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Motor neuron disorders: novel electrophysiologic approach (MUFDEC protocol)
Motor Unit Number Estimation (MUNE) and Quantitative EMG (Supplements to Clinical Neurophysiology, Vol. 60) Editors: M.B. Bromberg # 2009 Elsevier B.V. All rights reserved
Chapter 14
Motor neuron disorders: novel electrophysiologic approach (MUFDEC protocol) F.C. Wanga,*, N. Le Forestierb, P. Ge´rardc, J.C. Willerb, V. Meiningerd, D. Divee, A. Maertens de Noordhoutc and P. Boucheb a
Department of Neurophysiology, Me´decine Physique, CHU Lie`ge, 4000 Lie`ge, Belgium b Department of Neurology and Neurophysiology, Pitie´-Salpeˆtrie`re Hospital, 75651 Paris Cedex 13, France c Department of Neurology and Neurophysiology, CHR de la Citadelle, 4000 Lie`ge, Belgium d Department of Neurology, Pitie´-Salpeˆtrie`re Hospital, 75651 Paris Cedex 13, France e
Department of Neurology and Neurophysiology, CHUOA , 4130 Esneux, Belgium
1. Introduction Primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS) and X-linked spinobulbar muscular atrophy (Kennedy’s disease) are disorders characterized by progressive loss of upper motor neurons (UMN), lower motor neurons (LMN) or both. Clinically, PLS is usually considered to be a disorder of pure UMN loss, ALS mixed UMN and LMN loss, and Kennedy’s disease a disorder of LMN loss. There are data suggesting a degree of LMN loss in PLS, and little is known about motor unit (MU) loss and its rate in Kennedy’s disease. Motor unit number estimation (MUNE) is a unique neurophysiological technique that can directly assess LMN loss (Shefner, 2001). It can be used with other neurophysiological tests including a new neurophysiologic MUFDEC protocol: MU ¼ MUNE (motor unit *
Correspondence to: Dr. Franc¸ois C. Wang, Me´decine Physique, CHU Lie`ge, Sart Tilman B35, 4000 Lie`ge, Belgium. Tel.: þ32-4-3667788; Fax: þ32-4-3667230; E-mail: [email protected]
number estimation), F ¼ F-wave responses, DE ¼ decrement to repetitive stimulation, C ¼ CMAP (compound muscle action potential) score. The MUFDEC can indirectly assess the effects of LMN and UMN loss. We report the results of two studies applying these techniques and tests to subjects with PLS, ALS and Kennedy’s disease. The aims of study 1 were to document subclinical LMN involvement in PLS, to compare the degree of LMN loss involvement among the diseases, and to measure respective rate of MU loss. The aims of study 2 were to compare two MUNE techniques, the adapted multipoint stimulation (AMPS) and the statistical technique, and attempt to explain differences by the other parameters studied with the new MUFDEC neurophysiologic protocol. 2. Subjects 2.1. Study 1 Data were collected from consecutive subjects with ALS (n ¼ 16), PLS (n ¼ 8), and Kennedy’s disease (n ¼ 5). ALS subjects fulfilled revised El Escorial
144 criteria for definite diagnosis (Brooks et al., 2000). PLS subjects were diagnosed based on clinical evidence of a pseudobulbar and tetrapyramidal syndrome without clinical evidence for LMN involvement, and a disease duration of more than 5 years. Subjects with Kennedy’s disease had at least 37 CAG repeats. Each subject was evaluated twice, at baseline (T0) and 9–12 months later (T1). 2.2. Study 2 Data were collected from subjects with ALS (n ¼ 37), PLS (n ¼ 10), post-polio syndrome (n ¼ 2), and Kennedy’s disease (n ¼ 3). One hundred MUNE determinations were analyzed, using AMPS and statistical MUNE techniques. Some subjects were evaluated repeatedly at 3-month intervals. Seventy-five MUNE determinations were done in ALS subjects (1 determination in 17, 2 determinations in 11, 3 determinations in 4, 4 determinations in 1, and 5 determinations in 4), 15 in subjects with PLS (1 determination in 5 and 2 determinations in 5 others), 5 in subjects with post-polio syndrome (2 determinations in 1 and 3 determinations in another one) and in 5 subjects with Kennedy’s disease (1 determination in 2 and 3 determinations in 1). When MUNE was not possible to perform at a session only one value was accepted to avoid bias in estimating the feasibility of the two MUNE techniques through repeated evaluations in the same subject. Informed consent was obtained from all subjects. 3. Methods Subjects rested comfortably in a supine position. All data were collected using a Nicolet Viking IV EMG machine (Nicolet Instrument Corp.).
the tibial tuberosity to the tip of the medial malleolus and the reference electrode positioned over the medial tibia, just above the medial malleolus. For recording from the thenar muscle, the skin was cleaned by alcoholic solution and abrasive paste and active and reference electrodes were either self-adhesive (Nicolet, model 019–766300) cut in strips 3 0.8 cm (for MUNE) or Ambu (ref 700 10-K/C) self-adhesive (for CMAP score evaluation). The active electrode was placed over the thenar eminence, in close proximity to the muscle endplates, halfway between the midpoint of the distal wrist crease and the first metacarpophalangeal joint. The reference electrode was placed over the proximal phalanx of the thumb (Fig. 14.1). Recording artifacts induced by movement were minimized by a splint immobilization of forearm, wrist, hand and fingers in a neutral position. 3.2. Stimulation arrangements The common peroneal nerve was stimulated just medial to the lateral edge of the popliteal space. The median nerve was stimulated at the wrist 8 cm proximal to the active recording electrode. Supramaximal CMAPs were evoked by single stimuli of 0.2 ms duration using a bipolar stimulator (Medelec, Model LBS 53051). During the AMPS MUNE technique from the thenar muscle it was necessary to increase the selectivity in activation of isolated MUs and a monopolar stimulation was preferred to bipolar stimulation. The surface cathode (Medelec Model of monopolar stimulator) was moved over the median nerve course from the wrist to the elbow. The anode consisted of a self-adhesive adult ECG electrode (ConMed 1800–005) positioned over the dorsum of the distal forearm. 3.3. CMAP responses and CMAP score
3.1. Recording arrangements For recording from the tibialis anterior muscle, the active and reference electrodes were self-adhesive (Ambu, ref 700 10-K/C). The active electrode was placed one quarter of the distance from the tip of
CMAP responses were obtained from the tibialis anterior and thenar muscles bilaterally. CMAP waveforms were measured as the negative peak area. The CMAP score was calculated as the average of bilateral thenar and peroneal CMAP responses.
