Local cooling of the muscle resulted in significant increases in M wave surface areas in patients with ALS, myasthenia gravis, the Lambed-Eaton myasthenic syndrome, and also in controls. The most striking increases were seen in patients with early ALS who had minimal lower motor neuron involvement and/or little defect on neuromuscular transmission and patients with the myasthenic syndrome. Patients with myasthenia gravis had intermediate increases between these groups and the controls; there was a larger increase in M wave surface area in myasthenia gravis compared with controls but this could be accounted for by improvement in neuromuscular transmission. The large increase in M wave surface area in early ALS could be the result of temporal summation of individual muscle fibers in motor units with increased fiber densities. The increase in both ALS and the myasthenic syndrome could result also from the loss of a trophic factor causing changes at the muscle membrane, Key words: M wave temperaturh ALS myasthenia gravis myasthenic syndrome MUSCLE 81 NERVE 13:613-617 1990
M WAVE CHANGES WITH TEMPERATURE IN AMYOTROPHIC LATERAL SCLEROSIS AND DISORDERS OF NEUROMUSCULAR TRANSMISSION ERIC H. DENYS, MD
While studying the effect of temperature on neuromuscular transmission in amyotrophic lateral sclerosis (ALS), large changes in the amplitude of the evoked M wave were observed with relatively small changes in temperature. Technical artifacts, such as movement of the electrodes, were easily ruled out so a more detailed study was undertaken. MATERIALS AND METHODS
The following subjects participated in the study: 20 patients with a diagnosis of ALS, ages 26-72 (mean 54 years), 8 patients with myasthenia From the ALS and Neurornuscular Research Center, Pacific Presbyterian Medical Center, San Francisco, California. Acknowledgments: I am indebted to Dr. W.W. Hoffmann and F.H. Norris for comments on the manuscript. Supported by the ALS & Neuromuscular Research Foundation. Presented at the 35th Annual Meeting of the American Association of Electromyography and Electrodiagnosis, San Diego. October 7 and 8,
1988. Address reprint requests to Dr. Denys, at the ALS Research Center. 2351 Clay Street #416,San Francisco, CA 94115 Accepted for publication August 12, 1989. CCC 0148-639x/90/070613-05$04.00 8 I990 John Wiiey & Sons, Inc.
M Wave Changes with Temperature in ALS
gravis, ages 25-68 (mean 38 years), and 5 patients with the myasthenic syndrome, not associated with cancer, ages 46-70 (mean 54 years). Ten control subjects were free of disease, ages 24-72 (mean 41 years). Stimulating electrodes were placed over the ulnar nerve at the wrist; recording electrodes, either surface electrodes or subcutaneous stainless steel needles, were placed over the motor point of the abductor digiti quinti (AD V) and the base of the fifth digit. A thermistor (Yellow Springs Instrument C") was inserted in the muscle to monitor intramuscular temperature. Recordings were done at 35°C and repeated at a stable 30°C following local cooling by means of an ice pack placed over the hypothenar muscle. Single shocks were delivered but in some patients repetitive stimulation was also carried out at rates of two per second to test neuromuscular transmission (TE-4, TECA Corporation, White Plains, NY). The responses were recorded on film; the amplitudes were measured and the surface area of the negative components determined by means of a hand planimeter; the mean of three determinations was used as the final result. A concentric needle electrode study of the abductor digiti quinti was done to assess the pres-
MUSCLE & NERVE
July 1990
613
~
Table 1. Average % increase in surface area of the M wave following cooling of the abductor digiti quinti.
Table 2. Effect of temperature on the M wave in ALS as a function of atrophy.
