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The mean duration of motor unit action potentials in patients with myasthenia gravis
E l e c t r o e n c e p h a l o g r a p h y a n d Clinical N e u r o p h y s i o l o g y Elsevier P u b l i s h i n g C o m p a n y , A m s t e r d a m - Printed in T h e N e t h e r l a n d s
CLINICAL
697
NOTE
THE M E A N D U R A T I O N
OF M O T O R U N I T A C T I O N P O T E N T I A L S
IN P A T I E N T S W I T H M Y A S T H E N I A G R A V I S H . J. G . H . OOSTERHUIS, W . J. M . HOOTSMANS, H . B. VEENHUYZEN AND INE VAN ZADELHOFF
Department of Neurology, University of Amsterdam, Wilhelrnina Gasthuis, Amsterdam (The Netherlands') (Accepted for publication : December 9, 1971)
In routine examinations of patients with myasthenia gravis we noticed that the mean duration of the m o t o r unit action potentials (APm) was often shortened. This finding was suggestive of the presence of myopathic changes, but clinical and biochemical findings were inconsistent with this suggestion and no myopathic changes were found in muscle biopsy specimens. The literature supplies only scanty data on the A P m in myasthenia gravis; only Teasdall and Sears (1962) mentioned a shortened A P m in the orbicular muscle of the eye and the first interosseous muscle in patients with myasthenia gravis. Van der Most van Spijk (1964) found no change of the refractory period in patients with myasthenia gravis; this is an argument against the presence of myopathic changes. In view of the practical importance for the diagnosis of myasthenia gravis and its differentiation from other diseases, we determined the APm in the quadriceps and deltoid muscles in all patients with myasthenia gravis seen during the period 1965 1970. METHOD At a low level of contraction we tried to obtain a single pattern. The action potentials were derived via concentric needle electrodes (D1SA, type 13 K 0032, needle length 42 m m , diameter 0.65 m m , surface platina electrode 0.65 m m 2 ; cut under angle of 15°), using the method of Buchthal et al. (Buchthal et al. 1954a ; Buchthal and Rosenfalck 1955 ; Sacco et al. 1962). The APm was expressed as a percentage of the normal value for the corresponding age group; for this we made use of the normal values reported by Buchthal (1957). The action potentials were filmed ; the sweep duration of the film without delay line was 20 or 50 msec ; later, with the delay line, it was 50 msec. The amplification was 50-100 #V/cm ; the amplitudes of the action potentials varied from 150 to 400 #V and frequency range was 0.6-10,000 c/sec. The amplification factor was selected in proportion to the amplitudes to be recorded, thus eliminating the possible influence of the amplification on the duration of the action potentials. Possible changes of other parameters of the motor unit potential were not studied. The action potentials were measured directly from the film with the aid of a special projector ensuring a magnification of 7 diameters. The APm was determined from the durations of 15-20 action potentials, each of which was recognizable at least 3 times in the film.
The needle electrodes were always placed by one investigator (W.J.M.H.) and the duration of the action potentials was always measured by another (I.v.Z.). The standard error of measurement proved to be 0.34).5 msec. Measuring was done as a rule immediately before the patient took the next oral medication, but in some instances after an intramuscular injection of anticholinesterase. No precautions were taken to control the muscle temperature, which was not measured. PATIENTS The findings were obtained from 40 patients with myasthenia gravis, only some of w h o m were hospitalized. All patients had a complete neurological examination; in 16 patients a biopsy specimen was taken from the quadriceps muscle not used to measure the action potential. The clinical condition ranged from complete mobility to total bed-ridden disability with inability to use the test muscles more than once. The patients were divided into four categories according to muscle strength.
Deltoid muscle A. Can extend arms horizontally for 3 min: history indicates normal strength. This group includes patients with purely ocular myasthenia. B. Can extend arms horizontally for more than 1 min: history indicates slight fatiguability. C. Can extend arms horizontally for 30-60 sec: history indicates moderate symptoms. D. Can extend arms horizontally for less than 30 sec: history indicates severe symptoms. Quadriceps muscle A. Can easily perform 10 deep knee-bends ; history indicates normal strength. B. Can perform 10 deep knee-bends with difficulty; history indicates mild symptoms. C. Can perform a few deep knee-bends (sometimes only if assisted) : history indicates moderate symptoms. D. C a n n o t perform deep knee-bends; history indicates severe symptoms. Controls Forty-six patients in w h o m the APm had been measured Electroenceph. din. Neurophysiol., 1972, 32:697 700
698
n.J.G.H.
