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Corticosteroids and Functions in the Anterior Segment of the Eye
CORTICOSTEROIDS
AND
FUNCTIONS OF
DAVID MILLER, M . D . ,
JOSÉ D.
THE
PF.CZON, M . D . , Boston,
METHODS AND
THE
ANTERIOR
SEGMENT
AND
CLAIBORNE G. WHITWORTH,
M.D.
Massachusetts
It is now well known that a reversible elevation of intraocular pressure and impair ment of facility of outflow can be induced by application of corticosteroids to the eyes of certain human beings ' but the mecha nism remains obscure. The present experi mental investigation was carried out to re examine the changes in intraocular pressure and facility of outflow noted by other in vestigators, and to look for other, possibly related, influences of topical corticosteroid on the anterior segment of the eye. 1
IN
EYE*
the subject's refractive correction in place, minus lenses were placed before each eye until blur was reported. The final amplitude for each eye was determined when sym metry of blur between eyes was established. 4. Pupillary measurements recorded with the Smith-Kline pupillograph at an approxi mately constant time of day. The pupillary responses were averaged either with pencil and ruler or by a G. E. 225 digital computer with an analog converter, with similar results. 5. Photographs of the eyes, to record gross changes such as position of the lids. 6. Corneal thickness measurements using a split-image ocular device designed by David D. Donaldson. Each determination was the average of at least three readings. Three weeks after the conclusion of the corticosteroid testing, five subjects were given the vehicle (composed of polysorbate80, sodium chloride, chlorobutanol and water, without corticosteroid) to apply four times a day for two weeks to the eye that had not received corticosteroid.
2
MATERIALS
Eight healthy female volunteers between the ages of 20 and 26 years and two healthy male volunteers aged 30 and 48 years were given a corticosteroid preparation to be ap plied three to four times a day for six to eight weeks to one eye only. The other eye of each subject was untreated, for compari son. Three subjects used 0.1-percent dexamethasone and seven used 0.4-percent pred nisolone. Only one of the subjects had a positive family history of glaucoma. All had normal open angles by gonioscopy.
RESULTS
Weekly examinations included the follow ing test on both eyes:
INTRAOCULAR PRESSURE
All 10 subjects showed elevation of intra ocular pressure in the eye under corticoster oid treatment. Compared to the control eye, the increase of pressure ranged from 2.0 mm. Hg in two subjects to 13 mm. Hg in one subject. Data showing the progressive elevation, expressed as difference in the pressures between the two eyes, are pre sented in Table 1 (column A ) and Figure 1. In six subjects this difference reached its peak in five weeks and then declined, al though the corticosteroids were supposedly still being applied. In two other subjects the pressure decreased only after cessation of the treatment.
1. Applanation tonometry performed each time at approximately the same time of day. 2. Tonography performed with a certified Mueller electronic tonometer and EsterlineAngus recorder. 3. Measurement of accommodative ampli tude utilizing a phoropter and a target of J l letters held 33 cm. from the eyes. With * From the Glaucoma Consultation Service, Massachusetts Eye and Ear Infirmary. This work was supported in part by grants from the National Institute of Neurological Diseases and Blindness of the National Institutes of Health (Research Grant B-218) and from the Concordia Foundation, under the supervision of W . Morton Grant, M.D. 31
32 TABLE
1
ANALYSIS OF DATA
J . Β. V. C. J . C. Μ. Η. I). Ε. W. G. Ε. Η. C. Ρ. J- ΡΒ. Ρ.
