Journal of Neuro-Ophthalmology, March 1997, Volume 17, Issue 1

The Effect of Endrophonium Chloride on Muscle Balance in Normal Subjects and Those with Nonmyasthenic Strabismus

Because the Lancaster red-green test and the Hess screen are not widely used by most ophthalmologists, we used the alternate prism-cover test to study the effect of intravenous edrophonium chloride (Tensilon) on the ocular alignment of 30 normal subjects and 14 individuals with nonmyasthenic strabismus. After measurement of their baseline phorias and tropias, patients received an intravenous injection of Tensilon via the incremental dose technique until autonomic effects of the drug were noted or until 10 mg was administered. Another set of measurements of muscle balance was taken immediately postinjection and 2 and 5 min later. Apart from a small increase (mean, 2 prism dipoters; p = 0.004) in their exophoria at near, normal subjects exhibited no significant change in their phorias after Tensilon injection. One third to one half of the nonmyasthenic strabismics, however, showed a change in their vertical deviation after Tensilon (46% at distance and 38% at near), with the majority of them increasing their angle of squint. These changes were small (mean, 1.7 prism diopters; maximum, 5 prism diopters). In only one case did reversal of the direction of deviation occur. Tensilon produces a statistically significant increase in near exophorias of normal subjects and in vertical distance deviations of nonmyasthenic strabismics. These changes, however, are clinically insignificant and should not be considered to constitute a positive Tensilon test.

Journal of Neuro- Ophllmlmology 17( 1): 711, 1997. © 1997 Lippincoll- Raven Publishers, Philadelphia The Effect of Edrophonium Chloride on Muscle Balance in Normal Subjects and Those with Nonmyasthenic Strabismus R. Michael Siatkowski, M. D., Lavanya Shah, M. D., and William J. Feuer, M. S. Because the Lancaster red- green test and the Hess screen are not widely used by most ophthalmologists, we used the alter­nate prism- cover test to study the effect of intravenous edro­phonium chloride ( Tensilon) on the ocular alignment of 30 normal subjects and 14 individuals with nonmyasthenic strabismus. After measurement of their baseline phorias and tropins, patients received an intravenous injection of Tensi­lon via the incremental dose technique until autonomic effects of the drug were noted or until 10 mg was administered. An­other set of measurements of muscle balance was taken im­mediately postinfection and 2 and 5 min later. Apart from a small increase ( mean, 2 prism dipoters; /; = 0.004) in their exophoria at near, normal subjects exhibited no significant change in their phorias after Tensilon injection. One third to one half of the nonmyasthenic strabismics, however, showed a change in their vertical deviation after Tensilon ( 46% at dis­tance and 38% at near), with the majority of them increasing their angle of squint. These changes were small ( mean, 1.7 prism diopters; maximum, 5 prism diopters). In only one case did reversal of the direction of deviation occur. Tensilon pro­duces a statistically significant increase in near exophorias of normal subjects and in vertical distance deviations of nonmy­asthenic strabismics. These changes, however, are clinically insignificant and should not be considered to constitute a posi­tive Tensilon test. Key Words: Tensilon ( edrophonium)- Strabismus- Muscle balance. Myasthenia gravis ( MG) should be considered in the differential diagnosis of all patients with acquired ptosis and diplopia. Seventy- five percent of patients with MG have complaints related to extraocular muscle involve- Manuscript received May 29, 1996; accepted July 4, 1996. From the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida, U. S. A. Address correspondence and reprint requests to Dr. R. M. Siatkowski, 900 NW 17th Street, Miami, PL 33136, U. S. A. Presented in part as a poster at the annual meeting of the American Association of Pediatric Ophthalmology and Strabismus, Vancouver, BC, June 1994, and in part as a paper at the annual North American Neuro- Ophthalmology