Static Threshold Asymmetry in Early Glaucomatous Visual Field Loss

Static Threshold Asymmetry in Early Glaucomatous Visual Field Loss WILLIAM J. FEUER, MS, DOUGLAS R. ANDERSON, MD

Abstract: Ten normal subjects underwent static threshold visual field testing of both eyes with the Humphrey perimeter, with one eye tested twice. The mean sensitivity of the field seemed virtually identical in the two eyes, with the average difference between the right and left eyes (0.65 decibels [dB)) being no greater than the testing error as reflected in the difference between the same eye tested twice (0.7 dB). The authors provide the mathematical basis for recogni zing that a right eye- left eye difference in mean sensitivity might be abnor mal. Addit ional information is needed about the variance of the right eye-left eye difference in the population at large, but present information suggests that a 2-dB difference may be meaningful on a single examination . A 1.5-dB difference is statistically significant if confirmed on a second test , and a difference as small as 1 dB may be meaningful if shown consistently in a series of four examinations . In all cases , nonglaucomatous causes of field abnormality needs to be ruled out, and the genera lized asymmetry is most meaningful if it is consistent with asymmetry of cupping or intraocular pressure. Several cases are reported in which a mild (1 dB) generalized depression of the visual field is the only recognizable abnormality in the visual field in eyes with early glaucoma. Ophthalmology 96: 1285-1297, 1989

The presence or absence of earl y glaucomatous visual field loss has long been j udged evidence of a localized abnormality, such as a paracentral scotoma or a nerve fiber bundle defect ,' >' which are considered the most characteristic field defects of glaucoma. Such localized defects are recognized by comparing sensiti vity in the de-

Originall y recei ved : December 12, 1988. Revision accepte d : Feb ruary 17, 1989 . From the Basc om Palmer Eye Institute, Depa rtm ent of Ophth almology , University of Miami School of Medicine, Miam i. Presented at the ann ual spr ing meeting of the Association for Research in Vision and Oph thalmolog y, Saraso ta, May 6, 1988. Supported in part b y National Glaucoma Research, a program of The Am erican Health As sistance Found ation , Roc kville, Maryland ; in part by US Pub lic Health Service core ce nter gr ant P30 EY 021 80 awarded by the National Eye Institute, Bethesd a. Maryl and : and in part by Researc h to Preven t Blind ness , Inc , New York. New York. with a Senior Sci entific Investigator 's Award . Reprint req uests to Douglas R. And erson , MD , Bascom Palmer Eye Institute, PO Box 016880, Miami , FL 33 101 .

fective region with its surrounding region or som etimes to the opposite hemifield. The suprathreshold stat ic "selective perimetry" of Armaly'':" for glaucoma screening, later modified by Drance.?:? is directed toward th e recognition of these localized defects. In the era of automated static threshold perim etry, localized defects are recognized as clusters of points in characteristic locat ions at which th e sensitivity has fallen outside the normal range . Early localized defects produce unev enness in th e field, as reflected in corrected loss variance (CLV) or corrected pattern standard de viation (CPSD) indices. 10- 14 Even in later stages of the disease , when all locations in the field have reduced sensitivity, mo st typically som e areas in a nerve fiber bundle pattern are still affected more than oth ers, so that an underlying preference for damage to cert ain locations is stilI evident. Less attention has been paid to pure generalized depression (reduced sensit ivity at all locati ons with the loss of sensiti vity not recognizably greater in one region than another) as a sign of early glaucomat ous dam age. One reason is that the normal isopter position with kinetic perimetry is variabl e. Moreover, normal age-related 1285

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changes and afflictions such as cataract also result in generalized depression of sensitivity, making it a nonspecific sign for glaucoma, even in the presence of abnormal intraocular pressure (lOP). As automated static threshold perimetry developed, with its clearly defined range of normal sensitivity values at each location, cases were seen in which printouts comparing the threshold values obtained with the normal values showed sensitivity at all locations to be evenly depressed 6 to 8 decibels (dB) from the average normal range. More recently, generalized depression has been judged within Octopus (Interzeag, Schlieren, Switzerland) and Humphrey (Humphrey Instruments, Palo Alto, CA) programs for static threshold perimetry by means of global indices such as the mean defectlo-l2.1 5 or mean deviation. 14 In the absence of other conditions that might cause a depressed visual field, such cases of generalized reduction of sensitivity have to be considered to be examples of glaucomatous visual loss when in the presence of elevated lOP and large excavations of the optic nerve. Sensible criteria for recognition of glaucomatous generalized depression have seemed to be either: (I) depression outside the normal range, or (2) a change from previous sensitivity (even if the sensitivity is still in the normal range). In both cases the careful clinician requires that other glaucomatous signs be present, that there be no evidence of a nonglaucomatous cause, and also that the field abnormality is a confirmed reproducible change not due to long-term fluetuation.t'':" We examine the recognition of glaucomatous generalized depression by a third criterion, a difference in sensitivity between the two eyes. We propose that such an asymmetry between the two eyes may reveal very early glaucomatous damage, before any other sign is present, even while the sensitivity levels are normal in both eyes. The premise is that normally the two eyes are usually very well matched: that normally, if one eye has a higher than average sensitivity (or lower than average sensitivity), so does the other. Comparison of the field in the two eyes is analogous to comparison of the cup size in the two optic discs as a way to recognize abnormality, even when the cup size and configuration in each eye is, by itself, not recognizably abnormal. 19-27 The purpose of this study was to establish a statistical basis for comparing the average sensitivity of the right and left eyes as a criterion for abnormality of the visual field. In doing so, we expand on the observations of Brenton et al.28