A Maximum Rise in Intraocular Pressure (mm. Hg)
Β Maximum Decrease in CValue (microliters per mm. Hg 1955 calibration)
2 2 7 13 5 8 7 6 7 12
0.04 0.01 0.11 0.17 0.02 0.06 0.12 0.13 0.11 0.21
Gonioscopy in the two subjects who ex perienced the maximum change in intra ocular pressure revealed no abnormality of the angles. FACILITY OF AQUKOUS OUTFLOW
In all subjects the facility of aqueous outflow as measured by tonography decreased in the treated eye. The difference from the contralateral untreated eye ranged from 0.01 to 0.21 microliter per mm. Hg (1955 cali bration) as shown in Table 1 (column B ) . Seven of the 10 subjects had a decrease of C-value greater than 0.05 and this was asso ciated with an increase of intraocular pres sure greater than 6.0 mm. Hg. In general, the eyes which showed the greater reduction in C-value had the higher rise in intraocular pressure, and those eyes which showed a minimal change in C-value had a correspond ingly small rise in intraocular pressure. The C-values in both the control and test eyes varied too much from week to week for clear comparison of progress of increase in intra ocular pressure and progress of increase in outflow resistance. One to two weeks after the medication was stopped the C-\ alues of test eyes became normal and equal to those of the untreated eyes. r
PUPILS
All 10 subjects showed an enlargement of the pupil in the eye that received the corti
C Maximum Mydriasis (mm.) 1.1 2.0 0.6
—
1.7 0.8 0.7 0.6 0.9 0.8
D Maximum Alteration of Accommodation (diopters)
Κ Maximum Thickening of the Cornea (percent)
-0.25 -2.25 -0.75 0 -0.75
15.0 19.0 9.1 10.5 2.9
—
—
—
—
-0.25 +0.75 +0.75
7.0 7.8 7.2
costeroid but the pupillary reaction to light was not altered. The difference in pupil size between the pairs of eyes ranged from 0.6 to 2.0 mm. (table 1, column C ) . The change in the pupils was first noted between the second and fourth week of treatment and in timing tended to parallel the increase in in traocular pressure. In six subjects the mydriasis reached its maximum between the third and fifth week of medication and then started to decrease although the corticoster oids were supposedly still being applied. EYELIDS
In several subjects there appeared to be a slight drooping of the upper lid of the eye receiving corticosteroid but the difference was so small that it was not reliably measur able either directly or in photographs. In one subject, howe\-er, the ptosis in the treated eye was so great as to be unmistakable, the upper lid measuring three mm. lower than that of the other eye, with the eyes in pri mary position. The ptosis in this case was noted three weeks after start of treatment, continued to progress while the treatment was continued, and afterward gradually dis appeared until in four weeks it was no longer detectible. At the time when ptosis was greatest, application of 10 percent phen ylephrine to both eyes did not affect the degree of ptosis, that is, three-mm. difference in level of the upper lids persisted. Ex-
CORTICOSTEROIDS
A N D THE A N T E R I O R SEGMENT
33
One subject had a 2.25 diopter decrease in accommodation in the treated eye but no significant change in facility of outflow, and a tension rise no greater than 2.0 mm. Hg in this eye. Seven other subjects were tested and showed equivocal changes varying from a 0.75-diopter increase to 0.75-diopter de crease in accommodation. Data are presented in Table 1 (column D ) .
19 percent of the thickness of the untreated corneas. One patient who had a 15-percent increase in thickness of the cornea saw haloes with the corticosteroid-treated eye, and slitlamp microscopy of this eye showed irregularity of the corneal epithelium. No abnormality of endothelium was seen, and intraocular pressure was not elevated more than 2.0 mm. Hg in this eye. When a cor neal contact lens was placed on the cornea, the haloes diminished, and after corticoster oid was stopped the cornea returned to normal in one week.
