A genetic basis has been postulated for

Transcription

1 Intraocular pressure response to topical corticosteroids Bernard Becker The intraocular pressure response to topical betamethasone appears to be genetically determined. A study of patients with primary open-angle glaucoma, their relatives, glaucoma suspects, and volunteers shows three populations as to degree of responsiveness. It is suggested that these are the phenotypes which relate to the homozygous poor responder (nn), the heterozygous responder (ng), and the homozygous greater responder (gg). A genetic basis has been postulated for the intraocular pressure response which follows the topical application of potent corticosteroids. 1 " 4 Patients with primary open-angle glaucoma responded to topical betamethasone with dramatic pressure elevations in spite of continued antiglaucoma medication. The response showed the distribution of a single Gaussian population. The response of selected "normal" volunteers, however, demonstrated a bimodal distribution: About 70 per cent obtained a small rise in pressure; the other 30 per cent showed a much greater pressure elevation, but of lesser magnitude than that of the glaucoma population. 1 On the basis From the Department of Ophthalmology and the Oscar Johnson Institute, Washington University School of Medicine, St. Louis, Mo. This paper was presented at the Wilmer Residents Meeting, May 26, This investigation was supported in part by Research Grant B-621 from the National Institute of Neurological Diseases and Blindness, National Institutes of Health, Bethesda, Md., and a grant from Research to Prevent Blindness, Inc., New York, N. Y. 198 of these findings and studies of the corticosteroid response of the families of glaucoma patients, as well as of the relatives of the two types of responders in the volunteer population, it was postulated that patients with primary open-angle glaucoma behaved as if they were homozygous for the responsive trait (gg), and that the steroid provocative test revealed the heterozygous responsive state (ng) and separated it from the minimal response of the homozygous normal population (nn). 4 This hypothesis, therefore, predicted three phenotypes in unselected populations (nn, ng, and gg). The question arose as to whether the homozygous responsive state (gg) could be distinguished as a separate population from the heterozygous responsive group (ng) by a difference in the degree of pressure elevation produced by topical corticosteroids. Such a differentiation would be of enormous theoretical as well as clinical importance. In the studies of volunteer populations, in addition to the less responsive (nn) and more responsive (ng) populations, there was a suggestion of a small third population. Eyes in this group responded with

2 Volume 4 Number 2 IOP response to topical corticosteroids 199 even greater pressure elevation, resembling that of the eyes of patients with primary open-angle glaucoma. However, in the selected "normals" the number of such individuals amounted to only some 4 or 5 per cent of the population. In order to evaluate the second (ng) and possible third (gg) populations in more detail (and with more significant numbers), patients with untreated primary open-angle glaucoma, glaucoma suspects, and the offspring of patients with primary open-angle glaucoma were subjected to topical corticosteroids. The data so obtained have permitted a better characterization of the different phenotypes. Methods Selection of patients. Twenty-six patients were selected with "normotensive" primary open-angle glaucoma, proved by glaucomatous field loss (arcuate scotomata). At the time of selection, all had intraocular pressures of 23 mm. Hg or less, none had been subjected to any operation, and none was on glaucoma therapy. Fifteen had borderline outflow facilities (0.13 to 0.18) and 11 had outflow facilities greater than Seventy-five offspring of patients with primary open-angle glaucoma were also subjected to testing. In each instance the parent had characteristic field loss (arcuate scotoma), but only those offspring were selected who showed' no evidence of cupping, field loss, or pressures greater than 23 mm. Hg (before water). Thirty-seven of the 75 offspring had demonstrated at least one positive water provocative tonogram (Po/C > 100); 38 had had repeatedly negative water provocative tests. Fifty patients were classified as glaucoma suspects. They were selected from the tonography laboratory on the basis of a finding of a Po/C ratio greater than 100 after water on at least one occasion. All had open angles, no evidence of field loss or cupping of the optic nervehead, and applanation pressures less than 24 mm. Hg (before water). Fifty "normal" volunteers were recruited from employees and students of Washington University and the Medical School, and from personnel of the hospital. All had open angles, normal discs and fields, no family history of glaucoma, and negative water provocative tests (P o /C less than 100 before and after water). Procedure. Each subject had a careful eye examination including perimetry, ophthalmoscopy, gonioscopy, applanation tonometry, and water provocative tonography. They were then placed on topical betamethasone, 0 four times daily to one eye only. The volunteers and glaucomatous patients were followed at weekly intervals for six weeks with repeat applanation and tonographic measurements. The glaucoma suspects and offspring were seen at three weeks and six weeks. Visual fields were repeated whenever elevated pressures were noted, as well as at the end of the six-week treatment period. In all instances topical corticosteroids were discontinued if an applanation pressure of greater than 31 mm. Hg was noted. Results Primary open-angle glaucoma. Although patients in this group had been selected for low pressures in spite of their glaucoma ("low-pressure glaucoma"), because of dramatic pressure elevations only 10 of the 26 patients were permitted to complete six weeks of topical corticosteroids. As indicated in Table I, all eyes in this group developed pressures of 20 mm. Hg or more, and 24 (92 per cent) demonstrated pressures over 31 mm. Hg. Similarly, after topical corticosteroids, all eyes in this group had outflow facilities less than 0.18, and 22 (85 per cent) had outflow facilities less than 0.08 (Table II). Because all steroids were discontinued when pressures reached levels greater than 31 mm. Hg, it was not possible to characterize the population distribution of pressures or outflow facilities in this group of patients. Offspring. It was postulated that patients with primary open-angle glaucoma were genetically homozygous for the steroid responsive trait (gg). The offspring of such patients then should consist of only two populations; the heterozygous responsive state (ng) and the homozygous responsive state (gg). After topical corticosteroids 65 (87 per cent) of the offspring had a pressure elevation to 20 mm. Hg or higher, and 14 (19 per cent) had a pressure of greater than 31 mm. Hg (Table I). Seventy-two (96 per cent) had facilities below 0.18, "Betamethasone (9-alpha-fluoro 16-beta-methyl pred- per nisolone) was supplied as a microsuspension of 0.1 cent betamethasone alcohol with 10 per cent siilfacetamide by Dr. Reddin of the Schering Corporation, Bloomfield, N. J.