MATERIALS AND METHODS As part of their orientation to the nature of visual field examination, six beginning ophthalmology residents and four glaucoma fellows, 24 to 43 years of age (29.50 ± 5.66, mean ± standard deviation [SO]), underwent visual field examination with Program 30-2 of the Humphrey visual field analyzer. P "!' None had undergone visual field testing before. Four of them underwent the test twice on the right eye, followed by a single test to the left eye in a single session. Four of them underwent a test of 1286

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the right eye once , followed by testing of the left eye twice in a single session. Two underwent a test of the right eye first, followed by a test of the left eye, followed by a repeat test of the right eye in the same session. The different sequences were used to avoid introducing the error of a systematic influence of either fatigue or a learning effect. The results are presented in terms of mean deviation (MO) index, a mean of the differences of the threshold value obtained at each location from the average normal threshold (corrected for age) at that location, each difference weighted according to the normal variance of the values at that location. 14 The MO index is calculated automatically by Statpac software according to the following formula: MO

=

1 L..J ~ (Xi - Ni)}/{-1 ~ L.J - I} {-n i=1 sa n i=1 sa

where Xi is the measured threshold and N the normal reference threshold at point i and sa the variance of normal field measurements at point i. The number of test points (excluding the blind spot) is denoted by n. Also shown is the test-retest variability given as the SO of the measurement error calculated from two determinations of the threshold at ten representative points in the visual field, each difference weighted according to the normal variance of the test-retest difference at that location. This index, the short-term fluctuation (SF) is also calculated by the Statpac software with the formula: SF2 =

{~ ~ S~j}*{~ ~ (Xjl 10 j

e

l

10 j=1

?f}

2*S2j

where Xjl is the first and Xj2 the second threshold value. The normal intratest variance in point i is denoted by S~j. This formula gives a weighted SF index. Except for the weighting and a different selection of ten points used in the calculation, it is the same as the SF index (root mean square of individual SOs or RMS score) of the Octopus perimeter. IO•12,32

RESULTS Table 1 presents the raw data on the ten subjects (30 field tests). Of the 30 tests, six fields in three individuals had fixation losses between 20 and 38%, but otherwise all 30 tests were within the defined limits of test reliabilit y (false-positive and false-negative responses were each less than 30%, and fixation losses were less than 10%). The defined limit for fixation loss was set for an optimum sensitivity-specificity relationship in screening examination , but th is did not make the field unreliable for other purposes. The rate of fixation loss in the normal population is 9.6 ± 10.5%, and the rates in our series are thus not out of line with general experience. P r' " None of the MO values was outside normal limits" (-0.05 ± 1.73 dB, mean ± SO). As might be expected, one in a series of 30 fields had an SF that exceeded the 2.44 dB cutoff for the 95th percentile in the population at large (mean ± SO of SFin the population is 1.57 ± 0.65 dB).33 We could not

Test Sequence (eyes) OD,OD,OS

00, OS, OS

OD,OS,OD dB = decibels; 00 = right eye; OS = left eye. Table 2. Frequency of Mean Threshold Difference (dB) upon Retest at 74 Locations in the Same Eye Difference between Test 1 and Test 2 16 14 12 10 8 6 4 2 0 -2 -4 -6 -8 -10 -12

0.5 0.4

Subject No. 2

3

4

5

3 2 2 2 17 7 9 5 7 28 15 38 34 18 19 33 20 25 27 7 15 4 9 19 2 1 1 1

6

7

8

1 2 1 2 7 3 11 19 16 24 26 36 22 15 20 7 6 4 1 2 1 2

9 10 Total

3 1 5 9 18 19 12 4 2

1 0 0 3 2 13 1 50 9 131 31 278 29 192 4 59 8 0 1 2

0.001 .0 1

0.004 0.003 0.018 0.068 0.177 0.376 0.260 0.080 0.011 0.001 0.003

find any systematic trend to indicate either a learning or a fatigue effect in this young and alert group of subjects, the difference in MD between the first and second, the second and third, and the first and third tests being equivalent. Thus, the data seem reliable. The difference of the MD between the two eyes averaged 0.33 dB (not significantly different from 0 dB). The pertinent calculation is that the SD of the difference of the MD of the left eye from the right eye is 0.646 dB, with an average difference between the eyes (ignoring the sign) of 0.549 dB. In comparison, the average difference of the MD index between the first and second test on the same eye is 0.06 dB, again not significantly different from 0 dB. The SD of the difference of MD of the second test from the first test on the same eye is 0.845 dB with an average difference (ignoring the sign) of 0.699 dB. We also tabulated the test-retest difference between

-8

-6

8

Fig 1. Frequency distribution of test-retest difference of all points among ten subjects with the same eye tested in successive (740 duplicate determinations) superimposed on a normal distribution with SD of 2.47 dB.

thresholds determined at all individual locations from the visual field tested and retested on the same eye (Table 2). In our group of ten subjects, considering the two tests on the eye tested twice and ignoring two points in the region of the physiologic blind spot, there were 740 locations at which threshold was measured twice. Because of the standard thresholding strategy used, threshold measurements differed only by even numbers (when any point had duplicate threshold determinations within a single test, we used only the first determination when comparing the field with the second field on that eye). Thirty-eight percent ofthe locations had the same threshold on two occasions. Eighty-one percent of the locations had a threshold difference of - 2, 0, or +2 dB between the two tests. Ninetysix percent of the locations had values of -4, -2, 0, +2, or +4 dB. Ninety-nine percent of the locations had a difference in the inclusive interval from -6 to +6 dB. This frequency distribution is centered around 0 dB and has a standard deviation of 2.47 dB. The mean difference (ignoring the sign) between values on the two tests was 1.74 dB. Figure I shows this frequency tabulation of test-related difference in comparison with a normal distribution with 1287