OOSTERHUIS et al.
corresponding standard deviations (SD'!I,) in the clinically different groups of patients with myasthenia gravis are presented in Table 1 : those for the different groups of controls are given in Table lI. Table I shows that the AP., was shorter as the muscle examined was weaker. The differences between group A and B. A and D, B and D. and C and D were statistically significant (variance analysis P < 0.0l : Wilcoxon test P < 0.01 ). The range of AP,,, values in each of the four categories was considerable and, specifically in categories B and C, normal as well as very low values occurred. The difference in AP,, between groups B and C was not significant for either the deltoid or the quadriceps muscle. Table I1 shows that the normal controls had AP m values that were lower than the mean as indicated by Buchthal : the patients with muscle diseases had a subnormal AP,,,, as expected. The neurological patients and the group with fatigue and myalgia showed AP,, values Power than the normals, particularly for the deltoid muscle (although the muscles were clinically unaffected).
for some reason or who had been asked to serve as controls, were divided into four categories: I. 15 patients without neurological disease or symptoms of muscle disease, designated as normal. Age 12 52. I1.8 patients with a neurological disease without peripheral motor neurone or muscle involvement. Age 25 73. IIl. 10 patients complaining of fatigue or myalgia, with no clinical or laboratory evidence of organic disease (specifically no muscle disease), while a biopsy specimen from the quadriceps muscle showed normal features. Age 14 66. IV. 13 patients with muscle diseases. Diagnoses: muscular dystrophy, all types, 9 (age 23 61), myotonic dystrophy, 1 (age 40) ; dermatomyositis, 1 (age 28) : mitochondrial myopathy, 1 (age 58); central core disease. 1 (age 27).
Muscle biopsy (Prof. Dr. J. Bethlem. Neuropathological Laboratory) A biopsy specimen measuring 2 x 1 x 1 cm was taken under local anaesthesia from the quadriceps muscle contralateral to that used to measure the action potentials. Cryostat sections were stained for ATP-ase calcium activity. Paraffin sections were stained with haematoxylin-eosin and Gomori's trichrome stain. The minimal and maximal diameters of at least 200 muscle fibres were measured according to Brooke and Engel (1969).
ln[luence of anticholinesterases In 8 patients the AP m was measured before and after intramuscular injection of neostigmine or pyridostigmine (Mestinon). In the 2 patients whose muscle strength was unmistakably increased following anticholmesterase administration, the AP m lengthened significantly; in the remaining 6, strength as well as AP m remained about constant before and after anticholinesterase administration.
RESULTS The mean values of the individual APm (M°il) and the
TABLE I The AP m in 40 patients with myasthenia gravis. In some patients whose clinical condition permitted a transfer to another category, several measurements were made.
Number of measurements
M'}~
SD%
Muscle strength category
13 12 12 9
76 59 56 46
23 12 11 4
A B C D
Deltoid
Quadriceps . . . . . . . . . Number of M?,i, measurements 20 17 9 3
73 64 58 47
SD?I,
15 18 12 4
TABLE 1I The AP m in 46 control patients. Control category
Deltoid Number of M II~, measurements
SD%
15 8 10 11
10 13 15 1t
90 70 65 58
1 normal subjects lI neurol, patients III fatigue, myalgia IV muscle disease
Quadriceps Number of measurements
M'!;
SD"I,
15 4 10 10
86 73 72 62
9 8 14 18
Electroenceph. c/in. Neurophysiol., 1972, 32:697 700
699
MYASTHENIA GRAVIS
b~lluence (!f clinieal improvement A follow-up was made throughout the course of illness in 4 patients. The APm generally lengthened in accordance with the improvement in the clinical condition. Fig. 1 shows the AP m values and muscle strength rating in a young man with severe generalized myasthenia not involving the respiratory musculature. Six months after the onset of symptoms, at age 17, he was unable to walk without assistance and could not raise his arms. There was some improvement of muscle strength and lengthening of the AP m in the deltoid and the m e a n d u r a t i o n of m u s c l e a c t i o n p o t e n t i a l s (APm) a n d m u s c l e s t r e n g t h in M Y A S T H E N I A GRAVIS AP m
strength
%
t
I00
[
B
I
neostigm~f//. .
.
.
.
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.
.
.
.
.
.
.
.
.
.
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.
.
C
.
I
D
...... t
##
- .+sl' llLll
I
ACTH
/ i thymectomy
'70
m.qulldriceps nndettoideus . . . . .
strength strength
J Ap m ~ Ap m
Fig. 1. The lines (right) indicate the muscle strength with reference to the 4 categories A, B, C and D as described in the text ; open squares and circles indicate the mean duration of the muscle action potentials (APm). Intramuscular injections of neostigmine increased the muscle strength as well as the APm. The AP m measured is compared with the normal APm for age and sex (male, 19 years). quadriceps muscle after neostigmine injection. No improvement folfowed thymectomy. Substantial improvement was observed from the 10th day after institution of a course of ACTH (cortrophine-Z) medication (100 units per day during 10 days) ; this was manifest in strength as well as in APm. This patient's clinical condition has remained stationary since the end of 1967: he can keep his arms raised for a maximum of 1 min, walks without limitation but is unable to run or climb.