~
% Increase over control
N
%
10 8 20 5
18 28
Range
Atrophy*
N
Mean amplitude
MV (a SD)
Yo Increase surface area (+. SD)
0 1 2
6 9 5
8.4 5.2 3.3
(* 2.7) (a2.3) ( 2 1.5)
51 (* 23) 40 (k 15) 18(+ 3)
~~
Control Myasthenia gravis ALS Myasthenic syndrome
38 117
+ + +
56 111 585
0-42 15-58 13- 79 42-300
ence of denervation activity and to evaluate the number and configuration of the motor units. RESULTS
Cooling almost uniformly resulted in a larger amplitude (Fig. 1, Table 1). All control subjects except one had larger M wave surfaces at the lower temperature of 30°C. In patients with ALS, not only was there an increase in surface area of the M wave but the average change in all ALS patients combined was more than double that found in controls. The difference was statistically significant (P < .05). In some patients with ALS the changes following cooling were dramatic, while in others they were less marked; the possibility that the duration of disease and degree of denervation could play a role was therefore considered, especially since the EMG studies clearly revealed differences in the degree of involvement of the abductor digiti quinti between subjects. Patients were, therefore, grouped according to the degree of clinical atrophy in the hypothenar eminence, as represented in Table 2. The corresponding mean M wave amplitudes are included as well. Severely atrophic muscles were not studied because of the larger error factor in analyzing potentials of small amplitude.
3OoC
35°C
*O = No atrophy; 1 = slight; 2
=
moderate
Whereas one might have expected muscles with more advanced disease to show the largest changes in surface area of the M wave following cooling, the contrary was observed. The difference in M wave changes with cooling between the three groups of ALS patients was statistically significant for amplitude (ANOVA p < .01) and for surface area (P < .025) (Table 2). The largest increase was seen in patients with only minimal or no atrophy. The following individual observations were of interest: the three largest increases in M waves following cooling were 79%,72% and 74%; the first two values were obtained from muscles with no clinical atrophy; one patient suffered from predominantly upper motor neuron disease and no abnormalities were found in the abductor digiti quinti on needle electrode examination. The needle electrode examination in the second patient revealed only a few positive waves; slight atrophy was present in the third patient. Some ALS patients had defective neuromuscular transmission in the abductor digiti quinti when tested with repetitive stimuli at Plsec. When these patients were analyzed separately and divided according to the degree of atrophy, the same distribution of increased surface area was observed as in the total ALS population (Table 3), i.e., there were larger increases in the presence of minimal disease. The decrements themselves were how-
Table 3. Percent increase in surface area of M waves in the presence of a defect on neuromuscular transmission ALS-Abductor digiti quinti
JI
mV
2 msec
Atrophy
No. showing decrement at 21sec
Mean decrement ~
FIGURE 1. Compound muscle action potential of the hypothenar in a patient with amyotrophic lateral sclerosis at 35°C and following cooling of the muscle to 30°C.Note the increase in amplitude and surface area (+35%) at the lower temperature.
614
M Wave Changes with Temperature in ALS
0 1 2
316 519 415
~
~
% Increase surface area ~~~~
3 4% 10.3% 12.6%
MUSCLE 2% NERVE
53% 39% 19%
July 1990
ever, less marked in minimal disease, as previously reported.8 Patients with myasthenia gravis showed a mean M wave increase that fell between the controls and the ALS patients. Patients with the largest decrements tended to show the least increase in M wave amplitude, similar to that observed in ALS patients. All decrements were less pronounced following cooling, as expected from previous reports in the l i t e r a t ~ r e . ~ The five patients with the myasthenic syndrome, however, showed the most remarkable increases of all, with values of 42%, 56%, 87%, 100% and 300%. Special care was taken in these patients to allow sufficient rest between stimuli in light of the facilitatory effect of previous stimuli in this disorder.’ DISCUSSION