CORNEAL THICKNESS
CONTROL
The instrument used to measure corneal thickness was calibrated in comparative units but was not calibrated to yield absolute values in mm. Corneal measurements which were made on eight subjects showed in all an increase in the thickness of the cornea in the treated eyes, as listed in Table 1 (column E ) . The greatest difference in corneal thick ness between the treated and the control eyes became evident at about four weeks of treat ment. The increase was equivalent to 2.9 to
Five subjects who received the vehicle without corticosteroid in one eye during two weeks showed no difference between this eye and the contralateral untreated eye, in intra ocular pressure, facility of outflow, pupillary size, position of eyelids, accommodation or corneal thickness.
ophthalmometry did not reveal any abnor mality in the position of the globes. ACCOMMODATION
MEASUREMENTS
DISCUSSION
The fact that an increase of intraocular pressure and a decrease of facility of aque-
Fig. 1 (Miller, Peczon and Whitworth). The rise and fall of intraocular pressure in the course of local application of corticosteroids to one eye of each of 10 normal subjects is presented as the difference between the pressure in the treated eye and in the untreated companion eye. Administration began at time = 0. Arrows indicate when each subject discontinued all applications.
D A V I D MILLER, J O S É D. PECZON AND CLAIBORNE G.
ous outflow were observed in varying degree in at least eight out 10 subjects in the second or third week of application of corticosteroid drops is not surprising in view of similar published observations by others, but the findings of mydriasis, ptosis, thickening of the cornea and, in one case, impairment of accommodation are noteworthy because they are novel ami conceivably in some way re lated to the effects on pressure. None of the mechanisms underlying these various changes have been identified and, at this stage, one can only speculate upon the possibility that corticosteroids weaken smooth muscles of the eye and interfere with functions of the corneal endothelium. A search for correlation between the ef fects of corticosteroids on facility of outflow and intraocular pressure, and effects on other functions and properties of the anterior seg ment of the eye has, so far, not been reward ing. The degree of mydriasis has not been related to the amount of elevation of intra ocular pressure. In fact, the patient who had the greatest mydriasis had the least change in either intraocular pressure or facility of outflow. Likewise, ptosis in the case in which it was greatest was associated with one of the smallest changes in intraocular pressure (2.0 mm. H g ) and a decrease of C-value by only 0.04 microliter per mm. Hg. Weaken ing of accommodation in the one subject who exhibited a considerable change of 2.25 diopters was associated with the minimal degree of change in the intraocular pressure and in the C-value. Perhaps most intriguing is the thickening of the corneas noted in several subjects, since this might be explained by alteration of function of the corneal endothelium, and, if so, might be associated with changes in the endothelial cells of the corneoscleral trabecular meshwork in a position to influ
WHITWORTH
ence facility of outflow and intraocular pres sure. Here again search for correlation has yielded disappointing results. In the two eyes having the greatest thickening of cornea, the change in pressure and facility of outflow was minimal, whereas eyes having greater changes in pressure and facility of outflow usually had relatively slight alteration of corneal thickness. SUMMARY
Dexamethasone and prednisolone were applied to one eye of each of 10 normal subjects four times a day for six to eight weeks. In all subjects, the intraocular pres sure rose in the treated eye only. Those subjects showing an elevation greater than 5.0 mm. Hg also had a significant decrease in facility of outflow. All subjects developed a relative mydriasis of from 0.6 to 2.0 mm. in the treated eye, but in only one eye did accommodation become significantly im paired. All subjects developed a reversible slight ptosis of the upper lid of the eye receiving the corticosteroid. The thickness of the corneas in the treated eyes increased measurably. However, no correlation was found between the effects of corticosteroid on intraocular pressure and facility of out flow and the effects on accommodation, size or reactivity of the pupil, presence of ptosis or variation in corneal thickness. All changes were spontaneously reversible when corti costeroids were discontinued. The mecha nisms remain obscure. 243 Charles Street
(14).
ACKNOWLEDGMENTS
W e wish to thank Dr. Richard Rohb of the Massachusetts Eye and Ear Infirmary for his assis tance during many phases of the study, and Mr. Eugene Merrill of the Massachusetts Institute of Technology for his help in determining the pupil lary measurements.
REFERENCES 1. Armaly, M. F.: Effect of corticosteroids on intraocular pressure and fluid dynamics. I. and II. Α Μ Α Arch. Ophth!, 70 :482, 492, 1963. 2. Becker, B., and Mills, D. W . : Corticosteroids and intraocular pressure. A M A Arch. Ophth., 70:500, 1963.
