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Plasma Cortisol and the Intraocular Pressure Response to Topical Corticosteroids
PLASMA CORTISOL AND T H E INTRAOCULAR P R E S S U R E R E S P O N S E T O TOPICAL CORTICOSTEROIDS BERNARD BECKER, M.D.,
AND CONSTANCE K.
RAMSEY,
M.D.
St. Louis, Missouri
Levene and Schwartz 1 have reported a correlation between the response of intra ocular pressure to topically administered corticosteroids and the suppression of plasma cortisol 24 hours after an oral dose of dexamethasone. This finding suggested the possibility of a systemic marker for the topical responder. Such a marker would by pass many of the difficulties of topical test ing. Preliminary observations confirmed the above findings,1 but demonstrated that of 41 patients who failed to suppress plasma corti sol 24 hours after 8 A.M. administration of 0.75 mg of dexamethasone, 33 had sup pressed on determinations obtained at 4 P.M. (8 hours). These findings suggested early recovery rather than failure of suppression. Furthermore, we found it possible to obtain a better correlation in the same patients be tween the results of a nine-hour plasma cor tisol suppression2 and the classification as to topical corticosteroid response. This method also provided the opportunity for observa tion of the spontaneous circadian variation in plasma cortisol and so was used to com plete the present study. METHOD
Normal volunteers, glaucoma suspects, and patients with primary open-angle glauFrom the Department of Ophthalmology and the Oscar Johnson Institute, Washington University School of Medicine, St. Louis, Missouri. This investigation was supported by Grant 8 POl EY003336, from the National Eye Institute, Na tional Institutes of Health, Bethesda, Maryland. Presented in part at the Spring meeting of the As sociation for Research in Ophthalmology, Sarasota, Florida, April, 1969. Reprint requests to Bernard Becker, M.D., De partment of Ophthalmology, Washington Univer sity School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110.
coma were tested over a six-week period for intraocular pressure response to 0.1% dexa methasone (one drop four times daily, ad ministered to one eye selected at random). The intraocular pressure response was ex pressed as the absolute value of the applanation tonometer reading found at six weeks or at the termination of the test. According to their six-week intraocular pressure re sponse, 274 patients with open angles and no evidence of other ocular disease were tested and classified as nn ( < 20 mm H g ) , ng (20 to 31 mm H g ) , and gg ( > 31 mm Hg). 3 The gg group consisted of individuals with or without glaucomatous field loss. Plasma samples were obtained at 8 A.M. (0 hours), 4 P.M. (8 hours), and again at 8 A.M. the next morning (24 hours) with oral administration of 1 mg dexamethasone at 11 P.M. This allowed observation of the unsuppressed ratio of circadian variation in plasma cortisol (4 P.M./8 A.M.) in addition to the suppression ratio nine hours after dexamethasone (8 A . M ^ / 8 A . M . 0 ) . Patients were either hospitalized or remained in an ambulatory care unit overnight. Because of effects on cortisol levels noted in previous reports, 4 a history of medications used by each patient was obtained5 ; no patient in the study was severely depressed 6 ; morning samples were collected after an eight hour fast and afternoon samples were collected three to four hours after lunch.7 Blood sam ples were collected in heparinized tubes which contained no benzyl alcohol preservative 8 and were centrifuged within one hour. The plasma fraction was removed and stored frozen until analysis for free 11hydroxycorticosteroids by the fluorimetric method of Mattingly.9 Populations were matched as to race and sex. The gg group, with and without field loss, and the ng groups were matched as to
999
AMERICAN JOURNAL OF OPHTHALMOLOGY
