8-10 min; increased intraocular pressure was induced using a Langham scleral suction-cup system. The ocular pulsatile blood flow and the ophthalmic arterial ...
Investigative Ophthalmology & Visual Science, Vol. 31, No. 12, December 1990 Copyright © Association for Research in Vision and Ophthalmology
Intraocular Pressure-Dependent Light Sensitivity in Glaucoma Torsten Krakau,* Dovid Mullins,f and Maurice LonghamjThe intraocular pressure-dependent light sensitivity of discrete retinal points was measured using the Heijl-Krakau automated light-emitting diode perimeter with an appropriate software program. A total of 300 measurements of light sensitivity were recorded from six retinal points during the test period of 8-10 min; increased intraocular pressure was induced using a Langham scleral suction-cup system. The ocular pulsatile blood flow and the ophthalmic arterial pressure were measured in the same patients. The fluctuation of the light sensitivity was less than 5% over the test period in healthy eyes and remained unaffected by an intraocular-pressure increment of 20 mm Hg; a small decrease of sensitivity occurred at a pressure increment of 30 mm Hg. In glaucomatous eyes the light sensitivity was lower and the fluctuation of the light sensitivity at some but not all retinal points was substantially greater than in the controls. In the glaucomatous eyes, an intraocular-pressure increment of 20 mm Hg increased the fluctuation and decreased the light sensitivity. The pulsatile ocular blood flow was lower in the glaucomatous eyes but not severe enough to be solely responsible for the loss of vision. The coexistence of retinal points with normal and abnormal stabilities of light sensitivity in glaucomatous eyes was consistent with impaired blood flow in the lamina cribrosa. Invest Ophthalmol Vis Sci 31:2551-2559,1990
40-60 mm Hg; in similar conditions the light sensitivity of glaucomatous eyes decreased substantially. Short- and long-term fluctuations of light sensitivity in normal and glaucomatous eyes established that the fluctuation of differential light sensitivities was greater than normal in glaucoma and glaucoma suspects.5"9 Recently, a procedure for simultaneous recording of the differential light sensitivities at multiple retinal points as a function of time was described by Holmin and Krakau.10 The measurements were made at six retinal points during a test period of 30 min. The values were stable in normal eyes but not in glaucomatous eyes. This report extends these studies to an analysis of light sensitivity at experimentally induced increased IOP. The investigation was limited to a 10-min period, rather than the 30-min period used in the prior study.10 A preliminary report of thesefindingswas presented at the ARVO meeting in Sarasota, Florida.''
The influence of increased intraocular pressure (IOP) on the time-dependent stability of light sensitivity has not previously been studied. In 1955, Gaffner and Goldmann1 used dynamic and static manual perimetry to show decreased retinal sensitivity to relatively small IOP increments in normal eyes and a more substantial loss of sensitivity in glaucomatous eyes. Harrington,2 using static perimetry, reported that increased IOP induced transient visual loss in glaucomatous eyes that differed between discrete points on the retina, areas of relative scotoma being the most sensitive. Harrington ascribed the loss of light sensitivity to decreased ocular blood flow because the pressure effect was less in eyes with the higher ophthalmic arterial pressure (OAP). Drance3 confirmed Harrington's observations on the susceptibility of vision in relative scotomatous regions to increased IOP. In 1983 Langham,4 using Heijl-Krakau quantitative perimetry, reported unchanged light sensitivity in normal eyes when the IOP was increased to
Materials and Methods Ten normal and ten glaucoma subjects were tested; consent was obtained after the nature of the procedure had been explained fully. The normal group comprised six women and four men, ranging in age from 20-64 yr (mean, 35.7 ± 5.4 yr) with no apparent ocular disease. All had IOPs less than 21 mm Hg, outflow facilities exceeding 0.18 yu.1 min"1 mm Hg"1, and physiologic discs. The ten glaucoma patients (six
From the T h e Department of Experimental Ophthalmology, University of Lund, Malmoe, Sweden, and |The Ocular Pharmacology and Therapeutics Unit, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Submitted for publication: November 20, 1989; accepted May 17, 1990. Reprint requests: Dr. Maurice E. Langham, Wilmer Eye Institute, Woods Research Room 255, Johns Hopkins University School of Medicine, 601 North Broadway, Baltimore, MD 21205.
