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The “no treatment” approach to ocular hypertension
SURVEY OF OPHTHALMOLOGY
VOLUME
25
l
NUMBER
The “NO Treatment” Ocular
3* NOVEMBER-DECEMBER
Approach
1980
to
Hypertension
CHARLES D. PHELPS, M.D.
Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa Abstract. Should patients with ocular hypertension be treated to prevent glaucomatous visual field loss? Three considerations suggest that for most patients the answer is no. First, the average risk of visual field loss in untreated ocular hypertension is small. Population surveys and prospective studies indicate that no more than about one of every nine persons with intraocular pressures higher than 20 mm Hg will develop a visual field defect. Secondly, treatment of ocular hypertension to lower intraocular pressure is of unproven efficacy in preventing visual field defects. Thirdly, adverse reactions to glaucoma therapy occur frequently and are sometimes serious. Although pressure reduction may be indicated:for some patients who possess certain risk factors which make them especially susceptible to glaucomatous damage, for most patients “no treatment” is the best management. Untreated patients must be observed carefully with periodic visual field and optic disc examinations. (Sun Ophthalmol 25:175-182, 1980) Key words. glaucoma optic nerve susceptibility
l
intraocular pressure population studies
W
hat therapeutic plan is best for a patient who has high intraocular pressures but no evidence of pressureinduced ocular damage or dysfunction? Should medication be prescribed, or perhaps even an operation be performed, to lower intraocular pressure with the aim of preventing glaucomatous loss of vision? Or is the patient better served if we withhold treatment but arrange to examine the optic discs and visual fields at periodic intervals, prescribing treatment only if during a subsequent examination we detect signs of early optic nerve damage? The first alternative, reduction of pressure before it causes glaucomatous loss of vision,
l
ocular hypertension visual field loss
l
has great appeal and is certainly indicated in some cases. On the other hand, several considerations suggest that for the majority of patients with ocular hypertension a policy of close observation without treatment is the wiser course of action. These considerations include 1) the low risk of visual loss from ocular hypertension, 2) the unproven efficacy of prophylactive treatment, and 3) the high frequency and occasionally serious nature of adverse reactions to almost every form of glaucoma therapy. In this paper I will review what we currently know about the prognosis of untreated ocular hypertension, the benefits we 175
176
Surv Ophtholmol
25 (3) November-December
1980
PHELPS
TABLE 1 Prevalence of Visual Defects in Eyes with High Intraocular Pressures
High Intraocular Pressure Location of Study, reference Skvodesl Des Moines’ Rhonda Valley” Bedford’
Number Studied 7215 4628 4231 5941
persons eyes persons persons
Age
Criterion (mm Hg)
Total Number
VF abnormal: No. (%)
over 40 over 20 40-75 over 40
>22 >19 >20 >20
236 569 410 421
26(1LO) 60(10.2) 13( 3.2) 42( 9.8)
may anticipate from treatment, and the adverse reactions to treatment. We need this information if we are to weigh the possible benefits of any proposed therapy against its potential risks.
What is the Risk of High Intraocular Pressure? Untreated ocular hypertension may damage the eye in at least three ways. It may cause cornea1 edema with symptoms of pain, blurring, and halos; it may predispose to central retinal vein occlusion; and it may induce optic atrophy with glaucomatous cupping and nerve fiber bundle visual field defects. Cornea1 edema is rare in the absence of underlying cornea1 disease and occurs only with very high pressures or when the pressure abruptly increases. Because it is reversible when the pressure is lowered and is rarely the cause of permanent disability, cornea1 edema is usually a minor concern in the management of ocular hypertension. Central retinal vein occlusion, on the other hand, is a more serious concern because it may be associated with lasting visual dysfunction. Many studies indicate that patients with central retinal vein occlusion often have underlying glaucoma or ocular hypertension. ll*sa However, the incidence of central retinal vein occlusion in untreated ocular hypertension is unknown. Clinical experience suggests that it is quite low. The most important risk of untreated ocular hypertension is glaucomatous damage to the optic nerve. Glaucomatous loss of vision, once present, is usually permanent. The risk of visual field loss in ocular hypertension can be estimated in two ways. One way is to compare the prevalences of open-angle
glaucoma and ocular hypertension in a “cross-sectional” study of an unselected but defined population. The other way is to observe in a prospective or “longitudinal” study a group of patients with untreated ocular hypertension over a period of years to determine how many ultimately develop a glaucomatous visual field defect. To estimate the risk of visual field loss from population survey data, we must make two assumptions. The first assumption is that all cases of open-angle glaucoma come from the population pool of ocular hypertensives. (If some begin as low-tension glaucoma and later develop high intraocular pressure, we will overestimate the risk of visual field loss in ocular hypertension.) The second assumption is that the prevalences in the general population of open-angle glaucoma and ocular hypertension remain fairly constant from year to year. If these two assumptions are
TABLE 2 Prevalence of Visual Field Defects in Eyes with Differing Magnitudes of High Intramlar Pressure
Report/ intraocular pressure (mm Hg) Stromberg’ 22 to 25 26 to 30 31 to36 .36 Armal? 20 to 25 26 to 30 >30
Number of eyes
Number of (%) with visual field defects
144 49 14 29
1 ( 0.7) O( 0.0) 4 (28.6) 21 (72.4)
814 291 53
55 ( 6.8) 36 (12.4) 15(28.3)
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correct, and there is little reason to doubt them, then the ratio of open-angle glaucoma to ocular hypertension in the general population provides us with an estimate of the probability that an individual with ocular hypertension will develop a glaucomatous field defect at some time during his or her life. The results of four large population suryeys4.~.174 are listed in Table 1. The data from these studies suggest that an individual with ocular hypertension (i.e., an intraocular pressure of 20 mm Hg or higher) has, on the average, no more than a 1 in 10 chance of developing a visual field defect during his or her lifetime. The risk, of course, depends on the magnitude of the ocular hypertension. Data from two population surveys,6v *l displayed in Table 2, suggest that the overall risk of visual field loss is considerably less than 1: 10 when the level of ocular hypertension is between 20
and 25 mm Hg. When the pressure is above 30 mm Hg, the risk may be as high as 1: 3 or 1:2. The impression that ocular hypertension of mild to moderate severity progresses only infrequently to glaucomatous damage has been amply confirmed studies. 2,12,16,18,21,22,24,26,27.90,95
by prospective These
studies
(Table 3) show that the risk of visual field loss in patients with mild ocular hypertension followed without treatment for 5 years is less than 5%. The limited data available suggest that the risk does not increase much until the intraocular pressure exceeds 30 mm Hg. However, the number of patients followed without treatment at high levels of pressure is too small to allow any firm conclusions about the risk of visual field loss with intraocular pressures of 25,30,35, or 40 mm Hg. We also lack data about the risk if ocular hypertension is left untreated for longer periods, such
TABLE 3 Incidence of Visual Field Defects in Untreated Ocular Hypertension Report
Years of Followup
Initial Intraocular Pressure (mm Hg)
Proportion Developing Visual Field Defects/No. (‘%)
LinnCr and Strombergl’
>20
3/152
( 2.0)
GrahamI
>20
l/232
( 0.4)
Armaly*
<20 20 to 23 24 to 29 >29
2/3330 l/504 l/90 o/12
( ( ( (
0.1) 0.2) 1.1) 0.0)
Norskovla
5
20 to 24
l/136
( 0.7)
Schappert-Kimmijsern
5
22 to 30 >30
12/94 5/12
(12.8) (41.7)
5 to I
<20 >20
Wilensky et als9
5
Kitazawa et alI8 Sorenson et ala0 David et alI2
Glaucoma Collaborative Study*
7/720 4/124
( 1.0) ( 3.2)
>21
3/50
( 6.0)
9
>21
7/75
( 9.3)
15
>19
2/55
( 3.6)
3.5
21 to 25 26 to 30 >30
2175 3/25 7/17
( 2.7) (12.0) (41.2)
5to 13
<16 16 to 19 20 to 23 >23
20/2468 33/2343 26/826 211249
*Unpublished; Armaly, personal communication.
