narrow channel of visual function to test, we are more likely to detect a functional abnormality early on with relatively few cells lost from this discrete cell population, rather than detecting cell loss from the entire population of RGCs. Whichever theory is correct, they both provide a rationale for the testing of individual RGC channels.

What are the selective psychophysical tests? SAP is the non-selective luminance channel test, the brightness test of white-on-white. More selective tests might be

Fig. 4.

SWAP, motion perimetry, flicker, high pass spatial frequency perimetry, and FDP. It has been well established that SWAP defects occur at an early stage in glaucoma. In other words, fewer losses of ganglion cells can be detected with this particular psychophysical test. The problem with SWAP is that there is high variability in test results. The long-term fluctuation in SWAP is even greater than with SAP, and this makes detecting glaucomatous progression difficult. SWAP detects early glaucomatous damage (Fig. 8).

Motion detection testing uses a line stimulus, and the endpoint is when the patient can actually detect motion of the stimulus. It is the amplitude of the motion that is changed over the course of the test, and when the patient can actually detect

Fig. 5.

movement, he or she presses a button. There is a frequency-of-seeing curve which is developed for normals and the threshold is, by definition, when the patient can detect that motion 50% of the time. Motion detection may detect early abnormalities (Fig. 9). This is an area that needs a great deal of further work.

FDP is a technology that is now commercially available. It is sometimes used as a screening test. The endpoint is when the patient detects an optical illusion of the fusion of two alternating patterns, and the frequency of those stripes, if you will, becomes double (Fig. 10). This is the endpoint and this is when the patient clicks the button. Patients like this test better because there is less uncertainty about the endpoint. It is fairly rapid, at least when relatively few points are being tested. The commercially available program tests about 16 points in the visual field compared to 50 or so with SAP. There is relatively good agreement with SAP, at least for

Fig. 6.

glaucomatous defects that are fairly well developed (Fig. 11). Defects with FDP may precede standard white-on-white testing, but we have many questions to answer before we can recommend its use wholesale for following glaucoma patients (Fig. 12). For example, we do not yet know its sensitivity for detecting glaucoma or glaucomatous progression (Fig. 13).

Fortunately for the patient and the practitioner, glaucoma is a very slow disease. However, the slow pace of this disease makes it difficult for the psychophysicist studying glaucoma, the only way to validate a psychophysical test is to follow patients over a long period of time and to determine whether early defects correspond to the presence and progression of disease. Future challenges in psychophysical tests for glaucoma are listed in Figure 14.

Fig. 7.

Fig. 8.

Fig. 9.

Fig. 12.

Fig. 13.

Fig. 14.

The variability of perimetry

Reassessing an important clinical tool

Eve J. Higginbotham, Nancy Ellish and Rani Kalsi

Department of Ophthalmology, University of Maryland School of Medicine, Baltimore, MD, USA

Introduction

Every ophthalmologist who has managed glaucoma patients has faced the challenge of judging the validity of a patient’s visual field in the context of making a diagnosis of glaucoma. Perimetry is particularly tedious for a patient who has never undergone visual field testing, or if the last visual field was far enough in the past that the patient is essentially starting the learning curve again. As is true for any diagnostic test in this era of managed care, it has become difficult to obtain approval to perform the necessary repetitive testing in order to confirm or disprove whether the visual field is truly abnormal. Although the learning curve associated with perimetry has been well documented in the medical literature,1-3 visual field tests that have been repeated within two or three months of an initial field examination are often denied payment. Thus, to the extent that the clinician can improve the accuracy of the test on an initial trial, both the patient and the physician can benefit.

This study focused on the initial visual field test of naive patients (those who have either never previously undergone perimetric testing or who underwent testing more than two years earlier). Therefore, its purpose was to determine whether the ‘inferred validity’ of a patient’s first visual field data can be enhanced by having that patient undergo a simple screening field test before undergoing his or her first threshold test.

Before discussing the study, the following introductory topics will be reviewed: 1. factors that influence perimetric performance in patients; 2. variability of perimetric testing; 3. importance of clinical evaluation; and 4. rationale for the study.

Address for correspondence: Eve J. Higginbotham, MD, Department of Ophthalmology, University of Maryland School of Medicine, 419 W Redwood Street, Suite 580, Baltimore, MD 21201, USA. e-mail: fcwejh6786@aol.com

Glaucoma in the New Millennium, pp. 165–181

Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001

edited by Jonathan Nussdorf

© 2003 Kugler Publications, The Hague, The Netherlands

Variables that influence perimetric performance

To a large extent, perimetry depends on several factors, including specific patient characteristics and cooperation, involvement of the technician, and the environment. For the purposes of discussion, these factors will be divided into two categories: anatomical and non-anatomical factors.

Anatomical factors that influence perimetry

Refractive error

In his article, Standardizing the Measurement of Visual Fields, Johnson noted the importance of using the appropriate lens correction during perimetric testing. Failure to use adequate correction can result in increased variability of fields, refractive scotomas, and a variety of spurious test results.4 Thus, the appropriate lens must be used to ensure that the patient clearly sees the stimuli. However, some investigators have noted a relationship between the magnitude of refractive error and a decrease in differential light sensitivity in specific areas of the visual field. In one series, 120 eyes of 86 patients with normal-tension glaucoma and 197 eyes of 138 patients with primary open-angle glaucoma underwent visual field examination using the 30-2 and 10-2 programs of the Humphrey visual field analyzer. All patients had clear ocular media, refractive error of less than +1.00 diopter (D), and no retinal abnormalities. Myopic power was noted to be significantly and positively correlated with a depression in sensitivity in the lower cecocentral area in eyes with normal-tension glaucoma, as well as in those with primary open-angle glaucoma. Interestingly, only eyes that carried the diagnosis of normal-tension glaucoma showed a statistically significant negative correlation with the depression in the upper arcuate area.5

Corallo and coworkers6 also noted the occurrence of perimetric defects which correlated with refractive error. In their study, they included highly myopic patients (myopia greater than or equal to 7 D) with or without glaucoma. Patients were examined using the 30-2 program of the Humphrey visual field analyzer. Defects that could be ascribed to myopia included modification of the blind spot, peripheral absolute defects, and modifications of perimetric indexes such as mean deviation, pattern standard deviation, and short-term fluctuation. (Mean deviation is a weighted average of deviations compared with a normal database. Pattern standard deviation (PSD) takes into account factors which may diffusely influence the hill of vision, and short-term fluctuation refers to the variation that may occur at individual points.)

These findings suggest that the refractive error, even if it has been properly corrected, can influence specific findings in the visual field.

Pupil size

Both pupillary dilation and pupillary constriction have been noted to influence the results of perimetric testing. Lindenmuth and coworkers7 examined the effects of pupillary dilation on automated visual field testing in 18 healthy volunteers. The subjects underwent baseline, non-dilated field testing, and dilated testing using the 30-2 program of the Humphrey visual field analyzer. The investigators noted that the mean deviation worsened by 0.83 dB (SD 0.92 dB) in dilated visual fields compared with baseline fields. This difference was statistically significant (p =

0.001). Mendivil8 reported a decrease in threshold sensitivities in glaucomatous patients whose pupils had been dilated; these patients were tested with the Octopus 1-2-3 perimeter using the G1X program. He noted a difference in the mean defect of 3.01 dB (SD 1.52), which was statistically significant (p < 0.001). The PSD and corrected pattern standard deviation (CPSD) were altered as much as 1.51 dB (p < 0.01) and 1.73 dB (p < 0.05), respectively. The peripheral field was more affected than the central field.

Constriction of the pupil can also affect automated perimetry. Lindenmuth et al.9 assessed this effect in 20 healthy volunteers. Patients underwent baseline testing and were then re-tested with 2% pilocarpine. The mean defect worsened by an average of 0.67 dB (SD 0.67 dB). These artifactual decreases are due to variations in the retinal profile, which can be as steep as -0.62 dB/degree for a 3-mm pupil versus -0.34 dB/degree for an 8-mm pupil.10 Thus, it is important to maintain a consistent pupil size throughout visual field testing, both during and between the tests.

