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Hydroxyamphetamine Mydriasis in Normal Subjects
Hydroxyamphetamine Mydriasis in Normal Subjects Steven A. Cremer, H. Stanley Thompson, M.D., Kathleen B. Digre, M.D., and Randy H. Kardon, M.D.
Hydroxyamphetamine eyedrops are used to help localize the lesion in Horner's syndrome. Because normal variability in the response to the eye drops may influence the interpretation of test results in patients with Horner's syndrome, we studied both the interocular variability of the drug's mydriatic effect within each normal subject and the variation between individuals. We used photographs to document the variability among 26 normal SUbjects. Hydroxyamphetamine hydrobromide 1 % eyedrops (Paredrine) were placed in both eyes of normal subjects in the same way that patients with Horner's syndrome are tested. The drug produced a mean increase in pupil size of 1.96 mm (± 0.61 S.D.) in the 52 eyes tested. In normal subjects, the mydriatic effect of hydroxyamphetamine was symmetric in each pair of eyes. The mean interocular asymmetry of mydriasis as measured by the difference in dilation (right eye dilation minus left eye dilation) was -0.087 mm (± 0.29 S.D.). Thus, the variability of hydroxyamphetamine mydriasis from one eye to the other in a single subject was much lower than the variability between subjects.
P AREDRINE
(parahydroxyamphetamine hydrobromide 1 %) was introduced as a mydriatic
Accepted for publication April 5,1990. From the Department of Ophthalmology, University of Iowa, Iowa City, Iowa. This study was supported in part by an unrestricted grant to the University of Iowa Department of Ophthalmology from Research to Prevent Blindness, Inc., and in part by grant RR59 from Clinical Research Centers Branch of the National Institutes of Health. Reprint requests to H. Stanley Thompson, M.D., Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.
66
eyedrop in 1937.J.2 It was first used in combination with atropinic agents in an effort to hasten patients' recovery from cycloplegia and then as a gentle mydriatic." In the 1940s, it was a popular nasal decongestant and was used with a sulfathiazole suspension to treat sinus disease.' It was also used to treat cardiogenic shock' and cardiac arrhythmias," and was shown, unlike amphetamine sulphate, to have little or no effect on the central nervous systern." In the mid-1960s, it was concluded that, like tyramine, its adrenergic action resulted from the release of norepinephrine from nerve endings.t" In 1971, it was suggested" that because of its mode of action, hydroxyamphetamine might be useful as a diagnostic test to localize the lesion in Horner's syndrome. It has been repeatedly observed that hydroxyamphetamine causes less dilation of the affected pupil in Horner's syndrome when the lesion is in the postganglionic neuron.P:" but does dilate the affected pupil in preganglionic lesions. This effect has been demonstrated in cases of surgically placed lesions in humans" and rabbits." In recent years, hydroxyamphetamine has replaced epinephrine as the most reliable pharmacologic tool for identifying a postganglionic lesion in Horner's syndrome. When used as a diagnostic test for Horner's syndrome, hydroxyamphetamine is placed in both eyes and the pupillary response is noted 45 to 60 minutes later. Many factors deserve consideration when evaluating the localizing value of hydroxyamphetamine in Horner's syndrome. We evaluated the influence of the following factors: the variability of hydroxyamphetamine mydriasis among individuals; the symmetry of hydroxyamphetamine mydriasis between the two eyes of an individual; and the effect of patient age and iris color on hydroxyamphetamine mydriasis. We have attempted to define the normal range of hydroxyamphetamine mydriasis that would be expected under the conditions of testing used in Horner's syndrome.
©AMERICAN JOURNAL OF OPHTHALMOLOGY
110:66-70,
JULY,
1990
Vol. 110, No.1
Hydroxyamphetamine Mydriasis in Normal Subjects
For variation between eyes of a given individual (the interocular variation) in mydriasis, we plotted pupillary diameter for each subject's right eye, both before and after hydroxyamphetamine, against the corresponding pupillary diameter of the left eye to find whether hydroxyamphetamine produced significant anisocoria in normal subjects. Additionally, the dilation difference between the two eyes (mydriasis of the right eye minus mydriasis of the left eye) was calculated to quantify the interocular asymmetry. The contribution of measurement error was also evaluated by comparing the dilation difference between the two eyes as measured from photographs by two different observers.