( ( ( (
0.8) 1.4) 3.1) 8.4)
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Surv Ophthalmol
25 (3) November-December
1980
as 1520, or 25 years, because few prospective studies have been carried out for more than 10 years. Nevertheless, it is clear that only a small minority of patients with ocular hypertension will lose vision. Thus, if we treat all patients with ocular hypertension, we will be treating many unnecessarily. This raises the question of whether it is possible to identify those few patients with ocular hypertension who are especially susceptible to pressure-induced optic nerve damage. If so, we could be more selective about which patient we decide to treat. One “risk factor,” of course, is the severity of the ocular hypertension. Many other risk factors have been suggested, and several tests have been proposed. Some of the proposed tests of risk factors are concerned with the regulation of aqueous humor formation and outflow. These include tonography, the water drinking test, measurement of the diurnal variation of intraocular pressure, measurement of the corticosteroid response and of the response of intraocular pressure to a single dose of pilocarpine, epinephrine, or acetazolamide. The argument for the validity of these tests as predictors of glaucomatous damage usually rests on the observation that an “abnormal” result occurs in a large percentage of eyes with fully developed glaucoma but is found in only a small percentage of normal eyes. The conclusion may be reached that a patient with an “abnormal” result has glaucoma or is likely to develop glaucoma. The fallacy of this reasoning, of course, is that normal people outnumber people with open angle glaucoma in the general population by such a large amount (perhaps 200: 1) that an individual with an “abnormal” response to any one of these tests of aqueous dynamics is still many more times likely to be normal than to have glaucoma. Furthermore, few investigators have determined the frequencies of “abnormal” tests in patients with ocular hypertension. Each of the proposed tests measures some aspect of intraocular pressure regulation. Thus each is likely to be “abnormal” in a high percentage of eyes with ocular hypertension which, by definition, have abnormal intraocular pressure regulation. The ability of these tests to predict future visual field loss in ocular hypertensive patients can be proven only by prospective
PHELPS
studies. The prognostic utility of two of the tests, tonography and the water-drinking test, was evaluated prospectively in the recent Glaucoma Collaborative Study. Both tests provided some predictive information above that which was obtained simply by measuring intraocular pressure (Armaly M, personal communication). From a statistician’s point of view, this additional information was significant. Unfortunately, from a clinician’s point of view, the additional predictive information was so minimal that it scarcely justified the time and expense involved in performing the tests. Another group of tests or risk factors involves the optic nerve and its function. It has been proposed, for instance, that an optic disc with a large cup - large, that is, because of heredity is more susceptible to glaucomatous damage than is a disc with a small cup. This suggestion is based on the observation that patients with open angle glaucoma who have visual field loss in only one eye often have a large optic disc cup in the fellow eye.s~9One interpretation of this observation is that these patients were born with large optic cups which made them susceptible to glaucomatous damage. However, the large cup in the fellow eye could just as well indicate early damage to that disc which current methods of visual field testing were unable to detect, Whichever interpretation is correct, a small cup would seem to most clinicians to provide the disc with a wider margin of safety than a large cup. This clinical impression was recently confirmed in the Glaucoma Collaborative Study (Armaly M, personal communication). Angiographic tilling defects have been identified in glaucomatous optic discs and in eyes with ocular hypertension.z2~28 This suggests that an angiographic filling defect in the disc of a patient with ocular hypertension may presage loss of vision. Prospective studies are needed to confirm or disprove this hypothesis. Some investigators have tried to measure the effect on visual function or visually evoked cortical responses of sudden high elevations of intraocular pressure.8*‘a A challenge or stress test of this nature is attractive in theory, for it might directly measure the susceptibility of an individual eye to pressure-induced loss of vision.” However, there is no evidence that the pathogenesis of acute pressure amaurosis is at all the same as
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that of chronic glaucomatous loss of vision and, from a practical viewpoint, the tests are very difficult to perform and interpret. Other tests of visual function are currently under investigation in an attempt to find an indicator of early glaucomatous damage that is more sensitive than our current perimetric methods. Color vision testingle and measurement of contrast sensitivity’ are two especially interesting fields of research which may eventually provide simple clinical tests with prognostic significance. Possible systemic risk factors in ocular hypertension include a family history of glaucomatous blindness16 which may suggest a genetic susceptibility; diabetes mellitus;” low blood pressure from medication, blood loss, or arrhythmia; advancing age; and the presence of significant vasoocclusive disease elsewhere. Some, if not all, of these risk factors are probably important in determining the susceptibility of an optic nerve to damage. Unfortunately, with the exception of old age (Glaucoma Collaborative Study: Armaly M, personal communication), few risk factors have been conclusively verified in prospective studies. In summary, risk factors that definitely increase the probability of visual field loss include high intraocular pressure, old age, and large cup of the optic disc. Several other factors that may slightly increase the risk include low outflow facility, high intraocular pressure response to water drinking, and family history of glaucomatous blindness. Other factors may be significant, but remain unproven. In the future, with the assistance of sophisticated multivariate analysis by computer,18 we may be able to improve our risk estimates for individual patients. At present, even taking all known risk factors into consideration, we remain unable to predict with any degree of certainty which ocular hypertensive patient will develop glaucomatous blindness.
