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Retinal Autoregulation in Open-angle Glaucoma
Retinal Autoregulation in Open-angle Glaucoma J. E. GRUNWALD, MD, C. E. RIVA, DSc, R. A. STONE, MD, E. U. KEATES, MD, B. L. PETRIG, DSc
Abstract: The macular blood flow response to an induced change in intraocular pressure (autoregulation) was studied using the blue field entopic phenomenon in 11 open angle glaucoma patients, eight glaucoma suspects and 13 normal volunteers. A suction cup was used to raise the intraocular pressure (rOP) above its resting state (IOPres!)' IOPmax , the highest acutely increased lOP for which blood flow can be maintained constant by autoregulation, was 24.9 ± 1.5 mmHg (±1 SD) in the glaucoma patients, 30.8 ± 4.6 mmHg in the glaucoma suspects and 29.9 ± 3.6 mmHg in the normal subjects. The values for IOPmax - IOPres ! were 3.7 ± 4 .3mmHg, 4.7 ± 3.3 mmHg, and 14.3 ± 3 .1 mmHg, respectively. After the release of the suction cup, a hyperemic response was observed by 16 of 17 normal eyes, 10 of 14 glaucoma suspect eyes and only 9 of 19 glaucomatous eyes. These results suggest an abnormal autoregulation of macular retinal blood flow in open-angle glaucoma. [Key words: Autoregulation, blue field entoptic phenomenon, hyperemia, open-angle glaucoma, retinal blood flow.] Ophthalmology
91: 1690-1694, 1984
Vascular disturbances induced by elevated intraocular pressure (lOP) may be involved in the pathophysiology of glaucomatous optic nerve damage. I Although most studies have focused on the circulation of the optic disc, occasional reports have shown an impairment of retinal blood flow. A decreased retinal blood flow has been suggested as an explanation for the lower number of leukocytes seen entoptically by glaucoma patients. 2 An increased intraretinal fluorescein transit time 3 and a prolonged dye appearance rate in the ocular fundus 4 have been reported in fluorescein angiographic studies of glaucomatous eyes. Further, in patients with glaucoma, the intraretinal fluorescein transit time appears to increase with an increase in intraocular pressure, whereas in patients with ocular hypertension the fluorescein angiography is usually normal even at lOPs high enough to cause intermittent collapse of retinal blood vessels. 3 These latter findings suggest an impairment in the
From the Department of Ophthalmology, University of Pennsylvania School of Medicine, and the Scheie Eye Institute, Philadelphia. Supported by NIH Grant EY-03388 and EY·Q4075 from the National Eye Institute, by the Charles E. Goetz Teaching and Research Fund and the Pennsylvania Lions Sight Conservation and Eye Research Foundation, Inc. Reprint requests to Juan Grunwald, MD, Scheie Eye Institute, 51 North 39th Street, Philadelphia, PA 19104.
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autoregulation of the retinal blood flow in glaucoma. In other words, the glaucomatous eye may not be able to maintain normal retinal blood flow during periods of elevated lOP. It has also been suggested that optic nerve damage may occur secondary to a reduction in retinal blood flow which could cause ischemic damage to retinal ganglion cells and their axons. A superficial layer of retinal vessels around the optic disc has been identified in several mammalian species, including man. Based on the long path of these fine vessels and their relative lack of intercommunication with adjacent capillaries, it has been proposed that they may be particularly susceptible to an elevation of IOP.5 Experiments in cats seem to lend some support to this hypothesis. 6 In man, a single histopathologic study has found selective atrophy of these peripapillary capillaries in eyes from patients with chronic glaucoma. 7 In the present study, we have investigated retinal blood flow autoregulation in open-angle glaucoma and open-angle glaucoma suspects using a method described previously.8,9 This method, referred to here as autoregulation test, is based on the blue field entoptic phenomenon which allows a subject to perceive leukocytes moving in his own macular retinal capillaries. Our investigation demonstrates an abnormality in the autoregulation of retinal blood flow in patients with openangle glaucoma.
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MATERIALS AND METHODS The autoregulation test requires that subjects observe equal speed of leukocytes in both eyes at resting lOP. Patients are asked to look alternately into two blue field entoptoscopes (MIRA, BFE-I00), one in front of each eye. They compare the speed of the leukocytes in one eye with that in the other. After two drops of 0.5% proparacaine HCl, the lOP is measured by pneumatonometry (Digilab, Model 30R) and recorded as IOPres!' Next, the lOP is increased to an average of 40 mmHg by means of a suction cup applied .on the temporal sclera. At this pressure, the leukocytes are observed to be flowing slower in the eye with increased pressure than in the fellow eye. After four minutes, the lOP is measured and lowered in steps of 2 to 3 mmHg approximately every 30 seconds until the speed is judged to be the same in both eyes. The lOP is then determined. The lOP is again raised and the procedure is repeated. The average between the two lOPs of leukocyte speed equalization is recorded as IOP max ' Thus, IOPmax indicates the highest acutely increased lOP for which macular retinal blood flow can be maintained constant by autoregulation. The suction cup is then removed, and lOP is measured (IOPofT)' The patients are again asked to compare leukocyte speeds between both eyes. An immediate perception of a faster speed in the eye which had the suction cup than in the fellow eye is considered as indicative of a hyperemic response. The brachial blood pressure is then measured by sphygmomanometry.