1000
9hr. PLASMA CORTISOL SUPPRESSION BY DEXAMETHASONE (lmg)
1.30 1.10 Plasma Cortisol (8AM), (8AML,
Ui
.90
JUNE, 1970
the gg population with ratios over 65% leaves a population distributed in Gaussian fashion and not significantly different from the nn and ng population. The distribution of circadian variation ra tios among the nn, ng and gg subjects with and without field loss was similarly plotted (Fig. 3). The greater the ratio of cortisol at 8 hours/0 hours, the less the afternoon de-
70
.50
99.9
9hr. PLASMA CORTISOL SUPPRESSION BY DEXAMETHASONE (lmg) 32Î.I6
.30 99
.10mmHg<20 20-31 >31 glaucoma I OP After Topical D*cadron0.1%
Fig. 1 (Becker and Ramsey). Distribution of plasma Cortisol suppression ratios. Arrows indicate mean and lines one standard deviation from the mean. Open circles represent individuals without field loss; closed circles are patients with glaucomatous field loss. age, but the nn population had significantly more younger individuals. RESULTS
The distributions of plasma cortisol suppression ratios were compared among in dividuals classified as nn, ng and gg, with and without field loss. In Figure 1 the ratio of cortisol at 24 hours/cortisol at 0 hours is plotted along the ordinate. The greater this value, the less the suppression. A cumulative frequency plot of these data showed that the nn, ng and gg subjects with field loss (glau coma) appeared to be essentially identical single Gaussian populations (Fig. 2) with a mean value of 32% ± 16% ( S D ) . However, the gg phenotype without field loss presented a deviation from a straight line, suggesting more than one Gaussian population or possi bly a skew distribution. A ratio of 65% or more (mean + 2 SD for nn, ng and glaucomatous populations) was found in 2 1 % of the gg population without field loss, but in only 2 to 4% of the nn, ng and glaucoma groups (Table 1). Separating out those members of
|
90
S 80 «· 60
s40 "· 20
1' S ,
o ng o gg s field lots • gg î field loss (glaucoma)
0.20.01,
.20
.40
.60
.80
Plasma Cortisol - £ £ £ f (0 A M ) 0
Fig. 2 (Becker and Ramsey). Cumulative frequency plot of plasma cortisol suppression. TABLE 1 TOPICAL CORTICOSTEROID RESPONSE AND NINEH O U R PLASMA CORTISOL SUPPRESSION*
Phenotype
Plasma Cortisol 24 hours/0 hours 8 A.M.i
8 A.M.o
nn ng gg without field loss gg with field loss (glaucoma)
>65%
1/50 (2%) 3/68 (4%) 15/70(21%) 3/86(4%)
* 1 mg dexamethasone, 11 P.M.
INTRAOCULAR PRESSURE
VOL. 69, NO. 6
crease in plasma cortisol. A cumulative fre quency plot of these data showed that again the nn, ng and gg subjects with field loss (glaucoma) appeared to be essentially identi cal single Gaussian populations ( F i g . 4 ) with mean value of 6 6 % ± 1 4 % ( S D ) . T h e gg phenotype without field loss presented ei ther a different Gaussian distribution or more than one population. A ratio of 9 5 % or more (mean + 2 S D for the n n and n g groups) was found in 2 9 % of the gg popula tion without field loss, but in only 5 to 8 % of the nn, ng and glaucoma groups (Table 2)· Table 3 summarizes the occurrence of field loss in the total gg population. O n l y three of 18 patients ( 1 7 % ) with nine-hour plasma cortisol suppression ratios > 6 5 % showed field loss, whereas 83 of 138 patients ( 6 0 % ) with suppression ratios < 6 5 % had field loss. Similarly, field loss was present in only four of 24 patients ( 1 7 % ) with circadian variation of plasma cortisol ratios at 8 hours CIRCADIAN VARIATION PLASMA CORTISOL
1001
CIRCADIAN VARIATION PLASMA CORTISOL 99.9r .6« t.M 99-
1
95 90 80
1
6040 20-
1
Δηη
ong ogg I field loss • gg C field loss (glaucoma)
0.2
0.0li-^
.20
40
' .60 '
.80
PLASMA CORTISOL ^
X» 0
_l_ 1.20
^
Fig. 4 (Becker and Ramsey). Cumulative frequency plot of circadian variation ratios. TABLE 2 TOPICAL CORTICOSTEROID RESPONSE AND CIRCADIAN VARIATION OF PLASMA CORTISOL
Phenotype
Plasma Cortisol 4 P.M. >9S% 8 A.M.