An increase in the surface area of the M wave was observed after cooling in all experiments except in one of ten controls. The amplitude of the M wave was, with few exceptions, also larger. Because desynchronization caused by inevitable cooling of distal nerve branches will reduce M wave amplitudes, surface areas were used to reflect the underlying physiological changes in the muscle fibers. Temperature changes are likely to affect a number of neurophysiological and chemical processes such as nerve conduction in terminal branches, synaptic transmitter release and breakdown, muscle membrane depolarization and action potential propagation in muscle fibers. The changes in the M wave with cooling in controls is probably primarily caused by an effect on the muscle membrane. In 1949 Hodgkin and Katz reported similar large increases in action potential amplitude of the squid giant axon following cooling, attributed to a greater delay in the inactivation of sodium and potassium permeability than in the initial influx of sodium;” the falling phase of the action potential is therefore slower allowing for additional temporal summation of the individual muscle fiber potentials making up the M wave. That a similar effect of temperature was found in ALS patients should be no surprise; striking, however, was the more pronounced effect of cooling in these patients. It was, in fact, the large change in wave form during neuromuscular transmission experiments with cooling that triggered the initial study.6 Changes in amplitude of both motor and sensory compound action potentials, as
M Wave Changes with Temperature in ALS
a result of changes in temperature, have since been reported by several a u t h ~ r s ; ~ ~ the ’ ~ ~much ’’ larger changes in ALS as well as in myasthenia gravis and myasthenic syndrome patients deserve further comment. Disease obviously creates conditions different from normal which are susceptible to their own temperature influences. The only feature ALS shares with the other two diseases is an occasional defective neuromuscular t r a n s m i s ~ i o n . ~ ’One ~”~ could, therefore, postulate that defective neuromuscular synapses contribute to the temperature sensitivity. Cooling is known to reduce the decrement to repetitive stimulation in myasthenia g r a ~ i s It . ~could also account for a larger M wave surface area after a single stimulus since subthreshold synapses probably account for the small reduction in average M wave amplitude observed in myasthenia gravis compared with control^.^ No strict correlation existed, however, between the degree of decrement to repetitive stimulation and the increase of M wave surface areas in patients with myasthenia gravis, except for a tendency toward less increase in muscles with larger decrements. Although surprising, this most likely means that cooling is unable to restore function in more severely affected synapses, hence less increase in M wave surface area. The temperature effect was larger in the ALS group as a whole than in myasthenia gravis, despite much smaller decremental abnormalities (maximum 20%). Moreover, the temperature effect was largest in the least affected muscles, which also showed smaller and less frequent neuromsucular transmission failures. How does one explain this phenomenon? ALS is a disease where denervation and reinnervation occur simultaneously; in the early stages reinnervation is effective through collateral reinnervation and is reflected in a higher fiber density of the single motor unit potential. l8 Although reinnervation is effective early on and no decremental responses are recorded with repetitive stimuli at 2/sec, increased jitter is observed with single fiber EMG (SFEMG) reflecting the presence of immature synapses. Impaired conduction along newly formed sprouts can occur as well, especially in rapidly progressive disease, and is reflected in impulse blockings on SFEMG. It is in this setting that the cooling effect needs to be explained.18 A lower temperature will improve synaptic transmission and could optimize nerve conduction in newly formed sprout^.^ The increased action potential amplitude of individual muscle fibers
MUSCLE & NERVE
July 1990
615
with cooling and the associated slower declining phase will allow temporal summation to occur; slowing of action potential propagation in muscle fibers and intramuscular nerve branches may enhance this effect until desynchronization offsets it; this point may be delayed, however, by the higher fiber density causing a much larger compound action potential. This mechanism would prevail as long as the loss of motor neurons is compensated by sprouting and the number of muscle fibers remains the same. With further loss of motor units and muscle fibers, especially large units, enhanced temporal summation would cease and return to the same order as observed in controls. Myasthenic syndrome patients showed the most striking increase. The initial M waves were extremely reduced (0.5 mV, 1.6 mV, 0.5 mV, 0.35 mV, 2.1 mV); their increase, with cooling, can be interpreted as a partial normalization of synaptic transmission, through the same mechanism as in myasthenia gravis. The largest increase was seen in patients with the lowest initial amplitude and was directly correlated with the maximal amplitude