A Perimetric Technique Believed to Test Receptive Field Properties: Sequential Evaluation in Glaucoma and other Conditions

A PERIMETRIC T E C H N I Q U E BELIEVED T O T E S T R E C E P T I V E FIELD P R O P E R T I E S : S E Q U E N T I A L EVALUATION IN GLAUCOMA AND O T H E R CONDITIONS JAY M. ENOCH, P H . D . , AND BEVERLY LAWRENCE,

B.A.

St. Louis, Missouri

The Westheimer function

1-8

is believed to

field properties of certain retinal neurons.* In a limited area of field immediately sur­ rounding a small flashing test field, increas­ ing the stimulus area of a second or back­ ground field results in summation of its vi­ sual effect. We call this central area of the second field the "summation arm" of the Westheimer function. When the second field is further increased in diameter beyond the limits of the summation zone, an effect op­ posite to summation occurs. We call this the "inhibition arm" of the Westheimer func­ tion. Under certain test conditions a small additional outer summation-like zone was de­ scribed.9 This is not seen when the test is per­ formed as previously described4'8 and as we did in this study. Beyond such zones the re­ sponse function asymptotes and no further change in the threshold of the small flashing field occurs. Thus, there is a circumscribed area in the visual field that significantly in­ fluences the detectability of a small flashing test field located at its center. Within the circumscribed area there are two response zones, a central summation zone (Fig. 1, SA) and a larger surrounding inhibition­ like area. In diseases of the outer layer of the retina, pigment epithelium, and choroid the entire

Westheimer function exhibits reduced sensi­ tivity but its form is not altered. In diseases of the inner layer of the retina, the inhibi­ tion arm of the response may be partially or totally eliminated, j ' h e distinction between inner and outer retinal layers is tentatively made on the basis of vascular supply (choroidal vs. retinal support). To date we have found no ophthalmic disease that systemati­ cally alters the summation arm of the func­ tion. Because of its relative stability, the summation arm becomes useful as a refer­ ence or "anchor" for the response function. Thus, when looking at a given clinical record of the Westheimer function, one evaluates the sensitivity of the response, that is, one examines (on the graph) the static threshold and determines the vertical position of the summation arm or anchor, then one finds whether the inhibitory arm is present on this test date or has been altered since the last ex­ amination. By minimizing retinal image blur at the test point, intersession variance is greatly reduced and inter-observer variability is markedly diminished.8'4 As a safeguard in testing, a full Westheimer function is ini­ tially determined on each patient. If this is within expected bounds and if blur is mini­ mized, one tests only three key points in or­ der to evaluate the Westheimer function at the same point in the visual field on subse­ quent visits (Fig. 1, B ) .

From the Washington University School of Medicine, Department of Ophthalmology, St. Louis, Missouri. This study was supported in part by National Eye Institute research grant EY-00204 (Dr. Enoch), and in part by National Eye Insti­ tute contract l-EY-1-2514 (Bernard Becker, M.D.), National Institutes of Health, Bethesda, Mary­ land. Reprint requests to Jay M. Enoch, Ph.D., De­ partment of Ophthalmology, University of Florida College of Medicine, Gainesville, FL 32610. * Daw and Enoch1 extensively studied a patient previously described as a rod monochromat; he actually was a blue-cone monochromat. However, the previous analysis of his measured Westheimer function as being scotopic was valid.

When the Westheimer function has been simplified and shortened in the manner just described, it may be used to evaluate a pa­ tient's status in time, that is, progression of a disease or the efficacy of therapy can then be evaluated (within the capability of the test). The simplicity of the reduced examina­ tion allows the use of routine and noncomplex statistical procedures if desired. Ex­ amples of the use of the test for these pur­ poses are included in this study. If an anomaly exists central to the optic

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734

RECEPTIVE FIELD PROPERTIES

VOL. 80, NO. 4

nerve head, it is more difficult to measure the Westheimer function because visual sensi­ tivity tends to fall off markedly in time. This time-dependent loss in sensitivity has been termed a short-term saturation or visual fatigue-like effect. It is evaluated by using the flashing repeat static perimetric test.2'7-8 This response property (as evaluated by this test) is most useful as a means of localizing the locus of involvement of a disease process. METHOD

Westheimer function—A psychophysical method was used to define what we believe to be retinal receptive field characteristics by varying the size and luminance of a contin­ uously visible background field upon which was displayed a small, fixed size and lumi­ nance, slowly flashing stimulus. The experiments were conducted by using a Goldmann Haag-Streit perimeter with sta­ tic and flicker attachments. An added field was introduced and certain limited modifica­ tions were made on the equipment.2"4 Earlier studies more completely summarize the method.2'4'5'7 These luminous fields are superimposed. FIELD I—A small, regularly flashing test field (70 msec every 0.5 second) was cen­ tered on the point in the visual field to be tested. The just detectable (flashing static) threshold of this small field was first deter­ mined against the usual cupola background. The small flashing field was then set at a fixed luminance level above that threshold value (usually between 0.7 and 1.0 log units). 4 The standard pantograph arm on the perimeter provided the flashing test field. FIELD II—Field II was a background field continuously presented. It was centered about Field I with its area being altered, stepwise, over a large range down to that of Field I. Either the subject or the examiner varied the luminance of Field II by means of a neu­ tral density filter wedge. The examiner sought to determine when flashing Field I disap­ peared (by increasing Field II luminance) and then reappeared (by decreasing Field II