Society meeting, Tucson, AZ, February 1995. merit, and 90% eventually experience ocular symp­toms and signs ( 1,2). Although various studies arc available ( acetylcholine receptor antibodies, EMG, " sleep test," Tensilon tonography) ( 3- 6), the Tensi­lon test remains the diagnostic gold standard. An un­equivocally positive response to this test is one in which a weak muscle is directly observed to become stronger ( 7). However, interpretation of the Tensilon test may be difficult in the absence of a clearly defined end point, such as clinically obvious ptosis or ophthalmople­gia. Previous studies have examined the effect of Tensilon on ocular motility in both normal and strabismic subjects via the Hess screen and Lancaster red- green test ( 8- 10). There are a number of disadvantages to these techniques. Both tests are subjective and require additional equip­ment and/ or personnel. Moreover, these tests arc neither commonly available nor frequently used by most clini­cians. In contrast, all ophthalmologists and neuro-ophthalmologists, and many neurologists, have access to and experience with the simple equipment necessary for a prism- cover test. We evaluated the effect of Tensilon on the muscle balance of normal and nonmyasthenic strabismic subjects with use of the alternate prism- cover test ( APCT). MATERIALS AND METHODS After Institutional Review Board approval and written informed consent from each patient, 30 patients with normal ocular motility and 14 patients with nonmyas­thenic strabismus underwent pre- and post- Tensilon mo­tility evaluation. Normal ocular motility was defined as orthotropia at distance and near, although exophorias of = S8 prism diopters, esophorias of = S4 prism diop­ters, and hyperphorias of =£ 2 prism diopters were al­lowed for entrance into this group. Of the 30 patients in the normal group, 10 were orthophoric, six had an exo- 8 R. M. S1ATK0WSKI ET AL. TABLE 1. Etiologies of nonmyasthenic strabismus Infantile esotropia Superior oblique palsy Thyroid eye disease Posleataracl vertical rectus paresis Trauma Oculomotor palsy Basic exotropia minimize the " deviation building" effect of the test. For those patients with incomitant strabismus, care was taken to maintain their head in the same position for all measurements. Similar measurements were recorded at 2 and 5 min post- Tensilon. Additionally, lid position was evaluated in the same manner as described previ­ously. phoria at distance ( maximum 4 diopters), 11 had an exo-phoria at near ( maximum 8 prism diopters), three had an esophoria at near ( maximum 3 prism diopters); and two had a hyperphoria. The normal subjects included 17 men and 13 women, ranging in age from 23 to 46 years ( mean, 32 years). The nonmyasthenic strabismics in­cluded eight men and six women, aged 15- 79 years ( mean, 44 years). Etiologies of the strabismus in these patients are shown in Table 1. Examination included measurement of visual acuity, assessment of stereoacuity via the Titmus test, evaluation of versions, and quan­titation of phoria/ lropia at both distance and near. Lid position was also evaluated with measurements of pal­pebral fissure, margin- reflex distance, and levator func­tion. During pharmacologic testing, i. v. access was ob­tained via a 25- gauge butterfly catheter placed in either an antecubital or a forearm vein. Atropine was avail­able for intravenous use if necessary, but none of the subjects required it. An initial Tensilon dose of 2 mg was administered, and the patient was monitored for systemic effects, such as lid fasciculation, lacrimation, saliva-lion, nausea, or diaphoresis. If no such effects were ob­served after 30 s, another 2 mg was given. In this man­ner, 2- mg increments were administered until autono­mic effects or adverse reactions were noted or until a maximum of 10 mg Tensilon was given. Immedi­ately after receiving the final increment of Tensilon, pa­tients underwent complete evaluation of muscle balance. Using an accommodative target at both 20 feet and 14 inches, APCT was performed in the standard fash­ion; this test was carried out by the same examiner for 10 seconds in the primary position