145 3.5. Decremental response testing Trains of 10 supramaximal stimuli were applied at 3 Hz. CMAP decrement was determined as the percent difference between the fourth and first response. 3.6. F-index The F-index was the product of F-occurrence by F-amplitude. 3.7. Neurophysiological index (NI) The NI is based on the formula (De Carvalho and Swash, 2000): maximal CMAP negative peak amplitude/(distal motor latency x F-occurrence). 3.8. MUFDEC Fig. 14.1 Electrode placement for thenar MUFDEC protocol (MUNE, F- and decremental responses, CMAP score). The active electrode was placed halfway between the midpoint of the distal wrist crease and the first metacarpophalangeal joint. The reference electrode was placed over the proximal phalanx of the thumb. The ground electrode was fixed over the dorsum of the first intermetacarpal space. The surface cathode (monopolar stimulator) was positioned over the median nerve course. The anode consisted of a self-adhesive adult ECG electrode placed over the dorsum of the distal forearm. The supramaximal thenar CMAP was elicited by stimulation of the median nerve at the wrist 8 cm proximal to the active recording electrode, in a line measured first to the midpoint of the distal wrist crease and then to a point slightly ulnar to the tendon of the flexor carpi radialis muscle.
3.4. F-response testing Thenar F-responses were elicited with supramaximal 1 Hz stimulation. F-occurrence was expressed as the number of F-responses recorded in 32 trials. F-amplitude was measured as maximum peak-topeak from 32 superimposed traces and expressed as a percentage of the maximal CMAP peak-topeak amplitude.
The MUFDEC protocol was applied in each subject and included: (1) summed compound muscle action potential (CMAP) score (averaged CMAP responses from bilateral thenar and tibialis anterior), (2) thenar decremental response to 3 Hz repetitive stimulation, (3) thenar F-response index, (4) thenar MUNE using AMPS, and (5) neurophysiological index (2–5, evaluated on the less affected side, established clinically or on the basis of CMAP score data). 3.9. AMPS MUNE MUNE represents the ratio of the maximal CMAP divided by the average surface-recorded motor unit potential (SMUP). MUNE techniques differ in how single MUs are obtained. McComas et al. (1971) introduced the first MUNE technique, referred to as the incremental technique. Incremental stimulation was applied at one stimulation point on the nerve and the stimulus intensity was gradually increased from a subthreshold value until 11 increments in the muscle response were obtained. The average SMUP size was derived by dividing the negative peak or peak-to-peak amplitude of the
146 response by the number of increments. Brown and Milner-Brown (1976) introduced a modification in an attempt to eliminate the inherent problem of alternation that affect the incremental MUNE technique. The alternation phenomenon is attributed to motor axons with overlapping thresholds resulting in different combinations of activated axons at a constant stimulus intensity. In the alternative procedure, referred to as the multiple point stimulation technique (MPS), the nerve is stimulated at 10–20 distinct points and at each point, only the first all or nothing SMUP excited is included in the count. Kadrie et al. (1976) proposed an adapted MPS (AMPS) technique by combining elements of the incremental and MPS techniques. In this procedure, the nerve is stimulated at multiple points and at each point the stimulus voltage is increased in a graded manner until the first and one or two subsequent MUs are activated in an all or nothing manner. Two decades later, we updated and validated the AMPS technique for thenar muscles in 54 control subjects (Wang and Delwaide, 1995). To avoid alternation and ensure that any increment of the motor response corresponds to the activation of one single MU, specific criteria were established (see below). After the First International Symposium On MUNE (Wang et al., 2003), minor modifications were incorporated into the AMPS technique used in this study. Individual SMUPs and CMAPs were recorded with a gain of 50–500 V/division and a sweep of 2–5 ms/division. For the incremental stimulation portion, a weak intensity stimulus at 1 Hz rate was gradually increased from a subthreshold value by increment steps of 0.1–0.5 mA with as short as possible stimulation durations (0.01–0.1 ms). The hand temperature, measured at the midpoint of the distal wrist crease, was maintained above 30 C. The AMPS involves two steps. The first step consisted of eliciting the supramaximal thenar CMAP by stimulation of the median nerve at the wrist 8 cm proximal to the active recording electrode, in a line measured first to the midpoint of the distal wrist crease and then to a point slightly ulnar to the tendon of the flexor carpi radialis muscle (Fig. 14.1).
The second step consisted of estimating the mean MU size by collecting and averaging 10–20 well-identified SMUPs after stimulation at distinct points along the course of the median nerve. To minimize the effects of temporal dispersion, in each MUNE evaluation by AMPS, only one stimulation point was selected at the elbow. The other sites were selected at the distal part of the forearm. At each stimulation site, the stimulus intensity was gradually increased until the first, and then subsequent MUs were recruited. To be included in the estimation, SMUPs had to be evoked: (1) with distinct thresholds, (2) in an all or nothing fashion, (3) with no fractionating of the CMAP to successive identical stimuli, and (4) in an orderly and reproducible manner. At one specific stimulation point, two or three successive SMUPs were usually accepted in the count, but in favorable circumstances, four or more successive SMUPs met the selection criteria and were incorporated in the estimation. The gain was usually between 50 and 200 mV/division, but at times it was necessary to increase it to 500 mV/division to keep the complete evoked response on the screen, and with this condition only one new SMUP was accepted. The gain was never increased to 1 mV or more to prevent ignoring small SMUPs. SMUPs were eliminated from the estimation when they: (1) had similar morphology at two distinct stimulation points, (2) were predominantly positive waveforms, as they were supposed to be elicited from distant muscles, such as lumbrical muscles. CMAP and SMUP sizes were evaluated by initial negative peak area measurements. The duration for AMPS evaluation was the time from the beginning to the end of individual SMUP recruitment. 3.10. Statistical MUNE Statistical MUNE is a semi-automated procedure in which SMUP size is estimated by the variance of submaximal CMAPs using Poisson statistics. The method was applied in accordance with the consensus established at the First International
147 Symposium on MUNE (Bromberg, 2003). The MUNE was calculated using the weighted-mean statistical method assuming that the SMUP sizes in the untested ranges were proportional to the SMUPs in the tested ranges (Olney et al., 2000). The duration for statistical MUNE evaluation was measured from maximal CMAP recording to the end of the last run.