735

luminance). Mean values of each of the two sets of measurements of Field II luminance (and ranges of measurements) were plotted for each area (diameter) of Field II. The re­ sult comprised the Westheimer function. A modified Haag-Streit fixation projector was employed to form Field II. 2 ' 4 ' 6 ' 7 Luminance of Field II was varied at a rate of 0.1 log unit/second. FIELD III—The cupola of the Goldmann perimeter formed the surrounding field that we held at the usual luminance value (10.03 candelas/m2, 31.5 apostilbs, or 3.15 mL) throughout testing. The presence of this field minimized artifactual responses. The stimulus array was located at 5° on the 0° half meridian or radius on the Gold­ mann perimeter and an auxiliary fixation projector allowed control of fixation during testing.4 When studying lesions causing relative field loss or field loss without sharp bounda­ ries, we selected test loci in areas of relative scotoma. Control data were obtained from (relatively) uninvolved points in the same eye or the fellow eye at the same distance from the fovea. Flashing repeat static test—The flashing repeat static perimetric test was performed on all patients. The examiner determined the static threshold again and again for a fiveminute test period.2'5'8 First, the patient was given a pretest rest period of three to five minutes with his eyes closed; upon opening his eyes, the test was initiated immediately. The stimulus was adjusted from nonseeing to just seeing at the point in the visual field that was being evaluated. Light adaptation will influence results initially and natural fluctuations in sensitivity will cause some variance in response.10'11 However, in the normal individual the threshold will vary only modestly during the test period. In the presence of an anomaly central to the optic nerve head, sensitivity tends to fall off sharp­ ly within a short period of time. This was termed a short-term saturation or visual fatigue-like effect.8

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2.0 3.0 4.0 1.0 1 FIELD H , LOG BACKGROUND AREA (Minutes of Arc) Fig. 1 (Enoch and Lawrence). Case 3. Field II background log luminance is expressed on the ordinate; column 1 is the scale measured in candelas per square meters, column 2 in apostilbs, and column 3 in millilamberts. The specific log luminance value in millilamberts for Figure A is indicated just within the ordinate. SA corresponds to the summation arm of the Westheimer function. IA refers to the inhibition arm, and AP applies to the asymptotic portion of the curve. A, Westheimer function data for right fovea, on Jan. 2, 1973. Field I luminance was 1.0 log unit above the foveal flashing static threshold. The solid lines indicate the mean data sets; the broken lines give the measurement range for each background size (Field I I ) . B, The points of inflection of the data set in A are reproduced here. C, A hypothetical data set showing the inhibition arm somewhat flattened at a sub­ sequent examination time. D, The anchors (SA) of the two data sets (B and C) were brought into regis­ ter. One may then compare the two inhibition arms in order to see if a significant change in response has occurred. This is our conclusion because the entire ranges of data for both thresholds no longer overlap. This is a conservative criterion for judgment. The data ranges for the summation arm parts of the figures were not reproduced in order to minimize confusion. DM indicates the difference between the mean thresholds of the two data sets.

VOL. 80, NO. 4

RECEPTIVE FIELD PROPERTIES

Data analysis—The data for a normally shaped Westheimer function (Fig. 1, A) were taken from the right fovea of one pa­ tient (Case 3) on Jan. 2, 1973. The size of the flashing test field (Field I) was always equal to or smaller than the size of the small­ est steadily presented background field. Two sets of determinations were made for each background field size: flashing test field just invisible, and flashing test field just visible. The solid lines represent the mean and the dotted lines represent the range of the re­ sponses for each background size (Field I I ) . Three key points were selected and con­ nected (solid lines) in Figure 1, B. For prac­ tical purposes, these three points define the summation and inhibition arms of the func­ tion if blur is minimized at the test points and care is taken in examination. The key information (contained in the determination of the full Westheimer function) is fully ex­ pressed by this more limited test sample. This reduced examination time by a factor of more than 2. We assumed that the dimensions of the function do not alter in time. This as­ sumption has been borne out in prior testing. To compare two successive data sets, we made use of the fact that the summation arm is apparently not altered systematically in shape by ocular pathology, that is, while outer retinal layer and choroidal disease may shift the function up and down on the graph, summation arm shape did not appear to be consistently altered. (The upward and down­ ward shift of the function can also be de­ duced by studying the flashing static perimetric threshold for a small test object at the same test point.) Thus, one may make use of the two sets of test points defining the sum­ mation arm to anchor effectively the func­ tion for comparison with a second data set. We shifted successive data sets vertically on the graph to obtain the best overlap of the summation arm ( S A ) . The separation of the mean values for flashing test field (Field I) disappearance (upper-data set of each pair) and reappearance (lower data set) may not be wholly equal. Similarly, the range of de­

