We measured the maximal and minimal motor nerve conduction velocities of the ulnar nerve in 17 patients with spinal muscular atrophy (SMA), 27 patients with amyotrophic lateral sclerosis (ALS), and 40 age-matched control subjects. Crude values of the maximal and minimal motor nerve conduction velocities were reduced in both patient groups, but their difference in each patient was not statistically different from that of a control subject. The conduction velocities adjusted according to each patient's age were faster in SMA patients than in ALS patients. Among patients with either ALS or SMA, the age-adjusted conduction velocities were larger in those who had developed the disease at younger ages and suffered from it for shorter periods of time. These findings suggest that the motor nerve fibers regenerate more in younger patients in the early stages of the disease, particularly in SMA. Key words: collision method motor conduction velocity ulnar nerve amyotrophic lateral sclerosis spinal muscular atrophy MUSCLE & NERVE 14:lllO-1115 1991
.
..
MAXIMAL AND MINIMAL MOTOR NERVE CONDUCTION VELOCITIES IN PATIENTS WITH MOTOR NEURON DISEASES: CORRELATION WITH AGE OF ONSET AND DURATION OF ILLNESS MASAKAZU IIJIMA, MD, KEISUKE ARASAKI, MD, PhD, HlROYUKl IWAMOTO, MD,
and TAKA0 NAKANISHI, MD, PhD
I n healthy human beings, the maximal motor nerve conduction velocity (maxMCV) and compound muscle action potential (CMAP) amplitude decrease with age,13 linearly or n ~ n l i n e a r l yThe .~~ minimal motor nerve conduction velocity (minMCV) has also been shown to slow in normal human aging.' In patients with amyotrophic lateral sclerosis From the Neurophysiology Laboratory, Department of Neurology, University of Tsukuba. Tsukuba-City, Japan Acknowledgments: The authors thank Dr. Forbes H. Norris, Jr. (Pacific Medical Center, San Francisco, CA) for his critical comments and assistance in English. The authors also thank Ms Hiroko Akita for technical assistance. This study was supported by research grants from the Project Research, University of Tsukuba and the Research Committee for Specific Diseases, the Ministry of Health and Welfare, Japanese Government. Dr lilima's current affiliation is The Third Department of Internall Medicine, National Defence Medical College, Tokorozawa, Japan. Dr Nakanishi's current affiliation is Mishuku Hospital, Tokyo, Japan.
(ALS), the maxMCV slows in proportion to the reduction in the CMAP a m p l i t ~ d e , but ' ~ the data regarding the difference between the maxMCV and minMCV (dMCV) in ALS were confusin it was reduced,I5 the same," or even increased. In our previous study,I8 we showed that dMCV in ALS patients was unchanged, but did not separate effects of the disease process itself and those of aging. In atients with spinal muscular atrophy (SMA)," the maxMCV has usually been unaffected,8*1' but it was reduced in 2 studies.'6220 Thus, there is a literature controversy regarding changes in the maxMCV in SMA. The minMCV was apparently measured in only 1 study, and was found to be increased.' In the present study, we measured the maxMCV, minMCV, and CMAP in patients with SMA, those with ALS, and age-matched control subjects.
Y
Address reprint requests to Dr. K. Arasaki, Department of Neurology, Institute of Clinical Medicine, University of Tsukuba 1-1 -1 Tennodai, Tsukuba-City, Ibaraki-Pref. 305 Japan. Accepted for publication December 10, 1990
MATERIALS AND METHODS
CCC 0148-639X/91/01101110-06 $04.00 0 1991 John Wiley & Sons, Inc.