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3.11. Statistical analysis Mean values are reported with their standard deviations. The significance of differences between means was determined by the Student’s t-tests for independent samples or paired Student’s t-tests. When the variable under study evolved exponentially, a logarithmic transform of the values preceded Student’s t-tests. Correlations between associated variables have been calculated with regression analyses. In study 1, to discriminate the 3 groups of subjects (SLA, SLP and Kennedy), a stepwise discriminate analysis was carried out on all variables to determine which variables were significant. A canonical discriminant analysis was done on the selected variables. In study 2, for some subjects, MUNE could not be obtained because of technical conditions. These subjects were called “drop-out” and the others, “non drop-outs”. A multiple logistic regression was used to model the probability of being a drop-out. A stepwise selection was carried out to identify significant explicative variables. Statistical analyses are made on the maximum available data. Results are considered significant at P < 0.05. Calculations were carried out with statistical software SAS (Version 9.1). 4. Results 4.1. Study 1 Table 14.1 summarizes results in the three groups of subjects at T0 and T1. Demographics. There were no significant differences in mean ages among the 3 subject groups. The shortest mean disease duration at T0 was
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observed in ALS subjects (27 months) and the longest in Kennedy’s disease (317 months). CMAP scores. CMAP scores at T0 remained within normal limits in 88% of PLS subjects, in 80% of Kennedy’s disease subjects, and in 19% of ALS subjects. CMAP scores decreased between T0 and T1: 5% in PLS, 10% in Kennedy’s disease, and 39% in ALS. MUNE values. At T0, thenar MUNE remained within normal limits in 13% of PLS subjects, in 20% of Kennedy’s disease subjects, and in 50% of ALS subjects. Thenar MUNE was reduced in the 3 groups without significant difference between them. At T1, thenar MUNE in ALS subjects (28 33) was significantly lower than in PLS subjects (61 36). Thenar MUNE decline between T0 and T1 was 15% in PLS subjects, 7% in Kennedy’s disease, and 62% in ALS. Decrement. Thenar decrement was less than 10% in subjects with PLS and Kennedy’s disease, while among ALS subjects, decrement was greater than 10% in 50% of subjects at T0 and increased to 56% at T1. Neurophysiologic and F-index. There was no significant difference between mean NI and F-index of the 3 groups of subjects and between T0 and T1 in each group. The lowest mean NI was observed in ALS with a 72% NI decrease between T0 and T1. The highest mean F-index was established in PLS subjects with a 31% increase between T0 and T1. Stepwise regression. In 26 observations (14 subjects with ALS, 8 with PLS, 4 with Kennedy’s disease), data from 24 variables, at T0 (CMAP score, right and left tibial anterior CMAP amplitude and area, right and left thenar CMAP amplitude and area, CMAP score divided by disease duration, F-index, NI, amplitude and area decrement, mean SMUP size, MUNE and MUNE divided by disease duration) or considering differences between T0 and T1 (change in CMAP score, change in F-index, change in NI, change in amplitude and area decrement, change in mean SMUP size and change in MUNE), were available
148 TABLE 14.1 MUFDEC RESULTS IN PATIENTS WITH PRIMARY LATERAL SCLEROSIS (PLS, n ¼ 8), AMYOTROPHIC LATERAL SCLEROSIS (ALS, n ¼ 16) AND KENNEDY’S DISEASE (n ¼ 5) PLS T0 Age (years) Disease duration (months) CMAP score (mV.ms) Thenar MUNE Thenar decrement (%) NI F-index
58 14 122 61 34.3 11.3 (1/8) 72 52 (7/8) 54 (0/8) 76 51 211 122
ALS T1
T0
32.6 11.9 (2/8) 61 36 (7/8) 53 (0/8) 68 40 277 175
56 13 27 18 22.3 9.1 (13/16) 73 58 (8/16) 11 5 (8/16) 43 49 71 93
Kennedy T1
T0
T1
13.7 6.8 (16/16) 28 33 (15/16) 14 6 (9/16) 12 23 43 94
54 7 317 529 36.4 7.8 (1/5) 57 75 (4/5) 62 (0/5) 54 43 46 25
32.6 5.4 (1/5) 53 64 (4/8) 63 (0/8) 68 48 104 129
In parentheses: number of data beyond normal limits.
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for discriminant analysis. The significant variables to discriminate the 3 groups of subjects were right tibialis anterior CMAP area, CMAP score divided by disease duration, F-index and area decrement of thenar response. Canonical discriminate analysis. Canonical discriminate analysis was performed on the significant variables. Two distinct functions of the selected variables, CAN1 and CAN2, were established and illustrated in Fig. 14.2. By doing so, the 3 groups of subjects were discriminated on the base of neurophysiological data exclusively.
4.2. Study 2 Comparison between statistical and AMPS MUNE techniques in the same subjects are summarized in Table 14.2. Statistical and AMPS applicability. With the AMPS technique it was possible to obtain a MUNE in all 100 trials, without technical failures. With statistical MUNE it was not possible to determine a MUNE in 15 trials (distinct subjects) because of technical conditions. Good technical conditions require: (1) reliable scan,
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(2) CMAP size distribution skewed to the right at least 3 times out 4 runs, (3) reasonable degree of SMUP size variability to exclude excessive variability due to poor subject cooperation or optimal state of relaxation. Among subjects who could not be assessed by statistical MUNE, predictive features were significant decrease in CMAP score, in thenar MUNE evaluated by AMPS, in thenar NI, and an increase in thenar decremental. The probability of dropping-out from statistical MUNE, established by multiple logistical regression, increased with an increase in thenar decremental response. Statistical and AMPS values. In subjects evaluated by both techniques (n ¼ 85), mean thenar values were significantly greater with AMPS (100 81) than with statistical MUNE (71 33). There was a positive correlation (r ¼ 0.77) in MUNE values between both techniques. The best correlation coefficient (r ¼ 0.89) was obtained with AMPS values less than or equal to 100 compared to corresponding statistical values (Table 14.2 and Fig. 14.3). AMPS values less than 50 were significantly lower than their corresponding statistical values, and conversely
149
Fig. 14.2
Canonical discriminant analysis De: area decrement of thenar motor response; CMAP/DD: CMAP score divided by disease duration; right TA area: right tibialis anterior CMAP area.
for AMPS values more than 100. There was no significant difference by comparing AMPS values between 50 and 100 with their corresponding statistical MUNE. The mean duration for MUNE evaluations was 13 3 min for statistical method (n ¼ 85) and 13 4 min for AMPS (n ¼ 100). 5. Discussion Thenar MUNE evaluated by the AMPS method was more sensitive than CMAP area to detect MU loss, particularly in chronic diseases. In PLS and Kennedy’s disease, CMAP scores remained within normal limits in 11 of 13 subjects at T0, whereas thenar MUNE was decreased in 11 of 13 subjects. In ALS subjects at T0, CMAP scores were below the lower normal limit in 81% and thenar MUNEs in only 50%. This paradoxical result was due to the fact that thenar MUNE was evaluated on the less affected side whereas CMAP score included the more affected thenar muscle and both tibialis
anterior muscles which were sometimes predominantly denervated. The percentage change in thenar MUNE between T0 and T1 was greater than the percent drop in CMAP score and was the greater in ALS by comparison to diseases evolving more chronically. Bromberg et al. (1993) showed by a comparison between MUNE values, isometric strength, CMAP amplitude, SMUP amplitude, fiber density, macro-EMG potential amplitude, turns-toamplitude ratio, amplitude and recruitment pattern of low threshold voluntary MU in ALS, that MUNE measurements were best suited to provide insight into the true natural history of the disease process and might be clinically useful to follow progression and response in drug trials. By comparing MUNEs, mean thenar SMUPs and CMAPs, isometric hand grip strength, total Medical Research Council manual muscle testing score, Appel ALS rating scale and force vital capacity, Felice (1997) concluded that MUNE values were the most sensitive index for documenting changes in disease progression over time.