obtained with tetanic stimulation at 5O/second (Table 4). It is clear that whatever effect cooling had on presynaptic transmitter release by a single stimulus and hydrolysis of acetylcholine, it was far less than that caused by a train of stimuli at a rate of 50/second. Contrary to ALS, increased fiber density and temporal summation cannot be invoked as an explanation in the myasthenic syndrome. Since cooling is known to decrease presynaptic transmitter release to a single stimulus,l o the increase in M wave amplitude is, therefore, more likely the result of changes at the muscle membrane, including reduced hydrolysis of acetylcholine. Since the disease process in both ALS and the myasthenic syndrome involves the presynaptic part of the motor neuron,16 it is conceivable that a trophic effect on the muscle membrane, not necessarily linked to depolarization, is deficient. Such trophic effects have been described in the
Table 4. Myasthenic syndrome M-wave: Comparison of initial amplitude, cooling effect, rnax amplitude with tetanic stimulation. initial % Change with % Max. tetanic amplitude cooling from Decrement amplitude, Patient mV 35°C to 30°C at 2/sec mV ~
1
0.35
2 3
0.5
4 5
1.6 2.1
0.5
+300
14
+loo
10
30
87
46
56 42
22 38
13.5 9.2 6.2 4.6
+ + +
literature. Epineural colchicine, which blocks axoplasmic transport but has no effect on nerve conduction or neuromuscular transmission, induces fibrillation as well as acetylcholine hypersensitivity."" Uchitel et al,*' found extrajunctional acetylcholine sensitivity in muscle fibers of ALS patients without tetrodotoxin-resistant action potentials in 70% of fibers, contrary to denervation caused by nerve transection, suggesting a partial loss of trophic influences on the muscle fiber membrane. Fasciculation potentials result from unstable membrane potentials in the nerve and could similarly be the expression of failing trophic influences. Animal experiments with botulinum toxin mimicking the myasthenic syndrome have shown alterations in chemical constituents as well as changes in electrical excitability of muscle fibers similar to those found in denervation; l9 prolonged botulinum intoxication in humans and animals can result in fibrillation potentials.'* In light of these observations it is conceivable that the significant changes in surface areas of the M wave following cooling in ALS and the myasthenic syndrome are, in part, the expression of a diminished trophic effect. The death of the motor neuron in ALS is probably a slowly evolving process with loss of the associated trophic effect on the muscle preceding actual denervation.
REFERENCES
1. Albuquerque EX, Warnick JE, Tasse JR, Sansone FM: Effects of vinblastine and colchicine on neural regulation of the fast and slow skeletal muscles of the rat. Experimental Neurology 1972;373307-634. 2. Bernstein LT,Ante1 JD: Motor neuron disease: decremental responses to repetitive nerve stimulation. Neurology 1981;31~204-207. 3. Bolton CF, Sawa GM, Carter K: Temperature effects on the size of human sensory compound action potentials. J Neurol Neurosurg Psychiatry 1981;44 (5):407-413.
616
M Wave Changes with Temperature in ALS
4. Borenstein S,Desmedt JE: Temperature and weather correlates of myasthenic fatigue. Lancet 1974;2:63-66. 5. Davis FA, Jacobson S: Altered thermal sensitivity in injured and demyelinated nerve-a possible model of the temperature effect in multiple sclerosis.J Neurol Neurosurg Pychiat 1971;341551-561. 6. Denys EH: The effect of temperature on the compound action potential in neuromuscular disease and normal controls. Electroenceph Clin Neurophys 1977;4:598. 7. Denys EH, Dau PC, Lindstrom JM: Neuromuscular trans-
MUSCLE & NERVE
July 1990
mission before and after plasmapheresis and immunosuppressive therapy in myasthenia gravis and the myasthenic syndrome, in Dau PC (ed): P h m p h e r e s i s and the Immunobiology of Myasthenia Gruvis. Boston, Houghton Mifflin, 1979, pp 248-257. 8. Denys EH, Norris FH: Amyotrophic lateral sclerosis-impairment of neuromuscular transmission. Arch Neurol 1979; 36~202-205. 9. Desmedt JE, Borenstein S: The testing of neuromuscular transmission, in Vincken PJ and Bruyn GW (eds): Handbook of Clinical Neurology vol 7. Amsterdam, North Holland Publishing Co, 1970, pp 104- 115. 10. Fatt P, Katz B: Spontaneous subthreshold activity at motor nerve endings. J Physiol (Lond.) 1952; 117:109-128. 11. Fernandez HL, Ramirez BV: Muscle fibrillation induced by blockage of axoplasmic transport in motor nerves. Brain Res 1974; 79:385-395. 12. Gutmann L, Pratt L: Pathophysiologic aspects of human botulism. Arch Neurol 1976; 33:175- 179. 13. Hodgkin AL, Katz B: The effect of temperature on the electrical activity of the giant axon of the squid. J Physiol (Lond) 1949; 109:240-249.