We examined 17 patients with SMA (mean age 53.9 years), 27 patients with ALS (mean 57.8
1110
Motor Conduction in ALS and SMA
MUSCLE & NERVE
November 1991
years), and 40 age-matched control subjects (mean 57.0 years). There was no significant age difference among these groups ( P > 0.4). The diagnosis of MND was based on clinical examination and electromyogram (EMG) demonstration of evidence of lower motor neuron degeneration with regeneration. T h e differential diagnosis between SMA and ALS was based on absence of upper motor neuron signs in SMA in our evaluation at least 2 years after the onset of the first symptoms.” At the time of the study, the average durations of illness from the onset of first symptoms in the SMA and ALS groups were 98 k 67 months and 16 k 11 months, respectively. Each subject was tested by the collision method detailed elsewhere. ’,19 The ulnar nerve was stimulated at 3 points, at about 10 min (Sl) and 70 mm (S2) above the distal wrist crease and at the elbow (S3), and evoked activity of the abductor digiti minimi muscle (ADM) was recorded. Supramaxima1 shocks of 0.1 ms were given to 2 proximal points (S2 and S3), and submaximal ones given to the distal point ( S l ) . Collision of nerve impulses produced at S1 and those either at S2 or S3 were produced so that only those produced at S2 or S3, and free from collision, evoked the muscle response. The muscle responses were amplified by a differential amplifier (WPI DAM-60) with a frequency response of 1.0 Hz to 3 kHz (3 dB down), the output of which was led through an A-D converter to a Macintosh IIcx computer with a horizontal resolution of 25 ks/point and 256 points per channel. Using the computer, a submaximal motor response to a single stimulation at S1 (MSli’) was subtracted from a mixed motor response following paired stimulation at S2 and S1 or S3 and S1 ([MS2 + MSli’] or [MS3 + MSli’]). T h e resulting [MS2 + MSli’] - MSli’ or [MS3 + MSli’] MSli‘; i.e., MS2’ or MS3‘, respectively, should show muscle activity by orthodromic motor impulses evoked at S2 or S3 and free from collision. MCVs of motor nerve fibers giving rise to MS2‘ and MS3’ were calculated from their onset latencies, and were corrected for skin temperature according to the following equation: corrected conduction velocity = observed conduction velocity + Q (34.0 - observed skin temperature). We used 2.4 m/s per “C and 2.2 m/s per degree C as the Q values for the fastest-conducting and slow-conducting motor fibers, respectively.’ In order to eliminate effects of normal aging upon measured and corrected MCVs, we created
Motor Conduction in ALS and SMA
the following parameters: age-adjusted maxMCV (%) = an observed maxMCV divided by an expected maxMCV for a patient’s age, age-adjusted minMCV (%) = an observed minMCV divided by an expected minMCV for a patient’s age, an ageadjusted dMCV (m/s) = an observed dMCV minus an expected dMCV for a patient’s age, and ageadjusted CMAP (%) = an observed CMAP amplitude divided by an expected CMAP amplitude for a patient’s age. Expected values of the maxMCV, minMCV, dMCV, and CMAP amplitude for a given patient’s age were calculated by the following equations reported elsewhere’: an expected maxMCV = 64.42 - 0.05 age, an expected minMCV = 60.45 - 0.12 age, an expected dMCV = an expected maxMCV minus an expected minMCV, and an expected CMAP amplitude = 22.23 - 0.14 age. Statistical analysis of the results was done by the two-group nonparametric test (Mann- Whitney U test). Three-dimensional (3D) data analysis of the relationship among these parameters, the age of onset, and the duration of illness were performed by Systat. RESULTS MaxMCV, minMCV, dMCV and CMAP Amplitude in ALS and SMA Patients. T h e maxMCV and minMCV in the ALS group were 55.3 k 7.4 m/s and 43.6 7.6 m/s (mean k SD), respectively, signif-
*
icantly lower than the control maxMCV and minMCV (62.1 -+ 5.3 m/s and 53.8 k 6.1 m/s, respectively), P < 0.001. The dMCV in each patient with ALS (11.8 -+ 5.9 m/s) was not statistically different from that in the control group (8.5 -+ 4.6 m/s), P > 0.03. CMAP amplitude in the ALS group was 5.9 k 4.4 mV, which was smaller than that in the control group (14.2 f 3.7 mV), P < 0.00 1. The maxMCV and minMCV in the SMA group were 57.2 t 7.6 m/s and 45.3 2 8.2 m/s, respectively, and significantly (P < 0.005) lower than those in the control. However, in those SMA patients with the duration of illness of no more than 5 years (see below), the maxMCV (59.9 ? 5.5 m/s) and the minMCV (47.2 k 7.1 m/s) were not significantly reduced from those in the control ( P > 0.03). The dMCV in each patient with SMA (12.0 k 8.6 m/s) was not statistically different from that in the control group ( P > 0.05). CMAP amplitude in the SMA group was 9.1 k 6.2 mV, which was significantly smaller than that in the control group ( P < 0.001).
MUSCLE & NERVE
November 1991
1111
70
0 ONSETAGE 60
COURSEMO B
A
FIGURE 1. The age-adjusted maxMCV in relation to age of onset (onsetage) and duration of the clinical course (coursemo) in ALS (A) and SMA (B). The X and Y axes are the duration of clinical course in months and the age of onset in years, respectively. The Z axis shows the age-adjusted maxMCV. Follow-up was done up to 47 months in ALS patients and 250 months in SMA patients. The control value is shown as a line at 100.