of gaze for each patient each time it was employed, in an attempt to RESULTS Tables 2 and 3 list the means and standard deviations of the horizontal and vertical angles of strabismus for all subjects at distance and near at 2 min post- Tensilon injection. ( The 2- min data were chosen for further analy­sis because mean measurements at all three time inter­vals were similar). All normal subjects had 40 arc s of stereoacuity on the Titmus test, indicating bifoveation. In normal subjects, the pre- and post- Tensilon measure­ments at distance showed no significant change. Both horizontally and vertically, the vast majority of normals showed a < 1 prism diopter ( PD) change ( 86% and 90%, respectively). However, at near, the normals had a wors­ening of their exophoria. Although this amount of wors­ening was small ( 2 PD at 2 min), it was statistically significant ( p = 0.004). The maximum amount of ex­odeviation worsening was 6 PD. The near measurement of the vertical deviation did not change among the nor­mals- only one of 30 patients exhibited a slight wors­ening ( orthophoria to a hyperphoria of 1 PD). There was no statistical difference between the orthophoric and orthotropic normal subjects ( i. e., the presence of a small horizontal or vertical phoria, as defined earlier, made no difference in the response to Tensilon). Of the 10 sub­jects who were orthophoric at distance and near, two experienced an exophoria of 4 PD at near after Tensilon. No phorias were converted to tropias in any of the pa­tients. As a whole, the strabismic group behaved differently from the normals ( Table 4). Almost half ( 46%) of the strabismics had a worsening of their horizontal devia­tion at distance, compared with 7% of normals. The most striking change was the substantial number of Time Prc- Tcnsilon Post- Tensilon ( 2 min) Difference Distance Horizontal'' 1.0 + 2.4 0.9 + 2.2 - 0.1 ± 0.9 ( p = 0.6)'' TABLE 2. Norma measurements" Vertical'' 0.4 ± 1.5 0.3+ 1.0 - 0.1 ± 1.0 ( p = il subjec 0.6)'' ' As- Near i Horizontal'' 5.4 + 7.2 7.4 + 8.5 2.0 ± 3.5 (/; = 0.004)'' neasurements" Vertical'' 0.2 ± 0.9 0.3 ± 1.2 0.2 ± 0.6 ( p = 0.13)'' " Measurements arc given as the mean ± SD. '' For horizontal measurements, negative numbers represent an esodeviation, and positive numbers represent an exodeviation. For vertical deviations, negative numbers represent a decrease in liypertropia, and positive numbers represent an increase in hypcrtropia. '/; values are via paired / tests. ,/ Neiiro- Ophtlmlmol, Vol. 17, No. 1. 1997 EFFECT OF EDROPHONIUM CHLORIDE ON OCULAR ALIGNMENT TABLE 3. Nonmyaslhenic strabismics Time Distance measurements" Near measurements" Horizontal' Vertical" Horizontal" Vertical" Prc- Tensilon Post- Tensilon ( 2 min) Difference 1.0 ± 16.8 2.0+ 15.7 0.1 ± 2.9 ( p = 0.9)'' 10.9+ 12.2 12.8 ± 14.0 1.5± 2.8(/) 0.07)'' 3.0+ 16.3 7.2+ 15.2 1.3 ± 4.6 ( p 0.3)'' 9.0+ 13.0 10.0+ 12.7 0.3 ± 2.5 ( p 0.7)'' " Measurements arc given as the mean + SD. " For horizontal measurements, negative numbers represent an esodeviation, and positive numbers represent an cxodeviation. For vertical deviations, negative numbers represent a decrease in hyperlropia, and positive numbers represcnl an increase in hyperlropia. ' p values are via paired / tests. patients who had a change in their vertical devia­tion ( 46% at distance and 38% at near), with most of them demonstrating an increase in the angle of devia­tion ( 38% at distance and 23% at near). However, the amount of vertical change was statistically significant only at distance ( 1.7 PD at 5 min, /; = 0.047). The maximum amount of vertical change was 5 PD. Al­though the nonmyasthenic strabismic subjects also ex­hibited a tendency to worsen their exodeviation at near, it was not statistically significant. Pre- and post- Tensilon measurements at distance for the nonmyas­thenic strabismics are listed in Table 5. Only one patient in this study ( in the normal group) showed a reversal in the direction of the deviation. This patient exhibited a change from 1 PD esophoria to 1 PD exophoria, at near only. There was no change in lid position or versions in any of the patients. None of the