Correlation between AP,, and histology of the quadriceps musele An analysis of the data shows that there was no correlation between the mean diameter (maximum or minimum) of the muscle fibres and the AP m. Within the group of 16 patients, the clinical condition likewise showed no correlation either with the AP,,, or with the mean diameter. DISCUSSION Our study shows that t h e A P m, measured at a low level of contraction, was often shortened in patients with myasthenia gravis. This is of practical significance inasmuch as the diagnosis must not be rejected on the basis of this finding. Nor can it be stated that a shortened APM in patients with
myasthenia gravis indicates the presence of myopathic changes. Studies of muscle biopsy specimens (Fenichel and Shy 1963 ; Fenichel 1966 ; Oosterhuis et al. 1968)have revealed that the muscles in myasthenic patients sometimes show neurogenic changes; this was also the case in 6 of the 16 patients examined in our series. An explanation of the shortening of the AP m in patients with myasthenia gravis is probably to be sought in a diminution of the single fibre potentials which simultaneously contribute to the motor unit action potential. Investigations by Ekstedt and StMberg (1967), Ekstedt et al. (1969) and Biota and Ringqvist (1971) have shown that, in myasthenia gra,~is, a number of single fibres can be temporarily blocked, and that different motor end-plates in one muscle can be differently affected. In this way a "myopathic" EMG pattern is produced in histologically normal or neurogenically altered muscles. The absence of a correlation between APm and mean fibre diameter in our study suggests that functional disorders rather than anatomical changes are responsible for the shortening of the AP m. In a number of our patients theAP mlengthened following administration of anticholinesterases : in others, neostigmine or pyridostigmine exerted no influence. The AP,,~ was generally related to the strength of the muscle, although lhis was certainly not always the case. The difference in AP,,, was significant between g r o u p s A and B, A and D, B and D, and C and D; but not between groups B and C. Perhaps this was due to a too random choice of criteria used in separating B from C. The range was considerable, even within the groups. It is therefore evident that a positive contribution to the diagnosis of myasthenia gravis can hardly be made by measuring the APm. This is the more true because shortening of the AP,, was also observed in the control group, in two categories of patients in whom this was not expected. This applied in particular to the deltoid muscle. In this context it can be pointed out that no biopsy specimen from this muscle ~as examined in the groups of patients complaining of fatigue or myalgia; in this group, however, the quadriceps muscle was histologically normal, and there were no clinical or biochemical arguments in favour of an organic disease. The control patients with muscle diseases generally fulfilled expectations in this respect (AP,n decreased). The normal values reported by Buchthal (1957) arc 1020°.o higher than our experience indicates; this applies in particular to the older age groups. This was also the experience of Steinbrecher (1965), who used the method described by Buchthal. It is difficult to explain this discrepancy, but a systematic difference in measuring method seems a possibility. Since our patients were not especially "warmed up" for the examination, the intramuscular temperature may have been below 37"C. However. this would have been more likely to lengthen the AP m (Buchthal et al. 1954b : AP m lengthened by 10-30% with a decrease in intramuscular temperature by I°C). In actual practice, determination oftheAP min the manner described by Buchthal (1957) proved to involve a great deal of work. The findings obtait~ed, moreover, suggest thac this method (at least in our hands) produces too many false positive results to be very useful in individual diagnoses. What remains to be established is whether these false positive results are inherent in the method or must be ascribed to the
Eleetroenceph. olin. Neurophysiol.. 1972, 32: 69";' 700
H . J . G . H . OOSTERHUIS et al.