Relationship Among Age-adjusted maxMCV, minMCV, dMCV, CMAP, the Age of Onset and the Duration of Illness in ALS. Slowing of the maxMCV
and minMCV in ALS patients was likely to correlate not only with the duration of illness, but also the age of onset; the age-adjusted maxMCV (mean 90.0%) was reduced slightly less than the age-adjusted minMCV (mean, 81.5%), and both were decreased less in ALS patients with earlier onset of the disease and shorter duration of illness
(Figs. 1A and 2A). The age-adjusted dMCV in ALS patients was more influenced by the former (Fig. 3A). In ALS patients whose disease started in the fourth and fifth decades, the age-adjusted dMCV tended to be positive regardless of the duration of the disease. However, in those with the disease onset in the seventh and eighth decades, the age-adjusted dMCV was usually zero or negative. Changes in the age-adjusted CMAP in ALS pa-
ll 0
51 n
100 90
80 70
60 30 0 ONSETAGE COURSEMO
COURSEMO
A
B
FIGURE 2. The age-adjusted minMCV in relation to age of onset (onsetage) and duration of the clinical course (coursemo) in ALS (A) and SMA (B). Plot was done in the same manner as in Figure 1, except for the age-adjusted minMCV on the 2 axis.
1112
Motor Conduction in ALS and SMA
MUSCLE & NERVE
November 1991
20
15
t
10
5 Ba
0 20 0
n
J
ONSETAGE
ONSETAGE 80-50
5
COURSEMO
COURSEMO B
A
FIGURE 3.The age-adjusteddMCV in relation to age of onset (onsetage) and duration of the clinical course (coursemo) in ALS (A) and SMA (B). Plot was done in the same manner as in Figure 1, except for the age-adjusteddMCV on the 2 axis, and the control values shown as a line at 0.
tients, on the other hand, were much simpler: it was likely to be smaller in those with longer duration of the disease, whether it started early or late. Relationship Among Age-adjusted maxMCV, minMCV, dMCV, CMAP, the Age of Onset and the Duration of Illness in SMA Patients. The age-adjusted
maxMCV (mean 90.9%) and minMCV (mean 84.9%)in SMA were reduced to only the same degree as those in ALS, and were smaller only in cases where the onset age was higher or the duration of illness longer (Figs. 1B and 2B). The ageadjusted dMCV was positive in SMA patients, who became symptomatic in the third decade, or had suffered less than 60 months (Fig. 3B). The age-adjusted CMAP was correlated with both the age of onset and duration of illness: it tended to be smaller with longer duration and later onset of the disease. Comparing Age-adjusted dMCV and CMAP Between ALS and SMA Patients. The age-adjusted dMCV
was compared between 10 ALS patients and 4 SMA patients with the onset age and duration of illness statistically equivalent to each other: onset age 53.4 years in ALS and 51.3 years in SMA pa10.2 months in tients, P > 0.5; duration 25.0 ALS and 31.8 ? 5.1 months in SMA, P > 0.1. The age-adjusted dMCV in the SMA group ( 1 1.4 2 7.3
*
Motor Conduction in ALS and SMA
d s ) was larger than that in the ALS group (2.5 2 5.0 m/s), P < 0.01. We also compared the age-adjusted CMAP between the same 10 ALS and 4 SMA patients. The CMAP in the ALS group was 28.8 2 14.4%, whereas that in the SMA group was 66.6 32.9%, P < 0.01. Therefore, a decrease in the amplitude of CMAP in SMA patients may be much slower than that in ALS.
*
DISCUSSION
In the present study, we confirmed the results of previous studies that the maxMCV, minMCV, and CMAP were all decreased in ALS patients.*”’ Furthermore, we found that the maxMCV, minMCV, and CMAP in SMA patients were also decreased in comparison with age-matched control subjects. It has generally been believed that “nerve conduction studies of motor and sensory fibers in SMA are normal.”’ Indeed, Chaco and Hashimoto et al. reported that young adult patients with SMA and monomelic amyotrophy had normal maxMCV,’,” but the duration of illness in their cases was relatively short, i.e., 2 to 4 years in the former and mostly less than 5 years in the latter. Similarly, in a selected portion of our SMA patients with the duration of illness no more than 5 years, the maxMCV was not significantly reduced. However, consistent with our results in adults, in one-quarter to one-half of children with SMA, aged 2 months to 12 years, the maxMCV of the
MUSCLE & NERVE
November 1991
1113