Subjects and Methods Twenty-six normal subjects were used. None had any history of migraine headaches. Their mean age was 50.1 years (S.D. ± 15.8 years; range, 19 to 69 years). Hydroxyamphetamine (1 %) was placed into the conjunctival sac of each eye, both eyes were wiped, and 20 to 40 seconds later, in an effort to balance the dose in the two eyes, a second drop was placed in each eye. Photographs were taken just before the eye drops were given and 45 to 60 minutes after instillation. The photographs were taken with a Loewenfeld-Rosskothen camera" at 1:1 magnification using Polaroid film in moderately bright light. The pupil diameters of both eyes were measured directly from these photographs to the nearest tenth of a millimeter with a magnifying ruler. We considered two kinds of variability in hydroxyamphetamine mydriasis, variation between individuals and variation between the eyes of one individual. For the former, we measured the amount of mydriasis produced by hydroxyamphetamine in each of the 52 eyes of the 26 normal subjects by subtracting the predrop pupil size from the postdrop pupil size. From this, the mean mydriasis for the right and left eyes was calculated. The standard deviation of this mean represented the interindividual variation in mydriasis. We also investigated the effect of age and iris color (blue and green vs brown) on degree of mydriasis.
20 18 16 14
Results The mean pupillary dilation to hydroxyamphetamine for the combined 52 eyes was 1.96 mm (S.D. ± 0.61 mm), with a range of 0.5 to 3.1 mm (Fig. 1). The mean pupillary dilation of the right eyes was 1.94 mm (± 0.63 S.D.), and the mean dilation of the left eyes was 1.99 mm (± 0.68 S.D.) for the 26 normal subjects. No effect of age on hydroxyamphetamine mydriasis was found (Fig. 2). Additionally, no significant difference (P = .40) in mean mydriasis was observed in eyes of differing pigmentation (blue and green eyes, mean dilation = 2.04 ± 0.68 mm [N = 11 white subjects, 22 eyes]; brown eyes, mean dilation = 1.90 ± 0.55 mm
n=52 mean = l.%mm S.D. = O.61mm
Number 12 of
Eyes
67
Fig. 1 (Cremer and associates). Histogram shows the actual pupillary dilation in all 52 eyes (26 normal subjects) (mean = 1.96 ± 0.61 mm).
10 8 6 4
2
oJC:;:::::I_ <0.5
<1.0
<1.5
<2.0
<2.5
<3.0
<3.5
Actual Pupillary Dilation (mm)
<4.0
68
July, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
4 3
••
•
Mean Mydriasis 2 (mm)
•
•
1 0 10
20
30
••
• •
40
Age
[N = 15 subjects, 13 white, two oriental, 30 eyes]). The plot of diameter of the right eyes contrasted with diameter of the left eyes is shown both before and after the administration of hydroxyamphetamine in Figure 3. The graph shows that when hydroxyamphetamine is placed in both eyes of a normal individual, it generally does not produce an anisocoria. Additionally, the mean difference in dilation between the two eyes was only -0.087 mm ± 0.299 S.D. Thus, we found that the right eye to left eye variation in mydriasis was much less than variation from one person to another. The proportion of interocular variability attributable to measurement error was found to be 23.7% (95% confidence interval = 11.4% to 45.7%). Almost one fourth of the interocular response variability to hydroxyamphetamine could be accounted for on the basis of measurement variability from the photographs.