Lens opacification

Given that glaucoma typically occurs in an aging population, it is no surprise that the influence of lens opacification on perimetry has been exhaustively evaluated in the medical literature. Some investigators have noted a lack of a change in visual field indexes after cataract surgery,11 while others have noted improvement in the mean deviation.12 It appears that some of the differences that have been reported are related to specific characteristics of the patients in the series. Lam et al.3 performed visual field testing using program 30-2 of the Humphrey visual field analyzer in 24 patients before and after cataract extraction. The mean defect improved from -6.14 to -2.22 dB. There was no difference in short-term fluctuation (1.43 versus 1.43 dB) and little difference in PSD (2.54 versus 2.66). Only the presence of posterior subcapsular opacification in the visual axis correlated significantly with postoperative central threshold recovery. Similarly, Smith et al.12 noted a mean improvement in mean deviation of 1.68 dB; however, there was a worsening of 0.54 dB in CPSD. Gillies and Brooks13 also noted a statistically significant improvement in mean deviation following cataract extraction, but there was worsening in the PSD. Chen and Budenz14 reported improvements in the foveal threshold and mean deviation, whereas the mean PSD and CPSD worsened.

The different results between the studies of Lam et al.,3 Smith et al.12 and Gillies and Brooks13 may be related to a greater number of patients with moderate to advanced glaucoma in the latter studies, as well as to a variation in the specific types of cataract. Results of the studies of Smith12 and Gillies13 suggest that there may worsening of glaucoma following cataract extraction.

On the other hand, in a series of patients reported by Stewart and coworkers,11 no difference was noted with regard to average mean defect, PSD, and total decibel loss among 24 consecutive patients who underwent cataract extraction. It is important to point out that these patients evidenced nuclear sclerotic cataracts. Nevertheless, it is surprising that the study by Stewart and coworkers11 failed to demonstrate a statistically significant change in mean deviation, particularly when considering the studies by Budenz, Feur and Anderson,15 who used a simulated cataract device to quantify the effect of lens opacification. Glaucomatous patients with relative scotomas and healthy individuals underwent testing using a lightdiffusing piece of ground glass, which was positioned in front of the eye during

168 E.J. Higginbotham et al.

testing. This glass resulted in a mean decrease in perimetric threshold of 5.7 dB (SD 3.3 dB) within the area of the relative scotoma, 6.1 dB (SD 2.4 dB) in the unaffected areas, and 4.4 dB (SD 2.25.dB) at the fovea. CPSD was not affected. Considering that no statistically significant difference was noted between these areas, the investigators concluded that the simulated cataract resulted in a diffuse reduction in sensitivity. Considering these findings, it may be that the study by Stewart et al.11 did not have an adequate number of patients to be able to detect a difference.

All the above-mentioned studies used full threshold testing programs, either the 24-2 or 30-2 of the Humphrey visual field analyzer. Costagliola and coworkers16 used the G1 program of the Octopus system, and noted that the presence of cataract influenced visual field indexes that correspond to diffuse loss of sensitivity. Visual field indexes such as loss variance and corrected loss variance were not greatly affected since these indexes are influenced more by local defects in the visual field. A population survey, the Blue Mountains Eye Study, failed to find a correlation between cataract and visual field loss. However, it is important to note that suprathreshold screening visual fields were used in this study, and that lenses were assessed using photographs. Thus, the level of sensitivity was possibly not present in order to adequately detect any influence that the lens may have had on the visual field.17

The influence of lens opacification was noted in the era before automated perimetry. Lyne and Phillips18 pointed out the difference in the effect on the visual field when the opacification is in the lens rather than the cornea. These investigators noted that opacities in the posterior layers of the lens result in defects in the visual field on the side opposite the opacification, as opposed to corneal opacities which cause defects ipsilateral to the opacification. Thus, both the lens and the cornea can influence the assessment of the visual field.

Other anatomical factors

Other anatomical factors include posture and dermatochalasis. Recognizing that the body position can influence blood flow in the optic nerve head, Lietz and coworkers19 evaluated the influence that posture may have on the visual field. They noted that, among patients with either highor low-tension glaucoma, there was a deterioration in the visual field when patients were tested in the sitting position, which was not present when patients were in the supine position, or in controls. There are probably few clinicians who perform perimetry with patients in the supine position. However, practitioners should be aware that some patients may have an alteration in their ocular blood flow due to other reasons, and that this alteration can influence the visual field.

Dermatochalasis is a common occurrence in the aged population of patients with glaucoma. Fifteen visual fields of nine ocular hypertensive patients were evaluated and noted to poorly correlate with the clinical examination of the patients. Visual field testing was repeated either after the patient’s upper eyelid had been taped, or following blepharoplasty, and the spurious defects were noted to disappear. All the defects were superior in location. Thus, it is important for either the clinician or the technician, or both, to recognize the potential confounding factor of dermatochalasis and to consider taping the eyelid before perimetric testing.20

Non-anatomical influences on perimetric testing

In an editorial, Colm O’Brien21 noted that the “single most important factor influencing the quality of the visual field examination, and yet largely ignored by current perimetric software, is the interaction of the nature of the patient response with the demands of the examination procedure.” He mentioned motivation and anxiety as being contributing factors to performance. These ‘soft’ factors may be difficult to quantify; however, reasonable investigations have addressed factors such as patient experience, supervision, and drugs. Other factors that will be discussed here include lens holder, stimulus size, and diabetes.

There has been greater appreciation in recent years of the importance of perimetric experience in patients with and without glaucoma. Twenty-five naive patients underwent visual field testing five times at one-week intervals in one study. With repeated testing, visual field results improved in 21 of 37 eyes. Means of mean deviation improved significantly by 2.81 dB (p < 0.001) between the first two tests. However, when the improvement over tests 2 through 5 was quantified, it was difficult to measure any significant difference. The investigators noted a learning effect that was greater peripherally compared to centrally. They also noted that points with greater sensitivity improved more than ‘disturbed’ points did. Thus, confirmatory testing is very important.22

It is important to note that early disturbances at any given point in a visual field may indicate early progression of glaucoma. Werner and Drance23 examined 22 eyes of 22 patients, in whom visual field defects developed after they initially had normal field test results. In 13 of these patients, there was a disturbance in the visual field before development of the defects. This is in marked contrast to only six of 22 eyes with ocular hypertension that demonstrated disturbances. However, the challenge that clinicians face is distinguishing between fluctuation of the visual field and actual disease-related change in the field.

The potential influence of a patient’s fatigue on perimetric results cannot be underestimated. Two studies deserve mention. With the use of a customized 30point central threshold visual field program, 38 healthy subjects were repeatedly tested, three times in each eye with tests separated by two weeks. The investigators noted a decrease in mean sensitivity of 2.0 dB whenever the second eye was treated, suggesting a greater fatigue effect when the second eye was tested compared with the first eye.24 Gonzalez de la Rosa and Paraja25 examined healthy subjects as well as glaucomatous and ocular hypertensive patients. Patients with glaucoma and ocular hypertension showed a longer testing time compared with healthy subjects. The former group required 13.88 ± 1.25 minutes versus 13.26 ± 2.91 minutes for the control group. This study used a modified Delphi program on the Humphrey visual field analyzer, which made it possible to register consecutive measurements of mean deviation. In the abnormal eyes, there was a decrease of 2.98 dB on average from the beginning to the end of the test, compared with normal eyes in which there was a decrease of 2.22 dB. This finding suggests that the decline was not related to the severity of the visual fields, but it was noted that age was a more important factor than the severity of the defects. In reviewing the guidelines for ensuring the validity of visual fields, Johnson underscored the importance of allowing the patient to rest for five to 15 minutes if fatigue appeared to be playing a factor in the perimetric results.4

One sign of fatigue can be fixation loss. However, Henson and coworkers26

determined that fixation losses, although contributors to variability, do not significantly affect increased variability at locations where sensitivity is reduced. Thus, variability is likely attributed to several factors besides the number of fixation losses.

Some investigators have emphasized that the performance of visual fields according to strict protocols, as is done in clinical trials, should be supervised by certified ophthalmic technicians.4 However, a study by Van Coevorden and coworkers27 noted a benefit associated with supervision only when there were risk factors present for unreliable perimetric results. The investigators noted these risk factors to be advanced age, a low level of formal education, and previous results with high false positives and false negatives. Given the difficulty in determining a patient’s level of risk of an unreliable visual field result on the first visit, it is reasonable to consider supervision of all patients, rather than only a subset. Supervision can only help those patients undergoing perimetry, even patients who do not have risk factors for unreliable visual field results.

Other factors that may be influence perimetric results include the size of the stimulus,28 lens holder,29 diabetes,30 and alcohol and drug use.31,32 When patients with glaucoma were tested with stimuli ranging from I to V, Wall and coworkers28 noted that testing with stimulus V resulted in less variability in the visual fields compared to dimmer stimuli. These investigators noted a standard deviation of only 1-2 dB centrally versus 4-6 dB in the periphery (27°). Donahue29 noted a mild cecocentral depression in the visual field, which was related to an ill-positioned lens holder. Zucca et al.30 reported depression in the inferior temporal quadrant in diabetic patients compared to glaucomatous patients. Investigators failed to note a change in differential light sensitivity or short-term fluctuation when patients were under the influence of either alcohol31 or diazepam32 while undergoing testing with the Octopus 201 perimeter. The results of these studies differed from studies performed with the Humphrey perimeter (San Leandro, CA).

