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Effect of Trabecular Photocoagulation on the Aqueous Humor Dynamics of the Human Eye
AMERICAN SERIES 3
JOURNAL VOLUME 96
OF
OPHTHALMOLOGY®
NUMBER 2
AUGUST, 1983
EFFECT OF TRABECULAR PHOTOCOAGULATION ON THE AQUEOUS HUMOR DYNAMICS OF THE HUMAN EYE RICHARD F. BRUBAKER, M.D., AND THOMAS J. LIESEGANG, Rochester, Minnesota
M.D.
A group of 17 patients (ten men and seven women, ranging in age from 56 to 79 years) who had either chronic simple glaucoma or open-angle glaucoma and the exfoliation syndrome (pseudoexfoliation) underwent argon laser trabeculoplasty in one eye each. Shortly before and three months after this procedure, both eyes underwent a number of tests to determine the physiologic status of the aqueous circulation, the blood-ocular barrier, and the cornea. A therapeutically significant decrease in intraocular pressure was observed in nine of the 17 treated eyes (mean pretreatment value for the 17 eyes, 21 ± 5 mm Hg; mean posttreatment value, 14 ± 4 mm Hg). This decrease was associated with an improvement in the tonographic facility of outflow (mean pretreatment value, 0.11 ± 0.05 μΐ/min/mm Hg; mean posttreatment value, 0.18 ± 0.08 μΐ/min/mm Hg). Apparent resistance to aqueous outflow decreased from a mean pretreatment value of 14.2 ± 4 . 5 minunm Hg/μΐ to mean posttreatment value of 9.2 ± 3.0 min«mm Hg/μΐ). The other variables showed only small, statistically insignificant changes. Laser treatment of the trabeculum for open-angle glaucoma has been applied by clinical investigators whose hypotheses as to the mechanism of its beneficial effect fall into two categories. One group has attempted to penetrate or puncture the trabeculum to produce permanent open ings (trabeculopuncture).1"11 Goldschmidt
Accepted for publication May 24, 1983. From the Mayo Foundation, Rochester, Minneso ta. This study was supported by grant EY 00634 from the National Institutes of Health (Dr. Brubaker), and grants from Research to Prevent Blindness, Inc., New York, New York, the Grover Hermann Foundation, Pebble Beach, California, and'the Mayo Foundation, Rochester, Minnesota. Reprint requests to Richard F. Brubaker, M.D., Mayo Foundation, Rochester, MN 55905.
and Ticho12 discussed the theoretical basis for such an approach in detail. This surgical procedure does not produce long-lasting decreases in intraocular pres sure because of cicatricial closure of the puncture sites.13"15 The other group has hypothesized that nonperforating lesions are effective, safer, and produce longer-lasting benefi cial effects.16"24 The best results reported so far were those of Wise and Witter18"20 who hypothesized that equally spaced lesions of 50 μπι in diameter applied with an argon laser at a power setting of 0.78 to 1.17 W for 100 msec produce a shrinkage of the trabecular ring, decrease its diame ter, and increase the width of the intertrabecular spaces. The term laser tra
ct AMERICAN JOURNAL OF OPHTHALMOLOGY 96:139-147, 1983
139
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AMERICAN JOURNAL OF OPHTHALMOLOGY
beculoplasty has been used to describe this procedure. In either case, improvement in the tonographic facility of outflow is expect ed, and at least transient improvement has been reported by almost all investiga tors who have performed tonography in treated human subjects. To the best of our knowledge, no study of aqueous humor dynamics before and after laser trabeculoplasty has been pub lished, although Y. Kitazawa found that aqueous humor flow, measured by fluorophotometry, was not altered by laser tra beculoplasty (unpublished data). We measured aqueous humor dynamics in 17 patients by means of a fluorescein tracer before treatment and three months after laser trabeculoplasty by the protocol of Wise and Witter.18 SUBJECTS AND METHODS
Patients were drawn from our clinical practice and included only those who had chronic open-angle glaucoma either with or without the exfoliation syndrome. We excluded patients with secondary glauco ma inflammatory disease, a history of serious ocular trauma, rubeosis irides, or ocular surgery. Each patient in the study was a candidate for filtration surgery and each patient's glaucoma was not satisfac torily controlled by medical therapy. No patient was under 56 years of age. No eye in the study had a pretreatment intraocu lar pressure of more than 34 mm Hg. Each eye had a clear cornea and an angle open enough to allow accurate treatment of the trabecular meshwork. All the pa tients had intact lenses. Those who were using echothiopate iodide discontinued it one month before the study and used pilocarpine instead. All other drugs were continued at their usual dosage. The pretreatment studies of aqueous dynamics were carried out while medical treatment was continued. Shortly there after, the laser procedure was performed.