M Wave Changes with Temperature in ALS
4. Hulley WL, Wilbourn AJ, McGinty K: Sensory nerve ac-
tion potential amplitudes: alterations with temperature. Electroenceph Clin Neurophysiol 1978; 45: 24. 5. Lambert EH: Electromyography in amyotrophic lateral sclerosis, in Norris FH, Kurland LT (eds): Motor Neuron Diseases. New York, London, Grune and Stratton, 1969, pp 135- 153. 6. Oh SJ, Dwyer DS, Bradley RJ: Overlap myasthenic syndrome: combined myasthenia gravis and Eaton-Lambert syndrome. Neurology (NY) 1987; 37:1411-1414. 17. Ricker KG, Hertel G, Stodieck G: Increased voltage of the muscle action potential of normal subjects after local cooling. J Neurol 1977; 216:33-38. 18. Stalberg E, Sanders DB: The motor unit in ALS studies with different neurophysiological techniques, in F. Clifford Rose (ed): Research Progress in Motor Neurone Disease. London, Pitman Publishing, 1984, pp 105-122. 19. Thesleff S: Supersensitivity of skeletal muscle produced by botulinum toxin. J Physiol (Lond) 1960; 151:598-607. 20. Uchitel 0, Dubrovsky A: Electrophysiologic denervation changes of human muscle fibers in motor neuron diseases. Muscle N m e 1986; 9:748-755.
MUSCLE & NERVE
July 1990
617
M WAVE CHANGES WITH TEMPERATURE IN AMYOTROPHIC LATERAL SCLEROSIS AND DISORDERS OF NEUROMUSCULAR TRANSMISSION ERIC H. DENYS, MD
While studying the effect of temperature on neuromuscular transmission in amyotrophic lateral sclerosis (ALS), large changes in the amplitude of the evoked M wave were observed with relatively small changes in temperature. Technical artifacts, such as movement of the electrodes, were easily ruled out so a more detailed study was undertaken. MATERIALS AND METHODS
The following subjects participated in the study: 20 patients with a diagnosis of ALS, ages 26-72 (mean 54 years), 8 patients with myasthenia From the ALS and Neurornuscular Research Center, Pacific Presbyterian Medical Center, San Francisco, California. Acknowledgments: I am indebted to Dr. W.W. Hoffmann and F.H. Norris for comments on the manuscript. Supported by the ALS & Neuromuscular Research Foundation. Presented at the 35th Annual Meeting of the American Association of Electromyography and Electrodiagnosis, San Diego. October 7 and 8,
1988. Address reprint requests to Dr. Denys, at the ALS Research Center. 2351 Clay Street #416,San Francisco, CA 94115 Accepted for publication August 12, 1989. CCC 0148-639x/90/070613-05$04.00 8 I990 John Wiiey & Sons, Inc.
M Wave Changes with Temperature in ALS
gravis, ages 25-68 (mean 38 years), and 5 patients with the myasthenic syndrome, not associated with cancer, ages 46-70 (mean 54 years). Ten control subjects were free of disease, ages 24-72 (mean 41 years). Stimulating electrodes were placed over the ulnar nerve at the wrist; recording electrodes, either surface electrodes or subcutaneous stainless steel needles, were placed over the motor point of the abductor digiti quinti (AD V) and the base of the fifth digit. A thermistor (Yellow Springs Instrument C") was inserted in the muscle to monitor intramuscular temperature. Recordings were done at 35°C and repeated at a stable 30°C following local cooling by means of an ice pack placed over the hypothenar muscle. Single shocks were delivered but in some patients repetitive stimulation was also carried out at rates of two per second to test neuromuscular transmission (TE-4, TECA Corporation, White Plains, NY). The responses were recorded on film; the amplitudes were measured and the surface area of the negative components determined by means of a hand planimeter; the mean of three determinations was used as the final result. A concentric needle electrode study of the abductor digiti quinti was done to assess the pres-
MUSCLE & NERVE
July 1990
613
~
Table 1. Average % increase in surface area of the M wave following cooling of the abductor digiti quinti.