AND
FUNCTIONS OF
DAVID MILLER, M . D . ,
JOSÉ D.
THE
PF.CZON, M . D . , Boston,
METHODS AND
THE
ANTERIOR
SEGMENT
AND
CLAIBORNE G. WHITWORTH,
M.D.
Massachusetts
It is now well known that a reversible elevation of intraocular pressure and impair ment of facility of outflow can be induced by application of corticosteroids to the eyes of certain human beings ' but the mecha nism remains obscure. The present experi mental investigation was carried out to re examine the changes in intraocular pressure and facility of outflow noted by other in vestigators, and to look for other, possibly related, influences of topical corticosteroid on the anterior segment of the eye. 1
IN
EYE*
the subject's refractive correction in place, minus lenses were placed before each eye until blur was reported. The final amplitude for each eye was determined when sym metry of blur between eyes was established. 4. Pupillary measurements recorded with the Smith-Kline pupillograph at an approxi mately constant time of day. The pupillary responses were averaged either with pencil and ruler or by a G. E. 225 digital computer with an analog converter, with similar results. 5. Photographs of the eyes, to record gross changes such as position of the lids. 6. Corneal thickness measurements using a split-image ocular device designed by David D. Donaldson. Each determination was the average of at least three readings. Three weeks after the conclusion of the corticosteroid testing, five subjects were given the vehicle (composed of polysorbate80, sodium chloride, chlorobutanol and water, without corticosteroid) to apply four times a day for two weeks to the eye that had not received corticosteroid.
2
MATERIALS
Eight healthy female volunteers between the ages of 20 and 26 years and two healthy male volunteers aged 30 and 48 years were given a corticosteroid preparation to be ap plied three to four times a day for six to eight weeks to one eye only. The other eye of each subject was untreated, for compari son. Three subjects used 0.1-percent dexamethasone and seven used 0.4-percent pred nisolone. Only one of the subjects had a positive family history of glaucoma. All had normal open angles by gonioscopy.
RESULTS
Weekly examinations included the follow ing test on both eyes:
INTRAOCULAR PRESSURE
All 10 subjects showed elevation of intra ocular pressure in the eye under corticoster oid treatment. Compared to the control eye, the increase of pressure ranged from 2.0 mm. Hg in two subjects to 13 mm. Hg in one subject. Data showing the progressive elevation, expressed as difference in the pressures between the two eyes, are pre sented in Table 1 (column A ) and Figure 1. In six subjects this difference reached its peak in five weeks and then declined, al though the corticosteroids were supposedly still being applied. In two other subjects the pressure decreased only after cessation of the treatment.
1. Applanation tonometry performed each time at approximately the same time of day. 2. Tonography performed with a certified Mueller electronic tonometer and EsterlineAngus recorder. 3. Measurement of accommodative ampli tude utilizing a phoropter and a target of J l letters held 33 cm. from the eyes. With * From the Glaucoma Consultation Service, Massachusetts Eye and Ear Infirmary. This work was supported in part by grants from the National Institute of Neurological Diseases and Blindness of the National Institutes of Health (Research Grant B-218) and from the Concordia Foundation, under the supervision of W . Morton Grant, M.D. 31
32 TABLE
1
ANALYSIS OF DATA
J . Β. V. C. J . C. Μ. Η. I). Ε. W. G. Ε. Η. C. Ρ. J- ΡΒ. Ρ.