In another study, patients were tested after receiving either alcohol or triprolidine, an antihistamine that can depress the central nervous system, and their visual fields were adversely affected.33 In their review, Zulauf and Caprioli34 noted that the difference between these studies may be due to the perimeter. Since the Octopus presents its stimuli following a click, the patient receives warning. Therefore, even a subject who is inebriated may be able to ‘game’ the program and stay alert throughout the study. The Humphrey perimeter, on the other hand, does not give a click before presenting the stimulus.

Variability of fields

Regardless of whether the factors that influence the reliability of visual fields are anatomical or non-anatomical, the result of these factors is a visual field test that does not necessarily provide an indication of disease progression, but instead a reflection of ‘noise’ in perimetric testing. The challenge to the clinician is to determine the difference between the two phenomena.

The variability of visual fields has been assessed by several investigators. Wilensky and Joondeph35 tested 12 eyes of six normal volunteers with the 30-2 program of the Octopus 201 perimeter. These subjects were tested on four separate occasions during a four-week period. This testing was preceded by at least two

practice sessions in order to minimize a learning effect. In 11 of the 12 eyes, at least one of the 76 points tested in the visual field varied more than 4 dB between tests. Three of the 12 eyes showed adjacent points with a variance of 4 dB. This latter finding is significant, considering the importance of defining a relative scotoma based on the depression of adjacent points in a visual field.

Also using the Octopus 201 perimeter, but with the G1 program, Boeglin et al.36 assessed the long-term fluctuation of visual fields in patients with glaucoma. They examined 756 automated threshold fields of 167 eyes. These investigators discovered a strong relationship between the magnitude of fluctuation and sensitivity. When the initial sensitivity was 25-30 dB the 5th-95th percentile value for subsequent measurements was ±4 dB. When the initial sensitivity was 15 dB or less, the 90% range of subsequent values was a large magnitude, zero to near normal values. Boeglin et al.36 separated their cohort into two groups: patients with stable and unstable glaucoma. It was noted that mean fluctuation, as measured by the mean of the individual pointwise variances, was 7.0 dB2 in the stable group and 9.7 dB2 in the non-stable group. Moreover, there was greater fluctuation in the points as eccentricity increased.36 Similarly, Heijl and coworkers37 noted that variability was lowest in the most central visual field and at points that were initially normal on testing. This study was conducted in glaucomatous eyes using the 30-2 program of the Humphrey visual field analyzer. Zulauf and Caprioli34 noted that long-term fluctuation at a single test location generally increased by 0.2 dB for each 1-dB decrease in sensitivity. Because of the degree of fluctuation noted in these studies, it is important to base the assessment of either abnormality or progression on more than one visual field.

The importance of performing a confirmatory visual field test has been addressed in the medical literature. Katz and coworkers38 defined field loss in three different ways within a cohort of patients who underwent annual visual field testing for a period ranging from five to nine years. When incident field loss was defined as one or more normal fields followed by an abnormal field, the incidence of field loss was 63.6 per 1000 person-years of follow-up. This ratio was reduced when either two (27.6 per 1000 person-years of follow-up) or three visual fields (19.2 per 1000 person-years of follow-up) were used as the definition. For those patients who had one, two, and three consecutive abnormal results with the glaucoma hemifield test at the beginning of the study, 59.2%, 83.6%, and 89.1%, respectively, had an abnormal field three years later. In a series of normal, ocular hypertensive individuals, and patients with glaucoma, specificity was improved if two rather than one test were required. For example, when two tests were used to establish a normal visual field among ocular hypertensive individuals, specificity increased from 84.2 to 89.5% for one test versus two tests, respectively.39

In an effort to quantify visual field data and to provide the clinician with potential predictors of glaucoma field loss, indexes such as mean deviation, CPSD, and the glaucoma hemifield test have been developed. As mentioned earlier, the mean deviation, which is age-adjusted, is a weighted-average of deviations compared with a normal database. CPSD takes into account the variation that is inherent in normal subjects. An estimate of variation of the test locations is made, and adjustments are considered for measurement error. The glaucoma hemifield test compares groups of selected locations above and below the horizontal meridian. Visual fields that fall outside the specified p value, based on a prediction model derived from normal data, are considered abnormal.40

Indexes for reliability also have been developed: fixation losses, false negatives, and false positives. The blind spot is mapped near the beginning of the test, and throughout the test, stimuli are presented within the mapped blind spot. If the individual responds to the stimulus, a fixation loss is registered. At other times during the test, the machine will prepare to project a stimulus, but does not do so; if the patient responds nonetheless, then a false-positive response is registered. Alternatively, if a stimulus is presented in an area that previously yielded a response from the patient, and the patient fails to respond, a false-negative response is registered. Usually, test results are flagged as unreliable if the fixation losses are 20% or greater, or if the false-positive and false-negative rates are 33% or greater. In one series, patients with glaucoma were more likely to have unreliable visual field test results than were healthy individuals; the tests were performed using the 30-2 program of the Humphrey visual field analyzer. There was a higher degree of rejection among patients with glaucoma, due to the number of false-negative responses.41 Bickler-Bluth and coworkers42 also used the Humphrey 30-2 program to examine visual fields at baseline, and at six and 12 months, in 120 patients with established ocular hypertension. These investigators noted that 35% of patients exhibited low reliability field test results at baseline. This number decreased to 25% by 12 months. Fixation losses greater than 20% were the major reason for the unreliable results of full threshold tests. Substantial defects were identified more readily using CPSD than with mean deviation. The authors concluded that raising the fixation loss error to 33% would reduce the number of unreliable fields without sacrificing, to any great extent, the sensitivity or specificity of the perimetric test. Thus, these quantitative indexes can be helpful, but must be judged within the context of the experience of the patient, the probable diagnosis, and the appropriateness of the index.

Importance of clinical evaluation

Considering the high degree of variability of perimetry, the clinical examination of the patient is important. From the history of the patient, including family history and consideration of topical and systemic medications, to a careful examination of the optic nerve, the clinician needs to consider the relevance of an initial abnormal result of automated perimetry within the context of the entire scope of available clinical data. Considering that optic nerve damage can occur before evidence of perimetric defects,43 the optic nerve provides not only objective evidence of nerve damage, but also important evidence of early glaucoma. However, even this objective measure must be judged within the context of systemic disease and heredity. Because of the diurnal variation of intraocular pressure and the influence of corneal thickness and astigmatism on the accuracy of applanation tonometry,44,45 the pressure within the eye should be repeatedly and appropriately measured. It is also necessary to consider patients who have elevated intraocular pressure but never experience glaucoma, as well as those patients who never have elevated intraocular pressure but in whom glaucoma does develop. Neither intraocular pressure, perimetry, nor the optic nerve can be judged in isolation.

Rationale for the study

The unreliability of visual fields is a challenge for both the patient and the practitioner. In an era of managed care, it is particularly challenging to wrestle with a series of unreliable visual field test results when attempting to make the diagnosis of glaucoma. Insurance carriers will limit the number of field examinations that can be performed, and when subsequent field examinations are performed, the reimbursement is below the cost of performing these tests.

Much progress has been made within the last three years in automated perimetry, and the introduction of a perimetric device using frequency doubling technology (FDT) offers a portable and easy method to screen for perimetric abnormalities. However, it is unclear whether this device can be used as a method to train patients before they undergo their first automated test, or to reintroduce them to automated testing after a long gap. Zulauf and Caprioli34 noted that the first visual field result may often need to be eliminated and considered a ‘practice field’.38 Werner and colleagues39 did not note a learning curve when 20 glaucomatous patients underwent automated testing. These patients had previously been tested with manual perimetry.

Thus, the question arises as to whether FDT can be used as a method of improving the reliability of initial visual field results. If this is possible, it would be feasible for patients to undergo FDT testing in the waiting room of a practice, or elsewhere as part of a screening program, before undergoing threshold testing.

