Sensitivity of electrophysiological tests for upper and lower motor neuron dysfunction in ALS: A six‐month longitudinal study

By following a group of amyotrophic lateral sclerosis (ALS) patients longitudinally using lower motor neuron (LMN) and upper motor neuron (UMN) markers of dysfunction it may be possible to better understand the functional relationships between these motor systems in this disease. We used neurophysiological techniques to follow UMN and LMN dysfunction in a group of 28 patients with ALS, in comparison with the ALS functional rating scale (ALS‐FRS) score and the forced vital capacity (FVC). We used motor unit number estimation (MUNE), compound muscle action potential (CMAP) amplitude, and the Neurophysiological Index (NI) to quantify the LMN disorder, and transcranial motor stimulation to study cortical motor threshold, motor‐evoked response amplitude, central motor conduction time, and cortical silent period (CSP). The patients were studied shortly after diagnosis and then 6 months later, using both abductor digiti minimi muscles (ADM); ADM strength was initially >MRC 3 (Medical Research Council, UK). The NI and MUNE changed more than any other variable. CSP increased by about 30%, a change more marked than the slight increase observed in the cortical motor threshold (9%). The normal increase of CSP after acute muscle fatigue was preserved during disease progression. The CSP increase correlated with the MUNE rate of decay but not to the NI reduction, perhaps because NI includes F‐wave frequency in itscalculation. There was no definite correlation between UMN and LMNdysfunction or progression, but there was a link between CSP and LMN changes in ALS. The CSP may be a useful variable in following UMN dysfunction in clinical practice and in clinical trials. Muscle Nerve, 2010     

Clinical trials in ALS: a review of the role of clinical and neurophysiological measurements.

We have reviewed all the published clinical trials of ALS and, from those considered sufficiently large, and containing a control group, we have evaluated their methodology with regard to statistical power. This implies a critical analysis of the endpoint measurements. We have concluded that clinical endpoints used in clinical trials of ALS have frequently been insufficiently sensitive, non-linear, or even not intuitively highly relevant to the disease. We suggest that the ALS-FRS, perhaps also MUNE and the Neurophysiological Index, may be the best measures currently available. These techniques have complementary characteristics that allow them to be used to address different aspects of the disease and its treatment in various trials designs. In the past some trials may have failed to demonstrate a treatment effect because the chosen endpoint measures and the trial design were inappropriate.     

Motor unit number estimation,isometric strength,and electromyographic measures in amyotrophic lateral sclerosis

Pathologic progression in amyotrophic lateral sclerosis (ALS) results from motor neuron death, while the clinical expression also reflects the compensatory effects of collateral reinnervation consequent to lower motor neuron loss. In a cross-sectional study of ALS subjects, we made comparisons between motor unit number estimation (MUNE) values and several measures reflecting collateral reinnervation, including isometric strength, compound muscle action potential (CMAP) amplitude, surface motor unit action potential (S-MUAP) amplitude, fiber density (FD), macro-EMG potential amplitude, turns-to-amplitude (T/A) ratio, and amplitude and recruitment pattern of low threshold voluntary motor units in elbow flexor muscles. Before comparisons were made, testretest reproducibility of these measures was assessed in ALS subjects, and is highest for isometric strength, and lower but similar for EMG measures. When the effects of multiple comparisons are considered, borderline significant correlations are found between MUNE values and isometric strength. Neither MUNE values nor isometric strength are significantly correlated with macro-EMG amplitude, FD, T/A ratio, or amplitude and recruitment rate of low threshold voluntary motor units. There are significant correlations of CMAP and S-MUAP with MUNE values, but these are statistical artifacts with no independent interpretation. We conclude that collateral reinnervation prevents isometric strength and EMG measures from accurately reflecting lower motor neuron death in ALS. MUNE measurements are better suited to provide insight into the true natural history of the disease process and may be clinically useful to follow progression and response in drug trials. © 1993 John Wiley & Sons, Inc.     