3 200 Becker Investigative Ophthalmology April 1965 Table I. Applanation pressure after topical betamethasone (6 weeks)* Category Primary open-angle glaucoma (untreated) Offspring Suspects (P o /C > 100) Volunteers No Per cent with pressure elevation >20 >31 mm. Hg mm. Hg Betamethasone was discontinued when applanation pressures exceeded 31 mm. Hg. Table II. Outflow facility after topical betamethasone (6 weeks)* Per cent with decreased outflow facility Category Primary open-angle glaucoma (untreated) Offspring No < < Suspects (lvc > 100) Volunteers Betamethasone was discontinued when applanation pressures exceeded 31 mm. Hg. and 15 (20 per cent) had facilities of less than 0.08 (Table II). As illustrated in the cumulative per cent frequency plots of intraocular pressure (Fig. 1) and outflow facility (Fig. 2), straight lines were obtained for the untreated eyes, demonstrating a single Gaussian distribution curve. However, the eyes subjected to topical betamethasone deviated from the straight line cumulative frequency plots at the higher pressures and lower outflow facility values. The deviations took place at pressures greater than 31 mm. Hg and at outflow facilities less than In both instances the data suggested bimodal distributions with approximately 80 per cent in one responsive group and 20 per cent in the other consisting of the most responsive individuals. Since steroids were discontinued when pressures were known to be above 31 mm. Hg, the pressure deviations from the straight line would have been even greater had topical corticosteroids been maintained for the full six weeks. However, this would not have altered the per cent of the offspring population falling into the most responsive category. It seems reasonable to assume that the 19 to 20 per cent of the population which deviated from the linear plot by having pressure values greater than 31 mm. Hg or outflow facility less than 0.08 represents a crude estimate of the genetically homozygous responders (gg). By omitting the 14 patients (19 per cent) with pressures over 31 mm. Hg, one obtains a single Gaussian distribution for the remaining 64 offspring with a mean value of 23.8 mm. Hg (a ± 5.1) (Table III). This value should provide an approximate characterization of the heterozygous responsive state (ng). By similarly omitting the 15 patients with an outflow facility less than 0.08, one obtains r > o O.I I i I i i I i I o Untreated eye Treated eye I I i I I I I >4I Applanation Pressure (mmhg) Fig. 1. The effect of betamethasone on intraocular pressure. Comparison of cumulative per cent frequency plot of applanation intraocular pressures for 75 offspring of patients with proved primary open-angle glaucoma: untreated (open circles) and after six weeks of betamethasone (closed circles).

