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The Effect of Phenylephrine on Müller Muscle
The Effect of Phenylephrine on Miiller Muscle A Blepharogram Study of Eyelid Motion Robert G. Small, MD, Stephen R. Fransen, MD, Robert Adams, BS, Willis L. Owen, PhD, Robert B. Taylor III, MD Purpose: The blepharogram technique is used to study the effect of a drug on blinking. The authors show that ocular instillation of phenylephrine, a stimulant of Muller muscle of the eyelid, accelerates the up phase of the blink. Methods: Motion of a tiny search coil glued to the eyelid moving in a weak magnetic field modifies an induced alternating current which is amplified and used to display the position of the upper eyelid in degrees on the ordinate of a graph with time in milliseconds on the abscissa. The graph is called a blepharogram. Blepharogram studies and individual blink analysis show the effect of phenylephrine on eyelid motion (blinking). Results: Instillation of phenylephrine accelerated the up phase of the blink in all ten experimental subjects. In 65% of subjects, phenylephrine also produced or increased newly described N and M blepharogram patterns. Conclusion: This is the first instrumental detection of the effect of a pharmacologic agent on eyelid motion. The blepharogram technique provides insight into eyelid physiology and can be used to study any neuromuscular condition that affects eyelid motion. Ophthalmology 1995;102:599-606
Although eyelid function (blinking) is critical to the integrity of the eye and is altered in many neuromuscular conditions, there has been relatively little basic scientific interest in this subject. Up to 1988, eyelid motion was studied by observation, high-speed photography, or levers attached to the lid. t.z A significant methodologic advance was made in 1988 by Becker and Fuchs 3 who used the search coil technique to study eyelid motion. This method was used by others to study blinking in facial paralysis4 and botulinum treatment of blepharospasm. 5 We also used this method to study Horner syndrome. 6 Computer
Originally received: Nov 5, 1993. Revision accepted: October 16, 1994. From the Dean A. McGee Eye Institute and Department of Ophthalmology, University of Oklahoma, Oklahoma City. Presented at the American Academy of Ophthalmology Annual Meeting, Chicago, November 1993. Each author states that he has no proprietary interest in the development or marketing of this or a competing instrument. Reprint requests to Robert G. Small, MD, Dean A. McGee Eye Institute, 608 Stanton L. Young Blvd, Oklahoma City, OK 73104.
processing of the search coil signal is a refinement that offers exciting possibilities for clinical research. The blepharogram is a term used to describe computerized tracings of blinks obtained by the search coil technique. We used the blepharogram and blink analysis to show that in Horner syndrome the up phase of the blink is slowed, which we believe is due to loss of Muller muscle function. 6 Instillation of 10% phenylephrine into the eye produces a situation opposite to Horner syndrome because Muller muscle is stimulated. Contraction of Muller muscle produces an increase in the height of the vertical lid fissure in contrast to the ptosis of Horner syndrome. We wondered if phenylephrine instillation in healthy subjects would accelerate the up phase of the blink in contrast to the slowing noted in Horner syndrome. Ten experimental and ten control subjects were used to show that phenylephrine does accelerate the up phase of the blink. This is the first instrumental detection of a change in eyelid motion brought about by a pharmacologic agent. We noted characteristic blinking patterns in some blepharograms not previously described and suggest that Muller muscle activity is responsible for these patterns. 6 599
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Volume 102, Number 4, April1995
An elevation of the tracing at the beginning of a blink is a called an "N" pattern and at the beginning and end of the blink, an "M" pattern (Figs 1 and 2). The current study provides additional evidence that Muller muscle is responsible for N and M patterns.
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Instrumentation Instrumentation and methodology for the original device are discussed in a previous article. 6 The basic technique is briefly reviewed, and the improved device is considered here. A tiny search coil glued to the eyelid moves in a weak magnetic field produced by a field coil mounted on a modified slit lamp. The modified alternating current generated in the search coil is processed by a phase-sensitive lock-in amplifier whose voltage output is proportional to the angular position of the eyelid. A computer receives the signal and displays the position of the lid in degrees on the ordinate of a graph (Fig 3). Each degree on the ordinate equals 0.24 mm of eyelid excursion. The signal is measured at millisecond intervals, with time shown on the abscissa. A composite of 10 to 20 uniform selected voluntary blinks makes up the blepharogram. The original blepharogram device was modified by adding a second search coil and second lock-in amplifier so simultaneous blepharograms can be obtained from both eyelids. Figure 4 shows what the blepharogram of a single simultaneous right and left blink looks like on the computer screen. The blepharogram device is calibrated by attaching a search coil to the arm of an eyelid model and taking a series of measurements to determine a calibration factor for each series of blinks. Repeated studies with a dual eyelid model show the angular position of the search coil in each eyelid over a 60° range has a linear relation to the voltage generated. Thus, the blepharogram tracing
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obtained from the new instrument is an accurate representation of the simultaneous position of each lid during a blink in degrees on the ordinate and in milliseconds on the abscissa.