Plasma Cortisol 1600hf
on
gg without field loss gg with field loss (glaucoma)
mmHg<20 20-31
>31
glaucoma
IOP After Topical Decadron 0.1X
Fig. 3 (Becker and Ramsey). Distribution of circadian variation ratios. Arrows indicate mean and lines one standard deviation from the mean. Open circles represent no field loss. Closed circles are in dividuals with glaucomatous field loss.
3/50(6%) 5/60(8%)
20/70(29%) 4/86(5%)
/ 0 hours, > 9 5 % , but in 82 of 132 patients ( 6 2 % ) with circadian ratios < 9 5 % . These differences were significant at the 0.005 level. T h e co-occurrence in the same individuals of nine-hour plasma cortisol suppression ra tios > 6 5 % and circadian variation of plas ma cortisol ratios at 8 h o u r s / 0 hours, > 9 5 % was demonstrated in only one ( 2 % ) of 50 individuals classified as nn, one ( 2 % ) of the 60 in the ng population, and none of the 86 glaucomatous patients. This combination
1002
AMERICAN JOURNAL OF OPHTHALMOLOGY
JUNE, 1970
TABLE 3 FIELD LOSS AND PLASMA CORTISOL IN GG POPULATION
Factor
Total No.
No. with Field Loss
Nine-hour plasma cortisol suppression (24 hrs/0 hrs)
>65% <65%
18 138
3 (17%) 83 (60%)
Circadian variation of plasma cortisol (8 hrs/0 hrs)
>95% <95%
24 132
4 (17%) 82 (62%)
appeared, however, in 13 (19%) of the 70 members of the gg group without field loss. DISCUSSION
The phenotypes established by intraocular pressure response to topical corticosteroid testing are valuable in studying the inheri tance in glaucoma and in identifying individ uals to be followed for possible development of the overt disease.10 The gg population with and without field loss resemble one an other closely, and differ from the nn and ng groups with respect to water provocative testing, phenylthiourea taste testing, serum protein bound iodine and glucose tolerance testing.11 Testing of suppression and circa dian variation of plasma cortisol demon strates the first major difference found be tween a subgroup of individuals classified as gg without field loss (the 20 to 30% of gg subjects without field loss who show de creased suppression and circadian variation) and the glaucomatous subjects (gg with field loss). If the gg phenotypes with and without field loss are identical genetically, then the differences between the two subgroups may be related to an endocrine factor preventing the development of overt disease. The possi bility that endocrine studies may provide prognostic information as to the develop ment of glaucomatous field loss requires fur ther testing and a long period of followup. Although absolute pressure response to topical dexamethasone was used in our clas sification, evaluation of the results obtained using change in applanation pressure does not significantly alter the overall findings. Since the fluorimetric method lacks speci
ficity,9 the question arises as to whether cor tisol or a related substance is being mea sured. The use of more specific radioisotope measurements of serum cortisol should re solve this question. SUMMARY
Circadian variation as well as dexametha sone suppression of plasma cortisol were measured in 274 patients previously classi fied as to their intraocular pressure response to topical corticosteroids and visual fields. Decreased circadian variation and less suppression of plasma cortisol occurred more frequently in the high responder group (gg) without field loss. REFERENCES
1. Levene, R. Z., and Schwartz, B. : Depression of plasma cortisol and the steroid ocular pressure response. Arch. Ophth. 80:464, 1968. 2. Pavlatos, F. C, Smilo, R. P., and Forsham, P. H. : A rapid screening test for Cushing's syndrome, J. A. M. A. 193 :720, 1965. 3. Becker, B. : Intraocular pressure response to topical corticosteroids. Invest. Ophth. 4:198, 1965. 4. Streeten, D. H., Stevenson, C. T., Dalakos, T. G., Nicholas, J. J., Dennick, L. G., and Fellerman, H. : The diagnosis of hypercortisolism. Biochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contra ceptives. J. Clin. Endocrinol. 29:1191, 1969. 5. Werk, E., Jr., Choi, Y., Sholiton, L., Olinger, C, and Hague, N. : Interference in the effect of dexamethasone by diphenylhydantoin. New Eng. J. Med. 281:32, 1969. 6. Carroll, B. J., Martin, F. I. R., and Davies, B. : Resistance to suppression by dexamethasone of plasma. II. OHCS levels in severe depressive ill ness. Brit. Med. J. 3:285,1968. 7. Montagu, K. : Eating and corticosteroid levels. Brit. Med. J. 4:833, 1968. 8. Werk, E. E., Theiss, K. E., Choi, Y. K., and Mannell, R. T. : Interference of heparin containing benzyl alcohol in the fluorimetric determination of
VOL. 69, NO. 6
INTRAOCULAR PRESSURE
plasma corticosteroids. J. Clin. Endocrinol. 27:1350, 1967. 9. Mattingly, D. : A simple fluorimetric method for the estimation of free 11-hydroxycorticoids in human plasma. J. Clin. Path. 15:374, 1962.
