Journal of
J. Neurol. 214, 257--265 (1977)
Neurology ~) by Springer-Verlag 1977
The Regional Curare Test in Myasthenia Gravis G. Hertel, K. Ricker, and A. Hirsch Neurologische Universitiitsklinik Wtirzburg (Direktor: Prof. Dr. H. G. Mertens), Josef-Schneider-Stral~e 1l, D-8700 Wiirzburg, Federal Republic of Germany
Summary. 30 subjects without disturbance of neuromuscular transmission and 18 patients with myasthenia gravis were used in conducting the regional curare test. The adductor pollicis and the hypothenar muscles were studied with the 3/sec stimulation test. With three different dosages of curare one could find no reliable border between "normal" and "pathological". In the patients with myasthenia no definite relation could be found between the findings with the regional curare test and the clinical picture. The curare concentration reaching the muscle is probably quite variable from case to case as regards diffusion and volume in the tissue. The 3/sec stimulation test with registration from the deltoid muscle, and in certain cases the systemic curare test, appear more suitable than the regional curare test for routine diagnosis as well as indication for thymectomy. But for cases of ocular myasthenia showing no further weaknesses by the systemic curare test, the regional curare test can be put to use. The advantage lies in the higher concentration of curare which can thereby be brought to the muscle. The precautionary measures should be similar to those taken with the systemic curare test.
Key words: Myasthenia gravis - Curare test - Neuromuscular transmission of testing.
Zusammenfassung. Bei 30 Kontrollpersonen und 18 Myastheniepatienten wurde der lokale Curaretest durchgefiihrt. Mit der 3/sec-Stimulation wurde der Adduktor pollicis und der Hypothenar untersucht. Bei drei verschiedenen Curaredosierungen liel3 sich keine eindeutige Grenze zwischen ,,normal" und ,,pathologisch" finden. Bei den Myastheniepatienten bestand keine zuverl~issige Beziehung zwischen dem Ergebnis des lokalen Curaretests und dem klinischen Bild. Wahrscheinlich ist die den Muskel erreichende Curarekonzentration je nach Diffusion und Gewebsvolumen von Fall zu Fall recht unterschiedlich. Ftir die Routinediagnostik, aber auch ftir die Indikation zur Thymektomie,
258
G. Hertel et al. scheinen die 3 / s e c - S t i m u l a t i o n mit R e g i s t r i e r u n g v o m D e l t o i d e u s und in b e s o n d e r e n F~illen d e r systemische C u r a r e t e s t geeigneter als d e r l o k a l e C u r a r e test zu sein. Bei den F~tllen v o n okul~irer M y a s t h e n i e , die a u c h im systemischen C u r a r e t e s t keine weitere Schw~iche zeigen, k a n n a b e r der l o k a l e C u r a r e t e s t zur A n w e n d u n g k o m m e n . D e r Vorteil liegt d a n n in der hSheren C u r a r e k o n z e n t r a tion, die a n den M u s k e l h e r a n g e b r a c h t werden kann. Die Vorsichtsmal3nahm e n sollten die gleichen sein wie b e i m systemischen Curaretest.
The r e g i o n a l c u r a r e test has recently gained r e c o g n i t i o n for d i a g n o s i n g m y a s t h e n i a a n d i n d i c a t i n g a t h y m e c t o m y in o c u l a r m y a s t h e n i a [1, 2, 4]. In m o s t m y a s t h e n i c patients the safety f a c t o r o f n e u r o m u s c u l a r t r a n s m i s s i o n m a y also be d i m i n i s h e d in those muscles which show no weakness clinically [6]. T h e jitter is in these muscles increased [9]. The r e g i o n a l injection delivers a higher curare dose to the muscle t h a n does the systemic c u r a r e test. H o w e v e r , this test is limited to the h a n d muscles a n d m u s t be c o m b i n e d with s t i m u l a t i o n e l e c t r o m y o g r a p h y . W e were interested in w h e t h e r this e x a m i n a t i o n is clinically feasible for definitely d i a g n o s ing or e x c l u d i n g m y a s t h e n i a .
Methods [1] The volume of 720 ml of the distal upper limb is determined by submersion in water. A sphygmomanometer cuff is applied at the determined site and the unoccluded arm is held vertically for 30 sec. The cuff is inflated suprasystolically and the arm laid down after which curare, diluted in 20 ml of normal saline, is injected over 1 min into a vein on the back of the hand. The cuff is released 5 min later and neuromuscular stimulation is started after another min with 3/sec trains of stimuli delivered to the ulnar nerve at the wrist. Recording was made from the adductor pollicis and hypothenar muscles. The findings are compared to the values recorded prior to the curare injection. We used dimethyl-d-tubocurarine, the dosage of which is 1/3 compared to d-tubocurarine. 43 examinations were conducted on 30 subjects, aged 20 to 75 years, suffering from headaches, ischialgia, brain tumor, stroke or seizures (non-medicated). In cases of hemiparesis only the non-afflicted hand was used. The 18 myasthenia patients examined were between 13 and 73 years of age. Five patients were studied several times. Three patients had ocular myasthenia, 15 had slight to moderately severe faciopharyngeal myasthenia with involvement of the muscles of the shoulder girdle. (8 other patients with severe generalized myasthenia were excluded from the curare study). It was planned to discontinue Mestinon medication 12 hours before the study, but this was not possible in all cases.