Table 2. Effect of temperature on the M wave in ALS as a function of atrophy.
~
% Increase over control
N
%
10 8 20 5
18 28
Range
Atrophy*
N
Mean amplitude
MV (a SD)
Yo Increase surface area (+. SD)
0 1 2
6 9 5
8.4 5.2 3.3
(* 2.7) (a2.3) ( 2 1.5)
51 (* 23) 40 (k 15) 18(+ 3)
~~
Control Myasthenia gravis ALS Myasthenic syndrome
38 117
+ + +
56 111 585
0-42 15-58 13- 79 42-300
ence of denervation activity and to evaluate the number and configuration of the motor units. RESULTS
Cooling almost uniformly resulted in a larger amplitude (Fig. 1, Table 1). All control subjects except one had larger M wave surfaces at the lower temperature of 30°C. In patients with ALS, not only was there an increase in surface area of the M wave but the average change in all ALS patients combined was more than double that found in controls. The difference was statistically significant (P < .05). In some patients with ALS the changes following cooling were dramatic, while in others they were less marked; the possibility that the duration of disease and degree of denervation could play a role was therefore considered, especially since the EMG studies clearly revealed differences in the degree of involvement of the abductor digiti quinti between subjects. Patients were, therefore, grouped according to the degree of clinical atrophy in the hypothenar eminence, as represented in Table 2. The corresponding mean M wave amplitudes are included as well. Severely atrophic muscles were not studied because of the larger error factor in analyzing potentials of small amplitude.
3OoC
35°C
*O = No atrophy; 1 = slight; 2
=
moderate
Whereas one might have expected muscles with more advanced disease to show the largest changes in surface area of the M wave following cooling, the contrary was observed. The difference in M wave changes with cooling between the three groups of ALS patients was statistically significant for amplitude (ANOVA p < .01) and for surface area (P < .025) (Table 2). The largest increase was seen in patients with only minimal or no atrophy. The following individual observations were of interest: the three largest increases in M waves following cooling were 79%,72% and 74%; the first two values were obtained from muscles with no clinical atrophy; one patient suffered from predominantly upper motor neuron disease and no abnormalities were found in the abductor digiti quinti on needle electrode examination. The needle electrode examination in the second patient revealed only a few positive waves; slight atrophy was present in the third patient. Some ALS patients had defective neuromuscular transmission in the abductor digiti quinti when tested with repetitive stimuli at Plsec. When these patients were analyzed separately and divided according to the degree of atrophy, the same distribution of increased surface area was observed as in the total ALS population (Table 3), i.e., there were larger increases in the presence of minimal disease. The decrements themselves were how-
Table 3. Percent increase in surface area of M waves in the presence of a defect on neuromuscular transmission ALS-Abductor digiti quinti
JI
mV
2 msec
Atrophy
No. showing decrement at 21sec
Mean decrement ~
FIGURE 1. Compound muscle action potential of the hypothenar in a patient with amyotrophic lateral sclerosis at 35°C and following cooling of the muscle to 30°C.Note the increase in amplitude and surface area (+35%) at the lower temperature.