1003
10. Becker, B., and Shaffer, R. N. : Diagnosis and Therapy of the Glaucomas. Mosby, St. Louis, 1965. 11. Becker, B.: Glaucoma: Recent endocrine studies. Acta Soc. Ophth. Japan 73:2614, 1969.
VALIDITY O F MACKAY-MARG ELECTRONIC A P P L A N A T I O N T O N O M E T E R I N P A T I E N T S W I T H SCARRED IRREGULAR CORNEAS HERBERT E. KAUFMAN, M.D.,
C H I E L A. W I N D , M.D.,
AND STEPHEN R. WALTMAN,
M.D.
Gainesville, Florida Intraocular pressure measurement in pa tients with scarred edematous corneas is often difficult and unreliable. The Schätz to nometer was designed for normal corneas with a standard curvature and is inaccurate for those which deviate. Irregularities of the corneal surface which occur with corneal edema cause inaccurate readings with the Goldmann applanation tonometer.1 It seemed possible that electronic applana tion tonometry with an instrument such as the MacKay-Marg tonometer* might pro vide accurate pressure measurements in pa tients with scarred or irregular corneas. In normal human eyes the readings with this in strument are comparable to those using the Goldmann tonometer2 and previous work in our institution has shown that pressures re corded with the MacKay-Marg tonometer are comparable to those obtained by direct cannulation of the anterior chamber in rab bits.3 This is true if the rabbit corneas are normal, edematous from endothelial damage, or irregular following penetrating kertoplasty.3 The following study was undertaken to From the Department of Ophthalmology, College of Medicine, University of Florida. This project was supported in part by USPHS Grants NB-5398 and NB-08210 from the National Institute of Neu rological Diseases and Blindness and NIH Special Fellowship NB-1976. Reprint requests to Herbert E. Kaufman, M.D., Department of Ophthalmology, College of Medi cine, University of Florida, Gainesville, Florida 32601. * Model 205, Berkely Tonometer Company.
assess the accuracy of the MacKay-Marg to nometer in scarred and edematous human corneas by comparing measurements made with it to simultaneous measurements ob tained by cannulation of the anterior cham ber. Since the more complicated and expen sive electronic applanation tonometer is not universally available, readings were also taken with the Schijftz tonometer to deter mine if it might be useful in estimating ten sion in these problem eyes even if minor in accuracies existed. MATERIALS AND METHODS
Six patients with irregular, scarred, or edematous corneas who were candidates for penetrating keratoplasty were included in this study. Four had previous grafts, now vascularized ; one had herpetic keratitis with a previous conjunctival flap; and one had aphakic bullous keratopathy with corneal scarring. Figures 1, 2 and 3 are examples of representative patients. Attempts to estimate pressure with the Goldmann applanation tonometer demand absolute reproducibility in judging the area applanated in order to determine the pres sure required to flatten the cornea this fixed amount. Goldmann readings were grossly in accurate and not reproducible because the irregular corneal surfaces caused pooling of the fluorescein dye and irregular images of the circles. Therefore, only the MacKayMarg and Schi^tz tonometers were tested in cannulation studies.