What is the Effectiveness of Treatment in Preventing Glaucomatous Loss of Vision? Our intuition tells us that lowering the intraocular pressure in a patient with ocular hypertension should reduce the risk of losing vision. It is surprising how little evidence there is to support this assumption. Levene treated one eye of 59 ocular hypertensive patients with miotics.20 After five years one patient had lost vision in the
control eye, one patient had lost vision in the treated eye, and two patients had lost vision in both eyes. These results suggest that miotics are ineffective in preventing visual field defects in ocular hypertension. Investigators at Washington University in St. Louis treated one eye of 19 ocular hypertensive patients with epinephrine for 1 to 5 years.2e None of the 19 treated eyes lost vision, while 6 (32%) of the 19 untreated eyes lost vision. It is possible that epinephrine prevented loss of vision in the treated eye, but the unexpectedly high incidence of vision loss in the control eyes raises the possibility that systemically absorbed epinephrine in some way made the control eyes unusually susceptible to optic nerve damage. Thus, treatment of ocular hypertension with medication may or may not be effective in preventing visual loss from ocular hypertension. Demonstration of efficacy will require large scale clinical trials, because of the low incidence of visual field loss in untreated ocular hypertension.
What is the Risk of Treatment? Adverse reactions occur to all glaucomatous medications. Some are merely bothersome, but others are more serious. The more common side effects plus some rare but severe adverse reactions are listed in Table 4. The point of enumerating the potential disadvantages of glaucoma therapy is not that treatment should be withheld if indicated, but that the adverse reactions constitute a definite risk to the treated ocular hypertensive patients which must be considered and weighed against the risk of visual loss without treatment when decisions are made regarding therapy. Short-acting miotics such as pilocarpine and carbachol rarely cause severe reactions with permanent sequelae. However, they frequently blur vision enough to incapacitate a patient who before treatment had no visual complaints. Anticholinesterase miotics are cataractogenic, and both types of miotic may play a role in the pathogenesis of some retinal detachments. Epinephrine has few serious ocular side effects, except for cystoid macular edema in aphakic eyes, but it may raise blood pressure, exacerbate angina pectoris, or produce cardiac arrhythmias if enough is absorbed systemically. Timolol is relatively free of shortterm side effects. However, experience
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Surv Ophthalmol 25 (3) November-December 1980
with timolol is limited to less than five years, and more serious reactions may become known in the future. Thus, it should not be used indiscriminately as a treatment for ocular hypertension. Carbonic anhydrase inhibitors induce parasthesias, dull the appetite, and depress the spirits of a large proportion of treated patients. Much more disturbing are the rare but sometimes fatal idiosyncratic reactions, such as aplastic anemia. Every type of filtering operation, no matter how skilled the surgeon, may cause cataracts to progress or develop. More serious complications, such as bleb rupture with endophthalmitis, can lead to blindness. Finally, medical treatment places a financial burden on the patients and, to the extent that they must arrange their daily schedules around the times for instilling medications, alters their way of life.
What is the Best Management of Ocular Hypertension? We have seen that only about 1 in 10 patients with ocular hypertension will ever lose vision from glaucoma. We are not able at present to identify in advance which patient is going to lose vision. Although we assume that pressure-lowering treatment will prevent glaucomatous loss of vision, we lack definite proof. Adverse reactions to antiglaucoma medications are frequent. It is for these reasons that “no treatment” is often the best management for ocular hypertension. For some patients with ocular hypertension, of course, treatment is necessary. Intraocular pressure should be lowered whenever there is glaucomatous visual field loss in either eye, a documented increase in optic disc cupping, a central retinal vein occlusion, or cornea1 edema. For other patients, treatment is optional. This category includes patients with very high pressures; patients with large cups of the optic disc; elderly patients; patients who may be predisposed to visual damage by diabetes, cardiovascular disease, or other possible risk factors; or patients who are anxious about their elevated intraocular pressures. It also includes all patients in whom visual field testing is unreliable. The important thing to remember in managing this group of patients is that treatment is elective, not imperative. Toxic reactions to medications should be avoided. Carbonic anhydrase inhibitors and
PHELPS
TABLE 4 Common Adverse Reactions to Glaucoma lkerapy Miotics
Bothersome Poor night vision Induced myopia Decreased visual acuity in cataract patient Serious Retinal detachment Cataract Epinephrine
Bothersome Red eyes Allergy Serious Aphakic cystoid maculopathy Cardiovascular effects Carbonic Anhydrase Inhibitors
Bothersome Parasthesias Anorexia Lethargy Serious Renal stones Sulfa allergy Blood dyscrasia Timolol
Bradycardia Bronchospasm Central nervous system dysfunction ?? Other yet unreported reactions Surgery
Cataract Infection Hemorrhage
anticholinesterase miotics should be used with caution, epinephrine should be avoided if the patient has cardiovascular disease, and surgery is rarely indicated. The pressurelowering efficacy of the treatment regimen should be clearly established for each patient, so that the patient is not unnecessarily exposed to side effects of an ineffective medication. For the majority of patients with ocular hypertension, no treatment will be necessary. This does not mean that these patients have a form of ocular hypertension which is incapable of causing visual loss. It only means that the probability of their losing vision is judged to be less than the probability of adverse reactions to the treatment. Untreated patients must be carefully observed for the remainder of their lives. Patient education is extremely important.
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APPROACH
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Patients must be aware that they have a condition which is capable of slowly causing loss of vision and that they will not notice the visual loss in its early stages. Beginning optic nerve damage can be detected only if the patient returns periodically for careful and competent monitoring of the visual fields and optic discs. Visual field examinations should be done with a screening strategy that will detect early field defects at a stage when they are still imperceptible to the patient and possibly reversible s~26 During the first examination the appkarance of the optic discs should be recorded by photography, preferably with stereophotographs. Each time the patient returns, the optic discs should be carefully reexamined in search of subtle changes. In our clinic we follow patients yearly if the ocular hypertension is mild (20 to 24 mm Hg), every six months if it is moderate (25 to 29 mm Hg), and every three or four months if it is severe (30 mm Hg or higher). Each followup visit includes visual field examination and ophthalmoscopy. We are observing several hundred ocular hypertensive patients with this regimen and, of course, have had an occasional patient who has developed a visual field defect. In no instance, with this frequency of followup, has the defect been advanced enough for the patient to be aware of it. In summary, ocular hypertension is not a benign condition. It is capable of causing permanent impairment of vision. However, the risk of visual loss from mild to moderate ocular hypertension is low, and adverse reactions to therapy are common. Thus, for many patients, “no treatment” is the wisest policy. Lifetime surveillance of these untreated patients is mandatory so that optic nerve damage, if it occurs, will be detected at a very early stage.