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / December 1990
TOTAL NUMBER OF TRIALS:
Fig. 1. The Heijl-Krakau perimetric system used in this study. The columns on the left give the 16 levels of light intensity emitted by the light emitting diodes and the number of retinal points showing visual thresholds at each different intensity level. Q is the modal value of all thresholds. Degrees of eccentricity are indicated under the circle. The total number of trials and the number of times the blind spot is illuminated and seen by the observer is given. The right-hand section shows the 64 points examined in the central field. For convenience, points with thresholds equal to the modal value are shown as O. Points with thresholds higher or lower than modal value are given negative or positive values, respectively, according to the number of intensity steps from the modal value (the zeroes are added to underscore points with relative light sensitivity loss). The performance value is the sum of the product of the number of points and the intensity level.
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women and four men) ranged in age from 41-68 yr (55 ± 3 yr). The diagnosis of glaucoma was based on IOPs which exceeded 25 mm Hg at repeated visits, outflow facilities less than 0.15 ^tl min"1 mm Hg"1 in the absence of therapy, cupping and asymmetry of the discs, nerve fiber defects, and/or visual field abnormalities; one patient's glaucoma was classified as low tension, and laser trabeculoplasty was administered 2 yr before this study. All glaucoma patients were receiving therapy at the time of these investigations.
points. The test session for each individual point was divided into ten periods, and in each period, five trials per point and five exposures of the blind spot were made. The computer constructed a graphic display of the time course for each individual test point (Fig. 3). The "zigzag" pattern of the measurements reflect the upper and lower intensity levels determined by the staircase software program; it does not indicate short-term fluctuations of the light sensitivity. The trials occurred randomly in the one to six points under study.
Analytic Methods
Analysis of Test Results
The Heijl-Krakau automated flat-screen perimeter1213 was used for all differential light-sensitivity measurements (Fig. 1). The differential light sensitivity is defined as a light stimulus that can be recognized above background with a probability of 50% in a given retinal location.7 The ratio of the intensities between each 16 consecutive levels is 2. The exposure time of the light stimulus was 0.25 sec unless otherwise stated. The intrastimulus time was 2 sec when the patient did not respond, but when the patient responded the following light stimulus was initiated 0.5 sec later. All differential light-sensitivity determinations were based on the up-and-down staircase method.6"8
The average of the five results over time t was used for the calculations of means and deviations from the NUMBERS OF THE TARGRT •
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The software program was similar in logic to the central vision threshold program but had notable modifications. A variable number (1-6) of user-selected retinal points were tested continuously over an 8-10-min period. Each point in the central field was numbered (Fig. 2) to facilitate user selection of retinal
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No. 12
LIGHT SENSITIVITY RESPONSE TO INCREASED IOP / Krokou er ol
2553
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Fig. 3. Typical examples of the time-dependent stability of the light sensitivity in two normal subjects. The measurements were made at six retinal points. Points 1 and 6, points 19, 20, 24, and 43 are at 5°, 10°, and 15° of eccentricity, respectively (see Fig. 2). The ordinate gives the level of intensity. The abscissa indicates the ten test periods. The program was initiated at a light intensity of level 6.
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Influence of Increased IOP on Visual Threshold The continuous light-sensitivity measurement program could be stopped after any test period. In the incremental-pressure test, the pause was made at the end of the fourth period. During this pause a drop of anesthetic (0.5% proparacaine, Ophthetic; Alcon, Ft. Worth, TX) was placed on the temporal sclera, and the Langham scleral cup system (Ocular Blood Flow Lab, Timonium, MD) used to increase the IOP by 20 mm Hg. With the IOP increased, the program was continued for two periods. The cup was then removed from the eye and the program continued for a further four periods. IOP and Pulsatile Ocular Blood Flow Measurements The IOP was recorded using the Langham Ocular Blood Flow automated computer system (Ocular Blood Flow Lab). This system includes a self-calibration program based on a three-point (0, 15, and 40
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mean. The differential light sensitivities were expressed as the arithmetic mean ± the standard error of the mean. The values of the light sensitivities as a function of the test period were expressed in terms of a linear equation. Results from the first period were excluded from the analyses because this period was needed for the subject to reach the differential sensitivity level (Fig. 3). The scatter of the recorded results (dispersion) was defined as the arithmetic mean (± the standard error) of the deviation from the mean light-sensitivity threshold at each retinal point.