AND CONSTANCE K.
RAMSEY,
M.D.
St. Louis, Missouri
Levene and Schwartz 1 have reported a correlation between the response of intra ocular pressure to topically administered corticosteroids and the suppression of plasma cortisol 24 hours after an oral dose of dexamethasone. This finding suggested the possibility of a systemic marker for the topical responder. Such a marker would by pass many of the difficulties of topical test ing. Preliminary observations confirmed the above findings,1 but demonstrated that of 41 patients who failed to suppress plasma corti sol 24 hours after 8 A.M. administration of 0.75 mg of dexamethasone, 33 had sup pressed on determinations obtained at 4 P.M. (8 hours). These findings suggested early recovery rather than failure of suppression. Furthermore, we found it possible to obtain a better correlation in the same patients be tween the results of a nine-hour plasma cor tisol suppression2 and the classification as to topical corticosteroid response. This method also provided the opportunity for observa tion of the spontaneous circadian variation in plasma cortisol and so was used to com plete the present study. METHOD
Normal volunteers, glaucoma suspects, and patients with primary open-angle glauFrom the Department of Ophthalmology and the Oscar Johnson Institute, Washington University School of Medicine, St. Louis, Missouri. This investigation was supported by Grant 8 POl EY003336, from the National Eye Institute, Na tional Institutes of Health, Bethesda, Maryland. Presented in part at the Spring meeting of the As sociation for Research in Ophthalmology, Sarasota, Florida, April, 1969. Reprint requests to Bernard Becker, M.D., De partment of Ophthalmology, Washington Univer sity School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110.
coma were tested over a six-week period for intraocular pressure response to 0.1% dexa methasone (one drop four times daily, ad ministered to one eye selected at random). The intraocular pressure response was ex pressed as the absolute value of the applanation tonometer reading found at six weeks or at the termination of the test. According to their six-week intraocular pressure re sponse, 274 patients with open angles and no evidence of other ocular disease were tested and classified as nn ( < 20 mm H g ) , ng (20 to 31 mm H g ) , and gg ( > 31 mm Hg). 3 The gg group consisted of individuals with or without glaucomatous field loss. Plasma samples were obtained at 8 A.M. (0 hours), 4 P.M. (8 hours), and again at 8 A.M. the next morning (24 hours) with oral administration of 1 mg dexamethasone at 11 P.M. This allowed observation of the unsuppressed ratio of circadian variation in plasma cortisol (4 P.M./8 A.M.) in addition to the suppression ratio nine hours after dexamethasone (8 A . M ^ / 8 A . M . 0 ) . Patients were either hospitalized or remained in an ambulatory care unit overnight. Because of effects on cortisol levels noted in previous reports, 4 a history of medications used by each patient was obtained5 ; no patient in the study was severely depressed 6 ; morning samples were collected after an eight hour fast and afternoon samples were collected three to four hours after lunch.7 Blood sam ples were collected in heparinized tubes which contained no benzyl alcohol preservative 8 and were centrifuged within one hour. The plasma fraction was removed and stored frozen until analysis for free 11hydroxycorticosteroids by the fluorimetric method of Mattingly.9 Populations were matched as to race and sex. The gg group, with and without field loss, and the ng groups were matched as to
999
AMERICAN JOURNAL OF OPHTHALMOLOGY
1000
9hr. PLASMA CORTISOL SUPPRESSION BY DEXAMETHASONE (lmg)
1.30 1.10 Plasma Cortisol (8AM), (8AML,
Ui
.90
JUNE, 1970