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a standard deviation of 2.47 dB. From these data on 74 points each tested twice by undergoing the entire field test twice, one can also calculate the SF index (standard deviation ofthe measurement error). This value is somewhat larger than the 1.5 dB average SF calculated by the Statpac software of the Humphrey instrument in these same 20 duplicate tests on these ten subjects. The reason is that our calculation of SF based on 74 locations (instead of the sample often locations) was unweighted and included a higher representation of locations from the inherently more variable points at the edge of the 30° field. The SF values of 1.5 to 1.7 dB are reasonably representative. 16,33-36

DISCUSSION The data suggest that typically the sensitivity of the two eyes of an individual are well matched. When the two eyes of an individual are tested, the measured mean sensitivity of the two eyes is never exactly the same but includes a variability or measurement error that appears no larger than the difference in mean sensitivities obtained when the same eye is measured twice in succession. To interpret an interocular difference (right eye-left eye difference) of a certain magnitude as a sign of early glaucomatous damage in clinical practice, we must define the magnitude of the measurement error and variability of mean sensitivity. MEASUREMENT ERROR WITHIN A SINGLE TEST

The SF is calculated from the test-retest difference in threshold sensitivity from all or a representative sample of locations within the same testing session. For the Octopus, 10,12,32 it is calculated as: n

L (Xj2 - Xjl)2

je I

2n where Xji and Xj2 are the two threshold measurements at point j and n is the number of points tested (n = 10 in the standard Program 32). The SF (RMS score) is an estimate of the standard deviation of the single threshold determination at anyone location pooled over the n points examined. The SF for the Humphrey visual field analyzer is similar, but each value is weighted according to location.!" When all points are averaged to get a mean sensitivity of the field as a whole (or mean deviation or mean defect, derived as a subtraction from normal values), the error in the average value is less than the error in the individual measurements because, by chance, many of the errors in the positive direction will be balanced by other errors in the negative direction. If the SOs or "errors" of all points are assumed approximately equal or at least that SF is reasonably representative of the error in individual threshold measurements, it would be expected that the 1288

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error in the average of the measurements at n locations would be SF divided by the square root of n. For the calculation of mean sensitivity in the Octopus Program 32, n = 76, the number of tested points. For the Humphrey visual field analyzer Program 30-2, n = 74 for calculation of the MO because the two points that might include the blind spot are excluded in the Statpac program. In the Octopus Program G 1, for the calculation of mean defect, n = 59 (n = 118 ifboth phases of Program G I,are done)." MEASUREMENT ERROR ON DUPLICATE TESTS OF THE SAME EYE

When considering two consecutive tests on the same eye assuming that the mean sensitivity and the SF are unchanged, the expected SO ofthe difference between the two measured mean values is the square root of 2 times the measurement error, or

This follows directly from the general statistical property that the variance ofa difference oftwo variables with equal variances but without covariance (in this case two mean sensitivities of the two tests, each of which has a variance of (SF)2/n), is the sum of the two variances of the two variables. The formula can also be derived by noting that cn)(SF) will be the SO of the difference between two consecutive measurements at a point if SF is a reasonable estimate of the SO of repeat measures at that point. If the difference between measurements is averaged over all n points, the SO of the average difference will be (V2)(SF)/ ev'n} In both derivations it is assumed that the variance of repeat measure is the same at all locations, or that if it is not, then SF is at least reasonably representative. In any event, if n is close to 72, the SO of the difference of two mean values should be approximately one sixth of SF. In other words if SF is in the range of 1.5 to 1.8, one would expect the SO ofthe difference in duplicate average measurements to be 0.25 to 0.30 dB. Our actual findings of test-retest variability on the same eye with regard to the average sensitivity (represented by the MO index) was three or four times that amount. Table 3 shows the range of MO differences with a SO of 0.845 dB. With unweighted statistics (allowing more influence from the more variable peripheral points), the SO of the average difference is 1.012 dB. Only two individuals (Table 2) had any locations at which the threshold difference was outside the range of ±6 dB. Subject 9 had fatigued with an intratest SF of 3.97 by the time of the second test on the right eye. Subject 6 had an eyebrow artifact that changed in degree between the two tests. However, the SO of the difference (unweighted) remains high (1.02 dB) for the remaining eight individuals. If subject 4 is also eliminated (for no reason except that the average difference is an outlying value of 1.73 dB), then the SO of the difference (unweighted) is reduced, but only to 0.69, still at least twice that expected from the average SF in the group.

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STATIC THRESHOLD ASYMMETRY

Table 3. Repeat Test on the Same Eye Subject No.

Weighted statistics (from Statpac)* MO difference Pooled SF 10 Unweighted statistics* Average difference SO

t

SF 74

2

3

4

5

6

7

8

9

10

Average

SO

-0.30 1.42

-0.84 1.37

-0.98 1.34

1.50 1.25

0.30 1.24

-0.73 1.74

0.27 1.33

-0.30 1.33

1.12 2.88

-0.65 1.13

-0.06 1.50

0.845 0.51

-0.49 1.45 2.88 1.29

-1.11 1.35 7.04 1.42

-1.54 1.87 7.08 1.85

1.73 1.74 8.54 1.87

0.43 1.83 2.02 1.51

-0.92 3.22 2.38 2.43

0.24 3.33 1.04 1.60

-0.41 1.57 2.22 1.35

1.41 3.80 3.19 2.53

-0.70 1.28 4.72 1.25

-0.149

1.012

1.71

0.46

SO = standard deviation; MO = mean deviation; SF = short-term fluctuation. * Threshold values in decibels.