AUGUST, 1983
The eye received the same medical treat ment for three months and then the stud ies of aqueous dynamics were repeated. Each patient underwent two days of testing before and after the laser treat ment. On the first day of testing, fluores cein was applied topically and entered the anterior chamber from the cornea. On the second day, fluorescein was ad ministered systemically and entered the anterior chamber from the plasma. The first day's test was carried out to deter mine the rate of clearance of fluorescein from the anterior chamber and the per meability of the corneal endothelium to fluorescein. The second day's test was performed to determine the rate of ex change between the plasma and the an terior chamber and to measure the tono graphic resistance to outflow. Testing procedure, day 1—At 8 A.M. on the first day of testing the background fluorescence of the eye was measured. Immediately afterward 0.5% proparacaine was instilled into each eye, and fluorescein was placed into the central corneal stroma by iontophoresis.26 While there was sufficient fluorescence in the tear film, we measured the intraocular pressure with a Perkins tonometer. Im mediately after tonometry the excess dye was irrigated out of the cul-de-sac, leav ing a bright round 5-mm depot of fluores cein visible in the stroma. Timing of all subsequent measurements of fluores cence was made with reference to the time of iontophoresis of fluorescein. Fifteen minutes after iontophoresis (before any significant amount of fluores cein could have entered the anterior chamber), we measured the optical boundary function for fluorescence be tween the cornea and the anterior cham ber with a fluorophotometer.26 Thirty minutes after iontophoresis we measured the mass of the applied dose of fluores cein. This mass measurement was cor rected for the effects of extinction with an
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TRABECULOPLASTY AND AQUEOUS DYNAMICS
empirically derived function for our fluorophotometer and method of application of the dye. 25 Every hour for eight hours we measured the intensity of fluores cence in the corneal stroma and in the central portion of the anterior chamber. Each measurement of anterior chamber fluorescence was corrected for the effects of corneal fluorescence with the previous ly determined optical boundary function for that eye. The volume of the anterior chamber was measured at a convenient time between fluorescence measure ments with a photogrammetric tech nique 27 and a slit-lamp camera. The pa tient used his or her eyedrops at the usual dosage times during the procedure. At the completion of the fluorescence meas urements, we remeasured the intraocular pressures with a Perkins tonometer and measured endothelial cell size and cor neal thickness with a specular micro scope. We used the data from day 1 to calcu late the corneal transfer coefficient k«, (and thus the endothelial permeability to fluorescein) and the anterior chamber loss coefficient k0 by method 2 of Nagataki and Brubaker. 28 This method is a twodimensional equally spaced search for the pair of k values that produce the least sum of squares deviation between the observed data and the theoretic values predicted by the two-compartment model of Jones and Maurice. 29 Testing procedure, day 2—On the sec ond day of testing each fasting patient underwent baseline measurement of fluo rescent intensity in the cornea and ante rior chamber. These measurements were repeated hourly after the oral administra tion of fluorescein in capsules at a dosage of 7 mg/kg of body weight. Venipunctures were performed 45 minutes and two hours after dosing. We used these speci mens to determine the free plasma con centration of fluorescein. The free plasma concentration was determined from the
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combined measurements of fluorescence intensity and fluorescence polarization. 30 Fluorescence intensity measurements were made in the anterior chamber at hourly intervals for five hours. At the end of the fluorescence measurements, a four-minute Schi0tz tonogram was ob tained by the method of Grant. 31 We used the fluorescence intensity data to calculate the diffusional exchange coefficient between the anterior chamber and the plasma, kd. The method was a modification of the method described by Araie and associates. 32 We calculated the flow of aqueous humor through the an terior chamber with the following formu la: flow = (k0 — kd) x volume of the anterior chamber. Sequence of testing—On a convenient day after the test procedures each patient underwent an argon laser trabeculoplasty in one eye. The 50-μηι spot diameter was measured in air and found to be within 4% of its nominal value. The patient was followed up clinically for three months and continued the same schedule of med ical treatment. At the end of the threemonth follow-up period, the complete set of tests was repeated. Statistical analysis—We compared the results of the tests in the treated eye before treatment to the results in the treated eye after treatment to determine the effect of the laser trabeculoplasty. The results in the untreated eye at both test periods were also compared to deter mine the reproducibility of the test pro cedures in this group of patients. We used Student's t-test for paired samples and the Wilcoxon test for paired samples to determine the probability of an ob served difference resulting from chance. Probabilities greater than .05 were as sumed to result from chance and not from the laser treatment. The coefficient of variation was estimated for each test from the differences between each paired mea surement in the untreated eye. We used
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AMERICAN JOURNAL OF OPHTHALMOLOGY
these coefficients of variation to calculate the statistical power of the entire experi mental procedure for each of the mea sured variables. In determining the sta tistical power, we accepted a ß error of 0.2 as being reasonable. RESULTS
There were significant changes in only three of the measured variables in the 17 eyes that underwent laser treatment of the trabeculum. The mean intraocular pressure in these eyes was 21 ± 5 mm Hg before treatment; this decreased to 14 ± 4 mm Hg three months after treatment (P < .001) (Tables 1 and 2). The tonographic C value increased from 0.11 ± 0.05 to 0.18
AUGUST, 1983
± 0.08 μΐ/min/mm Hg three months after treatment (P<.01). The calculation factor of apparent resistance to aqueous out flow, which is simply the intraocular pressure divided by the rate of flow of aqueous humor, decreased from 14.2 ± 4.5 min»mm Hg/μΐ before treatment to 9.2 ± 3.0 min'mm Hg/μΐ after treatment (P < .01). The other variables tested showed small changes between the two test sessions but none was statistically significant (Tables 3 to 5). The data indi cated that the decrease in intraocular pressure was brought about by an im provement in outflow of aqueous humor rather than by a suppression of the rate of aqueous humor formation.
TABLE 1 EFFECT OF ARGON LASER TRABECULOPLASTY ON INTRAOCULAR PRESSURE IN RESPONDERS
PaHpnf Wn SPY 1 AllClll l i U · ,
ÎJKJA,
Age (yrs)
Drugs Used
2, M, 74*
Parasympathomimetic; adrenergic blocker; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic agonist; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker
3, F , 79*
5, M, 79 6, M, 61 8, M, 69 9, M, 70
13, F, 75 15, F, 74* 16, F , 72*
*Exfoliation syndrome (pseudoexfoliation).
Intraocular Pressure (mm Hg) Treated Eye Untreated Eye Preoperative Postoperative Preoperative Postoperative
24
8
21
22
34
18
18
15
25
7
21
17
20
12
18
17
23
12
22
23
16
8
15
12
29
15
29
27
20
14
17
13
24
12
18
14
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TRABECULOPLASTY AND AQUEOUS DYNAMICS
143
TABLE 2 EFFECT OF ARGON LASER TRABECULOPLASTY ON INTRAOCULAR PRESSURE IN NONRESPONDERS
Patient No Sex Age (yrs) 1, M, 73 4, F, 56
7, M, 63 10, M, 73* 11, F , 78 12, M, 69 14, M, 56 17, F, 70
Drugs Used Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic blocker; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic blocker Parasympathomimetic; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic agonist
Intraocular Pressure (mm Hg) Treated Eye Untreated Eye Preoperative Postoperative Preoperaltive Postoperative
14
15
16
13
19
18
18
21
25
22
15
13
17
14
16
15
20
18
14
14
22
18
14
20
14
13
14
13
16
13
16
14
'Exfoliation syndrome (pseudoexfoliation).