Discussion
The results of our study help clarify what the anticipated response to hydroxyamphetamine will be in normal individuals. It is important to know how much difference in mydriasis is to be expected between the two eyes of a normal individual if this difference is to be used as a localizing test in Horner's syndrome. We found little interocular difference in the hydroxyamphetamine mydriasis (mean = -0.087 mm ± 0.299 S.D.), which indicates that when a difference is found, the test should have diagnostic
••
• •• • • • • • •• 50
60
Fig. 2 (Cremer and associates) . Regression shows the lack of relationship between age and the mean mydriasis (average of right and left eye mydriasis for each individual) when using two drops of 1.0% hydroxyamphetamine hydrobromide (correlation coefficient IT] = 0.0).
70
value. Our conclusions support those of van der Wiel and van Cijn" (mean = 0.0075 mm ± 0.30 S.D.). We demonstrated that the degree of hydroxyamphetamine mydriasis varies among individuals. Factors that may influence the degree of apparent hydroxyamphetamine mydriasis include difference in the level of alertness at the beginning and end of the test (a person who becomes sleepy by the end of the test might exhibit less mydriasis); differences in the penetration of hydroxyamphetamine through the cornea; the amount of norepinephrine stores in nerve endings available for release; and the number of adrenergic receptors on the dilator muscle. In our normal subjects, these factors produced little, if any, interocular differences in response and must have exerted a relatively symmetric effect on the two eyes. Despite the interindividual variability, the difference in response between the two eyes of a given individual is negligible. We interpret this finding to mean that as a localizing test in Horner's syndrome, hydroxyamphetamine mydriasis should be useful, because the interindividual variability does not influence the localizing value within an individual. Neither the age nor the iris color of the subject appeared to influence the amount of mydriasis to 1 % hydroxyamphetamine in our subjects. Smith and Smith," however, reported that the pupils of elderly subjects dilate slightly more with 0.5% hydroxyamphetamine than those of younger subjects. One way of reconciling this difference is to consider that the increase in permeability of an aging cornea may cause a higher effective concentration of the
Vol. 110, No. 1
-. E E
CD CD
8
7
5
...-
4
CD
o
before hydroxyamphetamine
[]
after hydroxyamphetamine
Fig. 3 (Cremer and associates). Effect of hydroxyampbetamine on pupil diameter in normal eyes. Plot of right eye diameter vs left eye diameter for 26 normal subjects, before (circles) and after hydroxyamphetamine (squares). The right and left pupils are of nearly equal diameter, as shown by the close proximity of the points to the diagonal line of equality. Any deviation from this line represents an anisocoria. Hydroxyamphetamine generally does not produce anisocoria in normal subjects because the postdrop points are no further from the line of equality than the predrop points.
'line of no anisocoria
>-
W
3
CD
2 1 1
2
3
4
5
69
c
6
E as
.-Q
Hydroxyamphetamine Mydriasis in Normal Subjects
7
6
8
Right Eye Diameter (mm) drug at the nerve ending whenever a submaximal concentration of hydroxyamphetamine is given topically. The 0.5% solution used by Smith and Smith" may not have been strong enough to release all of the norepinephrine stores from the nerve endings. This was suggested by Mensher," who photographed the pupils of 20 normal volunteers (Fig. 4), and it
was later discussed by Gillum." Therefore, at submaximal concentrations of topically applied hydroxyamphetamine (0.5%), corneal permeability differences among age groups may influence the mydriatic effect. At higher concentrations of the drug (that is, two drops of 1.0%), however, mydriasis does not appear to differ as a function of age.
4.0
3.0
Anisocoria (mm)
2.0
1.0 0.02%
-.....---.......,...----.-----r--
0.0 +--......