References Arden GB, Jacobson JJ: A simple grating test for contrast sensitivity: Preliminary results indicate value in screening for glaucoma. Invest Ophthalmol 17:23-32, 1978 Armaly MF: Ocular pressure and visual fields: A ten-year followup study. Arch Ophthalmol 81:25-40, 1969 Armaly MF: Selective perimetry for glaucomatous defects in ocular hypertension. Arch Ophthalmol 87:518-524, 1972 Armaly MF: On the distribution of applanation pressure and arcuate scotoma. in Pater-
son G, Miller SJH, Paterson GD (eds): Drug Mechanisms in Glaucoma. Boston, Little,
Brown, 1966, pp 167-189 5. Armaly MF: Optic cup in normal and glaucomatous eyes. Invest Ophthalmol 9: 425-429, 1970 6. Armaly MF: Interpretation of tonometry and ophthalmoscopy. Invest Ophthalmol 11:75-79, 1972 7. Bankes JLK, Perkins ES, Tsolakis S, Wright JE: Bedford Glaucoma Survey. Br Med J 1:791-796, 1968 8. Bartl G, Benedikt 0, Hiti H, Mandl V: Das elektrophysiologische Verhalten gesunder und glaukomkranker menschlicher Augen bei kurzzeitiger intraocularer Druckbelastung. Albrecht von Graefes Arch Klin Exp Ophthalmol 195:201-206, 1975 9. Becker 9: Cup/disc ratio and topical corticosteroid testing. Am J Ophthalmol 70: 681-685, 1970 10. Becker B: Diabetes mellitus and primary open-angle glaucoma. Am J Ophthalmol 71:1-16, 1971 II. Bertelsen TI: The relationship between thrombosis in the retinal veins and primary glaucoma. Acta Ophthalmol39:603-613, 1961 12. David R, Livingston DG, Luntz MH: Ocular hypertension a longterm followup of treated and untreated patients. Br J Ophthalmol 61:668-674, 1977 13. Drance SM: Studies in the susceptibility of the eye to raised intraocular pressure. Arch Ophthalmol 68:478-485, 1962 14. Goldmann H, Blok P: On a possibility to connect quantitatively ocular hypertension and damage to the optic nerve. Albrecht von Graefes Arch Klin Exp Ophthalmol 183: 232-243, 197 1 15. Graham PA: The definition of pre-glaucoma: A prospective study. Trans Ophthalmol Sot UK 88:153-165, 1968 16. Hart WM, Yablonski M, Kass MA, Becker B: Multivariate analysis of the risk of visual field loss. Arch Ophthalmol 97:1455-1458, 1979 17. Hollows FC, Graham PA: Intraocular pressure, glaucoma, and glaucoma suspects in a defined population. Br J Ophthalmol SO: 570-586, 1966 18. Kitazawa Y, Horie T, Aoki S, et al: Untreated ocular hypertension. Arch Ophthalmol 95:1180-1184, 1977 19. Lakowski R, Drance SM: Acquired dyschromatopsias: The earliest functional losses in glaucoma. Dot Ophthalmol Proc Series 19:159-165, 1978 20. Levene R: Uniocular miotic theraov. Trans Am Acad Ophthalmol Otolary&ol 79: 376-380. 1975 21. Linn6r E, Stromberg U: Ocular hypertension, in Lydhecker W (ed): Glaucoma: Tutzing Sym-
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Surv Ophthalmol 25 (3) November-December 1980
posium. Basel, S Karger, 1967, pp 187-214 22, Loebl M, Schwartz B: Fluorescein angiographic defects of the optic disc in ocular hypertension. Arch Ophthalmol95:1980-1984, 1977 23. Norskov K: Routine tonometry in ophthalmic practice. II. Five-year followup. Acta Ophthalmol 48:873-895, 1970 24. Perkins ES: The Bedford Glaucoma Survey. I. Long-term follow-up of borderline cases. Br J Ophthalmol 57:179-185, 1973 25. Perkins ES: The Bedford Glaucoma Survey. II. Rescreening of normal population. Br J Ophthalmol 57:186-192, 1973 26. Phelps CD: Visual field defects in open-angle glaucoma: progression and regression. Dot Ophthalmoi Proc Series 19: 187-196, 1978 27. Schappert-Kimmijser J: A five-year follow-up of subjects with intraocular pressure of 22-30 mm Hg without anomalies of optic nerve and visual field typical for glaucoma at first investigation. Ophthalmologica 162:289-295, 1971 28. Schwartz B, Rieser JC, Fishbein SL: Fluorescein angiographic defects of the optic disc in glaucoma. Arch Ophthalmol 95:1961-1974, 1977 29. Shin DH, Kolker AB, Kass MA, et al: Longterm epinephrine therapy of ocular hypertension. Arch Ophthalmol 94:2059-2060, 1976 30. Sorensen PN, Nielsen NV, Norskov K: Ocular hypertension: A 15-year follow-up. Acta Ophthalmol g&363-372, 1978
3 1. Stromberg U: Ocular hypertension. Acta Ophthalmol, Suppl, 69:1-75, 1962 32. Vannas S, Tarkkanen A: Retinal vein occlusion and glaucoma: tonographic study of the incidence of glaucoma and of its prognostic significance. Br J Ophthalmol 44:583-589, 1960 JT, Podos SM, Becker B: 33. Wilensky Prognostic indicators in ocular hypertension. Arch Ophthalmol 91:20&202, 1974 The following references, not cited in the text, provide additional insight into the controversies regarding the management of ocular hypertension: Anderson DR: The management of elevated intraocular pressure with normal optic discs and visual fields. I. Therapeutic approach based on high risk factors. Surv Ophthalmol 21: 479-489, 1977 Hoskins HD: The management of elevated intraocular pressure with normal optic discs and visual fields. II. An approach to early therapy. Surv Ophthalmol 21:479, 489-493, 1977 ‘Ocular hypertension’ or ‘early Editorials: glaucoma’. Arch Ophthalmol 95:585-589, 1977 Reprint requests should be addressed to C.S. O’Brien Library, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242.