700 parameter as such, which is too little specific to be clinically useful. In this respect, more recent m e t h o d s of measuring the A P m can perhaps be of use (Kopec and H a u s m a n o w a Petrusewicz 1969; Magora and G o n e n 1970). SUMMARY The mean duration of m o t o r unit action potentials (AP m) was measured in 40 patients with myasthenia gravis in different clinical conditions. Findings were obtained from the quadriceps and the deltoid muscles. In 16 patients a muscle biopsy specimen was taken from the contralateral quadriceps muscle. The findings warrant the following conclusions : 1. The APm is often shortened in patients with myasthenia gravis, in particular those with little muscle strength. 2. The A Pm is a parameter of low specificity, for important deviations from normal were observed in patients without organic neurological disease or neurological patients without peripheral motor neurone or muscle involvement. 3. The shortening o f t h e A P m does not seem to result from any anatomical change in the muscle. 4. It is postulated that shortening of t h e A P m results from diminution of the single fibre potentials (Ekstedt et al. 1967, 1969), which simultaneously contribute to the motor unit action potential. RESUME D U R E E M O Y E N N E DES P O T E N T I E L S D'UNITES MOTRICES CHEZ DES A T T E I N T S DE M Y A S T H E N I E G R A V E
D'ACTION MALADES
La dur6e moyenne des potentiels d'action d'unit6s motrices (PAm) a 6t~ mesur6e chez 40 malades atteints de myasth6nie grave dans diff6rentes conditions cliniques. Ces donn6es ont 6t6 obtenues au niveau des muscles quadriceps et deltoide. Chez 16 malades, une biopsie musculaire a 6t6 prdlev6e au niveau du muscle quadriceps controlatdral. Les r6sultats conduisent aux conclusions suivantes: I. Le PA m est souvent raccourci chez les malades atteints de myasthdnie grave, en particulier chez ceux qui ont peu de force musculaire. 2. Le PAm est un param6tre de faible sp6cificit6, car d'importantes d6viations de la norme s'observent chez des malades sans atteinte neurologique organique ou chez des malades neurologiques sans participation des muscles ou des motoneurones p6riph6riques. 3. Le raccourcissement du PAm ne para~t pas r6sulter d'une modification anatomique quelconque fi l'intdrieur du muscle. 4. Les auteurs concluent que le raccourcissement du PAm r6sulte de la diminution des potentiels de fibre isol6e (Ekstedt et al., 1967, 1969) qui contribuent de fa~;on conj ointe aux potentiels d'action de l'unit6 motrice.
REFERENCES BLOM, S. and RINGQVIST, 1. Neurophysiological findings in myasthenia gravis. Electroenceph. clin. Neurophysiol., 1971, 30: 4 7 7 4 8 7 . BROOKE, M. H. and ENGEL, W. K. The histografic analysis of h u m a n muscle biopsies with regard to fiber types. Neurology (Minneap.), 1969, 19:221 233. BUCHTHAL, F. An introduction to electromyography. Scand. Univ. Books, Gytdendal, Kobenhavn, 1957, 36 p. BUCHTHAL, F. and ROSENFALCK, P. Action potential parameters in different h u m a n muscles. Acta psychiat. scan&, 1955, XXX: 125 131. BUCHTHAL, F., GULD, C. and ROSENFALCK, P. Action potential parameters in normal h u m a n muscle and their dependence on physical variables. Acre physiol, scand.. 1954a, 32:200 218. BUCHTHAL, F., PINELLI, P. and ROSENFALCK, P. Action potential parameters in normal h u m a n muscle and their physiological determinants. Acta physiol, scand., 1954b, 32 : 219-229. EKSTEDT, J. and STALBERG, E. Myasthenia gravis. Diagnostic aspects by a new electrophysiological method. Opusc. med. (Stockh.), 1967, 12:73 76. EKSTEDT, J., STALBERG, E. and BROMAN, ./\. Are all motor end-plates equally affected in a myasthenic muscle? Electroenceph. clin. Neurophysiol.. 1969, 2 7 : 7 2 6 727. FENICHEL, G. M. Muscle lesions in myasthenia gravis. Ann. N.Y. Acad. Sci., 1966, 135:62 67. FENICHEL, G. M. and SHY, G. M. Muscle biopsy experience in myasthenia gravis. Arch. Neurol. (Chic.), 1963, 9: 237 243. KoPEc, J. and HAUSMANOWA-PETRUSEWICZ,1. Histogram of muscle potentials recorded automatically with the aid of the averaging computer " A n o p s " . E/ectromyography, 1969, 4:371 381. MAGORA, A. and GONEN, B. A new technique for the extraction of the activity of single motor units from the electromyography of maximal contraction. Electromyography, 1970, 2 : 1 5 5 170. MOST VAN SPIJK, O. VAN DER. Refractory and irresponsive periods in the muscles of myasthenic patients. Ned. T. Geneesk., 1964, 108: 1554~1556. OOSTERHUIS, H. J. G. H., BETHLEM, J. and FELTKAMP, T. E. W. Muscle pathology, t h y m o m a and immunological abnormalities in patients with myasthenia gravis. J. Neurol. Neurosurq. Psychiat., 1%8, 31 : 460 463. SAf'CO, G., BUCHTHAL, F. and ROSENFAL('K, P. Motor unit potentials at different ages. Arch. Neurol. (Chic'.), 1962, 6 : 4 ~ 51. STEINBRECHER, W. Elektromyographie in Klinik und Praxis. Thieme, Stuttgart, 1965, 112 p. TEASDALL, R. D. and SEARS, M. L. Electromyographic evidence for myopathy. Amer. J. Ophthal.. 1962, 54: 541 546.
The statistical validity was checked by H. Mattie. The muscle biopsy specimens were assessed by Prof. Dr. J. Bethlem.
