Speed of Pupillary Light Response Following Topical Pilocarpine or Tropicamide

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INDOMETHACIN

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6. Grant, W . M . : Toxicology of the E y e Springfield, Thomas, 1962, p. 58. 7. Bonnet, P., Ponthus, P., Bonamour, G. and Neil, R. : Detection of gold contained in rabbit cornea. Bull. Soc. d'Ophtal. Paris. 51:440, 1939. Cited by Thomas, C. I." pp. 831 and 887). 8. Grant, W . M . : Toxicology of the Eye. Springfield, C. Thomas, 1962, p. 253. 9. Walsh, F. B. : Clinical Neuro-ophthalmology. Baltimore, Williams and Wilkins, 1957 ed. 2, p. 1211. 10. Zavilia, A . U. and Oliva, R. O. : Chryosis of the cornea in the course of sanocrysin treatment Klin. Mbl. Augenh. 102:94, 1939. In Thomas, C. I. ( e d ) The Cornea. Springfield, Thomas, 1955, p. 830. 11. Calkins, L. D. : Corneal epithelial changes occurring during chloroquine (Aralen) therapy.

SPEED

OF

STEPHAN

S.

Arch. Ophth. 60:981,1958. 12. Bernstein, H . N. : The ocular toxicity of chloroquine The Sight Saving Review 33:200» 1963. 13. Savin, L. H. : The association of ocular and articular disease. Tr. Ophth. Soc. U. K. 71:141, 1951. 14. Smith, J. L. : Ocular complications of rheumatic fever and rheumatoid arthritis. Am. J. Ophth. 43:575, 1957. 15. Gass, J. D. M. : Pathogenesis of disciform detachment of the neuroepithelium. Am. J. Ophth. 63:573 (pt. 2 ) , 1967. 16. Sternberg, T. H . and Laden, E. : Discoid lupus erythemotosus : Bilateral macular degeneration due to Arch. Derm. 79:116,1959. 17. Sams, W . M . : Chloroquine : Mechanism of actioa Mayo Clia Proc. 42:300, 1967.

PUPILLARY LIGHT

TOPICAL

RESPONSE

PILOCARPINE

MORGAN,

M.D.,

835

OR

ROBERT W.

FOLLOWING

TROPICAMIDE HOLLENHORST,

K E N N E T H N . OGLE, P H . D .

M.D.

AND

T

Rochester, Minnesota The speed of the pupillary response can be computed electronically and simultaneously recorded on the same time scale with the pupillary reaction curve by using the electronic infrared pupillometer of Lowenstein and Loewenfeld. "* The resulting curve is the derivative curve and is the same measurement they originally called the "differential curve." A typical pupillary light response curve (after a 5-msec exposure to light) and its derivative curve are illustrated in Figure 1. The pupillary response curve represents the actual diameter of the pupil during various phases of its reaction to a light stimulus. W e have called the initial diameter of the pupil at the time of exposure to light, P , and the total change in the diameter following the 1

From the Mayo Clinic and Mayo Foundation: Sections of Ophthalmology (Dr. Hollenhorst and Dr. Morgan), and of Biophysics (Dr. Ogle). Mayo Graduate School of Medicine (University of Minnesota). t Dr. Ogle died February 22, 1968. Correspondence and reprint requests to Section on Publications, Mayo Clinic 55901.

exposure to light, A P . The curve consists of a constriction phase followed by a dilation phase. Any point on the derivative curve indicates the rate of change of the pupil at that time during its reaction to light. The slope of any part of the derivative curve reflects the acceleration or deceleration of the change during that phase of the reaction. Inspection of Figure 1 shows that the first wave of the derivative curve is concurrent with the constriction phase of the pupillary response curve and that it consists of two parts : first, an acceleration phase ( A ) and, later, a deceleration phase ( D ) . The maximal rate of constriction ( M R C ) is indicated by the point of intersection of the lines having slopes A and D . Similarly, the dilation phase of the pupillary response curve produces a wave of the derivative curve. This second wave consists of two parts: first, an acceleration phase (Aa) and later, a deceleration phase ( D ) . c

C

0

E

D

To study the effects of topical autonomic drugs on the speed of the pupillary responses, we used pilocarpine ( 1 % ) and tro-

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N O V E M B E R , 1968

-Exposure

I

./"^-Pupillary reaction c u r v e Fig. 1 (Morgan, Hollenhorst and Ogle). Pupillary response curve (pupillary reaction curve) and its derivative curve for S-msec light flash.