Methods Informed consent was obtained from each subject. The study was approved for human subjects by the Institutional Review Board of the University of Oklahoma Health Sciences Center. The subject's chin is supported by a chin rest, and the forehead is positioned against a restraining strap. The eyes are fixed on a horizontal target. The subject is asked to blink as completely and quickly as possible (voluntary blinks). The clinician watches the subject while another investigator monitors the computer screen as 20 to 30 blinks are recorded. Ten to 20 uniform blinks are selected from all the recorded blinks for the blepharogram. If the subject looks away from the target, the lids move up and down with the eyes. The resulting irregular tracing is not included in the blepharogram. Also excluded from the blepharogram are eyelid saccades (slow lid closure and opening). Baseline simultaneous blepharograms on both eyelids were done in ten experimental and ten control subjects. Phenylephrine then was instilled three times in one eye of each of ten experimental subjects. Each subject was asked to keep the eyes closed for 1 minute. Instillation was repeated at 5-minute intervals until three drops were instilled. The phenylephrine effect was established by noting pupil dilation and 2- to 3-mm increase in height of the vertical lid fissure in each subject. After 30 minutes, the search coils were reglued to the lid, and simultaneous blepharograms were repeated. In ten control subjects, simultaneous blepharograms on both lids were done before and after instillation of artificial tears in the left eye. From the values for lid position and time, the following parameters were calculated and stored by the computer
Small et al · Effect of Phenylephrine on Muller Muscle
Figure 3. Original blepharogram device. The tracing is obtained from one lid only. Inset, detail of the search coil. (Courtesy Trans Am
Ophthalmol Soc 1992;90:34760.)
for every blink: amplitude down (degrees; I o = 0.24 mm), amplitude up (degrees), average velocity down (degrees/ second), average velocity up (degrees/second), duration of down phase of blink (milliseconds), duration of up phase of blink (milliseconds), ratio of time down to time up, maximum velocity down (degrees/second), maximum velocity up (degrees/second), and blink duration (milliseconds). The blepharograms and numeric values for all blink parameters were studied. Special attention was directed to the maximum upward velocity. This is the maximum speed in degrees per second the lid achieves in the up
phase of a blink. The computer calculates the derivative of the blink amplitude each millisecond to obtain the velocity. It then selects the five fastest blinks out of all the recorded blinks. Maximum upward blink velocity characteriL.es the maximum upward speed the lid can achieve and is defined as the mean of the five greatest individual maximum upward blink velocities. The maximum upward blink velocity was recorded in 52 normal eyelids. Simultaneous right and left maximum upward blink velocity values were obtained in 21 healthy subjects. Regression analyses were done to show the relation of maximum upward blink velocity to blink amplitude.
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The blepharograms of20 healthy subjects were studied for the presence or absence of N and M patterns before and the increase or appearance of patterns after phenylephrine instillation. In ten control subjects, blepharograms were studied for N and M patterns before and after artificial tear instillation.
Results In 52 normal eyelids, the average maximum upward blink velocity was 658 ± 172 degrees/second (mean± standard deviation). Simultaneous maximum upward blink velocity values of the right and left lids in 21 healthy subjects were within 10% in 13 subjects and 20% in 19 subjects. In all ten experimental subjects, the maximum upward blink velocity of the lid on the phenylephrine-stimulated side increased significantly (P < 0.02) in relation to the opposite lid in blinks recorded simultaneously. The mean relative percentage increase was 20.2% (Table 1). Artificial tear instillation in ten control subjects produced no consistent change in maximum upward blink velocity on the side of instillation in relation to the opposite lid (Table 2). Figure 5 is the simultaneous blepharogram of the phenylephrine-treated lid superimposed on the opposite lid of subject 8, showing increased amplitude and increased upward velocity in the treated lid. Analysis of maximum upward blink velocity measured sequentially in the same lid before and after phenylephrine instillation showed an average increase of 4.6% (Table 3). Analysis of maximum upward blink velocity in control lids before and after instillation of artificial tears recorded an average decrease of 8.6% (Table 4) (P = 0.19). The scattergram of all blinks of subjects 5, 6, 8, and 10, who have consistent blinking parameters, shows increased upward blink velocity in sequential studies after
phenylephrine instillation (R = 98; P < 0.01) (Fig 6). The average blink amplitude of the untreated lids is 43.3 c (standard deviation, 11.4 c). The average maximum upward blink velocity is 535.9 degrees/second (standard deviation, 170.5 degrees/second). In the treated lids, these values increased to 46.6c (standard deviation, 13.1 c) and 630.7 degrees/second (standard deviation, 214.7 degrees/ second). Figure 7 shows a scattergram of all blinks of all subjects before and after phenylephrine. Attention is directed to blinks with an amplitude of soc or more. Linear regression techniques are applied to each group. In the untreated group, the regression fit is significant (P = 0.0001) with a slope of 12.16 (r 2 = 0.985). The fit in the phenylephrinetreated group is significant (P = 0.0001; r 2 = 0.980). In this group, the slope of the regression line is 13.51. The test for equality of regression indicates that the slopes are significantly different (P ~ 0.01 ). This demonstrates that blinks of amplitude soc or more in the phenylephrinetreated group have a higher maximum upward blink velocity than blinks of the same amplitude in untreated eyes. There are 34 blinks with amplitudes of soc or more in the untreated group and 49 higher amplitude blinks in the treated group; this represents a statistically significant increase of 36% (P = 0.004). The average maximum upward blink velocity decreased 17.7% in sequential measurements in the lids that did not receive phenylephrine. The average maximum upward blink velocity decreased 6.2% in sequential measurements in the control lids that did not receive artificial tears (P = 0.11). In 12 (60%) of the 20 subjects used for studying N and M patterns, no N or M pattern was present before phenylephrine instillation. In five of these, an N or M pattern appeared after phenylephrine instillation. In eight (40%) subjects, an N or M pattern was present before phenylephrine instillation. In all eight subjects, one or both pat-
Table 1. Percent Increase of Maximum Upward Blink Velocity on Side of Phenylephrine Instillation Before Phenylephrine Subject No.
