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Intraocular pressure as a risk factor for visual field loss in pseudoexfoliative and in primary open-angle glaucoma
Intraocular Pressure as a Risk Factor for Visual Field Loss in Pseudoexfoliative and in Primary Open-angle Glaucoma Miguel A. Teus, MD, PhD, Miguel A. Castejo´n, MD, Miguel A. Calvo, MD, Patricia Pe´rez–Salaı´ces, MD, Ana Marcos, MD Objective: To analyze the relationship between intraocular pressure (IOP) and visual field loss in patients with primary open-angle glaucoma (POAG) and in those with pseudoexfoliative glaucoma (PEXG). Design: A cross-sectional, observational study. Participants: Thirty-one patients with PEXG and 31 patients with POAG that was newly diagnosed were included in this study. MainOutcome Measures: The authors recorded the untreated IOP and the amount of the visual field loss, at presentation, in both study groups. Results: The authors found a significant relationship between IOP and visual field mean deviation (MD) index (P ⫽ 0.0001, r ⫽ 0.68) in PEXG but not in POAG eyes (P ⫽ 0.7). Conclusion: The authors found that untreated IOP levels can explain the amount of visual field loss, as measured by the MD index, much better in patients with PEXG than in comparable patients with POAG. Thus, vulnerability of the optic nerve head to increased IOP appears to be different in these two diagnostic categories. Ophthalmology 1998;105:2225–2230 Pseudoexfoliation (PEX) is a common cause of open-angle glaucoma worldwide.1,2 Although it was once thought that pseudoexfoliative glaucoma (PEXG) was only a subtype of primary open-angle glaucoma (POAG), it is now becoming clear that there are many differences between them. For instance, intraocular pressure (IOP) at diagnosis is usually higher in PEXG than in POAG,3 thus making treatment of patients with PEXG more difficult than patients with POAG.4 Furthermore, it seems that PEXG eyes usually have greater diurnal IOP fluctuation than POAG eyes5 and that visual fields are usually more damaged in PEXG than in POAG.6 Nevertheless, confusion exists, because some investigators still include patients with PEXG along with patients with POAG in the same study group when trying to delineate the natural evolution of the glaucomatous disease,7 thus assuming that both POAG and PEXG share the same risk factors for optic nerve damage. The relationship between the level of untreated IOP and the state of the visual field at presentation is very weak in POAG.8 We believe that this fact suggests that in this
Originally received: September 17, 1997. Revision accepted: June 25, 1998. Manuscript no. 97617. From the Department of Ophthalmology, “Prı´ncipe de Asturias” Hospital, University of Alcala´ de Henares, Madrid, Spain. Presented at the American Academy of Ophthalmology annual meeting, San Francisco, California, October 1997. Address correspondence to Miguel A. Teus, MD, PhD, Servicio de Oftalmologı´a, Hospital “Prı´ncipe de Asturias,” Carretera Alcala´-Meco s/n, Alcala´ de Henares, Madrid, Spain.
disease, optic nerve head susceptibility to pressure-induced injury is quite different from patient to patient. Furthermore, POAG is now believed to be a multifaceted disease, comprising several populations that differ in appearance of the optic disc damage,9 as well as in several other relevant clinical characteristics such as IOP, type of visual field damage, and migraine prevalence.10 We believe that the intensity of the correlation between untreated IOP and the amount of visual field loss at diagnosis is an indicator of how pressure dependent the disease is, and so it can give information about the pathogenic mechanisms of the optic nerve damage. Thus, if a particular type of glaucoma shows a good correlation between untreated IOP and the amount of visual field loss at diagnosis, we could anticipate further damage if IOP remains unchanged. Conversely, we could expect these particular eyes not to show further worsening of their visual field if IOP is lowered sufficiently, as they may be less dependent on other risk factors for glaucomatous damage than on increased IOP itself. Therefore, the study of the untreated IOP–visual field loss correlation can give useful information about visual prognosis in glaucoma. This is why, in the current study, we investigate the relationship between the untreated IOP level and the degree of visual field loss, at presentation, in both patients with PEXG and those with POAG.
Materials and Methods We studied consecutive newly diagnosed patients with PEXG and those with POAG, referred to our institution for evaluation by
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Ophthalmology Volume 105, Number 12, December 1998 primary care ophthalmologists. This is a cross-sectional, observational study. Informed consent was obtained in all cases after the procedure was fully explained to the patients, and only those willing to enter the study were accepted. No Institutional Review Board approval was required for this particular study. Because untreated IOP was one of the variables studied, any patient under antiglaucomatous therapy underwent a 3-week washout period before the first qualifying examination at our department. To be eligible for the study, the patient’s first examination at our glaucoma unit had to be performed within 3 months of the initial diagnosis made by the general ophthalmologist. To be included in the study, patients with PEXG had to meet the following inclusion criteria: (1) clinically evident deposition of pseudoexfoliative material on the anterior lens capsule, (2) untreated IOP greater than 21 mmHg, in at least one eye, and (3) typical glaucomatous optic nerve damage. During the course of the study, we enrolled 31 patients with PEXG who fulfilled the inclusion criteria. The IOP was measured on 2 different days (qualifying examinations) between 10 AM and 12 PM, by the same examiner, and with the same calibrated applanation tonometer. The average of the two IOP measurements was taken as the “untreated IOP.” Patients with conditions in the anterior segment that could cause IOP elevation, other than PEX, such as occludable angles and signs of old trauma, were excluded. Fundus examination (performed in all cases by the same experienced clinician) had to show signs of typical glaucomatous optic nerve damage, such as focal notching of the neuroretinal rim or diffuse enlargement of the disc cup without a localized defect of the neuroretinal rim, leading to interocular cup– disc ratio asymmetry. Patients with POAG had to meet the same criteria (except that the anterior segment examination had to show no sign of PEX material deposition on the anterior lens capsule), and they had to be age-matched (within 5 years) with patients with PEXG. To make both study groups as similar as possible, the number of patients with POAG with untreated IOP less than 30 mmHg and more than 30 mmHg had to match the proportion found in the PEXG group (in which 20 patients had ⬍30 mmHg and 11 had ⱖ30 mmHg), so only the first consecutive 31 patients with POAG who fulfilled the clinical and matching criteria were included in the study. It is obvious that the IOP and age-matching procedures have induced some selection bias in the POAG group, as some otherwise eligible patients with POAG were excluded from the study. Nevertheless, we believe that, for the purposes of this particular study, it is of interest to compare patients with PEXG and those with POAG whose main difference is the clinical diagnosis and not the age or the untreated IOP level. The patients with POAG underwent the same examinations as those in the PEXG group, in the same fashion, and by the same clinician. For the purposes of this study, the diagnosis of glaucoma (either with or without pseudoexfoliation) was made before the visual field test was performed, because we deliberately wanted to include patients with visual field damage ranging from mild (even with normal or “borderline” results) to severe loss. Patients with visually significant cataract, spherical ametropia greater than 4 diopters, more than 1.5 diopters of astigmatism, amblyopia, retinal diseases, or any other condition that could affect visual field performance were excluded from the study. After the qualifying examinations, visual field was tested twice (within 1 month) with the Humphrey visual field analyzer (program 30 –2; Humphrey Instruments Inc, San Leandro, CA) using the appropriate refraction. We used a stimulus size III, and the results were analyzed with Statpac 2 (Humphrey Instruments, Inc.,
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San Leandro, CA). To be included in the study, patients had to be able to perform a reliable test on both instances, as defined by a false-negative response lower than 30%, a fixation loss rate lower than 20%, and a false-positive response rate lower than 15%. Pupil diameter was 3 mm or greater in all cases. Patients usually performed the visual field testing after antiglaucomatous medical therapy was instituted, so IOP was, at that moment, near normal limits. All the examinations were performed in a masked fashion, because the examiner was not aware of patient diagnosis. In both groups, when both eyes of the same patient fulfilled the inclusion criteria, only the eye with the higher untreated IOP was selected, so analysis was limited to only one eye per patient. Data results are given as mean ⫾ standard deviation, occasionally followed by the range of minimum–maximum values. Mann– Whitney U and chi-square tests were used for comparisons between groups. In linear regression analyses, both P and Pearson’s correlation coefficient values, along with the regression formula, are given. Statistical analysis was done with the Statview SE⫹Graphics (Abacus Concepts Inc, Berkeley, CA) program using a Macintosh PowerBook 1400cs/117 (Apple Computer Inc, Cupertino, CA) personal computer.
