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Effects of edrophonium on saccadic velocity in normal subjects and myasthenic and nonmyasthenic ocular palsies.

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Effects of Edrophonium on Saccadic
Velocity in Normal Subjects and Myasthenic
&d Nomyasthenic Ocular Palsies
Jason J. S. Barton, MD, FRCPC, Ana G. Huaman, MD, and James A. Sharpe, MD, FRCPC
We measured saccadic peak velocities in 8 patients with myasthenia gravis, 9 patients with proven nonmyasthenic
ocular palsies, and 3 controls. Patients followed a target moving to and from primary position at 1-second intervals
for 8 minutes. We measured the amplitudes and velocities of centrifugal saccades at the start of the task, after 3
minutes of the task (fatigue) and 1 minute after receiving IV edrophonium. The effects of fatigue, though prominent
in some myasthenic patients, did not distinguish between the groups. However, edrophonium increased saccadic peak
velocities in myasthenic patients but decreased them in both controls and nonmyasthenic patients. Analysis of saccades
by amplitude bins showed that these changes in peak velocity reflected shifts in the velocity-amplitude relationship.
Barton JJS, Huaman AG, Sharpe JA. Effects of edrophonium on saccadic velocity in normal subjects and
myasthenic and nonmyasthenic ocular palsies. Ann Neurol 1994;36:585-594
Along with electrophysiologic studies and assays for
antibodies to the acetylcholine receptor, a positive response to edrophonium has been used to diagnose myasthenia gravis {l}. The sensitivity of these tests is
much lower in ocular forms of the disease [2,31. Evaluation of edrophonium’s effect on ocular weakness can
be hampered by fluctuating strength and the subtlety
of change. To overcome these problems investigators
have used eye-movement recordings to quantify the
effects of fatigue and edrophonium on optokinetic nystagmus [4-81 and voluntary saccades {9-141. However, some studies had no controls Ell-131 or stated
only that controls were “non-myasthenic” [9}, while
others had controls with conditions that did not exclude myasthenia (i.e., phoria) [14} or that often coexist with myasthenia (i.e., thyroid ophthalmopathy)
[lo}. The criteria used to diagnose myasthenia gravis
were sometimes not stated [G, 9, 10, 131. Because
edrophonium can improve ocular motility in nonmyasthenic palsies [15-171, it is critical that the edrophonium response in patients known to have myasthenia
by other criteria be compared with that in patients
proved to have other causes of ocular weakness. Only
if these two groups respond differently can we be confident that a test result provides diagnostic information.
The relation between saccadic peak velocity and amplitude can be described by an exponential function
[lS}. It is not clear how edrophonium would affect this
relationship in myasthenia gravis. First, an increase in
contractile force might cause an increased peak velocity
for a saccade of a given amplitude. Second, saccadic
amplitudes and peak velocities might increase together,
without a change in the peak velocity-amplitude relationship. Last, intrasaccadic fatigue in myasthenia can
reduce amplitude despite high peak velocity early in
the saccade [l 1, 19,201, resulting in an inappropriately
high peak velocity for a given saccadic amplitude {13,
191; edrophonium might reduce intrasaccadic fatigue
and increase amplitude, leading to a redaction in peak
velocity for the measured amplitude 1131.
Most previous studies did not examine changes in
peak velocity-amplitude relationships {9, 11, 141, or
quantified data in terms of average amplitudes and
velocities [lo}, making it difficult to determine if a
change in the relationship had occurred. Also, there
are no data on the effects of edrophonium on the peak
velocity-amplitude relationship in nonmyasthenic palsies and normal subjects. We studied the effects of
edrophonium and fatigue on the peak-velocity amplitude relationship in 3 normal subjects, 8 myasthenic
patients with ocular involvement, and 9 patients with
proven nonmyasthenic palsies.
From the Neuro-ophthalmology Unit, Division of Neurology, The
Toronto Hospital Neurological Center, and the Playfair Neuroscience Unit, University of Toronto, Toronto, Ontario, Canada.
Address correspondence to Dr Barton, Division of Neurology, The
Toronto Hospital, 399 Bathurst Street, Toronto, Ontario, Canada
Subjects and Methods
Patients with ocular or generalized myasthenia were studied
only if they had both (1) a compatible clinical syndrome and
(2) electrophysiologic evidence for a disorder of the neuro-
MST 2%.