Age (yrs)/ Sex
Side of Instillation
2 3 4 5 6 7 8 9 10
33/F 28/F 31/M 31/M 24/F 27/F 28/M 27/F 25/F 30/F
L L L L L L R L R L
% Difference Right and Left
MUBV
Side of Greater MUBV
% Difference Right and Left
16.7 5.0 14.6 41.6 0.2 1.0 4.1 7.5 18.4 4.5
R L L R L L R L L L
11.6 33.2 22.4 12.6 35.8 8.2 15.6 47.4 13.2 12.1
• Mean, +20.2 MUBV = maximum upward blink velocity; R = right; L = left.
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After Phenylephrine
MUBV
Side of Greater MUBV
R L L L L L R L L L
% Relative Increase MUBV on Side of Phenylephrine Instillation•
+5.1 +28.2 +7.8 +54.2 +35.6 +7.2 +11.5 +39.9 +5.2 +7.6
Small et al · Effect of Phenylephrine on Miiller Muscle terns increased in amplitude in the lid on the side of phenylephrine instillation. The presence of patterns before and after phenylephrine was divided equally between male and female subjects. Figure 8 shows an M-pattern increase after phenylephrine (same subject as in Fig 2). In ten control subjects, no pattern effect was demonstrable after artificial tear instillation.
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The blepharogram is a computerized composite of selected blinks that represents a "typical" blink for a given subject. The down phase of the blink is always faster than the slower tapering up phase (Figs 1, 2, 4, 5, and 8). Figure 5 shows the simultaneous blepharogram of the phenylephrine-treated lid superimposed on the opposite untreated lid of subject 8. Increased blink amplitude and increased slope (velocity) of the up phase of the blink in the treated lid are evident. However, since the phenylephrine effect is more obvious in some subjects than others, the possibility of observer bias is introduced. To avoid this, we selected the experimental and control subjects at random and recorded every blink from each subject, not just the blinks selected for the blepharogram. Because simultaneously recorded right and left blinks are the most consistent and comparable, we compared the maximum upward blink velocity of all recorded blinks of all subjects in the phenylephrine-treated lids and the opposite untreated lids. The maximum upward blink velocity increased significantly (P < 0.02) in the phenylephrinetreated lids in all subjects. This change was not noted in the control group (Tables 1 and 2). We conclude that the phenylephrine-stimulated Miiller muscle increases the velocity of the up phase of the blink. This result is consistent with evidence from our earlier
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study of Horner syndrome which showed that the absence ofMiiller muscle activity slows the up phase of the blink. Miillerectomy also appears to decrease upward velocity in blinking; however, more patients who underwent this procedure must be studied to confirm this decrease. 6 The increase in the average maximum upward blink velocity after phenylephrine in sequential studies in the ten subjects is suggestive, but the effect was not significant at the 0.05 level (Tables 3 and 4) (P = 0.19). There is considerable normal variation in blink amplitude and velocity in some subjects studied at different times. However, in subjects with consistent blinking parameters, the phenylephrine effect can be demonstrated in sequential studies. The scattergram and straight-line regression equations of subjects 5, 6, 8, and 10 with consistent blinking parameters
Table 2. Percent Increase of Maximum Upward Blink Velocity on Side of Artificial Tear Instillation Before Artificial Tears Subject No.
Age (yrs)/ Sex
Side of Instillation
1 2 3 4 5 6 7 8 9 10
30/F 24/F 27/F 23/F 23/F 30/M 28/M 51/M 41/F 29/M
L L L L L L L L L L
After Artificial Tears
% Difference Right and Left
Side of Greater
% Difference Right and Left
Side of Greater
4.5 11.2 0.9 5.7 7.7 36.7 14.3 3.4 6.2 16.5
L L L L L R R R R L
14.5 16.3 6.1 7.1 3.5 30.3 35.2 24.9 16.6 8.8
L R R R R R R L L L
MUBV
MUBV
MUBV
MUBV
% Change of MUBV on Side of Artificial Tear Instillation•
+10.0 -27.5 -7.0 -12.8 -11.2 +6.4 -20.9 +28.3 +22.8 -7.8
*Mean, -2.0. MUBV = maximum upward blink velocity; L = left; R = right.
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Volume 102, Number 4, April1995
Table 3. Maximum Upward Blink Velocity Before and After Phenylephrine Instillation Subject No.
Side of Instillation
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620.1 513.7 455.5 468.9 646.04 821.5 826.9 401.5 714.1 768.1
535.7 449.6 480.7 792.7 889.5 1048.5 712.6 420.1 572.9 718.3
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-13.3 +5.5 +51 +31.8 +24.3 -14.8 +4.5 -21.9 -6.7
L = left; R = right. *Mean, 628.6 degrees/second. t Mean, 662.1 degrees/second. Mean, +4.6 degrees/second.
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studied sequentially show an increased slope, representing increased upward velocity in the treated lids (R = 0.98; P < 0.01) (Fig 6). In addition, the average amplitude and average maximum upward velocity increased in the treated lids. It is not surprising that in sequential studies the phenylephrine effect is not evident in the straight line regression equation of all blinks of all ten subjects because of the variability of blinking parameters recorded at different times noted above. However, the straight line regression
equations of all blinks in all subjects with a blink amplitude over 50° shows that the blinks in phenylephrinetreated lids have greater amplitudes, are significantly more numerous, and have higher maximum upward velocities (R = 0.99; P = 0.01) (Fig 7). This demonstrates that in any series of blinks, more blinks with greater amplitudes and higher maximum upward velocities will be in phenylephrine-treated lids. Because Muller muscle is stretched more in large amplitude blinks, one would expect these blinks to have a
Table 4. Maximum Upward Blink Velocity Before and After Artificial Tear Instillation Subject No.