Methods

This study was approved by the Institutional Review Board of our Institution. Patients were recruited from the glaucoma division of our ophthalmology department over a two-year period, 1998-1999, and were included in the study regardless of their diagnosis. Inclusion criteria included no prior perimetric experience or no visual field testing for more than two years before the study. Patients were excluded if a Humphrey visual field threshold test had been performed within the preceding two years. A list of randomized assignments was generated and technicians were instructed to consecutively assign patients to the list. Participants were randomized to one of two groups: 1. FDT before threshold testing, or 2. no FDT testing before threshold testing. Patients underwent testing using either SITA-stan- dard or full threshold testing using the Humphrey visual field analyzer (San Leandro, CA). Patients were tested using either the 24-2 program or the macula threshold, if the glaucoma was extremely advanced. The right eye was always tested first, and the technician remained in the room at all times. All subjects underwent a comprehensive ophthalmic evaluation, which included history, measurement of visual acuity, examination of the pupils, slit-lamp examination, gonioscopy, and dilated fundoscopic examination. A subset of patients underwent optic nerve fiber analysis using the GDx nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) as part of a comprehensive ophthalmic evaluation.

Student’s t test, or Wilcoxon rank-sum test, the non-parametric equivalent of the t test, were used to compare continuous variables. Fisher’s exact test was used to compare categorical variables.

Results

Initially, 66 patients were listed on the randomization list. Some patients were included non-consecutively and others had been added from a previous protocol. This previous protocol enrolled patients who had undergone FDT before threshold testing. This group was further refined as follows: There was one line which was not assigned to a patient, three lines which contained names of patients already listed (duplicates), and six patients were ineligible because they either underwent FDT testing after the Humphrey visual field test or had undergone a Humphrey visual field threshold test within two years of entering the study. Thus, 56 individuals were included in this non-randomized group.

A second group of 19 individuals was randomized as the study was initially designed. Two patients were eliminated, one due to a lost medical chart, and the other to the patient’s departure before completing the visual field examination. This group of 17 patients was labeled the randomized group (Table 1). Thus, a total of 73 individuals was included in the study. The age range for the entire group was 11-89 years. All but two patients were tested using the 24-2 software program in both eyes. One patient underwent testing with the 24-2 program in one eye and the macula threshold program in the fellow eye. One other patient underwent testing using the macula threshold program in both eyes.

The non-randomized and randomized groups were compared with regard to

Table 1. Comparison of randomized and non-randomized groups

*SITA indicates Swedish interactive threshold algorithm. Time is given as seconds (minutes). ** Student’s t test.

age, total testing time, pupillary diameter, mean deviation, PSD, false positives and negatives. All parameters were analyzed for right and left eyes separately. There was no significant difference between the groups, except for testing time in the right eye (p = 0.0195). There was a statistically significant association (p = 0.026) between the type of visual field test and the non-random versus random group. Of the 21 individuals who had a full threshold Humphrey visual field analyzer, 20 were in the non-random group. Thus, this difference most likely accounts for the longer time for Humphrey visual field testing in the non-random compared to the random group. Because of the similarities in the non-random and random groups, both groups were combined for further analyses.

Of the 73 patients in the study population, 35 (47.9%) underwent FDT testing first and 38 (52.1%) underwent Humphrey visual field testing only. Overall, 21 (29%) of the patients underwent full threshold testing, 51 (70%) had SITA-standard testing, and one (1.4%) underwent SITA testing in the right eye and full threshold testing in the left.

Overall, the group demonstrated reliable visual field results. When the number of fixation losses, false positives, and false negatives is examined, the percentage of patients with no misses in any category is remarkable (Table 2).

Comparison between full threshold and SITA tests demonstrated a statistically significant difference in the mean time to complete the two tests. SITA test took an average of 6.4 minutes in the right eye compared to 10.8 minutes for the full threshold (p = 0.0001). Similar results were found in the left eye (Table 3).

The reliability variables, i.e., fixation losses, false positives, and false negatives, were examined separately for the SITA and full threshold tests. During full threshold testing with the Humphrey 24-2 program, there was no difference between the

*HVF indicates Humphrey visual field; FDT, frequency doubling technology; Sens, sensitivity; Spec, specificity; and SITA, Swedish interactive threshold algorithm.

** For the right eye, only three people were in the full threshold, no FDT (Humphrey visual fields only) group. For the left eye, only four people were in the full threshold, no FDT group.

FDT-first group and the Humphrey visual field-only group. Neither was there a difference within the SITA group when we examined the FDT-first group compared to the no-FDT group for the right eye. There was no difference between groups for fixation losses or false negatives for the left eye. However, there was a statistically significant difference between groups for false positives regarding the left eye (p = 0.04).

We categorized the false-negative and false-positive variables as being reliable if there were no misses when the points were tested. If there was even one miss, the variable was considered ‘unreliable’. When the eyes that received full threshold testing were examined, there was no association between reliability variables and group for either the right or left eyes using a two-tailed Fisher’s exact test. With regard to SITA-standard, there was no association between reliability variables and group for the right eye. However, for the left eye, there was an association between false-positive rate and group (p = 0.04). Of the 21 subjects with SITA tests who had FDT first, 13 (62%) had reliable results. Of the 28 subjects with SITA tests but no FDT, only eight (29%) had reliable results. There was no association between false-negative rate and group for the left eye.

Forty-three (59%) of the individuals underwent optic nerve fiber analysis using GDx (Laser Diagnostic Technologies, San Diego, CA). GDx was considered normal if the neural net number was less than or equal to 30. A neural net number greater than 30 was considered abnormal. For the purposes of this analysis, we considered GDx as the gold standard, and defined the visual fields as abnormal based on the glaucoma hemifield test. Thus, we can determine that, when FDT was performed first among patients who underwent SITA, there was a trend towards greater sensitivity for both eyes. However, the specificity was poor. This trend was also noted when all fields were grouped together, but no such advantage was seen for

*SITA indicates Swedish interactive threshold algorithm.

the full threshold fields. It should be noted that the number of patients who underwent both full threshold field testing and optic nerve fiber analysis was very small. For the right eye, only three eyes were in the full threshold group with no FDT and for the left eye, only four eyes were in the full threshold group with no FDT (Table 4).

With the current sample size, we were able to detect differences between the means for mean deviation, and differences between proportion for the number of false positives and false negatives at the levels of power indicated in Table 5. This analysis was carried out for three categories of data: all visual fields, SITA subset, and full threshold subset.

Conclusions

This study did not show a clear advantage in performing FDT before threshold testing. However, there appeared to be a trend in favor of the FDT group, but this trend did not achieve statistical significance (Table 4). Nevertheless, the study did

reaffirm the findings of other studies, such as the reliability of SITA fields and the shorter testing times for SITA fields compared to full threshold testing.

As noted, a significant number of reliable visual field results were obtained. Using a lofty criterion of no misses for reliable field results, our data indicate that a large number of patients achieved this goal, ranging from 38.0-52.9%. The high degree of reliability could be related to the large proportion of visual fields performed with SITA. As mentioned earlier, SITA fields have been shown to demonstrate less inter-subject variability than full threshold fields.40 Moreover, when examining those patients who underwent SITA testing, a greater percentage of patients who underwent FDT first showed reliable results compared to no FDT. This finding may suggest a positive effect related to prior FDT testing. However, our current sample size may not be sufficient to detect small differences in the reliability parameters. Furthermore, it is of interest that the left eyes for each of the parameters tended to demonstrate higher values than the right eyes. Because the left eye was always tested second, this improvement may be related to a very small learning effect. Other investigators2,28 have noted the improved performance of the second eye.

The results of this study, as of others, demonstrated shorter testing times for SITA compared with full threshold testing. In the right eye, there was a reduction of 40.7% compared with full threshold testing, and 42.9% for the left eye. This reduction is greater than that described in previous reports. The difference is probably related to two factors: 1. Ours was a naive patient population and the calculations were only based on the initial visual field. 2. The socioeconomic mix of this study population may differ from other reported studies.

This study aimed to determine whether testing with FDT before automated perimetry provided a greater level of ‘inferred validity’ to initial automated field testing. The measure by which a ‘gold standard’ is determined in glaucoma is often difficult, given the difference in opinions that clinicians may have regarding the assessment of the optic nerve and nerve fiber layer. Thus, the GDx nerve fiber analyzer was arbitrarily chosen as a ‘gold standard’ to assess the sensitivity and specificity of these visual fields. The GDx can suffer from its own set of artifacts.51,52 However, at least it offers an unbiased estimate of the nerve fiber thickness which could be an indication of glaucoma.

In order to determine whether FDT may reduce the length of the learning curve, patients would need to undergo serial visual fields. Given that SITA testing results in less intersubject variability compared to other programs,40 a greater number of patients would have to be recruited in order to detect even smaller differences between groups, as noted previously. SITA testing has provided the profession with a shorter version of this tedious test, and it may be that serial testing using this program will demonstrate a reduced learning effect which has not been experienced previously with full threshold testing.