Results
Normal Subjects ( T a b l e 1). Using 0.05 m g of m e t h y l c u r a r i n e we f o u n d changes in the a m p l i t u d e o f the 1st or the 5th response o f m o r e t h a n 10% in three cases. In one case a d e c r e m e n t o f 24% a p p e a r e d in the a d d u c t o r pollicis, while in the h y p o t h e n a r muscles o f the s a m e h a n d no change o f a m p l i t u d e was evident. In two o t h e r cases a change of 11 a n d 18% respectively were r e c o r d e d in the h y p o -
The Regional Curare Test in Myasthenia Gravis
259
Table 1. Regional test in normal subjects with three different dosages of curare. The table shows the number of cases which exhibit a change with the 3/sec stimulation Dosages of methylcurarine Number of subjects studied
Extent of change in amplitude
0.05 mg n = 20 0.125 mg n = 16 0.2 mg n =7
Number of cases Reduction of the 1st potential after curare
Decrement of the 5th potential after curare
Adductor pollicis
Hypothenar Adductor pollicis muscles
Number of subjects with pathological Hypothenar change of muscles amplitude
0% 10%
17 3 0
10 8 2
19 0 1
20 0 0
0% 10%
7 3 6
9 2 5
12 0 4
16 0 0
0% 10%
0 0 7
3 0 4
2 0 5
5 0 2
t h e n a r muscles. No changes of a m p l i t u d e occurred in the a d d u c t o r pollicis of the same hand. 16 e x a m i n a t i o n s were m a d e with 0.125 mg methyl curarine. Six cases showed a change of a m p l i t u d e of more t h a n 10%. A reduction of the first a m p l i t u d e following the curare injection was f o u n d in the a d d u c t o r pollicis six times ( 1 1 - - 5 0 % ) a n d in the h y p o t h e n a r muscles five times (11--22%). I n the a d d u c t o r pollicis a decrement of the fifth potential was registered four times (20--75%) while n o d e c r e m e n t was recorded in the h y p o t h e n a r . All 7 cases studied showed a change in a m p l i t u d e using 0.2 mg. A r e d u c t i o n of 1 4 - - 6 2 % of the first potential was registered in all 7 subjects in the a d d u c t o r
Am )Nude
Hypother~ar
Adductor
100 % 8O 60 z,0 20
o
25%
~
43%
110°/o
6
~
lo
t
:;
/-,
6
lo
2or
Time following release of the tourniquet (min)
Fig. l. Regional test with 0.125 mg methyl curarine in a normal subject. Study of the hypothenar muscles and adductor pollicis with 3/sec stimulation. The illustration shows reduction of the amplitude of the first and fifth potential (white and striped columns respectively), different time intervals after the tourniquet is released. The 100% refers to the height of the amplitude prior to curare injection
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Table 2. Regional test with 0.05 mg methyl curarine. 9 patients with myasthenia gravis
Reduction of the Decrement of the amplitude of the 1st amplitude of the 5th potential after curare (%) potential after curare (%) Adductor pollicis S. St., male, 62 years old, onset at 56 years. Symptoms: faciobulbar, shoulder girdle, 0 neck; lifting both arms above head not possible.
Hypothenar Adductor muscles pollicis
Hypothenar muscles
0
0
0
K. Ch., female, 17 years old, onset at 12 years. Symptoms: right ptosis, neck, 0 shoulder girdle; thymectomy at 16 years.
20
0
0
S. R., male, 57 years old, onset at 53 years. Symptoms: faciopharyngeal, shoulder 16 girdle, respiratory muscles.
8
0
0
S. S., female, 14 years old, onset at 14 years. Symptoms: generalized weakness, leg muscles, shoulder girdle.
20
0
19
0
M. H., female, 36 years old, onset at 36 years. Symptoms: oculofaciopharyngeal; Deltoid 10% decrement.
9
20
50
0
W. H., female, 40 years old, onset at 35 years. Symptoms: oculofaciopharyngeal. Thymectomy at 36 years.
46
0
24
15
B. H., male, 24 years old, onset at 23 years. Symptoms: faciopharyngeal, neck, 50 shoulder girdle. Deltoid 73% decrement.
11
50
0
24
10
38
29
100
57
100
67
B. E., female, 24 years old, onset at 21 years. Symptoms: oculopharyngeal, neck. Thymectomy at 21 years. 2 years without symptoms. H. M., female, 18 years old, onset at 15 years. Symptoms: oculofaciopharyngeal, shoulder girdle.
pollicis a n d a reduction of 1 7 ~ 4 7 % was recorded in the h y p o t h e n a r muscles of 4 subjects. Five subjects also had a decrement in the a d d u c t o r pollicis (43--71%) a n d two subjects in the h y p o t h e n a r eminence (25 a n d 26%). Figure 1 shows one e x a m p l e with 0.125 mg. A d e c r e m e n t of the fifth potential was, with one exception, f o u n d only when a r e d u c t i o n of a m p l i t u d e of the first potential occurred w i t h o u t regard to the a m o u n t of curare injected. A reduction of the first potential appeared more frequently w i t h o u t a decrement of the fifth potential.
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Table 3. Regional test with 0.125 mg methyl curarine. 8 patients with myasthenia gravis Reduction of the Decrement of the amplitude of the 1st amplitude of the 5th potential after curare (%) potential after curare (%) Adductor pollicis S. St., male, 62 years old, onset at 56 years. Symptoms: faciopharyngeal, shoulder girdle, neck; lifting both arms above head not possible. D. R., female, 45 years old, onset at 39 years. Symptoms: oculofaciopharyngeal, shoulder girdle. Thymectomy at 40 years. B. H., male, 24 years old, onset at 23 years. Symptoms: faciopharyngeal, neck, shoulder girdle. Thymectomy at 24 years.
Hypothenar Adductor muscles pollicis
Hypothenar muscles
0
0
46
0
33
30
E. Ch., female, 53 years old, onset at 22 years. Symptoms: ocular, shoulder and pelvic girdle.
59
30
29
21
W. B., female, 54 years old, onset at 54 years. Symptoms: ocular, slight generalized weariness.
44
52
40
46
K. Ch., female, 17 years old, onset at 12 years. Symptoms: right ptosis in neck, shoulder girdle Thymectomy at 16 years. L. G., female, 25 years old, onset at 19 years. Symptoms: oculopharyngeal, neck. Thymectomy at 19 years. M. H., female, 36 years old, onset at 36 years. Symptoms: oculofaciopharyngeal.