150 TABLE 14.2 COMPARISON OF RESULTS DERIVED BY AMPS AND STATISTICAL MUNE Thenar MUNE
AMPS
Statistical MUNE
Correlation coefficient (r)
Student t-test (P)
All data AMPS < 100 AMPS < 50 AMPS [50, 100] AMPS > 100 Drop-out subjects Time to perform
100 81 47 31 21 12 78 15 175 71 0% 130 4
71 33 54 28 35 23 76 15 94 24 15% 130 3
0.77 0.89 0.87 0.38 0.49
0.002 0.008 < 0.001 0.6 < 0.001
400 r = 0.77 slope = 0.31
300 200 100 0 0
100
200
300
400
400 r = 0.48 slope= 0.31
100
r = 0.89 slope = 0.80
10 6 6 10
100
400
Fig. 14.3 Correlation study. A: positive correlation (0.77, linear scales) between results derived by the adapted multiple point stimulation (AMPS) method and statistical motor unit number estimate (MUNE). B: the best correlation coefficient (0.89, logarithm scales) was obtained by comparing AMPS values less than or equal to 100 to their corresponding statistical MUNE.
In ALS subjects, we found that when changes in NI (72%) and Findex (39%) between T0 and T1 were high, disease duration at T0 was shorter than in other subjects and there were more cases with decremental responses greater than 10%. These findings are consistent with a subacute course. We confirmed the observations of De Carvalho and Swash (2000) on the sensitivity of the NI and feel it might be an useful indicator of change in clinical practice and, as MUNE, a suitable endpoint in clinical trials. F-index is a new index to evaluate UMN dysfunction in ALS or PLS because F-wave occurrence depends not only on the number of active MU but also on motor excitability, while the latter and the MU size influence F-amplitude. In a previous study we showed that thenar decrement to 3 Hz repetitive nerve stimulation reflected activity or rate of progression of the motor neuron disease (Wang et al., 2001). Little is known about the natural history of MU loss in Kennedy’s disease. In the present study, the decreased thenar MUNE value at baseline with a subsequent very slow MUNE decline (7%) suggests that MU loss starts early in life and has a long-lasting subclinical course. This needs to be confirmed in a larger group.
151 In PLS, we found subclinical LMN involvement in 7 of 8 subjects, an intermediate rate of MU loss (15%) and an increase in the F-index probably related to the predominant UMN involvement. These data confirmed results published by Gooch et al. (2004) who found a 2.5% per month average MUNE decline in PLS. The identification of a LMN component in PLS might be interpreted as supporting the notion that PLS belonging to the Charcot ALS syndrome. Alternatively, the MU loss might be the consequence of the UMN involvement without primary degenerative process of anterior horns. In support, Arasaki et al. (2006) found a decrease in MUNE of hypothenar muscles within 30 h after cerebral infarction. They speculate that this could be due to trans-synaptic inhibition of the spinal alpha motor neurons. Results of discriminate analysis revealed that the right tibialis anterior area, CMAP score divided by disease duration, F-index and negative peak area decrement of thenar motor response were the 4 significant variables to distinguish the 3 groups of subjects. In conclusion, study 1 confirms that MUNE is a sensitive indicator of disease progression. However, for complete information about the different motor neuron diseases, it seemed useful to incorporate MUNE in a protocol that includes CMAP, F-wave and decrement measurements which provided data about medullar excitability, motoneurons, neuromuscular transmission and muscular fibers. Study 2 shows that statistical MUNE and AMPS in the same subject population reveal good correlations between the techniques, particularly for the lowest values. However, when MUNE values are less that 50, the AMPS technique underestimates compared to the statistical technique, while when MUNE values were greater than 100 the AMPS technique overestimates compared to the statistical technique. As there is no gold standard for the true number of functioning MUs in a muscle, it was not possible to identify the reasons of these differences. There was no significant difference between AMPS MUNE from 50 to 100 and
their corresponding statistical MUNE, but correlation between both series of data was not good. The reason of the latter result might be a link to the cancellation of several technical bias acting in opposite directions. There was a 15% drop-out of subjects with the statistical MUNE, particularly in the terminal stage with low values for CMAP score, thenar MUNE and NI and high decremental thenar responses. Thus, in ALS subjects, application of the statistical MUNE during the entire disease course remained uncertain, while the AMPS technique can be used at any time in the course of the disease. Both MUNE methods take the same time to be performed. References Arasaki, K., Igarashi, O., Ichikawa, Y., Machida, T., Shirozu, I., Hyodo, A. and Ushijima, R. (2006) Reduction in the motor unit number estimate (MUNE) after cerebral infarction. J. Neurol. Sci., 250: 27–32. Bromberg, M.B. (2003) Consensus. In: B. Bromberg (Ed.), Motor Unit Number Estimation (MUNE). Supplements to Clinical Neurophysiology, Vol. 55. Elsevier, Amsterdam, pp. 335–338. Bromberg, M.B., Forshew, D.A., Nau, K.L., Bromberg, J., Simmons, Z. and Fries, T.J. (1993) Motor unit number estimation, isometric strength, and electromyographic measures in amyotrophic lateral sclerosis. Muscle Nerve, 16: 1213–1219. Brooks, B.R., Miller, R.G., Swash, M. and Munsat, T.L. (for the World Federation of Neurology Research Group on Motor Neuron Diseases) (2000) El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. ALS Other Motor Neuron Disord., 1: 293–299. Brown, W.F. and Milner-Brown, H.S. (1976) Some electrical properties of motor units and their effects on the methods of estimating motor unit numbers. J. Neurol. Neurosurg. Psychiatry, 39: 249–257. De Carvalho, M. and Swash, M. (2000) Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve, 23: 344–352. Felice, K.J. (1997) A longitudinal study comparing thenar motor unit number estimates to other quantitative tests in patients with amyotrophic lateral sclerosis. Muscle Nerve, 20: 179–185. Gooch, C., Tang, M.X., Garcia, J., Del Bene, M., Batista, V., Gad, N., Montes, J., Rowland, L. and Mitsumoto, H. (2004) MUNE measures in ALS, FALS, PMA and PLS in a natural history biomarker study. ALS Other Motor Neuron Disord., 5: 113(Abstract).
152 Kadrie, H.A., Yates, S.K., Milner-Brown, H.S. and Brown, W.F. (1976) Multiple point electrical stimulation of ulnar and median nerves. J. Neurol. Neurosurg. Psychiatry, 39: 973–985. McComas, A.J., Fawcett, P.R., Campbell, M.J. and Sica, R.E.P. (1971) Electrophysiological estimation of the number of motor units within a human muscle. J. Neurol. Neurosurg. Psychiatry, 34: 121–131. Olney, R.K., Yuen, E.C. and Engstrom, J.W. (2000) Statistical motor unit number estimation: reproducibility and sources of error in patients with amyotrophic lateral sclerosis. Muscle Nerve, 23: 193–197. Shefner, J.M. (2001) Motor unit number estimation in human neurological diseases and animal models. Clin. Neurophysiol., 112: 955–964.
Wang, F.C. and Delwaide, P.J. (1995) Number and relative size of thenar motor units estimated by an adapted multiple point stimulation method. Muscle Nerve, 18: 969–979. Wang, F.C., De Pasqua, V., Ge´rard, P. and Delwaide, P.J. (2001) Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients. Neurology, 57: 897–899. Wang, F.C., Bouquiaux, O., De Pasqua, V., Maertens de Noordhout, A. and Delwaide, P.J. (2003) Adapted multiple point stimulation MUNE technique. In: M.B. Bromberg (Ed.), Motor Unit Number Estimation (MUNE). Supplements to Clinical Neurophysiology, Vol. 55, Elsevier, Amsterdam, pp. 41–45.