ulnar nerve was also slower than Therefore, we may conclude that the maxMCV decreases in adult SMA patients and in infantile and juvenile SMA patients. The present study was not a true longitudinal one, in which a given individual was studied re-. peatedly. For this reason, it was essential for us to eliminate aging effects in each patient in order to evaluate changes in the maxMCV, minMCV, dMCV, and CMAP amplitudes in a number of patients. Therefore, we used age-adjusted values of maxMCV, minMCV, dMCV, and CMAP amplitudes, instead of their crude values. To our knowledge, there have been no other studies on the relationship between dMCV in ALS and SMA patients and their aging. The positive age-adjusted dMCV in ALS patients who developed the disease in the fourth decade, or had suffered from it less than a year (Fig. 3A), means that slowing of minMCV was more than that of the maxMCV in these patients' category, even considering the relative decrease of minMCV in human aging.' On the contrary, zero or negative age-adjusted dMCV in ALS patients who developed the disease in the seventh or eighth decade, and had suffered from the disease for longer than a year (Fig. 3A), means that the maxMCV slowed equal to or more than the minMCV in older ALS patients. Thus, although dMCV in ALS has been a subject of substantial disc~ssion,'~~~~'~~'~~'~ it may not be worthwhile to assess dMCV per se without the information regarding the age of onset and duration of illness of each patient. Comparing ALS and SMA patients who had suffered for comparable periods of time, the ageadjusted maxMCV, minMCV, and CMAP were all much more reduced in ALS (Figs. 1A and l B , 2A and 2B). As slowing of the MCVs in ALS results from loss of the myelinated motor nerve fibers, atrophy of the axons, secondary changes in the myelin sheath5 or thin regenerated ax on^,'^ these findings are consistent with the ~ l i n i c a l ' ~ and p a t h o l o g i ~ a l ~ ~ ~observations '~'' that neuronal degeneration in ALS proceeds much faster than in SMA. Decreased age-adjusted maxMCVs (Figs. 1A and B) can easily be attributed to loss of large myelinated motor nerve fibers in the periphery,
which may be due to a neuronopathy, distal axonal dystrophy, or both.4 On the other hand, the minMCV probably reflects the functional integrity of motor nerve fibers with smaller diameters,' and its remarkable slowing in younger ALS patients (Fig. 2A) might result from these processes occurring predominantly in smaller motor nerve fibers. This selective degeneration of smaller motor nerve fibers in ALS, however, is unlikely; the process should be more r a n d o m i ~ e d . ~ , ' ~ Axonal regeneration is more active in younger mammals with nerve crush i n j ~ r y younger ,~ patients with complete section of their peripheral nerves,6 and in the intramuscular nerves (sprouting)15 of ALS patients in the early stages.23 In comparing ALS and SMA patients, axonal regeneration in SMA patients is usually more intense. 10,22*23 In the present study, the age-adjusted dMCV was larger only in the following two categories of ALS patients than in the controls: those who developed the disease at younger ages, and those who were in the early stages of the disease. The age-adjusted dMCV was also larger in SMA patients than those with ALS having the same duration of clinical symptoms (Fig. 3A and B). This parallelism between characteristics of the age-adjusted dMCV and those of axonal regeneration strongly suggests that an increase in dMCV is a result of nonselective regeneration of motor axons, which might be modulated by such factors as the patient's age and, of course, the disease process itself. It is well-known that thin, regenerated motor axons have abnormally slow conduction velocities and shortened internodal distance^.^ In ALS, remyelination occurs even in the ventral roots." It is likely that remyelinated motor axons in the younger ALS patients, in the present study, also had very slow conduction velocities and short internodal lengths, in addition to slow conduction in peripheral sprout^.'^ In consequence, the minMCV in these patients must have decreased beyond its normal range, resulting in an increase in dMCV. This concept is supported by a single motor unit study that disclosed abnormally slow axonal conduction velocity in ALS patients.'
REFERENCES
1. Arasaki K, Iijima M, Nakanishi T: Normal maximal and minimal motor nerve conduction velocities in adults determined by a collision method. Muscle Nerve (in press). 2. Borg J: Conduction velocity and refractory period of sin-
1114
Motor Conduction in ALS and SMA
gle motor nerve fibres in motor neuron disease. J Neurol Neurosurg Psychiatry 1984;47:349 - 353. 3. Bowe CM, Hildebrand C, Kocsis JD, Waxman SG: Morphological and physiological properties of neurons after
MUSCLE R NERVE
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long-term axonal regeneration: observations on chronic and delayed sequelae of peripheral nerve injury. J Neurol Sci 1989;91 :259- 292. 4. Bradley WG, Good P, Rasool CG, Adelman LS: Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral sclerosis. Ann Neurol 1983;14:267277. 5. Bradley WG: Recent views on amyotrophic lateral sclerosis with emphasis on electrophysiological studies. Muscle Nerue 1987;10:490-502. 6. Buchthal F, Kuehl V: Nerve conduction, tactile sensibility, and the electromyogram after suture or compression of peripheral nerve: a longitudinal study in man. J Neurol Neurosurg Psychiatry 1979;42:436-45 1. 7. Chaco J: Conduction velocity of motor nerve fibers in progressive spinal atrophy. Actu Neurol Scund 1970;46:119122. 