47
50
57
64
84
40
Faciopharyngeal Myasthenia. Only one patient had a pathological decrement of a m p l i t u d e o n testing the h a n d muscles before the a d m i n i s t r a t i o n of curare. P r o v o c a t i o n by exercise or ischemia was n o t used. Study with O.05 mg Methyl Curarine (Table 2). No certain correlation could be d e t e r m i n e d between the severity of the clinical picture a n d the reaction to curare in 9 patients. O n e p a t i e n t (Table 2, B.E.) was in full remission. She had not needed M e s t i n o n for 2 years a n d had n o symptoms. Using 0.05 mg methyl curarine regionally a distinct change in a m p l i t u d e of the a d d u c t o r pollicis a n d the hypot h e n a r e m i n e n c e were recorded.
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Art ditude 100 %
Hypothenar
80 60
25% =
40 20 I
I
I
I
T
'~"
2 4 6 8 10 30 /~F0 Time fottowing release of the tourniquet ( min )
t
Fig. 2. Regional test with 0.125 mg methyl curarine in a patient with faciopharyngeal myasthenia. Study of the hypothenar muscles. (Same illustration as in Fig. 1)
One patient (Table 2, S. St.) had a distinct weakness of the faciopharyngeal and thoracic muscles. An amplitude decrement of 45% occured in the deltoid muscle with the 3/sec stimulation. With the systemic curare test the weakness increased so considerably following 0.15 mg methyl curarine that the study had to be discontinued, while no change in amplitude was apparent in the hand muscles with the regional curare test. This patient had already been studied in regard to the hypothenar muscles several weeks earlier using 0.125 mg regionally. The amplitude remained unchanged with this dosage also (Table 3). Another patient (Table 2, K. Ch.) had such distinct bulbar symptoms that a systemic curare test could not be risked. Using 0.05 mg of methyl curarine regionally no change occured in the adductor pollicis; a reduction of the first potential of 20% was recorded in the hypothenar eminence only.
Study with O.125 mg Methyl Curarine (Table 3). Seven patients out of 8 had a distinct change of amplitude following curare. An example is shown in Figure 2. One of these patients (Table 3, D. R.) had a reduction of the first potential in the hypothenar muscles of 40% but no decrement of amplitude of the fifth potential. No change of amplitude was found in one patient who has already been discussed (Table 3, S. St.). Side Effects. In a 15 year old patient (Table 2, H.M.) serious bulbar symptoms became apparent following 0.05 mg methyl curarine after the release of the tourniquet. This girl suffered from a moderately severe generalized myasthenia, but she was medicated satisfactorily with 30 mg Mestinon twice daily and could go to school. Two other patients given 0.05 mg complained of light side effects such as heaviness of the eye lids, light headedness and drowsiness. The complaints occured immediately following the release of the tourniquet on the arm. In one patient (Table 3, K. Ch.) a threatening bulbar deterioration developed after 0.125 mg which required the injection of 1 mg Prostigmin i.v. Ocular Myasthenia. The following data were obtained from 3 patients with a clinical picture of myasthenia restricted to the ocular muscles:
The Regional Curare Test in Myasthenia Gravis
263
B. D., Male, 19 Years Old. The myasthenia started with double vision at the age of 7. Using 1 mg
methyl curarine systemically an increase of the paresis of the ocular muscles occured without involvement of other muscles. With the regional curare test an amplitude reduction of the first potential of 23% was registered in the hypothenar muscles following 0.125 mg methyl curarine. A decrement of the fifth potential did not occur. The adductor pollicis showed a decrement of the fifth potential of 36% but no reduction of the amplitude of the first potential. H.K., Male, 30 Years Old. Myasthenia set in several months earlier with double vision and slight ptosis. A Tensilon test showed no distinct improvement and therefore multiple sclerosis was brought into consideration. After 1 mg of methyl curarine injected systemically complete unilateral ptosis was evident and eye movement was considerably impaired. There were however no indications of involvement of other muscles. With the regional curare test using 0.125 mg methyl curarine a reduction of the first potential of 38% and a decrement of the fifth potential of 44% resulted in the hypothenar muscles. Following treatment with Mestinon, Prednisolon and Azathioprin the complaints receded completely in the course of 3 months. The clinical examination 6 months after the onset of the illness showed nothing conspicuous. With the systemic curare test using 1 mg slight double vision still occurred when changing the glance, but no ptosis. The regional curare test with 0.05 mg and 0.125 mg methyl curarine showed no more amplitude changes in the hypothenar eminence and adductor pollicis. B. R., Male, 41 Years Old. The myasthenia started several months ehrlier with unilateral ptosis following a long car drive. Examination six weeks later disclosed no additional signs. With 3/sec stimulation the amplitude of the hypothenar muscles was normal while the deltoid muscle showed a decrement of the fifth potential of 23%. With the systemic curare test using 0.75 mg methyl curarine distinct ocular and bulbar symptoms occurred. In the regional study using 0.2 mg we found a reduction of the first potential of 56% and a decrement of the fifth potential of 45% in the hypothenar muscles,
Discussion T h e p a r t i c u l a r difficulty o f the r e g i o n a l curare test lies in d e t e r m i n g the e x a c t b o r d e r b e t w e e n a n o r m a l a n d a p a t h o l o g i c a l reaction. B r o w n et al. [1] therefore tested n o r m a l subjects a n d m y a s t h e n i a patients with different dosages. They gave the n o r m a l subjects 0.5 m g d - t u b o c u r a r i n e (and m y a s t h e n i a patients 0.125 rag) and d e t e r m i n e d that in m o s t cases a considerable n e u r o m u s c u l a r block occurred. This d o s a g e is certainly quite high. S t a l b e r g et al. [10, 11] injected the same a m o u n t systemically i.v. a n d were a b l e to register a distinct increase o f j i t t e r in the a r m muscle o f the o t h e r side. F o l d e s et al. [2] f o u n d a r e d u c t i o n of a b o u t 10% o f the e r g o m e t r i c force in the h a n d on h e a l t h y subjects in the using 0.2 m g d - t u b o c u r a r i n e for the r e g i o n a l study. W e used m e t h y l - d - t u b o c u r a r i n e the d o s a g e o f which is 1/3 as c o m p a r e d to dt u b o c u r a r i n e . W i t h a m e d i u m d o s a g e o f 0.125 rag, 6 out o f 16 n o r m a l subjects s h o w e d a c h a n g e o f a m p l i t u d e ; using the lower dosage o f 0.05 m g this was nevertheless still the case in 3 out o f 10. The d o s a g e to which h e a l t h y subjects will definetly n o t react in the 3 / s e c test is therefore still lower. W h i l e s i m u l t a n e o u s l y s t u d y i n g the a d d u c t o r pollicis and h y p o t h e n a r muscles, several n o r m a l subjects s h o w e d this change in a m p l i t u d e in j u s t one o f the two muscles. This leads to the s u p p o s i t i o n t h a t the r e t r o g r a d e diffusion in the h a n d is not u n i f o r m a n d t h a t the c u r a r e c o n c e n t r a t i o n reaching the muscles varies. I n t e r p r e t i n g the changes in a m p l i t u d e in the 3/see test is m o r e difficult t h a n usual in the r e g i o n a l c u r a r e study. One m u s t consider the r e d u c t i o n o f a m p l i t u d e