Results Patient demographics are listed in Table 1. Mean age was 72.7 ⫾ 9.6 years (range, 53– 89 years) in patients with PEXG and 72.5 ⫾ 9.1 years (range, 53– 87 years) in patients with POAG (P ⫽ 0.9; Fig 1). Mean untreated IOP was 29.8 ⫾ 7.7 mmHg (range, 22–52) in PEXG group and 28.3 ⫾ 4.7 mmHg (range, 22–39) in POAG eyes (P ⫽ 0.9; Fig 2). Mean deviation (MD) index of the visual field was ⫺14.2 ⫾ 8.7 dB in patients with PEXG (range, ⫺0.2, ⫺29) and ⫺16.5 ⫾ 9.1 dB (range, ⫺1, ⫺29) in patients with POAG (P ⫽ 0.3). We found a significant correlation between untreated IOP and MD in patients with PEXG (P ⫽ 0.0001, r ⫽ 0.68, r2 ⫽ 0.47). Simple regression analysis is shown in Figure 3. Because it is known that the presence of a few outliers can influence the results of correlation and regression analyses, we repeated these analyses after excluding the four PEXG patients who had untreated IOP greater than 40 mmHg (and perhaps could be considered as outliers) and found almost the same significant correlation between IOP and MD (P ⫽ 0.004, r ⫽ 0.52). Conversely, no significant correlation was found in POAG group between the same parameters (P ⫽ 0.7, r ⫽ 0.09, r2 ⫽ 0.008). Simple regression analysis is shown in Figure 4. Corrected pattern standard deviation (CPSD) index of the visual field was 5.8 ⫾ 2.4 dB in patients with PEXG and 6.1 ⫾ 2.7 dB in patients with POAG (P ⫽ 0.4). We did not find a significant
Table 1. Demographic Data of the Patients Studied
Laterality (OD/OS) Sex (male/female)
PEXG Group
POAG Group
P
14/17 16/15
17/14 12/19
0.8* 0.7*
OD ⫽ right eye; OS ⫽ left eye; PEXG ⫽ pseudoexfoliative glaucoma; POAG ⫽ primary open-angle glaucoma. * Chi square test.
Teus et al 䡠 IOP and Visual Field Loss in PEXG and in POAG
Figure 1. Bar graph shows age distribution in both study groups. Primary open-angle glaucoma eyes are represented by black columns, and pseudoexfoliative glaucoma eyes are represented by dotted columns.
correlation between untreated IOP and CPSD in either group (P ⫽ 0.2 and P ⫽ 0.1, respectively).
Discussion Glaucomatous optic nerve damage etiology is complex and multifactorial, with many risk factors involved.11,12 Traditionally, IOP has been considered the main risk factor of this disease. In fact, population-based studies have shown that the probability of having glaucoma increases as IOP increases.13 Even in the so-called “normal pressure glaucoma,” in a given patient the eye with higher pressure usually is the eye with more advanced glaucomatous damage.14
Figure 2. Bar graph shows untreated intraocular pressure distribution in both study groups. Primary open-angle glaucoma eyes are represented by black columns, and pseudoexfoliative glaucoma eyes are represented by dotted columns.
Figure 3. Scattergram showing simple regression analysis between untreated intraocular pressure and visual field mean deviation index in the pseudoexfoliative glaucoma group (P ⫽ 0.001, r ⫽ 0.68).
Nevertheless, at least in POAG, it seems that each eye has a particular level of IOP that cannot be tolerated by the optic nerve, probably because each eye has a different susceptibility to pressure-induced damage.15 This fact could explain that, although it has been reported that a significant correlation between untreated IOP and visual field defect at diagnosis exists,8 the correlation coefficient found is very low (P ⫽ 0.0001, r ⫽ ⫺0.26). This means that IOP alone can explain only approximately 6% of the visual field loss in POAG. In addition, it has been reported that only a minority of patients with POAG actually show a significant and strong correlation between IOP and visual field damage, whereas in the majority of the POAG population, no significant correlation between these two parameters is found.16 In our study, we found no significant difference at diagnosis in the amount of visual field loss, as measured by MD, between patients with PEXG and those with POAG (P ⫽
Figure 4. Scattergram showing simple regression analysis between untreated intraocular pressure and visual field mean deviation index in the primary open-angle glaucoma group (P ⫽ 0.6, r ⫽ 0.09).