ReJerence: OOSTERHUIS, H. J. G. H., HOOTSMANS,W. J. M., VEENHUYZEN, H. B. and ZADEI.HO|.I., 1. VAN. The mean duration of motor unit action potentials in patients with myasthenia gravis. Electroenceph. din. Neurophysiol., 1972, 32:697 700.
CLINICAL
697
NOTE
THE M E A N D U R A T I O N
OF M O T O R U N I T A C T I O N P O T E N T I A L S
IN P A T I E N T S W I T H M Y A S T H E N I A G R A V I S H . J. G . H . OOSTERHUIS, W . J. M . HOOTSMANS, H . B. VEENHUYZEN AND INE VAN ZADELHOFF
Department of Neurology, University of Amsterdam, Wilhelrnina Gasthuis, Amsterdam (The Netherlands') (Accepted for publication : December 9, 1971)
In routine examinations of patients with myasthenia gravis we noticed that the mean duration of the m o t o r unit action potentials (APm) was often shortened. This finding was suggestive of the presence of myopathic changes, but clinical and biochemical findings were inconsistent with this suggestion and no myopathic changes were found in muscle biopsy specimens. The literature supplies only scanty data on the A P m in myasthenia gravis; only Teasdall and Sears (1962) mentioned a shortened A P m in the orbicular muscle of the eye and the first interosseous muscle in patients with myasthenia gravis. Van der Most van Spijk (1964) found no change of the refractory period in patients with myasthenia gravis; this is an argument against the presence of myopathic changes. In view of the practical importance for the diagnosis of myasthenia gravis and its differentiation from other diseases, we determined the APm in the quadriceps and deltoid muscles in all patients with myasthenia gravis seen during the period 1965 1970. METHOD At a low level of contraction we tried to obtain a single pattern. The action potentials were derived via concentric needle electrodes (D1SA, type 13 K 0032, needle length 42 m m , diameter 0.65 m m , surface platina electrode 0.65 m m 2 ; cut under angle of 15°), using the method of Buchthal et al. (Buchthal et al. 1954a ; Buchthal and Rosenfalck 1955 ; Sacco et al. 1962). The APm was expressed as a percentage of the normal value for the corresponding age group; for this we made use of the normal values reported by Buchthal (1957). The action potentials were filmed ; the sweep duration of the film without delay line was 20 or 50 msec ; later, with the delay line, it was 50 msec. The amplification was 50-100 #V/cm ; the amplitudes of the action potentials varied from 150 to 400 #V and frequency range was 0.6-10,000 c/sec. The amplification factor was selected in proportion to the amplitudes to be recorded, thus eliminating the possible influence of the amplification on the duration of the action potentials. Possible changes of other parameters of the motor unit potential were not studied. The action potentials were measured directly from the film with the aid of a special projector ensuring a magnification of 7 diameters. The APm was determined from the durations of 15-20 action potentials, each of which was recognizable at least 3 times in the film.
The needle electrodes were always placed by one investigator (W.J.M.H.) and the duration of the action potentials was always measured by another (I.v.Z.). The standard error of measurement proved to be 0.34).5 msec. Measuring was done as a rule immediately before the patient took the next oral medication, but in some instances after an intramuscular injection of anticholinesterase. No precautions were taken to control the muscle temperature, which was not measured. PATIENTS The findings were obtained from 40 patients with myasthenia gravis, only some of w h o m were hospitalized. All patients had a complete neurological examination; in 16 patients a biopsy specimen was taken from the quadriceps muscle not used to measure the action potential. The clinical condition ranged from complete mobility to total bed-ridden disability with inability to use the test muscles more than once. The patients were divided into four categories according to muscle strength.
Deltoid muscle A. Can extend arms horizontally for 3 min: history indicates normal strength. This group includes patients with purely ocular myasthenia. B. Can extend arms horizontally for more than 1 min: history indicates slight fatiguability. C. Can extend arms horizontally for 30-60 sec: history indicates moderate symptoms. D. Can extend arms horizontally for less than 30 sec: history indicates severe symptoms. Quadriceps muscle A. Can easily perform 10 deep knee-bends ; history indicates normal strength. B. Can perform 10 deep knee-bends with difficulty; history indicates mild symptoms. C. Can perform a few deep knee-bends (sometimes only if assisted) : history indicates moderate symptoms. D. C a n n o t perform deep knee-bends; history indicates severe symptoms. Controls Forty-six patients in w h o m the APm had been measured Electroenceph. din. Neurophysiol., 1972, 32:697 700
698
n.J.G.H.