It appears, then, that the difference in average measured sensitivity is not the simple result of test-retest measurement error or the presence of atypical individuals in our sample. Rather, there appears to be a true slight change in sensitivity level even in the short time between successive field tests. If it is seen that there was a homogenous change in sensitivity in the whole field between the two tests and that the change was sampled at 74 points, the change is statistically significant by the Student t values in Table 3 (paired t test, P < 0.05 for t > 1.99 with 73 degrees offreedom, n = 74) in all but one individual. (In other words, there is a measureable degree of "long-term" fluctuation in as short a time as 20 minutes). This change is equally balanced between increase or decrease in sensitivity, so that the average sensitivity in the group often individuals is only -0.06 and -0.15 dB for the weighted and unweighted average difference, respectively,in neither case statistically different from 0 dB. The difference in anyone individual may be a combination of such diverse things as fatigue or learning effects, a moment-to-moment change in neuronal physiology, or a drift in the psychophysic criterion used by the subject for registering a response. Whichever factor may predominate in a given individual on a pair of tests, the result is that the reproducibility of a global index of average sensitivity has a SD from 0.85 to 1.0 dB. As an illustrative example, Figure 2 shows the right eye of subject 3 tested at 10:47 AM and again at 11:04 AM on the same day. A histogram (Fig 3) shows a frequency distribution centered around an average difference of + 1.54 dB. A between-test SF calculation is little affected by the shift from a O-dB average difference. The SF is calculated from the square of the test-retest difference, and the higher frequency of +2 and +4 dB is balanced by a lower frequency of - 2 and -4 dB. DIFFERENCE BETWEEN THE TWO EYES

If there is an individual with a difference of mean sensitivity between the two eyes of 2 dB, the measured difference between the two eyes is an unlikely result of test-

retest variability with the two eyes in fact being identical. With a test-retest standard deviation ofabout 1 dB, fewer than 5% of eyes would have such a difference on immediate retesting. A 2-dB right eye-left eye difference therefore suggests that there is a true difference between the two eyes in this individual. It must then be asked how often such a true difference might be found in a normal disease-free population. In our small sample of ten subjects, the right eye-left eye difference in sensitivity in normal individuals is no different from the expected difference if the same eye were tested twice. However that does not rule out the possibility that there may be a small number of people in the population at large who have a true small difference in sensitivity between the two eyes, each eye by itself being entirely normal. A small difference might not be surprising, for example in the few individuals who have a slight anatomic difference between the two eyes, which may be manifest by a slight anisometropia. Such instances may be infrequent, perhaps not much affecting the overall frequency distribution of right eye-left eye differences. However, there is no evidence that the population has a measurable true right eye-left eye difference apart from disease. Even if real positive and negative right eye-left eye differences tended to cancel each other on average, the variability around the average would be greater than the test-retest variability. Brenton and co-workers" found that the SD of the right eye-left eye difference (Humphrey visual field analyzer, Program 30-2) in 20 normal subjects (ages, 22-47 years; mean, 31.3 years) was only 0.54 dB (range, -0.5-+ 1.1 dB). They considered ± 1.0 dB to be the 95% limit in the normal population and ± 1.4 dB to be the 99% limit. Their SD of 0.54 dB represents an even smaller interocular difference than we found (SD = 0.7 dB). Neither is larger than would be predicted by the measurement variability we found in retesting the same eye (SD = 0.85 dB). They also found a distribution of differences between equivalent (mirror image) points in the field to be identical with the distribution of difference we found with the same eye tested twice (SD of difference at individual points 2.2 dB compared with our 2.5 dB and 1289

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10:47 a.m.

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[ignoring the sign] MO of 1.6 dB compared with our finding of 1.7 dB). Johnson and associates" found a somewhat bigger interocular difference in their "normal controls" (age, 1078 years; mean , 39.2 years), with a mean interocular difference (ignoring the sign) of 1.0 dB (median, 0.8 dB). This corresponds to an SO of approximatel y 1.2 dB, assuming an average interocular difference of zero in the popula tion. (In a normal distribution around a mean value of zero, the average absolute value is 0.7979 times the SO,38 and the median value is 0.6745 times the SO). However, their group of controls was not necessarily free of disease, being taken from a neuro-ophthalmic practice and labeled normal controls because the y did not have a relative afferent pupillary defect. Some may have had mild visual abnormalities not detected on the standard clinical examination. 1290

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Perhaps the databases of normal ind ividuals for the Octopus and the Humphrey perimeters" contain the information on the distribution of measured mean sensitivity difference between the two eyes, from which a more accurate population frequenc y distribution could be derived that can be used for statistical calculation. Such larger databases would also allow testing the assumption that a mean right eye-left eye difference in the population as a whole is in fact zero (not different from zero because the right eye is typically tested first giving learning or fatigue effects, or perhaps there is a true slight population difference because of a dominance of one eye over the other in most of the population). Addit ionall y, we have assumed equ al variability in int erocular difference at all locations in the field and an unskewed Gaussian distribution of mean sensitivity values. A larger data set ma y deny these assumptions and lead to better ways to cal-