8. Daube JR: Electrophysiologic studies in the diagnosis and prognosis of motor neuron diseases. Neurologic Clinics 1985;3:473-493. 9. Hansen S , Ballantyne JP: A quantitative electrophysiological study of motor neurone disease. J Neurol Neurosurg Psychiatry 1978;41:773-783. 10. Hanyu N, Oguchi K, Yanagisawa N, Tsukagoshi H: Degeneration and regeneration of ventral root motor fibers in amyotrophic lateral sclerosis. J Neurol Sci 1982;55:99115. 1 1 . Hashimoto 0, Asada M, Ohta M, Kuroiwa Y: clinical observations of juvenile nonprogressive muscular atrophy localized in hand and forearm. J Neurol 1976;211:105- 110. 12. Hausmanova-Petrusewicz J , Kopec J: Motor nerve conduction velocity in anterior horn lesions. Electromyogruphy 1970;10:227- 237. 13. Kimura J: Principles and pitfalls of nerve conduction studies. Ann Neurol 1984;16:415-429. 14. Lambert EH: Electromyography in amyotrophic lateral sclerosis, in Norris FH, Kurland LT (eds): Motor Neuron
Motor Conduction in ALS and SMA
Diseases, New York, Grune & Stratton, 1969, pp 135-153. 15. Miglietta 0:Motor nerve fibers in amyotrophic lateral sclerosis. Am J Phys Med 1968;47:118- 124. 16. Moosa A, Dubowitz V: Motor nerve conduction velocity in spinal muscular atrophy of childhood. Arch Dis Child 1976;51:974-977. 17. Munsat T : Adult motor neuron diseases, in Rowland L (ed): Mem-tt’s Textbook of Neurology. Philadelphia, Lea & Febiger, 1989, pp 682-687. 18. Nakanishi T , Tamaki M, Arasaki K: Maximal and minimal motor nerve conduction velocities in amyotrophic lateral sclerosis. Neurology 1989;39:580-583. 19. Nakanishi T, Tamaki M, Mizusawa H, Akatsuka T , Kinoshita T: An experimental study for analyzing nerve conduction velocity. Electroencephalogr Clin Neurophysiol 1986;63:484-487. 20. Ryniewicz B: Motor and sensory conduction velocity in spinal muscular atrophy. Follow-up study. Electromyogr Clin Neurophysiol 1977;17:385- 39 1 . 21. Sobue G, Matsuoka Y, Murai E, Takayanagi T, Sobue I, Hashizume Y: Spinal and cranial motor nerve roots in amyotrophic lateral sclerosis and X-linked recessive bulbospinal muscular atrophy: morphometric and teased-fiber study. Acta Neuropathol (Berl) 1981;55:227-235. 22. Sobue G, Sahashi K, Takahashi A, Matsuoka Y, Muroga T, Sobue I:-Qegenerating compartment and functioning compartment of motor neurons in ALS: possible process of motor neuron loss. Neurology 1983;33:654-657. 23. Swash M, Schwartz MS: A longitudinal study of changes in motor units in motor neuron disease. J Neurol Scz 1982;56:185- 197. 24. Taylor PK: Non-linear effects of age on nerve conduction in adults. J Neurol Neurosurg Psychiaty 1984;66:223-234. 25. Wohlfart G: Collateral regeneration from residual motor nerve fibers in amyotrophic lateral sclerosis. Neurology 1957;7:124- 134.
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1115
.
..
MAXIMAL AND MINIMAL MOTOR NERVE CONDUCTION VELOCITIES IN PATIENTS WITH MOTOR NEURON DISEASES: CORRELATION WITH AGE OF ONSET AND DURATION OF ILLNESS MASAKAZU IIJIMA, MD, KEISUKE ARASAKI, MD, PhD, HlROYUKl IWAMOTO, MD,
and TAKA0 NAKANISHI, MD, PhD
I n healthy human beings, the maximal motor nerve conduction velocity (maxMCV) and compound muscle action potential (CMAP) amplitude decrease with age,13 linearly or n ~ n l i n e a r l yThe .~~ minimal motor nerve conduction velocity (minMCV) has also been shown to slow in normal human aging.' In patients with amyotrophic lateral sclerosis From the Neurophysiology Laboratory, Department of Neurology, University of Tsukuba. Tsukuba-City, Japan Acknowledgments: The authors thank Dr. Forbes H. Norris, Jr. (Pacific Medical Center, San Francisco, CA) for his critical comments and assistance in English. The authors also thank Ms Hiroko Akita for technical assistance. This study was supported by research grants from the Project Research, University of Tsukuba and the Research Committee for Specific Diseases, the Ministry of Health and Welfare, Japanese Government. Dr lilima's current affiliation is The Third Department of Internall Medicine, National Defence Medical College, Tokorozawa, Japan. Dr Nakanishi's current affiliation is Mishuku Hospital, Tokyo, Japan.
(ALS), the maxMCV slows in proportion to the reduction in the CMAP a m p l i t ~ d e , but ' ~ the data regarding the difference between the maxMCV and minMCV (dMCV) in ALS were confusin it was reduced,I5 the same," or even increased. In our previous study,I8 we showed that dMCV in ALS patients was unchanged, but did not separate effects of the disease process itself and those of aging. In atients with spinal muscular atrophy (SMA)," the maxMCV has usually been unaffected,8*1' but it was reduced in 2 studies.'6220 Thus, there is a literature controversy regarding changes in the maxMCV in SMA. The minMCV was apparently measured in only 1 study, and was found to be increased.' In the present study, we measured the maxMCV, minMCV, and CMAP in patients with SMA, those with ALS, and age-matched control subjects.