(
mm Hg) air-pressurized membrane verifier. The IOP recordings were made at 30-msec intervals, each measurement being completed in 9 /usec. The pulsatile blood flow (PBF) was evaluated from the IOP recording as described by Langham et al.14 and Silver et al.15 The OAP was evaluated from the relationship between the IOP and the pulse amplitude using a procedure described previously.1617 Results Control Subjects Visual performance based on visual screening of 64 central retinal points in the right and left eyes often subjects were 666 ± 14 and 680 ± 18, respectively; the corresponding modal values were 10.8 ± 0.3 and 10.8 ± 0.2, respectively. The mean ocular PBFs in the right and left eyes were 714 ± 23 and 705 ± 20 ix\ min"1, respectively. Recordings of the time dependency of the light sensitivity at six retinal points in two control subjects are shown in Figure 3. The linear-regression equations of the light intensity based on 270 measurements at the six retinal points during the second to tenth periods were y = 10.9 - 0.06t and y = 11.1 - 0.05t, where y is the light-intensity level at period t (each period is approximately 50 sec, the exact time being determined by the response time). The mean light sensitivities in these two subjects decreased less than 5% over the test period of 8-10 min. Table 1 summarizes the light sensitivities for all ten control subjects. Results in pairs of eyes did not differ
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / December 1990
2554
Table 1. The time-dependent light sensitivity in ten healthy subjects recorded over a period of 8-10 min Eccentricity 5° 10° 15° Total
Light sensitivity
Regression coefficient
11.4 ±0.6 10.6 ± 0.7 10.6 ±0.7 10.9 ±0.8
-0.039 ±0.081 -0.037 ±0.12 -0.036 ±0.10 -0.037 ±0.10
and the measurements resumed through periods seven to ten. The increased IOP had no effect (P < 0.5) on the differential light thresholds either during the time of increased IOP (periodsfiveand six) or following removal of the suction cup (periods seven to ten). A comparison of the differential light sensitivities before, during, and after approximately 2 min of increased IOP in all ten subjects is given in Table 2. The mean IOP was 17.5 ±0.5 mm Hg before increasing the IOP to a mean of 39.2 ± 1 mm Hg at the beginning of period five. After removal of the scleral cup at the end of period six, the IOP fell below the initial reading but recovered rapidly. The increased IOP did not affect the stability of the light intensities at 5, 10, and 15° of eccentricity (Tables 2, 3). Five of these subjects also were exposed to an IOP increment of 30 mm Hg during periodsfiveand six of the program. In these conditions, the light sensitivity declined by a mean of 1.2 ± 0.7 during the period of increased pressure and fully recovered during periods seven to ten. The mean systolic OAP of the ten control subjects was 80.9 ± 1.8 mm Hg. The PBF was 705 ± 45 ^1 min"1 and decreased to 425 ± 45 n\ min"1 when the IOP was increased by 20 mm Hg. The mean PBF in the five subjects with an IOP increment of 30 mm Hg was 355 ± 45 /zl min"1.
Scatter 0.44 0.50 0.55 0.50
± 0.22 ± 0.23 ±0.36 ± 0.28
The light sensitivity is expressed as the AM ± SE for all measurements during periods 2-10.
significantly (Fig. 4). In the normal subjects the mean regression equations for the left and right eyes were y = 11.0 - 0.05t and y = 11.0 - 0.05t, and the dispersions were 0.45 ±0.12 and 0.45 ±0.13, respectively. The time dependency of the light sensitivities were reproducible over periods of days and weeks. In four normal subjects, the mean linear-regression equations based on recordings at a total of 24 retinal points on days 1 and 6 were y = 11.0 ± 0.2t and 10.9 ± 0.2t, respectively. Similarly, the results in individual eyes of six normal subjects measured three to six times over 2 yr did not differ (P < 0.5). The influence of increased IOP on the light sensitivity in one of the control subjects is shown in Figure 5. This subject had an IOP of 17 mm Hg and a systolic OAP of 83 mm Hg. The light-sensitivity measurements in the first four periods were made before increasing the IOP to 37 mm Hg; the increased IOP was maintained through periods five and six. At the end of the sixth period the suction cup was removed,
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No. 12
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LIGHT SENSITIVITY RESPONSE TO INCREASED IOP / Krokou er ol
10 Fig. 5. The response of the time-dependent light sensitivities in a normal subject exposed to an IOP increment of 20 mm Hg. The results in thefirstfour periods were taken prior to the increased IOP and the results in periods 7-10 were taken following periods 5 and 6 of increased IOP.