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Ophthalmology Volume 105, Number 12, December 1998 0.3). This appears to contradict the results of other authors.2,6 Nevertheless, we believe that this apparent contradiction with the literature is not real. In our series, POAG patients’ IOP distribution had to match that of PEXG group, which resulted in a selected population of patients with POAG, not representative of the usual nonselected cases in which IOP distribution probably is different, with a predominance of normal or near-normal values of IOP at diagnosis.13 We also found a significant correlation between the untreated IOP level and the amount of visual field loss, as measured by the MD index in the PEXG group (P ⫽ 0.001, r ⫽ 0.68). We believe that this finding means that PEXG optic discs show a quite homogeneous vulnerability to pressure-induced optic nerve damage and, thus, that other risk factors such as blood supply disturbances17,18 may play a lesser role in these eyes. Conversely, the fact that POAG eyes showed no significant correlation between IOP and MD in our series indicates that in this case, vulnerability to IOP is quite different from eye to eye. This suggests that other risk factors, such as genetic characteristics,19 in addition to IOP, may play a significant role in POAG glaucomatous optic nerve damage development and that these unknown risk factors are distributed unevenly in this population. In fact, Nicolela and Drance10 have shown that the POAG population is heterogeneous, because optic nerve damage morphology can be used as a criterion to further divide the original POAG group into four subgroups. These subgroups showed significant differences in their demographic characteristics, prevalence of systemic risk factors, IOP levels, and pattern of their visual field damage. One of the risk factors that may play some role in glaucomatous optic nerve damage development is optic disc size. It has been reported that optic disc size may be larger in normal pressure glaucoma than in POAG, thus suggesting that the larger the optic disc size, the greater the vulnerability to IOP.20 Furthermore, it has been suggested that optic disc size asymmetry is a major risk factor for asymmetric glaucomatous optic nerve damage in normal pressure glaucoma.21 Interestingly, it seems that patients with PEXG may have smaller discs than POAG eyes.20 It is not, therefore, surprising that glaucoma populations with differences in optic disc size distribution could show a different relationship between untreated IOP and MD. We believe that these differences between POAG and PEXG in the distribution of optic nerve vulnerability to IOP, along with all other clinical characteristics of PEXG, are sufficient to consider PEXG and POAG as entirely different types of glaucoma. A valid criticism to this study is that, although MD is frequently used as representative of the amount of visual field loss,22 it measures the “average” defect of the visual field.23 Thus, it is not sensitive enough to small, localized defects that may be predominant in POAG.24 This fact would explain the lack of correlation found in the POAG group. We tried to avoid this potential source of error by selecting a group of patients with POAG whose IOP distribution was similar to that of the PEXG group, because it has been suggested that the visual field defect is usually focal
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with lower levels of IOP and mostly diffuse with higher levels of IOP.25 Therefore, we believe that matching IOP distribution in both groups is essential to obtain comparable data for analysis. Furthermore, we were not able to find a significant correlation between untreated IOP and CPSD, an index thought to be sensitive to small, localized defects in the visual field,23 in either study group. Thus, we believe our data support the hypothesis that visual field damage is much less dependent on absolute IOP level in patients with POAG than in PEXG eyes. Because MD is known to decrease with age,26 we selected age-matched patients, so aging is expected to affect both groups’ visual field results in the same way. Our results contradict those reported by Vogel et al,8 since they found a significant correlation between untreated IOP and the amount of visual field loss in POAG at presentation (P ⫽ 0.0001, r ⫽ ⫺0.26), and we did not (P ⫽ 0.7, r ⫽ 0.09). We believe that this difference in the statistical significance is because Vogel et al had a huge sample size (595 cases), a factor known to amplify the significance of the correlation and regression analyses. In fact, the small correlation coefficient between untreated IOP and visual field loss found in both series strongly suggests that this is the case and that there is no real conflict between both studies. Obviously, time of evolution is a very important factor to take into account, because glaucoma is a progressive disease. In this study, although we accepted only newly diagnosed patients and only a maximum of 3 months elapsed between the initial diagnosis by the general ophthalmologist and our first examination, we cannot be sure that the time of evolution is similar in both study groups. In fact, almost every study regarding epidemiology of glaucoma is flawed by the fact that the time of evolution of the disease in each patient is unknown, as glaucoma is usually a silent disease. Despite these limitations, we may conclude from the current study that we were able to find that untreated IOP levels can explain the amount of visual field loss, as measured by the MD index, much better in newly diagnosed PEXG than in comparable patients with POAG. This suggests that the susceptibility of the optic nerve head to damage from IOP is different in both entities. Caution is advised when interpreting results of studies regarding the natural evolution of the glaucomatous disease in which patients with PEXG and those with POAG are included in the same study group.
References 1. Ritch R. Exfoliation syndrome—the most common identifiable cause of open-angle glaucoma. J Glaucoma 1994;3: 176 – 8. 2. Moreno–Montan˜es J, Alvarez Serna A, Alcolea Paredes A. Pseudoexfoliative glaucoma in patients with open-angle glaucoma in the northwest of Spain. Acta Ophthalmol (Copenh) 1990;68:695–9. 3. Aasved H. Intraocular pressure in eyes with and without fibrillopathia epitheliocapsularis (so-called senile exfoliation
Teus et al 䡠 IOP and Visual Field Loss in PEXG and in POAG
4. 5. 6. 7. 8. 9. 10. 11.
12. 13.
14.
or pseudoexfoliation). Acta Ophthalmol (Copenh) 1971;49: 601–10. Pohjanpelto P. Long-term prognosis of visual field in glaucoma simplex and glaucoma capsulare. Acta Ophthalmol (Copenh) 1985;63:418 –23. Konstas AGP, Mantziris D A, Stewart WC. Diurnal intraocular pressure in untreated exfoliation and primary open-angle glaucoma. Arch Ophthalmol 1997;115:182–5. Lindblom B, Thorburn W. Prevalence of visual field defects due to capsular and simple glaucoma in Ha¨lsingland, Sweden. Acta Ophthalmol (Copenh) 1982;60:353– 61. Airaksinen PJ, Tuulonen A, Alanko HI. Rate and pattern of neuroretinal rim area decrease in ocular hypertension and glaucoma. Arch Ophthalmol 1992;110:206 –10. Vogel R, Crick RP, Newson RB, et al. Association between intraocular pressure and loss of visual field in chronic simple glaucoma. Br J Ophthalmol 1990;74:3– 6. Spaeth GL. A new classification of glaucoma including focal glaucoma. Surv Ophthalmol 1994; 38(Suppl May):S9 –S17. Nicolela MT, Drance SM. Various glaucomatous optic nerve appearances. Clinical correlations. Ophthalmology 1996;103: 640 –9. Armaly MF, Krueger DA, Maunder L, et al. Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual-field defects. Arch Ophthalmol 1980;98:2163–71. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma. A case-control study. Invest Ophthalmol Vis Sci 1985;26: 1105– 8. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991;109:1090 –5. Cartwright MJ, Anderson DR. Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma). Arch Ophthalmol 1988;106:898 –900.