-2.0
Fig. 4 (Cremer and associates). Hydroxyamphetamine hydrobromide dose response curve. Note 1.0% that the 0.5% concentration does not always produce full mydriasis. Data from 20 normal volunteers who ranged in age from 4 to 51 years are included. Life-size, selfdeveloping photographs were taken before and 60 minutes after instilling hydroxyamphetamine 1 % in the right eye only. The same 20 subjects were retested at least seven days later under identical conditions but with different concentrations of hydroxyamphetamine. 0.0
-1.0
Log of Concentration
70
AMERICAN JOURNAL OF OPHTHALMOLOGY
The interocular difference in hydroxyamphetamine mydriasis might be expected to vary in an individual daily. Day-to-day variation, however, should be part of the overall variability. Presumably, some of our subjects were examined on days when they dilated more than usual, and some on days when they dilated less than usual. Because the hydroxyamphetamine test is not used to follow the progression of a sympathetic deficit in a given patient, and is a one-time test for localization, the daily variation in the test within a given individual is not likely to have clinical significance. Because there is relatively little interocular variability in hydroxyamphetamine mydriasis in a normal individual, a mydriatic difference between the two eyes of a patient with Horner's syndrome is more likely to reflect differences in the number of existing postganglionic neurons than any right eye to left eye variability of the drug's effect.
References 1. Abbott, O. W., and Henry, C. M.: Paredrine. A clinical investigation of a sympathomimetic drug. Am. J. Med. Sci. 193:661, 1937. 2. Tassman, I. S.: The use of Paredrine in cycloplegia. Am. J. Ophthalmol. 21:1019, 1938. 3. Kronfeld, P. c.. McGarry, H. I., and Smith, H. E.: The effect of mydriatics upon the intraocular pressure in so-called primary wide-angle glaucoma. Am. J. Ophthalmol. 26:245, 1943. 4. Ornston, D. G.: Use of microcrystals of sulfathiazole in otolaryngologic practice. Arch. Otolaryngol. 41:337, 1945. 5. Altschule, M. D., and Iglauer, A.: The effect of Benzedrine and Paredrine on the circulation, metabolism and respiration in normal man. J. Clin. Invest. 19:497,1940.
July, 1990
6. Nathanson, M. H.: Rhythmic property of the human heart. Arch. Intern. Med. 72:613, 1943. 7. Trendelenburg, U., Muskus, A., Fleming, W. W., and Gomez Alonso de la Sierra, B.: Modification by reserpine of the action of sympathomimetic amines in spinal cats. A classification of sympathomimetic amines. J. Pharmacol. Exp. Ther. 138:170, 1962. 8. Lee, W. c., and Yeo, C. S.: Mechanism of cardiac activities of sympathomimetic amines on isolated auricles of rabbits. Arch. Int. Pharmacodyn. 15:93, 1964. 9. Gill, J. R., j-, Mason, D. T., and Bartter, F. c.. Effects of hydroxyamphetamine (Paredrine) on the function of the sympathetic nervous system in normotensive subjects. J. Pharmacol. Exp. Ther. 155:288,1967. 10. Thompson, H. S., and Mensher, J. H.: Adrenergic mydriasis in Horner's syndrome. The hydroxyamphetamine test for diagnosis of postganglionic defects. Am. J. Ophthalmol. 72:472, 1971. 11. Skarf, B., and Czarnecki, J. S. c.: Distinguishing postganglionic from preganglionic lesions. Studies in rabbits with surgically produced Horner's syndromes. Arch. Ophthalmol. 100:1319, 1982. 12. Van der Wiel, H. L., and van Gijn, J.: Horner's syndrome. Criteria for oculosympathetic denervation. J. Neurol. Sci. 56:293,1982. 13. - - : Localization of Horner's syndrome. Use and limitations of the hydroxyamphetamine test. J. Neurol. Sci. 59:229,1983. 14. Loewenfeld, I. E., and Rosskothen, H. D.: Infrared pupil camera. A new method for mass screening and clinical use. Am. J. Ophthalmol. 78:304, 1974. 15. Smith, S. E., and Smith, S. A.: Pharmacology of the pupil. In Kennard, c., and Rose, F. C. (eds.): Physiological Aspects of Clinical Neuro-Ophthalmology. London, Chapman and Hall, 1988, pp. 409417. 16. Mensher, J. A.: Hydroxyamphetamine dose response study. Possible diagnostic test relevance. Thesis. Iowa City, University of Iowa, 1972. . 17. Gillum, W. N.: Sympathetic stimulators and blockers. Ophthalmic Semin. 2:283, 1977.