Received Dec 16, 1993, and in revised form Feb 23, 1994.Accepted
for publication Mar 9, 1994.
Copyright 0 1994 by the American Neurological Association
muscular junction. The latter was defined as mean jitter
greater than 50 ksec in 20 fibers or more than 20 fibers
having jitter greater than 45 Fsec, with single-fiber electromyography [2 11. Patients either were not taking acetylcholinesterase inhibitors or had a brief washout period. For patients
with ocular myasthenia only, medication was withheld for
at least 24 hours prior to testing; patients with generalized
myasthenia were tested in the morning before their first daily
dose. Patients with a prior history of respiratory compromise
were excluded for safety.
Patients with ocular motor palsies of known etiology were
included only if they had either (1) imaging evidence of their
lesion or (2) a syndrome incompatible with myasthenia (i.e.,
third nerve with pupillary involvement, idiopathic polyneuritis), and also (3) if their disease was not known to be associated with myasthenia gravis (i.e., Graves’ disease). All but
one had neuropathic lesions (Table 1). Two of the authors
served as normal controls and 1 volunteer was recruited from
the community; their examination showed no signs of ocular
motor disturbance. The aims and methods of this study were
approved by the medical ethics committee of The Toronto
We recorded eye movements with magnetic search coil oculography (CNC Engineering, Seattle, WA), using 6-ft diameter field coils and search coils embedded in a silicone annulus
placed on the eye. Recordings were made on a rectilinear
ink-jet polygraph and digitized on-line at 200 Hz for analysis
by interactive programs using a PDP 11/73 computer. The
majority of subjects had binocular recordings. Subjects sat in
a stationary chair with their heads placed against a backrest.
An intravenous line was inserted in the antecubital vein prior
to recording and a slow infusion of normal saline started.
Subjects watched a 0.25-degree He-Ne laser spot backprojected onto a semitranslucent screen 1 m away. W e occluded the nonparetic eye in patients with strabismus; patients without tropia viewed the target binocularly. The target
stepped predictably at 1-second intervals between 20 degrees
left, primary, and 20 degrees right over 8.5 minutes (Fig 1A).
With patients in whom vertical limitations of movement were
the most prominent, 20 degrees up and 20 degrees down
were used instead of left or right. At 4 minutes 0.2 mg of
edrophonium was injected, followed 30 seconds later by 0.8
mg when the initial dose was tolerated (Fig 1B).
Saccades were identified by the computer as eye movements
with velocities greater than a threshold value of 46.9 degrees1
sec. The beginning of each saccade was defined as the time
when eye velocity first exceeded 3 1.3 degreesisec; similarly,
the end was defined as the time when velocity fell below this
value. W e analyzed saccades from the following three periods
of 1-minute duration: (1) at the onset of recording (initial
period), (2) after 3 minutes (fatigue period), and (3) 1 minute
after the final injection of edrophonium (edrophonium period) (see Fig 1B). If saccadic amplitude or velocity decreased
after edrophonium we also analyzed the final minute of recording to document recovery. Only saccades from primary
position to peripheral targets were used (i.e., centrifugal saccades, see Fig 1A). These were chosen to maximize observations of weakness of agonist muscles, because the passive
elastic restoring forces of orbital muscles and ligaments may
contribute to centripetal saccades.
Amplitudes were plotted against peak velocities in both
directions for all saccades from a given period. A curve was
Table 1 . Characteristics of Patients and Normal Subjects
Age (yr)
Myasthenia gravis patients
Nonmyasthenic patients
Normal subjects
right eye; os
Duration (mo)
Clinical Motility Defect
Adduction od
Abduction od
Abduction od
All extraocular muscles
All extraocular muscles
Elevation od, depression 0s
Abduction od, adduction ou
VI palsy 0s
I11 palsy 0s
All movements
VI palsy od
All movements
111 Palsy od
111, VI palsy 0 s
VI palsy 0s
I11 palsy od
left eye; ou
both eyes.
586 Annals of Neurology Vol 36 No 4 October 1994
Carcinomatous meningitis
Diabetes, pupil involving
Miller Fisher syndrome
Multiple sclerosis
Mitochondria1 myopathy
Intracavernous aneurysm
Cavernous sinus fistula
Progressive multifocal leukoencephalopathy
Intracavernous aneurysm
R (or U)
L (or D)
1 second
minutes 0
4 4.5
7 5 8.5
., .... ...