Side of Instillation
Before Tears (degrees/ second)*
After Tears (degrees/ second)t
%Change (degrees/ second)t
1 2 3 4 5 6 7 8 9 10
L L L L L L L L L L
897.9 772.6 465.7 938.1 989.8 427.0 892.4 717.1 515.6 745.6
779.1 558.2 492.9 828.2 783.6 428.5 790.9 925.8 567.1 535.5
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L = left. *Mean, 736.2 degrees/second. t Mean, 669.0 degrees/second. Mean, -8.6 degrees/second.
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faster up phase. Increased maximum upward blink velocity also may be related to increased blink amplitude per se. In either case, increased upward blink velocity is a result of phenylephrine instillation. We find voluntary blinks more consistent than spontaneous blinks. Spontaneous blinks are slower and more variable than voluntary blinks. Voluntary blinks are easier to elicit and more comfortable for the subject than reflex blinks. Although all subjects had widening of the vertical lid fissure after phenylephrine, resting lid position varies, and many subjects do not close their eyes completely each time they blink. The resulting variation in blink amplitude makes it impossible to use blink amplitude as an index of resting lid position. Variation in blink amplitude is shown in Figures 6 and 7. Nine often subjects showed decreased maximum upward blink velocity in the untreated lid in the less-consistent sequential measurements. The control subjects showed less slowing on the side that did not receive artificial tears but this difference did not reach statistical significance (P = O.ll). We currently are unsure of the relevance of this tendency. before phenylephrine
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Because phenylephrine stimulates the lid, could Hering law apply? Hering law originally applied to equal (motor) innervation of the extraocular yoke muscles and was later applied to the levator muscles. Hering law does not apply here because phenylephrine stimulates the (sympathetic) Muller muscle, not the levator muscle. Also, no ptosis occurred in the unstimulated lids. Muller muscle receives constant (tonic) sympathetic innervation and is responsible for the height of the vertical eyelid fissure. Phenylephrine increases the tonic contraction of Muller muscle. Muller muscle can be compared with a spring that maintains the vertical height of the lid fissure between blinks. We believe an increased springlike force adds to the action of the levator muscle and increases upward eyelid velocity after phenylephrine stimulation. Other authors state that simultaneous right and left blinks are identical. 3•7 We find simultaneous blinks to be similar but not identical in most subjects. The simultaneous maximum upward blink velocity of the right and left lids is within 10% in 70% of healthy subjects and within 20% in 90% of healthy subjects. However, the maximum upward blink velocity in 2 of 21 individuals without any
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Ophthalmology
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Volume 102, Number 4, April1995
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apparent lid abnormality varied up to 45%. Some subjects have unequal lid function not obvious on clinical examination. Subject 4 (Table 1) is an example of a marked difference in maximum upward blink velocity between the two eyelids (41.6% ). Even so, the subject demonstrated a dramatic increase in maximum upward blink velocity ofthe phenylephrine-stimulated lid. Phenylephrine stings and increases the pupil size and lid aperture, whereas artificial tears have no effect. This makes it difficult to mask drop instillation. Although this introduces the possibility of observer bias, we believe awareness of the drop instilled by ourselves and some subjects did not affect the results. Phenylephrine increased the N and M patterns in the blepharograms of all eight subjects who had these patterns before instillation. Figure 8 shows an increased M pattern after phenylephrine (same subject as Fig 2). Phenylephrine also produced new patterns in five other subjects. Thus, some phenylephrine pattern effect occurred in 13 (65%) of 20 subjects. There was no pattern effect after artificial tear instillation in the control subjects. Muller muscle must be responsible for the N and M patterns. These observations add to the evidence of this relation presented in the Horner syndrome study in which Nand M patterns were absent in blepharograms of the affected lid. 6 The patterns may be due to tonic action of Muller muscle if the orbicularis muscle relaxes momentarily just before the down phase of the blink (N pattern) and at the end of the blink (M pattern). The occurrence of N and M patterns in some subjects and not others suggests that
606
minute variations in the timing of nerve stimuli to the orbicularis and levator muscles may be responsible. Continuing experience with the blepharogram should provide additional insight into these interesting patterns. Electromyography shows that the levator muscle receives a nerve impulse only during upward eyelid motion. 8 Muller muscle has constant tonus. Powerful orbicularis muscle contraction easily overcomes the resistance of Muller muscle in moving the lid down, but when the lid moves upward the tonic action of Muller muscle adds to the action of the levator. The current study demonstrates this action and adds to evidence from the Horner syndrome study to show that Muller muscle contributes to upward eyelid motion. Phenylephrine also produces or increases the newly described N or M patterns in more than half of healthy subjects. We believe these velocity and pattern effects are produced by phenylephrine stimulation of Muller muscle in the upper eyelid. The blepharogram and blink analysis provide the first instrumental method of studying subtle changes in eyelid motion brought about by a pharmacologic agent. The blepharogram technique provides exciting insights into eyelid physiology and will be valuable for the investigation of any neuromuscular condition affecting the eyelid.
References I. Evinger C, Shaw MD, Peck CK, et a!. Blinking and associated eye movements in humans, guinea pigs, and rabbits. J Neurophysiol 1984;2:323-39. 2. Karson CN. Physiology of normal and abnormal blinking. Adv Neurol 1988;49:25-37. 3. Becker W, Fuchs AF. Lid-eye coordination during vertical gaze changes in man and monkey. J Neurophysiol 1988;60: 122'k5.2. 4. Sibony PA, Evinger C, Manning KA. Eyelid movements in facial paralysis. Arch Ophthalmol 1991;109:1555-61. 5. Manning KA, Evinger C, Sibony PA. Eyelid movements before and after botulinum therapy in patients with lid spasm. Ann Neurol 1990;28:653-60. 6. Small RG, Fransen SR, Adams R. The blepharogram in Homer's syndrome. Trans Am Ophthalmol Soc 1992;90: 347-60. 7. Evinger C, Manning KA, Sibony PA. Eyelid movements. Mechanisms and normal data. Invest Ophthalmol Vis Sci 1991;32:387-400. 8. Fuchs AF, Becker W, Ling, L, et a!. Discharge pattern of levator palpebrae superioris motomeurons during vertical lid and eye movements in the monkey. J Neurophysiol 1992;68:223-43.