Hydroxyamphetamine eyedrops are used to help localize the lesion in Horner's syndrome. Because normal variability in the response to the eye drops may influence the interpretation of test results in patients with Horner's syndrome, we studied both the interocular variability of the drug's mydriatic effect within each normal subject and the variation between individuals. We used photographs to document the variability among 26 normal SUbjects. Hydroxyamphetamine hydrobromide 1 % eyedrops (Paredrine) were placed in both eyes of normal subjects in the same way that patients with Horner's syndrome are tested. The drug produced a mean increase in pupil size of 1.96 mm (± 0.61 S.D.) in the 52 eyes tested. In normal subjects, the mydriatic effect of hydroxyamphetamine was symmetric in each pair of eyes. The mean interocular asymmetry of mydriasis as measured by the difference in dilation (right eye dilation minus left eye dilation) was -0.087 mm (± 0.29 S.D.). Thus, the variability of hydroxyamphetamine mydriasis from one eye to the other in a single subject was much lower than the variability between subjects.
P AREDRINE
(parahydroxyamphetamine hydrobromide 1 %) was introduced as a mydriatic
Accepted for publication April 5,1990. From the Department of Ophthalmology, University of Iowa, Iowa City, Iowa. This study was supported in part by an unrestricted grant to the University of Iowa Department of Ophthalmology from Research to Prevent Blindness, Inc., and in part by grant RR59 from Clinical Research Centers Branch of the National Institutes of Health. Reprint requests to H. Stanley Thompson, M.D., Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.
66
eyedrop in 1937.J.2 It was first used in combination with atropinic agents in an effort to hasten patients' recovery from cycloplegia and then as a gentle mydriatic." In the 1940s, it was a popular nasal decongestant and was used with a sulfathiazole suspension to treat sinus disease.' It was also used to treat cardiogenic shock' and cardiac arrhythmias," and was shown, unlike amphetamine sulphate, to have little or no effect on the central nervous systern." In the mid-1960s, it was concluded that, like tyramine, its adrenergic action resulted from the release of norepinephrine from nerve endings.t" In 1971, it was suggested" that because of its mode of action, hydroxyamphetamine might be useful as a diagnostic test to localize the lesion in Horner's syndrome. It has been repeatedly observed that hydroxyamphetamine causes less dilation of the affected pupil in Horner's syndrome when the lesion is in the postganglionic neuron.P:" but does dilate the affected pupil in preganglionic lesions. This effect has been demonstrated in cases of surgically placed lesions in humans" and rabbits." In recent years, hydroxyamphetamine has replaced epinephrine as the most reliable pharmacologic tool for identifying a postganglionic lesion in Horner's syndrome. When used as a diagnostic test for Horner's syndrome, hydroxyamphetamine is placed in both eyes and the pupillary response is noted 45 to 60 minutes later. Many factors deserve consideration when evaluating the localizing value of hydroxyamphetamine in Horner's syndrome. We evaluated the influence of the following factors: the variability of hydroxyamphetamine mydriasis among individuals; the symmetry of hydroxyamphetamine mydriasis between the two eyes of an individual; and the effect of patient age and iris color on hydroxyamphetamine mydriasis. We have attempted to define the normal range of hydroxyamphetamine mydriasis that would be expected under the conditions of testing used in Horner's syndrome.
©AMERICAN JOURNAL OF OPHTHALMOLOGY
110:66-70,
JULY,
1990
Vol. 110, No.1
Hydroxyamphetamine Mydriasis in Normal Subjects
For variation between eyes of a given individual (the interocular variation) in mydriasis, we plotted pupillary diameter for each subject's right eye, both before and after hydroxyamphetamine, against the corresponding pupillary diameter of the left eye to find whether hydroxyamphetamine produced significant anisocoria in normal subjects. Additionally, the dilation difference between the two eyes (mydriasis of the right eye minus mydriasis of the left eye) was calculated to quantify the interocular asymmetry. The contribution of measurement error was also evaluated by comparing the dilation difference between the two eyes as measured from photographs by two different observers.