737

terminations for each judgment may be dif­ ferent. Some variation in slopes also occurs. However, it was not difficult to overlap two data sets satisfactorily (Fig. 1, D ) . The data sets marked with X's (Fig. 1, C) are hypo­ thetic values for purposes of illustration. The practicality of the approach will be seen. The two sets of curves in Figure 1, D were vertically adjusted so that a common summa­ tion arm is shared. If the mean values in the depression (dip) between the two arms of the two data sets are set approximately equal, one can readily determine whether a significant change has occurred in the inhibi­ tion arm of the function, that is, one can then ask if the two sets of data taken at the largest test area (right hand values) are the same or different. The null hypothesis can be tested. If the null hypothesis is rejected, a significant change in the inhibition arm has occurred, assuming that our overlapping the summa­ tion arms was valid (Fig. 1, D ) . In a busy practice, routine statistical testing is not prac­ tical; a simplified scheme is necessary. In our laboratory a minimum of four pairs of determinations were made at each test point (that is, a minimum of eight determinations), or four for each mean value. The range of each data set is plotted about each mean value. The midpoint between the flashing-field-justdisappeared mean and the flashing-field-justreappeared mean is regarded as the threshold value. We regard a clinically meaningful change as one in which the two pairs of mean values and two sets of ranges (of the inhibi­ tion arm) do not overlap (Fig. 1, D ) . This is a conservative criterion. If a question arose as to whether a differ­ ence was real or if variance was great, the data set was repeated. We re-evaluated each background area and the function as a whole. We included three cases in order to dem­ onstrate our techniques. The three subjects were in a double-blind study designed to test the efficacy of diphenylhydantoin sodium (Dilantin sodium) in primary open-angle glaucoma. The question asked in the diphenyl­ hydantoin study was whether this agent helps

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VOL. 80, NO. 4

RECEPTIVE FIELD PROPERTIES

protect the function of the neural elements as it does in other anomalies of the central nervous system. (This agent is not meant to aid in the control of intraocular pressure.) The medication was given orally for one sixmonth period and a symptom equivalent con­ trol, phenobarbital, was given during another six-month period. The research team did not know which subject was receiving which drug at any given time. We chose these three sub­ jects for presentation because they had com­ pleted the course of testing and because they each illustrated an important point. We had been observing one patient (Case 3) for more than a year before he was admitted to the glaucoma project (Fig. 2). CASE REPORTS Case 1—This 72-year-old black man with pri­ mary open-angle glaucoma was initially referred to the Glaucoma Center in 1965 because of ocular hypertension; intraocular pressures were R.E.: 20 mm Hg, and L.E.: 32 mm Hg. He had full visual fields and open angles. During the five years he was followed in the Glaucoma Center his in­ traocular pressures were R.E.: below 20 mm Hg, and L.E.: in the range of 30 mm Hg. There was a suggestion of a nasal step in the left eye as early as 1968. In December 1971, he had a nasal step and a small shallow paracentral scotoma superior and nasal to fixation in his left eye. The nasal de­ fect was not plotted in January 1972; however, it was confirmed in July and the patient was re­ ferred to the Dilantin Contract Study. We plotted the visual field of his left eye at the outset of the study (Fig. 3). There was no history of significant ocular trauma, decreased vision, or ocular surgery. There was no family history of glaucoma. The patient began the study on Aug. 2, 1972. Physical examination at that time disclosed the fol­ lowing values: visual acuity, 20/20 in both eyes with correction; external examination, motility, and pupils were all within normal limits; slit-lamp ex­ amination revealed dense arcus senilis in both eyes with early nuclear sclerosis; gonioscopy revealed grade 2 angles 360°, in both eyes, with no angle re­ cession or peripheral anterior synechia; 24-hour in­

739

traocular pressures ranged from 14 to 22 mm Hg (R.E.), and 20 to 26 mm Hg (L.E.) ; tonography, R.E.: 19.3 with out flow facility of 0.12, and L.E.: 26 with out flow facility of 0.10; and the fundus of the dilated pupil revealed a cup/disk ratio of 0.5 (R.E.), and 0.6 (L.E.). Maculae and vessels in both eyes were normal. During the study, the patient received no intra­ ocular pressure-lowering medication. Intraocular pressures during the study ranged from 14 to 20 mm Hg (R.E.), and 14 to 29 mm Hg (L.E.). Sequential applanation tonometric determinations are reported in Table 1. Hematologic evaluation, urinalysis, and blood chemistry were all essentially within normal limits. A quantitative VDRL test was nonreactive; however, FT A absorbed was reactive (we do not know whether this patient was treated for syphilis).

Comment—At the outset of the study his left central field (Fig. 3) was normal. We selected two points (C, 15° on 225°; and D, 15° on 45°) for study. These are symmetri­ cally displaced from the fovea and are field areas often showing alteration in glaucoma. An area of relative field loss subsequently developed near point D and we followed changes in the patient's kinetic field in this area and measured his flashing static thresh­ old, his Westheimer function, and his repeat flashing static function* at this point and compared modifications in each indicator of response in time. The static thresholds of all three subjects are plotted in Figure 2. In all determinations described here, image blur was minimized at the test point. It is obvious that his flashing * Since the duration of each flash presentation was near the critical duration (70 msec), it is doubtful that the flashing static response differed in a substantial way from a more prolonged test target exposure. The flashing or pulsed stimulus (it is not a "flicker" test) has the advantage of forcing a judgment on each target presentation. It is also useful in discriminating between a loss or alteration of the local adaptation response and a loss due to a short-term saturation or visual fatigue-like factor.

Fig. 2 (Enoch and Lawrence). Flashing static perimetric thresholds at test and control points for the three patients reported during the entire test period. Sequential test point data were connected to minimize confusion. In Case 3, Point G was the test point and Point F was the center point.

AMERICAN JOURNAL OF OPHTHALMOLOGY

740

OCTOBER, 1975

Fig. 3 (Enoch and Lawrence). Case 1, left eye. Kinetic field record at the beginning of the test period. Points D and T were test loci; points C and S were control points. TABLE 1 APPLANATION TONOMETRY IN CASE 1

Date

Applanation Tonometry, mm Hg R.E.