There were a number of small changes in the mean values of the measured varia bles among the untreated eyes, that is, those eyes that did not undergo laser treatment of the trabeculum. None of the changes observed was statistically signifi cant when we compared pretreatment and posttreatment values for each eye. The mean intraocular pressure was 1 mm Hg lower in the untreated eyes at the last test session than it had been before treatment but this différence was not statistically significant (P > . 1). In nine treated eyes the intraocular pressure decreased 6 mm Hg or more. Thus, approximately, one half of the pa tients seemed to benefit from the proce dure and the other half did not. These two groups were analyzed separately. The responders had a dramatic improve ment in the tonographic C value, in the apparent resistance to aqueous outflow,
or in both. No significant change of any sort occurred in the nonresponders. The responders had higher starting intraocu lar pressures than the nonresponders. Also, there were more with exfoliation syndrome among the responders than among the nonresponders (four vs one). We found no other clinical differences between the two groups. DISCUSSION
Photocoagulation of the trabeculum of the glaucomatous human eye with power densities too low to produce clinically or histopathologically observable perfora tions in the canal of Schlemm can pro duce a sustained decrease in intraocular pressure. The most logical explanation for the therapeutic benefit of this procedure is that it improves the abnormally low tonographic facility of outflow which is the basis for the increased intraocular
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AUGUST, 1983
AMERICAN JOURNAL OF OPHTHALMOLOGY TABLE 3
EFFECT OF ARGON LASER TRABECULOPLASTY ON TESTED VARIABLES IN ALL EYES
Variable Intraocular pressure (mm Hg) Volume of anterior chamber (u.1) Flow of aqueous (μ,Ι/min) Apparent resistance to aqueous outflow (min·mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (x 10"3) (min -1 ) Endothelial permeability to fluorescein (x 10 ) (cm/min) Mean endothelial cell size (μπι ) Corneal thickness (μιη)
Treated Eyes (No. = 17) Preoperative Postoperative
Untreated Ey■es (No. = 17) Postoperative Preoperative
21 ± 6* 131 ± 41 1.57 ± 0.43
14 ± 4 135 ± 37 1.59 ± 0.68
18 ± 4 139 ± 38 1.92 ± 0.98
17 ± 4 140 ± 37 1.89 ± 0.94
14.2 ± 4.5*
9.2 ± 3.0
11.3 ± 5.6
11.0 ± 5.9
0.11 ± 0.05+
0.18 ± 0.08
0.15 ± 0.08
0.16 ± 0.08
2.0 ± 1.1
2.1 ± 1.3
2.0 ± 2.3
2.0 ± 1.3
1.90 ± 1.24
1.79 ± 0.83
1.76 ± 1.04
2.00 ± 0.79
480 ± 138 55 ± 3
473 ± 126 55 ± 4
461 ± 177 55 ± 3
463 ± 165 54 ± 4
*P < .001 by paired t-test. f P < .01 by paired f-test.
pressure. It would be surprising if this procedure altered the rate of formation of aqueous humor. Our study supported the hypothesis that the intraocular pressure decreases as a result of improvement in
outflow of aqueous humor. The rate of flow of aqueous humor through the an terior chamber and, probably, the rate of aqueous humor formation remain unal tered. This treatment procedure appar-
TABLE 4 EFFECT OF ARGON LASER TRABECULOPLASTY ON TESTED VARIABLES IN RESPONDERS
Variable Intraocular pressure (mm Hg) Volume of anterior chamber (μΐ) Flow of aqueous (μΐ/min) Apparent resistance to aqueous outflow (min»mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (x 10"3) (min -1 ) Endothelial permeability to fluorescein (X 10 ) (cm/min) Mean endothelial cell size (μιη ) Corneal thickness (μκι) *P < .001 by paired t-test. *P < .01 by paired f-test.
Treated Eyes (No. = 9) Preoperative Postoperative
Untreated Eyes (No. = 9) Preoperative Postoperative
24 ± 5* 111 ± 14 1.54 ± 0.53
12 ± 4 116 ± 22 1.43 ± 0.55
20 ± 4 120 ± 23 1.92 ± 0.88
15 ± 7 122 ± 21 1.89 ± 0.99
16.5 ± 4.4+
8.4 ± 3.1
12.9 ± 6.6
12.2 ± 7 . 1
0.09 ± 0.04*
0.21 ± 0.08
0.14 ± 0.09
0.14 ±0.07
2.61 ± 1.1
2.6 ± 1.4
2.9 ± 2.8
2.4 ± 1.6
1.94 ± 1.43
1.80 ± 0.77
1.58 ± 0.79
1.80 ± 0.82
522 ± 151 54 ± 3
516 ± 137 53 ± 4
494 ± 215 54 ± 3
491 ± 182 53 ± 4
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TABLE 5 EFFECT OF ARGON LASER TRABECULOPLASTY ON TESTED VARIABLES IN NONRESPONDERS
Variable Intraocular pressure (mm Hg) Volume of anterior chamber (μΐ) Flow of aqueous (μΐ/min) Apparent resistance to aqueous outflow (min · mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (x 10 -3 ) (min -1 ) Endothelial permeability to fluorescein (x 10 - ) (cm/min) Mean endothelial cell size (μπι ) Cornea! thickness (μπι)
Treated Eyes (No. = 8) Preoperative Postoperative
Untreated Eyes (No. = 8) Preoperative Postoperative
18 ± 4 * 154 ± 51 1.61 ± 0.31
16 ± 3 157 ± 39 1.77 ± 0.81
15 ± 1 160 ± 4 1 1.92 ± 1.15
15 ± 3 161 ± 42 1.90 ± 0.94
11.6 ± 3.1
10.1 ± 2 . 9
9.5 ± 3.9
9.6 ± 4.2
0.14 ± 0.5
0.14 ± 0.06
0.16 ±0.06
0.19 ± 0.08
1.4 ± 0.6
1.6 ± 1.0
0.9 ± 0.5
1.7 ± 0.9
1.85 ± 1.10
1.77 ± 0.94
1.97 ± 1.30
2.22 ± 0.75
433 ± 113 56 ± 3
426 ± 98 57 ± 4
424 ± 126 56±3
432 ± 149 56± 3
*P < .001 by paired t-test.
ently had no effect on the permeability of the blood-ocular barrier, the permeabili ty of the corneal endothelium, the vol ume of the anterior chamber, the mean endothelial cell size, or the corneal thick ness. The study was designed to permit each treated eye to serve as its own control. The fellow eye, which in most instances was glaucomatous but not necessarily to
the same degree as the treated eye, served as an untreated control to permit observation of the reproducibility of the test procedures. The coefficient of varia tion of each of the test procedures was calculated from the differences observed in the results of each of the untreated eyes measured at the two test periods (Table 6). We used these coefficients to determine the minimum effect that could
TABLE 6 VARIABILITY OF TEST PROCEDURES IN 17 FELLOW EYES
Test Intraocular pressure (mm Hg) Volume of anterior chamber (μΐ) Flow of aqueous (μΐ/min) Apparent resistance (min · mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (min - ) Endothelial permeability to fluorescein (cm/min) Mean endothelial cell size (μηι ) Corneal thickness (μπι) *α = 0.05; β = 0.20.