SUBJECTS Of the 49 primary open-angle glaucoma patients we screened, 16 observed the same leukocyte speed in both eyes. All 49 patients had a history of elevated lOP, typical glaucomatous optic nerve head cupping, and characteristic glaucomatous visual field loss documented by Goldmann kinetic perimetry in at least one eye. They had symmetrical visual acuity of 6/12 or better in both eyes. Out of 16 patients, only 11 were included in the autoregulation study. The other five were excluded because of a history of systemic hypertension and systemic drug therapy. The age of the 11 patients ranged between 36 and 64 years, mean = 51 ± 9 years (± 1 SD). Brachial systolic and diastolic blood pressures were between 110/70 and 140/80 mmHg (mean = 122/79 mmHg). The 11 patients studied had a visual acuity of 6/7.5 or better. In three patients, only one eye, selected at random, was tested. In the other eight patients, both eyes were evaluated, and the values of IOPresto lOP max and lOPoff in both eyes were averaged for analysis. The average difference in IOPmax between both eyes was 3.9 ± 2.7 mmHg (± 1 SD). Two patients had been recently diagnosed as having glaucoma, and they were studied before the initiation of glaucoma therapy. We performed the autoregulation test on three eyes of these two
RETINAL AUTOREGULATION
patients. The other nine patients were under one of the following topical treatment modalities: timolol (three patients), timolol and pilocarpine (three patients), timolol and epinephrine (one patient), or epinephrine (two patients). All glaucoma patients received the same treatment in both eyes. The extent of the glaucomatous damage was assessed according to the degree of optic nerve head cupping, the severity of visual field loss, and the lOP level. In each patient, the eye with at least two of the following parameters-larger cup/disc ratio, worse visual field defect, or higher lOP-was considered to have more advanced glaucomatous disease. Four of the 11 glaucoma patients in which the autoregulation test was performed had visual field defects in only one eye. Central visual field function was also further evaluated by Amsler chart testing, using plate 4. Amsler chart testing was normal in 15 eyes. The other four eyes observed small scotomas in the periphery of the grid. Glaucoma suspects had open iridocorneal angles, consistently elevated lOPs above 23 mmHg, cup/disc ratio of 0.5 or smaller and no evidence of visual field loss on Goldmann kinetic perimetry. We performed the autoregulation study in eight glaucoma suspects who observed equal speed of leukocytes in both eyes, had no history of systemic hypertension and were not receiving systemic drug therapy. The age of these eight patients ranged between 38 and 67 years (mean = 53 ± 10 years). Brachial systolic and diastolic blood pressure ranged between 105/50 and 145/90 mmHg (mean, 126/76 mmHg). In two of the eight glaucoma suspects, only one eye was tested. In the remaining six, both eyes were evaluated and the values of IOPresto IOPmax and IOPoff in both eyes were averaged for analysis. The average difference in IOPmax between both eyes was 2.2 ± 1.8 mmHg. Three patients (five eyes measured) did not receive any treatment. The other five were under one of the following treatment modalities: epinephrine (two patients), epinephrine and pilocarpine (one patient), timolol (one patient), or timolol and carbachol (one patient). All glaucoma suspects on therapy received the same treatment in both eyes. The examiner was unaware of the patient's diagnosis at the time of the study. Glaucoma patients and glaucoma suspects were compared to a group of 13 normal controls with an age ranging between 32 and 75 years (mean, 48 ± 17 years) and with brachial systolic and diastolic blood pressures ranging between 105/55 and 140/90 mmHg (mean, 116/74 mmHg). These subjects had no history of glaucoma or elevated intraocular pressures, had normal optic nerve heads with a cup disc ratio of 0.4 or smaller and IOPres! less than 21 mmHg at the time of the study. In nine subjects, only one eye was tested. In the other four, both eyes were evaluated and the values ofIOPresto IOP max , and IOPoffin both eyes were averaged for analysis. The average difference in IOPmax between both eyes was 2.4 ± 1.7 mmHg. Blue field simulation experiments. # 1: Effect of reduced visibility of the leukocytes on the estimation ofleukocyte speed. Several of our glaucoma patients reported that 1691
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the leukocytes appeared less sharp in one eye than in the other at resting as well as at elevated lOP. We conducted the following experiment to investigate whether an alteration in the visibility of the leukocytes affects the perception ofleukocyte speed. Tilting the 430 nm interference filter of the entoptoscope causes a shift of the wavelength of maximum light transmission toward shorter frequencies, resulting in a continuous decrease in the sharpness and contrast of the leukocytes until the particles completely disappear. We determined the speed of leukocytes under optimal and threshold viewing conditions of the BFE phenomenon in four eyes of four normal volunteers. Optimal viewing was obtained with the interference filter parallel to the plane of the iris. For this study we defined as threshold visibility that obtained with the filter positioned at an angle of tilt 10% smaller than the angle at which the leukocytes completely disappear. For each of these two viewing conditions we determined the mean speed of the leukocytes using the blue field simulation technique. 10 Briefly, in this technique a computer generated display of simulated leukocytes appears on a CRT screen, and subjects are asked to adjust the speed of the computer simulated particles to match that of their own entoptically observed leukocytes. For each of the above two viewing conditions, subjects adjusted the speed of computer simulated leukocytes 15 times to match their own leukocytes, and an average mean speed was determined. #2: Effect of an acute elevation of lOP on the perception of speed of simulated leukocytes in glaucoma patients. This experiment was performed in order to investigate whether an acute elevation of lOP could alter, by itself, the perception of the actual speed of the leukocytes in a glaucomatous patient. Three glaucoma patients were asked to observe the computer simulated Table 1. Comparison of Clinical Parameters of Glaucoma Patients who Perceived Symmetric and Asymmetric Leukocyte Speeds between Eyes Leukocyte Speed
Age (years) Known duration of glaucoma (years) lOP (mmHg)11 10PoD - 10Pos (mmHg), absolute Highest lOP measured in the past (mmHg) lOP highest 00 - lOP highest as (mmHg), absolute Larger cup/disc ratio Cup/disc ratio 00 - cup/disc ratio as, absolute No. patients
Symmetric
Asymmetric
55 ± 9*
69 ± 11t
3.5 ± 2.9 21.9 ± 4.5 2.3 ± 1.7
5.9 ± 4.9§ 19.2 ± 5.1 2.0 ± 2.7
27.6 ± 4.7
29.0 ± 7.6
1.5 ± 1.4 0.65 ± 0.15
4.1 ± 3.5+ 0.61 ± 0.17
0.12 ± 0.09 16
0.17 ± 0.16 33
lOP = intraocular pressure; 00 = right eye; as = left eye. * Standard deviation. t P < 0.001, +P < 0.01, and §P < 0.05, significantly different by two tailed Student's t-test II lOP in the eye with highest lOP at the time of the test.