picamide ( 0 . 5 % ) . These drugs were chosen because of their clinical popularity and because of their different pharmacologic actions. Pilocarpine, a miotic drug, is a directacting parasympathomimetic agent which directly stimulates cholinergic smooth muscle cells. Tropicamide, a mydriatic drug, is a parasympatholytic agent which acts by binding the cholinergic smooth muscle receptor sites, blocking the action of acetylcholine. MATERIALS AND METHODS INSTRUMENTATION Pupillary diameter and rate of change were measured simultaneously by the electronic infrared pupillometer '* and recorded on ultraviolet-sensitive Kodak Linagraph direct-print paper in the Honeywell Visicorder recording instrument. The stimulator unit was of the open-loop (Maxwellian-view) type, and the duration of each exposure and that of the following period of darkness automatically were controlled electronically. The accuracy of the timing was periodically checked with an oscilloscope. 5

7

SUBJECTS The subjects were four adults with normal ocular structures (table 1) ; two of the four had a low degree of myopia. Two sub-

jects had brown irides and two had blue irides. No spectacles or contact lenses were worn by the subjects during the experiments. TABLE 1 CHARACTERISTICS OF SUBJECTS IN STUDY Subject

Age (yr) 30 33 28 25

Sex

Iris Color

Refractive Error

M M M F

Brown Brown Blue Blue

Myopia Myopia Emmetropia Emmetropia

PROTOCOL Each subject was seated at the pupillometer in the usual manner; the subject observed a fixation light only with the right eye. The experiments were performed in a dimly illuminated room, and each subject was given adequate time to adapt to this illumination. A 5-msec exposure of infraredfree light followed by a 5-second interval of darkness was used in all cases. The intensity of the stimulating light was about 5 log units above the visual threshold. A preliminary base line recording of the pupillary response was made prior to the instillation of each drug. A single drop (ap-

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SPEED OF PUPILLARY LIGHT RESPONSE

proximately 0.03 ml) of one of the drugs was then administered directly onto the right cornea from a 1-ml tuberculin syringe through a 23-gauge, thin-walled, disposable needle. The eyelids were then closed for 15 seconds. The pupillary responses of each subject as affected by each of the drugs were recorded every two minutes for 30 minutes. The responses to a series of at least five exposures (more if the subject was having difficulty in controlling blinking) were recorded at every two-minute interval. Only the consensual responses of the right pupil were measured in this study. On the basis of previous observations, the first response in each series of exposure was not used. The pertinent characteristics of three subsequent responses in each series were measured, average, and evaluated. RESULTS

The following measurements (fig. 1) were recorded: ( 1 ) pupillary diameter, P, at the moment of light stimulation; ( 2 ) change in pupillary diameter, AP, caused by the light stimulus; ( 3 ) maximal rate of pupillary constriction, M R C ; ( 4 ) acceleration of pupillary constriction, A ; ( 5 ) deceleration of pupillary constriction, D ; ( 6 ) acceleration of pupillary dilation, A ; and ( 7 ) deceleration of pupillary dilation, D . c

C

d

d

The results are presented in graphs in which the averages of the measurements for each subject are plotted against the time elapsed since instillation of the drug. T o minimize apparent differences between data for individual subjects, the graphs have been adjusted to show an initial pupillary diameter of the same size in all the subjects. Figures 2 and 3 show the changes observed in P and in AP of the pupillary response curves after the instillation of the drugs. Figures 4, 5 and 6 show the effects of the two drugs on the constriction phase of the pupillary response to light stimulation. Figures 7 and 8 depict the acceleration ( A ) and deceleration d

( D ) of the dilation phase of the pupillary response to light after instillation of these two drugs. d

DISCUSSION Figure 2 shows smooth curves of increasing (tropicamide) or decreasing (pilocarpine) values for P as each drug took effect. These results were comparable to the findings of other workers. ' It was difficult to detect the time of onset of action of each drug from these curves; the average curves were smooth and there was no one point at which the drugs took effect in all subjects. The latency period appeared to be six to eight minutes for each of the drugs. 8 9

The average change in pupillary diameter during light stimulation (fig. 3) was quite similar for both drugs. The AP remained fairly constant during the latency period for each drug and then decreased as each drug became effective. There were no significant differences in the AP-versus-time curves between the miotic and the mydriatic drugs. Figures 3 and 4 reveal a similarity between the drugs in the time course of the change in pupil diameter due to a light stimulus and in the maximal rate of constriction. This suggests that both the amount of pupillary constriction due to a light stimulus and the peak speed of that constriction may be common indicators of the effect of these drugs on the musculature of the iris. In discussing the effects of pilocarpine on the normal pupil, Lowenstein and Loewenfeld stated that the constrictability ( A P ) of miotic pupils was "mechanically limited" and that the difference between the constrictability of miotic and nonmiotic pupils was on the basis of the mechanical limitations of a smaller pupil. The results of the present study suggested to us a different basis for AP. Because the AP-versus-time curves and the MRC-versus-time curves were so similar after the instillation of either drug, we sought a common pharmacologic basis for these effects of the drugs, regardless of whether miosis or mydriasis 10