15. Anderson DR. Glaucoma: the damage caused by pressure. XLVI Edward Jackson Memorial Lecture. Am J Ophthalmol 1989;108:485–95. 16. Schulzer M, Drance SM, Carter CJ, et al. Biostatistical evidence for two distinct chronic open angle glaucoma populations. Br J Ophthalmol 1990;74:196 –200. 17. Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A populationbased assessment. Arch Ophthalmol 1995;113:216 –21. 18. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994;117: 603–24. 19. Lichter PR. Genetic clues to glaucoma’s secrets. The L Edward Jackson Memorial Lecture. Part 2. Am J Ophthalmol 1994;117:706 –27. 20. Tuulonen A, Airaksinen PJ. Optic disc size in exfoliative, primary open angle, and low-tension glaucoma. Arch Ophthalmol 1992;110:211–3. 21. Tomita G, Nyman K, Raitta C, Kawamura M. Interocular asymmetry of optic disc size and its relevance to visual field loss in normal-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 1994;232:290 – 6. 22. Yamagami J, Araie M, Shirato S. A comparative study of optic nerve head in low- and high-tension glaucomas. Graefes Arch Clin Exp Ophthalmol 1992;230:446 –50. 23. Flammer J, Drance SM, Augustiny L, Funkhauser A. Quantification of glaucomatous visual field defects with automated perimetry. Invest Ophthalmol Vis Sci 1985;26:176 – 81. 24. Tezel G, Tezel TH. The comparative analysis of optic disc damage in exfoliative glaucoma. Acta Ophthalmol (Copenh) 1993;71:744 –50. 25. Samuelson TW, Spaeth GL. Focal and diffuse visual field defects: their relationship to intraocular pressure. Ophthalmic Surg 1993;24:519 –25. 26. Jaffe GJ, Alvarado JA, Juster RP. Age-related changes of the normal visual field. Arch Ophthalmol 1986;104:1021–5.
Discussion by Douglas E. Gaasterland, MD For more than 150 years, physicians have been aware that intraocular pressure (IOP) elevation high above the normal range is associated with blindness. For nearly 150 years, ophthalmologists have recognized the characteristic optic disc cupping that follows prolonged IOP elevation. There have been, in this century, ample clinical and laboratory demonstrations of glaucomatous optic neuropathy after disease-provoked IOP elevation in previously normal human eyes and after experimentally induced IOP elevation in previously normal eyes of primates.1,2 These have yielded improved understanding of development of glaucomatous optic neuropathy associated with IOP elevation. We tend to extrapolate from these studies to the puzzling clinical situation of glaucomatous optic neuropathy in the absence of elevations of IOP. In addition, we recognize there are individual patients resistant to having glaucomatous optic neuropathy develop despite levels of IOP that we believe should be damaging.
Presented at the American Academy of Ophthalmology annual meeting, San Francisco, California, October 1997. Address correspondence to University Ophthalmic Consultants of Washington, 4910 Massachusetts Avenue, NW, Suite 210, Washington, DC 20016.
In the current clinical study, Teus and associates examine the relation of pretreatment level of IOP and the amount of visual field defect at the time of glaucoma diagnosis in 2 series of 31 patients: 1 group with primary open-angle glaucoma (POAG) selected to match in age and IOP the other, with open-angle glaucoma secondary to pseudoexfoliation (PEXG). They explain the rationale, in the Discussion section of the manuscript, for their assumption that the duration of disease before testing is similar for both groups. Their hypothesis appears to be that POAG is a mix of conditions, with some patients having pressure-independent loss and others having pressure-dependent loss of visual function, whereas in PEXG the loss is pressure dependent. They include a substantial review of the literature related to this issue. They state that a correlation of level of IOP and amount of visual field loss at diagnosis allows characterization of types of glaucoma as having pressure-dependent or -independent neuropathy. They indicate this characterization affects both disease management and the validity of mixing the types in clinical studies. The authors find that their 31 patients with PEXG exhibit a statistically significant correlation between IOP and the mean deviation index for threshold visual fields, but not their 31 selected patients with POAG. No significant relation is uncovered, in either
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Ophthalmology Volume 105, Number 12, December 1998 Table 1. Number (%) with Specified Visual Field Mean Deviation*
Mean Deviation
Pseudoexfoliation Glaucoma
Primary Open-angle Glaucoma
0 to ⫺10 More than ⫺10, to ⫺20 More than ⫺20, to ⫺30 Total
10 (32.3) 13 (41.9) 8 (25.8) 31 (100)
12 (38.7) 5 (16.1) 14 (45.2) 31 (100)
* Studying a larger number of subjects, bringing the distributions into better balance, might diminish the differences between groups.
of their groups of patients, between IOP and the corrected pattern standard deviation index, a measure of localized visual field scotomata. They conclude that this study indicates that patients with PEXG have more of a relation of their initial visual field defect and their initial IOP than patients with POAG, supporting the concept that there is a difference in “susceptibility.” We should consider whether their sampling is representative and their methods are sound. As they point out, larger studies of POAG have identified a relation between initial IOP and visual field defect.3 Careful study of their scatterplots shows that there is, among their patients with POAG, a substantially smaller proportion with an intermediate-magnitude mean deviation and a greater proportion with a large mean deviation compared to their patients with PEXG (Table 1). A physician experienced and wise in the conduct of ophthalmic clinical trials recently said that to interpret an outcome (as of a footrace), it is important to know, indisputably, that conditions were equal at the start (Aaron Kassoff, MD, personal communication, 1995). Such caution should be heeded in reading the report of Teus et al, because they assume equal duration and similar course of disease before testing in their two groups. We know that neither POAG nor PEXG develops quickly in most patients. Further, the patients were referred to the authors with newly diagnosed glaucoma; there may have been a selection bias on the part of the referring physician. Ideally, the basis for a glaucoma diagnosis is
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discovery of characteristic glaucomatous optic neuropathy, a condition that may not be recognized by the patient. Thus, discovery and diagnosis may be delayed. The optic nerve insult may have been evolving for a long or short time; for any specific patient, the amount of time is unknown. Finally, if the diagnosis and selection are based on finding IOP elevation, then subsequent measurements are subject to regression to the mean. Neither the investigators in the current study nor the reader knows the previous IOP behavior or duration of elevation in the enrolled patients. When the IOP gets unusually high, say above 30, the integral of time and amount of elevation probably become important in patients, as is known to be the case in experimental glaucoma.4,5 Although in the current study we might question the methods, particularly the eligibility criteria, recruitment, and number enrolled, the message from this report, that visual system damage in patients with PEXG appears more directly related to level of IOP than in patients with POAG, is clinically relevant. The authors’ speculation, that treatment to reduce IOP in PEXG compared with POAG is more likely to stabilize the disease, has proved true in at least one study.6 References 1. Caprioli J. Clinical evaluation of the optic nerve in glaucoma. Trans Am Ophthalmol Soc 1994;92:589 – 641. 2. Gaasterland D, Kupfer C. Experimental glaucoma in the rhesus monkey. Invest Ophthalmol 1974;13:455–7. 3. Vogel R, Crick RP, Newson RB, et al. Association between intraocular pressure and loss of visual field in chronic simple glaucoma. Br J Ophthalmol 1990;74:3– 6. 4. Gaasterland D, Tanishima T, Kuwabara T. Axoplasmic flow during chronic experimental glaucoma. I. Light and electron microscopic studies of the monkey optic nervehead during development of glaucomatous cupping. Invest Ophthalmol Vis Sci 1978;17:838 – 46. 5. Pederson JE, Gaasterland DE. Laser-induced primate glaucoma. I. Progression of cupping. Arch Ophthalmol 1984;102: 1689 –92. 6. To¨rnqvist G, Drolsum LK. Trabeculectomies. A long-term study. Acta Ophthalmol (Copenh) 1991;69:450 – 4.