FEUER AND ANDERSON

•

culate probabilities." If the frequencydistribution changes with age in these larger population samples,' we would suspect that among the putative normals there were some with undetected disease or that there were acquired asymmetric changes in the eye within the normal population. Examples might include the effects of normal increase in thickness and opacity (light scatter) that occurs in the crystalline lens with age without it being termed a cataract or perhaps retinal pigment epithelial or receptor layer changes that represent aging changes not considered frank maculopathy. Whether these mild changes are considered disease states that occur frequently but are not part of the normal population or are considered normal for age, it will be important to know how often such asymmetric changes occur in eyes that are otherwise normal or at least are nonglaucomatous. Then the approach we suggest (comparing the mean sensitivity of the two eyes) can be used more accurately. For the moment, however, we would suggest that it does not violate the existing data to assume an SD of the right eye-left eye mean difference to be approximately 0.7 to 0.9 dB. If twice the SD includes 96% of the normal population, a right eye-left eye difference of 1.5 dB might be noteworthy on a routine field test, and a 2-dB difference even more so. Any borderline finding bears repeating , however. A true difference should still be present on repeat testing, whereas an artifact or statistical accident should not. REPEATED TESTS

If prepared to undertake repeat testing, one can be suspicious of even smaller right eye-left eye differences (e.g., 1 dB) if the difference is in keeping with other clinical signs. An interocular difference of only I dB could rea-

STATIC THRESHOLD ASYMMETRY

27

19

18

1

a

-6

+2 +4

+6

Fig 3. Histogram of difference at 74 locations on duplicate testing of right eye of subject 3. The mode is +2 dB (mean , 0.98 dB).

sonably happen once as a chance occurrence ' based on measurement variability. If it is indeed a chance occurrence, half the time a repeat test would show the other eye to have a higher sensitivity. If, however, the same eye again has a higher sensitivity on repeat test (P = 0.5), one might be even more suspicious that a true difference existed and do the test a third time . A chance of three consecutive tests showing the same eye to be more sensitive SIGNIFICANT RIGHT EYE - LEFT EYE DIFFERENCE (P<0.05l FOR SEVERAL POPULATION STANDARD DEVIATIONS. SD~O. 7 SO-0.8 SO-0.9

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Fig 4. Statistical significance (P < 0.05) ofa right eye-left

eye difference in average sensitivity for one to four repetitions of the static threshold visual field test. If the interocular difference exceedsthat represented by the solid line, the difference is statistically significant . Ordinates are given for several population SDs including the 0.9 SD suggested as a present reasonable conservative estimate .

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1291

OPHTHALMOLOGY

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=

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eraged together, and the overall mean difference is obtained. Working from the normal distribution of expected right eye-left eye differencethe SD of the overall difference expected is reduced by a factor of one over the square root of 2 for two tests, one over the square root of 3 for three tests, one over the square root of 4 for four tests, etc. Although in principal, the test might be repeated any number of times; three or four tests is probably the practical limit of tests that one would be willing to undertake clinically to show a small difference between the two eyes. Moreover, the additional statistical power gained by additional testing is small. With such a strategy, a correction must be made for the fact that, with repeated testing, one increases the likelihood of reaching statistical significance by chance. When allowing up to four tests in comparing two average sensitivities, a simple and suitable correction" is to require that the observed difference be 2.33 times the SD instead of the traditional 1.96 times the SD to achieve statistical significance (P < 0.05). This approach can be presented graphically (Fig 4) in which the magnitude of the overall mean difference required to achieve statistical significance (P < 5%) is given

Table 4. Intraocular Pressures (mmHg) before Treatment (case 1) Date

•

left eye.

is 0.25. Continuing this procedure, considering only which eye is more sensitive, it would take six consecutive tests with the same eye being more sensitive to conclude (P < 0.05) that one eye was more sensitive than the other. If the magnitude of the difference is taken into account in addition to the direction ofthe difference, a statistically significant conclusion can be reached more quickly. With repeated tests, the mean values for the right eye are averaged together, the mean values for the left eye are av-

RIGHT EYE ACTUAL

20221616 21 22 21 22 22 20 21 22 23 24 25 23 21 22 2123 24 24 26252522 22 22 22 24 25262627242022 24 192123 26 27 28 2500 24 24 2123 23 26262624 23 2325 23 24 262624 27 26 25 23 22 24 262527 24232625

I

-30

I

o

NORMAL

DIFFERENCE

+++05 ++++++ ++++++++ ++++++++++ +++++++05++ +++++++26++ ++++++++++ ++++++++ ++++++ + + + +

I

o

20202021 21 22 22 22 22 22 22 23 24 24 24 24 23 23 2123 2425262525242323 23 24 2627 28 28 26 25 24 24 23 24 26 27 28 28 27 26 25 24 22 24 2526 26 27 26 25 24 23 23 24 25 25 26 25 25 24 23 2324 252524 22232424

+30 -30

o

+30

o

-30

+30

LEFT EYE ACTUAL

2022 24 24 24 21 24 24 23 24 2425.272523 25 22 23 2424242424262522 2523 27231726282826272525 252406 25XJ 28 27 27 26 21 25242625262727272725 2525212526282724 24 24 25 26 26 24 23232625

I

-30

1292

I

o

DIFFERENCE

+ + + + ++++++ + + + + + + + + + + + + + + + + + + ++08+++++++ ++20+++++++ ++++++++++ + + + + + + + + ++++++ ++++

I

o

NORMAL

21202020 22 22 22 22 22 21 23 23 24 24 24 24 23 22 23 23 24 252526252423 21 24242526282827262423 242526272828 27 26 24 23 23 24 25 26 27 26 26 25 24 22 2425252625252423 242525242323 24242322

I

o

I

+30

+30

o

-30

Fig 5. Visual field of subject I on May 23, 1985 (Octopus Program 32). The mean sensitivity ofthe right eye is 23.5 dB and of the left eye 24.8 dB (difference, 1.3 dB)(Table 2). However, none of the sensitivity values is depressed more than 5 dB from the normal values for his/her age, and there is no region where sensitivity is locally reduced more than elsewhere.