470 ±35 and 433 ± 44, respectively; the corresponding modal values were 8.3 ± 0.5 and 8.6 ± 0.5. These values are significantly below those of the control subjects (P < 0.001). Areas of relative scotoma were absent in the central fields of 14 of the 20 glaucoma-
Table 2. The influence of increased IOP on the light sensitivity in control subjects Period
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Series III
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Series I comprised control subjects not exposed to a period of increased IOP; Series II comprised the same ten control subjects exposed to an IOP increment of 20 mm Hg during periods 5 and 6; Series III comprised 5 of the same 10 control subjects exposed to an IOP increment of 30 mm Hg during periods 5 and 6. The results are based on light sensitivity measurements taken from six retinal points in each subject.
tous eyes; the remaining six eyes had discrete areas of relative scotoma, and two eyes of one subject had almost complete loss of the superior fields. (Areas of relative scotoma were defined as having thresholds at two or more levels above the modal value). Recordings of the time dependency of the light sensitivities in two glaucoma patients are shown in Figure 6. Both patients had excellent visual fixation during the test period (fixation indices were 100%). The light sensitivities in areas 17 and 18 of the first patient and area 30 of the second patient remained steady during the 8-10-min period; there were significant fluctuations in the remaining retinal points. The mean systolic OAPs in these two patients were 85 and 93 mm Hg. The PBFs in the same eyes were 459 and 520 n\ min"1, (below the mean PBF of the control subjects). Both subjects were receiving topical hypotensive treatment (0.5% ophthalmic solution of the 0-adrenoceptor blocker timolol two times a day). The mean linear regression of the light sensitivities in these two patients were y = 8.7 - 0.15t and y = 9.5 - 0.1 It, and the scatter was 0.73 ± 0.45 and 0.82 ± 0.43, respectively. The results of similar studies on the ten glaucoma patients are summarized in Table 4. The instability of the time-dependent light sensitivity in these patients persisted in repeated studies made over both short- and long-term intervals. The influence of a transient increase of 20 mm Hg IOP on the time-dependent light sensitivity was recorded in five of the ten glaucoma patients (Table 5), and a representative result is shown in Figure 7. At the end of period four, the IOP was increased by 20 mm Hg and remained elevated through periods five and six. The increased IOP caused decreased light sensitivity in two of the six retinal points studied. After removal of the scleral cup the light sensitivity recovered. Similar responses to increased IOP at some but not at all retinal points were found in all glaucoma patients. The PBF in thefiveglaucomatous patients was 510 ± 55 /x\ min"1 and 250 ± 48 fi\ min"1 at the increased IOP. The OAP was 87 ± 3 mm Hg.
Table 3. The influence of eccentricity on light sensitivity and on the regression coefficient in ten healthy subjects exposed to an IOP increment of 20 mm Hg Eccentricity
Light sensitivity
Regression coefficient
Scatter
5° 10° 15°
10.8 ± 0.87 10.4 ± 1.0 10.3 ± 1.5
-0.034 ± 0.09 -0.040 ±0.15 -0.058 ±0.14
0.47 ±0.15 0.60 ± 0.32 0.54 ± 0.30
The IOP was increased 20 mm Hg for periods 5 and 6 of the total test of ten periods
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INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / December 1990
Vol. 31
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Discussion The incremental light-intensity technique used in this study was simple to operate and well tolerated by the patients. The adoption of a well-lit background and a light stimulus of 0.25-sec duration gave excellent stability and reproducible results in healthy eyes both at normal and increased IOP. Glaucomatous eyes, including those with no field loss, had retinal points with fluctuating light sensitivities coexisting with neighbouring points that were stable both in the undisturbed eye and at increased IOP. The choice of the 0.25-sec stimulus was based on observations of Holmin and Krakau10 that differences between the time-dependent light sensitivities of normal and glaucomatous eyes was related to the duration of the stimulus. They observed the difference to be less when the duration of the light stimulus was increased from 0.25-1.0 sec. The test used in our study differed from that used in the earlier study in respect of a shorter test period and a greater number of measurements. Nevertheless, the conclusions from the two studies were similar: time-dependent light Table 4. The light sensitivity and the linear regression coefficient over the test period of 8-10 min in ten glaucoma subjects Eccentricity
Light sensitivity
Regression coefficient
Scatter
5° 10° 15°
9.5 ± 1.3 8.3 ± 1.4 8.3 ± 1.5
-0.15 ±0.25 -0.16 ±0.27 -0.15 ±0.29
1.4 ±0.48 1.5 ±0.52 1.7 ±0.12
'4 ' 6 Period
Fig. 6. Typical recordings of the time-dependent light sensitivities in glaucomatous eyes of two patients. The measurements were made at six retinal points. Both patients were on treatment with topical 0.5% timolol twice daily. The mean initial light sensitivities of the centralfieldswere 8.7 ± 0.53 and 10.5 ± 0.6, and the IOPs were 22 and 26 mm Hg, respectively.