.... ..
F i g 1 . Experimental design. (A) Path of target during saccadic
taJ k. Arrows indicate centrifugal target movements. (B) Time of experiment. Boxes indicate time periods during which
sur-r-adrJusere analyzed. Shaded box represents the time of
edrophuiiiimi injection.
fitted to the data by the computer, using the formula, PV =
( 1 - e - N C ) , where PV = peak velocity, V,,
= asyrnptotic velocity, A = amplitude, and C = constant [18]. The
value derived from the curve, which as an asymptotic
peak velocity denotes a theoretical maximum velocity for
that time period, was used to compare performance across
the different periods. We calculated a fatigue index F using
I, and similarly an edrophonium
the formula, F - I / F
F , where I, F, and E are the V,
index E with E - F / E
values from the initial, fatigue, and edrophonium periods,
In patients undergoing binocular recordings, four V,, values were obtained from each period, for example, right eye
abducting, right eye adducting, left eye abducting, left eye
adducting. Because not all directions would necessarily be
affected by a lesion, we further separated the saccades into
the following three groups: (1) affected motion, (2) yoke of
affected motion, and (3) uninvolved motions. For a left sixth
nerve palsy, then, these three groups would be (1) left eye
abduction, affected; (2) right eye adduction, yoke; and (3)
rightward motions of both eyes, uninvolved.
To evaluate the ability of the fatigue index and the edrophonium index to distinguish between the three groups of
subjects, we used a nonparametric method, the KruskalWallis test, because inspection of our data indicated that distributions were not normal. If this was significant we used a
Dunn procedure to test for differences between one group
and another.
Changes in the V,, calculated by the computer-fitted
curve could result from one of two phenomena. First, a true
increase in the peak velocity-amplitude relationship would
increase V-. However, a change in the range of amplitudes
analyzed can also alter V,, artifactually. Inclusion of high
amplitude saccades in an analysis can result in a higher calculated V,.
To determine whether a true shift of the peak
velocity-amplitude relationship occurred after edrophonium
we divided a subject’s saccades into amplitude bins of 5 degrees’ width (except for the first bin, which contained saccades of 0 to 2.5 degrees amplitude). W e calculated the mean
peak velocity for saccades falling in each bin for the fatigue
and edrophonium periods. W e then measured the difference
in mean bin peak velocities from these two periods. The
average and standard error of this difference was plotted for
each group and a linear-regression line drawn by the method
of least squares. A two-way student’s t test determined
whether the slopes of the lines were different from zero.
Because it is not known whether myasthenic saccades conform to the exponential function relating peak velocity to
amplitude for normal saccades, we also used these amplitude
bin data to validate our use of this exponential function to
describe saccades in myasthenic and nonmyasthenic patients.
The “goodness of fit” of any line can be measured by caiculating the root mean square error (RMSE) of the data to the
fitted line. Unstable transmission at the neuromuscular junction in myasthenia might cause increased variability of saccadic peak velocities, which would be reflected in an increase
in the RMSE. However, fitting an exponential function to
the average peak velocities of amplitude bins, rather than
to the peak Velocities of individual saccades, should reveal
whether the underlying peak-velocity amplitude relationship
still follows an exponential function in myasthenia, despite
the increased variability of individual saccades. Therefore,
we fitted the same exponential function to the average peak
velocities of amplitude bins from the initial and fatigue periods for all eye movements of patients and normal subjects
(with three or more bins in a given direction). We calculated
RMSE and used the Kruskal-Wallis test to determine
whether it differed between the three groups.
Examples of eye movement tracings from Patient 1
with recent onset of myasthenia and Patient 15 with
I11 and VI nerve palsies due to an intracavernous aneurysm are shown in Figure 2. After edrophonium, the
saccades of the myasthenic patient were larger in amplitude and faster; target overshoot is demonstrated by
the smaller centripetal saccades occurring shortly after
large centrifugal saccades. In contrast, the saccades of
the nonmyasthenic patient were noticeably slower after
edrophonium; this slowing disappeared by the recovery period, however.