the gg population with ratios over 65% leaves a population distributed in Gaussian fashion and not significantly different from the nn and ng population. The distribution of circadian variation ra tios among the nn, ng and gg subjects with and without field loss was similarly plotted (Fig. 3). The greater the ratio of cortisol at 8 hours/0 hours, the less the afternoon de-
70
.50
99.9
9hr. PLASMA CORTISOL SUPPRESSION BY DEXAMETHASONE (lmg) 32Î.I6
.30 99
.10mmHg<20 20-31 >31 glaucoma I OP After Topical D*cadron0.1%
Fig. 1 (Becker and Ramsey). Distribution of plasma Cortisol suppression ratios. Arrows indicate mean and lines one standard deviation from the mean. Open circles represent individuals without field loss; closed circles are patients with glaucomatous field loss. age, but the nn population had significantly more younger individuals. RESULTS
The distributions of plasma cortisol suppression ratios were compared among in dividuals classified as nn, ng and gg, with and without field loss. In Figure 1 the ratio of cortisol at 24 hours/cortisol at 0 hours is plotted along the ordinate. The greater this value, the less the suppression. A cumulative frequency plot of these data showed that the nn, ng and gg subjects with field loss (glau coma) appeared to be essentially identical single Gaussian populations (Fig. 2) with a mean value of 32% ± 16% ( S D ) . However, the gg phenotype without field loss presented a deviation from a straight line, suggesting more than one Gaussian population or possi bly a skew distribution. A ratio of 65% or more (mean + 2 SD for nn, ng and glaucomatous populations) was found in 2 1 % of the gg population without field loss, but in only 2 to 4% of the nn, ng and glaucoma groups (Table 1). Separating out those members of
|
90
S 80 «· 60
s40 "· 20
1' S ,
o ng o gg s field lots • gg î field loss (glaucoma)
0.20.01,
.20
.40
.60
.80
Plasma Cortisol - £ £ £ f (0 A M ) 0
Fig. 2 (Becker and Ramsey). Cumulative frequency plot of plasma cortisol suppression. TABLE 1 TOPICAL CORTICOSTEROID RESPONSE AND NINEH O U R PLASMA CORTISOL SUPPRESSION*
Phenotype
Plasma Cortisol 24 hours/0 hours 8 A.M.i
8 A.M.o
nn ng gg without field loss gg with field loss (glaucoma)
>65%
1/50 (2%) 3/68 (4%) 15/70(21%) 3/86(4%)
* 1 mg dexamethasone, 11 P.M.
INTRAOCULAR PRESSURE
VOL. 69, NO. 6
crease in plasma cortisol. A cumulative fre quency plot of these data showed that again the nn, ng and gg subjects with field loss (glaucoma) appeared to be essentially identi cal single Gaussian populations ( F i g . 4 ) with mean value of 6 6 % ± 1 4 % ( S D ) . T h e gg phenotype without field loss presented ei ther a different Gaussian distribution or more than one population. A ratio of 9 5 % or more (mean + 2 S D for the n n and n g groups) was found in 2 9 % of the gg popula tion without field loss, but in only 5 to 8 % of the nn, ng and glaucoma groups (Table 2)· Table 3 summarizes the occurrence of field loss in the total gg population. O n l y three of 18 patients ( 1 7 % ) with nine-hour plasma cortisol suppression ratios > 6 5 % showed field loss, whereas 83 of 138 patients ( 6 0 % ) with suppression ratios < 6 5 % had field loss. Similarly, field loss was present in only four of 24 patients ( 1 7 % ) with circadian variation of plasma cortisol ratios at 8 hours CIRCADIAN VARIATION PLASMA CORTISOL
1001
CIRCADIAN VARIATION PLASMA CORTISOL 99.9r .6« t.M 99-
1
95 90 80
1
6040 20-
1
Δηη
ong ogg I field loss • gg C field loss (glaucoma)
0.2
0.0li-^
.20
40
' .60 '
.80
PLASMA CORTISOL ^
X» 0
_l_ 1.20
^
Fig. 4 (Becker and Ramsey). Cumulative frequency plot of circadian variation ratios. TABLE 2 TOPICAL CORTICOSTEROID RESPONSE AND CIRCADIAN VARIATION OF PLASMA CORTISOL
Phenotype
Plasma Cortisol 4 P.M. >9S% 8 A.M.