In conclusion, perimetric testing remains an ongoing challenge for patients and clinicians. However, SITA has provided patients with welcome relief from the long testing times associated with full threshold testing. Future studies will need to correlate confirmatory SITA testing with clinical findings before we can be sure that this algorithm offers a greater level of inferred validity compared to full threshold testing. Nevertheless, perimetric testing, because of its subjective nature must always be considered in the context of both anatomical and non-anatomical influences on its accuracy. Until more objective measures are available, the importance of a carefully performed clinical evaluation remains paramount.

Acknowledgment

This study was supported in part by an unrestricted grant from Research to Prevent Blindness (New York, NY).

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27.Van Coevorden RE, Mills RP, Chen YY, Barneby HS: Continuous visual field test supervision may not always be necessary. Ophthalmology 106:178-181, 1999

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29.Donahue SP: Lens holder artifact simulating glaucomatous defect in automated perimetry. Arch Ophthalmol 116:1681-1683, 1998

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40.Hilton S, Katz J, Zeger S: Classifying visual field data. Statistics in Medicine 15:1349-1364, 1996

41.Katz J, Sommer A: Reliability indexes of automated perimetric tests. Arch Ophthalmol 106:1252-1254, 1988

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48.Bengtsson B, Heijl A: Evaluation of a new perimetric threshold strategy, SITA, in patients with manifest and suspect glaucoma. Acta Ophthalmol Scand 76:268-272, 1998

49.Bengtsson B, Heijl A, Olsson J: Evaluation of a new threshold visual field strategy, SITA, in normal subjects. Acta Ophthalmol Scand 76:165-169, 1998

50.Bengtsson B, Heijl A: SITA Fast, a new rapid perimetric threshold test: description of methods and evaluation in patients with manifest and suspect glaucoma. Acta Ophthalmol Scand 76:431-437, 1998

51.Shirato S, Inoue R, Fukushima K, Suzuki Y: Clinical evaluation of SITA: a new family of perimetric testing strategies. Graefe’s Arch Clin Exp Ophthalmol 237:29-34, 1999

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Round table

Visual field

Eve J. Higginbotham, MD, presiding

Panel: Alan S. Crandall, MD

George A. (Jack) Cioffi, MD

Dr Higginbotham: Maybe I could pose a question to the other panelists while we are waiting for questions from the audience. Do you have a preference in new patients for using the 24-2 SITA-standard or SITA-fast? What are you using in your practice, Alan?

Dr Crandall: I use the SITA-standard.

Dr Cioffi: We mentioned this yesterday. I use SITA-standard as well. Harry Quigley said he was using SITA-fast as his initial test, which surprised me. Again, I don’t think the time saving is that great over SITA-standard, and the variability goes up.

Dr Higginbotham: I guess one of the things I didn’t mention about the SITA-stan- dard in terms of the difference between standard and fast is that the SITA-stan- dard will threshold selective points if they fall outside the predicted range of error, whereas with the SITA-fast, you are going to miss that opportunity. So, like my two colleagues, I use the SITA-standard as my first field.

Question from the audience: I wanted to ask the panel if there were studies to show an increased variability with higher refractive errors. I was interested in that because, for a number of years having very liberal access to disposable contact lenses, I frequently put, as I mentioned once to Eve, contact lenses on eyes with higher refractive errors, and it seemed to me that it increased the accuracy of the Humphrey full threshold.

Dr Cioffi: With Humphrey full threshold you have to correct high refractive errors. It doesn’t tolerate much in the way of blur and you also have to correct for the testing distance in a presbyopic patient, and probably what you were eliminating were optical aberrations of the periphery of lenses with a contact lens on.

Dr Higginbotham: Yes, I remember our conversation. That was over a decade ago, I think. Certainly, as I reviewed the literature, particularly of myopes, it makes a big difference, and in this one particular study that I referenced, the magnitude

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was extraordinary. I have a question for the audience. How many people, if any out there, have listened to all these lectures about SITA and SWAP and are leaving confused about which test you are getting in your own offices?

We have a question from the audience. Many patients with multiple reproducible standard automated perimetry test defects appear to improve markedly when switched to SITA-fast. What is the cause, and how can they be followed? Do you need to switch back to standard testing in these patients?

Dr Cioffi: I would. I think this is exactly what we were talking about earlier. If you have an abnormality – I get a lot of referrals based on SITA-fast because there are weird changes on it and it is a variability factor. You have more variability and the best referral is the old Fastpac, because it was used all over the place. It was quick, but it was just so variable that, from time to time, you could get almost anything, and so it is that function that I talked about. If the test time goes down, the variability generally goes up.

Dr Higginbotham: I only use the SITA-fast in those instances in which I am getting very variable fields on the SITA-standard. If I have an elderly patient, then I will switch to the SITA–fast. Fastpac is similar to the SITA-fast and I consider the SITAstandard in the same ballpark as the full threshold. So, I think I would use the SITA-fast as an exception to the rule.

Dr Cioffi: Some patients can’t take fields. Some of the patients we see, we just mark on their charts, “don’t give fields”. Some patients are simply incapable of it, and you have to follow them with other parameters.

Dr Higginbotham: In those patients, I just follow as if they were babies, disc photos and periodic exams, but mostly disc photos.

Update on perimetry

New developments

Chris A. Johnson

Discoveries in Sight/Devers Eye Institute, Legacy Health Systems, Portland, OR, USA

Introduction

In recent years, there have been a number of advances in perimetry and visual field testing. Most of these new developments have been directed toward two primary areas: 1. test procedures that are more sensitive and are therefore better able to detect pathological changes in the visual pathways, and 2. efficient test strategies that are able to obtain the same amount of information as conventional test procedures, but in a fraction of the time. This chapter provides a brief review of a new efficient test strategy, the Swedish Interactive Threshold Algorithms (SITA), as well as two new perimetric test procedures, Short Wavelength Automated Perimetry (SWAP) and Frequency Doubling Technology (FDT) perimetry. Additionally, it will briefly discuss methods for detecting progression of visual field loss, which is currently one of the major challenges in the management of glaucoma patients.

The Swedish Interactive Threshold Algorithms

The objective of conventional automated perimetry is to provide valid, reliable visual field information within a reasonable time period. Although the staircase procedures originally designed for conventional automated perimetry were able to provide high quality information, these test procedures are rather time-consuming. In addition to taxing clinical resources, long perimetric testing times result in greater errors and variability on the part of the patient, as well as sensitivity reductions due to fatigue. It is possible to make staircase procedures more efficient (such as the FASTPAC procedure), but only at the expense of increased variability.1

The family of Swedish Interactive Threshold Algorithms (SITA) were designed to provide more efficient threshold testing strategies while maintaining the same

Address for correspondence: Chris A. Johnson, PhD, Discoveries in Sight/Devers Eye Institute, Legacy Health Systems, 1040 NW 22nd Avenue, Portland, OR 97210, USA.

e-mail: CAJohnso@discoveriesinsight.org

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edited by Jonathan Nussdorf

© 2003 Kugler Publications, The Hague, The Netherlands

accuracy and reliability of conventional test procedures. SITA-standard was designed to replace the Full Threshold test procedure and SITA-fast was designed to replace FASTPAC. Recent investigations have verified that SITA-standard and SITAfast are 35-50% faster than their Full Threshold and FASTPAC counterparts, respectively, while maintaining equivalent accuracy and reliability characteristics.2-8

The SITA strategy is based on Bayesian statistics that are used as part of a maximum likelihood estimation procedure to provide forecasting of threshold sensitivities for individual visual field locations. For readers interested in obtaining more detailed information, Vingrys and Pianta9 have published an excellent overview of the application of maximum likelihood techniques for threshold determinations in automated perimetry.

The SITA strategy consists of three main components: 1. probability density functions (pdfs) at each visual field location for normal and glaucomatous visual fields; 2. likelihood functions, also known as frequency-of-seeing curves; and 3. neighborhood analysis of visual field results for locations surrounding each visual field location. A probability density function (pdf) is essentially a frequency distribution of threshold sensitivity values at a given visual field location for the population at large. For example, Figure 1 presents an illustrative example of a pdf for normal persons (age-adjusted) for an individual visual field location. In this example, a sensitivity of 34 dB is the most frequent value found in the normal population. Progressively higher and lower sensitivity values become successively less frequent. The frequency of sensitivity values higher than 39 or lower than 29 is very low. Typically, a maximum likelihood procedure begins testing at the mean value of the a priori pdf, which in the illustrative case presented in Figure 1 would be 34 dB. For example, if the stimulus is seen, then threshold is most likely to be in the upper portion of the distribution. The lower portion of the distribution is truncated (except for a small allowance for false positive responses), and a revised pdf is generated by multiplying the adjusted distribution by a likelihood function (frequency of seeing curve). This revised distribution is then used to establish the value of the next stimulus presentation. The process continues until there is a small interval between the upper and lower bounds of the revised pdf distribution. It can readily be appreciated that this method is capable of producing an accurate estimate of threshold within a few presentations.