Peak velocity-amplitude curves derived from these
same patients are shown in Figure 3. The effects of
fatigue on the curves of either patient were not distinct.
However, edrophonium caused a marked increase in
amplitude range and higher velocities in the myasthenic patient, whereas the nonmyasthenic patient had
decreased saccadic velocities, visible as a downward
shift in the curve. This downward shift occurred not
only in the affected left eye but also in the unaffected
yoke movements of the clinically unaffected right eye
of this subject with neuropathy.
The validity of using the exponential function displayed as curves in Figure 3 was examined with the
bin data from the initial and fatigue periods (see Subjects and Methods). The average RMSEs for the myasthenic, nonmyasthenic, and normal subjects are given
in Table 2. The mean value of RMSE for myasthenic
patients was not significantly different from that of either nonmyasthenic patients or normal subjects. We
Barton et al: Effects of Edrophonium on Saccadic Velocity
Patient 1 - Myasthenia
Patient 1 - Myasthenia
Right eye
Left eye
1868 msec
conclude that even if individual saccades have a more
variable relation between amplitude and peak velocity,
the overall behavior of the system can still be described
by an exponential function, as in normals.
Asymptotic peak velocities (V,,)
obtained from
peak velocity-amplitude curves like those of Figure 3
were plotted for all subjects. In Figure 4A the V,,
value of the initial period is plotted against the V,
value of the fatigue period for each subject. Most
points fell near the diagonal line of identity, regardless
of the group the subject belongs to. In contrast, Figure
4B plots the V,, of the fatigue period versus the V,
of the edrophonium period for each subject. The myasthenic group’s response differed from that of the normal and nonmyasthenic groups. V,
in most myasthenic patients increased after edrophonium, causing
the points to fall above the line of identity, whereas it
decreased in normal subjects and nonmyasthenic patients.
Annals of Neurology Vol 36 No 4 October 1994
Fig 2. Examples of saccades made by Patient 1 with myasthenia
(A) and Patient 15 with IeJt 111 and VI newe palsies due to
an intracaz~ernousaneurysm ( B ) .following targets stepped 20
degrees right and left.
The fatigue index ( F - Z/F + I ) and the edrophonium index ( E - F / E
F ) were derived from the
values plotted in Figure 4. These indices are replotted
in Figure 5 for the three groups according to clinically
affected motions, yoke motions, and unaffected motions. In addition, box plot diagrams are provided for
the data of each group as a whole (Fig 5). The data
did not show a difference in the behavior of muscles
distinguished on the basis of their clinical involvement,
for either myasthenic or nonmyasthenic palsies. However, these indices confirm the observations made in
Figure 4, i.e., the fatigue index did not differ significantly between the three groups (Fig 5A; F[2,71) =
3.88; 0.05 < p < 0.10), although in four instances eye
movements of 2 myasthenic patients (Patients 7 and
Patient 15 - Non-myasthenia
Patient 15 - Non-myasthenia
8) did show a large decline. On the other hand, the
edrophonium index did differ significantly (Fig 5B;
F[2,71) = 37.65; p < 0.001). The myasthenic group
differed from both nonmyasthenic and normal groups,
but the nonmyasthenic and normal groups did not differ from each other. Two myasthenic patients with recent onset of symptoms (Patients 1 and 7) had large
improvements after edrophonium that lay beyond the
results of the rest of the group.
The differences of the mean peak velocities in amplitude bins before and after edrophonium were averaged
within each group. The mean differences are plotted
in Figure 6 against the center amplitude of each bin.
For all three groups the relation is linear. In myasthenic
patients there was an increase in bin peak velocities
after edrophonium. In nonmyasthenic patients there
was, instead, a decrease. The decrease in normal sub-
jects was similar but not as great as that in the nonmyasthenic patients. This analysis by amplitude bins
showed that the changes in asymptotic peak velocity
with edrophonium in both groups resulted not only
from changes in amplitude but also from true shifts of
the peak velocity-amplitude curve.