4 Volume 4 Number 2 IOP response to topical corticosteroids r 3! i 50 ; ± Outflow Facility (C) 0.23 ±.06 o Untreated eye Treated.40 Fig. 2. The effect of topical betamethasone on outflow facility. Comparison of cumulative per cent frequency plot of outflow facilities for 75 offspring of patients with proved primary open-angle glaucoma: untreated (open circles) and after six weeks of betamethasone (closed circles). Table III. Applanation pressures after topical betamethasone (6 weeks)* estimates of mean values for different phenotypes Category Mean ± o Offspring < 31 mm. Hg 23.8 ± 5.1 Suspects < 31 mm. Hg 24.6 ±4.8 Volunteers < 20 mm. Hg 15.7 ± 2.4 > 20 mm. Hg 24.6 ± mm. Hg 23.4 ± 4.9 "Betamethasone was discontinued when applanation pressures exceeded 31 mm. Hg. a single bell-shaped curve with a mean value for outflow facility of 0.13 (a- ± 0.03). Glaucoma suspects. Of the 50 glaucoma suspects selected because of a positive water provocative test but no other manifestations of glaucoma, 49 (98 per cent) of the steroid-treated eyes demonstrated pressures of 20 mm. Hg or more, and 12 (24 per cent) had pressure rises to greater than 31 mm. Hg (Table I). Similarly, 48 (96 per cent) had facilities less than 0.18, and 15 (30 per cent) had facilities of less than 0.08 (Table II). The cumulative frequency plots for applanation pressure (Fig. 3) and outflow facility (Fig. 4) demonstrated normal distributions in the untreated eyes, but evidence of more than one population in the treated eyes. The points of deviation from the linear plots were again at pressure values greater than 31 mm. Hg and outflow facilities less than When the eyes responding with pressures over 31 mm. Hg or outflow facilities less than 0.08 were omitted, and the data replotted, Gaussian distributions were obtained for both intraocular pressures and outflow facilities. Mean values in these populations for applanation pressure and outflow facility were 24.6 (a ± 4.8) (Table III) and 0.12 (a ± 0.04) (Table IV). The 99.99r o> o f- I6.4±2.6 o Untreated eye Treated eye 27.0 ±6.0 i i I i i i i i I i i i >4I Applanation Pressure (mmhg) Fig. 3. The effect of topical betamethasone on intraocular pressure. Comparison of cumulative per cent frequency plot of applanation intraocular pressures for 50 glaucoma suspects (Po/C > 100 after water): untreated (open circles) and after six weeks of betamethasone (closed circles).

5 202 Becker Investigative Ophthalmology April r 99.99r 0.20 t *3.0 o Untreoted eye Treated eye Outflow Facility (C) I I I I 1 I I I I I I I I I i I i II Applanation Pressure (mmhq) Fig. 4. The effect of topical betamethasone on outflow facility. Comparison of cumulative per cent frequency plot of outflow facilities for 50 glaucoma suspects (Po/C > 100 after water): untreated (open circles) and after six weeks of betamethasone (closed circles). Fig. 5. The effect of topical betamethasone on intraocular pressure. Comparison of cumulative per cent frequency plot of a.pplanation intraocular pressures for 50 volunteers: untreated (open circles ) and after six weeks of betamethasone (closed circles). Table IV. Outflow facility after topical betamethasone (6 weeks)* estimates of mean values for different phenotypes Category Mean ± a Offspring > ±0.03 Suspects > ±0.04 Volunteers > ±0.03 < ± ± Betamethasone was discontinued when applanation pressures exceeded 31 mm. Hg. independent estimates of the heterozygous responder population are in reasonable agreement with those obtained from the offspring population. Volunteers. Although efforts were made to eliminate all patients with glaucoma, a family history of glaucoma, or any ocular abnormality, there was a large number of volunteers who demonstrated considerable pressure elevation. Fifteen (30 per cent) of the 50 volunteers had an applanation pressure of 20 mm. Hg or more after topical corticosteroids, and 2 (4 per cent) had values that rose to over 31 mm. Hg (Table I). Outflow facility was less than 0.18 in 16 (32 per cent) and below 0.08 in 2 (4 per cent) (Table II). Cumulative frequency distributions of intraocular pressures (Fig. 5) and outflow facilities (Fig. 6) of the volunteers clearly showed single populations in the untreated eyes but more than one population in the betamethasone-treated eyes. There were sharp breaks from the straight line plots at pressures greater than 19 mm. Hg and at outflow facilities less than If the volunteers were divided into two groups on the basis of the pressure or outflow facility values, then separate Gaussian distribution curves were obtained for the two populations. The curves for the