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of the first potential after curare as well as the decrement of the fifth potential: no definite relation of these two values could be found (Figs. 1 and 2). The first potential was frequently lowered without a decrement of the fifth potential. In most of our myasthenia patients a more pronounced decrease in amplitude was found with the regional curare test as compared to normal subjects. However no definite correlation could be determined between the severity of the myasthenia and the reaction to the regional injection of curare. In one case of faciopharyngeal myasthenia no change in amplitude at all was recorded following 0.05 mg of methyl curarine; in another case only a slight decrease of the first potential occurred in one of two hand muscles studied. Using the regional curare test, myasthenia could not have been diagnosed in these two patients even though a curare dosage which could cause some healthy subjects to show a distinct change of amplitude was used. For routine diagnostic procedure of myasthenia the regional curare test seems to us to be less appropriate due to this uncertainty and the difficulty in performing it. For the diagnosis, the study of proximal muscles, such as the deltoid, gives considerably more reliable information with the 3/sec test [5]. The hand muscles are however seldom struck with myasthenia. We found in 23 myasthenia patients / 17 cases of a pathological decrement of amplitude in the deltoid muscle, but in only 3 of these cases was there evidence in the hand muscles [7]. In difficult cases the systemic curare test should be preferred [3, 8, 9]. In this test the subclinical involvement of all muscles can be judged. We were able to demonstrate in 25 of 60 myasthenia patients a participation of muscles with no clinical manifestations by means of the systemic curare test. 20 patients who clinically had only ocular myasthenia were shown to have a weakness of mainly proximal muscles by the systemic curare test. These findings are important in deciding the need for thymectomy. On the other hand, we were able to exclude myasthenia positively in 79 cases with the help of the systemic curare test. These findings were confirmed by further observation of the patients in 17 of whom a psychiatric disturbance became apparent [7]. The regional curare test is not essentially safer for the patient than the systemic test. Two of our patients developed bulbar symptoms suddenly after the tourniquet was released. The precautionary measures must therefore be basically the same as for the systemic test. On the other hand in 2 of our patients with ocular myasthenia we found evidence of generalized involvement only by means of the regional curare test. In another case the involvement of bulbar muscles had already been determined by the systemic curare test. The regional test also showed increased sensitivity to curare in the hand muscles. In known cases of ocular myasthenia in which no generalization is made apparent by the 3/sec test or the systemic curare test, the regional test can be put to use. The findings however must be carefully interpretated, especially in regard to the indication for thymectomy.
References
1. Brown, J. C., Charlton, J. E., White, D. J. K.: A regional technique for the study of sensitivity to curare in human muscle. J. Neurol. Neurosurg. Psychiat. 38, 18--26 (1975)
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2. Foldes, F., Glaser, G.: Diagnostic tests in myasthenia gravis. An overview. Ann. New York Acad. Sc. 183, 275--286 (1971) 3. Hertel, G., Ricker, K.: Der Curare-Test in der Diagnostik der Myasthenia gravis. Dtsch. med. Wschr. 102, 90--92 (1977) 4. Horowitz, S. H., Genkins, G., Kornfeld, P., Papatestas, A. E.: Regional curare test in evaluation of ocular myasthenia. Arch. Neurol. 32, 84--88 (1975) 5. Ozdemir, C., Young, R. R.: Electrical testing in myasthenia gravis. Ann. New York Acad. Sc. 183, 287--307 (1971) 6. Paton, W. D., Waud, D. R.: The margin of safety of neuromusculartransmission. J. Physiol. (London) 191, 59--90 (1967) 7. Ricker, K., Hertel, G.: Klinische Wertigkeit diagnostischer Methoden. In: Myasthenia gravis. Edit. G. Hertel, H. G. Mertens, K. Ricker, K. Schimrigk. Stuttgart: Thieme 1977 8. Rowland, L. P., Aranow, H., Hoefer, P. F.: Observations onthe curare test in the differential diagnosis of myasthenia gravis. In: H. R. Viets, edit. Myasthenia gravis: A symposium, pp. 4 1 1 4 3 4 . Springfield (Ill.): Thomas 1961 9. Simpson, J. A.: Myasthenia gravis and myasthenic syndromes. In: J. N. Walton, edit. Disorders of voluntary muscle. 3rd edit, pp. 653 692. Edinburgh, London: Churchill Livingstone 1974 10. Schwartz, M. S., Stalberg, E.: Single fibre electromyographic studies in myasthenia gravis with repetitive nerve stimulation. J. Neurol. Neurosurg. Psychiat. 38, 678--682 (1975) 11. Stalberg, E., Schiller, H. H., Schwartz, M.: Safety factor in single human motor endplates studied in vivo with single fibre electromyography. J. Neurol. Neurosurg. Psychiat. 38, 799--804 (1975)
Received August 23, 1976
J. Neurol. 214, 257--265 (1977)
Neurology ~) by Springer-Verlag 1977
The Regional Curare Test in Myasthenia Gravis G. Hertel, K. Ricker, and A. Hirsch Neurologische Universitiitsklinik Wtirzburg (Direktor: Prof. Dr. H. G. Mertens), Josef-Schneider-Stral~e 1l, D-8700 Wiirzburg, Federal Republic of Germany
Summary. 30 subjects without disturbance of neuromuscular transmission and 18 patients with myasthenia gravis were used in conducting the regional curare test. The adductor pollicis and the hypothenar muscles were studied with the 3/sec stimulation test. With three different dosages of curare one could find no reliable border between "normal" and "pathological". In the patients with myasthenia no definite relation could be found between the findings with the regional curare test and the clinical picture. The curare concentration reaching the muscle is probably quite variable from case to case as regards diffusion and volume in the tissue. The 3/sec stimulation test with registration from the deltoid muscle, and in certain cases the systemic curare test, appear more suitable than the regional curare test for routine diagnosis as well as indication for thymectomy. But for cases of ocular myasthenia showing no further weaknesses by the systemic curare test, the regional curare test can be put to use. The advantage lies in the higher concentration of curare which can thereby be brought to the muscle. The precautionary measures should be similar to those taken with the systemic curare test.