Subjects and Methods Twenty-six normal subjects were used. None had any history of migraine headaches. Their mean age was 50.1 years (S.D. ± 15.8 years; range, 19 to 69 years). Hydroxyamphetamine (1 %) was placed into the conjunctival sac of each eye, both eyes were wiped, and 20 to 40 seconds later, in an effort to balance the dose in the two eyes, a second drop was placed in each eye. Photographs were taken just before the eye drops were given and 45 to 60 minutes after instillation. The photographs were taken with a Loewenfeld-Rosskothen camera" at 1:1 magnification using Polaroid film in moderately bright light. The pupil diameters of both eyes were measured directly from these photographs to the nearest tenth of a millimeter with a magnifying ruler. We considered two kinds of variability in hydroxyamphetamine mydriasis, variation between individuals and variation between the eyes of one individual. For the former, we measured the amount of mydriasis produced by hydroxyamphetamine in each of the 52 eyes of the 26 normal subjects by subtracting the predrop pupil size from the postdrop pupil size. From this, the mean mydriasis for the right and left eyes was calculated. The standard deviation of this mean represented the interindividual variation in mydriasis. We also investigated the effect of age and iris color (blue and green vs brown) on degree of mydriasis.
20 18 16 14
Results The mean pupillary dilation to hydroxyamphetamine for the combined 52 eyes was 1.96 mm (S.D. ± 0.61 mm), with a range of 0.5 to 3.1 mm (Fig. 1). The mean pupillary dilation of the right eyes was 1.94 mm (± 0.63 S.D.), and the mean dilation of the left eyes was 1.99 mm (± 0.68 S.D.) for the 26 normal subjects. No effect of age on hydroxyamphetamine mydriasis was found (Fig. 2). Additionally, no significant difference (P = .40) in mean mydriasis was observed in eyes of differing pigmentation (blue and green eyes, mean dilation = 2.04 ± 0.68 mm [N = 11 white subjects, 22 eyes]; brown eyes, mean dilation = 1.90 ± 0.55 mm
n=52 mean = l.%mm S.D. = O.61mm
Number 12 of
Eyes
67
Fig. 1 (Cremer and associates). Histogram shows the actual pupillary dilation in all 52 eyes (26 normal subjects) (mean = 1.96 ± 0.61 mm).
10 8 6 4
2
oJC:;:::::I_ <0.5
<1.0
<1.5
<2.0
<2.5
<3.0
<3.5
Actual Pupillary Dilation (mm)
<4.0
68
July, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
4 3
••
•
Mean Mydriasis 2 (mm)
•
•
1 0 10
20
30
••
• •
40
Age
[N = 15 subjects, 13 white, two oriental, 30 eyes]). The plot of diameter of the right eyes contrasted with diameter of the left eyes is shown both before and after the administration of hydroxyamphetamine in Figure 3. The graph shows that when hydroxyamphetamine is placed in both eyes of a normal individual, it generally does not produce an anisocoria. Additionally, the mean difference in dilation between the two eyes was only -0.087 mm ± 0.299 S.D. Thus, we found that the right eye to left eye variation in mydriasis was much less than variation from one person to another. The proportion of interocular variability attributable to measurement error was found to be 23.7% (95% confidence interval = 11.4% to 45.7%). Almost one fourth of the interocular response variability to hydroxyamphetamine could be accounted for on the basis of measurement variability from the photographs.
Discussion
The results of our study help clarify what the anticipated response to hydroxyamphetamine will be in normal individuals. It is important to know how much difference in mydriasis is to be expected between the two eyes of a normal individual if this difference is to be used as a localizing test in Horner's syndrome. We found little interocular difference in the hydroxyamphetamine mydriasis (mean = -0.087 mm ± 0.299 S.D.), which indicates that when a difference is found, the test should have diagnostic
••
• •• • • • • • •• 50
60
Fig. 2 (Cremer and associates) . Regression shows the lack of relationship between age and the mean mydriasis (average of right and left eye mydriasis for each individual) when using two drops of 1.0% hydroxyamphetamine hydrobromide (correlation coefficient IT] = 0.0).