Coefficient of Variation (%)
Minimal* Detectable Difference (%)
18 7 40 47 47
21 .8 47 55 56
65
77
71 6 3
84 8 4
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AMERICAN JOURNAL OF OPHTHALMOLOGY
be detected reliably with our sample size of 17 treated patients. These estimates showed that a small effect of laser photocoagulation could have been missed but that a large effect would have been de tected. Thus, we could not conclude from the study that this treatment procedure produced no change in the blood-ocular barrier, in the rate of aqueous formation, or in the corneal function but only that large changes were not produced, chang es of the order of magnitude observed in intraocular pressure and in outflow resist ance. We concluded that laser trabeculoplasty produces its beneficial effect by im proving the outflow of aqueous humor. This effect most probably occurs by im provement of canalicular outflow, that is, flow into the canal of Schlemm and out of the eye by way of the collector chan nels of the canal. Our data did not permit us to determine the precise mechanism responsible for the improvement in out flow. A number of plausible possibilities are worthy of consideration. It seems, however, on the basis of the microscopic appearance of the trabeculum after treat ment with this power density, that gross perforation into the canal of Schlemm is not necessary or even desirable to pro duce a sustained improvement in out flow. 18,20,33 REFERENCES 1. Hager, H.: Besondere mikrochirurgische Ein griffe. 2. Teil. Erste Erfahrungen mit dem ArgonLaser-Gerat 800. Klin. Monatsbl. Augenheilkd. 162:437, 1973. 2. Krasnov, M. M.: Laseropuncture of anterior chamber angle in glaucoma. Am. J. Ophthalmol. 75:674, 1973. 3. Ticho, U., and Zauberman, H.: Argon laser application to the angle structures in the glaucomas. Arch. Ophthalmol. 94:61, 1976. 4. Ticho, U., Mahler, J., Sekeles, E., Bruchim, A., Admony, M., Weinberger, Z., Lougnot, D. J., and Goldschmidt, C. R.: Low-energy laser trabeculotomies in primates. Exp. Eye Res. 33:11, 1981. 5. Ticho, U. : Laser application to angle structures in animals and in human glaucomatous eyes. Adv. Ophthalmol. 69:201, 1977.
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6. Dannheim, F., and Rassow, B.: Zur lasertrabekulopunkture. III. Versuche am Rhesusaffen. Ophthalmologica 173:40, 1976. 7. Fechner, P. U., Teichman, I., and Teichman, U. D.: Long term results of laser trabeculopuncture method. Klin. Monatsbl. Augenheilkd. 162:437, 1973. 8. Stiegler, G.: Laser treatment of the anterior segment of the eye with a new glaucoma research laser. Klin. Monatsbl. Augenheilkd. 169:677, 1976. 9. : Laser-trabekulotomie und laser-iridektomie. Drei jähe erfahrung mit dem glaukomresearch-laser (Britt). Klin. Monatsbl. Augenheilkd. 175:333, 1979. 10. : Glaucoma treated with the pulsed argon laser. Klin. Monatsbl. Augenheilkd. 178:379, 1981. 11. Teichmann, I., Teichmann, K. D., and Fech ner, P. U.: Glaucoma operation with the argon laser. Eye Ear Nose Throat Mon. 55:209, 1976. 12. Goldschmidt, C. R., and Ticho, U.: Theoreti cal approach to laser trabeculotomy. Med. Phys. 5:92, 1978. 13. Ticho, U., Cadet, J. C , Mahler, J., Sekeles, E., and Bruchim, A.: Argon laser trabeculotomies in primates. Evaluation by histological and perfusion studies. Invest. Ophthalmol. Vis. Sei. 17:667, 1978. 14. Wickham, M. G., Worthen, D. M., and Bind er, P. S.: Physiological effects of laser trabeculotomy in rhesus monkey eyes. Invest. Ophthalmol. Vis. Sei. 16:624, 1977. 15. van der Zypen, E., and Fankhauser, F.: The ultrastructural features of laser trabeculopuncture and cyclodialysis. Problems related to successful treatment of chronic simple glaucoma. Ophthalmo logica 179:189, 1979. 16. Worthen, D. M., and Wickham, M. G.: Laser trabeculotomy in monkeys. Invest. Ophthalmol. 12:707, 1973. 17. : Argon laser trabeculotomy. Trans. Am. Acad. Ophthalmol. Otolaryngol. 78(OP):371, 1974. 18. Wise, J. B., and Witter, S. L.: Argon laser therapy for open-angle glaucoma. Arch. Ophthalmol. 97:319, 1979. 19. : Glaucoma treatment by trabecular tightening with the argon laser. Int. Ophthalmol. Clin. 21:69, 1981. 20. : Long-term control of adult open angle glaucoma by argon laser treatment. Ophthalmology 88:197, 1981. 21. Wilensky, J. T., and Jampol, L.: Laser thera py for open angle glaucoma. Ophthalmology 88:213, 1981. 22. Sutton, G. E., Christensen, G. R., and Rec ords, R. E.: Trabeculotomy with continuous argon laser. Trans. Ophthalmol. Soc. U.K. 101:118, 1981. 23. Schwartz, A. L., Whitten, M. E., Bleiman, B., and Martin, D. : Argon laser trabecular surgery in uncontrolled phakic open angle glaucoma. Ophthal mology 88:203, 1981. 24. Pohjanpelto, P. : Argon laser treatment of the anterior chamber angle for increased intraocular pressure. Acta Ophthalmol. 59:211, 1981.
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25. Coakes, R. L., and Brubaker, R. F.: Method of measuring aqueous humor flow and corneal endothelial permeability using a fluorophotometry nomogram. Invest. Ophthalmol. Vis. Sei. 18:288, 1979. 26. Brubaker, R. F., and Coakes, R. L.: Use of a xenon flash tube as the excitation, source in a new slit-lamp fluorophotometer. Am. J. Ophthalmol. 86:474, 1978. 27. Johnson, S. B., Coakes, R. L., and Brubaker, R. F.: A simple photogrammetric method of measur ing anterior chamber volume. Am. J. Ophthalmol. 85:469, 1978. 28. Nagataki, S., and Brubaker, R. F.: Effect of pilocarpine on aqueous humor formation in human beings. Arch. Ophthalmol. 100:818, 1982. 29. Jones, R. F., and Maurice, D. M.: New meth
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ods of measuring the rate of aqueous flow in man with fluorescein. Exp. Eye Res. 5:208, 1966. 30. Brubaker, R. F., Penniston, J. T., Grotte, D. A., and Nagataki, S.: Measurement of fluorescein binding in human plasma using fluorescence polari zation. Arch. Ophthalmol. 100:625, 1982. 31. Grant, W. M.: Tonographic method for mea suring the facility and rate of aqueous flow in human eyes. Arch. Ophthalmol. 44:204, 1950. 32. Araie, M., Sawa, M., Nagataki, S., and Mishima, S.: Aqueous humor dynamics in man as studied by oral fluorescein. Jpn. J. Ophthalmol. 24:346, 1980. 33. Rodrigues, M. M., Spaeth, G. L., and Donohoo, P. : Electron microscopy of argon laser therapy in phakic open-angle glaucoma. Ophthalmology 89:198, 1982.