Key words: Myasthenia gravis - Curare test - Neuromuscular transmission of testing.
Zusammenfassung. Bei 30 Kontrollpersonen und 18 Myastheniepatienten wurde der lokale Curaretest durchgefiihrt. Mit der 3/sec-Stimulation wurde der Adduktor pollicis und der Hypothenar untersucht. Bei drei verschiedenen Curaredosierungen liel3 sich keine eindeutige Grenze zwischen ,,normal" und ,,pathologisch" finden. Bei den Myastheniepatienten bestand keine zuverl~issige Beziehung zwischen dem Ergebnis des lokalen Curaretests und dem klinischen Bild. Wahrscheinlich ist die den Muskel erreichende Curarekonzentration je nach Diffusion und Gewebsvolumen von Fall zu Fall recht unterschiedlich. Ftir die Routinediagnostik, aber auch ftir die Indikation zur Thymektomie,
258
G. Hertel et al. scheinen die 3 / s e c - S t i m u l a t i o n mit R e g i s t r i e r u n g v o m D e l t o i d e u s und in b e s o n d e r e n F~illen d e r systemische C u r a r e t e s t geeigneter als d e r l o k a l e C u r a r e test zu sein. Bei den F~tllen v o n okul~irer M y a s t h e n i e , die a u c h im systemischen C u r a r e t e s t keine weitere Schw~iche zeigen, k a n n a b e r der l o k a l e C u r a r e t e s t zur A n w e n d u n g k o m m e n . D e r Vorteil liegt d a n n in der hSheren C u r a r e k o n z e n t r a tion, die a n den M u s k e l h e r a n g e b r a c h t werden kann. Die Vorsichtsmal3nahm e n sollten die gleichen sein wie b e i m systemischen Curaretest.
The r e g i o n a l c u r a r e test has recently gained r e c o g n i t i o n for d i a g n o s i n g m y a s t h e n i a a n d i n d i c a t i n g a t h y m e c t o m y in o c u l a r m y a s t h e n i a [1, 2, 4]. In m o s t m y a s t h e n i c patients the safety f a c t o r o f n e u r o m u s c u l a r t r a n s m i s s i o n m a y also be d i m i n i s h e d in those muscles which show no weakness clinically [6]. T h e jitter is in these muscles increased [9]. The r e g i o n a l injection delivers a higher curare dose to the muscle t h a n does the systemic c u r a r e test. H o w e v e r , this test is limited to the h a n d muscles a n d m u s t be c o m b i n e d with s t i m u l a t i o n e l e c t r o m y o g r a p h y . W e were interested in w h e t h e r this e x a m i n a t i o n is clinically feasible for definitely d i a g n o s ing or e x c l u d i n g m y a s t h e n i a .
Methods [1] The volume of 720 ml of the distal upper limb is determined by submersion in water. A sphygmomanometer cuff is applied at the determined site and the unoccluded arm is held vertically for 30 sec. The cuff is inflated suprasystolically and the arm laid down after which curare, diluted in 20 ml of normal saline, is injected over 1 min into a vein on the back of the hand. The cuff is released 5 min later and neuromuscular stimulation is started after another min with 3/sec trains of stimuli delivered to the ulnar nerve at the wrist. Recording was made from the adductor pollicis and hypothenar muscles. The findings are compared to the values recorded prior to the curare injection. We used dimethyl-d-tubocurarine, the dosage of which is 1/3 compared to d-tubocurarine. 43 examinations were conducted on 30 subjects, aged 20 to 75 years, suffering from headaches, ischialgia, brain tumor, stroke or seizures (non-medicated). In cases of hemiparesis only the non-afflicted hand was used. The 18 myasthenia patients examined were between 13 and 73 years of age. Five patients were studied several times. Three patients had ocular myasthenia, 15 had slight to moderately severe faciopharyngeal myasthenia with involvement of the muscles of the shoulder girdle. (8 other patients with severe generalized myasthenia were excluded from the curare study). It was planned to discontinue Mestinon medication 12 hours before the study, but this was not possible in all cases.