patients exhibited the severe side effects of bradycardia, syncope, or vomiting. How­ever, five patients became nauseated, and six complained of dizziness. The mean Tensilon dose administered was 7.1 mg. Seventeen patients ( 39%) received the entire 10- mg dose. DISCUSSION The clinical situation occasionally arises in which the diagnosis of MG must be considered in a patient with­out a clear end point for Tensilon testing; for instance, as many as 23% of myasthenics with diplopia have clinically normal eyelids ( 6). In the evaluation of MG, the i. v. Tensilon test in combination with APCT may offer several advantages over the Hess screen and Lan­caster red- green tests. The APCT allows one to quan­tify measurement of a phoria or tropia in prism diopters, as opposed to degrees, a roughly twice- larger unit of measurement. With the APCT, even small deviations are easily observed and quantified. Additionally, the APCT allows the examiner to more easily separate and quantitate the individual horizontal and vertical com­ponents of the angle of deviation. ( This is important because small vertical deviations may be much more clinically significant than horizontal deviations owing to the differences in fusional amplitudes). A further advantage of the APCT is that use of the occluder com­pletely dissociates the eyes compared with red- green glasses, which are only partly dissociative. With par­tial dissociation, the angle of strabismus may be affected by the patients' fusional control of their phoric com­ponent; complete dissociation eliminates this variable. Furthermore, with red- green glasses, the relative phoric and tropic components of the total deviation are diffi­cult to separate, whereas this distinction is easily made by the combined use of the cover- uncover and simul­taneous and alternate prism- cover tests. Additionally, in patients with anomalous retinal correspondence, complete reliance on subjective sensory phenomena may lead to inaccurate interpretations of the Tensilon test. Finally, Tensilon's side effect of diaphoresis may lead to fogging of the glasses used in the Lancaster or Hess screens from condensed perspiration, as noted by previ­ous authors ( 8). TABLE 4. Comparison of normals and strabismics: horizontal and vertical deviations after Tensilon Horizontal deviations Vertical deviations Distance Near Distance Near Normals Strabismics Normals Strabismics Normals Strabismics Normals Strabismics Worse" 2 ( 7%) 6 ( 46%) Same" 26 ( 86%) 7 ( 54%) Better 2 ( 7%) 0 p = 0.007" 12( 40%) 5( 39%) 1( 3%) 5( 38%) 15( 50%) 6( 46%) 27( 90%) 7( 54%) 3( 10%) 2( 15%) 2( 7%) 1( 8%) p = 0.9" /; = 0.014" I ( 3%) 29 ( 97%) 0 3 ( 23%) 8 ( 62%) 2 ( 15%) /; = 0.007" " Worse and Same refer, respectively, to changes in the angle of deviation > 2 PD 2 min after Tensilon injection. "/) values via exact chi- squared tests. ,/ Neitro- Ophtlialmol. Vol 17, No. I. 1997 10 R. M. SIATKOWSKI ET AL. TABLE 5. Pre- and post- Tensilon distance measurements of strabismic patients Pre- Tensilon 2 min post- Tensilon Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 RHT4 LHT 25, XT 10 LHT 14 LHT 25, ET 6 XT 6 RHT6 LHT 14, XT 8 ET25 ET 6, RHT 3 RHT 40, XT 25 RHT 15 ET 40, RHT 4 XT 22, RHT 3 ET 10 RHT 5 LHT 25, XT 10 LHT 9 LHT 30, ET 6 XT 8 RHT 6 LHT 18, XT 10 ET30 ET 12, RHT 4 RHT 45, XT 30 RHT 20 ET 40, RHT 6 XT 25, RHT 8 ET 14 XT, exotropia; HT, hypcrtropia; ET, esotropia; R, right; L, left. Previous studies that have evaluated the effect of Ten­silon on ocular motility have reported no significant change in normal subjects or in a majority of nonmyas-thenic strabismics ( 5,8,9). In the myasthenic patients, paradoxic responses ( significant worsening of deviation) were frequently seen ( 8,9). In our study, a reversal in deviation direction occurred only once and was not clini­cally significant. When such a response is encountered in a clinical situation, one should strongly consider the di­agnosis of MG. The statistically significant worsening of exophoria at near to an accommodative target at 14 inches in normal subjects may not have been observed in the other reports ( 8- 10) because of the testing distances used in