VOLUME
25
l
NUMBER
The “NO Treatment” Ocular
3* NOVEMBER-DECEMBER
Approach
1980
to
Hypertension
CHARLES D. PHELPS, M.D.
Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa Abstract. Should patients with ocular hypertension be treated to prevent glaucomatous visual field loss? Three considerations suggest that for most patients the answer is no. First, the average risk of visual field loss in untreated ocular hypertension is small. Population surveys and prospective studies indicate that no more than about one of every nine persons with intraocular pressures higher than 20 mm Hg will develop a visual field defect. Secondly, treatment of ocular hypertension to lower intraocular pressure is of unproven efficacy in preventing visual field defects. Thirdly, adverse reactions to glaucoma therapy occur frequently and are sometimes serious. Although pressure reduction may be indicated:for some patients who possess certain risk factors which make them especially susceptible to glaucomatous damage, for most patients “no treatment” is the best management. Untreated patients must be observed carefully with periodic visual field and optic disc examinations. (Sun Ophthalmol 25:175-182, 1980) Key words. glaucoma optic nerve susceptibility
l
intraocular pressure population studies
W
hat therapeutic plan is best for a patient who has high intraocular pressures but no evidence of pressureinduced ocular damage or dysfunction? Should medication be prescribed, or perhaps even an operation be performed, to lower intraocular pressure with the aim of preventing glaucomatous loss of vision? Or is the patient better served if we withhold treatment but arrange to examine the optic discs and visual fields at periodic intervals, prescribing treatment only if during a subsequent examination we detect signs of early optic nerve damage? The first alternative, reduction of pressure before it causes glaucomatous loss of vision,
l
ocular hypertension visual field loss
l
has great appeal and is certainly indicated in some cases. On the other hand, several considerations suggest that for the majority of patients with ocular hypertension a policy of close observation without treatment is the wiser course of action. These considerations include 1) the low risk of visual loss from ocular hypertension, 2) the unproven efficacy of prophylactive treatment, and 3) the high frequency and occasionally serious nature of adverse reactions to almost every form of glaucoma therapy. In this paper I will review what we currently know about the prognosis of untreated ocular hypertension, the benefits we 175
176
Surv Ophtholmol
25 (3) November-December
1980
PHELPS
TABLE 1 Prevalence of Visual Defects in Eyes with High Intraocular Pressures
High Intraocular Pressure Location of Study, reference Skvodesl Des Moines’ Rhonda Valley” Bedford’
Number Studied 7215 4628 4231 5941
persons eyes persons persons
Age
Criterion (mm Hg)
Total Number
VF abnormal: No. (%)
over 40 over 20 40-75 over 40
>22 >19 >20 >20
236 569 410 421
26(1LO) 60(10.2) 13( 3.2) 42( 9.8)
may anticipate from treatment, and the adverse reactions to treatment. We need this information if we are to weigh the possible benefits of any proposed therapy against its potential risks.
What is the Risk of High Intraocular Pressure? Untreated ocular hypertension may damage the eye in at least three ways. It may cause cornea1 edema with symptoms of pain, blurring, and halos; it may predispose to central retinal vein occlusion; and it may induce optic atrophy with glaucomatous cupping and nerve fiber bundle visual field defects. Cornea1 edema is rare in the absence of underlying cornea1 disease and occurs only with very high pressures or when the pressure abruptly increases. Because it is reversible when the pressure is lowered and is rarely the cause of permanent disability, cornea1 edema is usually a minor concern in the management of ocular hypertension. Central retinal vein occlusion, on the other hand, is a more serious concern because it may be associated with lasting visual dysfunction. Many studies indicate that patients with central retinal vein occlusion often have underlying glaucoma or ocular hypertension. ll*sa However, the incidence of central retinal vein occlusion in untreated ocular hypertension is unknown. Clinical experience suggests that it is quite low. The most important risk of untreated ocular hypertension is glaucomatous damage to the optic nerve. Glaucomatous loss of vision, once present, is usually permanent. The risk of visual field loss in ocular hypertension can be estimated in two ways. One way is to compare the prevalences of open-angle
glaucoma and ocular hypertension in a “cross-sectional” study of an unselected but defined population. The other way is to observe in a prospective or “longitudinal” study a group of patients with untreated ocular hypertension over a period of years to determine how many ultimately develop a glaucomatous visual field defect. To estimate the risk of visual field loss from population survey data, we must make two assumptions. The first assumption is that all cases of open-angle glaucoma come from the population pool of ocular hypertensives. (If some begin as low-tension glaucoma and later develop high intraocular pressure, we will overestimate the risk of visual field loss in ocular hypertension.) The second assumption is that the prevalences in the general population of open-angle glaucoma and ocular hypertension remain fairly constant from year to year. If these two assumptions are
TABLE 2 Prevalence of Visual Field Defects in Eyes with Differing Magnitudes of High Intramlar Pressure
Report/ intraocular pressure (mm Hg) Stromberg’ 22 to 25 26 to 30 31 to36 .36 Armal? 20 to 25 26 to 30 >30
Number of eyes
Number of (%) with visual field defects
144 49 14 29
1 ( 0.7) O( 0.0) 4 (28.6) 21 (72.4)
814 291 53
55 ( 6.8) 36 (12.4) 15(28.3)
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correct, and there is little reason to doubt them, then the ratio of open-angle glaucoma to ocular hypertension in the general population provides us with an estimate of the probability that an individual with ocular hypertension will develop a glaucomatous field defect at some time during his or her life. The results of four large population suryeys4.~.174 are listed in Table 1. The data from these studies suggest that an individual with ocular hypertension (i.e., an intraocular pressure of 20 mm Hg or higher) has, on the average, no more than a 1 in 10 chance of developing a visual field defect during his or her lifetime. The risk, of course, depends on the magnitude of the ocular hypertension. Data from two population surveys,6v *l displayed in Table 2, suggest that the overall risk of visual field loss is considerably less than 1: 10 when the level of ocular hypertension is between 20
and 25 mm Hg. When the pressure is above 30 mm Hg, the risk may be as high as 1: 3 or 1:2. The impression that ocular hypertension of mild to moderate severity progresses only infrequently to glaucomatous damage has been amply confirmed studies. 2,12,16,18,21,22,24,26,27.90,95
by prospective These
studies
(Table 3) show that the risk of visual field loss in patients with mild ocular hypertension followed without treatment for 5 years is less than 5%. The limited data available suggest that the risk does not increase much until the intraocular pressure exceeds 30 mm Hg. However, the number of patients followed without treatment at high levels of pressure is too small to allow any firm conclusions about the risk of visual field loss with intraocular pressures of 25,30,35, or 40 mm Hg. We also lack data about the risk if ocular hypertension is left untreated for longer periods, such
TABLE 3 Incidence of Visual Field Defects in Untreated Ocular Hypertension Report
Years of Followup
Initial Intraocular Pressure (mm Hg)
Proportion Developing Visual Field Defects/No. (‘%)
LinnCr and Strombergl’
>20
3/152
( 2.0)
GrahamI
>20
l/232
( 0.4)
Armaly*
<20 20 to 23 24 to 29 >29
2/3330 l/504 l/90 o/12
( ( ( (
0.1) 0.2) 1.1) 0.0)
Norskovla
5
20 to 24
l/136
( 0.7)
Schappert-Kimmijsern
5
22 to 30 >30
12/94 5/12
(12.8) (41.7)
5 to I
<20 >20
Wilensky et als9
5
Kitazawa et alI8 Sorenson et ala0 David et alI2
Glaucoma Collaborative Study*
7/720 4/124
( 1.0) ( 3.2)
>21
3/50
( 6.0)
9
>21
7/75
( 9.3)
15
>19
2/55
( 3.6)
3.5
21 to 25 26 to 30 >30
2175 3/25 7/17
( 2.7) (12.0) (41.2)
5to 13
<16 16 to 19 20 to 23 >23
20/2468 33/2343 26/826 211249
*Unpublished; Armaly, personal communication.