A Maximum Rise in Intraocular Pressure (mm. Hg)
Β Maximum Decrease in CValue (microliters per mm. Hg 1955 calibration)
2 2 7 13 5 8 7 6 7 12
0.04 0.01 0.11 0.17 0.02 0.06 0.12 0.13 0.11 0.21
Gonioscopy in the two subjects who ex perienced the maximum change in intra ocular pressure revealed no abnormality of the angles. FACILITY OF AQUKOUS OUTFLOW
In all subjects the facility of aqueous outflow as measured by tonography decreased in the treated eye. The difference from the contralateral untreated eye ranged from 0.01 to 0.21 microliter per mm. Hg (1955 cali bration) as shown in Table 1 (column B ) . Seven of the 10 subjects had a decrease of C-value greater than 0.05 and this was asso ciated with an increase of intraocular pres sure greater than 6.0 mm. Hg. In general, the eyes which showed the greater reduction in C-value had the higher rise in intraocular pressure, and those eyes which showed a minimal change in C-value had a correspond ingly small rise in intraocular pressure. The C-values in both the control and test eyes varied too much from week to week for clear comparison of progress of increase in intra ocular pressure and progress of increase in outflow resistance. One to two weeks after the medication was stopped the C-\ alues of test eyes became normal and equal to those of the untreated eyes. r
PUPILS
All 10 subjects showed an enlargement of the pupil in the eye that received the corti
C Maximum Mydriasis (mm.) 1.1 2.0 0.6
—
1.7 0.8 0.7 0.6 0.9 0.8
D Maximum Alteration of Accommodation (diopters)
Κ Maximum Thickening of the Cornea (percent)
-0.25 -2.25 -0.75 0 -0.75
15.0 19.0 9.1 10.5 2.9
—
—
—
—
-0.25 +0.75 +0.75
7.0 7.8 7.2
costeroid but the pupillary reaction to light was not altered. The difference in pupil size between the pairs of eyes ranged from 0.6 to 2.0 mm. (table 1, column C ) . The change in the pupils was first noted between the second and fourth week of treatment and in timing tended to parallel the increase in in traocular pressure. In six subjects the mydriasis reached its maximum between the third and fifth week of medication and then started to decrease although the corticoster oids were supposedly still being applied. EYELIDS
In several subjects there appeared to be a slight drooping of the upper lid of the eye receiving corticosteroid but the difference was so small that it was not reliably measur able either directly or in photographs. In one subject, howe\-er, the ptosis in the treated eye was so great as to be unmistakable, the upper lid measuring three mm. lower than that of the other eye, with the eyes in pri mary position. The ptosis in this case was noted three weeks after start of treatment, continued to progress while the treatment was continued, and afterward gradually dis appeared until in four weeks it was no longer detectible. At the time when ptosis was greatest, application of 10 percent phen ylephrine to both eyes did not affect the degree of ptosis, that is, three-mm. difference in level of the upper lids persisted. Ex-
CORTICOSTEROIDS
A N D THE A N T E R I O R SEGMENT
33
One subject had a 2.25 diopter decrease in accommodation in the treated eye but no significant change in facility of outflow, and a tension rise no greater than 2.0 mm. Hg in this eye. Seven other subjects were tested and showed equivocal changes varying from a 0.75-diopter increase to 0.75-diopter de crease in accommodation. Data are presented in Table 1 (column D ) .
19 percent of the thickness of the untreated corneas. One patient who had a 15-percent increase in thickness of the cornea saw haloes with the corticosteroid-treated eye, and slitlamp microscopy of this eye showed irregularity of the corneal epithelium. No abnormality of endothelium was seen, and intraocular pressure was not elevated more than 2.0 mm. Hg in this eye. When a cor neal contact lens was placed on the cornea, the haloes diminished, and after corticoster oid was stopped the cornea returned to normal in one week.
CORNEAL THICKNESS
CONTROL
The instrument used to measure corneal thickness was calibrated in comparative units but was not calibrated to yield absolute values in mm. Corneal measurements which were made on eight subjects showed in all an increase in the thickness of the cornea in the treated eyes, as listed in Table 1 (column E ) . The greatest difference in corneal thick ness between the treated and the control eyes became evident at about four weeks of treat ment. The increase was equivalent to 2.9 to
Five subjects who received the vehicle without corticosteroid in one eye during two weeks showed no difference between this eye and the contralateral untreated eye, in intra ocular pressure, facility of outflow, pupillary size, position of eyelids, accommodation or corneal thickness.
ophthalmometry did not reveal any abnor mality in the position of the globes. ACCOMMODATION
MEASUREMENTS
DISCUSSION
The fact that an increase of intraocular pressure and a decrease of facility of aque-
Fig. 1 (Miller, Peczon and Whitworth). The rise and fall of intraocular pressure in the course of local application of corticosteroids to one eye of each of 10 normal subjects is presented as the difference between the pressure in the treated eye and in the untreated companion eye. Administration began at time = 0. Arrows indicate when each subject discontinued all applications.