Statistical motor unit number estimation: reproducibility and sources of error in patients with amyotrophic lateral sclerosis

The reliability of motor unit number estimation (MUNE) for assessment of the long-term course of ALS is dependent on the reproducibility of the technique. We report our results with the statistical method of MUNE on the ulnar nerve/hypothenar muscle in 16 ALS patients who were studied on 52 occasions. On each occasion, MUNE was performed twice with one electrode placement and once with a different placement. For each MUNE, mean surface motor unit potential amplitude was determined within three different recording ranges or windows at different stimulus intensities. The MUNE results had excellent reproducibility with coefficients of variation of 19% and test-retest correlation coefficients from 0.75 to 0.86. With examination of sources for variability, the reproducibility of statistical MUNE is not affected by minor variation in stimulation and recording electrode placement but may be improved by modifying methods for recording window selection. The high reproducibility of statistical MUNE supports its reliability for estimating the rate of motor unit loss in ALS.     

Bayesian statistical MUNE method

We have developed a new method of motor unit number estimation (MUNE) for assessing diseases such as amyotrophic lateral sclerosis (ALS). We used data from the whole stimulus-response curve and then performed a Bayesian statistical analysis. The Bayesian method uses mathematical equations that express the basic elements of motor unit activation after electrical stimulation and allows for the sources of variability and uncertainty in this formulation. The Bayesian MUNE method was used to determine the most probable number of motor units in 8 normal subjects, 49 ALS subjects, and 3 subjects with progressive lower motor neuron (LMN) weakness. In normals the number of motor units was calculated to be 75-85 in hand and 40-58 in foot muscles. In ALS subjects the number of motor units per muscle was less than in normal subjects. In 17 ALS subjects and 3 subjects with LMN weakness the median, ulnar, or peroneal nerve was studied on repeated occasions over an average of 189 days (range 63-1,071) and the number of motor units progressively declined, with a half-life ranging from 62-834 days. The results of our MUNE technique were reproducible on replicate studies. A Bayesian statistical MUNE method is a new approach that can be used to study ALS patients serially for assessment and treatment trials.     

Repeater F-waves in amyotrophic lateral sclerosis: Electrophysiologic indicators of upper or lower motor neuron involvement?

ObjectiveTo extract insight about the mechanism of repeater F-waves (Frep) by exploring their correlation with electrophysiologic markers of upper and lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS).MethodsThe correlations of Frep parameters with clinical scores and the results of neurophysiological index (NI), MScanfit MUNE, F/M amplitude ratio (F/M%), single and paired-pulse transcranial magnetic stimulation (TMS), and triple stimulation technique (TST) studies, recorded from abductor digiti minimi (ADM) and abductor pollicis brevis (APB) muscles of 35 patients with ALS were investigated.ResultsFrep parameters were correlated with NI and MScanfit MUNE in ADM muscle and F/M% in both muscles. None of the Frep parameters were correlated with clinical scores or TST and TMS measures. While the CMAP amplitudes were similar in the two recording muscles, there was a more pronounced decrease of F-wave persistence in APB, probably heralding the subsequent split hand phenomenon.ConclusionOur findings suggest that the presence and density of Freps are primarily related to the degree of lower motor neuron loss and show no correlation with any of the relatively extensive set of parameters for upper motor neuron dysfunction.SignificanceFreps are primarily related to lower motor neuron loss in ALS.     

Thenar motor unit number estimates using the multiple point stimulation technique: Reproducibility studies in als patients and normal subjects

Thenar motor unit number estimate (MUNE) reproducibility was assessed in 20 patients with amyotrophic lateral sclerosis (ALS) and 16 normal subjects using the multiple point stimulation (MPS) technique. The MUNE was calculated by dividing the thenar compound muscle action potential negative-peak (n-p) area by the mean n-p area of 10 lowest threshold, all-or-nothing, surface-recorded motor unit action potentials. Two trials (test–retest) were performed by the same examiner either on separate days or on the same day with new electrode placements. The mean test MUNE was 43.4 (SD: 35.9, range: 6–145) for ALS patients and 219.4 (SD: 80.8, range: 122–368) for normal subjects. Test–retest MUNE differences were not significant for ALS patients or normal subjects. The test–retest correlation coefficient (r) was 0.99 for ALS patients and 0.85 for normal subjects. The mean difference between test–retest values was 10% for ALS patients and 17% for normal subjects. Test–retest reproducibility of the thenar MUNE using the MPS technique is high in both ALS patients and normal subjects. The reliability of the MPS technique in estimating motor unit numbers may make it a useful outcome measure in following the course of patients with progressive lower motor neuron disease, especially those enrolled in experimental drug trials.© 1995 John Wiley &Sons, Inc.     