70
value. Our conclusions support those of van der Wiel and van Cijn" (mean = 0.0075 mm ± 0.30 S.D.). We demonstrated that the degree of hydroxyamphetamine mydriasis varies among individuals. Factors that may influence the degree of apparent hydroxyamphetamine mydriasis include difference in the level of alertness at the beginning and end of the test (a person who becomes sleepy by the end of the test might exhibit less mydriasis); differences in the penetration of hydroxyamphetamine through the cornea; the amount of norepinephrine stores in nerve endings available for release; and the number of adrenergic receptors on the dilator muscle. In our normal subjects, these factors produced little, if any, interocular differences in response and must have exerted a relatively symmetric effect on the two eyes. Despite the interindividual variability, the difference in response between the two eyes of a given individual is negligible. We interpret this finding to mean that as a localizing test in Horner's syndrome, hydroxyamphetamine mydriasis should be useful, because the interindividual variability does not influence the localizing value within an individual. Neither the age nor the iris color of the subject appeared to influence the amount of mydriasis to 1 % hydroxyamphetamine in our subjects. Smith and Smith," however, reported that the pupils of elderly subjects dilate slightly more with 0.5% hydroxyamphetamine than those of younger subjects. One way of reconciling this difference is to consider that the increase in permeability of an aging cornea may cause a higher effective concentration of the
Vol. 110, No. 1
-. E E
CD CD
8
7
5
...-
4
CD
o
before hydroxyamphetamine
[]
after hydroxyamphetamine
Fig. 3 (Cremer and associates). Effect of hydroxyampbetamine on pupil diameter in normal eyes. Plot of right eye diameter vs left eye diameter for 26 normal subjects, before (circles) and after hydroxyamphetamine (squares). The right and left pupils are of nearly equal diameter, as shown by the close proximity of the points to the diagonal line of equality. Any deviation from this line represents an anisocoria. Hydroxyamphetamine generally does not produce anisocoria in normal subjects because the postdrop points are no further from the line of equality than the predrop points.
'line of no anisocoria
>-
W
3
CD
2 1 1
2
3
4
5
69
c
6
E as
.-Q
Hydroxyamphetamine Mydriasis in Normal Subjects
7
6
8
Right Eye Diameter (mm) drug at the nerve ending whenever a submaximal concentration of hydroxyamphetamine is given topically. The 0.5% solution used by Smith and Smith" may not have been strong enough to release all of the norepinephrine stores from the nerve endings. This was suggested by Mensher," who photographed the pupils of 20 normal volunteers (Fig. 4), and it
was later discussed by Gillum." Therefore, at submaximal concentrations of topically applied hydroxyamphetamine (0.5%), corneal permeability differences among age groups may influence the mydriatic effect. At higher concentrations of the drug (that is, two drops of 1.0%), however, mydriasis does not appear to differ as a function of age.
4.0
3.0
Anisocoria (mm)
2.0
1.0 0.02%
-.....---.......,...----.-----r--
0.0 +--......