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AMERICAN JOURNAL OF OPHTHALMOLOGY

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N O V E M B E R , 1968

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F'S- 2 (Morgan, Hollenhorst and Ogle). Effect of pilocarpine and tropicamide on diameter of pupil ( P ) . Broken lines represent average curves.

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6 10 Tim« from

14 18 22 26 instillation o f d r u g - m i n u t o s

was produced. It appeared to us that each of the drugs had the effect of hmiting the number of motor units, or muscle fibers, of the iris sphincter which were available for contraction after the parasympathetic stimulation in the pupillary light reflex. In view of the different pharmacologic actions of these two drugs, this concept should be considered more closely. Pilocarpine produces miosis by directly stimulating the motor units of the iris sphincter and maintaining this stimulation for some time ; this effect obviously limits the number of iris sphincter motor units remaining available for pupillary constriction as a response to the light reflex. Tropicamide, on the other hand, binds the cholinergic receptor sites of the iris sphincter, which prevents acetylchor

30

line from stimulating the fibers and results in mydriasis ; again, this in effect is decreasing the number of sphincter motor units available for pupillary constriction following a light stimulus. We think that the diameter of the pupil ( P ) at any time during the action of the drug is an indication of the number of sphincter motor units affected by the drug up to that time or, reciprocally, AP is an indication of the limitation of the number of motor units available to constrict the pupil after stimulation by the efferent arc of the pupillary light reflex. This is illustrated in Figure 9 where a linear relationship between the maximal rate of constriction ( M R C ) and the availability of iris sphincter motor units (as indicated by P ) is evident. For

839

SPEED OF PUPILLARY LIGHT RESPONSE

V O L . 66, N O . S

o

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Fig. 3 ( Morgan, Hollenhorst and Ogle). Effect of pilocarpine and tropicamide on change in pupillary diameter ( A P ) due to light stimulation. Broken lines represent average curves. o

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of d r u g - m i n u t e s

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Fig. 4 (Morgan, Hollenhorst and Ogle). Effect of pilocarpine and tropicamide on maximal rate of constriction of pupil ( M R C ) . Broken lines represent average curves.

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840

AMERICAN JOURNAL OF OPHTHALMOLOGY

Pilocarpine

40

3

0

N O V E M B E R , 1968

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32

VOL.

66, N O . 5

841

SPEED OF PUPILLARY LIGHT RESPONSE

6f

A

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A

O

A

0 •

Fig. 7 (Morgan, Hollenhorst and Ogle). Effect of pilocarpine and tropicamide on acceleration of dilation of pupil (Ad). Broken lines represent average curves.

o

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A

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O A

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A

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A

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each drug, such a linear relationship was seen een :o a after the pupil had constricted or dilated to critical diameter. ion The curves of acceleration of constriction mi( A ) plotted against time (fig. 5 ) are simiase lar for both drugs. There is a slight increase ing in the acceleration of constriction during what appears to be the latency period for for ase each drug, followed by a gradual decrease lusas the drugs increasingly affect the iris musfolculature. These measurements seem to follow a course generally parallel to that for for ugs AP and MRC, suggesting that the drugs :ter limit the general ability of the iris sphincter ing to respond to light stimulation. Assuming opno significant changes in the mechanical properties of the iris which would tend to opoppose its movement (such as mass, internal nal and external friction, and stiffness, a dimiminution of AP, MRC, and A should be be expected as the drugs take effect. This pre>rec

c

sumably would be due to the smaller number of iris sphincter motor units operating to constrict the pupil while the iris was under the influence of the autonomic drugs, in contrast to the larger number of motor units available in an iris not under the influence of such drugs. Figure 10 shows a linear relationship between the acceleration of constriction and the availability of iris sphincter motor units (again indicated by P ) . The similarity of Figures 9 and 10 lends support to the thesis that M R C and A (as well as A P ) depend on the same factor—namely, the number of motor units of the iris sphincter available for contraction in response to stimulation. c

Further support for our thesis is provided by the work of Lowenstein and Loewenfeld" in which they found that decreasing the intensity of the light stimulus produced a decrease in A , in MRC, and in AP. The effect c