Results
Normal Subjects ( T a b l e 1). Using 0.05 m g of m e t h y l c u r a r i n e we f o u n d changes in the a m p l i t u d e o f the 1st or the 5th response o f m o r e t h a n 10% in three cases. In one case a d e c r e m e n t o f 24% a p p e a r e d in the a d d u c t o r pollicis, while in the h y p o t h e n a r muscles o f the s a m e h a n d no change o f a m p l i t u d e was evident. In two o t h e r cases a change of 11 a n d 18% respectively were r e c o r d e d in the h y p o -
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259
Table 1. Regional test in normal subjects with three different dosages of curare. The table shows the number of cases which exhibit a change with the 3/sec stimulation Dosages of methylcurarine Number of subjects studied
Extent of change in amplitude
0.05 mg n = 20 0.125 mg n = 16 0.2 mg n =7
Number of cases Reduction of the 1st potential after curare
Decrement of the 5th potential after curare
Adductor pollicis
Hypothenar Adductor pollicis muscles
Number of subjects with pathological Hypothenar change of muscles amplitude
0% 10%
17 3 0
10 8 2
19 0 1
20 0 0
0% 10%
7 3 6
9 2 5
12 0 4
16 0 0
0% 10%
0 0 7
3 0 4
2 0 5
5 0 2
t h e n a r muscles. No changes of a m p l i t u d e occurred in the a d d u c t o r pollicis of the same hand. 16 e x a m i n a t i o n s were m a d e with 0.125 mg methyl curarine. Six cases showed a change of a m p l i t u d e of more t h a n 10%. A reduction of the first a m p l i t u d e following the curare injection was f o u n d in the a d d u c t o r pollicis six times ( 1 1 - - 5 0 % ) a n d in the h y p o t h e n a r muscles five times (11--22%). I n the a d d u c t o r pollicis a decrement of the fifth potential was registered four times (20--75%) while n o d e c r e m e n t was recorded in the h y p o t h e n a r . All 7 cases studied showed a change in a m p l i t u d e using 0.2 mg. A r e d u c t i o n of 1 4 - - 6 2 % of the first potential was registered in all 7 subjects in the a d d u c t o r
Am )Nude
Hypother~ar
Adductor
100 % 8O 60 z,0 20
o
25%
~
43%
110°/o
6
~
lo
t
:;
/-,
6
lo
2or
Time following release of the tourniquet (min)
Fig. l. Regional test with 0.125 mg methyl curarine in a normal subject. Study of the hypothenar muscles and adductor pollicis with 3/sec stimulation. The illustration shows reduction of the amplitude of the first and fifth potential (white and striped columns respectively), different time intervals after the tourniquet is released. The 100% refers to the height of the amplitude prior to curare injection
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Table 2. Regional test with 0.05 mg methyl curarine. 9 patients with myasthenia gravis
Reduction of the Decrement of the amplitude of the 1st amplitude of the 5th potential after curare (%) potential after curare (%) Adductor pollicis S. St., male, 62 years old, onset at 56 years. Symptoms: faciobulbar, shoulder girdle, 0 neck; lifting both arms above head not possible.
Hypothenar Adductor muscles pollicis
Hypothenar muscles
0
0
0
K. Ch., female, 17 years old, onset at 12 years. Symptoms: right ptosis, neck, 0 shoulder girdle; thymectomy at 16 years.
20
0
0
S. R., male, 57 years old, onset at 53 years. Symptoms: faciopharyngeal, shoulder 16 girdle, respiratory muscles.
8
0
0
S. S., female, 14 years old, onset at 14 years. Symptoms: generalized weakness, leg muscles, shoulder girdle.
20
0
19
0
M. H., female, 36 years old, onset at 36 years. Symptoms: oculofaciopharyngeal; Deltoid 10% decrement.
9
20
50
0
W. H., female, 40 years old, onset at 35 years. Symptoms: oculofaciopharyngeal. Thymectomy at 36 years.
46
0
24
15
B. H., male, 24 years old, onset at 23 years. Symptoms: faciopharyngeal, neck, 50 shoulder girdle. Deltoid 73% decrement.
11
50
0
24
10
38
29
100
57
100
67
B. E., female, 24 years old, onset at 21 years. Symptoms: oculopharyngeal, neck. Thymectomy at 21 years. 2 years without symptoms. H. M., female, 18 years old, onset at 15 years. Symptoms: oculofaciopharyngeal, shoulder girdle.
pollicis a n d a reduction of 1 7 ~ 4 7 % was recorded in the h y p o t h e n a r muscles of 4 subjects. Five subjects also had a decrement in the a d d u c t o r pollicis (43--71%) a n d two subjects in the h y p o t h e n a r eminence (25 a n d 26%). Figure 1 shows one e x a m p l e with 0.125 mg. A d e c r e m e n t of the fifth potential was, with one exception, f o u n d only when a r e d u c t i o n of a m p l i t u d e of the first potential occurred w i t h o u t regard to the a m o u n t of curare injected. A reduction of the first potential appeared more frequently w i t h o u t a decrement of the fifth potential.
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Table 3. Regional test with 0.125 mg methyl curarine. 8 patients with myasthenia gravis Reduction of the Decrement of the amplitude of the 1st amplitude of the 5th potential after curare (%) potential after curare (%) Adductor pollicis S. St., male, 62 years old, onset at 56 years. Symptoms: faciopharyngeal, shoulder girdle, neck; lifting both arms above head not possible. D. R., female, 45 years old, onset at 39 years. Symptoms: oculofaciopharyngeal, shoulder girdle. Thymectomy at 40 years. B. H., male, 24 years old, onset at 23 years. Symptoms: faciopharyngeal, neck, shoulder girdle. Thymectomy at 24 years.
Hypothenar Adductor muscles pollicis
Hypothenar muscles
0
0
46
0
33
30
E. Ch., female, 53 years old, onset at 22 years. Symptoms: ocular, shoulder and pelvic girdle.
59
30
29
21
W. B., female, 54 years old, onset at 54 years. Symptoms: ocular, slight generalized weariness.
44
52
40
46
K. Ch., female, 17 years old, onset at 12 years. Symptoms: right ptosis in neck, shoulder girdle Thymectomy at 16 years. L. G., female, 25 years old, onset at 19 years. Symptoms: oculopharyngeal, neck. Thymectomy at 19 years. M. H., female, 36 years old, onset at 36 years. Symptoms: oculofaciopharyngeal.