JOURNAL VOLUME 96
OF
OPHTHALMOLOGY®
NUMBER 2
AUGUST, 1983
EFFECT OF TRABECULAR PHOTOCOAGULATION ON THE AQUEOUS HUMOR DYNAMICS OF THE HUMAN EYE RICHARD F. BRUBAKER, M.D., AND THOMAS J. LIESEGANG, Rochester, Minnesota
M.D.
A group of 17 patients (ten men and seven women, ranging in age from 56 to 79 years) who had either chronic simple glaucoma or open-angle glaucoma and the exfoliation syndrome (pseudoexfoliation) underwent argon laser trabeculoplasty in one eye each. Shortly before and three months after this procedure, both eyes underwent a number of tests to determine the physiologic status of the aqueous circulation, the blood-ocular barrier, and the cornea. A therapeutically significant decrease in intraocular pressure was observed in nine of the 17 treated eyes (mean pretreatment value for the 17 eyes, 21 ± 5 mm Hg; mean posttreatment value, 14 ± 4 mm Hg). This decrease was associated with an improvement in the tonographic facility of outflow (mean pretreatment value, 0.11 ± 0.05 μΐ/min/mm Hg; mean posttreatment value, 0.18 ± 0.08 μΐ/min/mm Hg). Apparent resistance to aqueous outflow decreased from a mean pretreatment value of 14.2 ± 4 . 5 minunm Hg/μΐ to mean posttreatment value of 9.2 ± 3.0 min«mm Hg/μΐ). The other variables showed only small, statistically insignificant changes. Laser treatment of the trabeculum for open-angle glaucoma has been applied by clinical investigators whose hypotheses as to the mechanism of its beneficial effect fall into two categories. One group has attempted to penetrate or puncture the trabeculum to produce permanent open ings (trabeculopuncture).1"11 Goldschmidt
Accepted for publication May 24, 1983. From the Mayo Foundation, Rochester, Minneso ta. This study was supported by grant EY 00634 from the National Institutes of Health (Dr. Brubaker), and grants from Research to Prevent Blindness, Inc., New York, New York, the Grover Hermann Foundation, Pebble Beach, California, and'the Mayo Foundation, Rochester, Minnesota. Reprint requests to Richard F. Brubaker, M.D., Mayo Foundation, Rochester, MN 55905.
and Ticho12 discussed the theoretical basis for such an approach in detail. This surgical procedure does not produce long-lasting decreases in intraocular pres sure because of cicatricial closure of the puncture sites.13"15 The other group has hypothesized that nonperforating lesions are effective, safer, and produce longer-lasting benefi cial effects.16"24 The best results reported so far were those of Wise and Witter18"20 who hypothesized that equally spaced lesions of 50 μπι in diameter applied with an argon laser at a power setting of 0.78 to 1.17 W for 100 msec produce a shrinkage of the trabecular ring, decrease its diame ter, and increase the width of the intertrabecular spaces. The term laser tra
ct AMERICAN JOURNAL OF OPHTHALMOLOGY 96:139-147, 1983
139
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beculoplasty has been used to describe this procedure. In either case, improvement in the tonographic facility of outflow is expect ed, and at least transient improvement has been reported by almost all investiga tors who have performed tonography in treated human subjects. To the best of our knowledge, no study of aqueous humor dynamics before and after laser trabeculoplasty has been pub lished, although Y. Kitazawa found that aqueous humor flow, measured by fluorophotometry, was not altered by laser tra beculoplasty (unpublished data). We measured aqueous humor dynamics in 17 patients by means of a fluorescein tracer before treatment and three months after laser trabeculoplasty by the protocol of Wise and Witter.18 SUBJECTS AND METHODS
Patients were drawn from our clinical practice and included only those who had chronic open-angle glaucoma either with or without the exfoliation syndrome. We excluded patients with secondary glauco ma inflammatory disease, a history of serious ocular trauma, rubeosis irides, or ocular surgery. Each patient in the study was a candidate for filtration surgery and each patient's glaucoma was not satisfac torily controlled by medical therapy. No patient was under 56 years of age. No eye in the study had a pretreatment intraocu lar pressure of more than 34 mm Hg. Each eye had a clear cornea and an angle open enough to allow accurate treatment of the trabecular meshwork. All the pa tients had intact lenses. Those who were using echothiopate iodide discontinued it one month before the study and used pilocarpine instead. All other drugs were continued at their usual dosage. The pretreatment studies of aqueous dynamics were carried out while medical treatment was continued. Shortly there after, the laser procedure was performed.
AUGUST, 1983
The eye received the same medical treat ment for three months and then the stud ies of aqueous dynamics were repeated. Each patient underwent two days of testing before and after the laser treat ment. On the first day of testing, fluores cein was applied topically and entered the anterior chamber from the cornea. On the second day, fluorescein was ad ministered systemically and entered the anterior chamber from the plasma. The first day's test was carried out to deter mine the rate of clearance of fluorescein from the anterior chamber and the per meability of the corneal endothelium to fluorescein. The second day's test was performed to determine the rate of ex change between the plasma and the an terior chamber and to measure the tono graphic resistance to outflow. Testing procedure, day 1—At 8 A.M. on the first day of testing the background fluorescence of the eye was measured. Immediately afterward 0.5% proparacaine was instilled into each eye, and fluorescein was placed into the central corneal stroma by iontophoresis.26 While there was sufficient fluorescence in the tear film, we measured the intraocular pressure with a Perkins tonometer. Im mediately after tonometry the excess dye was irrigated out of the cul-de-sac, leav ing a bright round 5-mm depot of fluores cein visible in the stroma. Timing of all subsequent measurements of fluores cence was made with reference to the time of iontophoresis of fluorescein. Fifteen minutes after iontophoresis (before any significant amount of fluores cein could have entered the anterior chamber), we measured the optical boundary function for fluorescence be tween the cornea and the anterior cham ber with a fluorophotometer.26 Thirty minutes after iontophoresis we measured the mass of the applied dose of fluores cein. This mass measurement was cor rected for the effects of extinction with an