614
M Wave Changes with Temperature in ALS
0 1 2
316 519 415
~
~
% Increase surface area ~~~~
3 4% 10.3% 12.6%
MUSCLE 2% NERVE
53% 39% 19%
July 1990
ever, less marked in minimal disease, as previously reported.8 Patients with myasthenia gravis showed a mean M wave increase that fell between the controls and the ALS patients. Patients with the largest decrements tended to show the least increase in M wave amplitude, similar to that observed in ALS patients. All decrements were less pronounced following cooling, as expected from previous reports in the l i t e r a t ~ r e . ~ The five patients with the myasthenic syndrome, however, showed the most remarkable increases of all, with values of 42%, 56%, 87%, 100% and 300%. Special care was taken in these patients to allow sufficient rest between stimuli in light of the facilitatory effect of previous stimuli in this disorder.’ DISCUSSION
An increase in the surface area of the M wave was observed after cooling in all experiments except in one of ten controls. The amplitude of the M wave was, with few exceptions, also larger. Because desynchronization caused by inevitable cooling of distal nerve branches will reduce M wave amplitudes, surface areas were used to reflect the underlying physiological changes in the muscle fibers. Temperature changes are likely to affect a number of neurophysiological and chemical processes such as nerve conduction in terminal branches, synaptic transmitter release and breakdown, muscle membrane depolarization and action potential propagation in muscle fibers. The changes in the M wave with cooling in controls is probably primarily caused by an effect on the muscle membrane. In 1949 Hodgkin and Katz reported similar large increases in action potential amplitude of the squid giant axon following cooling, attributed to a greater delay in the inactivation of sodium and potassium permeability than in the initial influx of sodium;” the falling phase of the action potential is therefore slower allowing for additional temporal summation of the individual muscle fiber potentials making up the M wave. That a similar effect of temperature was found in ALS patients should be no surprise; striking, however, was the more pronounced effect of cooling in these patients. It was, in fact, the large change in wave form during neuromuscular transmission experiments with cooling that triggered the initial study.6 Changes in amplitude of both motor and sensory compound action potentials, as
M Wave Changes with Temperature in ALS
a result of changes in temperature, have since been reported by several a u t h ~ r s ; ~ ~ the ’ ~ ~much ’’ larger changes in ALS as well as in myasthenia gravis and myasthenic syndrome patients deserve further comment. Disease obviously creates conditions different from normal which are susceptible to their own temperature influences. The only feature ALS shares with the other two diseases is an occasional defective neuromuscular t r a n s m i s ~ i o n . ~ ’One ~”~ could, therefore, postulate that defective neuromuscular synapses contribute to the temperature sensitivity. Cooling is known to reduce the decrement to repetitive stimulation in myasthenia g r a ~ i s It . ~could also account for a larger M wave surface area after a single stimulus since subthreshold synapses probably account for the small reduction in average M wave amplitude observed in myasthenia gravis compared with control^.^ No strict correlation existed, however, between the degree of decrement to repetitive stimulation and the increase of M wave surface areas in patients with myasthenia gravis, except for a tendency toward less increase in muscles with larger decrements. Although surprising, this most likely means that cooling is unable to restore function in more severely affected synapses, hence less increase in M wave surface area. The temperature effect was larger in the ALS group as a whole than in myasthenia gravis, despite much smaller decremental abnormalities (maximum 20%). Moreover, the temperature effect was largest in the least affected muscles, which also showed smaller and less frequent neuromsucular transmission failures. How does one explain this phenomenon? ALS is a disease where denervation and reinnervation occur simultaneously; in the early stages reinnervation is effective through collateral reinnervation and is reflected in a higher fiber density of the single motor unit potential. l8 Although reinnervation is effective early on and no decremental responses are recorded with repetitive stimuli at 2/sec, increased jitter is observed with single fiber EMG (SFEMG) reflecting the presence of immature synapses. Impaired conduction along newly formed sprouts can occur as well, especially in rapidly progressive disease, and is reflected in impulse blockings on SFEMG. It is in this setting that the cooling effect needs to be explained.18 A lower temperature will improve synaptic transmission and could optimize nerve conduction in newly formed sprout^.^ The increased action potential amplitude of individual muscle fibers