L.E.*

8/2/72 9/1/72

22 16

26 24

9/29/72 11/3/72 12/6/72

18 20 18

27 28 23

1/9/73 2/8/73 3/8/73

10 18 14

14 28 19

4/6/73 S/8/73 6/7/73 7/6/73 8/3/73

20 20 16 17 17

23 29 24 19 19

* Eye described in this paper.

Medication

Contract medica­ tion started

Westheimer Function Normal

Central Visual Field Normal

Point D, normal; Point T, Deteriorating inhibition arm lost Contract medica­ tion changed

Contract ended

Point D, inhibition arm lost Improved Vague area Slight improvement Deteriorating

RECEPTIVE FIELD PROPERTIES

VOL. 80, NO. 4

static threshold (Fig. 2, top right) showed some increase in sensitivity at point D, and then a fall in sensitivity at the beginning of 1973. Data at point C (the control point) simply oscillate about Goldmann 2b. Data at subsequent test point T and control point S compare with D and C. We selected a sample set of this patient's repeat flashing static test data determined at test point T randomly (Fig. 4 ) . His deter­ minations were reasonably stable, suggesting that there was probably no involvement cen­ tral to the optic nerve head, a typical finding in primary open-angle glaucoma. This set of data was obtained after glaucomatous field changes and alteration in the Westheimer function had occurred. We compiled a month-by-month determi­ nation of his Westheimer function and cen­ tral field (Fig. 5, parts A and B ) . In the in­ terest of conserving space, a few fields were deleted, but the trends are evident. The Westheimer function' for the control point C (Fig. 5, part A, top) demonstrates an es­ sentially unchanged field throughout. There was some variation in the West­ heimer function from session to session (Fig. 5, part A, point D ) , but the function

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remained fundamentally consistent on repeti­ tion. We noted kinetic field changes in the area of interest on Dec. 6, 1972, when a rela­ tive scotoma developed between point D and the fovea. An additional test and control point were added at that time; these were points T (12° on 44°) and S (12° on 225°) (Figs. 3 and 5, part A ) . The inhibition arm of the Westheimer function was already flat­ tened at point T, but was normal at control point S (Fig. 5, part C) and at test point D (Fig. 5, part A) on that date. The relative scotoma expanded to include point D and a substantive change in the Westheimer func­ tion occurred at this point by March 1973 (Fig. 5, part B). The inhibition arm of the response at point D was lost and did not re­ cover during the test series, although there was a hint of recovery in July. Statistically, however, the latter change may not be signif­ icant. The inhibition arm of the Westheimer function at point T remained flattened throughout the balance of the study. West­ heimer functions at control points C and S remained virtually unchanged throughout the study. The static threshold (Fig. 2, upper right) at the points indicated follows the course sug-

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AMERICAN JOURNAL OF OPHTHALMOLOGY

742

OCTOBER, 1975

TABLE 2 APPLANATION TONOMETRY IN CASE 2

Date

Applanation Tonometry, mm rig R.E.*

L.E.

11/2/71 12/14/71

29 29

26 27

1/11/72 2/15/72 3/14/72 4/11/72 5/9/72 6/6/72

24 29 30 32 28 30

20 26 28 30 22 31

7/5/72 8/8/72 9/7/72 10/10/72 11/9/72

25 29 33 31 34

25 27 32 27 35

Medication Pilocarpine Contract medica­ tion started

Westheimer Function

Point B, inhibition arm lost Superior defect

Inhibition arm improved

Contract medica­ tion changed

Central Visual Field

Improved to normal

Inhibition arm deteriorating Inhibition arm lost

Deteriorating

Contract ended

* Eye described in this paper. gested by the kinetic fields in Figure 5, part B. The loss of the inhibition arm of the Westheimer function occurred after initial kinetic field and static threshold changes and did not exhibit significant recovery. These sets of data provided a unique op­ portunity to relate the point in time when change in the Westheimer function occurred relative to the change in visual field proper­ ties in primary open-angle glaucoma. Differ­ ent technicians compiled field data and West­ heimer function data. The two data sets were joined several months later in all three cases except for those obtained during the first treatment regimen in Case 3 where the same person (B.L.) obtained all data.

Case 2—This 70-year-old black woman with primary open-angle glaucoma in her right eye joined the study in November 1971. Her past ocular history was noncontributory. There was no ocular pain, redness, halos, or round lights. A daughter and a son had primary openangle glaucoma. Her ocular examination included the following values: visual acuity was 20/25+, in both eyes; external examination, motility, and pupils were within normal limits; slit-lamp examination re­ vealed mild nuclear sclerosis of both eye lenses; gonioscopy revealed grade 1 to 2 angles 360°, in both eyes, with repeated negative dilation pro­ vocative tests; fundus revealed a 0.7 cup/disk ratio with normal maculae and vessels; 24-hour intraocular pressures ranged from 22 to 33 mm Hg (R.E.), and 20 to 30 mm Hg (L.E.) ; tonography, R.E.: 30.4 with outflow facility of 0.25, and L.E.: 24.8 with outflow facility of 0.17. The patient received pilocarpine 4% in both

Fig. 5 (Enoch and Lawrence). Case 1. Sequential Westheimer functions with several parallel central kinetic field records obtained at approximately the same time. A, the top left Westheimer function data set refers to the control point C; all other Westheimer function data on parts A and B refer to test point D. An additional test (T) and control point (S) were added to the experiment on Dec. 6, 1972. Westheimer functions obtained at these two loci are shown in part C with the upper left data set referring to control point S and all other data referring to test point T. Stippled (or dotted) areas on the field represent the blind spot (I»e unless otherwise designated). Horizontal line patterns signify areas of relative scotoma. The Field II background log luminance scale (millilamberts) to the left of the Westheimer functions is not specific for any data set: the scale applies to the entire chart. Specific values for each data set are designated just within the ordinate. Horizontal dashed lines, also present just within the ordinate, separate the specific luminance values measured on the different dates.