Although eyelid function (blinking) is critical to the integrity of the eye and is altered in many neuromuscular conditions, there has been relatively little basic scientific interest in this subject. Up to 1988, eyelid motion was studied by observation, high-speed photography, or levers attached to the lid. t.z A significant methodologic advance was made in 1988 by Becker and Fuchs 3 who used the search coil technique to study eyelid motion. This method was used by others to study blinking in facial paralysis4 and botulinum treatment of blepharospasm. 5 We also used this method to study Horner syndrome. 6 Computer
Originally received: Nov 5, 1993. Revision accepted: October 16, 1994. From the Dean A. McGee Eye Institute and Department of Ophthalmology, University of Oklahoma, Oklahoma City. Presented at the American Academy of Ophthalmology Annual Meeting, Chicago, November 1993. Each author states that he has no proprietary interest in the development or marketing of this or a competing instrument. Reprint requests to Robert G. Small, MD, Dean A. McGee Eye Institute, 608 Stanton L. Young Blvd, Oklahoma City, OK 73104.
processing of the search coil signal is a refinement that offers exciting possibilities for clinical research. The blepharogram is a term used to describe computerized tracings of blinks obtained by the search coil technique. We used the blepharogram and blink analysis to show that in Horner syndrome the up phase of the blink is slowed, which we believe is due to loss of Muller muscle function. 6 Instillation of 10% phenylephrine into the eye produces a situation opposite to Horner syndrome because Muller muscle is stimulated. Contraction of Muller muscle produces an increase in the height of the vertical lid fissure in contrast to the ptosis of Horner syndrome. We wondered if phenylephrine instillation in healthy subjects would accelerate the up phase of the blink in contrast to the slowing noted in Horner syndrome. Ten experimental and ten control subjects were used to show that phenylephrine does accelerate the up phase of the blink. This is the first instrumental detection of a change in eyelid motion brought about by a pharmacologic agent. We noted characteristic blinking patterns in some blepharograms not previously described and suggest that Muller muscle activity is responsible for these patterns. 6 599
Ophthalmology
Volume 102, Number 4, April1995
An elevation of the tracing at the beginning of a blink is a called an "N" pattern and at the beginning and end of the blink, an "M" pattern (Figs 1 and 2). The current study provides additional evidence that Muller muscle is responsible for N and M patterns.
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Instrumentation Instrumentation and methodology for the original device are discussed in a previous article. 6 The basic technique is briefly reviewed, and the improved device is considered here. A tiny search coil glued to the eyelid moves in a weak magnetic field produced by a field coil mounted on a modified slit lamp. The modified alternating current generated in the search coil is processed by a phase-sensitive lock-in amplifier whose voltage output is proportional to the angular position of the eyelid. A computer receives the signal and displays the position of the lid in degrees on the ordinate of a graph (Fig 3). Each degree on the ordinate equals 0.24 mm of eyelid excursion. The signal is measured at millisecond intervals, with time shown on the abscissa. A composite of 10 to 20 uniform selected voluntary blinks makes up the blepharogram. The original blepharogram device was modified by adding a second search coil and second lock-in amplifier so simultaneous blepharograms can be obtained from both eyelids. Figure 4 shows what the blepharogram of a single simultaneous right and left blink looks like on the computer screen. The blepharogram device is calibrated by attaching a search coil to the arm of an eyelid model and taking a series of measurements to determine a calibration factor for each series of blinks. Repeated studies with a dual eyelid model show the angular position of the search coil in each eyelid over a 60° range has a linear relation to the voltage generated. Thus, the blepharogram tracing
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Materials and Methods
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obtained from the new instrument is an accurate representation of the simultaneous position of each lid during a blink in degrees on the ordinate and in milliseconds on the abscissa.
Methods Informed consent was obtained from each subject. The study was approved for human subjects by the Institutional Review Board of the University of Oklahoma Health Sciences Center. The subject's chin is supported by a chin rest, and the forehead is positioned against a restraining strap. The eyes are fixed on a horizontal target. The subject is asked to blink as completely and quickly as possible (voluntary blinks). The clinician watches the subject while another investigator monitors the computer screen as 20 to 30 blinks are recorded. Ten to 20 uniform blinks are selected from all the recorded blinks for the blepharogram. If the subject looks away from the target, the lids move up and down with the eyes. The resulting irregular tracing is not included in the blepharogram. Also excluded from the blepharogram are eyelid saccades (slow lid closure and opening). Baseline simultaneous blepharograms on both eyelids were done in ten experimental and ten control subjects. Phenylephrine then was instilled three times in one eye of each of ten experimental subjects. Each subject was asked to keep the eyes closed for 1 minute. Instillation was repeated at 5-minute intervals until three drops were instilled. The phenylephrine effect was established by noting pupil dilation and 2- to 3-mm increase in height of the vertical lid fissure in each subject. After 30 minutes, the search coils were reglued to the lid, and simultaneous blepharograms were repeated. In ten control subjects, simultaneous blepharograms on both lids were done before and after instillation of artificial tears in the left eye. From the values for lid position and time, the following parameters were calculated and stored by the computer
Small et al · Effect of Phenylephrine on Muller Muscle
Figure 3. Original blepharogram device. The tracing is obtained from one lid only. Inset, detail of the search coil. (Courtesy Trans Am
Ophthalmol Soc 1992;90:34760.)