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empirically derived function for our fluorophotometer and method of application of the dye. 25 Every hour for eight hours we measured the intensity of fluores cence in the corneal stroma and in the central portion of the anterior chamber. Each measurement of anterior chamber fluorescence was corrected for the effects of corneal fluorescence with the previous ly determined optical boundary function for that eye. The volume of the anterior chamber was measured at a convenient time between fluorescence measure ments with a photogrammetric tech nique 27 and a slit-lamp camera. The pa tient used his or her eyedrops at the usual dosage times during the procedure. At the completion of the fluorescence meas urements, we remeasured the intraocular pressures with a Perkins tonometer and measured endothelial cell size and cor neal thickness with a specular micro scope. We used the data from day 1 to calcu late the corneal transfer coefficient k«, (and thus the endothelial permeability to fluorescein) and the anterior chamber loss coefficient k0 by method 2 of Nagataki and Brubaker. 28 This method is a twodimensional equally spaced search for the pair of k values that produce the least sum of squares deviation between the observed data and the theoretic values predicted by the two-compartment model of Jones and Maurice. 29 Testing procedure, day 2—On the sec ond day of testing each fasting patient underwent baseline measurement of fluo rescent intensity in the cornea and ante rior chamber. These measurements were repeated hourly after the oral administra tion of fluorescein in capsules at a dosage of 7 mg/kg of body weight. Venipunctures were performed 45 minutes and two hours after dosing. We used these speci mens to determine the free plasma con centration of fluorescein. The free plasma concentration was determined from the
141
combined measurements of fluorescence intensity and fluorescence polarization. 30 Fluorescence intensity measurements were made in the anterior chamber at hourly intervals for five hours. At the end of the fluorescence measurements, a four-minute Schi0tz tonogram was ob tained by the method of Grant. 31 We used the fluorescence intensity data to calculate the diffusional exchange coefficient between the anterior chamber and the plasma, kd. The method was a modification of the method described by Araie and associates. 32 We calculated the flow of aqueous humor through the an terior chamber with the following formu la: flow = (k0 — kd) x volume of the anterior chamber. Sequence of testing—On a convenient day after the test procedures each patient underwent an argon laser trabeculoplasty in one eye. The 50-μηι spot diameter was measured in air and found to be within 4% of its nominal value. The patient was followed up clinically for three months and continued the same schedule of med ical treatment. At the end of the threemonth follow-up period, the complete set of tests was repeated. Statistical analysis—We compared the results of the tests in the treated eye before treatment to the results in the treated eye after treatment to determine the effect of the laser trabeculoplasty. The results in the untreated eye at both test periods were also compared to deter mine the reproducibility of the test pro cedures in this group of patients. We used Student's t-test for paired samples and the Wilcoxon test for paired samples to determine the probability of an ob served difference resulting from chance. Probabilities greater than .05 were as sumed to result from chance and not from the laser treatment. The coefficient of variation was estimated for each test from the differences between each paired mea surement in the untreated eye. We used
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AMERICAN JOURNAL OF OPHTHALMOLOGY
these coefficients of variation to calculate the statistical power of the entire experi mental procedure for each of the mea sured variables. In determining the sta tistical power, we accepted a ß error of 0.2 as being reasonable. RESULTS
There were significant changes in only three of the measured variables in the 17 eyes that underwent laser treatment of the trabeculum. The mean intraocular pressure in these eyes was 21 ± 5 mm Hg before treatment; this decreased to 14 ± 4 mm Hg three months after treatment (P < .001) (Tables 1 and 2). The tonographic C value increased from 0.11 ± 0.05 to 0.18
AUGUST, 1983
± 0.08 μΐ/min/mm Hg three months after treatment (P<.01). The calculation factor of apparent resistance to aqueous out flow, which is simply the intraocular pressure divided by the rate of flow of aqueous humor, decreased from 14.2 ± 4.5 min»mm Hg/μΐ before treatment to 9.2 ± 3.0 min'mm Hg/μΐ after treatment (P < .01). The other variables tested showed small changes between the two test sessions but none was statistically significant (Tables 3 to 5). The data indi cated that the decrease in intraocular pressure was brought about by an im provement in outflow of aqueous humor rather than by a suppression of the rate of aqueous humor formation.
TABLE 1 EFFECT OF ARGON LASER TRABECULOPLASTY ON INTRAOCULAR PRESSURE IN RESPONDERS
PaHpnf Wn SPY 1 AllClll l i U · ,
ÎJKJA,
Age (yrs)
Drugs Used
2, M, 74*
Parasympathomimetic; adrenergic blocker; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic agonist; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker
3, F , 79*
5, M, 79 6, M, 61 8, M, 69 9, M, 70
13, F, 75 15, F, 74* 16, F , 72*
*Exfoliation syndrome (pseudoexfoliation).
Intraocular Pressure (mm Hg) Treated Eye Untreated Eye Preoperative Postoperative Preoperative Postoperative
24
8
21
22
34
18
18
15
25
7
21
17
20
12
18
17
23
12
22
23
16
8
15
12
29
15
29
27
20
14
17
13
24
12
18
14
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TRABECULOPLASTY AND AQUEOUS DYNAMICS
143
TABLE 2 EFFECT OF ARGON LASER TRABECULOPLASTY ON INTRAOCULAR PRESSURE IN NONRESPONDERS
Patient No Sex Age (yrs) 1, M, 73 4, F, 56
7, M, 63 10, M, 73* 11, F , 78 12, M, 69 14, M, 56 17, F, 70
Drugs Used Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic blocker; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic blocker Parasympathomimetic; adrenergic blocker Parasympathomimetic; carbonic anhydrase inhibitor Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic agonist; adrenergic blocker Parasympathomimetic; adrenergic agonist
Intraocular Pressure (mm Hg) Treated Eye Untreated Eye Preoperative Postoperative Preoperaltive Postoperative
14
15
16
13
19
18
18
21
25
22
15
13
17
14
16
15
20
18
14
14
22
18
14
20
14
13
14
13
16
13
16
14
'Exfoliation syndrome (pseudoexfoliation).