Y
Address reprint requests to Dr. K. Arasaki, Department of Neurology, Institute of Clinical Medicine, University of Tsukuba 1-1 -1 Tennodai, Tsukuba-City, Ibaraki-Pref. 305 Japan. Accepted for publication December 10, 1990
MATERIALS AND METHODS
CCC 0148-639X/91/01101110-06 $04.00 0 1991 John Wiley & Sons, Inc.
We examined 17 patients with SMA (mean age 53.9 years), 27 patients with ALS (mean 57.8
1110
Motor Conduction in ALS and SMA
MUSCLE & NERVE
November 1991
years), and 40 age-matched control subjects (mean 57.0 years). There was no significant age difference among these groups ( P > 0.4). The diagnosis of MND was based on clinical examination and electromyogram (EMG) demonstration of evidence of lower motor neuron degeneration with regeneration. T h e differential diagnosis between SMA and ALS was based on absence of upper motor neuron signs in SMA in our evaluation at least 2 years after the onset of the first symptoms.” At the time of the study, the average durations of illness from the onset of first symptoms in the SMA and ALS groups were 98 k 67 months and 16 k 11 months, respectively. Each subject was tested by the collision method detailed elsewhere. ’,19 The ulnar nerve was stimulated at 3 points, at about 10 min (Sl) and 70 mm (S2) above the distal wrist crease and at the elbow (S3), and evoked activity of the abductor digiti minimi muscle (ADM) was recorded. Supramaxima1 shocks of 0.1 ms were given to 2 proximal points (S2 and S3), and submaximal ones given to the distal point ( S l ) . Collision of nerve impulses produced at S1 and those either at S2 or S3 were produced so that only those produced at S2 or S3, and free from collision, evoked the muscle response. The muscle responses were amplified by a differential amplifier (WPI DAM-60) with a frequency response of 1.0 Hz to 3 kHz (3 dB down), the output of which was led through an A-D converter to a Macintosh IIcx computer with a horizontal resolution of 25 ks/point and 256 points per channel. Using the computer, a submaximal motor response to a single stimulation at S1 (MSli’) was subtracted from a mixed motor response following paired stimulation at S2 and S1 or S3 and S1 ([MS2 + MSli’] or [MS3 + MSli’]). T h e resulting [MS2 + MSli’] - MSli’ or [MS3 + MSli’] MSli‘; i.e., MS2’ or MS3‘, respectively, should show muscle activity by orthodromic motor impulses evoked at S2 or S3 and free from collision. MCVs of motor nerve fibers giving rise to MS2‘ and MS3’ were calculated from their onset latencies, and were corrected for skin temperature according to the following equation: corrected conduction velocity = observed conduction velocity + Q (34.0 - observed skin temperature). We used 2.4 m/s per “C and 2.2 m/s per degree C as the Q values for the fastest-conducting and slow-conducting motor fibers, respectively.’ In order to eliminate effects of normal aging upon measured and corrected MCVs, we created
Motor Conduction in ALS and SMA
the following parameters: age-adjusted maxMCV (%) = an observed maxMCV divided by an expected maxMCV for a patient’s age, age-adjusted minMCV (%) = an observed minMCV divided by an expected minMCV for a patient’s age, an ageadjusted dMCV (m/s) = an observed dMCV minus an expected dMCV for a patient’s age, and ageadjusted CMAP (%) = an observed CMAP amplitude divided by an expected CMAP amplitude for a patient’s age. Expected values of the maxMCV, minMCV, dMCV, and CMAP amplitude for a given patient’s age were calculated by the following equations reported elsewhere’: an expected maxMCV = 64.42 - 0.05 age, an expected minMCV = 60.45 - 0.12 age, an expected dMCV = an expected maxMCV minus an expected minMCV, and an expected CMAP amplitude = 22.23 - 0.14 age. Statistical analysis of the results was done by the two-group nonparametric test (Mann- Whitney U test). Three-dimensional (3D) data analysis of the relationship among these parameters, the age of onset, and the duration of illness were performed by Systat. RESULTS MaxMCV, minMCV, dMCV and CMAP Amplitude in ALS and SMA Patients. T h e maxMCV and minMCV in the ALS group were 55.3 k 7.4 m/s and 43.6 7.6 m/s (mean k SD), respectively, signif-
*
icantly lower than the control maxMCV and minMCV (62.1 -+ 5.3 m/s and 53.8 k 6.1 m/s, respectively), P < 0.001. The dMCV in each patient with ALS (11.8 -+ 5.9 m/s) was not statistically different from that in the control group (8.5 -+ 4.6 m/s), P > 0.03. CMAP amplitude in the ALS group was 5.9 k 4.4 mV, which was smaller than that in the control group (14.2 f 3.7 mV), P < 0.00 1. The maxMCV and minMCV in the SMA group were 57.2 t 7.6 m/s and 45.3 2 8.2 m/s, respectively, and significantly (P < 0.005) lower than those in the control. However, in those SMA patients with the duration of illness of no more than 5 years (see below), the maxMCV (59.9 ? 5.5 m/s) and the minMCV (47.2 k 7.1 m/s) were not significantly reduced from those in the control ( P > 0.03). The dMCV in each patient with SMA (12.0 k 8.6 m/s) was not statistically different from that in the control group ( P > 0.05). CMAP amplitude in the SMA group was 9.1 k 6.2 mV, which was significantly smaller than that in the control group ( P < 0.001).