( ( ( (
0.8) 1.4) 3.1) 8.4)
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Surv Ophthalmol
25 (3) November-December
1980
as 1520, or 25 years, because few prospective studies have been carried out for more than 10 years. Nevertheless, it is clear that only a small minority of patients with ocular hypertension will lose vision. Thus, if we treat all patients with ocular hypertension, we will be treating many unnecessarily. This raises the question of whether it is possible to identify those few patients with ocular hypertension who are especially susceptible to pressure-induced optic nerve damage. If so, we could be more selective about which patient we decide to treat. One “risk factor,” of course, is the severity of the ocular hypertension. Many other risk factors have been suggested, and several tests have been proposed. Some of the proposed tests of risk factors are concerned with the regulation of aqueous humor formation and outflow. These include tonography, the water drinking test, measurement of the diurnal variation of intraocular pressure, measurement of the corticosteroid response and of the response of intraocular pressure to a single dose of pilocarpine, epinephrine, or acetazolamide. The argument for the validity of these tests as predictors of glaucomatous damage usually rests on the observation that an “abnormal” result occurs in a large percentage of eyes with fully developed glaucoma but is found in only a small percentage of normal eyes. The conclusion may be reached that a patient with an “abnormal” result has glaucoma or is likely to develop glaucoma. The fallacy of this reasoning, of course, is that normal people outnumber people with open angle glaucoma in the general population by such a large amount (perhaps 200: 1) that an individual with an “abnormal” response to any one of these tests of aqueous dynamics is still many more times likely to be normal than to have glaucoma. Furthermore, few investigators have determined the frequencies of “abnormal” tests in patients with ocular hypertension. Each of the proposed tests measures some aspect of intraocular pressure regulation. Thus each is likely to be “abnormal” in a high percentage of eyes with ocular hypertension which, by definition, have abnormal intraocular pressure regulation. The ability of these tests to predict future visual field loss in ocular hypertensive patients can be proven only by prospective
PHELPS
studies. The prognostic utility of two of the tests, tonography and the water-drinking test, was evaluated prospectively in the recent Glaucoma Collaborative Study. Both tests provided some predictive information above that which was obtained simply by measuring intraocular pressure (Armaly M, personal communication). From a statistician’s point of view, this additional information was significant. Unfortunately, from a clinician’s point of view, the additional predictive information was so minimal that it scarcely justified the time and expense involved in performing the tests. Another group of tests or risk factors involves the optic nerve and its function. It has been proposed, for instance, that an optic disc with a large cup - large, that is, because of heredity is more susceptible to glaucomatous damage than is a disc with a small cup. This suggestion is based on the observation that patients with open angle glaucoma who have visual field loss in only one eye often have a large optic disc cup in the fellow eye.s~9One interpretation of this observation is that these patients were born with large optic cups which made them susceptible to glaucomatous damage. However, the large cup in the fellow eye could just as well indicate early damage to that disc which current methods of visual field testing were unable to detect, Whichever interpretation is correct, a small cup would seem to most clinicians to provide the disc with a wider margin of safety than a large cup. This clinical impression was recently confirmed in the Glaucoma Collaborative Study (Armaly M, personal communication). Angiographic tilling defects have been identified in glaucomatous optic discs and in eyes with ocular hypertension.z2~28 This suggests that an angiographic filling defect in the disc of a patient with ocular hypertension may presage loss of vision. Prospective studies are needed to confirm or disprove this hypothesis. Some investigators have tried to measure the effect on visual function or visually evoked cortical responses of sudden high elevations of intraocular pressure.8*‘a A challenge or stress test of this nature is attractive in theory, for it might directly measure the susceptibility of an individual eye to pressure-induced loss of vision.” However, there is no evidence that the pathogenesis of acute pressure amaurosis is at all the same as
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TO OCULAR HYPERTENSION
that of chronic glaucomatous loss of vision and, from a practical viewpoint, the tests are very difficult to perform and interpret. Other tests of visual function are currently under investigation in an attempt to find an indicator of early glaucomatous damage that is more sensitive than our current perimetric methods. Color vision testingle and measurement of contrast sensitivity’ are two especially interesting fields of research which may eventually provide simple clinical tests with prognostic significance. Possible systemic risk factors in ocular hypertension include a family history of glaucomatous blindness16 which may suggest a genetic susceptibility; diabetes mellitus;” low blood pressure from medication, blood loss, or arrhythmia; advancing age; and the presence of significant vasoocclusive disease elsewhere. Some, if not all, of these risk factors are probably important in determining the susceptibility of an optic nerve to damage. Unfortunately, with the exception of old age (Glaucoma Collaborative Study: Armaly M, personal communication), few risk factors have been conclusively verified in prospective studies. In summary, risk factors that definitely increase the probability of visual field loss include high intraocular pressure, old age, and large cup of the optic disc. Several other factors that may slightly increase the risk include low outflow facility, high intraocular pressure response to water drinking, and family history of glaucomatous blindness. Other factors may be significant, but remain unproven. In the future, with the assistance of sophisticated multivariate analysis by computer,18 we may be able to improve our risk estimates for individual patients. At present, even taking all known risk factors into consideration, we remain unable to predict with any degree of certainty which ocular hypertensive patient will develop glaucomatous blindness.