There were a number of small changes in the mean values of the measured varia bles among the untreated eyes, that is, those eyes that did not undergo laser treatment of the trabeculum. None of the changes observed was statistically signifi cant when we compared pretreatment and posttreatment values for each eye. The mean intraocular pressure was 1 mm Hg lower in the untreated eyes at the last test session than it had been before treatment but this différence was not statistically significant (P > . 1). In nine treated eyes the intraocular pressure decreased 6 mm Hg or more. Thus, approximately, one half of the pa tients seemed to benefit from the proce dure and the other half did not. These two groups were analyzed separately. The responders had a dramatic improve ment in the tonographic C value, in the apparent resistance to aqueous outflow,
or in both. No significant change of any sort occurred in the nonresponders. The responders had higher starting intraocu lar pressures than the nonresponders. Also, there were more with exfoliation syndrome among the responders than among the nonresponders (four vs one). We found no other clinical differences between the two groups. DISCUSSION
Photocoagulation of the trabeculum of the glaucomatous human eye with power densities too low to produce clinically or histopathologically observable perfora tions in the canal of Schlemm can pro duce a sustained decrease in intraocular pressure. The most logical explanation for the therapeutic benefit of this procedure is that it improves the abnormally low tonographic facility of outflow which is the basis for the increased intraocular
144
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AMERICAN JOURNAL OF OPHTHALMOLOGY TABLE 3
EFFECT OF ARGON LASER TRABECULOPLASTY ON TESTED VARIABLES IN ALL EYES
Variable Intraocular pressure (mm Hg) Volume of anterior chamber (u.1) Flow of aqueous (μ,Ι/min) Apparent resistance to aqueous outflow (min·mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (x 10"3) (min -1 ) Endothelial permeability to fluorescein (x 10 ) (cm/min) Mean endothelial cell size (μπι ) Corneal thickness (μιη)
Treated Eyes (No. = 17) Preoperative Postoperative
Untreated Ey■es (No. = 17) Postoperative Preoperative
21 ± 6* 131 ± 41 1.57 ± 0.43
14 ± 4 135 ± 37 1.59 ± 0.68
18 ± 4 139 ± 38 1.92 ± 0.98
17 ± 4 140 ± 37 1.89 ± 0.94
14.2 ± 4.5*
9.2 ± 3.0
11.3 ± 5.6
11.0 ± 5.9
0.11 ± 0.05+
0.18 ± 0.08
0.15 ± 0.08
0.16 ± 0.08
2.0 ± 1.1
2.1 ± 1.3
2.0 ± 2.3
2.0 ± 1.3
1.90 ± 1.24
1.79 ± 0.83
1.76 ± 1.04
2.00 ± 0.79
480 ± 138 55 ± 3
473 ± 126 55 ± 4
461 ± 177 55 ± 3
463 ± 165 54 ± 4
*P < .001 by paired t-test. f P < .01 by paired f-test.
pressure. It would be surprising if this procedure altered the rate of formation of aqueous humor. Our study supported the hypothesis that the intraocular pressure decreases as a result of improvement in
outflow of aqueous humor. The rate of flow of aqueous humor through the an terior chamber and, probably, the rate of aqueous humor formation remain unal tered. This treatment procedure appar-
TABLE 4 EFFECT OF ARGON LASER TRABECULOPLASTY ON TESTED VARIABLES IN RESPONDERS
Variable Intraocular pressure (mm Hg) Volume of anterior chamber (μΐ) Flow of aqueous (μΐ/min) Apparent resistance to aqueous outflow (min»mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (x 10"3) (min -1 ) Endothelial permeability to fluorescein (X 10 ) (cm/min) Mean endothelial cell size (μιη ) Corneal thickness (μκι) *P < .001 by paired t-test. *P < .01 by paired f-test.
Treated Eyes (No. = 9) Preoperative Postoperative
Untreated Eyes (No. = 9) Preoperative Postoperative
24 ± 5* 111 ± 14 1.54 ± 0.53
12 ± 4 116 ± 22 1.43 ± 0.55
20 ± 4 120 ± 23 1.92 ± 0.88
15 ± 7 122 ± 21 1.89 ± 0.99
16.5 ± 4.4+
8.4 ± 3.1
12.9 ± 6.6
12.2 ± 7 . 1
0.09 ± 0.04*
0.21 ± 0.08
0.14 ± 0.09
0.14 ±0.07
2.61 ± 1.1
2.6 ± 1.4
2.9 ± 2.8
2.4 ± 1.6
1.94 ± 1.43
1.80 ± 0.77
1.58 ± 0.79
1.80 ± 0.82
522 ± 151 54 ± 3
516 ± 137 53 ± 4
494 ± 215 54 ± 3
491 ± 182 53 ± 4
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145
TABLE 5 EFFECT OF ARGON LASER TRABECULOPLASTY ON TESTED VARIABLES IN NONRESPONDERS
Variable Intraocular pressure (mm Hg) Volume of anterior chamber (μΐ) Flow of aqueous (μΐ/min) Apparent resistance to aqueous outflow (min · mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (x 10 -3 ) (min -1 ) Endothelial permeability to fluorescein (x 10 - ) (cm/min) Mean endothelial cell size (μπι ) Cornea! thickness (μπι)
Treated Eyes (No. = 8) Preoperative Postoperative
Untreated Eyes (No. = 8) Preoperative Postoperative
18 ± 4 * 154 ± 51 1.61 ± 0.31
16 ± 3 157 ± 39 1.77 ± 0.81
15 ± 1 160 ± 4 1 1.92 ± 1.15
15 ± 3 161 ± 42 1.90 ± 0.94
11.6 ± 3.1
10.1 ± 2 . 9
9.5 ± 3.9
9.6 ± 4.2
0.14 ± 0.5
0.14 ± 0.06
0.16 ±0.06
0.19 ± 0.08
1.4 ± 0.6
1.6 ± 1.0
0.9 ± 0.5
1.7 ± 0.9
1.85 ± 1.10
1.77 ± 0.94
1.97 ± 1.30
2.22 ± 0.75
433 ± 113 56 ± 3
426 ± 98 57 ± 4
424 ± 126 56±3
432 ± 149 56± 3
*P < .001 by paired t-test.
ently had no effect on the permeability of the blood-ocular barrier, the permeabili ty of the corneal endothelium, the vol ume of the anterior chamber, the mean endothelial cell size, or the corneal thick ness. The study was designed to permit each treated eye to serve as its own control. The fellow eye, which in most instances was glaucomatous but not necessarily to
the same degree as the treated eye, served as an untreated control to permit observation of the reproducibility of the test procedures. The coefficient of varia tion of each of the test procedures was calculated from the differences observed in the results of each of the untreated eyes measured at the two test periods (Table 6). We used these coefficients to determine the minimum effect that could
TABLE 6 VARIABILITY OF TEST PROCEDURES IN 17 FELLOW EYES
Test Intraocular pressure (mm Hg) Volume of anterior chamber (μΐ) Flow of aqueous (μΐ/min) Apparent resistance (min · mm Hg/μΐ) Tonographic C value (μΐ/min/mm Hg) Blood-aqueous barrier exchange coefficient (min - ) Endothelial permeability to fluorescein (cm/min) Mean endothelial cell size (μηι ) Corneal thickness (μπι) *α = 0.05; β = 0.20.