Chapter 14
Motor neuron disorders: novel electrophysiologic approach (MUFDEC protocol) F.C. Wanga,*, N. Le Forestierb, P. Ge´rardc, J.C. Willerb, V. Meiningerd, D. Divee, A. Maertens de Noordhoutc and P. Boucheb a
Department of Neurophysiology, Me´decine Physique, CHU Lie`ge, 4000 Lie`ge, Belgium b Department of Neurology and Neurophysiology, Pitie´-Salpeˆtrie`re Hospital, 75651 Paris Cedex 13, France c Department of Neurology and Neurophysiology, CHR de la Citadelle, 4000 Lie`ge, Belgium d Department of Neurology, Pitie´-Salpeˆtrie`re Hospital, 75651 Paris Cedex 13, France e
Department of Neurology and Neurophysiology, CHUOA , 4130 Esneux, Belgium
1. Introduction Primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS) and X-linked spinobulbar muscular atrophy (Kennedy’s disease) are disorders characterized by progressive loss of upper motor neurons (UMN), lower motor neurons (LMN) or both. Clinically, PLS is usually considered to be a disorder of pure UMN loss, ALS mixed UMN and LMN loss, and Kennedy’s disease a disorder of LMN loss. There are data suggesting a degree of LMN loss in PLS, and little is known about motor unit (MU) loss and its rate in Kennedy’s disease. Motor unit number estimation (MUNE) is a unique neurophysiological technique that can directly assess LMN loss (Shefner, 2001). It can be used with other neurophysiological tests including a new neurophysiologic MUFDEC protocol: MU ¼ MUNE (motor unit *
Correspondence to: Dr. Franc¸ois C. Wang, Me´decine Physique, CHU Lie`ge, Sart Tilman B35, 4000 Lie`ge, Belgium. Tel.: þ32-4-3667788; Fax: þ32-4-3667230; E-mail: [email protected]
number estimation), F ¼ F-wave responses, DE ¼ decrement to repetitive stimulation, C ¼ CMAP (compound muscle action potential) score. The MUFDEC can indirectly assess the effects of LMN and UMN loss. We report the results of two studies applying these techniques and tests to subjects with PLS, ALS and Kennedy’s disease. The aims of study 1 were to document subclinical LMN involvement in PLS, to compare the degree of LMN loss involvement among the diseases, and to measure respective rate of MU loss. The aims of study 2 were to compare two MUNE techniques, the adapted multipoint stimulation (AMPS) and the statistical technique, and attempt to explain differences by the other parameters studied with the new MUFDEC neurophysiologic protocol. 2. Subjects 2.1. Study 1 Data were collected from consecutive subjects with ALS (n ¼ 16), PLS (n ¼ 8), and Kennedy’s disease (n ¼ 5). ALS subjects fulfilled revised El Escorial
144 criteria for definite diagnosis (Brooks et al., 2000). PLS subjects were diagnosed based on clinical evidence of a pseudobulbar and tetrapyramidal syndrome without clinical evidence for LMN involvement, and a disease duration of more than 5 years. Subjects with Kennedy’s disease had at least 37 CAG repeats. Each subject was evaluated twice, at baseline (T0) and 9–12 months later (T1). 2.2. Study 2 Data were collected from subjects with ALS (n ¼ 37), PLS (n ¼ 10), post-polio syndrome (n ¼ 2), and Kennedy’s disease (n ¼ 3). One hundred MUNE determinations were analyzed, using AMPS and statistical MUNE techniques. Some subjects were evaluated repeatedly at 3-month intervals. Seventy-five MUNE determinations were done in ALS subjects (1 determination in 17, 2 determinations in 11, 3 determinations in 4, 4 determinations in 1, and 5 determinations in 4), 15 in subjects with PLS (1 determination in 5 and 2 determinations in 5 others), 5 in subjects with post-polio syndrome (2 determinations in 1 and 3 determinations in another one) and in 5 subjects with Kennedy’s disease (1 determination in 2 and 3 determinations in 1). When MUNE was not possible to perform at a session only one value was accepted to avoid bias in estimating the feasibility of the two MUNE techniques through repeated evaluations in the same subject. Informed consent was obtained from all subjects. 3. Methods Subjects rested comfortably in a supine position. All data were collected using a Nicolet Viking IV EMG machine (Nicolet Instrument Corp.).
the tibial tuberosity to the tip of the medial malleolus and the reference electrode positioned over the medial tibia, just above the medial malleolus. For recording from the thenar muscle, the skin was cleaned by alcoholic solution and abrasive paste and active and reference electrodes were either self-adhesive (Nicolet, model 019–766300) cut in strips 3 0.8 cm (for MUNE) or Ambu (ref 700 10-K/C) self-adhesive (for CMAP score evaluation). The active electrode was placed over the thenar eminence, in close proximity to the muscle endplates, halfway between the midpoint of the distal wrist crease and the first metacarpophalangeal joint. The reference electrode was placed over the proximal phalanx of the thumb (Fig. 14.1). Recording artifacts induced by movement were minimized by a splint immobilization of forearm, wrist, hand and fingers in a neutral position. 3.2. Stimulation arrangements The common peroneal nerve was stimulated just medial to the lateral edge of the popliteal space. The median nerve was stimulated at the wrist 8 cm proximal to the active recording electrode. Supramaximal CMAPs were evoked by single stimuli of 0.2 ms duration using a bipolar stimulator (Medelec, Model LBS 53051). During the AMPS MUNE technique from the thenar muscle it was necessary to increase the selectivity in activation of isolated MUs and a monopolar stimulation was preferred to bipolar stimulation. The surface cathode (Medelec Model of monopolar stimulator) was moved over the median nerve course from the wrist to the elbow. The anode consisted of a self-adhesive adult ECG electrode (ConMed 1800–005) positioned over the dorsum of the distal forearm. 3.3. CMAP responses and CMAP score
3.1. Recording arrangements For recording from the tibialis anterior muscle, the active and reference electrodes were self-adhesive (Ambu, ref 700 10-K/C). The active electrode was placed one quarter of the distance from the tip of
CMAP responses were obtained from the tibialis anterior and thenar muscles bilaterally. CMAP waveforms were measured as the negative peak area. The CMAP score was calculated as the average of bilateral thenar and peroneal CMAP responses.
145 3.5. Decremental response testing Trains of 10 supramaximal stimuli were applied at 3 Hz. CMAP decrement was determined as the percent difference between the fourth and first response. 3.6. F-index The F-index was the product of F-occurrence by F-amplitude. 3.7. Neurophysiological index (NI) The NI is based on the formula (De Carvalho and Swash, 2000): maximal CMAP negative peak amplitude/(distal motor latency x F-occurrence). 3.8. MUFDEC Fig. 14.1 Electrode placement for thenar MUFDEC protocol (MUNE, F- and decremental responses, CMAP score). The active electrode was placed halfway between the midpoint of the distal wrist crease and the first metacarpophalangeal joint. The reference electrode was placed over the proximal phalanx of the thumb. The ground electrode was fixed over the dorsum of the first intermetacarpal space. The surface cathode (monopolar stimulator) was positioned over the median nerve course. The anode consisted of a self-adhesive adult ECG electrode placed over the dorsum of the distal forearm. The supramaximal thenar CMAP was elicited by stimulation of the median nerve at the wrist 8 cm proximal to the active recording electrode, in a line measured first to the midpoint of the distal wrist crease and then to a point slightly ulnar to the tendon of the flexor carpi radialis muscle.