The utility of motor unit number estimation methods versus quantitative motor unit potential analysis in diagnosis of ALS

Objective

To compare the diagnostic utility of motor unit number estimation (MUNE) methods to motor unit potential (MUP) analysis in amyotrophic lateral sclerosis (ALS).

The use of statistical MUNE in a multicenter clinical trial

Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. In diseases characterized by progressive motor unit loss, such as amyotrophic lateral sclerosis (ALS), MUNE may be useful to monitor disease progression or beneficial response to treatment. As part of a multicenter, placebo-controlled, randomized, double-blind clinical trial testing the efficacy of creatine in patients with ALS, statistical MUNE was measured in 104 patients tested monthly for 6 months. The objective was to determine whether MUNE was a reliable and sensitive outcome measure in the context of a multicenter trial. Formal training and reliability testing was required for all MUNE evaluators. Testing of normal controls showed a high degree of test-retest reliability. All patient data were combined as the experimental treatment showed no efficacy. There was a 23% decline in MUNE over 6 months. The technique as employed in this trial overemphasized the presence of small motor units; this problem was partially addressed by poststudy data monitoring and censuring. Thus, MUNE can be used reliably as an outcome measure in multicenter clinical trials; specific remedies are suggested for the difficulties encountered in this study.     

Monitoring disease progression using high‐density motor unit number estimation in amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS), progressive motor neuron loss causes severe weakness. Functional measurements tend to underestimate the underlying pathology because of collateral reinnervation. A more direct marker of lower motor neuron loss is of significant importance. We evaluated high‐density motor unit number estimation (MUNE), as compared with the ALS Functional Rating Scale (ALSFRS) and maximal compound muscle action potential (CMAP) amplitude, for monitoring and classifying disease progression. MUNE showed good reproducibility (intraclass correlation coefficient = 0.86). MUNE showed a significantly greater decrease than the ALSFRS, the Medical Research Council (MRC) scale, and CMAP amplitude. Patients could be stratified into groups with rapidly or slowly progressive disease based on a decrement in MUNE at 4 months from baseline; ALSFRS score at 8 months was significantly lower in the rapidly progressive group. MUNE was sensitive to motor neuron loss early in the disease course when compared to other clinical measures. Stratification of patients based on a decrease in MUNE seems feasible. Muscle Nerve, 2010     

Clinical and neurophysiological evaluation of progression in amyotrophic lateral sclerosis

There is a need for a sensitive neurophysiological measure of disease progression in following the course of patients with amyotrophic lateral sclerosis (ALS). We studied two groups of nine ALS patients, one with slow progression (Group A) and the other with rapid progression (Group B). We evaluated muscle strength scores using the Medical Research Council (MRC) scale in limb and trunk muscles, forced vital capacity (FVC), and ALS functional rating scale (ALS-FRS) scores. Maximal voluntary isometric contraction (MVIC) of the abductor digiti minimi muscle (ADM) was measured, using a digital device. We also measured M-wave amplitude and area in the ADM, and the distal motor latency and F-wave frequency in the ulnar nerve; from these data, the neurophysiological index (NI) was calculated, as described previously. In both groups, the NI was the most sensitive measure of change, with the smallest coefficient of variation. We conclude that the NI, which requires no special technology and no new clinical or technical skills to use, is sensitive to change, and therefore may be useful in clinical trials, as well as in a clinical setting.     

Sources of error in the spike-triggered averaging method of motor unit number estimation (MUNE)

Motor unit number estimation (MUNE) is an electrophysical technique to estimate the number of motor units innervating a muscle or muscle group. MUNE may be useful as a measure of progression of lower motor neuron loss in amyotrophic lateral sclerosis (ALS). Several methods of MUNE have been developed. The spike-triggered averaging method can be readily performed on EMG machines with signal averaging capabilities and is suitable for estimating the number of motor neurons innervating proximal muscles. We have used MUNE as a measure of disease state in a drug efficacy trial for ALS. From our experience with this method we have identified sources of error which can affect MUNE accuracy. We have investigated these sources and report their effect on MUNE.© 1995 John Wiley & Sons, Inc.     