OOSTERHUIS et al.
corresponding standard deviations (SD'!I,) in the clinically different groups of patients with myasthenia gravis are presented in Table 1 : those for the different groups of controls are given in Table lI. Table I shows that the AP., was shorter as the muscle examined was weaker. The differences between group A and B. A and D, B and D. and C and D were statistically significant (variance analysis P < 0.0l : Wilcoxon test P < 0.01 ). The range of AP,,, values in each of the four categories was considerable and, specifically in categories B and C, normal as well as very low values occurred. The difference in AP,, between groups B and C was not significant for either the deltoid or the quadriceps muscle. Table I1 shows that the normal controls had AP m values that were lower than the mean as indicated by Buchthal : the patients with muscle diseases had a subnormal AP,,,, as expected. The neurological patients and the group with fatigue and myalgia showed AP,, values Power than the normals, particularly for the deltoid muscle (although the muscles were clinically unaffected).
for some reason or who had been asked to serve as controls, were divided into four categories: I. 15 patients without neurological disease or symptoms of muscle disease, designated as normal. Age 12 52. I1.8 patients with a neurological disease without peripheral motor neurone or muscle involvement. Age 25 73. IIl. 10 patients complaining of fatigue or myalgia, with no clinical or laboratory evidence of organic disease (specifically no muscle disease), while a biopsy specimen from the quadriceps muscle showed normal features. Age 14 66. IV. 13 patients with muscle diseases. Diagnoses: muscular dystrophy, all types, 9 (age 23 61), myotonic dystrophy, 1 (age 40) ; dermatomyositis, 1 (age 28) : mitochondrial myopathy, 1 (age 58); central core disease. 1 (age 27).
Muscle biopsy (Prof. Dr. J. Bethlem. Neuropathological Laboratory) A biopsy specimen measuring 2 x 1 x 1 cm was taken under local anaesthesia from the quadriceps muscle contralateral to that used to measure the action potentials. Cryostat sections were stained for ATP-ase calcium activity. Paraffin sections were stained with haematoxylin-eosin and Gomori's trichrome stain. The minimal and maximal diameters of at least 200 muscle fibres were measured according to Brooke and Engel (1969).
ln[luence of anticholinesterases In 8 patients the AP m was measured before and after intramuscular injection of neostigmine or pyridostigmine (Mestinon). In the 2 patients whose muscle strength was unmistakably increased following anticholmesterase administration, the AP m lengthened significantly; in the remaining 6, strength as well as AP m remained about constant before and after anticholinesterase administration.
RESULTS The mean values of the individual APm (M°il) and the
TABLE I The AP m in 40 patients with myasthenia gravis. In some patients whose clinical condition permitted a transfer to another category, several measurements were made.
Number of measurements
M'}~
SD%
Muscle strength category
13 12 12 9
76 59 56 46
23 12 11 4
A B C D
Deltoid
Quadriceps . . . . . . . . . Number of M?,i, measurements 20 17 9 3
73 64 58 47
SD?I,
15 18 12 4
TABLE 1I The AP m in 46 control patients. Control category
Deltoid Number of M II~, measurements
SD%
15 8 10 11
10 13 15 1t
90 70 65 58
1 normal subjects lI neurol, patients III fatigue, myalgia IV muscle disease
Quadriceps Number of measurements
M'!;
SD"I,
15 4 10 10
86 73 72 62
9 8 14 18
Electroenceph. c/in. Neurophysiol., 1972, 32:697 700
699
MYASTHENIA GRAVIS
b~lluence (!f clinieal improvement A follow-up was made throughout the course of illness in 4 patients. The APm generally lengthened in accordance with the improvement in the clinical condition. Fig. 1 shows the AP m values and muscle strength rating in a young man with severe generalized myasthenia not involving the respiratory musculature. Six months after the onset of symptoms, at age 17, he was unable to walk without assistance and could not raise his arms. There was some improvement of muscle strength and lengthening of the AP m in the deltoid and the m e a n d u r a t i o n of m u s c l e a c t i o n p o t e n t i a l s (APm) a n d m u s c l e s t r e n g t h in M Y A S T H E N I A GRAVIS AP m
strength
%
t
I00
[
B
I
neostigm~f//. .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
C
.
I
D
...... t
##
- .+sl' llLll
I
ACTH
/ i thymectomy
'70
m.qulldriceps nndettoideus . . . . .
strength strength
J Ap m ~ Ap m
Fig. 1. The lines (right) indicate the muscle strength with reference to the 4 categories A, B, C and D as described in the text ; open squares and circles indicate the mean duration of the muscle action potentials (APm). Intramuscular injections of neostigmine increased the muscle strength as well as the APm. The AP m measured is compared with the normal APm for age and sex (male, 19 years). quadriceps muscle after neostigmine injection. No improvement folfowed thymectomy. Substantial improvement was observed from the 10th day after institution of a course of ACTH (cortrophine-Z) medication (100 units per day during 10 days) ; this was manifest in strength as well as in APm. This patient's clinical condition has remained stationary since the end of 1967: he can keep his arms raised for a maximum of 1 min, walks without limitation but is unable to run or climb.