We found that in myasthenia gravis, edrophonium
causes an increase in the saccadic asymptotic peak velocity (V,,) derived from plots of the peak velocityamplitude curve. This increase resulted in part from an
increased amplitude range but also reflected an upward
shift in the peak velocity-amplitude curve, as demonstrated by analysis of saccadic amplitude bins. Unlike
Schmidt and colleagues [13], we did not find any myasthenic patient with a decrease in the peak velocity-
Barton et al: Effects of Edrophonium on Saccadic Velocity
Patient 1 - left eye
Patient 1- right eye
I .
saccadic amplitude (deg)
saccadic amplitude (deg)
amplitude relationship. We also found that nonmyasthenic patients exhibited an edrophonium response
opposite to that of myasthenic patients; their V, decreased and the peak velocity-amplitude curve shifted
downwards. A decrease was also seen in normal subjects. Our method did not elicit a significant fatigue
effect in normal subjects or either patient group C22).
Some investigators advocate the use of Lancaster
red-green 1231 and Hess screen tests [ 2 4 ) to estimate
changes in diplopia with edrophonium. However, reductions in the separation of diplopic images can result
from either strengthening or weakening of one muscle
relative to its yoke muscle [25}. Thus, the specificity
of diplopia tests can be affected by the paradoxical
weakening observed in both myasthenic 126, 277 and
nonmyasthenic conditions 1261. The complexity of interpreting diplopia tests is illustrated by the finding of
decreased, increased, or reversed separation of dipio-
590 Annals of Neurology Vol 36 No 4 October 1994
Fig 3. Peak velocity-amplitude plots and curves for the same
2 patients in Figure 2. (A)Patient 1 with myasthenia. (B)
Patient 15 with ldt intracavemous aneurysm. Dots are data
points of indioidual saccades. Circles are average peak velocities
for amplitude bins, plotted against the center amplitude of
the bin.
pic images after edrophonium in myasthenia C23). Although Retzlaff and co-workers C231 did not find any
changes in nonmyasthenics, our finding of saccadic
slowing after edrophonium in normal subjects and
nonmyasthenic patients suggests that such changes
might confound diplopia tests. In contrast, eye movement recordings allow direct analysis of the movements of each eye separately, with true measures of
improvement or worsening after edrophonium.
Studies of the effect of edrophonium on the optokinetic response documented increased frequency and
amplitude of quick phases of nystagmus in myasthenic
Patient 15 - left eye
b:, .;k .
' ,
Root Mean Square Error
(Bin-Averaged Data)
Mean (SD)
Mean (SD)
Initial Period
Fatigue Period
16.31 (7.17)
14.94 (7.59)
14.55 (7.50)
14.53 (8.61)
17.46 (10.40)
15.71 (8.83)
The mean and one standard deviation are shown, with the number
of observations below. There is no significant difference berween
the groups in either the initial or fatigue period.
e -
Table 2. Root Mean Square Errors of the Fitted Exponential
Function t o Average Peak Velocitiesfor Amplitude Bins
Mean (SD)
patients [4, 51. Spector and collaborators C7, 81 found
increased amplitude and velocity but a variable effect
on frequency. However, the interdependence of frequency, amplitude, and velocity and the variability of
the optokinetic response even within individuals makes
quantification of the result difficult [b}.
Visually guided saccades are a better controlled measure of ocular motility because the examiner can set
target frequency and amplitude. Metz and associates
[9] found increased saccadic peak velocities in 6 myasthenic patients but did not examine amplitude to determine whether increased velocity was due simply to
increased amplitude. Baloh and Keesey [lo] noted increases in both average amplitude and average peak
velocity and plotted peak velocity-amplitude curves,
but did not comment on changes in this relationship.
Yee and colleagues [ 111 mentioned increases in amplitude and overshoots in 2 patients but had no controls.
Spooner and Baloh El21 described a patient in whom
edrophonium caused overshooting saccades, but the
Barton et al: Effects of Edrophonium on Saccadic Velocity 591
+ myasthenia
o non-myasthenia
Vmax of
500 -
0.2 -
250 -
(F-I / F t I )
f 8 *
Vmax of initial period ("/set)
Vmax of
edrophonium 500
(" / sec)
* 7
Fig 4. (A) Vmxfrom initial period plotted against V, from
the fatigue period for each patient (see Fig IB). Points falling
on the diagonal line indicate no change. Solid diamonds are
data for myasthenicpatients, empty diamonds for nonmyasthenic patients, and asterisks for normal subjects. (B) V,
from the fatigue period plotted against V, from the edrophonium period, using the same conventions.
increased peak velocity was appropriate for the increased amplitude. In the study of Schmidt and coworkers { 131, edrophonium decreased the normalized
peak velocity-amplitude value in 2 myasthenic patients
who started with abnormally high peak velocities, but
it increased this normalized value in 2 other myasthenics with hypometric saccades.