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Table 2. Autoregulatory Parameters Parameter 10Pmax (mmHg) 10Prest (mmHg) 10Pm" - 10Prest (mmHg) 10Poff (mmHg) Perception of hyperemia (% eyes)§ No. patients
Normal Volunteers 29.9 15.8 14.3 11.1
Glaucoma Suspects
Glaucoma Patients
± ± ± ±
3.6* 30.8 ± 4.6 24.9 2.7 25.9 ± 5.4t 21.0 3.1 4.7 ± 3.3t 3.7 4.7 18.3 ± 5.0+ 13.7
± ± ± ±
94 13
71 8
47 11
1.5t 4.3+ 4.3t 5.0
lOP = intraocular pressure. * ±1 standard deviation. tSignificantly different from normal (P < 0.001) by two-tailed Student's t-test and Wilcoxon rank sum test. +Significantly different from normal (P < 0.01) by two tailed student's t-test and Wilcoxon rank sum test. §Perception of a faster leukocyte speed than that observed in the fellow eye, immediately following the release of the suction cup.
leukocytes with the right eye and adjust the speed of these particles to match the speed of the leukocytes seen entoptically by the left eye looking into a blue field entoptoscope. Five adjustments of the simulated leukocytes speed were performed. A suction cup was placed on the eye observing the computer simulated particles, and five additional adjustments of the simulated leukocytes were made during a seven-minute period at an elevated lOP of approximately 35 mmHg. The same experiment was repeated with the right eye looking at the blue field entoptoscope and the left eye looking at the computer simulated leukocytes.
RESULTS Among the 49 glaucoma patients tested for the perception of the blue field phenomenon at resting lOP, 33 described a difference in baseline leukocyte speed between eyes; 28 of the 33 patients (85%) observed slower leukocyte speed in the eye with more advanced glaucomatous damage. Compared to the patients who observed asymmetric speeds, those who observed the same speed in both eyes were younger, had a disease of shorter duration and had a smaller difference between eyes in the highest recorded lOP (Table 1); their disease was probably less advanced and more symmetric in nature. Because of the design of the testing protocol, patients who observed asymmetric leukocyte speeds were excluded from the autoregulation study. The measurements of IOPresl> IOPmax , IOPoff and the percentage of eyes that perceived a hyperemic response are presented in Table 2 for the 11 glaucomatous patients, eight glaucoma suspects and 13 normal volunteers. IOPmax ranged from 26 mmHg to 40 mmHg (average IOPmax , 29.9 ± 3.6 mmHg) in normal subjects, from 24 to 40 mmHg (average IOPmax , 30.8 ± 4.6 mmHg) in glaucoma suspects, and from 22 mmHg to 30 mmHg (average IOPmax , 24.9 ± 1.5 mmHg) in glaucomatous patients. Average IOPmax was 25.8 ± 3.1
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Table 3. Average lOPmax in Glaucomatous Eyes Receiving Different Glaucoma Medications and No Medications Medication
No. Eyes
Timolol Timolol and Pilocarpine Timolol and Epinephrine Epinephrine No treatment
5 5 2 4 3
Total
Table 5. Effect of Acute Elevation of Intraocular Pressure on Estimation of Leukocyte Speed
Average lOPmax 25.2 25.0 24.5 25.9 24.5
± ± ± ± ±
3.1 1.4 0.7 3.0 4.8
19
2 3
mmHg in the four glaucomatous eyes that did not have any visual field loss, and 24.9 ± 2.6 in the other 15 eyes that showed visual field loss. In Table 2, we also calculated IOP max - IOPresl> which represents the range of acutely increased lOPs above IOPrest for which the retina can maintain a constant leukocyte speed under the conditions of these experiments. Average IOPmax - IOPrest was 14,3 ± 3,1 mmHg in normal subjects, 4,7 ± 3,3 in glaucoma suspects, and 3.7 ± 4,3 in glaucomatous patients, The hyperemic re~ sponse to acute reduction in lOP, which was observed by 16 out of 17 normal eyes, and 10 out of 14 glaucoma suspect eyes, was only seen by nine out of 19 glaucomatous eyes. Nine of the ten glaucomatous eyes that did not observe a reactive hyperemia had an IOPmax - IOPrest value smaller than 5 mmHg. Table 3 shows average IOPmax for glaucomatous eyes receiving different glaucoma medications and for eyes receiving no medications. No statistically significant differences in the average IOPmax were found between the glaucomatous eyes under treatment (average IOPmax , 25,2 ± 2,3 mmHg) and those without treatment (average IOP max , 24,5 ± 4,8 mmHg), and between the glaucoma suspect eyes under treatment (average IOPmax , 29,6 ± 3.8 mmHg) and those without treatment (average IOPmax , 30,6 ± 5.6 mmHg), The results of simulation experiment #1 appear in Table 4, which shows the ratio between the mean leukocyte speeds under optimal and threshold perception of the entoptic leukocytes. No significant difference in mean leukocyte speed was found between both conditions of visibility (paired t-test). The simulation experiment #2 showed that in glaucoma patients the average Table 4. Effect of Decreased Contrast on Estimation of Leukocyte Speed Patient No.