-2.0
Fig. 4 (Cremer and associates). Hydroxyamphetamine hydrobromide dose response curve. Note 1.0% that the 0.5% concentration does not always produce full mydriasis. Data from 20 normal volunteers who ranged in age from 4 to 51 years are included. Life-size, selfdeveloping photographs were taken before and 60 minutes after instilling hydroxyamphetamine 1 % in the right eye only. The same 20 subjects were retested at least seven days later under identical conditions but with different concentrations of hydroxyamphetamine. 0.0
-1.0
Log of Concentration
70
AMERICAN JOURNAL OF OPHTHALMOLOGY
The interocular difference in hydroxyamphetamine mydriasis might be expected to vary in an individual daily. Day-to-day variation, however, should be part of the overall variability. Presumably, some of our subjects were examined on days when they dilated more than usual, and some on days when they dilated less than usual. Because the hydroxyamphetamine test is not used to follow the progression of a sympathetic deficit in a given patient, and is a one-time test for localization, the daily variation in the test within a given individual is not likely to have clinical significance. Because there is relatively little interocular variability in hydroxyamphetamine mydriasis in a normal individual, a mydriatic difference between the two eyes of a patient with Horner's syndrome is more likely to reflect differences in the number of existing postganglionic neurons than any right eye to left eye variability of the drug's effect.
References 1. Abbott, O. W., and Henry, C. M.: Paredrine. A clinical investigation of a sympathomimetic drug. Am. J. Med. Sci. 193:661, 1937. 2. Tassman, I. S.: The use of Paredrine in cycloplegia. Am. J. Ophthalmol. 21:1019, 1938. 3. Kronfeld, P. c.. McGarry, H. I., and Smith, H. E.: The effect of mydriatics upon the intraocular pressure in so-called primary wide-angle glaucoma. Am. J. Ophthalmol. 26:245, 1943. 4. Ornston, D. G.: Use of microcrystals of sulfathiazole in otolaryngologic practice. Arch. Otolaryngol. 41:337, 1945. 5. Altschule, M. D., and Iglauer, A.: The effect of Benzedrine and Paredrine on the circulation, metabolism and respiration in normal man. J. Clin. Invest. 19:497,1940.
July, 1990
6. Nathanson, M. H.: Rhythmic property of the human heart. Arch. Intern. Med. 72:613, 1943. 7. Trendelenburg, U., Muskus, A., Fleming, W. W., and Gomez Alonso de la Sierra, B.: Modification by reserpine of the action of sympathomimetic amines in spinal cats. A classification of sympathomimetic amines. J. Pharmacol. Exp. Ther. 138:170, 1962. 8. Lee, W. c., and Yeo, C. S.: Mechanism of cardiac activities of sympathomimetic amines on isolated auricles of rabbits. Arch. Int. Pharmacodyn. 15:93, 1964. 9. Gill, J. R., j-, Mason, D. T., and Bartter, F. c.. Effects of hydroxyamphetamine (Paredrine) on the function of the sympathetic nervous system in normotensive subjects. J. Pharmacol. Exp. Ther. 155:288,1967. 10. Thompson, H. S., and Mensher, J. H.: Adrenergic mydriasis in Horner's syndrome. The hydroxyamphetamine test for diagnosis of postganglionic defects. Am. J. Ophthalmol. 72:472, 1971. 11. Skarf, B., and Czarnecki, J. S. c.: Distinguishing postganglionic from preganglionic lesions. Studies in rabbits with surgically produced Horner's syndromes. Arch. Ophthalmol. 100:1319, 1982. 12. Van der Wiel, H. L., and van Gijn, J.: Horner's syndrome. Criteria for oculosympathetic denervation. J. Neurol. Sci. 56:293,1982. 13. - - : Localization of Horner's syndrome. Use and limitations of the hydroxyamphetamine test. J. Neurol. Sci. 59:229,1983. 14. Loewenfeld, I. E., and Rosskothen, H. D.: Infrared pupil camera. A new method for mass screening and clinical use. Am. J. Ophthalmol. 78:304, 1974. 15. Smith, S. E., and Smith, S. A.: Pharmacology of the pupil. In Kennard, c., and Rose, F. C. (eds.): Physiological Aspects of Clinical Neuro-Ophthalmology. London, Chapman and Hall, 1988, pp. 409417. 16. Mensher, J. A.: Hydroxyamphetamine dose response study. Possible diagnostic test relevance. Thesis. Iowa City, University of Iowa, 1972. . 17. Gillum, W. N.: Sympathetic stimulators and blockers. Ophthalmic Semin. 2:283, 1977.