Correlation between AP,, and histology of the quadriceps musele An analysis of the data shows that there was no correlation between the mean diameter (maximum or minimum) of the muscle fibres and the AP m. Within the group of 16 patients, the clinical condition likewise showed no correlation either with the AP,,, or with the mean diameter. DISCUSSION Our study shows that t h e A P m, measured at a low level of contraction, was often shortened in patients with myasthenia gravis. This is of practical significance inasmuch as the diagnosis must not be rejected on the basis of this finding. Nor can it be stated that a shortened APM in patients with
myasthenia gravis indicates the presence of myopathic changes. Studies of muscle biopsy specimens (Fenichel and Shy 1963 ; Fenichel 1966 ; Oosterhuis et al. 1968)have revealed that the muscles in myasthenic patients sometimes show neurogenic changes; this was also the case in 6 of the 16 patients examined in our series. An explanation of the shortening of the AP m in patients with myasthenia gravis is probably to be sought in a diminution of the single fibre potentials which simultaneously contribute to the motor unit action potential. Investigations by Ekstedt and StMberg (1967), Ekstedt et al. (1969) and Biota and Ringqvist (1971) have shown that, in myasthenia gra,~is, a number of single fibres can be temporarily blocked, and that different motor end-plates in one muscle can be differently affected. In this way a "myopathic" EMG pattern is produced in histologically normal or neurogenically altered muscles. The absence of a correlation between APm and mean fibre diameter in our study suggests that functional disorders rather than anatomical changes are responsible for the shortening of the AP m. In a number of our patients theAP mlengthened following administration of anticholinesterases : in others, neostigmine or pyridostigmine exerted no influence. The AP,,~ was generally related to the strength of the muscle, although lhis was certainly not always the case. The difference in AP,,, was significant between g r o u p s A and B, A and D, B and D, and C and D; but not between groups B and C. Perhaps this was due to a too random choice of criteria used in separating B from C. The range was considerable, even within the groups. It is therefore evident that a positive contribution to the diagnosis of myasthenia gravis can hardly be made by measuring the APm. This is the more true because shortening of the AP,, was also observed in the control group, in two categories of patients in whom this was not expected. This applied in particular to the deltoid muscle. In this context it can be pointed out that no biopsy specimen from this muscle ~as examined in the groups of patients complaining of fatigue or myalgia; in this group, however, the quadriceps muscle was histologically normal, and there were no clinical or biochemical arguments in favour of an organic disease. The control patients with muscle diseases generally fulfilled expectations in this respect (AP,n decreased). The normal values reported by Buchthal (1957) arc 1020°.o higher than our experience indicates; this applies in particular to the older age groups. This was also the experience of Steinbrecher (1965), who used the method described by Buchthal. It is difficult to explain this discrepancy, but a systematic difference in measuring method seems a possibility. Since our patients were not especially "warmed up" for the examination, the intramuscular temperature may have been below 37"C. However. this would have been more likely to lengthen the AP m (Buchthal et al. 1954b : AP m lengthened by 10-30% with a decrease in intramuscular temperature by I°C). In actual practice, determination oftheAP min the manner described by Buchthal (1957) proved to involve a great deal of work. The findings obtait~ed, moreover, suggest thac this method (at least in our hands) produces too many false positive results to be very useful in individual diagnoses. What remains to be established is whether these false positive results are inherent in the method or must be ascribed to the
Eleetroenceph. olin. Neurophysiol.. 1972, 32: 69";' 700
H . J . G . H . OOSTERHUIS et al.
700 parameter as such, which is too little specific to be clinically useful. In this respect, more recent m e t h o d s of measuring the A P m can perhaps be of use (Kopec and H a u s m a n o w a Petrusewicz 1969; Magora and G o n e n 1970). SUMMARY The mean duration of m o t o r unit action potentials (AP m) was measured in 40 patients with myasthenia gravis in different clinical conditions. Findings were obtained from the quadriceps and the deltoid muscles. In 16 patients a muscle biopsy specimen was taken from the contralateral quadriceps muscle. The findings warrant the following conclusions : 1. The APm is often shortened in patients with myasthenia gravis, in particular those with little muscle strength. 2. The A Pm is a parameter of low specificity, for important deviations from normal were observed in patients without organic neurological disease or neurological patients without peripheral motor neurone or muscle involvement. 3. The shortening o f t h e A P m does not seem to result from any anatomical change in the muscle. 4. It is postulated that shortening of t h e A P m results from diminution of the single fibre potentials (Ekstedt et al. 1967, 1969), which simultaneously contribute to the motor unit action potential. RESUME D U R E E M O Y E N N E DES P O T E N T I E L S D'UNITES MOTRICES CHEZ DES A T T E I N T S DE M Y A S T H E N I E G R A V E
D'ACTION MALADES
La dur6e moyenne des potentiels d'action d'unit6s motrices (PAm) a 6t~ mesur6e chez 40 malades atteints de myasth6nie grave dans diff6rentes conditions cliniques. Ces donn6es ont 6t6 obtenues au niveau des muscles quadriceps et deltoide. Chez 16 malades, une biopsie musculaire a 6t6 prdlev6e au niveau du muscle quadriceps controlatdral. Les r6sultats conduisent aux conclusions suivantes: I. Le PA m est souvent raccourci chez les malades atteints de myasthdnie grave, en particulier chez ceux qui ont peu de force musculaire. 2. Le PAm est un param6tre de faible sp6cificit6, car d'importantes d6viations de la norme s'observent chez des malades sans atteinte neurologique organique ou chez des malades neurologiques sans participation des muscles ou des motoneurones p6riph6riques. 3. Le raccourcissement du PAm ne para~t pas r6sulter d'une modification anatomique quelconque fi l'intdrieur du muscle. 4. Les auteurs concluent que le raccourcissement du PAm r6sulte de la diminution des potentiels de fibre isol6e (Ekstedt et al., 1967, 1969) qui contribuent de fa~;on conj ointe aux potentiels d'action de l'unit6 motrice.