for every blink: amplitude down (degrees; I o = 0.24 mm), amplitude up (degrees), average velocity down (degrees/ second), average velocity up (degrees/second), duration of down phase of blink (milliseconds), duration of up phase of blink (milliseconds), ratio of time down to time up, maximum velocity down (degrees/second), maximum velocity up (degrees/second), and blink duration (milliseconds). The blepharograms and numeric values for all blink parameters were studied. Special attention was directed to the maximum upward velocity. This is the maximum speed in degrees per second the lid achieves in the up
phase of a blink. The computer calculates the derivative of the blink amplitude each millisecond to obtain the velocity. It then selects the five fastest blinks out of all the recorded blinks. Maximum upward blink velocity characteriL.es the maximum upward speed the lid can achieve and is defined as the mean of the five greatest individual maximum upward blink velocities. The maximum upward blink velocity was recorded in 52 normal eyelids. Simultaneous right and left maximum upward blink velocity values were obtained in 21 healthy subjects. Regression analyses were done to show the relation of maximum upward blink velocity to blink amplitude.
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601
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Volume 102, Number 4, April1995
The blepharograms of20 healthy subjects were studied for the presence or absence of N and M patterns before and the increase or appearance of patterns after phenylephrine instillation. In ten control subjects, blepharograms were studied for N and M patterns before and after artificial tear instillation.
Results In 52 normal eyelids, the average maximum upward blink velocity was 658 ± 172 degrees/second (mean± standard deviation). Simultaneous maximum upward blink velocity values of the right and left lids in 21 healthy subjects were within 10% in 13 subjects and 20% in 19 subjects. In all ten experimental subjects, the maximum upward blink velocity of the lid on the phenylephrine-stimulated side increased significantly (P < 0.02) in relation to the opposite lid in blinks recorded simultaneously. The mean relative percentage increase was 20.2% (Table 1). Artificial tear instillation in ten control subjects produced no consistent change in maximum upward blink velocity on the side of instillation in relation to the opposite lid (Table 2). Figure 5 is the simultaneous blepharogram of the phenylephrine-treated lid superimposed on the opposite lid of subject 8, showing increased amplitude and increased upward velocity in the treated lid. Analysis of maximum upward blink velocity measured sequentially in the same lid before and after phenylephrine instillation showed an average increase of 4.6% (Table 3). Analysis of maximum upward blink velocity in control lids before and after instillation of artificial tears recorded an average decrease of 8.6% (Table 4) (P = 0.19). The scattergram of all blinks of subjects 5, 6, 8, and 10, who have consistent blinking parameters, shows increased upward blink velocity in sequential studies after
phenylephrine instillation (R = 98; P < 0.01) (Fig 6). The average blink amplitude of the untreated lids is 43.3 c (standard deviation, 11.4 c). The average maximum upward blink velocity is 535.9 degrees/second (standard deviation, 170.5 degrees/second). In the treated lids, these values increased to 46.6c (standard deviation, 13.1 c) and 630.7 degrees/second (standard deviation, 214.7 degrees/ second). Figure 7 shows a scattergram of all blinks of all subjects before and after phenylephrine. Attention is directed to blinks with an amplitude of soc or more. Linear regression techniques are applied to each group. In the untreated group, the regression fit is significant (P = 0.0001) with a slope of 12.16 (r 2 = 0.985). The fit in the phenylephrinetreated group is significant (P = 0.0001; r 2 = 0.980). In this group, the slope of the regression line is 13.51. The test for equality of regression indicates that the slopes are significantly different (P ~ 0.01 ). This demonstrates that blinks of amplitude soc or more in the phenylephrinetreated group have a higher maximum upward blink velocity than blinks of the same amplitude in untreated eyes. There are 34 blinks with amplitudes of soc or more in the untreated group and 49 higher amplitude blinks in the treated group; this represents a statistically significant increase of 36% (P = 0.004). The average maximum upward blink velocity decreased 17.7% in sequential measurements in the lids that did not receive phenylephrine. The average maximum upward blink velocity decreased 6.2% in sequential measurements in the control lids that did not receive artificial tears (P = 0.11). In 12 (60%) of the 20 subjects used for studying N and M patterns, no N or M pattern was present before phenylephrine instillation. In five of these, an N or M pattern appeared after phenylephrine instillation. In eight (40%) subjects, an N or M pattern was present before phenylephrine instillation. In all eight subjects, one or both pat-
Table 1. Percent Increase of Maximum Upward Blink Velocity on Side of Phenylephrine Instillation Before Phenylephrine Subject No.
Age (yrs)/ Sex
Side of Instillation
2 3 4 5 6 7 8 9 10
33/F 28/F 31/M 31/M 24/F 27/F 28/M 27/F 25/F 30/F
L L L L L L R L R L
% Difference Right and Left
MUBV
Side of Greater MUBV
% Difference Right and Left
16.7 5.0 14.6 41.6 0.2 1.0 4.1 7.5 18.4 4.5
R L L R L L R L L L
11.6 33.2 22.4 12.6 35.8 8.2 15.6 47.4 13.2 12.1
• Mean, +20.2 MUBV = maximum upward blink velocity; R = right; L = left.
602
After Phenylephrine
MUBV
Side of Greater MUBV
R L L L L L R L L L
% Relative Increase MUBV on Side of Phenylephrine Instillation•
+5.1 +28.2 +7.8 +54.2 +35.6 +7.2 +11.5 +39.9 +5.2 +7.6
Small et al · Effect of Phenylephrine on Miiller Muscle terns increased in amplitude in the lid on the side of phenylephrine instillation. The presence of patterns before and after phenylephrine was divided equally between male and female subjects. Figure 8 shows an M-pattern increase after phenylephrine (same subject as in Fig 2). In ten control subjects, no pattern effect was demonstrable after artificial tear instillation.