FEUER AND ANDERSON

•

STATIC THRESHOLD ASYMMETRY

Table 5. Series of Octopus Fields with Asymmetric Sensitivity (case 1) December 1, 1983

March 22, 1984

May 23, 1985

June 20, 1985

December 3, 1986

23.7 24.7 1.0

24.3 25.0 0.7

23.5 24.8 1.3

23.7 24.5 0.8

23.5 24.6 1.1

1.4 0.6

0.6 0.9

0.6 0.7

1.7 4.0

0.9 1.1

Mean sensitivity 00 OS Change RMS (dB) 00 OS

dB = decibels; RMS = root mean square; 00 = right eye; OS = left eye. Table 6. Perimetry on Seven Occasions (case 2) October 7, 1985

October 7, 1985

October 19, 1985

October 25, 1985

October 25, 1985*

November 8, 1985t

February 8, 1986

27.1 25.8 1.3

28.1 27.4 0.7

28.1 28.0 0.1

28.5 27.6 0.7

28.6 27.9 0.9

28.6 27.5 1.1

28.8 27.5 1.3

1.8 1.3

0.9 1.1

1.3 1.3

0.9 0.4

0.9 1.1

1.4 0.7

1.0 1.4

1.5 1.3

1.4 1.7

1.5 1.3

1.1 1.3

1.2 1.3

Mean sensitivity (dB) 00 OS Change CLV (dB) 00 OS SF (dB) 00 OS

1.9 0.9

dB = decibels; 00 = right eye; OS = left eye; CLV = corrected loss variance; SF = short-term fluctuation. * After epinephrine to make intraocular pressure in left eye lower than the right. t Pressure spontaneously equal in the two eyes on this day. Table 7. Untreated Intraocular Pressure (mmHg) (case 2)

00 OS 00

=

October 7, 1985

October 19, 1985

October 25, 1985

October 25, 1985

November 8, 1985

31 34

27 28

26 40

30 24

35 35

right eye; OS

=

left eye.

according to the number of tests done. Values are given based on the estimate that the SO of the interocular difference is in the range of 0.7 to 0.9 dB, but it can be adapted to future better estimates by simply changing the ordinate scale. As a rule of thumb, an approximation consistent with our data is that a 2-dB difference is probably real, but confirmation by a second test is prudent. An average 1.5dB difference must be maintained on retest to be accepted. An average 1.25-dB difference must be found on three tests to be accepted, and an average difference as small as 1 dB on four consecutive tests is statistically significant. These guidelines are based on our estimate of the amongperson right eye-left eye variance. The within-person variance, which is actually the relevant variance for this statistical test, should be the same or less than the amongperson variance. Thus, these approximate rules are conservative.

CASE REPORTS Even with only the present approximation of the SD of the interocular difference in the population, we can use asymmetric mean sensitivity as an early sign of glaucomatous nerve damage if we are careful to ensure that it corresponds to a suspicious asymmetry of cupping or of lOP, and that there are no asymmetric congenital features, anatomic differences, age-related changes, or frank disease states that could account for the observed differences. Likewise, there must be no tocalized defects or artifacts that account for the difference in mean sensitivity. Consider, for example, the case of a man who before age 60 had normal symmetric lOP but, in the year from August 1983 to August 1984, had persistent elevation of pressure in the right eye (Table 4). Results of his disc and visual field examination (Fig 5) were normal by the usual standards, but the right eye always had a reduction in sensitivity compared with the left (1dB average difference) which persisted into 1986 and thereafter,

1293

OPHTHALMOLOGY

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SEPTEMBER 1989

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VOLUME 96

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NUMBER 9

RIGHT EYE MEAN

27

NORMAL

22

24

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26

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Fig 6. Visual field of subject 2 on October 25, 1985 (Octopus Program GI). None of the sensitivity values is outside the normal range, and neither is any of the calculated indices.

Q

----

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-------

even though the pressure was equalized and normalized by timolol treatment to the right eye (Table 5). A second illustrative case is that of a man with mean sensitivity ofthe field always higher in the right eye on one test with Program

1294

---- -----

32 and six consecutive tests with Program G 1 (both phases) of the Octopus perimeter, making a total of 13 visual field examinations (Table 6). He had elevated lOP in both eyes, with the lOP always higher in the left eye than in the right eye except for

FEUER AND ANDER SON

•

STATIC THRESHOLD ASYMMETRY

Table 8. Mean Values (mmHg) of Visual Field (case 3)

one occasio n when th e left eye pressure 'was lowered by topical epinephrine (to estab lish that th e field asymmetry was due to a subtle degree of damage to the left eye rather than a reversible pressure-induced alteration of physiology) and on one subsequent occasion when the pressure was spontaneously equal (Table 7). The MD and the CLV global indices were within normal limits, and the CLV index was not asymmetric between the two eyes. Figure 6 is an example of his field examination results. The third case is a woman who presented with lO Ps usuall y equal in the two eyes bu t sometimes with the pressure I to 4 mmHg higher in the left eye. She had apparently normal discs and fields. Static threshold perimetry showed a consistent asymmetric reduction of sensitivity in the left eye (Table 8; Fig 7), and kinetic perimetry showed a corresponding perceptible asymmetry in isopter position on several previous occasions (Fig 8). These cases are reported here to show that the principle of looking at asymmetry can be applied to several of the commonly used q uantitative methods of n pri m l't rv N o t " II in-;:h n f' P < "f"