Originally received: September 17, 1997. Revision accepted: June 25, 1998. Manuscript no. 97617. From the Department of Ophthalmology, “Prı´ncipe de Asturias” Hospital, University of Alcala´ de Henares, Madrid, Spain. Presented at the American Academy of Ophthalmology annual meeting, San Francisco, California, October 1997. Address correspondence to Miguel A. Teus, MD, PhD, Servicio de Oftalmologı´a, Hospital “Prı´ncipe de Asturias,” Carretera Alcala´-Meco s/n, Alcala´ de Henares, Madrid, Spain.
disease, optic nerve head susceptibility to pressure-induced injury is quite different from patient to patient. Furthermore, POAG is now believed to be a multifaceted disease, comprising several populations that differ in appearance of the optic disc damage,9 as well as in several other relevant clinical characteristics such as IOP, type of visual field damage, and migraine prevalence.10 We believe that the intensity of the correlation between untreated IOP and the amount of visual field loss at diagnosis is an indicator of how pressure dependent the disease is, and so it can give information about the pathogenic mechanisms of the optic nerve damage. Thus, if a particular type of glaucoma shows a good correlation between untreated IOP and the amount of visual field loss at diagnosis, we could anticipate further damage if IOP remains unchanged. Conversely, we could expect these particular eyes not to show further worsening of their visual field if IOP is lowered sufficiently, as they may be less dependent on other risk factors for glaucomatous damage than on increased IOP itself. Therefore, the study of the untreated IOP–visual field loss correlation can give useful information about visual prognosis in glaucoma. This is why, in the current study, we investigate the relationship between the untreated IOP level and the degree of visual field loss, at presentation, in both patients with PEXG and those with POAG.
Materials and Methods We studied consecutive newly diagnosed patients with PEXG and those with POAG, referred to our institution for evaluation by
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Ophthalmology Volume 105, Number 12, December 1998 primary care ophthalmologists. This is a cross-sectional, observational study. Informed consent was obtained in all cases after the procedure was fully explained to the patients, and only those willing to enter the study were accepted. No Institutional Review Board approval was required for this particular study. Because untreated IOP was one of the variables studied, any patient under antiglaucomatous therapy underwent a 3-week washout period before the first qualifying examination at our department. To be eligible for the study, the patient’s first examination at our glaucoma unit had to be performed within 3 months of the initial diagnosis made by the general ophthalmologist. To be included in the study, patients with PEXG had to meet the following inclusion criteria: (1) clinically evident deposition of pseudoexfoliative material on the anterior lens capsule, (2) untreated IOP greater than 21 mmHg, in at least one eye, and (3) typical glaucomatous optic nerve damage. During the course of the study, we enrolled 31 patients with PEXG who fulfilled the inclusion criteria. The IOP was measured on 2 different days (qualifying examinations) between 10 AM and 12 PM, by the same examiner, and with the same calibrated applanation tonometer. The average of the two IOP measurements was taken as the “untreated IOP.” Patients with conditions in the anterior segment that could cause IOP elevation, other than PEX, such as occludable angles and signs of old trauma, were excluded. Fundus examination (performed in all cases by the same experienced clinician) had to show signs of typical glaucomatous optic nerve damage, such as focal notching of the neuroretinal rim or diffuse enlargement of the disc cup without a localized defect of the neuroretinal rim, leading to interocular cup– disc ratio asymmetry. Patients with POAG had to meet the same criteria (except that the anterior segment examination had to show no sign of PEX material deposition on the anterior lens capsule), and they had to be age-matched (within 5 years) with patients with PEXG. To make both study groups as similar as possible, the number of patients with POAG with untreated IOP less than 30 mmHg and more than 30 mmHg had to match the proportion found in the PEXG group (in which 20 patients had ⬍30 mmHg and 11 had ⱖ30 mmHg), so only the first consecutive 31 patients with POAG who fulfilled the clinical and matching criteria were included in the study. It is obvious that the IOP and age-matching procedures have induced some selection bias in the POAG group, as some otherwise eligible patients with POAG were excluded from the study. Nevertheless, we believe that, for the purposes of this particular study, it is of interest to compare patients with PEXG and those with POAG whose main difference is the clinical diagnosis and not the age or the untreated IOP level. The patients with POAG underwent the same examinations as those in the PEXG group, in the same fashion, and by the same clinician. For the purposes of this study, the diagnosis of glaucoma (either with or without pseudoexfoliation) was made before the visual field test was performed, because we deliberately wanted to include patients with visual field damage ranging from mild (even with normal or “borderline” results) to severe loss. Patients with visually significant cataract, spherical ametropia greater than 4 diopters, more than 1.5 diopters of astigmatism, amblyopia, retinal diseases, or any other condition that could affect visual field performance were excluded from the study. After the qualifying examinations, visual field was tested twice (within 1 month) with the Humphrey visual field analyzer (program 30 –2; Humphrey Instruments Inc, San Leandro, CA) using the appropriate refraction. We used a stimulus size III, and the results were analyzed with Statpac 2 (Humphrey Instruments, Inc.,
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San Leandro, CA). To be included in the study, patients had to be able to perform a reliable test on both instances, as defined by a false-negative response lower than 30%, a fixation loss rate lower than 20%, and a false-positive response rate lower than 15%. Pupil diameter was 3 mm or greater in all cases. Patients usually performed the visual field testing after antiglaucomatous medical therapy was instituted, so IOP was, at that moment, near normal limits. All the examinations were performed in a masked fashion, because the examiner was not aware of patient diagnosis. In both groups, when both eyes of the same patient fulfilled the inclusion criteria, only the eye with the higher untreated IOP was selected, so analysis was limited to only one eye per patient. Data results are given as mean ⫾ standard deviation, occasionally followed by the range of minimum–maximum values. Mann– Whitney U and chi-square tests were used for comparisons between groups. In linear regression analyses, both P and Pearson’s correlation coefficient values, along with the regression formula, are given. Statistical analysis was done with the Statview SE⫹Graphics (Abacus Concepts Inc, Berkeley, CA) program using a Macintosh PowerBook 1400cs/117 (Apple Computer Inc, Cupertino, CA) personal computer.