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AMERICAN JOURNAL OF OPHTHALMOLOGY

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Fig. 6 (Enoch and Lawrence). Case 2, right eye. Kinetic visual field record at the beginning of the test period. Point B was the test point and point A was chosen as control point for this test series, Nov. 2,1971

eyes, four times daily, throughout the year of the study. Intraocular pressures ranged from 24 to 37 mm Hg (R.E.), and 20 to 37 mm Hg (L.E.) during the year of the study. Sequential applanation tonometric determinations are listed in Table 2. Hemotologic evaluation showed a mild leukopenia. Urinalysis was within normal limits; blood chemistry showed an elevated cholesterol level and abnormal glucose tolerance test. Skull and optic foramena x-ray films were within normal limits.

Comment—The primary open-angle glaucomatous field loss was fairly well advanced in the right eye (Fig. 6) at the outset of the study. Point A (7° on 240°) was the control test point and point B (7° on 60°), located in an area of relative field loss, served as the test point. Her kinetic field, static threshold, and Westheimer function improved during the first six-month period while the improve­ ment in her visual field and other responses regressed during the second six-month pe­ riod. Her situation can best be appreciated

by following her kinetic field (Fig. 7), which started to improve almost immediately. The field recorded by the technician on Jan. 11, 1972, is odd. Her condition exacerbated ac­ cording to the field on July 5, with the situa­ tion deteriorating from that time onward. She changed medication after May 11. Her flashing static threshold (Fig. 2, upper left) roughly follows the kinetic field course, al­ though sensitivity on Aug. 7 and Sept. 7, seems disproportionately high. (Fortunate­ ly, control point A was in an area largely unaffected by the fluctuations in the field.) With practice, the patient's Westheimer function (Fig. 7) measurement ranges nar­ rowed (compare Dec. 14, 1971, with Sept. 7,1972). The Westheimer function improved on Feb. 15; this improvement lasted until May or June. We observed a steady decline in the inhibition arm from that time. The changes in the Westheimer function seemed

VOL. 80, NO. 4

RECEPTIVE FIELD PROPERTIES

to be lagging the kinetic field changes less in Case 2 than in Case 1. In Case 2, transient reversal of inhibition arm loss was unequi­ vocally demonstrated in glaucoma. This underscored the reversibility of these changes up to a certain point in the progres­ sion of thcdisease. Her repeat static finding remained relatively stable throughout (Fig. 8). Case 3—This 56-year-old black man, referred to the Glaucoma Center with the probable diagnosis of tobacco-alcohol amblyopia and questionable glau­ coma, had a six-year history of difficulty with both distance and near vision. He had progressive loss of both visual acuity, greater in his left eye, and color vision, in both eyes. He supposedly had 20/20 vision, in both eyes, and normal color vision in the Armed Forces. The patient had a history of heavy alcoholic intake "whenever he gets the money." He denied DT's, seizures, drinking moonshine, or illegal alco­ holic beverages. The patient did not have a con­ tributory history of exposure to other toxins. He had smoked one half to one package of cigarettes per day for many years. A Farnsworth 100-hue test Oct. 19, 1971, re­ vealed poor hue discrimination, typically seen in individuals with a history of alcoholism. There seemed to be a slight tendency toward the deutan axis. The patient had repeated injections of hydroxocobalamin, during 1972. He had been treated for syphilis and had a positive FTA Abs with a nega­ tive cerebrospinal fluid VDRL test. The patient be­ gan the Dilantin study in February 1973. At that time, ocular examination values were as follows: visual acuity (Fig. 9) ; fundus (dilated) revealed a 0.8 cup/disk ratio (R.E.), and 0.7 cup/disk ratio (L.E.) with normal maculae and vessels; slit-lamp examination was unremarkable; 24-hour intraocular pressures ranged from 19 to 40 mm Hg (R.E.), and 19 to 22 mm Hg (L.E.) while receiving pilocarpine 4%, four times daily, and epinephrine hydrochloride (Glaucon) 2%, twice a day, to his right eye; tonography, R.E.: 22 with outflow fa­ cility of 0.32, and L.E.: 22 with outflow facility of 0.25. The year of the diphenylhydantoin study, the patient received the following medication to the right eye: pilocarpine 4%, four times daily, epine­ phrine hydrochloride 2%, twice a day; and Con­ tract medication. Intraocular pressures during the study ranged from 15 to 33 mm Hg (R.E.) and 17 to 36 mm Hg (L.E.). Sequential applanation tonometric determi­ nations are reported in Table 3. The patient was somewhat unreliable in taking his medications. We did not note progression in disk cupping during the year of the study. Hematologic evaluation, blood chemistry, and urinalysis were within normal limits.