00

OS Change

August 29, 1985 (Octopus)

March 3, 1986 (Octopus)

January 7, 1988 (Humphrey)

25.2 24.1 1.1

23.3 22.4 0.9

+ 0.51 -0.54 -1.1

00 = right eye; OS = left eye. I-dB difference between the two eyes are genuine pathologic defects, but these cases show that genu ine abnormalities as small as I dB can be recognized if they are reproducible and in keeping with the clinical circumstances. We do not know if such mild abnormalities will always progress any more than we know that other very mild field defects will progress, but when striving to recognize the earliest stage in glaucomatous damage, asymmetry nf c:pnc:iflvih! ~hn1l 1 r1 hp ~ rnnno t hp p~rlv Ci: lonc;:. fnr \:vh lr h

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OPHTHALMOLOGY

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SEPTEMBER 1989

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VOLUME 96

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NUMBER 9

Fig 8. Visual field of subject 3 on March 30, 1982 (Go ldmann kinetic perimetry). The isopters of the I-Ie , I-2e, and I-3e stimul i are deviated slightly inward in the left eye compared with the right. Given that the slope of the hill of vision is approximately 0.4 dB per degree in this patient along the horizontal meridian nasally, the 50 inward deviation of the isopte rs on the nasal side corresponds to approx imatel y a 2-dB sma ller sensitivity in this region , the left eye compared with the right. Temporally, the inward deviation is not so mark ed, and the average right eye-left eye difference shown over the entire central 30 0 approximates the I dB shown by static perimetry subsequently (Table 8).

NONSPECIFICITY FOR GLAUCOMA We should make note of asymmetry in mean sensitivity that is outside the limits of variability in the normal population. Asymmetry offield scores has also been used previously to recognize glaucoma with the Friedman analyzer."! From mathematical considerations alone , it can only be said that such asymmetry is unlikely to be due to random variabilit y. Before it can be concluded that the finding represents early glaucomatous damage or other pathologic condition, it is important to rule out artifactitious causes of asymmetry, such as a lens rim or eyelid artifact present in the field of one eye but not in the other. Eyebrow artifacts or other localized perturbations of the field, whether real or artifactual, are common and will certainl y cause asymmetry of the mean sensitivity between the two eyes. In fact, the criteria described in this article should not be applied when there is a localized field defect (which requires diagnostic interpretation on its own) because localized reductions of sensitivity wilI affect the overall mean sensitivity and , if asymmetric, will produce an asymmetric mean sensitivity. We have provided the basis for recognizing generalized depression by means of asymmetry of mean sensitivity in the absence of obvious localized abnormalities or any apparent artifact. It is wise to confirm any subtle findings on a second occasion because a small technical artifact may not be recognized as the explanation for the asymmetry. Inverting the testing order (left eye first) during the second session may help exclude possible learning or fatigue effects. Even when the visual field asymmetry is established as reproducible, the clinical evaluation must take into account other possible causes, such as asymmetric pupil size, mild or asymmetric cataract, evidence of ocular asym1296

metry in the form of anisometriopia, mild ambl yopia, etc. The sign of an asymmetric field as a glaucomatous defect is most meaningful when it is reproducible and corresponds to an asymmetry of lOP or a suspicious asymmetry of disc cupping.

REFERENCES 1. Aulhorn E, Harrns H. Early visual field defects in glaucorna. In: LeydheckerW. ed. Glaucoma: Tutzing Symposium. Basel: S Karger. 1967; 151-86. (XXth International Congress of Ophthalm ology: Symp osium in Tutzing Castle, August 5-10, 1966). 2. Orance SM. The glaucomatous visual field. Br J Ophthalmol 1972 ; 56:186-200. 3. Greve EL. Single and multiple stimulus static perimetry in glaucoma ; the two phases of perimetry [Thesis]. Doc Ophthalmol 1973; 36:1-

355 . 4. Armaly MF. Ocular pressure and visual fields: a ten-year follow-up stud y. Arc h Ophtha lmol 1969; 81:25- 40. 5. Armaly MF. Visual field defects in early op en angle glaucoma. Trans Am Ophthalmol Soc 1971; 69:147-62. 6. Armaly MF. Selective perimetry for glaucom atous defect s in oc ular hypertension. Arch Ophthalmol1972; 87:518-24. 7. Rock WJ, Orance SM, Morgan RW. A modif ication of the Armaly visual field screening technique for glaucoma . Can J Ophthalmol 1971; 6:283 -92. 8. Orance SM, Brais P, Fairclou gh M, Bryett J. A screening method for temporal visual defects in chronic simple glaucoma. Can J Ophthalmol 1972; 7:428-9. 9. Rock WJ, Orance SM, Morgan RW. Visual field screening in glaucoma. An evaluation of the Armaly techn ique for screening glaucomatous visual fields. Arch Ophthalmol1973; 89 :287-90. 10. Flammer J. Orance SM, August iny L. Funkhouser A. Quantification of glau comatous visual field defe ct s with automated perimetry . Invest Ophthalmol Vis Sci 1985; 26 :176-81 . 11. Bebie H. Computerized techniques of visual field analysis. In: Orance