D A V I D MILLER, J O S É D. PECZON AND CLAIBORNE G.
ous outflow were observed in varying degree in at least eight out 10 subjects in the second or third week of application of corticosteroid drops is not surprising in view of similar published observations by others, but the findings of mydriasis, ptosis, thickening of the cornea and, in one case, impairment of accommodation are noteworthy because they are novel ami conceivably in some way re lated to the effects on pressure. None of the mechanisms underlying these various changes have been identified and, at this stage, one can only speculate upon the possibility that corticosteroids weaken smooth muscles of the eye and interfere with functions of the corneal endothelium. A search for correlation between the ef fects of corticosteroids on facility of outflow and intraocular pressure, and effects on other functions and properties of the anterior seg ment of the eye has, so far, not been reward ing. The degree of mydriasis has not been related to the amount of elevation of intra ocular pressure. In fact, the patient who had the greatest mydriasis had the least change in either intraocular pressure or facility of outflow. Likewise, ptosis in the case in which it was greatest was associated with one of the smallest changes in intraocular pressure (2.0 mm. H g ) and a decrease of C-value by only 0.04 microliter per mm. Hg. Weaken ing of accommodation in the one subject who exhibited a considerable change of 2.25 diopters was associated with the minimal degree of change in the intraocular pressure and in the C-value. Perhaps most intriguing is the thickening of the corneas noted in several subjects, since this might be explained by alteration of function of the corneal endothelium, and, if so, might be associated with changes in the endothelial cells of the corneoscleral trabecular meshwork in a position to influ
WHITWORTH
ence facility of outflow and intraocular pres sure. Here again search for correlation has yielded disappointing results. In the two eyes having the greatest thickening of cornea, the change in pressure and facility of outflow was minimal, whereas eyes having greater changes in pressure and facility of outflow usually had relatively slight alteration of corneal thickness. SUMMARY
Dexamethasone and prednisolone were applied to one eye of each of 10 normal subjects four times a day for six to eight weeks. In all subjects, the intraocular pres sure rose in the treated eye only. Those subjects showing an elevation greater than 5.0 mm. Hg also had a significant decrease in facility of outflow. All subjects developed a relative mydriasis of from 0.6 to 2.0 mm. in the treated eye, but in only one eye did accommodation become significantly im paired. All subjects developed a reversible slight ptosis of the upper lid of the eye receiving the corticosteroid. The thickness of the corneas in the treated eyes increased measurably. However, no correlation was found between the effects of corticosteroid on intraocular pressure and facility of out flow and the effects on accommodation, size or reactivity of the pupil, presence of ptosis or variation in corneal thickness. All changes were spontaneously reversible when corti costeroids were discontinued. The mecha nisms remain obscure. 243 Charles Street
(14).
ACKNOWLEDGMENTS
W e wish to thank Dr. Richard Rohb of the Massachusetts Eye and Ear Infirmary for his assis tance during many phases of the study, and Mr. Eugene Merrill of the Massachusetts Institute of Technology for his help in determining the pupil lary measurements.
REFERENCES 1. Armaly, M. F.: Effect of corticosteroids on intraocular pressure and fluid dynamics. I. and II. Α Μ Α Arch. Ophth!, 70 :482, 492, 1963. 2. Becker, B., and Mills, D. W . : Corticosteroids and intraocular pressure. A M A Arch. Ophth., 70:500, 1963.