747

Comment—This case was complex. There was evidence of prior syphilitic involvement and the presence of tobacco-alcohol ambly­ opia and primary open-angle glaucoma. Throughout our study, there were some fluc­ tuations in his responses; he repeatedly re­ turned to alcohol but was cooperative at most test sessions. There were two therapeutic periods: during the first course he was treated with hydroxocobalamin for his to­ bacco-alcohol amblyopia, and during the sec­ ond treatment period he was included in the diphenylhydantoin evaluation study. We examined the patient initially in our laboratory on Oct. 17, 21, and 29, 1971. At that time he had substantial field loss. His kinetic field on Oct. 29, is shown in Figure 10. Test data were taken repeatedly in an area of relative field loss (point G, 12° on 128°) and an area of essentially normal response (point F, 12° on 217°) located at the same distance from the fovea as point G. Data on foveal response were also assembled (Fig. 1, A ) . At the outset, his right visual acuity was poor (Fig. 9) and the inhibition arm of the Westheimer function in the fovea was somewhat flattened. Fixation was good. The flashing repeat static (Fig. 11) at the control point F (Fig. 10) remained relatively stable. However, the flashing repeat static at test point G (Fig. 12), exhibited a decline in sensitivity in time, typical of a short-term saturation or visual fatigue-like effect. This signified involvement central to the optic nerve head.8 At the same time his Westheimer function1 (Fig. 13, part A) showed a loss of the inhibition arm at point G, but normal form at control point F ; this indicated inner retinal involvement as well. On Oct. 21, 1971, point G had lower sensitivity (0.5 log unit) than point F on the flashing static test (Fig. 2). It would be valuable to know if the outer retinal layer was involved (a local electroretinogram would aid in such a decision). Foveally, the inner retinal layer was prob­ ably involved to a lesser degree. We began treating the tobacco-alcohol amblyopia on Oct. 29, 1971, with a series of 17 intramuscular injections of 1,000 jug of

A

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FIELD II LOG AREA (Minute* of Arc)1 Fig. 7 (Enoch and Lawrence). Case 2, right eye. Sequential Westheimer function data with several parallel central kinetic field records obtained at approximately the same time. The upper left data set (part A) was obtained from control point A. All other Westheimer function data were obtained from test point B.

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EQUIVALENT GOLDMANN SIZE I

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FIELD 1 LOG AREA (Minutes of Arc)2 The stippled or dotted areas on fields represent the blind spot (Ije unless otherwise designated). The horizontal line patterns signify areas of relative scotoma (see Figure 5, second paragraph).

AMERICAN JOURNAL OF OPHTHALMOLOGY

750

OCTOBER, 1975

2 3 TIME (Minutes) Fig. 8 (Enoch and Lawrence). Case 2, right eye. Flashing repeat static perimetric test data, test point B, Sept. 7,1972.

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VOL. 80, NO. 4

RECEPTIVE FIELD PROPERTIES

hydroxocobalamin (Vitamin B12b) at ap­ proximately two-week intervals. Little change was noted after the first injection, or im­ mediately after the second injection. How­ ever, between the second and third injections dramatic improvements were recorded in all response parameters. The improvement in the Goldmann I'3e kinetic perimetric isopter oc­ curred on Dec. 8 (Fig. 14). The visual sat­ uration or fatigue-like effect previously ob­ served on the flashing repeat static test (Fig. 12, a-c) was no longer present (Fig. 12, D). On Nov. 23, the inhibition arm of the West­ heimer function showed marked recovery (Fig. 13, part A). Foveal Westheimer func­ tion data took on a relatively normal appear­

751

ance that was sustained. At that time, flash­ ing static thresholds at both points F and G also showed improvement (Fig. 2). Visual acuity improved in both eyes by Dec. 8 (Fig. 9). Most functions showed continued or sus­ tained improvement throughout the course of treatment except the Westheimer function at point G (Fig. 13, A, bottom), and the static threshold (Fig. 2). We initially noted de­ terioration in these functions on April 4, 1972. The field determined on May 30, showed some deterioration near test point G. After termination of the hydroxocobalamin treatment on June 26, the fate of the various parameters varied. The flashing repeat static test at point G remained relatively steady

TABLE 3 APPLANATION TONOMETRY IN CASE 3

Date

Applanation Tonometry, mm Hg R.E.'

L.E.

10/18/71

35

21

12/8/71 1/4/72 3/2/72 3/16/72 3/30/72 4/6/72 4/11/72 4/18/72 5/3/72

32 21 33 31 39 33 27 17 25

26 21 19 20 26 21 22 17 21

6/1/72 7/11/72

27 19

19 17

10/9/72 1/8/73 1/16/73

21 29 19

20 26 19

2/15/73 3/14/73 4/12/73 5/14/73 6/12/73 7/18/73

32 22 16 19 22 28

22 24 18 19 22 24

8/17/73 9/24/73 10/25/73 12/7/73 1/4/74 2/5/74

23 28 29 20 33 19

20 19 19 17 36 17

* Eye described in this paper.