Plasma Cortisol 1600hf
on
gg without field loss gg with field loss (glaucoma)
mmHg<20 20-31
>31
glaucoma
IOP After Topical Decadron 0.1X
Fig. 3 (Becker and Ramsey). Distribution of circadian variation ratios. Arrows indicate mean and lines one standard deviation from the mean. Open circles represent no field loss. Closed circles are in dividuals with glaucomatous field loss.
3/50(6%) 5/60(8%)
20/70(29%) 4/86(5%)
/ 0 hours, > 9 5 % , but in 82 of 132 patients ( 6 2 % ) with circadian ratios < 9 5 % . These differences were significant at the 0.005 level. T h e co-occurrence in the same individuals of nine-hour plasma cortisol suppression ra tios > 6 5 % and circadian variation of plas ma cortisol ratios at 8 h o u r s / 0 hours, > 9 5 % was demonstrated in only one ( 2 % ) of 50 individuals classified as nn, one ( 2 % ) of the 60 in the ng population, and none of the 86 glaucomatous patients. This combination
1002
AMERICAN JOURNAL OF OPHTHALMOLOGY
JUNE, 1970
TABLE 3 FIELD LOSS AND PLASMA CORTISOL IN GG POPULATION
Factor
Total No.
No. with Field Loss
Nine-hour plasma cortisol suppression (24 hrs/0 hrs)
>65% <65%
18 138
3 (17%) 83 (60%)
Circadian variation of plasma cortisol (8 hrs/0 hrs)
>95% <95%
24 132
4 (17%) 82 (62%)
appeared, however, in 13 (19%) of the 70 members of the gg group without field loss. DISCUSSION
The phenotypes established by intraocular pressure response to topical corticosteroid testing are valuable in studying the inheri tance in glaucoma and in identifying individ uals to be followed for possible development of the overt disease.10 The gg population with and without field loss resemble one an other closely, and differ from the nn and ng groups with respect to water provocative testing, phenylthiourea taste testing, serum protein bound iodine and glucose tolerance testing.11 Testing of suppression and circa dian variation of plasma cortisol demon strates the first major difference found be tween a subgroup of individuals classified as gg without field loss (the 20 to 30% of gg subjects without field loss who show de creased suppression and circadian variation) and the glaucomatous subjects (gg with field loss). If the gg phenotypes with and without field loss are identical genetically, then the differences between the two subgroups may be related to an endocrine factor preventing the development of overt disease. The possi bility that endocrine studies may provide prognostic information as to the develop ment of glaucomatous field loss requires fur ther testing and a long period of followup. Although absolute pressure response to topical dexamethasone was used in our clas sification, evaluation of the results obtained using change in applanation pressure does not significantly alter the overall findings. Since the fluorimetric method lacks speci
ficity,9 the question arises as to whether cor tisol or a related substance is being mea sured. The use of more specific radioisotope measurements of serum cortisol should re solve this question. SUMMARY
Circadian variation as well as dexametha sone suppression of plasma cortisol were measured in 274 patients previously classi fied as to their intraocular pressure response to topical corticosteroids and visual fields. Decreased circadian variation and less suppression of plasma cortisol occurred more frequently in the high responder group (gg) without field loss. REFERENCES
1. Levene, R. Z., and Schwartz, B. : Depression of plasma cortisol and the steroid ocular pressure response. Arch. Ophth. 80:464, 1968. 2. Pavlatos, F. C, Smilo, R. P., and Forsham, P. H. : A rapid screening test for Cushing's syndrome, J. A. M. A. 193 :720, 1965. 3. Becker, B. : Intraocular pressure response to topical corticosteroids. Invest. Ophth. 4:198, 1965. 4. Streeten, D. H., Stevenson, C. T., Dalakos, T. G., Nicholas, J. J., Dennick, L. G., and Fellerman, H. : The diagnosis of hypercortisolism. Biochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contra ceptives. J. Clin. Endocrinol. 29:1191, 1969. 5. Werk, E., Jr., Choi, Y., Sholiton, L., Olinger, C, and Hague, N. : Interference in the effect of dexamethasone by diphenylhydantoin. New Eng. J. Med. 281:32, 1969. 6. Carroll, B. J., Martin, F. I. R., and Davies, B. : Resistance to suppression by dexamethasone of plasma. II. OHCS levels in severe depressive ill ness. Brit. Med. J. 3:285,1968. 7. Montagu, K. : Eating and corticosteroid levels. Brit. Med. J. 4:833, 1968. 8. Werk, E. E., Theiss, K. E., Choi, Y. K., and Mannell, R. T. : Interference of heparin containing benzyl alcohol in the fluorimetric determination of
VOL. 69, NO. 6
INTRAOCULAR PRESSURE
plasma corticosteroids. J. Clin. Endocrinol. 27:1350, 1967. 9. Mattingly, D. : A simple fluorimetric method for the estimation of free 11-hydroxycorticoids in human plasma. J. Clin. Path. 15:374, 1962.