30
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sensitivities were stable in healthy but not in glaucomatous eyes. The constancy of the differential light sensitivity at normal and elevated IOP in normal eyes agrees with observations of other investigators. Jaeger et al.18 and Palena et al.19 reported that visual acuity and the peripheral and central fields of healthy eyes were unchanged when the IOP was increased to the retinal arterial diastolic pressure. At higher IOPs visual defects began to appear in locations and in a pattern similar to those prevalent in eyes with early glaucoma; finally as the IOP was increased further, and the ocular perfusion pressure approached zero, visual blackout occurred. In similar studies Langham4 reported the visual performance of healthy subjects to be unaffected when the IOP was increased to 60 mm Hg for several minutes, but that vision was rapidly lost as the IOP came within 5 mm Hg of the OAP. The relative independence of vision to elevated IOP in healthy eyes is frequently ascribed to the ability of the blood flow to the retina and optic nerve to remain unchanged when the ocular perfusion pressure is reduced. Blood flow autoregulation in the retina has been observed in response to hypercapnia,20"22 hypoxia,21 and elevated IOP.23 Evidence for a similar autoregulation of bloodflowto the vessels of the optic nerve in healthy eyes has been more controversial,24 but recent experimental evidence favors the view that blood flow to the optic nerve is sustained with little change at substantially elevated IOP.25"28 The hemodynamics of the glaucomatous eyes differed from normal eyes in that the PBF was abnor-
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LIGHT SENSITIVITY RESPONSE TO INCREASED IOP / Krokou er QI
No. 12
Table 5. Comparison of the effect of an IOP increase of 20 mm Hg on the light sensitivity of ten normal and five glaucomatous eyes
Eyes
Initial period
Period of increased IOP
Final period
Normal Glaucoma I Glaucoma II
11.1 ± 0 . 6 8.5 ± 1.9 6.2 ± 1.1
11.1 ± 0 . 6 6.3 ±0.2 3.6 ± 1.0
11.0 ± 0 . 5 8.1 ±0.9 6.3 ± 1.2
The columns give the AM ± SE of the light sensitivities for periods 2-4, 5-6, and 7-10, respectively. Glaucoma I are nonscotomatous retinal points. Glaucoma II are retinal points within relative scotomatous areas.
mally low despite the OAP is frequently exceeding those in normal eyes. However, the PBF in the glaucomatous eyes was substantially higher than in patients with diabetic retinopathy.29 Consequently the abnormally low ciliary arterial blood flow in the glaucomatous eye cannot be the sole cause of visual
to increased IOP, is contradicted by the spatial and time-dependent characteristics of retinal light sensitivity. Histologic and electron microscopic studies establish the development of morphologic changes indicative of a mechanical weakening of the optic nerve in glaucomatous eyes;42"45 however it is unclear whether these degenerative changes are the result of increased IOP or are the consequence of local ischemia. A structurally weak lamina cribosa, abnormally sensitive to the IOP, would tend to bow outwards and thereby endanger the functional integrity of the optic nerves. However, loss of nervefibersdue to mechanical stress would not explain the spontaneous fluctuation of the light sensitivity at a steady state IOP and the increased fluctuation of the light sensitivity at elevated IOP, unless one invokes vascular impairment resulting from the mechanical changes.