Medication

Westheimer Function

Hydroxocobalamin Point G, inhibition arm lost started 10/29/71 Inhibition arm impi

Central Visual Field Superior defect

Pilocarpine started ■

Epinephrine hydro- I nhibition arm detei chloride started Hydroxocobalamin Inhibition arm lost ended 6/26/72 Contract medica­ tion started

Slight improvement Contract medica­ tion changed Deteriorating

Contract ended

752

AMERICAN JOURNAL OF OPHTHALMOLOGY

OCTOBER, 1975

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Fig. 10 (Enoch and Lawrence). Case 3, right eye. Kinetic visual field record at the outset of the test sequence. Point G is the test point, point F the control point, Oct. 29, 1971. CM

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Fig. 12 (Enoch and Lawrence). Case 3. Sequential flashing repeat static perimetric test data at test point G. In b, the open triangles indicate retest response after a brief rest period. In a, b, and c, the symbols on line 4eNV indicate that the stimulus was not visible. In c and d, note the dramatic recovery between the second and third injec­ tion of hydroxocobalamin. This improvement was sustained.

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FIELD H LOG AREA (Minutes of Arc) 2 Fig. 13 (Enoch and Lawrence). Case 3, right eye. Sequential Westheimer function test data with several parallel central kinetic field records obtained at approximately the same time. The upper left data set (part A) was obtained from control point F. All other Westheimer function data were obtained from test point G. The stippled or dotted areas on the fields represent the blind spot (I2e unless otherwise desig­ nated). The horizontal line patterns signify areas of relative scotoma (see Fig. S, second paragraph).

756

AMERICAN JOURNAL OF OPHTHALMOLOGY

OCTOBER, 1975

Fig. 14 (Enoch and Lawrence). Case 3, right eye. Kinetic I«e visual field records, obtained during the early course of therapy for tobacco-alcohol amblyopia, show gen­ eral kinetic field improvements that occurred parallel with other test parameters. Con­ nected dots, Oct. 29,1971; solid line, Nov. 15,1971; dots and dashes, Dec. 8,1971.

(Fig. 12, f). The kinetic field slowly deteri­ orated (Figs. 13, parts A, bottom, and B), The inhibition arm of the Westheimer func­ tion subsequently showed no improvement, including during the second course of treat­ ment (Fig. 13, part B). The flashing static threshold at points F and G showed a fluc­ tuating course over the years. The initial im­ provement in visual acuity in the fovea was largely maintained, with fluctuations occurr­ ing in the intervening period. Neither the symptom equivalent control medication nor diphenylhydantoin, administered for a 12month period, substantially altered the mea­ sured parameters (Figs. 2, 9, 12, and 13, parts A and B ) . The patient clearly improved with hyroxocobalamin therapy. Depending on the mea­ sured parameter, that improvement was sus­

tained for a short or long period after cessa­ tion of the treatment. The second course of therapy (in terms of the measured parame­ ters) did not seem to alter the continued slow downhill course of the visual response in his peripheral field. Applanation tonometer determinations— We attempted to relate these measurements to Westheimer function and visual field changes. One patient (Case 2) maintained high pressures in her right eye. The changes in visual responses could not be anticipated on the basis of applanation tonometry, al­ though continued pressures of 30 mm Hg would not improve long-term prognosis. An­ other patient (Case 1) exhibited pressure fluctuations in his left eye that correlated poorly with visual test changes. There may have been a possible relation-

VOL. 80, NO. 4

RECEPTIVE FIELD PROPERTIES

ship between the higher pressures recorded in the right eye of another patient (Case 3) in March and April 1972 (resulting in pilocarpine treatment) and subsequent central field and Westheimer function changes. In the Westheimer function experiment, Field I was set at 0.8 to 1.0 log unit above the flash­ ing static threshold. Thus, even if the static threshold was altered, the Westheimer func­ tion should not have been meaningfully af­ fected by alteration of pupil diameter. On the other hand, visual field determinations can be somewhat sensitive to changes in pupil size. The pupil of the last patient varied between 2 and 4 mm (in time). Since he was not reliable regarding the self-admin­ istration of medication, a registered nurse administered the hydroxocobalamin injec­ tions. DISCUSSION

No single parameter characterizes visual performance since several variables are at play at any given moment. Periodic exacer­ bations and remissions of disease processes tend to make attempted analyses difficult. Be­ cause of such fluctuations, it becomes desir­ able to follow the course of the individual pa­ tient. We believe the Westheimer function and the -flashing repeat static threshold tests are valuable additions to the visual held tesTarmamentarium. We have shown how the Westheimer technique can be greatly speeded up in order to make it a more acceptable clinical test. From these data, significant alteration in response can be readily identified without complex statistical analysis. If one accepts the relatively conservative position of nonoverlap of data ranges as the criterion for meaningful change, then there can be little question of rejection of the null hypothesis in a more formal statistical analysis. Repeated testing resolves questions of reliability of the observer or of changes observed. These tests can be used as part of a pro­ gram to test sequentially the efficacy of a therapeutic regimen or to follow the course of