MUSCLE & NERVE
November 1991
1111
70
0 ONSETAGE 60
COURSEMO B
A
FIGURE 1. The age-adjusted maxMCV in relation to age of onset (onsetage) and duration of the clinical course (coursemo) in ALS (A) and SMA (B). The X and Y axes are the duration of clinical course in months and the age of onset in years, respectively. The Z axis shows the age-adjusted maxMCV. Follow-up was done up to 47 months in ALS patients and 250 months in SMA patients. The control value is shown as a line at 100.
Relationship Among Age-adjusted maxMCV, minMCV, dMCV, CMAP, the Age of Onset and the Duration of Illness in ALS. Slowing of the maxMCV
and minMCV in ALS patients was likely to correlate not only with the duration of illness, but also the age of onset; the age-adjusted maxMCV (mean 90.0%) was reduced slightly less than the age-adjusted minMCV (mean, 81.5%), and both were decreased less in ALS patients with earlier onset of the disease and shorter duration of illness
(Figs. 1A and 2A). The age-adjusted dMCV in ALS patients was more influenced by the former (Fig. 3A). In ALS patients whose disease started in the fourth and fifth decades, the age-adjusted dMCV tended to be positive regardless of the duration of the disease. However, in those with the disease onset in the seventh and eighth decades, the age-adjusted dMCV was usually zero or negative. Changes in the age-adjusted CMAP in ALS pa-
ll 0
51 n
100 90
80 70
60 30 0 ONSETAGE COURSEMO
COURSEMO
A
B
FIGURE 2. The age-adjusted minMCV in relation to age of onset (onsetage) and duration of the clinical course (coursemo) in ALS (A) and SMA (B). Plot was done in the same manner as in Figure 1, except for the age-adjusted minMCV on the 2 axis.
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Motor Conduction in ALS and SMA
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20
15
t
10
5 Ba
0 20 0
n
J
ONSETAGE
ONSETAGE 80-50
5
COURSEMO
COURSEMO B
A
FIGURE 3.The age-adjusteddMCV in relation to age of onset (onsetage) and duration of the clinical course (coursemo) in ALS (A) and SMA (B). Plot was done in the same manner as in Figure 1, except for the age-adjusteddMCV on the 2 axis, and the control values shown as a line at 0.
tients, on the other hand, were much simpler: it was likely to be smaller in those with longer duration of the disease, whether it started early or late. Relationship Among Age-adjusted maxMCV, minMCV, dMCV, CMAP, the Age of Onset and the Duration of Illness in SMA Patients. The age-adjusted
maxMCV (mean 90.9%) and minMCV (mean 84.9%)in SMA were reduced to only the same degree as those in ALS, and were smaller only in cases where the onset age was higher or the duration of illness longer (Figs. 1B and 2B). The ageadjusted dMCV was positive in SMA patients, who became symptomatic in the third decade, or had suffered less than 60 months (Fig. 3B). The age-adjusted CMAP was correlated with both the age of onset and duration of illness: it tended to be smaller with longer duration and later onset of the disease. Comparing Age-adjusted dMCV and CMAP Between ALS and SMA Patients. The age-adjusted dMCV
was compared between 10 ALS patients and 4 SMA patients with the onset age and duration of illness statistically equivalent to each other: onset age 53.4 years in ALS and 51.3 years in SMA pa10.2 months in tients, P > 0.5; duration 25.0 ALS and 31.8 ? 5.1 months in SMA, P > 0.1. The age-adjusted dMCV in the SMA group ( 1 1.4 2 7.3
*
Motor Conduction in ALS and SMA
d s ) was larger than that in the ALS group (2.5 2 5.0 m/s), P < 0.01. We also compared the age-adjusted CMAP between the same 10 ALS and 4 SMA patients. The CMAP in the ALS group was 28.8 2 14.4%, whereas that in the SMA group was 66.6 32.9%, P < 0.01. Therefore, a decrease in the amplitude of CMAP in SMA patients may be much slower than that in ALS.