47
50
57
64
84
40
Faciopharyngeal Myasthenia. Only one patient had a pathological decrement of a m p l i t u d e o n testing the h a n d muscles before the a d m i n i s t r a t i o n of curare. P r o v o c a t i o n by exercise or ischemia was n o t used. Study with O.05 mg Methyl Curarine (Table 2). No certain correlation could be d e t e r m i n e d between the severity of the clinical picture a n d the reaction to curare in 9 patients. O n e p a t i e n t (Table 2, B.E.) was in full remission. She had not needed M e s t i n o n for 2 years a n d had n o symptoms. Using 0.05 mg methyl curarine regionally a distinct change in a m p l i t u d e of the a d d u c t o r pollicis a n d the hypot h e n a r e m i n e n c e were recorded.
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G. Hertel et al.
Art ditude 100 %
Hypothenar
80 60
25% =
40 20 I
I
I
I
T
'~"
2 4 6 8 10 30 /~F0 Time fottowing release of the tourniquet ( min )
t
Fig. 2. Regional test with 0.125 mg methyl curarine in a patient with faciopharyngeal myasthenia. Study of the hypothenar muscles. (Same illustration as in Fig. 1)
One patient (Table 2, S. St.) had a distinct weakness of the faciopharyngeal and thoracic muscles. An amplitude decrement of 45% occured in the deltoid muscle with the 3/sec stimulation. With the systemic curare test the weakness increased so considerably following 0.15 mg methyl curarine that the study had to be discontinued, while no change in amplitude was apparent in the hand muscles with the regional curare test. This patient had already been studied in regard to the hypothenar muscles several weeks earlier using 0.125 mg regionally. The amplitude remained unchanged with this dosage also (Table 3). Another patient (Table 2, K. Ch.) had such distinct bulbar symptoms that a systemic curare test could not be risked. Using 0.05 mg of methyl curarine regionally no change occured in the adductor pollicis; a reduction of the first potential of 20% was recorded in the hypothenar eminence only.
Study with O.125 mg Methyl Curarine (Table 3). Seven patients out of 8 had a distinct change of amplitude following curare. An example is shown in Figure 2. One of these patients (Table 3, D. R.) had a reduction of the first potential in the hypothenar muscles of 40% but no decrement of amplitude of the fifth potential. No change of amplitude was found in one patient who has already been discussed (Table 3, S. St.). Side Effects. In a 15 year old patient (Table 2, H.M.) serious bulbar symptoms became apparent following 0.05 mg methyl curarine after the release of the tourniquet. This girl suffered from a moderately severe generalized myasthenia, but she was medicated satisfactorily with 30 mg Mestinon twice daily and could go to school. Two other patients given 0.05 mg complained of light side effects such as heaviness of the eye lids, light headedness and drowsiness. The complaints occured immediately following the release of the tourniquet on the arm. In one patient (Table 3, K. Ch.) a threatening bulbar deterioration developed after 0.125 mg which required the injection of 1 mg Prostigmin i.v. Ocular Myasthenia. The following data were obtained from 3 patients with a clinical picture of myasthenia restricted to the ocular muscles:
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263
B. D., Male, 19 Years Old. The myasthenia started with double vision at the age of 7. Using 1 mg
methyl curarine systemically an increase of the paresis of the ocular muscles occured without involvement of other muscles. With the regional curare test an amplitude reduction of the first potential of 23% was registered in the hypothenar muscles following 0.125 mg methyl curarine. A decrement of the fifth potential did not occur. The adductor pollicis showed a decrement of the fifth potential of 36% but no reduction of the amplitude of the first potential. H.K., Male, 30 Years Old. Myasthenia set in several months earlier with double vision and slight ptosis. A Tensilon test showed no distinct improvement and therefore multiple sclerosis was brought into consideration. After 1 mg of methyl curarine injected systemically complete unilateral ptosis was evident and eye movement was considerably impaired. There were however no indications of involvement of other muscles. With the regional curare test using 0.125 mg methyl curarine a reduction of the first potential of 38% and a decrement of the fifth potential of 44% resulted in the hypothenar muscles. Following treatment with Mestinon, Prednisolon and Azathioprin the complaints receded completely in the course of 3 months. The clinical examination 6 months after the onset of the illness showed nothing conspicuous. With the systemic curare test using 1 mg slight double vision still occurred when changing the glance, but no ptosis. The regional curare test with 0.05 mg and 0.125 mg methyl curarine showed no more amplitude changes in the hypothenar eminence and adductor pollicis. B. R., Male, 41 Years Old. The myasthenia started several months ehrlier with unilateral ptosis following a long car drive. Examination six weeks later disclosed no additional signs. With 3/sec stimulation the amplitude of the hypothenar muscles was normal while the deltoid muscle showed a decrement of the fifth potential of 23%. With the systemic curare test using 0.75 mg methyl curarine distinct ocular and bulbar symptoms occurred. In the regional study using 0.2 mg we found a reduction of the first potential of 56% and a decrement of the fifth potential of 45% in the hypothenar muscles,