10 0 ·10
The blepharogram is a computerized composite of selected blinks that represents a "typical" blink for a given subject. The down phase of the blink is always faster than the slower tapering up phase (Figs 1, 2, 4, 5, and 8). Figure 5 shows the simultaneous blepharogram of the phenylephrine-treated lid superimposed on the opposite untreated lid of subject 8. Increased blink amplitude and increased slope (velocity) of the up phase of the blink in the treated lid are evident. However, since the phenylephrine effect is more obvious in some subjects than others, the possibility of observer bias is introduced. To avoid this, we selected the experimental and control subjects at random and recorded every blink from each subject, not just the blinks selected for the blepharogram. Because simultaneously recorded right and left blinks are the most consistent and comparable, we compared the maximum upward blink velocity of all recorded blinks of all subjects in the phenylephrine-treated lids and the opposite untreated lids. The maximum upward blink velocity increased significantly (P < 0.02) in the phenylephrinetreated lids in all subjects. This change was not noted in the control group (Tables 1 and 2). We conclude that the phenylephrine-stimulated Miiller muscle increases the velocity of the up phase of the blink. This result is consistent with evidence from our earlier
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study of Horner syndrome which showed that the absence ofMiiller muscle activity slows the up phase of the blink. Miillerectomy also appears to decrease upward velocity in blinking; however, more patients who underwent this procedure must be studied to confirm this decrease. 6 The increase in the average maximum upward blink velocity after phenylephrine in sequential studies in the ten subjects is suggestive, but the effect was not significant at the 0.05 level (Tables 3 and 4) (P = 0.19). There is considerable normal variation in blink amplitude and velocity in some subjects studied at different times. However, in subjects with consistent blinking parameters, the phenylephrine effect can be demonstrated in sequential studies. The scattergram and straight-line regression equations of subjects 5, 6, 8, and 10 with consistent blinking parameters
Table 2. Percent Increase of Maximum Upward Blink Velocity on Side of Artificial Tear Instillation Before Artificial Tears Subject No.
Age (yrs)/ Sex
Side of Instillation
1 2 3 4 5 6 7 8 9 10
30/F 24/F 27/F 23/F 23/F 30/M 28/M 51/M 41/F 29/M
L L L L L L L L L L
After Artificial Tears
% Difference Right and Left
Side of Greater
% Difference Right and Left
Side of Greater
4.5 11.2 0.9 5.7 7.7 36.7 14.3 3.4 6.2 16.5
L L L L L R R R R L
14.5 16.3 6.1 7.1 3.5 30.3 35.2 24.9 16.6 8.8
L R R R R R R L L L
MUBV
MUBV
MUBV
MUBV
% Change of MUBV on Side of Artificial Tear Instillation•
+10.0 -27.5 -7.0 -12.8 -11.2 +6.4 -20.9 +28.3 +22.8 -7.8
*Mean, -2.0. MUBV = maximum upward blink velocity; L = left; R = right.
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Volume 102, Number 4, April1995
Table 3. Maximum Upward Blink Velocity Before and After Phenylephrine Instillation Subject No.
Side of Instillation
Before Phenylephrine (degrees/second)*
After Phenylephrine (degrees/second)t
1 2 3 4 5 6 7 8 9 10
L L L L L L R L R L
620.1 513.7 455.5 468.9 646.04 821.5 826.9 401.5 714.1 768.1
535.7 449.6 480.7 792.7 889.5 1048.5 712.6 420.1 572.9 718.3
%Change (degrees/ second)t -14.6
-13.3 +5.5 +51 +31.8 +24.3 -14.8 +4.5 -21.9 -6.7
L = left; R = right. *Mean, 628.6 degrees/second. t Mean, 662.1 degrees/second. Mean, +4.6 degrees/second.
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studied sequentially show an increased slope, representing increased upward velocity in the treated lids (R = 0.98; P < 0.01) (Fig 6). In addition, the average amplitude and average maximum upward velocity increased in the treated lids. It is not surprising that in sequential studies the phenylephrine effect is not evident in the straight line regression equation of all blinks of all ten subjects because of the variability of blinking parameters recorded at different times noted above. However, the straight line regression
equations of all blinks in all subjects with a blink amplitude over 50° shows that the blinks in phenylephrinetreated lids have greater amplitudes, are significantly more numerous, and have higher maximum upward velocities (R = 0.99; P = 0.01) (Fig 7). This demonstrates that in any series of blinks, more blinks with greater amplitudes and higher maximum upward velocities will be in phenylephrine-treated lids. Because Muller muscle is stretched more in large amplitude blinks, one would expect these blinks to have a
Table 4. Maximum Upward Blink Velocity Before and After Artificial Tear Instillation Subject No.
Side of Instillation
Before Tears (degrees/ second)*
After Tears (degrees/ second)t
%Change (degrees/ second)t
1 2 3 4 5 6 7 8 9 10
L L L L L L L L L L
897.9 772.6 465.7 938.1 989.8 427.0 892.4 717.1 515.6 745.6
779.1 558.2 492.9 828.2 783.6 428.5 790.9 925.8 567.1 535.5
-14.2 -32.2 +5.7 -12.4 -23.2 +0.3 -12.1 +25.4 +9.5 -32.8
L = left. *Mean, 736.2 degrees/second. t Mean, 669.0 degrees/second. Mean, -8.6 degrees/second.