*
DISCUSSION
In the present study, we confirmed the results of previous studies that the maxMCV, minMCV, and CMAP were all decreased in ALS patients.*”’ Furthermore, we found that the maxMCV, minMCV, and CMAP in SMA patients were also decreased in comparison with age-matched control subjects. It has generally been believed that “nerve conduction studies of motor and sensory fibers in SMA are normal.”’ Indeed, Chaco and Hashimoto et al. reported that young adult patients with SMA and monomelic amyotrophy had normal maxMCV,’,” but the duration of illness in their cases was relatively short, i.e., 2 to 4 years in the former and mostly less than 5 years in the latter. Similarly, in a selected portion of our SMA patients with the duration of illness no more than 5 years, the maxMCV was not significantly reduced. However, consistent with our results in adults, in one-quarter to one-half of children with SMA, aged 2 months to 12 years, the maxMCV of the
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ulnar nerve was also slower than Therefore, we may conclude that the maxMCV decreases in adult SMA patients and in infantile and juvenile SMA patients. The present study was not a true longitudinal one, in which a given individual was studied re-. peatedly. For this reason, it was essential for us to eliminate aging effects in each patient in order to evaluate changes in the maxMCV, minMCV, dMCV, and CMAP amplitudes in a number of patients. Therefore, we used age-adjusted values of maxMCV, minMCV, dMCV, and CMAP amplitudes, instead of their crude values. To our knowledge, there have been no other studies on the relationship between dMCV in ALS and SMA patients and their aging. The positive age-adjusted dMCV in ALS patients who developed the disease in the fourth decade, or had suffered from it less than a year (Fig. 3A), means that slowing of minMCV was more than that of the maxMCV in these patients' category, even considering the relative decrease of minMCV in human aging.' On the contrary, zero or negative age-adjusted dMCV in ALS patients who developed the disease in the seventh or eighth decade, and had suffered from the disease for longer than a year (Fig. 3A), means that the maxMCV slowed equal to or more than the minMCV in older ALS patients. Thus, although dMCV in ALS has been a subject of substantial disc~ssion,'~~~~'~~'~~'~ it may not be worthwhile to assess dMCV per se without the information regarding the age of onset and duration of illness of each patient. Comparing ALS and SMA patients who had suffered for comparable periods of time, the ageadjusted maxMCV, minMCV, and CMAP were all much more reduced in ALS (Figs. 1A and l B , 2A and 2B). As slowing of the MCVs in ALS results from loss of the myelinated motor nerve fibers, atrophy of the axons, secondary changes in the myelin sheath5 or thin regenerated ax on^,'^ these findings are consistent with the ~ l i n i c a l ' ~ and p a t h o l o g i ~ a l ~ ~ ~observations '~'' that neuronal degeneration in ALS proceeds much faster than in SMA. Decreased age-adjusted maxMCVs (Figs. 1A and B) can easily be attributed to loss of large myelinated motor nerve fibers in the periphery,
which may be due to a neuronopathy, distal axonal dystrophy, or both.4 On the other hand, the minMCV probably reflects the functional integrity of motor nerve fibers with smaller diameters,' and its remarkable slowing in younger ALS patients (Fig. 2A) might result from these processes occurring predominantly in smaller motor nerve fibers. This selective degeneration of smaller motor nerve fibers in ALS, however, is unlikely; the process should be more r a n d o m i ~ e d . ~ , ' ~ Axonal regeneration is more active in younger mammals with nerve crush i n j ~ r y younger ,~ patients with complete section of their peripheral nerves,6 and in the intramuscular nerves (sprouting)15 of ALS patients in the early stages.23 In comparing ALS and SMA patients, axonal regeneration in SMA patients is usually more intense. 10,22*23 In the present study, the age-adjusted dMCV was larger only in the following two categories of ALS patients than in the controls: those who developed the disease at younger ages, and those who were in the early stages of the disease. The age-adjusted dMCV was also larger in SMA patients than those with ALS having the same duration of clinical symptoms (Fig. 3A and B). This parallelism between characteristics of the age-adjusted dMCV and those of axonal regeneration strongly suggests that an increase in dMCV is a result of nonselective regeneration of motor axons, which might be modulated by such factors as the patient's age and, of course, the disease process itself. It is well-known that thin, regenerated motor axons have abnormally slow conduction velocities and shortened internodal distance^.^ In ALS, remyelination occurs even in the ventral roots." It is likely that remyelinated motor axons in the younger ALS patients, in the present study, also had very slow conduction velocities and short internodal lengths, in addition to slow conduction in peripheral sprout^.'^ In consequence, the minMCV in these patients must have decreased beyond its normal range, resulting in an increase in dMCV. This concept is supported by a single motor unit study that disclosed abnormally slow axonal conduction velocity in ALS patients.'
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Motor Conduction in ALS and SMA
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