3.4. F-response testing Thenar F-responses were elicited with supramaximal 1 Hz stimulation. F-occurrence was expressed as the number of F-responses recorded in 32 trials. F-amplitude was measured as maximum peak-topeak from 32 superimposed traces and expressed as a percentage of the maximal CMAP peak-topeak amplitude.
The MUFDEC protocol was applied in each subject and included: (1) summed compound muscle action potential (CMAP) score (averaged CMAP responses from bilateral thenar and tibialis anterior), (2) thenar decremental response to 3 Hz repetitive stimulation, (3) thenar F-response index, (4) thenar MUNE using AMPS, and (5) neurophysiological index (2–5, evaluated on the less affected side, established clinically or on the basis of CMAP score data). 3.9. AMPS MUNE MUNE represents the ratio of the maximal CMAP divided by the average surface-recorded motor unit potential (SMUP). MUNE techniques differ in how single MUs are obtained. McComas et al. (1971) introduced the first MUNE technique, referred to as the incremental technique. Incremental stimulation was applied at one stimulation point on the nerve and the stimulus intensity was gradually increased from a subthreshold value until 11 increments in the muscle response were obtained. The average SMUP size was derived by dividing the negative peak or peak-to-peak amplitude of the
146 response by the number of increments. Brown and Milner-Brown (1976) introduced a modification in an attempt to eliminate the inherent problem of alternation that affect the incremental MUNE technique. The alternation phenomenon is attributed to motor axons with overlapping thresholds resulting in different combinations of activated axons at a constant stimulus intensity. In the alternative procedure, referred to as the multiple point stimulation technique (MPS), the nerve is stimulated at 10–20 distinct points and at each point, only the first all or nothing SMUP excited is included in the count. Kadrie et al. (1976) proposed an adapted MPS (AMPS) technique by combining elements of the incremental and MPS techniques. In this procedure, the nerve is stimulated at multiple points and at each point the stimulus voltage is increased in a graded manner until the first and one or two subsequent MUs are activated in an all or nothing manner. Two decades later, we updated and validated the AMPS technique for thenar muscles in 54 control subjects (Wang and Delwaide, 1995). To avoid alternation and ensure that any increment of the motor response corresponds to the activation of one single MU, specific criteria were established (see below). After the First International Symposium On MUNE (Wang et al., 2003), minor modifications were incorporated into the AMPS technique used in this study. Individual SMUPs and CMAPs were recorded with a gain of 50–500 V/division and a sweep of 2–5 ms/division. For the incremental stimulation portion, a weak intensity stimulus at 1 Hz rate was gradually increased from a subthreshold value by increment steps of 0.1–0.5 mA with as short as possible stimulation durations (0.01–0.1 ms). The hand temperature, measured at the midpoint of the distal wrist crease, was maintained above 30 C. The AMPS involves two steps. The first step consisted of eliciting the supramaximal thenar CMAP by stimulation of the median nerve at the wrist 8 cm proximal to the active recording electrode, in a line measured first to the midpoint of the distal wrist crease and then to a point slightly ulnar to the tendon of the flexor carpi radialis muscle (Fig. 14.1).
The second step consisted of estimating the mean MU size by collecting and averaging 10–20 well-identified SMUPs after stimulation at distinct points along the course of the median nerve. To minimize the effects of temporal dispersion, in each MUNE evaluation by AMPS, only one stimulation point was selected at the elbow. The other sites were selected at the distal part of the forearm. At each stimulation site, the stimulus intensity was gradually increased until the first, and then subsequent MUs were recruited. To be included in the estimation, SMUPs had to be evoked: (1) with distinct thresholds, (2) in an all or nothing fashion, (3) with no fractionating of the CMAP to successive identical stimuli, and (4) in an orderly and reproducible manner. At one specific stimulation point, two or three successive SMUPs were usually accepted in the count, but in favorable circumstances, four or more successive SMUPs met the selection criteria and were incorporated in the estimation. The gain was usually between 50 and 200 mV/division, but at times it was necessary to increase it to 500 mV/division to keep the complete evoked response on the screen, and with this condition only one new SMUP was accepted. The gain was never increased to 1 mV or more to prevent ignoring small SMUPs. SMUPs were eliminated from the estimation when they: (1) had similar morphology at two distinct stimulation points, (2) were predominantly positive waveforms, as they were supposed to be elicited from distant muscles, such as lumbrical muscles. CMAP and SMUP sizes were evaluated by initial negative peak area measurements. The duration for AMPS evaluation was the time from the beginning to the end of individual SMUP recruitment. 3.10. Statistical MUNE Statistical MUNE is a semi-automated procedure in which SMUP size is estimated by the variance of submaximal CMAPs using Poisson statistics. The method was applied in accordance with the consensus established at the First International
147 Symposium on MUNE (Bromberg, 2003). The MUNE was calculated using the weighted-mean statistical method assuming that the SMUP sizes in the untested ranges were proportional to the SMUPs in the tested ranges (Olney et al., 2000). The duration for statistical MUNE evaluation was measured from maximal CMAP recording to the end of the last run.