FEUER AND ANDERSON

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SM, Anderson DR, eds . Automatic Perimetry in Glaucoma: A Practical Guide. Orlando: Grune & Stratton , 1985; 147-60. 12. Flammer J. The concept of visual field indices . Graefes Arch Clin Exp OphthalmoI1986; 224 :389-92. 13. Sommer A, Duggan C, Auer C , Abbey H. Analytic approaches to the interpretation of automated threshold perimetric data for the diagnosis of early glaucoma. Trans Am Ophthalmol Soc 1985; 83 :250-67. 14. Heijl A, Lindgren G, Olsson J. A package for the statistical analysis of visual fields. Doc Ophthalmol Proc Ser 1987; 49:153-68. (Seventh International Visual Field Symposium; Amsterdam, September 1986.) 15. Flammer J, Jenni F, Bebie H, Keller B. The Octopus glaucoma G1 program. Glaucoma 1987; 9:67-72. 16. Flammer J, Drance SM, Zulauf M. Differential light threshold : shortand long-term fluctuation in patients with glaucoma , normal controls , and patients with suspected glaucoma. Arch Ophthalmol1984; 102: 704-6. 17. Flammer J, Drance SM, Schulzer M. Covariates of the long-term fluctuation of the differential light threshold. Arch Ophthalmol1984; 102: 880-2. 18. Flammer J. Fluctuations in the visual field. In: Drance SM, and Anderson DR, eds. Automatic Perimetry in Glaucoma: A Practical Guide. Orlando: Grune & Stratton, 1985; 161-73. 19. Armaly MF. Optic cup in normal and glaucomatous eyes. Invest Ophthalmol1970; 9:425-9. 20. Armaly MF. The correlation between appearance of the optic cup and visual function. Trans Am Acad Ophthal Otolaryng 1969; 73:898 913 . 21 . Fishman RS. Optic disc asymmetry: a sign of ocu lar hypertension. Arch Ophthalmol1970; 84 :590-4. 22. Pickard R. Variations in the size of the physiological cup and their relation to glaucoma. Proc R Soc Med 1921; 14(Sect. OphthalmoL): 31-40. 23. Snydacker D. The normal optic disc : ophthalmoscopic and photographic studies . Am J Ophthalmol 1964; 58 :958-64. 24. Armaly MF_Genetic determination of cup/disc ratio of the optic nerve. Arch Ophthalmol1967; 78:35-43. 25. Richardson KT. Optic cup symmetry in normal newbom infants. Invest OphthalmoI1968; 7:137-40. 26 . Schw artz B, Reinstein NM , Lieberman OM. Pallor of the optic disc : quantitative photographic evaluation . Arch Ophthalmol1973; 89:27886 .

STATIC THRESHOLD ASYMMETRY

27. Colenbrander MC. Measurement of the excavat ion. Ophthalmologica 1960; 139:491-3. 28. Brenton RS, Phelps CD, Rojas P, Woolson RF.lnteroculardifferences in the visual field in normal subjects. Invest Ophthalmo l Vis Sci 1986; 27 :799-805. 29. Heijl A. The Humphrey Field Analyzer , construction and co ncepts. Doc Ophthalmol Proc Ser 1985; 42:77-84. (Sixth International Visual Field Symposium, Santa Margherita Ligure, May 27-31, 1984). 30. Heijl A. The Humphrey Field Analyzer: concepts and clinical results . Doc Ophthalmol Proc Ser 1985; 43:55-64. (Second European Glaucoma Symposium, Helsinki, May 1984). 31. Heijl A. Humphrey Field Analyzer. In: Orance SM, Anderson DR, eds . Automatic Perimetry in Glaucoma: A Practical Guide. Orlando : Grune & Stratton, 1985; 129-40. 32. Bebie H, Fankhauser F, Spahr J. Static perimetry: accuracy and fluctuations . Acta Ophthalmol1976; 54 :339-48. 33. Heijl A, Lindgren G, Olsson J. Reliability parameters in computerized perimetry. Doc Ophthalmol Proc Ser 1987; 49:593-600. (Seventh International Visual Field Symposium ; Amsterdam, September 1986). 34. Katz J, Sommer A. Reliability indexes of automated perimetric tests . Arch Ophthalmol1988; 106:1252-4. 35. Flammer J, Orance SM, Fankhouser F, Augustiny L. Differential light threshold in automated static perimetry : factor s influencing short-term fluctuat ion. Arch Ophthalmol1984; 102:876-9. 36. Brenton RS. Fluctuations on the Humphrey and Octopus perimeters. Invest Ophthalmol Vis Sci 1987; 28:767-71 . 37 . Johnson LN, Hill RA, Bartholomew MJ. Correlation of afferent pupillary defect with visual field loss on automa ted perimetry . Ophthalmolog y 1988; 95 :1649-55. 38. Leone FC, Nelson LS, Nottingham RB. The folded normal distribution. Technometrics 1961 ; 3:543-50. 39. Heijl A, Lindgren G, Olsson J. Normal variability of static perimetric threshold values across the central visual field. Arch Ophthalmol 1987; 105:1544-9. 40. Armitage P, McPherson CK , Rowe BC. Repeated significance tests on accumulating data . J Roy Stat Soc [Ser A] 1969; 132:235-44. 41. Sponsel WE, Hobley A, Henson DB, et aI. Quantitative supra-threshold static perimetry : the value of field score and asymmetry analysis in the early detection of chronic open angle glaucoma. Doc Ophthalmol Proc Ser 1987; 49:217-29. (Seventh International Visual Field Symposium ; Amsterdam, Septemb er 1986).

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