Speedth,/SpeedoPt Ratio·
1 2 3 4
0.89 0.94 0.92 1.07
Average ratio
RETINAL AUTOREGULATION
0.96 ± 0.08
* Ratio between mean leukocyte speed at threshold (Speed th ,) and optimal (Speed oPI) perception of the blue field entoptic phenomenon.
Patient No.
Speedelev/Speed,e'l Ratio·
Right eye Left eye
1.01 1.06
Right eye Left eye
0.83 0.97
Right eye Left eye
0.94 0.90
Average ratio
0.95 ± 0.08
* Ratio between the entoptic leukocytes speed determined while the fellow eye looking at the simulated leukocytes has intraocular pressure of 35 mmHg (Speed elev) and IOP,esl (Speed,e'I)'
speed of the simulated leukocytes, when adjusted at resting lOP to match the speed of the leukocytes observed entoptically in the other eye, did not differ significantly from the value obtained when the same matching was performed while the lOP was increased to about 35 mmHg in the eye looking at the simulated particles (paired t-test) (Table 5).
DISCUSSION Glaucoma patients. with good central acuity and relatively full visual fields may demonstrate abnormalities of central vision such as impaired contrast sensitivityll or color vision. 12 In applying the autoregulation test to glaucoma patients, therefore, a question arises whether an altered perception of the BFE phenomenon could influence the determination of IOPmax • In simulation experiment # 1, we investigated the effect of a decreased visibility of the entoptic particles, a phenomenon reported by some of the glaucoma patients. The results of this experiment suggest that this effect does not have a major influence on the judgment of the leukocyte speed and therefore is most probably not responsible for the lower IOPmax value obtained in glaucomatous eyes. We have also investigated whether an acute increase in lOP could alter the perception of the actual speed of leukocytes in glaucoma patients causing, for example, the leukocytes to appear slower than they actually are, thus influencing the measurement oflOPmax ' The results of simulation experiment #2 indicate that an acute increase in lOP does not have a major influence in the perception of speed of simulated leukocytes in glaucoma patients. The results of this study suggest an abnormality of the retinal circulation in glaucoma patients, First, the parameter IOP max is significantly decreased in glaucomatous eyes compared to normal eyes. A direct effect of anti-glaucomatous therapy on IOPmax appears to be unlikely since the average IOPmax in three untreated 1693
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eyes was very close to the average IOPmax obtained from the treated eyes. Second, IOPmax - IOPres! was significantly decreased in glaucomatous eyes compared to normal eyes. This parameter represents the range of acutely increased lOPs above IOPres! for which the macular retinal circulation can maintain a constant blood flow. Because the IOPres! was obtained from eyes under treatment in most of the cases, this range may have been smaller prior to the beginning of treatment. In fact, in 14 of the 19 glaucomatous eyes tested, lOPs had been recorded in the past which were higher than the IOPmax measured in our study. Although nothing is known about the autoregulation of the retinal circulation in response to chronic pressure elevations, it must be considered that retinal blood flow may be impaired under such conditions. Finally, the absence of hyperemia in most of the glaucomatous eyes with an extremely small IOP max - IOPres! value further supports our contention that autoregulation of the retinal circulation is impaired in glaucomatous eyes. This effect results, most probably, from the lack of autoregulatory vasodilatation that normally occurs when the lOP is increased. 13 In contrast to glaucomatous eyes, average lOPmax is unaffected in glaucoma suspect eyes. Glaucoma suspect eyes, however, have an average IOPmax - IOPres! value which is smaller than that of normal eyes because their IOPres! is elevated. Abnormal autoregulation of the. retinal circulation could lead to impairment of blood flow during periods when the lOP is increased above IOP max • Whether this finding is important in explaining the pathogenesis of giaucomatous optic atrophy is not answered directly by the present study. Certainly, such retinal circulatory impairment could be associated with damage of the retinal ganglion cells and progression of the glaucomatous optic nerve disease, as suggested by others. 2- 7 Glaucomatous visual impairment is thought to be the result of a pathologic process occurring in the optic nerve head. This study shows an abnormality of the retinal blood flow autoregulation. Perhaps a similar regulatory abnormality may be present in the circulation of the optic nerve head.
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ACKNOWLEDGMENT The authors thank Ms. Joan Baine for technical help in the experiments and Ms. Virginia Mesibov for editing the manuscript.
REFERENCES 1. Harrington DO. The pathogenesis of the glaucoma field; clinical evidence that Circulatory insufficiency in the optic nerve is the primary cause of visual field loss in glaucoma. Am J Ophthalmol 1959; 47(pt 2):177-85. 2. Baurmann H, Fink H, Cornelius P. Entoptische Zirkulationsmessungen an den Augen Glaukomkranker. Klin Monatsbl Augenheilkd 1974; 165:477-82. 3. Spaeth GL. Fluorescein angiography: its contribution towards understanding the mechanisms of visual loss in glaucoma. Trans Am Ophthalmol Soc 1975; 73:491-553. 4. Moses RA. Intraocular blood flow from analysis of angiograms. Invest Ophthalmol Vis Sci 1983; 24:354-60. 5. Henkind P. New observations on the radial peripapillary capillaries. Invest Ophthalmol 1967; 6:103-8. 6. Alterman M, Henkind P. Radial peripapillary capillaries of the retina. II. Possible role in Bjerrum scotoma. Br J Ophthalmol 1968; 52:2631. 7. Komzweig AL, Eliasoph I, Feldstein M. Selective atrophy 01 the radial peripapillary capillaries in chronic glaucoma. Arch Ophthalmol 1968; 80:696-702. 8. Riva CE, Sinclair SH, Grunwald JE. Autoregulation of retinal circulation in response to decrease of perfusion pressure. Invest Ophthalmol Vis Sci 1981; 21:34-8. 9. Grunwald JE, Sinclair SH, Riva CEo Autoregulation of the retinal circulation in response to decrease of intraocular pressure below normal. Invest Ophthalmol Vis Sci 1982; 23:124-7. 10. Riva CE, Petrig B. Blue field entoptiC phenomenon and blood velocity in the retinal capillaries. J Opt Soc Am 1980; 70:1234-8. 11. Atkin A, Bodis-Wollner I, Wolkstein M, et al. Abnormalities of central contrast sensitivity in glaucoma. Am J Ophthalmol 1979; 88:205-
11.