These studies did not clarify how edrophonium affects peak velocity-amplitude curves in myasthenia.
While 1 patient had no change {121, 2 had increased
1133 and 2 had decreased 1131 normalized velocityamplitude values. Our study shows that the predominant effect of edrophonium in myasthenia is an increase in the peak velocity-amplitude relationship.
592 Annals of Neurology Vol 36 No 4 October 1994
Fig 5 . (A) Fatigue index (F - IIF + I) plottedfor all three
patient groups, with motions separated into the following three
classes of clinical involvement: aflected, yoked to affected, and unaffected and unyoked movements. Box plots of data are shown;
boxes indicate median and upper (UQ)
and lower quartiles
(LQ), while vertical lines extend to the furthest data points lying within the limits of UQ
1.5 x (UQ - L a , and LQ
- 1.5 x (UQ - LQ). Small circles represent data points lying beyond these limits. (B) Edrophonium index (E - FIE +
F) plotted in the same fashion. ( I = Vmxfrom initial period,
F = V, from fatigue period, E = Vmxfrom edrophonium
nium, resulting in a depolarizing blockade not unlike
that induced by succinylcholine during anaesthesia.
Unmasked conjugate central adaptation would also explain the occurrence of similarly dramatic weakness in
yoke muscles of the normal eye. The slowing of saccades in normal individuals and normal non-yoked
muscles of patients suggests that the usual 10-mg dose
of edrophonium is too high and tips normal muscle
function into subclinical cholinergic excess.
group mean of
individual peak
amplitude bin\
hetiire and after
(' w )
Supported by Medical Research Council of Canadagrants 9004FEN1222-21813 (J.B.) and MT 5404 and ME 5509 CJ.S.1, and Universicy
of Toronto Beattie and Elizabeth Barford Fellowships (A.G.H.)
center amplitude of bins (")
P. Nguyen provided technical assistance with the ocular recordings.
F i g 6. The difference in peak zielocities for amplitude bins before
and after edrophonium. plotted as a function of the center amplitude for each bin. Differences were calculated by subtracting the
ar'evage bin tielocity in the fatigue period from that in the edrophoniuni period for each indiiidual. Points represent the mean
of-the differeni-esfor each group, u i t h bars indicating one standard error. Linear-regressionlines are plotted according to leastquart method. Solid diamonds are from the myasthenic group,
empty diamonds the nonmyasthenic group, and the asterisks
wifh the dotted line are from normal subjects.
There are fewer data on the response in nonmyasthenic patients and normal subjects. Edrophonium decreased amplitude or peak velocity of quick phases of
optokinetic nystagmus in nonmyasthenic patients and
a few normal controls 17,81, but no change was noted
in other studies 14-61. Metz and colleagues {7] did
not find a significant change in saccadic velocity. There
are no previous reports on the edrophonium response
of the peak velocity-amplitude relationship. We found
that in both normal controls and nonmyasthenic palsies
there was a decrease in the peak velocity-amplitude
relationship after edrophonium, which was opposite to
the effect of myasthenia.
The mechanism of the reduction of saccadic velocities in nonmyasthenic ocular palsies after edrophonium
is unclear. In some patients the decrease was similar
to that of normal subjects, but in others it was more
profound. One explanation may be an unmasking of
central adaptive effects. Neuropathic weakness is often
accompanied by adaptation in the central nervous system, leading to a compensatory increase in the discharge of neurons during gaze in the paretic direction.
(This phenomenon may be responsible for the abducting nystagmus in internuclear ophthalmoplegia
1281.) The increased discharge at the remaining neuromuscular junctions may create a cholinergic excess
when acetylcholinesterase is inhibited by edropho-
Presented in part at the XV World Congress of Neurology, Vancouver, British Columbia, Canada, September 6, 1993, and published
in abstract form (Can J Neurol Sci 1993;2O[suppl 4]:S43).
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effect, velocity, palsies, myasthenia, nonmyasthenic, norman, ocular, edrophonium, subjects, saccadic
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