6 Volume 4 Number 2 IOP response to topical corticosteroidsw a, 50 "E O.2O±.O5 " Outflow Facility (C) o Untreated eye treated eye Fig. 6. The effect of topical betamethasone on outflow facility. Comparison of cumulative per cent frequency plot of outflow facilities for 50 volunteers: untreated (open circles) and after six weeks of betamethasone (closed circles). lesser responders were characterized by a mean applanation pressure after topical betamethasone of 15.7 mm. Hg (a- ± 2.4) and outflow facility 0.22 (o- ± 0.03). The values should approximately characterize the homozygous poor steroid responder (nn). Furthermore, the cumulative frequency distribution plots of eyes that deviated from the original straight lines after topical corticosteroids also presented as normal distributions, with a mean pressure value of 24.6 mm. Hg (a ± 5.2) and an outflow facility 0.12 (a- ± 0.05) (Tables III and IV). If the two eyes with pressures greater than 31 mm. Hg and outflow facilities less than 0.08 were omitted, the estimates for the heterozygous (ng) population became 23.4 mm. Hg (a ± 4.9) and outflow facility 0.13 (o- ± 0.04). The values are again in remarkably good agreement with those obtained from the offspring and suspect populations (Tables III and IV)..40 Discussion From the data presented, it would appear that individuals with primary openangle glaucoma almost all respond to topical corticosteroids with rises in intraocular pressure to values over 31 mm. Hg. Although this most responsive population (gg) could not be characterized because of the dangers of further field loss from marked pressure elevations, 5 it is likely that mean values would exceed 40 to 45 mm. Hg. Unfortunately it is not known whether or not the entire glaucoma population would provide a single Gaussian distribution (gg). The presence of small numbers of poor responders (nn) and heterozygous responders (ng) among patients with proved primary open-angle glaucoma is not ruled out. Furthermore, it remains to be determined whether all individuals who fall into the presumed homozygous responsive state (gg) have or will develop primary open-angle glaucoma. If primary open-angle glaucoma is recessively inherited, then the glaucoma offspring population should include individuals who are genetically glaucomatous as well as a large group of heterozygous carriers of the glaucomatous trait. Although the intraocular pressures and outflow facilities are distributed in Gaussian fashion in this population, the corticosteroid provocative test demonstrates a bimodal distribution both for intraocular pressure and for outflow facility in the steroid-treated eye. The antimodes occur at 31 mm. Hg applanation pressure and 0.08 outflow facility. If the 20 per cent of patients who fall into the most responsive category represent the homozygous responsive population (gg), then the remaining 80 per cent provides a reasonable characterization of the heterozygous responsive state (ng). It is not possible from these data to characterize further the presumed homozygous responsive population because pressure elevations were not permitted to reach their true sixweek value. It is also not known whether the homozygous responsive state is synony-