What is the Effectiveness of Treatment in Preventing Glaucomatous Loss of Vision? Our intuition tells us that lowering the intraocular pressure in a patient with ocular hypertension should reduce the risk of losing vision. It is surprising how little evidence there is to support this assumption. Levene treated one eye of 59 ocular hypertensive patients with miotics.20 After five years one patient had lost vision in the
control eye, one patient had lost vision in the treated eye, and two patients had lost vision in both eyes. These results suggest that miotics are ineffective in preventing visual field defects in ocular hypertension. Investigators at Washington University in St. Louis treated one eye of 19 ocular hypertensive patients with epinephrine for 1 to 5 years.2e None of the 19 treated eyes lost vision, while 6 (32%) of the 19 untreated eyes lost vision. It is possible that epinephrine prevented loss of vision in the treated eye, but the unexpectedly high incidence of vision loss in the control eyes raises the possibility that systemically absorbed epinephrine in some way made the control eyes unusually susceptible to optic nerve damage. Thus, treatment of ocular hypertension with medication may or may not be effective in preventing visual loss from ocular hypertension. Demonstration of efficacy will require large scale clinical trials, because of the low incidence of visual field loss in untreated ocular hypertension.
What is the Risk of Treatment? Adverse reactions occur to all glaucomatous medications. Some are merely bothersome, but others are more serious. The more common side effects plus some rare but severe adverse reactions are listed in Table 4. The point of enumerating the potential disadvantages of glaucoma therapy is not that treatment should be withheld if indicated, but that the adverse reactions constitute a definite risk to the treated ocular hypertensive patients which must be considered and weighed against the risk of visual loss without treatment when decisions are made regarding therapy. Short-acting miotics such as pilocarpine and carbachol rarely cause severe reactions with permanent sequelae. However, they frequently blur vision enough to incapacitate a patient who before treatment had no visual complaints. Anticholinesterase miotics are cataractogenic, and both types of miotic may play a role in the pathogenesis of some retinal detachments. Epinephrine has few serious ocular side effects, except for cystoid macular edema in aphakic eyes, but it may raise blood pressure, exacerbate angina pectoris, or produce cardiac arrhythmias if enough is absorbed systemically. Timolol is relatively free of shortterm side effects. However, experience
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Surv Ophthalmol 25 (3) November-December 1980
with timolol is limited to less than five years, and more serious reactions may become known in the future. Thus, it should not be used indiscriminately as a treatment for ocular hypertension. Carbonic anhydrase inhibitors induce parasthesias, dull the appetite, and depress the spirits of a large proportion of treated patients. Much more disturbing are the rare but sometimes fatal idiosyncratic reactions, such as aplastic anemia. Every type of filtering operation, no matter how skilled the surgeon, may cause cataracts to progress or develop. More serious complications, such as bleb rupture with endophthalmitis, can lead to blindness. Finally, medical treatment places a financial burden on the patients and, to the extent that they must arrange their daily schedules around the times for instilling medications, alters their way of life.
What is the Best Management of Ocular Hypertension? We have seen that only about 1 in 10 patients with ocular hypertension will ever lose vision from glaucoma. We are not able at present to identify in advance which patient is going to lose vision. Although we assume that pressure-lowering treatment will prevent glaucomatous loss of vision, we lack definite proof. Adverse reactions to antiglaucoma medications are frequent. It is for these reasons that “no treatment” is often the best management for ocular hypertension. For some patients with ocular hypertension, of course, treatment is necessary. Intraocular pressure should be lowered whenever there is glaucomatous visual field loss in either eye, a documented increase in optic disc cupping, a central retinal vein occlusion, or cornea1 edema. For other patients, treatment is optional. This category includes patients with very high pressures; patients with large cups of the optic disc; elderly patients; patients who may be predisposed to visual damage by diabetes, cardiovascular disease, or other possible risk factors; or patients who are anxious about their elevated intraocular pressures. It also includes all patients in whom visual field testing is unreliable. The important thing to remember in managing this group of patients is that treatment is elective, not imperative. Toxic reactions to medications should be avoided. Carbonic anhydrase inhibitors and
PHELPS
TABLE 4 Common Adverse Reactions to Glaucoma lkerapy Miotics
Bothersome Poor night vision Induced myopia Decreased visual acuity in cataract patient Serious Retinal detachment Cataract Epinephrine
Bothersome Red eyes Allergy Serious Aphakic cystoid maculopathy Cardiovascular effects Carbonic Anhydrase Inhibitors
Bothersome Parasthesias Anorexia Lethargy Serious Renal stones Sulfa allergy Blood dyscrasia Timolol
Bradycardia Bronchospasm Central nervous system dysfunction ?? Other yet unreported reactions Surgery
Cataract Infection Hemorrhage
anticholinesterase miotics should be used with caution, epinephrine should be avoided if the patient has cardiovascular disease, and surgery is rarely indicated. The pressurelowering efficacy of the treatment regimen should be clearly established for each patient, so that the patient is not unnecessarily exposed to side effects of an ineffective medication. For the majority of patients with ocular hypertension, no treatment will be necessary. This does not mean that these patients have a form of ocular hypertension which is incapable of causing visual loss. It only means that the probability of their losing vision is judged to be less than the probability of adverse reactions to the treatment. Untreated patients must be carefully observed for the remainder of their lives. Patient education is extremely important.
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APPROACH
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Patients must be aware that they have a condition which is capable of slowly causing loss of vision and that they will not notice the visual loss in its early stages. Beginning optic nerve damage can be detected only if the patient returns periodically for careful and competent monitoring of the visual fields and optic discs. Visual field examinations should be done with a screening strategy that will detect early field defects at a stage when they are still imperceptible to the patient and possibly reversible s~26 During the first examination the appkarance of the optic discs should be recorded by photography, preferably with stereophotographs. Each time the patient returns, the optic discs should be carefully reexamined in search of subtle changes. In our clinic we follow patients yearly if the ocular hypertension is mild (20 to 24 mm Hg), every six months if it is moderate (25 to 29 mm Hg), and every three or four months if it is severe (30 mm Hg or higher). Each followup visit includes visual field examination and ophthalmoscopy. We are observing several hundred ocular hypertensive patients with this regimen and, of course, have had an occasional patient who has developed a visual field defect. In no instance, with this frequency of followup, has the defect been advanced enough for the patient to be aware of it. In summary, ocular hypertension is not a benign condition. It is capable of causing permanent impairment of vision. However, the risk of visual loss from mild to moderate ocular hypertension is low, and adverse reactions to therapy are common. Thus, for many patients, “no treatment” is the wisest policy. Lifetime surveillance of these untreated patients is mandatory so that optic nerve damage, if it occurs, will be detected at a very early stage.