12. Poinoosawmy D, Nagasubramanian S, Gloster J. Colour vision in patients with chronic simple glaucoma and ocular hypertension. Br J Ophthalmol 1980; 64:852-7. 13. Wilson TM, Constable IJ, Cooper RL, Alder VA. Image splitting-a technique for measuring retinal vascular reactivity. Br J Ophthalmol 1981; 65:291-3.
Abstract: The macular blood flow response to an induced change in intraocular pressure (autoregulation) was studied using the blue field entopic phenomenon in 11 open angle glaucoma patients, eight glaucoma suspects and 13 normal volunteers. A suction cup was used to raise the intraocular pressure (rOP) above its resting state (IOPres!)' IOPmax , the highest acutely increased lOP for which blood flow can be maintained constant by autoregulation, was 24.9 ± 1.5 mmHg (±1 SD) in the glaucoma patients, 30.8 ± 4.6 mmHg in the glaucoma suspects and 29.9 ± 3.6 mmHg in the normal subjects. The values for IOPmax - IOPres ! were 3.7 ± 4 .3mmHg, 4.7 ± 3.3 mmHg, and 14.3 ± 3 .1 mmHg, respectively. After the release of the suction cup, a hyperemic response was observed by 16 of 17 normal eyes, 10 of 14 glaucoma suspect eyes and only 9 of 19 glaucomatous eyes. These results suggest an abnormal autoregulation of macular retinal blood flow in open-angle glaucoma. [Key words: Autoregulation, blue field entoptic phenomenon, hyperemia, open-angle glaucoma, retinal blood flow.] Ophthalmology
91: 1690-1694, 1984
Vascular disturbances induced by elevated intraocular pressure (lOP) may be involved in the pathophysiology of glaucomatous optic nerve damage. I Although most studies have focused on the circulation of the optic disc, occasional reports have shown an impairment of retinal blood flow. A decreased retinal blood flow has been suggested as an explanation for the lower number of leukocytes seen entoptically by glaucoma patients. 2 An increased intraretinal fluorescein transit time 3 and a prolonged dye appearance rate in the ocular fundus 4 have been reported in fluorescein angiographic studies of glaucomatous eyes. Further, in patients with glaucoma, the intraretinal fluorescein transit time appears to increase with an increase in intraocular pressure, whereas in patients with ocular hypertension the fluorescein angiography is usually normal even at lOPs high enough to cause intermittent collapse of retinal blood vessels. 3 These latter findings suggest an impairment in the
From the Department of Ophthalmology, University of Pennsylvania School of Medicine, and the Scheie Eye Institute, Philadelphia. Supported by NIH Grant EY-03388 and EY·Q4075 from the National Eye Institute, by the Charles E. Goetz Teaching and Research Fund and the Pennsylvania Lions Sight Conservation and Eye Research Foundation, Inc. Reprint requests to Juan Grunwald, MD, Scheie Eye Institute, 51 North 39th Street, Philadelphia, PA 19104.
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autoregulation of the retinal blood flow in glaucoma. In other words, the glaucomatous eye may not be able to maintain normal retinal blood flow during periods of elevated lOP. It has also been suggested that optic nerve damage may occur secondary to a reduction in retinal blood flow which could cause ischemic damage to retinal ganglion cells and their axons. A superficial layer of retinal vessels around the optic disc has been identified in several mammalian species, including man. Based on the long path of these fine vessels and their relative lack of intercommunication with adjacent capillaries, it has been proposed that they may be particularly susceptible to an elevation of IOP.5 Experiments in cats seem to lend some support to this hypothesis. 6 In man, a single histopathologic study has found selective atrophy of these peripapillary capillaries in eyes from patients with chronic glaucoma. 7 In the present study, we have investigated retinal blood flow autoregulation in open-angle glaucoma and open-angle glaucoma suspects using a method described previously.8,9 This method, referred to here as autoregulation test, is based on the blue field entoptic phenomenon which allows a subject to perceive leukocytes moving in his own macular retinal capillaries. Our investigation demonstrates an abnormality in the autoregulation of retinal blood flow in patients with openangle glaucoma.