Results Patient demographics are listed in Table 1. Mean age was 72.7 ⫾ 9.6 years (range, 53– 89 years) in patients with PEXG and 72.5 ⫾ 9.1 years (range, 53– 87 years) in patients with POAG (P ⫽ 0.9; Fig 1). Mean untreated IOP was 29.8 ⫾ 7.7 mmHg (range, 22–52) in PEXG group and 28.3 ⫾ 4.7 mmHg (range, 22–39) in POAG eyes (P ⫽ 0.9; Fig 2). Mean deviation (MD) index of the visual field was ⫺14.2 ⫾ 8.7 dB in patients with PEXG (range, ⫺0.2, ⫺29) and ⫺16.5 ⫾ 9.1 dB (range, ⫺1, ⫺29) in patients with POAG (P ⫽ 0.3). We found a significant correlation between untreated IOP and MD in patients with PEXG (P ⫽ 0.0001, r ⫽ 0.68, r2 ⫽ 0.47). Simple regression analysis is shown in Figure 3. Because it is known that the presence of a few outliers can influence the results of correlation and regression analyses, we repeated these analyses after excluding the four PEXG patients who had untreated IOP greater than 40 mmHg (and perhaps could be considered as outliers) and found almost the same significant correlation between IOP and MD (P ⫽ 0.004, r ⫽ 0.52). Conversely, no significant correlation was found in POAG group between the same parameters (P ⫽ 0.7, r ⫽ 0.09, r2 ⫽ 0.008). Simple regression analysis is shown in Figure 4. Corrected pattern standard deviation (CPSD) index of the visual field was 5.8 ⫾ 2.4 dB in patients with PEXG and 6.1 ⫾ 2.7 dB in patients with POAG (P ⫽ 0.4). We did not find a significant
Table 1. Demographic Data of the Patients Studied
Laterality (OD/OS) Sex (male/female)
PEXG Group
POAG Group
P
14/17 16/15
17/14 12/19
0.8* 0.7*
OD ⫽ right eye; OS ⫽ left eye; PEXG ⫽ pseudoexfoliative glaucoma; POAG ⫽ primary open-angle glaucoma. * Chi square test.
Teus et al 䡠 IOP and Visual Field Loss in PEXG and in POAG
Figure 1. Bar graph shows age distribution in both study groups. Primary open-angle glaucoma eyes are represented by black columns, and pseudoexfoliative glaucoma eyes are represented by dotted columns.
correlation between untreated IOP and CPSD in either group (P ⫽ 0.2 and P ⫽ 0.1, respectively).
Discussion Glaucomatous optic nerve damage etiology is complex and multifactorial, with many risk factors involved.11,12 Traditionally, IOP has been considered the main risk factor of this disease. In fact, population-based studies have shown that the probability of having glaucoma increases as IOP increases.13 Even in the so-called “normal pressure glaucoma,” in a given patient the eye with higher pressure usually is the eye with more advanced glaucomatous damage.14
Figure 2. Bar graph shows untreated intraocular pressure distribution in both study groups. Primary open-angle glaucoma eyes are represented by black columns, and pseudoexfoliative glaucoma eyes are represented by dotted columns.
Figure 3. Scattergram showing simple regression analysis between untreated intraocular pressure and visual field mean deviation index in the pseudoexfoliative glaucoma group (P ⫽ 0.001, r ⫽ 0.68).
Nevertheless, at least in POAG, it seems that each eye has a particular level of IOP that cannot be tolerated by the optic nerve, probably because each eye has a different susceptibility to pressure-induced damage.15 This fact could explain that, although it has been reported that a significant correlation between untreated IOP and visual field defect at diagnosis exists,8 the correlation coefficient found is very low (P ⫽ 0.0001, r ⫽ ⫺0.26). This means that IOP alone can explain only approximately 6% of the visual field loss in POAG. In addition, it has been reported that only a minority of patients with POAG actually show a significant and strong correlation between IOP and visual field damage, whereas in the majority of the POAG population, no significant correlation between these two parameters is found.16 In our study, we found no significant difference at diagnosis in the amount of visual field loss, as measured by MD, between patients with PEXG and those with POAG (P ⫽
Figure 4. Scattergram showing simple regression analysis between untreated intraocular pressure and visual field mean deviation index in the primary open-angle glaucoma group (P ⫽ 0.6, r ⫽ 0.09).