MUSCLE & NERVE
July 1990
615
with cooling and the associated slower declining phase will allow temporal summation to occur; slowing of action potential propagation in muscle fibers and intramuscular nerve branches may enhance this effect until desynchronization offsets it; this point may be delayed, however, by the higher fiber density causing a much larger compound action potential. This mechanism would prevail as long as the loss of motor neurons is compensated by sprouting and the number of muscle fibers remains the same. With further loss of motor units and muscle fibers, especially large units, enhanced temporal summation would cease and return to the same order as observed in controls. Myasthenic syndrome patients showed the most striking increase. The initial M waves were extremely reduced (0.5 mV, 1.6 mV, 0.5 mV, 0.35 mV, 2.1 mV); their increase, with cooling, can be interpreted as a partial normalization of synaptic transmission, through the same mechanism as in myasthenia gravis. The largest increase was seen in patients with the lowest initial amplitude and was directly correlated with the maximal amplitude obtained with tetanic stimulation at 5O/second (Table 4). It is clear that whatever effect cooling had on presynaptic transmitter release by a single stimulus and hydrolysis of acetylcholine, it was far less than that caused by a train of stimuli at a rate of 50/second. Contrary to ALS, increased fiber density and temporal summation cannot be invoked as an explanation in the myasthenic syndrome. Since cooling is known to decrease presynaptic transmitter release to a single stimulus,l o the increase in M wave amplitude is, therefore, more likely the result of changes at the muscle membrane, including reduced hydrolysis of acetylcholine. Since the disease process in both ALS and the myasthenic syndrome involves the presynaptic part of the motor neuron,16 it is conceivable that a trophic effect on the muscle membrane, not necessarily linked to depolarization, is deficient. Such trophic effects have been described in the
Table 4. Myasthenic syndrome M-wave: Comparison of initial amplitude, cooling effect, rnax amplitude with tetanic stimulation. initial % Change with % Max. tetanic amplitude cooling from Decrement amplitude, Patient mV 35°C to 30°C at 2/sec mV ~
1
0.35
2 3
0.5
4 5
1.6 2.1
0.5
+300
14
+loo
10
30
87
46
56 42
22 38
13.5 9.2 6.2 4.6
+ + +
literature. Epineural colchicine, which blocks axoplasmic transport but has no effect on nerve conduction or neuromuscular transmission, induces fibrillation as well as acetylcholine hypersensitivity."" Uchitel et al,*' found extrajunctional acetylcholine sensitivity in muscle fibers of ALS patients without tetrodotoxin-resistant action potentials in 70% of fibers, contrary to denervation caused by nerve transection, suggesting a partial loss of trophic influences on the muscle fiber membrane. Fasciculation potentials result from unstable membrane potentials in the nerve and could similarly be the expression of failing trophic influences. Animal experiments with botulinum toxin mimicking the myasthenic syndrome have shown alterations in chemical constituents as well as changes in electrical excitability of muscle fibers similar to those found in denervation; l9 prolonged botulinum intoxication in humans and animals can result in fibrillation potentials.'* In light of these observations it is conceivable that the significant changes in surface areas of the M wave following cooling in ALS and the myasthenic syndrome are, in part, the expression of a diminished trophic effect. The death of the motor neuron in ALS is probably a slowly evolving process with loss of the associated trophic effect on the muscle preceding actual denervation.
REFERENCES
1. Albuquerque EX, Warnick JE, Tasse JR, Sansone FM: Effects of vinblastine and colchicine on neural regulation of the fast and slow skeletal muscles of the rat. Experimental Neurology 1972;373307-634. 2. Bernstein LT,Ante1 JD: Motor neuron disease: decremental responses to repetitive nerve stimulation. Neurology 1981;31~204-207. 3. Bolton CF, Sawa GM, Carter K: Temperature effects on the size of human sensory compound action potentials. J Neurol Neurosurg Psychiatry 1981;44 (5):407-413.
616
M Wave Changes with Temperature in ALS
4. Borenstein S,Desmedt JE: Temperature and weather correlates of myasthenic fatigue. Lancet 1974;2:63-66. 5. Davis FA, Jacobson S: Altered thermal sensitivity in injured and demyelinated nerve-a possible model of the temperature effect in multiple sclerosis.J Neurol Neurosurg Pychiat 1971;341551-561. 6. Denys EH: The effect of temperature on the compound action potential in neuromuscular disease and normal controls. Electroenceph Clin Neurophys 1977;4:598. 7. Denys EH, Dau PC, Lindstrom JM: Neuromuscular trans-
MUSCLE & NERVE
July 1990
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