GRUNWALD, et al
•
MATERIALS AND METHODS The autoregulation test requires that subjects observe equal speed of leukocytes in both eyes at resting lOP. Patients are asked to look alternately into two blue field entoptoscopes (MIRA, BFE-I00), one in front of each eye. They compare the speed of the leukocytes in one eye with that in the other. After two drops of 0.5% proparacaine HCl, the lOP is measured by pneumatonometry (Digilab, Model 30R) and recorded as IOPres!' Next, the lOP is increased to an average of 40 mmHg by means of a suction cup applied .on the temporal sclera. At this pressure, the leukocytes are observed to be flowing slower in the eye with increased pressure than in the fellow eye. After four minutes, the lOP is measured and lowered in steps of 2 to 3 mmHg approximately every 30 seconds until the speed is judged to be the same in both eyes. The lOP is then determined. The lOP is again raised and the procedure is repeated. The average between the two lOPs of leukocyte speed equalization is recorded as IOP max ' Thus, IOPmax indicates the highest acutely increased lOP for which macular retinal blood flow can be maintained constant by autoregulation. The suction cup is then removed, and lOP is measured (IOPofT)' The patients are again asked to compare leukocyte speeds between both eyes. An immediate perception of a faster speed in the eye which had the suction cup than in the fellow eye is considered as indicative of a hyperemic response. The brachial blood pressure is then measured by sphygmomanometry.
SUBJECTS Of the 49 primary open-angle glaucoma patients we screened, 16 observed the same leukocyte speed in both eyes. All 49 patients had a history of elevated lOP, typical glaucomatous optic nerve head cupping, and characteristic glaucomatous visual field loss documented by Goldmann kinetic perimetry in at least one eye. They had symmetrical visual acuity of 6/12 or better in both eyes. Out of 16 patients, only 11 were included in the autoregulation study. The other five were excluded because of a history of systemic hypertension and systemic drug therapy. The age of the 11 patients ranged between 36 and 64 years, mean = 51 ± 9 years (± 1 SD). Brachial systolic and diastolic blood pressures were between 110/70 and 140/80 mmHg (mean = 122/79 mmHg). The 11 patients studied had a visual acuity of 6/7.5 or better. In three patients, only one eye, selected at random, was tested. In the other eight patients, both eyes were evaluated, and the values of IOPresto lOP max and lOPoff in both eyes were averaged for analysis. The average difference in IOPmax between both eyes was 3.9 ± 2.7 mmHg (± 1 SD). Two patients had been recently diagnosed as having glaucoma, and they were studied before the initiation of glaucoma therapy. We performed the autoregulation test on three eyes of these two
RETINAL AUTOREGULATION
patients. The other nine patients were under one of the following topical treatment modalities: timolol (three patients), timolol and pilocarpine (three patients), timolol and epinephrine (one patient), or epinephrine (two patients). All glaucoma patients received the same treatment in both eyes. The extent of the glaucomatous damage was assessed according to the degree of optic nerve head cupping, the severity of visual field loss, and the lOP level. In each patient, the eye with at least two of the following parameters-larger cup/disc ratio, worse visual field defect, or higher lOP-was considered to have more advanced glaucomatous disease. Four of the 11 glaucoma patients in which the autoregulation test was performed had visual field defects in only one eye. Central visual field function was also further evaluated by Amsler chart testing, using plate 4. Amsler chart testing was normal in 15 eyes. The other four eyes observed small scotomas in the periphery of the grid. Glaucoma suspects had open iridocorneal angles, consistently elevated lOPs above 23 mmHg, cup/disc ratio of 0.5 or smaller and no evidence of visual field loss on Goldmann kinetic perimetry. We performed the autoregulation study in eight glaucoma suspects who observed equal speed of leukocytes in both eyes, had no history of systemic hypertension and were not receiving systemic drug therapy. The age of these eight patients ranged between 38 and 67 years (mean = 53 ± 10 years). Brachial systolic and diastolic blood pressure ranged between 105/50 and 145/90 mmHg (mean, 126/76 mmHg). In two of the eight glaucoma suspects, only one eye was tested. In the remaining six, both eyes were evaluated and the values of IOPresto IOPmax and IOPoff in both eyes were averaged for analysis. The average difference in IOPmax between both eyes was 2.2 ± 1.8 mmHg. Three patients (five eyes measured) did not receive any treatment. The other five were under one of the following treatment modalities: epinephrine (two patients), epinephrine and pilocarpine (one patient), timolol (one patient), or timolol and carbachol (one patient). All glaucoma suspects on therapy received the same treatment in both eyes. The examiner was unaware of the patient's diagnosis at the time of the study. Glaucoma patients and glaucoma suspects were compared to a group of 13 normal controls with an age ranging between 32 and 75 years (mean, 48 ± 17 years) and with brachial systolic and diastolic blood pressures ranging between 105/55 and 140/90 mmHg (mean, 116/74 mmHg). These subjects had no history of glaucoma or elevated intraocular pressures, had normal optic nerve heads with a cup disc ratio of 0.4 or smaller and IOPres! less than 21 mmHg at the time of the study. In nine subjects, only one eye was tested. In the other four, both eyes were evaluated and the values ofIOPresto IOP max , and IOPoffin both eyes were averaged for analysis. The average difference in IOPmax between both eyes was 2.4 ± 1.7 mmHg. Blue field simulation experiments. # 1: Effect of reduced visibility of the leukocytes on the estimation ofleukocyte speed. Several of our glaucoma patients reported that 1691