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faster up phase. Increased maximum upward blink velocity also may be related to increased blink amplitude per se. In either case, increased upward blink velocity is a result of phenylephrine instillation. We find voluntary blinks more consistent than spontaneous blinks. Spontaneous blinks are slower and more variable than voluntary blinks. Voluntary blinks are easier to elicit and more comfortable for the subject than reflex blinks. Although all subjects had widening of the vertical lid fissure after phenylephrine, resting lid position varies, and many subjects do not close their eyes completely each time they blink. The resulting variation in blink amplitude makes it impossible to use blink amplitude as an index of resting lid position. Variation in blink amplitude is shown in Figures 6 and 7. Nine often subjects showed decreased maximum upward blink velocity in the untreated lid in the less-consistent sequential measurements. The control subjects showed less slowing on the side that did not receive artificial tears but this difference did not reach statistical significance (P = O.ll). We currently are unsure of the relevance of this tendency. before phenylephrine
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Because phenylephrine stimulates the lid, could Hering law apply? Hering law originally applied to equal (motor) innervation of the extraocular yoke muscles and was later applied to the levator muscles. Hering law does not apply here because phenylephrine stimulates the (sympathetic) Muller muscle, not the levator muscle. Also, no ptosis occurred in the unstimulated lids. Muller muscle receives constant (tonic) sympathetic innervation and is responsible for the height of the vertical eyelid fissure. Phenylephrine increases the tonic contraction of Muller muscle. Muller muscle can be compared with a spring that maintains the vertical height of the lid fissure between blinks. We believe an increased springlike force adds to the action of the levator muscle and increases upward eyelid velocity after phenylephrine stimulation. Other authors state that simultaneous right and left blinks are identical. 3•7 We find simultaneous blinks to be similar but not identical in most subjects. The simultaneous maximum upward blink velocity of the right and left lids is within 10% in 70% of healthy subjects and within 20% in 90% of healthy subjects. However, the maximum upward blink velocity in 2 of 21 individuals without any
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Ophthalmology
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Volume 102, Number 4, April1995
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apparent lid abnormality varied up to 45%. Some subjects have unequal lid function not obvious on clinical examination. Subject 4 (Table 1) is an example of a marked difference in maximum upward blink velocity between the two eyelids (41.6% ). Even so, the subject demonstrated a dramatic increase in maximum upward blink velocity ofthe phenylephrine-stimulated lid. Phenylephrine stings and increases the pupil size and lid aperture, whereas artificial tears have no effect. This makes it difficult to mask drop instillation. Although this introduces the possibility of observer bias, we believe awareness of the drop instilled by ourselves and some subjects did not affect the results. Phenylephrine increased the N and M patterns in the blepharograms of all eight subjects who had these patterns before instillation. Figure 8 shows an increased M pattern after phenylephrine (same subject as Fig 2). Phenylephrine also produced new patterns in five other subjects. Thus, some phenylephrine pattern effect occurred in 13 (65%) of 20 subjects. There was no pattern effect after artificial tear instillation in the control subjects. Muller muscle must be responsible for the N and M patterns. These observations add to the evidence of this relation presented in the Horner syndrome study in which Nand M patterns were absent in blepharograms of the affected lid. 6 The patterns may be due to tonic action of Muller muscle if the orbicularis muscle relaxes momentarily just before the down phase of the blink (N pattern) and at the end of the blink (M pattern). The occurrence of N and M patterns in some subjects and not others suggests that
606
minute variations in the timing of nerve stimuli to the orbicularis and levator muscles may be responsible. Continuing experience with the blepharogram should provide additional insight into these interesting patterns. Electromyography shows that the levator muscle receives a nerve impulse only during upward eyelid motion. 8 Muller muscle has constant tonus. Powerful orbicularis muscle contraction easily overcomes the resistance of Muller muscle in moving the lid down, but when the lid moves upward the tonic action of Muller muscle adds to the action of the levator. The current study demonstrates this action and adds to evidence from the Horner syndrome study to show that Muller muscle contributes to upward eyelid motion. Phenylephrine also produces or increases the newly described N or M patterns in more than half of healthy subjects. We believe these velocity and pattern effects are produced by phenylephrine stimulation of Muller muscle in the upper eyelid. The blepharogram and blink analysis provide the first instrumental method of studying subtle changes in eyelid motion brought about by a pharmacologic agent. The blepharogram technique provides exciting insights into eyelid physiology and will be valuable for the investigation of any neuromuscular condition affecting the eyelid.
References I. Evinger C, Shaw MD, Peck CK, et a!. Blinking and associated eye movements in humans, guinea pigs, and rabbits. J Neurophysiol 1984;2:323-39. 2. Karson CN. Physiology of normal and abnormal blinking. Adv Neurol 1988;49:25-37. 3. Becker W, Fuchs AF. Lid-eye coordination during vertical gaze changes in man and monkey. J Neurophysiol 1988;60: 122'k5.2. 4. Sibony PA, Evinger C, Manning KA. Eyelid movements in facial paralysis. Arch Ophthalmol 1991;109:1555-61. 5. Manning KA, Evinger C, Sibony PA. Eyelid movements before and after botulinum therapy in patients with lid spasm. Ann Neurol 1990;28:653-60. 6. Small RG, Fransen SR, Adams R. The blepharogram in Homer's syndrome. Trans Am Ophthalmol Soc 1992;90: 347-60. 7. Evinger C, Manning KA, Sibony PA. Eyelid movements. Mechanisms and normal data. Invest Ophthalmol Vis Sci 1991;32:387-400. 8. Fuchs AF, Becker W, Ling, L, et a!. Discharge pattern of levator palpebrae superioris motomeurons during vertical lid and eye movements in the monkey. J Neurophysiol 1992;68:223-43.