757

an anomaly. The value of a data set is depen­ dent on the proper selection of loci for test and control points. One makes use of one's knowledge of the course of the anomaly and picks those test loci that will probably provide valued data. The optimum sizes of back­ ground field to use at a given test point in studies of the Westheimer function were de­ scribed.2 If blur is corrected, there seems to be little variance in the dimensions of the function for most people, paying attention to spectacle magnification properties. The latter can often be assessed by plotting the normal blind spot and considering its field location and size:12 In this study we demonstrated the time course of change in the inhibition arm of the Westheimer function relative to kinetic vi­ sual field change (Case 1) in primary openangle glaucoma. We clearly showed that the loss of the inhibition arm of the Westheimer function is reversible in primary open-angle glaucoma, at least to a certain stage in the disease (Case 2 ) . We were able to differen­ tiate the most probable cause of the loss of the inhibition arm of the Westheimer func­ tion in a complex of disease states, through analysis of several response parameters in conjunction with a therapeutic regimen in Case 3. That is, since anomalous response at point G in this patient comprised more than one response level (inner retinal layer and central to the optic nerve head), and since functional improvement occurred in all re­ sponse parameters after therapy specifically for tobacco-alcohol amblyopia, we concluded that the most probable cause of the field de­ terioration at this point during the first course of therapy was the tobacco-alcohol ambly­ opia rather than the glaucoma. The West­ heimer function at test point G in Case 3 showed inhibition loss and loss of sensitivity just before cessation of the hydroxocobala­ min treatment, but the improvement in re­ sponse to the flashing static perimetric test at the same point, foveal acuity, and the foveal Westheimer function were largely maintained. Thus, exacerbation of the dis-

758

AMERICAN JOURNAL OF OPHTHALMOLOGY

ease process at visualfieldpoint G was prob­ ably limited to the inner retinal layer. Since the effects of tobacco-alcohol amblyopia were apparently not limited to the inner retinal layer initially, one could hypothesize that the exacerbation was caused by the primary openangle glaucoma that clearly affects this re­ gion, or by the combined action of the glaucomatous disease process and the tobaccoalcohol amblyopia. The applanation tonometric determinations in March and April 1973 (Table 3) seem to lend weight to this argu­ ment. Neither diphenylhydantoin nor the control drug seemed to affect the course of the disease of this patient at this state of progression. The data on one patient (Case 1) suggest another interesting finding (Fig. 5). There seemed to be recovery of the kinetic field, while at two separate points in the field the Westheimer function remained abnormal. The flashing static perimetric threshold also showed improvement on July 6, 1973 (Fig. 2). Repeat flashing static perimetric data were essentially normal on that date. This is the first time we recorded a clearly abnormal Westheimer function (loss of inhibition arm at two test points) while other response pa­ rameters at the same locus revealed relatively normal (or improved) function. Usually, we tested areas of abnormal function as a means of locating areas of abnormal Westheimer response. This finding suggests that this ap­ proach needs to be reconsidered. SUMMARY

We used a technique to simplify and speed up a perimetric test (Westheimer function). Through sequential testing, the technique was successfully used to evaluate pathologic find­ ings and partially to evaluate treatment regi­ mens in three subjects. One patient had an onset of kineticfieldchanges and Westheimer function alteration with primary open-angle glaucoma. Temporary remissions of altera­ tions in the Westheimer function and kinetic visual field loss occurred in patients with glaucoma and tobacco-alcohol (complicated)

OCTOBER, 1975

amblyopia. Using these techniques it is pos­ sible to localize an anomaly in the outer ret­ inal layer, the inner retinal layer, and central to the optic nerve head. We divided the in­ ner and outer retinal layers on a vascular sup­ port basis. ACKNOWLEDGMENT

We thank Kenneth Buerk, M.D., for patient se­ lection; Allan Mandell, M.D., for assistance in preparing the summaries of patient histories; and Allan Kolker, M.D., for assistance in selecting the fields points tested in Case 1. REFERENCES

1. Daw, N. W., and Enoch, J. M.: Contrast sensitivity, Westheimer function, and Stiles-Craw­ ford effect in a blue cone monochromat. Vision Res. 13:1669, 1973. 2. Enoch, J. M., and Sunga, R. N.: Develop­ ment of quantitative perimetric tests. Doc. Ophthalmol. 26:215, 1969. 3. Enoch, J. M., Sunga, R. N., and Bachmann, E.: A static perimetric technique believed to test receptive field properties. 1. Extension of Westheimer's experiments on spatial interaction. Am. J. Ophthalmol. 70:113, 1970. 4. : A static perimetric technique believed to test receptive field properties. 2. Adaptation of the method to the quantitative perimeter. Am J. Ophthalmol. 70:126, 1970. 5. Enoch, J. M., Berger, R. and Birns, R.: A static perimetric technique believed to test recep­ tive field properties. Extension and verification of the analysis. Doc. Ophthalmol. 29:127, 1970. 6. : A static perimetric technique believed to test receptive field properties. Responses near visual field lesions with sharp borders. Doc. Oph­ thalmol. 29:154, 1970. 7. Sunga, R. N., and Enoch, J. M.: A static perimetric technique believed to test receptive field properties. 3. Clinical trials. Am. J. Ophthalmol. 70:244, 1970. 8. : Further perimetric analysis of patients with lesions of the visual pathways. Am. J. Oph­ thalmol. 70:403, 1970. 9. Westheimer, G., and Wiley, R. W.: Distance effects in human scotopic retinal interaction. J. Physiol. 206:129, 1970. 10. Clarke, F. J. J.: Systematic variations in the absolute threshold for flashing lights. In The Per­ ception and Application of Flashing Lights. Lon­ don, Adam Hilger, Ltd., 1971, pp. 375-378. 11. Ronchi, L., and Barca, L.: On a modified version of the repeat static perimetric test. Atti Fond. G. Ronchi. 28:305, 1973. 12. Fankhauser, F., and Enoch, J. M.: The effects of blur upon perimetric thresholds. Arch. Ophthalmol. 86:240, 1962.