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the leukocytes appeared less sharp in one eye than in the other at resting as well as at elevated lOP. We conducted the following experiment to investigate whether an alteration in the visibility of the leukocytes affects the perception ofleukocyte speed. Tilting the 430 nm interference filter of the entoptoscope causes a shift of the wavelength of maximum light transmission toward shorter frequencies, resulting in a continuous decrease in the sharpness and contrast of the leukocytes until the particles completely disappear. We determined the speed of leukocytes under optimal and threshold viewing conditions of the BFE phenomenon in four eyes of four normal volunteers. Optimal viewing was obtained with the interference filter parallel to the plane of the iris. For this study we defined as threshold visibility that obtained with the filter positioned at an angle of tilt 10% smaller than the angle at which the leukocytes completely disappear. For each of these two viewing conditions we determined the mean speed of the leukocytes using the blue field simulation technique. 10 Briefly, in this technique a computer generated display of simulated leukocytes appears on a CRT screen, and subjects are asked to adjust the speed of the computer simulated particles to match that of their own entoptically observed leukocytes. For each of the above two viewing conditions, subjects adjusted the speed of computer simulated leukocytes 15 times to match their own leukocytes, and an average mean speed was determined. #2: Effect of an acute elevation of lOP on the perception of speed of simulated leukocytes in glaucoma patients. This experiment was performed in order to investigate whether an acute elevation of lOP could alter, by itself, the perception of the actual speed of the leukocytes in a glaucomatous patient. Three glaucoma patients were asked to observe the computer simulated Table 1. Comparison of Clinical Parameters of Glaucoma Patients who Perceived Symmetric and Asymmetric Leukocyte Speeds between Eyes Leukocyte Speed
Age (years) Known duration of glaucoma (years) lOP (mmHg)11 10PoD - 10Pos (mmHg), absolute Highest lOP measured in the past (mmHg) lOP highest 00 - lOP highest as (mmHg), absolute Larger cup/disc ratio Cup/disc ratio 00 - cup/disc ratio as, absolute No. patients
Symmetric
Asymmetric
55 ± 9*
69 ± 11t
3.5 ± 2.9 21.9 ± 4.5 2.3 ± 1.7
5.9 ± 4.9§ 19.2 ± 5.1 2.0 ± 2.7
27.6 ± 4.7
29.0 ± 7.6
1.5 ± 1.4 0.65 ± 0.15
4.1 ± 3.5+ 0.61 ± 0.17
0.12 ± 0.09 16
0.17 ± 0.16 33
lOP = intraocular pressure; 00 = right eye; as = left eye. * Standard deviation. t P < 0.001, +P < 0.01, and §P < 0.05, significantly different by two tailed Student's t-test II lOP in the eye with highest lOP at the time of the test.
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Table 2. Autoregulatory Parameters Parameter 10Pmax (mmHg) 10Prest (mmHg) 10Pm" - 10Prest (mmHg) 10Poff (mmHg) Perception of hyperemia (% eyes)§ No. patients
Normal Volunteers 29.9 15.8 14.3 11.1
Glaucoma Suspects
Glaucoma Patients
± ± ± ±
3.6* 30.8 ± 4.6 24.9 2.7 25.9 ± 5.4t 21.0 3.1 4.7 ± 3.3t 3.7 4.7 18.3 ± 5.0+ 13.7
± ± ± ±
94 13
71 8
47 11
1.5t 4.3+ 4.3t 5.0
lOP = intraocular pressure. * ±1 standard deviation. tSignificantly different from normal (P < 0.001) by two-tailed Student's t-test and Wilcoxon rank sum test. +Significantly different from normal (P < 0.01) by two tailed student's t-test and Wilcoxon rank sum test. §Perception of a faster leukocyte speed than that observed in the fellow eye, immediately following the release of the suction cup.
leukocytes with the right eye and adjust the speed of these particles to match the speed of the leukocytes seen entoptically by the left eye looking into a blue field entoptoscope. Five adjustments of the simulated leukocytes speed were performed. A suction cup was placed on the eye observing the computer simulated particles, and five additional adjustments of the simulated leukocytes were made during a seven-minute period at an elevated lOP of approximately 35 mmHg. The same experiment was repeated with the right eye looking at the blue field entoptoscope and the left eye looking at the computer simulated leukocytes.
RESULTS Among the 49 glaucoma patients tested for the perception of the blue field phenomenon at resting lOP, 33 described a difference in baseline leukocyte speed between eyes; 28 of the 33 patients (85%) observed slower leukocyte speed in the eye with more advanced glaucomatous damage. Compared to the patients who observed asymmetric speeds, those who observed the same speed in both eyes were younger, had a disease of shorter duration and had a smaller difference between eyes in the highest recorded lOP (Table 1); their disease was probably less advanced and more symmetric in nature. Because of the design of the testing protocol, patients who observed asymmetric leukocyte speeds were excluded from the autoregulation study. The measurements of IOPresl> IOPmax , IOPoff and the percentage of eyes that perceived a hyperemic response are presented in Table 2 for the 11 glaucomatous patients, eight glaucoma suspects and 13 normal volunteers. IOPmax ranged from 26 mmHg to 40 mmHg (average IOPmax , 29.9 ± 3.6 mmHg) in normal subjects, from 24 to 40 mmHg (average IOPmax , 30.8 ± 4.6 mmHg) in glaucoma suspects, and from 22 mmHg to 30 mmHg (average IOPmax , 24.9 ± 1.5 mmHg) in glaucomatous patients. Average IOPmax was 25.8 ± 3.1
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Table 3. Average lOPmax in Glaucomatous Eyes Receiving Different Glaucoma Medications and No Medications Medication
No. Eyes
Timolol Timolol and Pilocarpine Timolol and Epinephrine Epinephrine No treatment
5 5 2 4 3
Total
Table 5. Effect of Acute Elevation of Intraocular Pressure on Estimation of Leukocyte Speed
Average lOPmax 25.2 25.0 24.5 25.9 24.5
± ± ± ± ±
3.1 1.4 0.7 3.0 4.8
19
2 3
mmHg in the four glaucomatous eyes that did not have any visual field loss, and 24.9 ± 2.6 in the other 15 eyes that showed visual field loss. In Table 2, we also calculated IOP max - IOPresl> which represents the range of acutely increased lOPs above IOPrest for which the retina can maintain a constant leukocyte speed under the conditions of these experiments. Average IOPmax - IOPrest was 14,3 ± 3,1 mmHg in normal subjects, 4,7 ± 3,3 in glaucoma suspects, and 3.7 ± 4,3 in glaucomatous patients, The hyperemic re~ sponse to acute reduction in lOP, which was observed by 16 out of 17 normal eyes, and 10 out of 14 glaucoma suspect eyes, was only seen by nine out of 19 glaucomatous eyes. Nine of the ten glaucomatous eyes that did not observe a reactive hyperemia had an IOPmax - IOPrest value smaller than 5 mmHg. Table 3 shows average IOPmax for glaucomatous eyes receiving different glaucoma medications and for eyes receiving no medications. No statistically significant differences in the average IOPmax were found between the glaucomatous eyes under treatment (average IOPmax , 25,2 ± 2,3 mmHg) and those without treatment (average IOP max , 24,5 ± 4,8 mmHg), and between the glaucoma suspect eyes under treatment (average IOPmax , 29,6 ± 3.8 mmHg) and those without treatment (average IOPmax , 30,6 ± 5.6 mmHg), The results of simulation experiment #1 appear in Table 4, which shows the ratio between the mean leukocyte speeds under optimal and threshold perception of the entoptic leukocytes. No significant difference in mean leukocyte speed was found between both conditions of visibility (paired t-test). The simulation experiment #2 showed that in glaucoma patients the average Table 4. Effect of Decreased Contrast on Estimation of Leukocyte Speed Patient No.