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AMERICAN JOURNAL OF OPHTHALMOLOGY

N O V E M B E R , 1968

Pilocarpin»

Fig. 8 (Morgan, Hollenhorst and Ogle). Effect of pilocarpine and tropicamide on deceleration of dilation of pupil (Dd). Broken lines represent average curves.

si II i

«S

«

L Tropic omide

6

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18

22

26

30

Time from instillation of drug-minutes

of a less intense light stimulus would be a decrease in the strength of the light reflex, a resultant decrease in the amount of acetylcholine released at the iris sphincter, and, consequently, contraction of fewer sphincter motor units. This result is achieved, then, both by the autonomic drugs and by a less intense light stimulus. The curves showing the deceleration of constriction ( D ) plotted against time (fig. 6) were similar for each drug and, furthermore, although of lesser magnitude, they tended to be parallel to the A -versus-time curves (fig. 5 ) . Because AP, MRC, and A decreased as the drugs became effective, the later phase (deceleration) of pupillary constriction would also be expected to diminish. Or, stated c

c

c

*

otherwise, the amount of deceleration required was dependent on the amount of acceleration that had occurred. The characteristics of the dilation phase logically should depend on the characteristics of the constriction phase. In normal eyes, a constriction of great extent should be followed by a dilation of equally great extent and a lesser constriction should be followed by a lesser dilation. Similarly, a rapid dilation should be expected to follow a rapid constriction and a slower dilation should follow a slower constriction. The results of this study support this hypothesis. In courses generally parallel to the Ao-versus-time and D versus-time curves, the acceleration (fig. 7 ) and deceleration (fig. 8 ) curves for the dilac

Pilocorpina

—-

Fig. 9 (Morgan, Hollenhorst and Ogle). Relationship between maximal rate of constriction of pupil and pupillary diameter as affected by pilocarpine and tropicamide.

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3

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d i o m t t a r - mm

6

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V O L . 66, N O . S

843

SPEED OF PUPILLARY LIGHT RESPONSE

> Fig. 10 (Morgan, Hollenhorst and Ogle). Relationship between acceleration of constriction of pupil and pupillary diameter as affected by pilocarpine and tropicamide.

Pilocarpin*

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tion phase showed a slight increase during the latency period followed by a gradual decrease as the drugs affected the activity of the iris musculature. Again, the curves for both drugs were quite similar. Of all the parts of the derivative curve, D was the least affected by the drugs. This finding may be explained in that the D slope values were small under any circumstance and, therefore, would reflect changes in the slope less impressively than would changes in the other slopes. d

d

CONCLUSIONS 1. The derivative curve proved to be of great value in understanding the pupillary reactions. It was a sensitive and accurate tool for analyzing the speed of the movements of the pupil, and provided a different vantage point from which to examine pupillary action and the effects of drugs on the pupil. 2. Both a mydriatic and a miotic drug were used, and each affected the pupillary light reflex similarly in that each caused a diminution in the extent and speed of the pupillary reaction. 3. The physiologic mechanism for the diminution in the extent and speed of the pupillary light reaction by each drug is proposed to be the limitation of the number of iris sphincter motor units remaining available for contraction following the parasympathetic stimulation resulting from exposure to light."

6

7

10

«

dlomtttr - mm

4. The characteristics of the dilation phase of the pupillary light reaction were observed to be generally parallel to the characteristics of the constriction phase. SUMMARY The infrared electronic pupillometer was used to study the action of pilocarpine and tropicamide on the pupillary light reaction by examining the changes produced by each drug in the pupillary response curve and its derivative curve. Except for the pupillary diameter changes (miosis versus mydriasis), both drugs affected the pupillary light reaction similarly, despite having different pharmacologic actions. A possible mechanism for this similarity was proposed. REFERENCES 1. Lowenstein, O. and Loewenfeld, I. E. : Mutual role of sympathetic and parasympathetic in shaping of the pupillary reflex to light: Pupillographic studies. Arch. Neurol. 64:341, 1950. 2. Lowenstein, O. and Loewenfeld, I. E. : Types of central autonomic innervation and fatigue: Pupillographic studies. Arch. Neurol. 66:580, 1951. 3. Lowenstein, O. and Loewenfeld, I. E. : Disintegration of central autonomic regulation during fatigue and its reintegration by psychosensory controlling mechanisms. I. Disintegration: Pupillographic studies. J. Nerv. Ment. Dis. 1 1 5 : 1 , 1952. 4. Lowenstein, O. and Loewenfeld, I. E. : Disintegration of central autonomic regulation during fatigue and its reintegration by psychosensory controlling mechanisms. II. Reintegration: Pupillographic studies. J. Nerv. Ment Dis. 115:121, 1952. 5. Lowenstein, O. and Loewenfeld, I. E. : Electronic pupillography : A new instrument and some clinical applications. Arch. Ophth. 59:352, 1958.