REFERENCES BLOM, S. and RINGQVIST, 1. Neurophysiological findings in myasthenia gravis. Electroenceph. clin. Neurophysiol., 1971, 30: 4 7 7 4 8 7 . BROOKE, M. H. and ENGEL, W. K. The histografic analysis of h u m a n muscle biopsies with regard to fiber types. Neurology (Minneap.), 1969, 19:221 233. BUCHTHAL, F. An introduction to electromyography. Scand. Univ. Books, Gytdendal, Kobenhavn, 1957, 36 p. BUCHTHAL, F. and ROSENFALCK, P. Action potential parameters in different h u m a n muscles. Acta psychiat. scan&, 1955, XXX: 125 131. BUCHTHAL, F., GULD, C. and ROSENFALCK, P. Action potential parameters in normal h u m a n muscle and their dependence on physical variables. Acre physiol, scand.. 1954a, 32:200 218. BUCHTHAL, F., PINELLI, P. and ROSENFALCK, P. Action potential parameters in normal h u m a n muscle and their physiological determinants. Acta physiol, scand., 1954b, 32 : 219-229. EKSTEDT, J. and STALBERG, E. Myasthenia gravis. Diagnostic aspects by a new electrophysiological method. Opusc. med. (Stockh.), 1967, 12:73 76. EKSTEDT, J., STALBERG, E. and BROMAN, ./\. Are all motor end-plates equally affected in a myasthenic muscle? Electroenceph. clin. Neurophysiol.. 1969, 2 7 : 7 2 6 727. FENICHEL, G. M. Muscle lesions in myasthenia gravis. Ann. N.Y. Acad. Sci., 1966, 135:62 67. FENICHEL, G. M. and SHY, G. M. Muscle biopsy experience in myasthenia gravis. Arch. Neurol. (Chic.), 1963, 9: 237 243. KoPEc, J. and HAUSMANOWA-PETRUSEWICZ,1. Histogram of muscle potentials recorded automatically with the aid of the averaging computer " A n o p s " . E/ectromyography, 1969, 4:371 381. MAGORA, A. and GONEN, B. A new technique for the extraction of the activity of single motor units from the electromyography of maximal contraction. Electromyography, 1970, 2 : 1 5 5 170. MOST VAN SPIJK, O. VAN DER. Refractory and irresponsive periods in the muscles of myasthenic patients. Ned. T. Geneesk., 1964, 108: 1554~1556. OOSTERHUIS, H. J. G. H., BETHLEM, J. and FELTKAMP, T. E. W. Muscle pathology, t h y m o m a and immunological abnormalities in patients with myasthenia gravis. J. Neurol. Neurosurq. Psychiat., 1%8, 31 : 460 463. SAf'CO, G., BUCHTHAL, F. and ROSENFAL('K, P. Motor unit potentials at different ages. Arch. Neurol. (Chic'.), 1962, 6 : 4 ~ 51. STEINBRECHER, W. Elektromyographie in Klinik und Praxis. Thieme, Stuttgart, 1965, 112 p. TEASDALL, R. D. and SEARS, M. L. Electromyographic evidence for myopathy. Amer. J. Ophthal.. 1962, 54: 541 546.
The statistical validity was checked by H. Mattie. The muscle biopsy specimens were assessed by Prof. Dr. J. Bethlem.
ReJerence: OOSTERHUIS, H. J. G. H., HOOTSMANS,W. J. M., VEENHUYZEN, H. B. and ZADEI.HO|.I., 1. VAN. The mean duration of motor unit action potentials in patients with myasthenia gravis. Electroenceph. din. Neurophysiol., 1972, 32:697 700.