Speedth,/SpeedoPt Ratio·
1 2 3 4
0.89 0.94 0.92 1.07
Average ratio
RETINAL AUTOREGULATION
0.96 ± 0.08
* Ratio between mean leukocyte speed at threshold (Speed th ,) and optimal (Speed oPI) perception of the blue field entoptic phenomenon.
Patient No.
Speedelev/Speed,e'l Ratio·
Right eye Left eye
1.01 1.06
Right eye Left eye
0.83 0.97
Right eye Left eye
0.94 0.90
Average ratio
0.95 ± 0.08
* Ratio between the entoptic leukocytes speed determined while the fellow eye looking at the simulated leukocytes has intraocular pressure of 35 mmHg (Speed elev) and IOP,esl (Speed,e'I)'
speed of the simulated leukocytes, when adjusted at resting lOP to match the speed of the leukocytes observed entoptically in the other eye, did not differ significantly from the value obtained when the same matching was performed while the lOP was increased to about 35 mmHg in the eye looking at the simulated particles (paired t-test) (Table 5).
DISCUSSION Glaucoma patients. with good central acuity and relatively full visual fields may demonstrate abnormalities of central vision such as impaired contrast sensitivityll or color vision. 12 In applying the autoregulation test to glaucoma patients, therefore, a question arises whether an altered perception of the BFE phenomenon could influence the determination of IOPmax • In simulation experiment # 1, we investigated the effect of a decreased visibility of the entoptic particles, a phenomenon reported by some of the glaucoma patients. The results of this experiment suggest that this effect does not have a major influence on the judgment of the leukocyte speed and therefore is most probably not responsible for the lower IOPmax value obtained in glaucomatous eyes. We have also investigated whether an acute increase in lOP could alter the perception of the actual speed of leukocytes in glaucoma patients causing, for example, the leukocytes to appear slower than they actually are, thus influencing the measurement oflOPmax ' The results of simulation experiment #2 indicate that an acute increase in lOP does not have a major influence in the perception of speed of simulated leukocytes in glaucoma patients. The results of this study suggest an abnormality of the retinal circulation in glaucoma patients, First, the parameter IOP max is significantly decreased in glaucomatous eyes compared to normal eyes. A direct effect of anti-glaucomatous therapy on IOPmax appears to be unlikely since the average IOPmax in three untreated 1693
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eyes was very close to the average IOPmax obtained from the treated eyes. Second, IOPmax - IOPres! was significantly decreased in glaucomatous eyes compared to normal eyes. This parameter represents the range of acutely increased lOPs above IOPres! for which the macular retinal circulation can maintain a constant blood flow. Because the IOPres! was obtained from eyes under treatment in most of the cases, this range may have been smaller prior to the beginning of treatment. In fact, in 14 of the 19 glaucomatous eyes tested, lOPs had been recorded in the past which were higher than the IOPmax measured in our study. Although nothing is known about the autoregulation of the retinal circulation in response to chronic pressure elevations, it must be considered that retinal blood flow may be impaired under such conditions. Finally, the absence of hyperemia in most of the glaucomatous eyes with an extremely small IOP max - IOPres! value further supports our contention that autoregulation of the retinal circulation is impaired in glaucomatous eyes. This effect results, most probably, from the lack of autoregulatory vasodilatation that normally occurs when the lOP is increased. 13 In contrast to glaucomatous eyes, average lOPmax is unaffected in glaucoma suspect eyes. Glaucoma suspect eyes, however, have an average IOPmax - IOPres! value which is smaller than that of normal eyes because their IOPres! is elevated. Abnormal autoregulation of the. retinal circulation could lead to impairment of blood flow during periods when the lOP is increased above IOP max • Whether this finding is important in explaining the pathogenesis of giaucomatous optic atrophy is not answered directly by the present study. Certainly, such retinal circulatory impairment could be associated with damage of the retinal ganglion cells and progression of the glaucomatous optic nerve disease, as suggested by others. 2- 7 Glaucomatous visual impairment is thought to be the result of a pathologic process occurring in the optic nerve head. This study shows an abnormality of the retinal blood flow autoregulation. Perhaps a similar regulatory abnormality may be present in the circulation of the optic nerve head.
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ACKNOWLEDGMENT The authors thank Ms. Joan Baine for technical help in the experiments and Ms. Virginia Mesibov for editing the manuscript.
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