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6. King, G. W . : Recording pupil changes for clinical diagnosis. Electronics 32:67, 1959. 7. Stark, L. : Environmental clamping of biological systems : Pupil servomechanism. J. Optical Soc. Am. 52:925, 1962. 8. Ogle, K. N., Whisnant, R. A . and Hazelrig, J. B. : Quantitative study of pupil response to miotic drugs. Invest. Ophth. 5:176, 1966. 9. Gambill, H . D., Ogle, K. N. and Kearns, T. P. : Mydriatic effect of four drugs determined with pupillograph. Arch. Ophth. 77:740, 1967. 10. Lowenstein, O. and Loewenfeld, I. E. : Effect of physostigmine and pilocarpine on iris sphincter

ELSCHNIG'S

N O V E M B E R , 1968

of normal man: Is it competitive or additive? Pupillographic studies. Arch. Ophth. 50:311, 1953. 11. Lowenstein, O. and Loewenfeld, I. E : Influence of retinal adaptation upon the pupillary reflex to light in normal man: I. Effect of adaptation to bright light on the pupillary threshold. Am. J. Ophth. 48 ( p t 2 ) :536, 1959. 12. Morgan, S. S. : The Effects of Certain Autonomic Drugs on the Speed of the Pupillary Response To Light Thesis, Mayo Graduate School of Medicine (University of Minnesota), Rochester, 1967.

SPOTS A N D HYPERTENSIVE

CHOROIDOPATHY

PETER H . MORSE, M . D . Baltimore, Maryland

Hypertensive choroidopathy, often called albuminuric choroiditis, is frequently obscured by concomitant hypertensive retinopathy and retinal edema. In malignant hypertension four types of fundus lesions associated with choroidal vascular changes are recognized clinically. Pale yellow or reddish patches bordered to a varying extent by pigment deposits: black isolated spots of pigment with a surrounding yellow or red halo (Elschnig's spots) ; chains of pigment flecks arranged linearly along the course of a yellow-white sclerosed choroidal vessel (Siegrist's spots) ; and yellow or red patches of chorioretinal atrophy. 1

These ophthalmoscopically visible manifestations of hypertensive choroidopathy are seen pathologically as necrosis and thinning of the pigment epithelium in some places, with proliferation and clumping in others, often overlying irregularly distributed sclerotic to obliterative changes in the choriocapillaris. Ischemic infarcts of the choriocapillaris are seen in the acute stage. These and other previously observed clinicopathologic findings are described elsewhere. " 2

8

From the Wilmer Ophthalmological Institute, Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland, 21205.

The purpose of this paper is to report a case demonstrating uncommonly seen Elschnig's spots, as well as fluorescein angiograms and illustrative histopathologic findings. CASE REPORT A 35-year-old Negro woman was first seen at the Wilmer Institute in January 26, 1966, complaining of headaches, blurred vision and flickering spots in both eyes of four to five weeks' duration. Her corrected visual acuity in the right eye was 20/50 + 3 and in the left eye 20/200. Intraocular pressure was 7/5.5 or 12.2 mm H g (Schiotz) in each eye. Slitlamp examination revealed normal anterior segments. Ophthalmoscopic examination revealed clear media bilaterally with papilledema, narrowed arterioles, A - V compression, flame-shaped retinal hemorrhages, hard yellow exudates and macular star figures, more pronounced in the left eye. Her blood pressure was 270/150 mm Hg. She was admitted the same day to the Osier Medicine Service. Her past history was one of good health. In addition to her headaches and ocular complaints she had experienced polydypsia, polyuria, nocturia, and a 10-pound weight loss over the previous four to five weeks. Physical examination showed the patient to be afebrile with a blood pressure of 220/110 mm Hg. The heart had a systolic murmur with an S-4 gallop. A chest X-ray revealed the lungs to be clear but the heart showed signs of left ventricular hypertrophy. Urinalysis gave a 4-plus reaction for protein and had 10 to 12 red cells per high-powered field and a few clumps of white cells. The hematocrit was 28%, white blood cell count, 8,000, and the peripheral smear showed microangiopathic hemolytic anemia. Platelets were 132,000 and reticulocytes 1.4%. A sero-