Discussion T h e p a r t i c u l a r difficulty o f the r e g i o n a l curare test lies in d e t e r m i n g the e x a c t b o r d e r b e t w e e n a n o r m a l a n d a p a t h o l o g i c a l reaction. B r o w n et al. [1] therefore tested n o r m a l subjects a n d m y a s t h e n i a patients with different dosages. They gave the n o r m a l subjects 0.5 m g d - t u b o c u r a r i n e (and m y a s t h e n i a patients 0.125 rag) and d e t e r m i n e d that in m o s t cases a considerable n e u r o m u s c u l a r block occurred. This d o s a g e is certainly quite high. S t a l b e r g et al. [10, 11] injected the same a m o u n t systemically i.v. a n d were a b l e to register a distinct increase o f j i t t e r in the a r m muscle o f the o t h e r side. F o l d e s et al. [2] f o u n d a r e d u c t i o n of a b o u t 10% o f the e r g o m e t r i c force in the h a n d on h e a l t h y subjects in the using 0.2 m g d - t u b o c u r a r i n e for the r e g i o n a l study. W e used m e t h y l - d - t u b o c u r a r i n e the d o s a g e o f which is 1/3 as c o m p a r e d to dt u b o c u r a r i n e . W i t h a m e d i u m d o s a g e o f 0.125 rag, 6 out o f 16 n o r m a l subjects s h o w e d a c h a n g e o f a m p l i t u d e ; using the lower dosage o f 0.05 m g this was nevertheless still the case in 3 out o f 10. The d o s a g e to which h e a l t h y subjects will definetly n o t react in the 3 / s e c test is therefore still lower. W h i l e s i m u l t a n e o u s l y s t u d y i n g the a d d u c t o r pollicis and h y p o t h e n a r muscles, several n o r m a l subjects s h o w e d this change in a m p l i t u d e in j u s t one o f the two muscles. This leads to the s u p p o s i t i o n t h a t the r e t r o g r a d e diffusion in the h a n d is not u n i f o r m a n d t h a t the c u r a r e c o n c e n t r a t i o n reaching the muscles varies. I n t e r p r e t i n g the changes in a m p l i t u d e in the 3/see test is m o r e difficult t h a n usual in the r e g i o n a l c u r a r e study. One m u s t consider the r e d u c t i o n o f a m p l i t u d e
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of the first potential after curare as well as the decrement of the fifth potential: no definite relation of these two values could be found (Figs. 1 and 2). The first potential was frequently lowered without a decrement of the fifth potential. In most of our myasthenia patients a more pronounced decrease in amplitude was found with the regional curare test as compared to normal subjects. However no definite correlation could be determined between the severity of the myasthenia and the reaction to the regional injection of curare. In one case of faciopharyngeal myasthenia no change in amplitude at all was recorded following 0.05 mg of methyl curarine; in another case only a slight decrease of the first potential occurred in one of two hand muscles studied. Using the regional curare test, myasthenia could not have been diagnosed in these two patients even though a curare dosage which could cause some healthy subjects to show a distinct change of amplitude was used. For routine diagnostic procedure of myasthenia the regional curare test seems to us to be less appropriate due to this uncertainty and the difficulty in performing it. For the diagnosis, the study of proximal muscles, such as the deltoid, gives considerably more reliable information with the 3/sec test [5]. The hand muscles are however seldom struck with myasthenia. We found in 23 myasthenia patients / 17 cases of a pathological decrement of amplitude in the deltoid muscle, but in only 3 of these cases was there evidence in the hand muscles [7]. In difficult cases the systemic curare test should be preferred [3, 8, 9]. In this test the subclinical involvement of all muscles can be judged. We were able to demonstrate in 25 of 60 myasthenia patients a participation of muscles with no clinical manifestations by means of the systemic curare test. 20 patients who clinically had only ocular myasthenia were shown to have a weakness of mainly proximal muscles by the systemic curare test. These findings are important in deciding the need for thymectomy. On the other hand, we were able to exclude myasthenia positively in 79 cases with the help of the systemic curare test. These findings were confirmed by further observation of the patients in 17 of whom a psychiatric disturbance became apparent [7]. The regional curare test is not essentially safer for the patient than the systemic test. Two of our patients developed bulbar symptoms suddenly after the tourniquet was released. The precautionary measures must therefore be basically the same as for the systemic test. On the other hand in 2 of our patients with ocular myasthenia we found evidence of generalized involvement only by means of the regional curare test. In another case the involvement of bulbar muscles had already been determined by the systemic curare test. The regional test also showed increased sensitivity to curare in the hand muscles. In known cases of ocular myasthenia in which no generalization is made apparent by the 3/sec test or the systemic curare test, the regional test can be put to use. The findings however must be carefully interpretated, especially in regard to the indication for thymectomy.
References
1. Brown, J. C., Charlton, J. E., White, D. J. K.: A regional technique for the study of sensitivity to curare in human muscle. J. Neurol. Neurosurg. Psychiat. 38, 18--26 (1975)
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2. Foldes, F., Glaser, G.: Diagnostic tests in myasthenia gravis. An overview. Ann. New York Acad. Sc. 183, 275--286 (1971) 3. Hertel, G., Ricker, K.: Der Curare-Test in der Diagnostik der Myasthenia gravis. Dtsch. med. Wschr. 102, 90--92 (1977) 4. Horowitz, S. H., Genkins, G., Kornfeld, P., Papatestas, A. E.: Regional curare test in evaluation of ocular myasthenia. Arch. Neurol. 32, 84--88 (1975) 5. Ozdemir, C., Young, R. R.: Electrical testing in myasthenia gravis. Ann. New York Acad. Sc. 183, 287--307 (1971) 6. Paton, W. D., Waud, D. R.: The margin of safety of neuromusculartransmission. J. Physiol. (London) 191, 59--90 (1967) 7. Ricker, K., Hertel, G.: Klinische Wertigkeit diagnostischer Methoden. In: Myasthenia gravis. Edit. G. Hertel, H. G. Mertens, K. Ricker, K. Schimrigk. Stuttgart: Thieme 1977 8. Rowland, L. P., Aranow, H., Hoefer, P. F.: Observations onthe curare test in the differential diagnosis of myasthenia gravis. In: H. R. Viets, edit. Myasthenia gravis: A symposium, pp. 4 1 1 4 3 4 . Springfield (Ill.): Thomas 1961 9. Simpson, J. A.: Myasthenia gravis and myasthenic syndromes. In: J. N. Walton, edit. Disorders of voluntary muscle. 3rd edit, pp. 653 692. Edinburgh, London: Churchill Livingstone 1974 10. Schwartz, M. S., Stalberg, E.: Single fibre electromyographic studies in myasthenia gravis with repetitive nerve stimulation. J. Neurol. Neurosurg. Psychiat. 38, 678--682 (1975) 11. Stalberg, E., Schiller, H. H., Schwartz, M.: Safety factor in single human motor endplates studied in vivo with single fibre electromyography. J. Neurol. Neurosurg. Psychiat. 38, 799--804 (1975)
Received August 23, 1976