1003
10. Becker, B., and Shaffer, R. N. : Diagnosis and Therapy of the Glaucomas. Mosby, St. Louis, 1965. 11. Becker, B.: Glaucoma: Recent endocrine studies. Acta Soc. Ophth. Japan 73:2614, 1969.
VALIDITY O F MACKAY-MARG ELECTRONIC A P P L A N A T I O N T O N O M E T E R I N P A T I E N T S W I T H SCARRED IRREGULAR CORNEAS HERBERT E. KAUFMAN, M.D.,
C H I E L A. W I N D , M.D.,
AND STEPHEN R. WALTMAN,
M.D.
Gainesville, Florida Intraocular pressure measurement in pa tients with scarred edematous corneas is often difficult and unreliable. The Schätz to nometer was designed for normal corneas with a standard curvature and is inaccurate for those which deviate. Irregularities of the corneal surface which occur with corneal edema cause inaccurate readings with the Goldmann applanation tonometer.1 It seemed possible that electronic applana tion tonometry with an instrument such as the MacKay-Marg tonometer* might pro vide accurate pressure measurements in pa tients with scarred or irregular corneas. In normal human eyes the readings with this in strument are comparable to those using the Goldmann tonometer2 and previous work in our institution has shown that pressures re corded with the MacKay-Marg tonometer are comparable to those obtained by direct cannulation of the anterior chamber in rab bits.3 This is true if the rabbit corneas are normal, edematous from endothelial damage, or irregular following penetrating kertoplasty.3 The following study was undertaken to From the Department of Ophthalmology, College of Medicine, University of Florida. This project was supported in part by USPHS Grants NB-5398 and NB-08210 from the National Institute of Neu rological Diseases and Blindness and NIH Special Fellowship NB-1976. Reprint requests to Herbert E. Kaufman, M.D., Department of Ophthalmology, College of Medi cine, University of Florida, Gainesville, Florida 32601. * Model 205, Berkely Tonometer Company.
assess the accuracy of the MacKay-Marg to nometer in scarred and edematous human corneas by comparing measurements made with it to simultaneous measurements ob tained by cannulation of the anterior cham ber. Since the more complicated and expen sive electronic applanation tonometer is not universally available, readings were also taken with the Schijftz tonometer to deter mine if it might be useful in estimating ten sion in these problem eyes even if minor in accuracies existed. MATERIALS AND METHODS
Six patients with irregular, scarred, or edematous corneas who were candidates for penetrating keratoplasty were included in this study. Four had previous grafts, now vascularized ; one had herpetic keratitis with a previous conjunctival flap; and one had aphakic bullous keratopathy with corneal scarring. Figures 1, 2 and 3 are examples of representative patients. Attempts to estimate pressure with the Goldmann applanation tonometer demand absolute reproducibility in judging the area applanated in order to determine the pres sure required to flatten the cornea this fixed amount. Goldmann readings were grossly in accurate and not reproducible because the irregular corneal surfaces caused pooling of the fluorescein dye and irregular images of the circles. Therefore, only the MacKayMarg and Schi^tz tonometers were tested in cannulation studies.