The primary difference between SITA-standard and SITA-fast is that SITA-fast accepts a greater amount of error in the threshold estimate than SITA-standard, and therefore a fewer number of stimulus trials are needed to establish the threshold estimate. Upon completion of the test procedure, each location is compared to its immediate neighbors and a final adjustment of the threshold estimate is made on the basis of these comparisons.

SITA is currently limited to programs 10-2, 24-2, 30-2 and 60-4 on the HFA II (700 series) and can only be used with white, size III stimuli. Threshold sensitivity values obtained by SITA are analyzed by the internal statistical package, STATPAC,6 in the same manner as the traditional Full Threshold staircase strategies. STATPAC has been revised such that patients tested with SITA are compared with normative SITA data from 330 age-corrected individuals.7 For each test location and global index, STATPAC indicates when the patient has a low probability of falling within the normal range.

Single field analysis printouts derived from SITA examinations are highly similar to those from Full Threshold and FASTPAC examinations and are presented in

SENSITIVITY (dB)

Fig. 1. An illustrative example of a normal probability density function (pdf) for an individual visual field location. In this example, the mean of the pdf is 34 dB.

the same format. An example of the printout for SITA-standard is shown in Figure 2 for a glaucoma patient with superior visual field loss. SITA-fast results for the same eye are presented in Figure 3.

The benefits of shorter test times and less fatigue provided by using SITA make it highly suitable for routine clinical use, both for defect detection and for monitoring progression. Although longitudinal clinical trials are still required to validate SITA’s performance for monitoring progression, the results of such investigations are likely to be positive.

The differences in accuracy and reliability between SITA-standard and SITAfast should be considered when deciding on their use. SITA-fast appears suitable for populations likely to be predominantly normal, or where traditional perimetry tests may be too difficult. However, if diagnosis and monitoring of visual field loss are most important, the greater accuracy and reliability of SITA-standard is probably desirable.

How do we go about comparing new SITA results to previous findings using the traditional staircase test strategies? Comparisons among visual field test results are always the most informative when all tests are performed using the same strategy. For this reason, when attempting to identify progressive loss, it is inappropriate to switch back and forth between staircase and SITA strategies, or between SITA-standard and SITA-fast. It has been suggested that comparisons based on pointwise total and pattern deviation probability plots, rather than decibel values, may be employed for comparing the results obtained with SITA to those acquired using traditional staircase strategies, although establishing a new baseline is the most desirable alternative.10 The time to switch test strategies and establish a new baseline is when the patient’s visual field appears to be stable. If the patient’s recent visual field history suggests that there is progressive loss or visual field results are unstable, it is not a good time to change testing strategies.

Fig. 2. An example of the printed output for SITA-standard. Results for the right eye of a patient with superior glaucomatous visual field loss is presented.

Fig. 3. An example of the printed output for SITA-fast for the same eye as that shown in Figure 2.

190 C.A. Johnson

Short Wavelength Automated Perimetry

Short Wavelength Automated Perimetry (SWAP) uses a bright yellow background and a large (Goldmann size V) blue stimulus to isolate and measure the sensitivity of the short-wavelength-sensitive (blue) visual pathways. The bright yellow background suppresses the sensitivity of the middle (green) and long (red) wavelength mechanisms and permits the sensitivity of the short wavelength sensitive mechanisms to be evaluated. Using the optimum stimulus conditions for SWAP (implemented on the Humphrey Field Analyzer II – Model 750), approximately 17 dB of isolation of the short-wavelength-sensitive pathways can be achieved.11 These optimal stimulus conditions consist of a 100 cd/m2 (315 asb) yellow background (Schott OG 530 filter) and a size V blue stimulus (Omega 440-nm interference filter). Several investigators have reported that isolation of short-wavelength-sen- sitive mechanisms is maintained over the entire operating range of SWAP, even in areas of severe glaucomatous visual field loss.12,13

Large scale prospective longitudinal evaluations conducted at two independent laboratories have shown that SWAP losses in glaucoma are larger and progress at a greater rate than conventional automated perimetry deficits. In patients at risk of developing glaucoma, SWAP losses appear earlier than standard visual field defects and are predictive of future glaucomatous visual field loss that develops for conventional automated perimetry.16,18 SWAP deficits can be detected approximately three to five years prior to the development of visual field loss with conventional white-on-white perimetry. Results from these and other laboratories confirm that SWAP provides the earliest and most sensitive indication of glaucomatous visual field loss. SWAP deficits have also been reported to be correlated with glaucomatous optic disc abnormalities and retinal nerve fiber layer losses early in the glaucomatous disease process.

An example of SWAP’s earlier detection of glaucomatous visual field loss is shown in Figure 4, which presents a comparison of conventional automated perimetry (top) and SWAP (bottom) in the right eye of a glaucoma suspect over a fiveyear period of time. For both tests, locations with normal sensitivity are indicated by open circles, locations with sensitivity lower than the normal 5% probability level are shaded gray, and locations with sensitivity below the normal 1% probability level are solid black circles. It can be observed that a SWAP deficit in the form of a superior nasal step begins to appear in year 1 and then progresses over the next four years. Conventional automated perimetry results begin to show the appearance of the superior nasal step about four years after it appears for SWAP.

Progression of glaucomatous visual field loss occurs more rapidly for SWAP than for conventional automated perimetry. An example of standard (white-on- white) and SWAP perimetry results obtained over a five-year period in the right eye of a patient with progressive glaucomatous visual field loss is presented in Figure 5. For SWAP, superior and inferior defects are present in year 1 and progress rapidly over the next four years. For standard automated perimetry, the defect appears in year 3 and then progresses more gradually in years 4 and 5.

An example of the printed output for SWAP on the Humphrey Field Analyzer II Model 750 is presented in Figure 6. Similar to conventional white-on-white automated perimetry, SWAP results present the sensitivity values in dB, a gray scale representation of test results, total and pattern deviation probability plots, visual field indices, reliability indices and other relevant information. When assess-

ing a SWAP visual field for evidence of an abnormality, we should direct more attention to the probability plots than to the gray scale, because the gray scale for SWAP has not been optimized.

In addition to its utility in glaucoma patients and glaucoma suspects, SWAP has also been reported to be useful for evaluation of various types of retinal dis- ease,39-41 optic neuropathies other than glaucoma,42 and chiasmal and post-chiasmal lesions.42,43

As with all perimetric test procedures, there are some difficulties associated with SWAP. One problem is that normal age-related yellowing of the lens and early cataract development decrease the amount of short wavelength light that is transmitted to the retina. Moss and associates44 evaluated a group of patients with cataract and age-matched normal subjects with SWAP and standard automated perimetry (SAP). Patients with anterior cortical cataract showed slightly greater amounts of sensitivity loss for SAP than for SWAP, patients with posterior subcapsular cataract demonstrated greater losses for SWAP than for SAP, and nuclear cataract produced similar sensitivity reductions for both procedures.

These results can be accounted for on the basis of differences in stimulus size and background luminance for conventional automated perimetry and SWAP. SAP uses a small (Size III) target and a relatively low background luminance (10 cd/ m2). Under these conditions, the pupil size becomes larger, allowing peripheral anterior cortical opacities to produce their maximal effect. In addition, contrast reductions from scattered light affect the detection of small targets more than large targets. These two factors can account for SAP being more affected by anterior cortical cataract than SWAP. On the other hand, the higher luminance background used by SWAP will cause the pupil to constrict. Thus, a centrally located opacity such as a posterior subcapsular cataract will produce a greater attenuation of sensitivity for SWAP than for SAP.

In order to account for SWAP sensitivity losses that are due to the lens it is necessary to measure its transmission properties, a procedure that is not practical for routine clinical testing. However, Sample and colleagues reported that the lens produced a diffuse, generalized reduction in short wavelength sensitivity, while glaucomatous deficits for SWAP typically occur in localized regions.48 By examining asymmetry in SWAP sensitivity for nerve fiber bundle areas across the horizontal midline, in a manner similar to the glaucoma hemifield test (GHT), they were able to demonstrate high sensitivity and specificity for detecting glaucomatous SWAP deficits without having to correct for lens transmission losses. The pattern deviation probability plot, which has been adjusted for diffuse, widespread sensitivity loss, can also help to reveal localized sensitivity deficits for SWAP.