Coefficient of Variation (%)
Minimal* Detectable Difference (%)
18 7 40 47 47
21 .8 47 55 56
65
77
71 6 3
84 8 4
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AMERICAN JOURNAL OF OPHTHALMOLOGY
be detected reliably with our sample size of 17 treated patients. These estimates showed that a small effect of laser photocoagulation could have been missed but that a large effect would have been de tected. Thus, we could not conclude from the study that this treatment procedure produced no change in the blood-ocular barrier, in the rate of aqueous formation, or in the corneal function but only that large changes were not produced, chang es of the order of magnitude observed in intraocular pressure and in outflow resist ance. We concluded that laser trabeculoplasty produces its beneficial effect by im proving the outflow of aqueous humor. This effect most probably occurs by im provement of canalicular outflow, that is, flow into the canal of Schlemm and out of the eye by way of the collector chan nels of the canal. Our data did not permit us to determine the precise mechanism responsible for the improvement in out flow. A number of plausible possibilities are worthy of consideration. It seems, however, on the basis of the microscopic appearance of the trabeculum after treat ment with this power density, that gross perforation into the canal of Schlemm is not necessary or even desirable to pro duce a sustained improvement in out flow. 18,20,33 REFERENCES 1. Hager, H.: Besondere mikrochirurgische Ein griffe. 2. Teil. Erste Erfahrungen mit dem ArgonLaser-Gerat 800. Klin. Monatsbl. Augenheilkd. 162:437, 1973. 2. Krasnov, M. M.: Laseropuncture of anterior chamber angle in glaucoma. Am. J. Ophthalmol. 75:674, 1973. 3. Ticho, U., and Zauberman, H.: Argon laser application to the angle structures in the glaucomas. Arch. Ophthalmol. 94:61, 1976. 4. Ticho, U., Mahler, J., Sekeles, E., Bruchim, A., Admony, M., Weinberger, Z., Lougnot, D. J., and Goldschmidt, C. R.: Low-energy laser trabeculotomies in primates. Exp. Eye Res. 33:11, 1981. 5. Ticho, U. : Laser application to angle structures in animals and in human glaucomatous eyes. Adv. Ophthalmol. 69:201, 1977.
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6. Dannheim, F., and Rassow, B.: Zur lasertrabekulopunkture. III. Versuche am Rhesusaffen. Ophthalmologica 173:40, 1976. 7. Fechner, P. U., Teichman, I., and Teichman, U. D.: Long term results of laser trabeculopuncture method. Klin. Monatsbl. Augenheilkd. 162:437, 1973. 8. Stiegler, G.: Laser treatment of the anterior segment of the eye with a new glaucoma research laser. Klin. Monatsbl. Augenheilkd. 169:677, 1976. 9. : Laser-trabekulotomie und laser-iridektomie. Drei jähe erfahrung mit dem glaukomresearch-laser (Britt). Klin. Monatsbl. Augenheilkd. 175:333, 1979. 10. : Glaucoma treated with the pulsed argon laser. Klin. Monatsbl. Augenheilkd. 178:379, 1981. 11. Teichmann, I., Teichmann, K. D., and Fech ner, P. U.: Glaucoma operation with the argon laser. Eye Ear Nose Throat Mon. 55:209, 1976. 12. Goldschmidt, C. R., and Ticho, U.: Theoreti cal approach to laser trabeculotomy. Med. Phys. 5:92, 1978. 13. Ticho, U., Cadet, J. C , Mahler, J., Sekeles, E., and Bruchim, A.: Argon laser trabeculotomies in primates. Evaluation by histological and perfusion studies. Invest. Ophthalmol. Vis. Sei. 17:667, 1978. 14. Wickham, M. G., Worthen, D. M., and Bind er, P. S.: Physiological effects of laser trabeculotomy in rhesus monkey eyes. Invest. Ophthalmol. Vis. Sei. 16:624, 1977. 15. van der Zypen, E., and Fankhauser, F.: The ultrastructural features of laser trabeculopuncture and cyclodialysis. Problems related to successful treatment of chronic simple glaucoma. Ophthalmo logica 179:189, 1979. 16. Worthen, D. M., and Wickham, M. G.: Laser trabeculotomy in monkeys. Invest. Ophthalmol. 12:707, 1973. 17. : Argon laser trabeculotomy. Trans. Am. Acad. Ophthalmol. Otolaryngol. 78(OP):371, 1974. 18. Wise, J. B., and Witter, S. L.: Argon laser therapy for open-angle glaucoma. Arch. Ophthalmol. 97:319, 1979. 19. : Glaucoma treatment by trabecular tightening with the argon laser. Int. Ophthalmol. Clin. 21:69, 1981. 20. : Long-term control of adult open angle glaucoma by argon laser treatment. Ophthalmology 88:197, 1981. 21. Wilensky, J. T., and Jampol, L.: Laser thera py for open angle glaucoma. Ophthalmology 88:213, 1981. 22. Sutton, G. E., Christensen, G. R., and Rec ords, R. E.: Trabeculotomy with continuous argon laser. Trans. Ophthalmol. Soc. U.K. 101:118, 1981. 23. Schwartz, A. L., Whitten, M. E., Bleiman, B., and Martin, D. : Argon laser trabecular surgery in uncontrolled phakic open angle glaucoma. Ophthal mology 88:203, 1981. 24. Pohjanpelto, P. : Argon laser treatment of the anterior chamber angle for increased intraocular pressure. Acta Ophthalmol. 59:211, 1981.
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25. Coakes, R. L., and Brubaker, R. F.: Method of measuring aqueous humor flow and corneal endothelial permeability using a fluorophotometry nomogram. Invest. Ophthalmol. Vis. Sei. 18:288, 1979. 26. Brubaker, R. F., and Coakes, R. L.: Use of a xenon flash tube as the excitation, source in a new slit-lamp fluorophotometer. Am. J. Ophthalmol. 86:474, 1978. 27. Johnson, S. B., Coakes, R. L., and Brubaker, R. F.: A simple photogrammetric method of measur ing anterior chamber volume. Am. J. Ophthalmol. 85:469, 1978. 28. Nagataki, S., and Brubaker, R. F.: Effect of pilocarpine on aqueous humor formation in human beings. Arch. Ophthalmol. 100:818, 1982. 29. Jones, R. F., and Maurice, D. M.: New meth
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ods of measuring the rate of aqueous flow in man with fluorescein. Exp. Eye Res. 5:208, 1966. 30. Brubaker, R. F., Penniston, J. T., Grotte, D. A., and Nagataki, S.: Measurement of fluorescein binding in human plasma using fluorescence polari zation. Arch. Ophthalmol. 100:625, 1982. 31. Grant, W. M.: Tonographic method for mea suring the facility and rate of aqueous flow in human eyes. Arch. Ophthalmol. 44:204, 1950. 32. Araie, M., Sawa, M., Nagataki, S., and Mishima, S.: Aqueous humor dynamics in man as studied by oral fluorescein. Jpn. J. Ophthalmol. 24:346, 1980. 33. Rodrigues, M. M., Spaeth, G. L., and Donohoo, P. : Electron microscopy of argon laser therapy in phakic open-angle glaucoma. Ophthalmology 89:198, 1982.