References Arden GB, Jacobson JJ: A simple grating test for contrast sensitivity: Preliminary results indicate value in screening for glaucoma. Invest Ophthalmol 17:23-32, 1978 Armaly MF: Ocular pressure and visual fields: A ten-year followup study. Arch Ophthalmol 81:25-40, 1969 Armaly MF: Selective perimetry for glaucomatous defects in ocular hypertension. Arch Ophthalmol 87:518-524, 1972 Armaly MF: On the distribution of applanation pressure and arcuate scotoma. in Pater-
son G, Miller SJH, Paterson GD (eds): Drug Mechanisms in Glaucoma. Boston, Little,
Brown, 1966, pp 167-189 5. Armaly MF: Optic cup in normal and glaucomatous eyes. Invest Ophthalmol 9: 425-429, 1970 6. Armaly MF: Interpretation of tonometry and ophthalmoscopy. Invest Ophthalmol 11:75-79, 1972 7. Bankes JLK, Perkins ES, Tsolakis S, Wright JE: Bedford Glaucoma Survey. Br Med J 1:791-796, 1968 8. Bartl G, Benedikt 0, Hiti H, Mandl V: Das elektrophysiologische Verhalten gesunder und glaukomkranker menschlicher Augen bei kurzzeitiger intraocularer Druckbelastung. Albrecht von Graefes Arch Klin Exp Ophthalmol 195:201-206, 1975 9. Becker 9: Cup/disc ratio and topical corticosteroid testing. Am J Ophthalmol 70: 681-685, 1970 10. Becker B: Diabetes mellitus and primary open-angle glaucoma. Am J Ophthalmol 71:1-16, 1971 II. Bertelsen TI: The relationship between thrombosis in the retinal veins and primary glaucoma. Acta Ophthalmol39:603-613, 1961 12. David R, Livingston DG, Luntz MH: Ocular hypertension a longterm followup of treated and untreated patients. Br J Ophthalmol 61:668-674, 1977 13. Drance SM: Studies in the susceptibility of the eye to raised intraocular pressure. Arch Ophthalmol 68:478-485, 1962 14. Goldmann H, Blok P: On a possibility to connect quantitatively ocular hypertension and damage to the optic nerve. Albrecht von Graefes Arch Klin Exp Ophthalmol 183: 232-243, 197 1 15. Graham PA: The definition of pre-glaucoma: A prospective study. Trans Ophthalmol Sot UK 88:153-165, 1968 16. Hart WM, Yablonski M, Kass MA, Becker B: Multivariate analysis of the risk of visual field loss. Arch Ophthalmol 97:1455-1458, 1979 17. Hollows FC, Graham PA: Intraocular pressure, glaucoma, and glaucoma suspects in a defined population. Br J Ophthalmol SO: 570-586, 1966 18. Kitazawa Y, Horie T, Aoki S, et al: Untreated ocular hypertension. Arch Ophthalmol 95:1180-1184, 1977 19. Lakowski R, Drance SM: Acquired dyschromatopsias: The earliest functional losses in glaucoma. Dot Ophthalmol Proc Series 19:159-165, 1978 20. Levene R: Uniocular miotic theraov. Trans Am Acad Ophthalmol Otolary&ol 79: 376-380. 1975 21. Linn6r E, Stromberg U: Ocular hypertension, in Lydhecker W (ed): Glaucoma: Tutzing Sym-
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Surv Ophthalmol 25 (3) November-December 1980
posium. Basel, S Karger, 1967, pp 187-214 22, Loebl M, Schwartz B: Fluorescein angiographic defects of the optic disc in ocular hypertension. Arch Ophthalmol95:1980-1984, 1977 23. Norskov K: Routine tonometry in ophthalmic practice. II. Five-year followup. Acta Ophthalmol 48:873-895, 1970 24. Perkins ES: The Bedford Glaucoma Survey. I. Long-term follow-up of borderline cases. Br J Ophthalmol 57:179-185, 1973 25. Perkins ES: The Bedford Glaucoma Survey. II. Rescreening of normal population. Br J Ophthalmol 57:186-192, 1973 26. Phelps CD: Visual field defects in open-angle glaucoma: progression and regression. Dot Ophthalmoi Proc Series 19: 187-196, 1978 27. Schappert-Kimmijser J: A five-year follow-up of subjects with intraocular pressure of 22-30 mm Hg without anomalies of optic nerve and visual field typical for glaucoma at first investigation. Ophthalmologica 162:289-295, 1971 28. Schwartz B, Rieser JC, Fishbein SL: Fluorescein angiographic defects of the optic disc in glaucoma. Arch Ophthalmol 95:1961-1974, 1977 29. Shin DH, Kolker AB, Kass MA, et al: Longterm epinephrine therapy of ocular hypertension. Arch Ophthalmol 94:2059-2060, 1976 30. Sorensen PN, Nielsen NV, Norskov K: Ocular hypertension: A 15-year follow-up. Acta Ophthalmol g&363-372, 1978
3 1. Stromberg U: Ocular hypertension. Acta Ophthalmol, Suppl, 69:1-75, 1962 32. Vannas S, Tarkkanen A: Retinal vein occlusion and glaucoma: tonographic study of the incidence of glaucoma and of its prognostic significance. Br J Ophthalmol 44:583-589, 1960 JT, Podos SM, Becker B: 33. Wilensky Prognostic indicators in ocular hypertension. Arch Ophthalmol 91:20&202, 1974 The following references, not cited in the text, provide additional insight into the controversies regarding the management of ocular hypertension: Anderson DR: The management of elevated intraocular pressure with normal optic discs and visual fields. I. Therapeutic approach based on high risk factors. Surv Ophthalmol 21: 479-489, 1977 Hoskins HD: The management of elevated intraocular pressure with normal optic discs and visual fields. II. An approach to early therapy. Surv Ophthalmol 21:479, 489-493, 1977 ‘Ocular hypertension’ or ‘early Editorials: glaucoma’. Arch Ophthalmol 95:585-589, 1977 Reprint requests should be addressed to C.S. O’Brien Library, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242.