7 204 Beeker Investigative Ophthalmology April 1965 mous with genetic glaucoma or just correlated closely with it. Similarly, the selected population with suspected glaucoma appears to be bimodally distributed only after topical corticosteroids. Here the 70 to 75 per cent presumed to be heterozygous responders give characteristics very similar to those found in the offspring population (Tables III and IV). The homozygous responsive population is again difficult to characterize because it proved necessary to discontinue steroids in 4 of the 12 patients whose intraocular pressure exceeded 31 mm. Hg. A cumulative frequency plot of the 12 eyes presents as a straight line, however, with a mean pressure of 39.2 mm. Hg (a ± 5.3). This must be considered a minimum estimate, however. In the volunteer population one would expect three phenotypes. It is reasonable to assume that the first population which is least responsive represents the homozygous (nn) state. In the present small series, this population is characterized after steroid treatment by a mean pressure of 15.7 mm. Hg (o- ± 2.4) and an outflow facility of 0.22 (o- ± 0.03). This demonstrates the "normal" pharmacologic degree of pressure elevation (averaging approximately 1.5 mm.) and the decrease of outflow facility (averaging 0.06) that occurs after administration of topical betamethasone for six weeks. On the basis of these values one may conclude that after this amount of corticosteroid, pressure elevations greater than 20 mm. Hg or outflow facilities below 0.16 are noted in only 2.5 per cent of individuals who are homozygous poor responders (nn). The number of individuals presumed to be homozygous responders (gg) in the volunteer population is only 2 (4 per cent). Although the two individuals appear to respond quite differently from the rest of the population, and could not be continued on betamethasone for more than three and four weeks, respectively, one cannot be certain whether they truly represent homozygous responders or belong to the heterozygous responder group. In either case the values obtained characterizing the heterozygous responsive population (ng) among volunteers agrees remarkably well with that population as determined in offspring and suspects (Tables III and IV). If one defines the heterozygous population approximately as having a mean pressure value of 24 mm. Hg with a standard deviation of ± 5 mm. Hg, then it is clear that values of 35 mm. Hg or over are going to be exceedingly rare among heterozygous responders (ng), and that, as the pressure approaches such values, the probability is great that one is dealing with homozygous responders (gg). On the other hand, a considerable number of heterozygous responders (ng) appear to demonstrate pressures after topical betamethasone in the range of 14 to 20 mm. Hg. These overlap markedly with values found in the homozygous poor responders (nn). Pressures falling in this range are therefore difficult to classify. Similarly, if one takes 0.13 ± 0.04 as the mean outflow facility after steroids for the heterozygous responder, then values below 0.05 strongly suggest the homozygous responsive state (gg). On the other hand, the range of facilities between 0.16 and 0.21 overlap with the homozygous state (nn). One may speculate as to the prevalence of the presumed responsive gene in the population. If one assumes a prevalence of 0.2, then 4 per cent of the population should be homozygous responders (gg), 32 per cent heterozygous responders (ng), and 64 per cent homozygous poor responders (nn). This agrees closely with the data obtained on volunteers. Even more striking is the prediction that can be made from such a prevalence as to the offspring of homozygous responders. They should consist of 20 per cent homozygous responders (gg) and 80 per cent heterozygous responders (ng). Such predictions are reasonably confirmed in both the pressure and outflow facility data of the present study. However, it must be emphasized that the volunteers as well as the offspring

8 Volume 4 Number 2 IOP response to topical corticosteroids 205 and glaucoma suspects were selected so as to exclude those with overt glaucoma or even spontaneous pressure elevations. In addition, volunteers were not accepted who had a family history of glaucoma. Such selection suggests that the prevalence of the gene in the population is higher than the 0.2 indicated by the data and may be closer to 0.3. It is tempting to conclude that the homozygous responders (gg) represent the primary open-angle glaucoma population and that the heterozygous steroid responders (ng) represent the carriers of the glaucoma gene. The fact that offspring of glaucoma patients responded to topical corticosteroids as if they were the offspring of homozygous responders tends to support this concept. However, the identity of steroid responsiveness and the glaucoma trait remains to be proved. A close association of the two would explain the present data equally well. Studies on large unselected populations followed repeatedly over long periods of time should permit an evaluation of these hypotheses. Further family and twin studies are needed. Most important is the follow-up of individuals who appear entirely normal except to steroid provocative testing. When such individuals can be fit with reasonable certainty into one of the three presumed genetic states, close follow-up will determine the relationship of this classification to primary open-angle glaucoma. REFERENCES 1. Becker, B., and Mills, D. W.: Corticosteroids and intraocular pressure, Arch. Ophth. 70: 500, Armaly, M. F.: Effect of corticosteroids on intraocular pressure and fluid dynamics: I. The effect of dexamethasone in the normal eye, Arch. Ophth. 70: 482, Armaly, M. F.: Effect of corticosteroids on intraocular pressure and fluid dynamics: II. The effect of dexamethasone in the glaucomatous eye, Arch. Ophth. 70: 492, Becker, B., and Hahn, K. A.: Topical corticosteroids and heredity in primary open-angle glaucoma, Am. J. Ophth. 57: 543, Kolker, A. E., Becker, B., and Mills, D. W.: Intraocular pressure and visual fields: Effects of corticosteroids, Arch. Ophth. 72: 772, 1964.