Two additional difficulties with SWAP are that it takes a couple of minutes longer than conventional automated perimetry, and its variability is moderately greater than for conventional automated perimetry.49,50 Recently, it has been reported that the application of maximum likelihood (SITA-like) procedures can reduce test time for SWAP by 25-30%, with variability characteristics that are as good or better than full threshold procedures.51 Further optimization of these methods should reduce testing time further. Although SWAP has a few complicating factors, as outlined above, methods of handling these issues have also been developed. SWAP has clearly been shown to be a useful clinical diagnostic procedure for glaucoma, particularly in early stages of the disease. With the advent of

Fig. 6. An example of the printed output for SWAP for the left eye of a patient with visual field loss in the superior arcuate nerve fiber bundle region. (Reprinted with permission from Demirel S and Johnson CA: Incidence and prevalence of short wavelength automated perimetry (SWAP) deficits in ocular hypertensive patients. Am J Ophthalmol 131:712-713, 2001.)

more robust and efficient test strategies, SWAP should be an even more useful and practical clinical tool.

Frequency Doubling Technology perimetry

When a low spatial frequency sinusoidal grating (1 cycle per degree or less) undergoes high temporal frequency counterphase flicker (15 Hz or greater), the grating appears to have twice as many light and dark bars than are actually present, i.e., its spatial frequency appears to be doubled. The frequency doubling effect has been reported to be mediated by a subset of magnocellular (M cell) retinal ganglion cells that have a non-linear response to contrast.52 Because these cells are sparse and may be easily damaged early in glaucoma, it was felt by Maddess52 that the frequency doubling effect might be a good means of screening for early glaucomatous visual field loss. Indeed, their initial results revealed high sensitivity and specificity for detection of glaucomatous visual field loss.

The commercial version of FDT perimetry incorporates a display of 16 square targets 10° x 10° in size (four per visual field quadrant), plus a round central 5° diameter target (C-20 pattern). A second stimulus pattern adds two additional squares between 20 and 30° along the horizontal meridian (N-30 pattern). The two stimulus displays are shown schematically in Figure 7.

The FDT full threshold test procedure determines the minimum amount of stimulus contrast necessary to detect the target. As with conventional automated perimetry, the patient is instructed to press a response button each time a stimulus is detected, and contrast of the stimulus is adjusted between trials according to a Modified Binary Search (MOBS) procedure, an accurate and reliable variation of a staircase test strategy.53,54 The FDT stimulus consists of a 0.25 cycle per degree sinusoidal grating undergoing 25 Hz counterphase flicker. Stimulus duration is 720 msec, consisting of a 160 msec ramping up of contrast, 400 msec at the designated contrast level and a 160 msec ramping down of contrast. The ramping up

Fig. 7. Schematic representations of the C-20 and N-30 stimulus displays for FDT perimetry. (Reprinted with permission from Demirel S and Johnson CA: Incidence and prevalence of short wavelength automated perimetry (SWAP) deficits in ocular hypertensive patients. Am J Ophthalmol 131:712-713, 2001.)

196 C.A. Johnson

and down of contrast is performed to avoid temporal transients at stimulus onset and offset that might affect the response to the target. A variable interstimulus interval of up to 500 msec is provided between stimulus presentations to avoid a rhythmic presentation sequence. Presentation of stimuli at different locations is determined according to a pseudorandom sequence. In addition to threshold determinations, the FDT test procedure also presents ‘catch’ trials to check for excessive false positive errors, false negative errors and fixation losses. The full threshold test procedure takes about five minutes per eye to perform.

A number of investigators have now reported that the full threshold FDT test procedure has high sensitivity and specificity for detection of glaucomatous visual field loss and many other optic neuropathies.54-62 Performance characteristics are comparable to those obtained for conventional automated perimetry. There is also preliminary evidence that FDT threshold testing may detect glaucomatous damage prior to conventional automated perimetry.63 Figure 8 presents an example of the left eye of a patient who was judged to have characteristic glaucomatous changes to the optic nerve head, but whose visual field for conventional automated perimetry (left panel) was normal. FDT results (right panel) for this eye suggest a partial superior arcuate nerve fiber bundle-type pattern of visual field loss. Longitudinal follow-up will be necessary to definitively establish that these deficits represent detection of early glaucomatous damage.

In addition to its good performance characteristics for detection of visual field loss, FDT perimetry also has many other desirable attributes as a clinical diagnostic test procedure. Test results are minimally affected by blur of up to 6 diopters, and pupil size changes do not influence the findings as long as the pupillary diameter is above 2 mm. Learning and practice effects are also minimal. Unlike conventional automated perimetry, where test-retest reliability increases by a factor of more than 300% in areas of moderate to advanced visual field loss, FDT testretest reliability only increases by about 20-30% when going from normal visual field regions to those with moderate to severe damage.64 Recent evaluations of frequency-of-seeing curves for FDT have verified that FDT thresholds exhibit high reliability, even in areas of glaucomatous visual field loss.65 Additionally, FDT perimetry requires minimal training to use, is relatively portable, and has an ageadjusted normative database66 and a statistical analysis package for immediate evaluation of test results.67 Because of the relatively short test time and its simplicity, patients prefer FDT perimetry over conventional automated perimetry.

In addition to the threshold testing, there are two rapid screening procedures available for FDT, both of which utilize the 17 location C-20 stimulus presentation pattern. Both of the screening tests take between 30 and 60 seconds per eye to perform, and both have been reported to have good performance characteristics for detecting visual field loss.61,68

The first screening procedure (C-20-1) presents stimuli with a contrast level corresponding to the normal age-corrected 1% probability level. If the stimulus is detected, the location is not tested further. If it is missed, the same stimulus is presented a second time. If it is again missed, the location is classified as having a ‘mild’ sensitivity loss and a stimulus at the 0.5% probability level is presented. If the 0.5% probability level stimulus is not detected, the location is classified as having a ‘moderate’ sensitivity loss and a final stimulus at maximum contrast (100%) is presented. If this stimulus is not detected, the location is classified as having a ‘severe’ sensitivity loss. The C-20-1 screening procedure is designed to

Fig. 8. A comparison of SAP results (left panel) and FDT findings (right panel) in the left eye of a patient with evidence of a glaucomatous optic neuropathy. SAP results are normal, whereas FDT findings suggest the presence of a partial superior arcuate nerve fiber bundle defect (although longitudinal follow-up will be necessary to verify that this is early glaucomatous visual field loss).

optimize specificity. Because the strategy has been optimized to provide high specificity, some early glaucomatous visual field defects may be missed, although its overall detection rate is still very good. The high specificity of this test strategy is most appropriate for mass screening and rapid evaluation of the population at large.

The second screening procedure (C-20-5) is similar to the one described previously, except that targets are initially presented at the normal age-corrected 5% probability level. If the stimulus is detected, then no further testing is performed at that location and the sensitivity is designated as being within normal limits. If the stimulus is missed, the 5% probability level is presented again. If it is missed again, then a stimulus at the 2% probability level is presented. If this stimulus is missed, then the 1% probability level stimulus is presented. Different gray scale values are used to indicate locations with sensitivity that is within normal limits, worse than the 5% probability level, worse than the 2% probability level, or worse than the 1% probability level.

A Viewfinder software package is also available for FDT to download test results to a PC for permanent storage of results and also to provide an extended printout of test results. As shown in Figure 9, the results for both left and right eyes are presented on the same sheet of paper to facilitate comparisons, and a pattern deviation probability plot is presented in addition to the total deviation probability plot. This plot is derived by adjusting the overall height of the visual field for general increases or decreases in sensitivity for the entire visual field and then presenting areas of localized visual field loss. Both the total deviation and pattern deviation probability plots are determined in the same manner as the Humphrey Field Analyzer uses, and are intended to reflect the amount of diffuse and localized sensitivity loss that is present.

FDT perimetry is a relatively new test procedure that has initially been introduced with two Full Threshold test procedures, two screening procedures, a statistical analysis package and a software package and cable for permanently storing patient data on a PC. In addition, a primer for FDT perimetry is available, which provides background information on the test procedures and analysis package, as well as a large series of examples obtained in patients with a variety of ocular and neurological visual disorders.67 In its present form, FDT perimetry is a useful and efficient technique for detection of visual field loss produced by glaucoma and other ocular disorders.27,54-58,60-63,68-72 With further refinement of the procedure, in conjunction with additional investigations, the capabilities of FDT perimetry to monitor progression of glaucomatous visual field loss will be identified. Additional features under development include new analysis procedures (glaucoma change probability, Bebie’s curves) a new ‘smart’ threshold estimation strategy to reduce test time, and a 24-2 stimulus presentation pattern with smaller targets to enhance the ability to detect subtle changes.