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Ophthalmology Volume 105, Number 12, December 1998 0.3). This appears to contradict the results of other authors.2,6 Nevertheless, we believe that this apparent contradiction with the literature is not real. In our series, POAG patients’ IOP distribution had to match that of PEXG group, which resulted in a selected population of patients with POAG, not representative of the usual nonselected cases in which IOP distribution probably is different, with a predominance of normal or near-normal values of IOP at diagnosis.13 We also found a significant correlation between the untreated IOP level and the amount of visual field loss, as measured by the MD index in the PEXG group (P ⫽ 0.001, r ⫽ 0.68). We believe that this finding means that PEXG optic discs show a quite homogeneous vulnerability to pressure-induced optic nerve damage and, thus, that other risk factors such as blood supply disturbances17,18 may play a lesser role in these eyes. Conversely, the fact that POAG eyes showed no significant correlation between IOP and MD in our series indicates that in this case, vulnerability to IOP is quite different from eye to eye. This suggests that other risk factors, such as genetic characteristics,19 in addition to IOP, may play a significant role in POAG glaucomatous optic nerve damage development and that these unknown risk factors are distributed unevenly in this population. In fact, Nicolela and Drance10 have shown that the POAG population is heterogeneous, because optic nerve damage morphology can be used as a criterion to further divide the original POAG group into four subgroups. These subgroups showed significant differences in their demographic characteristics, prevalence of systemic risk factors, IOP levels, and pattern of their visual field damage. One of the risk factors that may play some role in glaucomatous optic nerve damage development is optic disc size. It has been reported that optic disc size may be larger in normal pressure glaucoma than in POAG, thus suggesting that the larger the optic disc size, the greater the vulnerability to IOP.20 Furthermore, it has been suggested that optic disc size asymmetry is a major risk factor for asymmetric glaucomatous optic nerve damage in normal pressure glaucoma.21 Interestingly, it seems that patients with PEXG may have smaller discs than POAG eyes.20 It is not, therefore, surprising that glaucoma populations with differences in optic disc size distribution could show a different relationship between untreated IOP and MD. We believe that these differences between POAG and PEXG in the distribution of optic nerve vulnerability to IOP, along with all other clinical characteristics of PEXG, are sufficient to consider PEXG and POAG as entirely different types of glaucoma. A valid criticism to this study is that, although MD is frequently used as representative of the amount of visual field loss,22 it measures the “average” defect of the visual field.23 Thus, it is not sensitive enough to small, localized defects that may be predominant in POAG.24 This fact would explain the lack of correlation found in the POAG group. We tried to avoid this potential source of error by selecting a group of patients with POAG whose IOP distribution was similar to that of the PEXG group, because it has been suggested that the visual field defect is usually focal
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with lower levels of IOP and mostly diffuse with higher levels of IOP.25 Therefore, we believe that matching IOP distribution in both groups is essential to obtain comparable data for analysis. Furthermore, we were not able to find a significant correlation between untreated IOP and CPSD, an index thought to be sensitive to small, localized defects in the visual field,23 in either study group. Thus, we believe our data support the hypothesis that visual field damage is much less dependent on absolute IOP level in patients with POAG than in PEXG eyes. Because MD is known to decrease with age,26 we selected age-matched patients, so aging is expected to affect both groups’ visual field results in the same way. Our results contradict those reported by Vogel et al,8 since they found a significant correlation between untreated IOP and the amount of visual field loss in POAG at presentation (P ⫽ 0.0001, r ⫽ ⫺0.26), and we did not (P ⫽ 0.7, r ⫽ 0.09). We believe that this difference in the statistical significance is because Vogel et al had a huge sample size (595 cases), a factor known to amplify the significance of the correlation and regression analyses. In fact, the small correlation coefficient between untreated IOP and visual field loss found in both series strongly suggests that this is the case and that there is no real conflict between both studies. Obviously, time of evolution is a very important factor to take into account, because glaucoma is a progressive disease. In this study, although we accepted only newly diagnosed patients and only a maximum of 3 months elapsed between the initial diagnosis by the general ophthalmologist and our first examination, we cannot be sure that the time of evolution is similar in both study groups. In fact, almost every study regarding epidemiology of glaucoma is flawed by the fact that the time of evolution of the disease in each patient is unknown, as glaucoma is usually a silent disease. Despite these limitations, we may conclude from the current study that we were able to find that untreated IOP levels can explain the amount of visual field loss, as measured by the MD index, much better in newly diagnosed PEXG than in comparable patients with POAG. This suggests that the susceptibility of the optic nerve head to damage from IOP is different in both entities. Caution is advised when interpreting results of studies regarding the natural evolution of the glaucomatous disease in which patients with PEXG and those with POAG are included in the same study group.
References 1. Ritch R. Exfoliation syndrome—the most common identifiable cause of open-angle glaucoma. J Glaucoma 1994;3: 176 – 8. 2. Moreno–Montan˜es J, Alvarez Serna A, Alcolea Paredes A. Pseudoexfoliative glaucoma in patients with open-angle glaucoma in the northwest of Spain. Acta Ophthalmol (Copenh) 1990;68:695–9. 3. Aasved H. Intraocular pressure in eyes with and without fibrillopathia epitheliocapsularis (so-called senile exfoliation
Teus et al 䡠 IOP and Visual Field Loss in PEXG and in POAG
4. 5. 6. 7. 8. 9. 10. 11.
12. 13.
14.
or pseudoexfoliation). Acta Ophthalmol (Copenh) 1971;49: 601–10. Pohjanpelto P. Long-term prognosis of visual field in glaucoma simplex and glaucoma capsulare. Acta Ophthalmol (Copenh) 1985;63:418 –23. Konstas AGP, Mantziris D A, Stewart WC. Diurnal intraocular pressure in untreated exfoliation and primary open-angle glaucoma. Arch Ophthalmol 1997;115:182–5. Lindblom B, Thorburn W. Prevalence of visual field defects due to capsular and simple glaucoma in Ha¨lsingland, Sweden. Acta Ophthalmol (Copenh) 1982;60:353– 61. Airaksinen PJ, Tuulonen A, Alanko HI. Rate and pattern of neuroretinal rim area decrease in ocular hypertension and glaucoma. Arch Ophthalmol 1992;110:206 –10. Vogel R, Crick RP, Newson RB, et al. Association between intraocular pressure and loss of visual field in chronic simple glaucoma. Br J Ophthalmol 1990;74:3– 6. Spaeth GL. A new classification of glaucoma including focal glaucoma. Surv Ophthalmol 1994; 38(Suppl May):S9 –S17. Nicolela MT, Drance SM. Various glaucomatous optic nerve appearances. Clinical correlations. Ophthalmology 1996;103: 640 –9. Armaly MF, Krueger DA, Maunder L, et al. Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual-field defects. Arch Ophthalmol 1980;98:2163–71. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma. A case-control study. Invest Ophthalmol Vis Sci 1985;26: 1105– 8. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991;109:1090 –5. Cartwright MJ, Anderson DR. Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma). Arch Ophthalmol 1988;106:898 –900.
15. Anderson DR. Glaucoma: the damage caused by pressure. XLVI Edward Jackson Memorial Lecture. Am J Ophthalmol 1989;108:485–95. 16. Schulzer M, Drance SM, Carter CJ, et al. Biostatistical evidence for two distinct chronic open angle glaucoma populations. Br J Ophthalmol 1990;74:196 –200. 17. Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A populationbased assessment. Arch Ophthalmol 1995;113:216 –21. 18. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994;117: 603–24. 19. Lichter PR. Genetic clues to glaucoma’s secrets. The L Edward Jackson Memorial Lecture. Part 2. Am J Ophthalmol 1994;117:706 –27. 20. Tuulonen A, Airaksinen PJ. Optic disc size in exfoliative, primary open angle, and low-tension glaucoma. Arch Ophthalmol 1992;110:211–3. 21. Tomita G, Nyman K, Raitta C, Kawamura M. Interocular asymmetry of optic disc size and its relevance to visual field loss in normal-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 1994;232:290 – 6. 22. Yamagami J, Araie M, Shirato S. A comparative study of optic nerve head in low- and high-tension glaucomas. Graefes Arch Clin Exp Ophthalmol 1992;230:446 –50. 23. Flammer J, Drance SM, Augustiny L, Funkhauser A. Quantification of glaucomatous visual field defects with automated perimetry. Invest Ophthalmol Vis Sci 1985;26:176 – 81. 24. Tezel G, Tezel TH. The comparative analysis of optic disc damage in exfoliative glaucoma. Acta Ophthalmol (Copenh) 1993;71:744 –50. 25. Samuelson TW, Spaeth GL. Focal and diffuse visual field defects: their relationship to intraocular pressure. Ophthalmic Surg 1993;24:519 –25. 26. Jaffe GJ, Alvarado JA, Juster RP. Age-related changes of the normal visual field. Arch Ophthalmol 1986;104:1021–5.