these studies ( 50- 100 cm). Additionally, the measurements stated in their reports do not separate the deviations into horizontal and vertical compo­nents, making further comparison in this regard diffi­cult. We observed that nonmyasthenic strabismics may ex­hibit a worsening of their deviation, particularly the ver­tical component at distance. One possible explanation for this finding is that most strabismics have subnormal fu-sional mechanisms, often with secondary sensory com­ponents to their deviations. When the motor component of fusion is altered or disrupted ( even minimally) by i. v. Tensilon, the strabismic patient's subnormal sensory fu­sion may result in a change in the objectively observed deviation. Indeed, there is evidence that Tensilon de­creases saccadic velocities in nonmyasthenic strabismics ( 11), perhaps by unmasking central adaptive effects and creating a subclinical cholinergic excess at the neuro­muscular junction. A similar effect was found on the saccadic velocities of normal subjects, perhaps account­ing for the worsening of exophoria at near that we ob­served. Although many clinicians assume that changes in the clinical exam induced by Tensilon last only a min­ute or two, this is not the case. The similarity of our data at 2 and 5 min postinfection indicates that the ef­fect of Tensilon on ocular alignment lasts at least this long. Indeed, data supplied from the manufacturer state that the effects induced by intravenous edropho­nium may persist up to 10 min. Thus, the more cumber­some and time- consuming intramuscular neostigmine test need not be employed in order to produce mea­surable changes in ocular alignment for diagnostic pur­poses. In summary, we found that Tensilon may produce a mild worsening of an exodeviation at near in nor­mal subjects. The amount of worsening was small ( mean, 2 PD; maximum, 6 PD) and clinically insig­nificant. Apart from this finding, normals exhibited no significant change in their phorias after Tensilon. Of the nonmyasthenic strabismics, one third to one half showed a change in their vertical deviation ( 46% at distance and 38% at near), with a majority of them worsening. Again, the amounts of change were small ( maximum 5 PD) and of little clinical significance. Finally, a reversal in deviation direction was seen in only one of our subjects and should continue to be re­garded as a clinical finding primarily associated with MG. A future study should concentrate on results of Tensilon testing on ocular alignment in EMG- or anti- Ach receptor- antibody- positive myasthenics without pto­sis or obvious ophthalmoplegia. We speculate that there are larger and more variable changes in ocular alignment, as well as paradoxic and reversal responses, in this group. Combined i. v. Tensilon/ APCT is easy to use and readily available and may be particularly useful in those patients who do not have ptosis or obvious lag of duc-tions and in whom the diagnosis of MG is entertained. Small changes (< 5 prism diopters) in near exophorias and distance vertical deviations do not, in themselves, constitute a positive Tensilon test. We recommend the incremental dose technique for Tensilon administration, since in most cases use of the entire vial is unnecessary and may result in an increased incidence of adverse side effects. Acknowledgment: Research was supported in part by Pub­lic Health Service grant EY- 10900, by an unrestricted grant from Research to Prevent Blindness, Inc., and by a Dept. of Ophthalmology Research grant. REFERENCES 1. Glaser JS. Neuro- ophthalmology, 2nd ed. Philadelphia: JB Lippin-cott Co., 1990: 392- 7. 2. Bastiaensen LAK, van Gasteren JMHY, Frenken CWGM, Leylen ACM. Diagnostic problems in ( ocular) myasthenia. Doc Ophthal­mol l979; 46( 2): 381- 90. 3. Kelly JJ, Daube JR, Lennon VA, Howard FM, Younge BR. The laboratory diagnosis of mild myasthenia gravis. Aim Neurol 1982; 12: 238^ 12. 4. Seybold ME. The office test for ocular myasthenia gravis. Arch Neurol 1986; 43: 842- 3. J Ncwo- Opluhalnml, Vol. 17. No. I. 1997 EFFECT OF EDROPHONIUM CHLORIDE ON OCULAR ALIGNMENT II 5. Glaser JS. 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