Monitoring progression of glaucomatous visual field loss

The ability to accurately distinguish progression of visual field loss from variability represents one of the major challenges in the management of glaucoma patients. Test-retest variability can be three to four times higher in areas of glaucomatous visual field loss than in areas with normal visual field sensitivity.73,74

Fig. 9. An example of the printed output for FDT performed on both eyes of a patient with early glaucomatous visual field loss in both eyes. The output is produced by the Viewfinder software package available for the FDT.

Because of this, it is not possible to accurately determine progression or nonprogression of glaucomatous visual field loss on the basis of just a few visual fields using SAP.

Visual field results from the Ocular Hypertension Treatment Study (OHTS) provide an excellent illustration of the magnitude of this problem.75 At baseline, eligible patients were required to have two normal, reliable visual field examinations for each eye. A visual field endpoint is reached if a patient develops a visual field abnormality, as defined by a GHT or a corrected pattern standard deviation (CPSD) value that is beyond normal limits (p < 0.05), a deficit that is consistent with glaucoma, and confirmation of the presence and location of the deficit on subsequent retest examinations. More than 85% of the initial visual field defects in the OHTS trial were not confirmed on retest, indicating that visual field progression cannot be distinguished from variability on the basis of a single follow-up visual field.

There are several procedures currently used to determine visual field progression. Each of them has particular strengths and weaknesses. Subjective clinical judgment is the oldest and simplest method of determining visual field progression, although it is especially vulnerable to bias, errors and variability among different evaluators. The normal tension glaucoma study has employed expert clinical judgment for evaluating visual field progression, but found that suspected changes had to be confirmed on four out of six follow-up visual fields in order to attain high specificity for visual field progression.76

Classification systems, such as the scoring systems employed by the Advanced Glaucoma Intervention Study (AGIS)77 and the Collaborative Initial Glaucoma Treatment Study (CIGTS),78 have been used as a method of indicating different severity of glaucomatous visual field damage. The advantages of using classification systems are that they are relatively easy to use and a single value or category can be employed to describe the entire visual field. The disadvantages of classification systems are that they are not necessarily linear (e.g., the difference between 2 and 4 may not be the same as the difference between 10 and 12). In addition, classification systems are not necessarily based on population statistics, but rather are often determined by subjective expert opinion.

Linear regression techniques such as Progressor79,80 examine changes in visual field sensitivity as a function of time for individual visual field locations. To achieve high specificity, it is not only necessary to determine a rate of visual field progression (dB loss per year), but also it is essential that this rate be statistically significantly different from zero. Progressor uses a rate of –1 dB per year for central locations –2 dB per year for locations at the outer edge of the central 30° visual field. The advantage of using linear regression as a means of determining visual field progression is that it is based on objective, quantitative statistical procedures. The primary disadvantage associated with linear regression techniques is that a large number of visual fields (minimum of seven to eight visual fields) are needed to achieve good sensitivity for determining progressive visual field loss.81

Event analysis, such as the procedures used by the glaucoma change probability (GCP) analysis for the Humphrey Field Analyzer,82,83 compares the results of fol- low-up visual fields to one or more visual fields obtained at baseline. The GCP analysis procedure takes into account the increase in variability that typically occurs at more peripheral eccentricities and with larger amounts of visual field loss. For each patient, a baseline visual field is constructed by averaging the results of

the first two visual fields in a series. Each subsequent follow-up visual field is then compared to baseline on a point-by-point basis. Locations with changes from baseline that are within the expected variability limits are indicated by a small dot to denote no significant change. Locations with an increase in sensitivity that is greater than the expected variability limits are denoted by an open triangle to indicate significant improvement, and locations with a deterioration of sensitivity that is beyond the expected variability limits are marked with a solid triangle to indicate significant progressive loss. Because the analysis takes into account both eccentricity and sensitivity, larger changes are needed at peripheral locations and in damaged visual field areas in order to meet this criterion. It has been found that to maintain high specificity for determining visual field progression with this technique, one or more confirming visual fields must be performed when progressive visual field loss is suspected.84

The recent multicenter clinical trials in glaucoma all use different criteria for defining glaucomatous visual field progression, which also exemplifies the difficulty of this problem. The AGIS77 adds up the values of clustered points that are beyond normal limits on the Humphrey Field Analyzer total deviation plot for various regions of the visual field, and a score between 0 and 20 is derived from these values. Progression is defined as an increase in the AGIS visual field score of 4 or more from baseline values, confirmed on two successive visual field examinations. The CIGTS78 uses a method that is similar to AGIS. However, scoring of the visual field is based on the Total Deviation probability levels of clustered abnormal points rather than the actual total deviation values. A score of 0 is given for visual field locations that are within normal limits, with scores of 1-4 assigned to visual field locations with sensitivity below the normal 5%, 2%, 1% and 0.5% total deviation probability levels, respectively. The scores for each location are added and then divided by a constant conversion factor to produce a score between 0 (normal visual field) to 20 (severely damaged visual field). Progression is defined as a change in the CIGTS visual field score of three or more that is confirmed on two successive visual fields.

The Early Manifest Glaucoma Trial (EMGT)85 bases its determination of visual field progression on the GCP analysis, except that the pattern deviation values are used rather than the total deviation values used on the commercially available version of the GCP analysis. The GCP method takes the average of the first two visual fields in a series as its baseline, and then compares each subsequent visual field to the averaged baseline visual field. At each visual field location, the pattern deviation value for the follow-up visual field is compared to the pattern deviation value for the averaged baseline visual field. If the difference is within the expected test-retest variability for glaucoma patients, a small dot is printed to indicate that the visual field location has undergone no significant change from baseline. Locations that are significantly better (p < 0.05) than baseline values are denoted by an open triangle and those that are significantly worse (p < 0.05) are indicated by a filled triangle. Test-retest variability increases moderately with increasing eccentricity, and increases considerably with increasing visual field sensitivity losses. Thus, larger changes are required for damaged visual field locations and those at greater eccentricities in order to meet the p < 0.05 statistical significance criterion. The EMGT defines visual field progression as three or more visual field locations that are significantly worse than baseline values on a follow-up examination that are confirmed on two successive follow-up visual field examinations.

202 C.A. Johnson

The OHTS86 defines progression as the development of glaucomatous visual field loss as determined by a GHT or CPSD that is beyond normal limits (p < 0.05) in conjunction with a pattern of loss that is consistent with glaucoma. Initially, one subsequent visual field confirming the deficit was needed for a determination of progression. This has subsequently been modified, and two successive visual field examinations confirming the visual field loss are now required for a determination of progressive visual field loss.

The Normal Tension Glaucoma (NTG) study found that to achieve good specificity (prevent over-calling of progression), it was necessary to have confirmation of progression on two out of three follow-up visual fields, followed by an additional two out of three confirming visual fields over the next six-month period.76 The significance of using different criteria for defining progressive glaucomatous visual field loss is not inconsequential. Using the same longitudinal visual field data set, Katz et al.87,88 have shown that different rates of visual field progression can be obtained, depending on the method of analyzing the visual field. A comparison of different methods employed by the AGIS, CIGTS and EMGT studies demonstrated rates of progression that could vary by a factor of 2 or more. What can be done to improve our ability to distinguish visual field progression? There appear to be three areas where enhancements can be made. Firstly, it is important to develop better analysis methods. The current evaluation procedures for determining visual field progression are based on conventional statistical analysis methods. Although these have been helpful, it is possible that other methods may be more effective. There are a number of new approaches to data analysis (neural networks, fuzzy logic, chaos analysis, image processing) that have been applied to problems for which conventional statistical methods have been unsuc-

cessful.

Secondly, we need to develop test procedures that have lower variability. If we are able to improve the reproducibility of visual function tests, then it may be possible to distinguish subtle progressive visual field changes from longand shortterm variability. In this view, Chauhan and colleagues84 have reported that in the majority of glaucoma patients undergoing progressive visual field loss, high-pass resolution perimetry (HRP) was able to distinguish the progressive change an average of 18 months earlier than for SAP. Reductions in variability will thus help to distinguish progressive glaucomatous visual field loss.

Finally, there is a need to develop tests that are more sensitive and that are able to indicate larger changes than for SAP. A good example of this type of test procedure is SWAP. Longitudinal investigations of SWAP clearly indicate that it detects glaucomatous defects prior to SAP, SWAP defects are larger than those found with SAP, and SWAP defects progress at a more accelerated rate than those found with SAP.14,22

Until we are able to develop improved test procedures and analysis methods, the statistical procedures provided by the Humphrey Field Analyzer (GCP, change analysis, overview analysis, etc.) and the Progressor program can be of great assistance in the determination of progressive glaucomatous visual field loss.

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