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3.11. Statistical analysis Mean values are reported with their standard deviations. The significance of differences between means was determined by the Student’s t-tests for independent samples or paired Student’s t-tests. When the variable under study evolved exponentially, a logarithmic transform of the values preceded Student’s t-tests. Correlations between associated variables have been calculated with regression analyses. In study 1, to discriminate the 3 groups of subjects (SLA, SLP and Kennedy), a stepwise discriminate analysis was carried out on all variables to determine which variables were significant. A canonical discriminant analysis was done on the selected variables. In study 2, for some subjects, MUNE could not be obtained because of technical conditions. These subjects were called “drop-out” and the others, “non drop-outs”. A multiple logistic regression was used to model the probability of being a drop-out. A stepwise selection was carried out to identify significant explicative variables. Statistical analyses are made on the maximum available data. Results are considered significant at P < 0.05. Calculations were carried out with statistical software SAS (Version 9.1). 4. Results 4.1. Study 1 Table 14.1 summarizes results in the three groups of subjects at T0 and T1. Demographics. There were no significant differences in mean ages among the 3 subject groups. The shortest mean disease duration at T0 was
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observed in ALS subjects (27 months) and the longest in Kennedy’s disease (317 months). CMAP scores. CMAP scores at T0 remained within normal limits in 88% of PLS subjects, in 80% of Kennedy’s disease subjects, and in 19% of ALS subjects. CMAP scores decreased between T0 and T1: 5% in PLS, 10% in Kennedy’s disease, and 39% in ALS. MUNE values. At T0, thenar MUNE remained within normal limits in 13% of PLS subjects, in 20% of Kennedy’s disease subjects, and in 50% of ALS subjects. Thenar MUNE was reduced in the 3 groups without significant difference between them. At T1, thenar MUNE in ALS subjects (28 33) was significantly lower than in PLS subjects (61 36). Thenar MUNE decline between T0 and T1 was 15% in PLS subjects, 7% in Kennedy’s disease, and 62% in ALS. Decrement. Thenar decrement was less than 10% in subjects with PLS and Kennedy’s disease, while among ALS subjects, decrement was greater than 10% in 50% of subjects at T0 and increased to 56% at T1. Neurophysiologic and F-index. There was no significant difference between mean NI and F-index of the 3 groups of subjects and between T0 and T1 in each group. The lowest mean NI was observed in ALS with a 72% NI decrease between T0 and T1. The highest mean F-index was established in PLS subjects with a 31% increase between T0 and T1. Stepwise regression. In 26 observations (14 subjects with ALS, 8 with PLS, 4 with Kennedy’s disease), data from 24 variables, at T0 (CMAP score, right and left tibial anterior CMAP amplitude and area, right and left thenar CMAP amplitude and area, CMAP score divided by disease duration, F-index, NI, amplitude and area decrement, mean SMUP size, MUNE and MUNE divided by disease duration) or considering differences between T0 and T1 (change in CMAP score, change in F-index, change in NI, change in amplitude and area decrement, change in mean SMUP size and change in MUNE), were available
148 TABLE 14.1 MUFDEC RESULTS IN PATIENTS WITH PRIMARY LATERAL SCLEROSIS (PLS, n ¼ 8), AMYOTROPHIC LATERAL SCLEROSIS (ALS, n ¼ 16) AND KENNEDY’S DISEASE (n ¼ 5) PLS T0 Age (years) Disease duration (months) CMAP score (mV.ms) Thenar MUNE Thenar decrement (%) NI F-index
58 14 122 61 34.3 11.3 (1/8) 72 52 (7/8) 54 (0/8) 76 51 211 122
ALS T1
T0
32.6 11.9 (2/8) 61 36 (7/8) 53 (0/8) 68 40 277 175
56 13 27 18 22.3 9.1 (13/16) 73 58 (8/16) 11 5 (8/16) 43 49 71 93
Kennedy T1
T0
T1
13.7 6.8 (16/16) 28 33 (15/16) 14 6 (9/16) 12 23 43 94
54 7 317 529 36.4 7.8 (1/5) 57 75 (4/5) 62 (0/5) 54 43 46 25
32.6 5.4 (1/5) 53 64 (4/8) 63 (0/8) 68 48 104 129
In parentheses: number of data beyond normal limits.
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for discriminant analysis. The significant variables to discriminate the 3 groups of subjects were right tibialis anterior CMAP area, CMAP score divided by disease duration, F-index and area decrement of thenar response. Canonical discriminate analysis. Canonical discriminate analysis was performed on the significant variables. Two distinct functions of the selected variables, CAN1 and CAN2, were established and illustrated in Fig. 14.2. By doing so, the 3 groups of subjects were discriminated on the base of neurophysiological data exclusively.
4.2. Study 2 Comparison between statistical and AMPS MUNE techniques in the same subjects are summarized in Table 14.2. Statistical and AMPS applicability. With the AMPS technique it was possible to obtain a MUNE in all 100 trials, without technical failures. With statistical MUNE it was not possible to determine a MUNE in 15 trials (distinct subjects) because of technical conditions. Good technical conditions require: (1) reliable scan,
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(2) CMAP size distribution skewed to the right at least 3 times out 4 runs, (3) reasonable degree of SMUP size variability to exclude excessive variability due to poor subject cooperation or optimal state of relaxation. Among subjects who could not be assessed by statistical MUNE, predictive features were significant decrease in CMAP score, in thenar MUNE evaluated by AMPS, in thenar NI, and an increase in thenar decremental. The probability of dropping-out from statistical MUNE, established by multiple logistical regression, increased with an increase in thenar decremental response. Statistical and AMPS values. In subjects evaluated by both techniques (n ¼ 85), mean thenar values were significantly greater with AMPS (100 81) than with statistical MUNE (71 33). There was a positive correlation (r ¼ 0.77) in MUNE values between both techniques. The best correlation coefficient (r ¼ 0.89) was obtained with AMPS values less than or equal to 100 compared to corresponding statistical values (Table 14.2 and Fig. 14.3). AMPS values less than 50 were significantly lower than their corresponding statistical values, and conversely
149
Fig. 14.2
Canonical discriminant analysis De: area decrement of thenar motor response; CMAP/DD: CMAP score divided by disease duration; right TA area: right tibialis anterior CMAP area.
for AMPS values more than 100. There was no significant difference by comparing AMPS values between 50 and 100 with their corresponding statistical MUNE. The mean duration for MUNE evaluations was 13 3 min for statistical method (n ¼ 85) and 13 4 min for AMPS (n ¼ 100). 5. Discussion Thenar MUNE evaluated by the AMPS method was more sensitive than CMAP area to detect MU loss, particularly in chronic diseases. In PLS and Kennedy’s disease, CMAP scores remained within normal limits in 11 of 13 subjects at T0, whereas thenar MUNE was decreased in 11 of 13 subjects. In ALS subjects at T0, CMAP scores were below the lower normal limit in 81% and thenar MUNEs in only 50%. This paradoxical result was due to the fact that thenar MUNE was evaluated on the less affected side whereas CMAP score included the more affected thenar muscle and both tibialis
anterior muscles which were sometimes predominantly denervated. The percentage change in thenar MUNE between T0 and T1 was greater than the percent drop in CMAP score and was the greater in ALS by comparison to diseases evolving more chronically. Bromberg et al. (1993) showed by a comparison between MUNE values, isometric strength, CMAP amplitude, SMUP amplitude, fiber density, macro-EMG potential amplitude, turns-toamplitude ratio, amplitude and recruitment pattern of low threshold voluntary MU in ALS, that MUNE measurements were best suited to provide insight into the true natural history of the disease process and might be clinically useful to follow progression and response in drug trials. By comparing MUNEs, mean thenar SMUPs and CMAPs, isometric hand grip strength, total Medical Research Council manual muscle testing score, Appel ALS rating scale and force vital capacity, Felice (1997) concluded that MUNE values were the most sensitive index for documenting changes in disease progression over time.
150 TABLE 14.2 COMPARISON OF RESULTS DERIVED BY AMPS AND STATISTICAL MUNE Thenar MUNE
AMPS
Statistical MUNE
Correlation coefficient (r)
Student t-test (P)
All data AMPS < 100 AMPS < 50 AMPS [50, 100] AMPS > 100 Drop-out subjects Time to perform
100 81 47 31 21 12 78 15 175 71 0% 130 4
71 33 54 28 35 23 76 15 94 24 15% 130 3
0.77 0.89 0.87 0.38 0.49
0.002 0.008 < 0.001 0.6 < 0.001
400 r = 0.77 slope = 0.31
300 200 100 0 0
100
200
300
400
400 r = 0.48 slope= 0.31
100
r = 0.89 slope = 0.80
10 6 6 10
100
400
Fig. 14.3 Correlation study. A: positive correlation (0.77, linear scales) between results derived by the adapted multiple point stimulation (AMPS) method and statistical motor unit number estimate (MUNE). B: the best correlation coefficient (0.89, logarithm scales) was obtained by comparing AMPS values less than or equal to 100 to their corresponding statistical MUNE.