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Focal ischemia or mechanical stretching of nerve fibers in the lamina cribrosa of glaucomatous eyes are believed to be the causes of irreversible nerve damage.4'24'28'30"32 A collagenous septa spanning the scleral foramen provides a supporting framework to the nerve bundles of the optic nerve and to the surrounding capillary network. These vessels are attached to collagenous bands which run parallel to the surface of the eye and, consequently, are especially susceptible to compression and distortion from the internal pressure of the eye.4'33 Impairment of the spatial distribution of blood flow to the optic nervefiberspassing through the lamina cribrosa would explain the fluctuation of the differential light sensitivity at a constant IOP and the increased fluctuation of the light sensitivity with small increments of IOP. Blood flow in capillary systems is rhythmic with a periodic ebb andflowof blood modulated by myogenic mechanisms and by changes in the local vascular perfusion pressure.34 Complete transient collapse of individual vessels occurs when the transmural pressure decreases to a critical level; vasodilatation then follows as metabolites accumulate in the occluded vessels. On this basis the fluctuation of the light sensitivity reflects transient changes in ocular blood flow to the affected nerve bundles at constant IOP. The view that the blood flow to the lamina cribrosa is impaired in the glaucomatous eye agrees with the prevalence of transient splinter-shaped hemorrhages which frequently herald visual loss.35"41 The alternative explanation that nerve damage in the glaucomatous eye is the result of a structurally weak lamina cribrosa, which is abnormally sensitive
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Period Fig. 7. The response of the light sensitivity in a male glaucoma patient (age 68 yr) to an IOP increment of 20 mm Hg. The patient had been treated with an oral beta-blpcker (atenolol) for hypertension and with ophthalmic timolol (0.5% b.i.d.) and 2% pilocarpine t.i.d. for 2 years. Visual field defects developed and the patient was admitted to the hospital for laser trabeculoplasty on the right eye. The above recordings were made 1 day prior to surgery; the initial IOP was 30 mm Hg and was increased to 40 mm Hg for periods 5 and 6.
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / December 1990
Furthermore, mechanical stress would not explain the presence of normal retinal points coexisting with partial scotomatous areas having unstable time-dependent light sensitivities. Our conclusion that impairment of blood flow is the predominant cause of the light-sensitivity loss in glaucomatous eyes is supported by recent measurements of the light sensitivity in patients treated with ocular hypotensive drugs that either increase or decrease PBF.46 In long-term treatment of a glaucoma patient, it was found that continued loss of light sensitivity was associated with decreased PBF and that changing medication to a drug that increased PBF improved the light sensitivity substantially.47 Key words: time-dependent light sensitivity, perimetry, ocular pulsatile bloodflow,glaucoma, intraocular pressure Acknowledgments The authors thank the Swedish Foundation of Kjell and Maerta Beijer and Johns Hopkins University for their support.
References 1. Gafner F and Goldmann H: Experimentelle untersuchungen uber den zusammehnang von augendrucksteigerung und gesichtsfeldschadigung, Ophthalmologica 130:357, 1955. 2. Harrington DO: Pathogenesis of the glaucomatous field defects: Individual variations in pressure sensitivity. In Conference on Glaucoma, Newell F, editor. New York, Josiah Macy Jr. Foundation, 1960 pp. 259-310. 3. Drance SM: Studies in the susceptibility of the eye to raised intraocular pressure. Arch Ophthalmol 68:478, 1960. 4. Langham ME: Visual sensitivity to intraocular pressure. In Glaucoma Update II, Kreiglstein GK and Leydhecker W, editors. Berlin, Springer-Verlag, 1983, pp. 161-167. 5. Bebie H, Fankhauser F, and Spahr J: Static perimetry: Accuracy and fluctuations. Acta Ophthalmol (Copenh) 54:339, 1976. 6. Werner EB and Drance SM: Early visual field disturbances in glaucoma. Arch Ophthalmol 95:1173, 1977. 7. Rammer J, Drance SM, and Schulzer M: Estimation of the components of variance of the differential light threshold. Doc Ophthalmol 35:383, 1983. 8. Heijl A and Drance SM: Change in differential threshold in patients with glaucoma during prolonged perimetry. Br J Ophthalmol 100:512, 1979. 9. Flammer J: The concept of visual field indices. Graefes Arch Clin Exp Ophthalmol 224:389, 1986. 10. Holmin C and Krakau CET: Variability of glaucomatous visualfielddefects in computerized perimetry. Graefes Arch Clin Exp Ophthalmol 210:235, 1979. 11. Mullins DW, Krakau CET, and Langham ME: Continuous measurement of visual threshold response in discrete retinal points. ARVO Abstracts. Invest Ophthalmol Vis Sci 30(Suppl):178, 1989. 12. Heijl A and Krakau CET: An automatic static perimeter, design and pilot study. Acta Ophthalmol (Copenh) 53:293, 1975. 13. Krakau CET: Aspects of the design of an automatic perimeter. Acta Ophthalmol (Copenh) 56:389, 1978.
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