Discussion by Douglas E. Gaasterland, MD For more than 150 years, physicians have been aware that intraocular pressure (IOP) elevation high above the normal range is associated with blindness. For nearly 150 years, ophthalmologists have recognized the characteristic optic disc cupping that follows prolonged IOP elevation. There have been, in this century, ample clinical and laboratory demonstrations of glaucomatous optic neuropathy after disease-provoked IOP elevation in previously normal human eyes and after experimentally induced IOP elevation in previously normal eyes of primates.1,2 These have yielded improved understanding of development of glaucomatous optic neuropathy associated with IOP elevation. We tend to extrapolate from these studies to the puzzling clinical situation of glaucomatous optic neuropathy in the absence of elevations of IOP. In addition, we recognize there are individual patients resistant to having glaucomatous optic neuropathy develop despite levels of IOP that we believe should be damaging.
Presented at the American Academy of Ophthalmology annual meeting, San Francisco, California, October 1997. Address correspondence to University Ophthalmic Consultants of Washington, 4910 Massachusetts Avenue, NW, Suite 210, Washington, DC 20016.
In the current clinical study, Teus and associates examine the relation of pretreatment level of IOP and the amount of visual field defect at the time of glaucoma diagnosis in 2 series of 31 patients: 1 group with primary open-angle glaucoma (POAG) selected to match in age and IOP the other, with open-angle glaucoma secondary to pseudoexfoliation (PEXG). They explain the rationale, in the Discussion section of the manuscript, for their assumption that the duration of disease before testing is similar for both groups. Their hypothesis appears to be that POAG is a mix of conditions, with some patients having pressure-independent loss and others having pressure-dependent loss of visual function, whereas in PEXG the loss is pressure dependent. They include a substantial review of the literature related to this issue. They state that a correlation of level of IOP and amount of visual field loss at diagnosis allows characterization of types of glaucoma as having pressure-dependent or -independent neuropathy. They indicate this characterization affects both disease management and the validity of mixing the types in clinical studies. The authors find that their 31 patients with PEXG exhibit a statistically significant correlation between IOP and the mean deviation index for threshold visual fields, but not their 31 selected patients with POAG. No significant relation is uncovered, in either
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Ophthalmology Volume 105, Number 12, December 1998 Table 1. Number (%) with Specified Visual Field Mean Deviation*
Mean Deviation
Pseudoexfoliation Glaucoma
Primary Open-angle Glaucoma
0 to ⫺10 More than ⫺10, to ⫺20 More than ⫺20, to ⫺30 Total
10 (32.3) 13 (41.9) 8 (25.8) 31 (100)
12 (38.7) 5 (16.1) 14 (45.2) 31 (100)
* Studying a larger number of subjects, bringing the distributions into better balance, might diminish the differences between groups.
of their groups of patients, between IOP and the corrected pattern standard deviation index, a measure of localized visual field scotomata. They conclude that this study indicates that patients with PEXG have more of a relation of their initial visual field defect and their initial IOP than patients with POAG, supporting the concept that there is a difference in “susceptibility.” We should consider whether their sampling is representative and their methods are sound. As they point out, larger studies of POAG have identified a relation between initial IOP and visual field defect.3 Careful study of their scatterplots shows that there is, among their patients with POAG, a substantially smaller proportion with an intermediate-magnitude mean deviation and a greater proportion with a large mean deviation compared to their patients with PEXG (Table 1). A physician experienced and wise in the conduct of ophthalmic clinical trials recently said that to interpret an outcome (as of a footrace), it is important to know, indisputably, that conditions were equal at the start (Aaron Kassoff, MD, personal communication, 1995). Such caution should be heeded in reading the report of Teus et al, because they assume equal duration and similar course of disease before testing in their two groups. We know that neither POAG nor PEXG develops quickly in most patients. Further, the patients were referred to the authors with newly diagnosed glaucoma; there may have been a selection bias on the part of the referring physician. Ideally, the basis for a glaucoma diagnosis is
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discovery of characteristic glaucomatous optic neuropathy, a condition that may not be recognized by the patient. Thus, discovery and diagnosis may be delayed. The optic nerve insult may have been evolving for a long or short time; for any specific patient, the amount of time is unknown. Finally, if the diagnosis and selection are based on finding IOP elevation, then subsequent measurements are subject to regression to the mean. Neither the investigators in the current study nor the reader knows the previous IOP behavior or duration of elevation in the enrolled patients. When the IOP gets unusually high, say above 30, the integral of time and amount of elevation probably become important in patients, as is known to be the case in experimental glaucoma.4,5 Although in the current study we might question the methods, particularly the eligibility criteria, recruitment, and number enrolled, the message from this report, that visual system damage in patients with PEXG appears more directly related to level of IOP than in patients with POAG, is clinically relevant. The authors’ speculation, that treatment to reduce IOP in PEXG compared with POAG is more likely to stabilize the disease, has proved true in at least one study.6 References 1. Caprioli J. Clinical evaluation of the optic nerve in glaucoma. Trans Am Ophthalmol Soc 1994;92:589 – 641. 2. Gaasterland D, Kupfer C. Experimental glaucoma in the rhesus monkey. Invest Ophthalmol 1974;13:455–7. 3. Vogel R, Crick RP, Newson RB, et al. Association between intraocular pressure and loss of visual field in chronic simple glaucoma. Br J Ophthalmol 1990;74:3– 6. 4. Gaasterland D, Tanishima T, Kuwabara T. Axoplasmic flow during chronic experimental glaucoma. I. Light and electron microscopic studies of the monkey optic nervehead during development of glaucomatous cupping. Invest Ophthalmol Vis Sci 1978;17:838 – 46. 5. Pederson JE, Gaasterland DE. Laser-induced primate glaucoma. I. Progression of cupping. Arch Ophthalmol 1984;102: 1689 –92. 6. To¨rnqvist G, Drolsum LK. Trabeculectomies. A long-term study. Acta Ophthalmol (Copenh) 1991;69:450 – 4.