In ALS subjects, we found that when changes in NI (72%) and Findex (39%) between T0 and T1 were high, disease duration at T0 was shorter than in other subjects and there were more cases with decremental responses greater than 10%. These findings are consistent with a subacute course. We confirmed the observations of De Carvalho and Swash (2000) on the sensitivity of the NI and feel it might be an useful indicator of change in clinical practice and, as MUNE, a suitable endpoint in clinical trials. F-index is a new index to evaluate UMN dysfunction in ALS or PLS because F-wave occurrence depends not only on the number of active MU but also on motor excitability, while the latter and the MU size influence F-amplitude. In a previous study we showed that thenar decrement to 3 Hz repetitive nerve stimulation reflected activity or rate of progression of the motor neuron disease (Wang et al., 2001). Little is known about the natural history of MU loss in Kennedy’s disease. In the present study, the decreased thenar MUNE value at baseline with a subsequent very slow MUNE decline (7%) suggests that MU loss starts early in life and has a long-lasting subclinical course. This needs to be confirmed in a larger group.
151 In PLS, we found subclinical LMN involvement in 7 of 8 subjects, an intermediate rate of MU loss (15%) and an increase in the F-index probably related to the predominant UMN involvement. These data confirmed results published by Gooch et al. (2004) who found a 2.5% per month average MUNE decline in PLS. The identification of a LMN component in PLS might be interpreted as supporting the notion that PLS belonging to the Charcot ALS syndrome. Alternatively, the MU loss might be the consequence of the UMN involvement without primary degenerative process of anterior horns. In support, Arasaki et al. (2006) found a decrease in MUNE of hypothenar muscles within 30 h after cerebral infarction. They speculate that this could be due to trans-synaptic inhibition of the spinal alpha motor neurons. Results of discriminate analysis revealed that the right tibialis anterior area, CMAP score divided by disease duration, F-index and negative peak area decrement of thenar motor response were the 4 significant variables to distinguish the 3 groups of subjects. In conclusion, study 1 confirms that MUNE is a sensitive indicator of disease progression. However, for complete information about the different motor neuron diseases, it seemed useful to incorporate MUNE in a protocol that includes CMAP, F-wave and decrement measurements which provided data about medullar excitability, motoneurons, neuromuscular transmission and muscular fibers. Study 2 shows that statistical MUNE and AMPS in the same subject population reveal good correlations between the techniques, particularly for the lowest values. However, when MUNE values are less that 50, the AMPS technique underestimates compared to the statistical technique, while when MUNE values were greater than 100 the AMPS technique overestimates compared to the statistical technique. As there is no gold standard for the true number of functioning MUs in a muscle, it was not possible to identify the reasons of these differences. There was no significant difference between AMPS MUNE from 50 to 100 and
their corresponding statistical MUNE, but correlation between both series of data was not good. The reason of the latter result might be a link to the cancellation of several technical bias acting in opposite directions. There was a 15% drop-out of subjects with the statistical MUNE, particularly in the terminal stage with low values for CMAP score, thenar MUNE and NI and high decremental thenar responses. Thus, in ALS subjects, application of the statistical MUNE during the entire disease course remained uncertain, while the AMPS technique can be used at any time in the course of the disease. Both MUNE methods take the same time to be performed. References Arasaki, K., Igarashi, O., Ichikawa, Y., Machida, T., Shirozu, I., Hyodo, A. and Ushijima, R. (2006) Reduction in the motor unit number estimate (MUNE) after cerebral infarction. J. Neurol. Sci., 250: 27–32. Bromberg, M.B. (2003) Consensus. In: B. Bromberg (Ed.), Motor Unit Number Estimation (MUNE). Supplements to Clinical Neurophysiology, Vol. 55. Elsevier, Amsterdam, pp. 335–338. Bromberg, M.B., Forshew, D.A., Nau, K.L., Bromberg, J., Simmons, Z. and Fries, T.J. (1993) Motor unit number estimation, isometric strength, and electromyographic measures in amyotrophic lateral sclerosis. Muscle Nerve, 16: 1213–1219. Brooks, B.R., Miller, R.G., Swash, M. and Munsat, T.L. (for the World Federation of Neurology Research Group on Motor Neuron Diseases) (2000) El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. ALS Other Motor Neuron Disord., 1: 293–299. Brown, W.F. and Milner-Brown, H.S. (1976) Some electrical properties of motor units and their effects on the methods of estimating motor unit numbers. J. Neurol. Neurosurg. Psychiatry, 39: 249–257. De Carvalho, M. and Swash, M. (2000) Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve, 23: 344–352. Felice, K.J. (1997) A longitudinal study comparing thenar motor unit number estimates to other quantitative tests in patients with amyotrophic lateral sclerosis. Muscle Nerve, 20: 179–185. Gooch, C., Tang, M.X., Garcia, J., Del Bene, M., Batista, V., Gad, N., Montes, J., Rowland, L. and Mitsumoto, H. (2004) MUNE measures in ALS, FALS, PMA and PLS in a natural history biomarker study. ALS Other Motor Neuron Disord., 5: 113(Abstract).
152 Kadrie, H.A., Yates, S.K., Milner-Brown, H.S. and Brown, W.F. (1976) Multiple point electrical stimulation of ulnar and median nerves. J. Neurol. Neurosurg. Psychiatry, 39: 973–985. McComas, A.J., Fawcett, P.R., Campbell, M.J. and Sica, R.E.P. (1971) Electrophysiological estimation of the number of motor units within a human muscle. J. Neurol. Neurosurg. Psychiatry, 34: 121–131. Olney, R.K., Yuen, E.C. and Engstrom, J.W. (2000) Statistical motor unit number estimation: reproducibility and sources of error in patients with amyotrophic lateral sclerosis. Muscle Nerve, 23: 193–197. Shefner, J.M. (2001) Motor unit number estimation in human neurological diseases and animal models. Clin. Neurophysiol., 112: 955–964.
Wang, F.C. and Delwaide, P.J. (1995) Number and relative size of thenar motor units estimated by an adapted multiple point stimulation method. Muscle Nerve, 18: 969–979. Wang, F.C., De Pasqua, V., Ge´rard, P. and Delwaide, P.J. (2001) Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients. Neurology, 57: 897–899. Wang, F.C., Bouquiaux, O., De Pasqua, V., Maertens de Noordhout, A. and Delwaide, P.J. (2003) Adapted multiple point stimulation MUNE technique. In: M.B. Bromberg (Ed.), Motor Unit Number Estimation (MUNE). Supplements to Clinical Neurophysiology, Vol. 55, Elsevier, Amsterdam, pp. 41–45.