Motor unit number estimation (MUNE): Where are we now?

Estimation of the number of motor units (MUNE) in specific muscles is important to monitor outcome in progressive neurogenic disorders, with potential application in clinical trials. However, in spite of recent developments to identify the most convenient technique for MUNE, all current methods have individual shortcomings. It is essential to understand the scientific concepts that support MUNE and the many methods already proposed. In particular, the core role of the compound muscle action potential (CMAP) size in the estimation process is undervalued. Operator-dependent variation in CMAP amplitude or area is the main factor underlying MUNE stability. At present, MUNIX, as standardized in many centers, is probably the best accepted method. Future developments should be based on full understanding of the neurophysiological concepts underlying the MUNE calculation, in order to find a quick, well-tolerated, operator-friendly and reliable method to apply more universally in clinical practice.     

Amyotrophic lateral sclerosis: new developments in diagnostic markers

There is an intensive search for diagnostic markers in amyotrophic lateral sclerosis (ALS). Protein analysis (proteomics) of the cerebrospinal fluid (CSF) appears particularly promising using mass spectrometry and 2-D gel electrophoresis to detect low and high molecular weight proteins, respectively. It is open whether protein changes specific for ALS will be found. This also holds true for inflammatory proteins such as the cytokine monocyte chemoattractant protein-1 which has been detected in CSF in ALS and for other cytokines such as interleukin-1beta. Increases of the protein Nogo A and B in muscle tissue and decreases of the growth factor vascular endothelial growth factor in blood may also be useful for monitoring the course of ALS. Clinical neurophysiology provides markers for upper and lower motor neuron damage. A very sensitive method to detect early upper motor neuron involvement is the transcranial magnetic stimulation modification 'triple stimulation technique' which can show significant changes in patients without clinical upper motor neuron signs. The loss of lower motor neurons can be closely monitored by MUNE techniques (motor unit number estimate). In modern imaging, the MRI technique DTI (diffusion tensor imaging) has the greatest diagnostic potential for ALS. It can separate between normal and ALS in group comparisons and may be improved to be diagnostic in individual patients. Voxel-based morphometry can reliably demonstrate regional cortical atrophy in motor areas and beyond although it is not appropriate for use in individual patients.     

运动单位数目估计在肌萎缩侧索硬化患者随访中的作用

目的 比较多点刺激法和递增法运动单位数目估计在肌萎缩侧索硬化(ALS)患者随访中的作用及差异.方法 120例ALS患者在诊断时,随访3、6、9、12个月时分别进行多点刺激法或递增法运动单位数目估计.多点刺激法:刺激电极分别于腕、腕上6 cm、肘、肘上6 cm,4点刺激正中神经,以超强刺激诱发最大波幅M波;然后从0刺激开始逐渐增加刺激强度直到出现可辨认的单个运动单位电位,逐渐增大刺激强度,记录3个递增的M波.递增法:刺激电极于腕点刺激正中神经,以超强刺激诱发最大M波值,之后自阈强度刺激开始,逐渐增加刺激强度,收集10个递增的M波.比较两种方法在患者随访中所得运动单位数目估计数值的变化及差异.结果 在ALS患者诊断时,随访3、9、12个月时,两种方法所测运动单位数目无差异,均表现为进行性下降;在随访6个月时,多点刺激法所得数值高于递增法(88±6和47±5;t=1.72,P=0.04).结论 多点刺激法和递增法运动单位数目估计可用于ALS患者的随访研究,在疾病不同时期,两种方法所得数值可以不同.     

Nerve conduction studies in amyotrophic lateral sclerosis

We studied 137 ulnar nerves and abductor digiti minimi (ADM) muscles in 70 patients with amyotrophic lateral sclerosis (ALS), and correlated the results with ADM strength graded on the Medical Research Council (MRC) scale, to address the potential value of a standardized neurophysiological assessment of this nerve-muscle system. The ulnar nerves of 35 normal subjects matched for age, gender, and height served as controls. Reduced compound muscle action potential (CMAP) amplitude and area in the ADM muscle recordings correlated strongly with weakness. Distal motor latency, proximal conduction time, and F-wave frequency were abnormal with minimally detectable weakness. In weaker ADM muscles, conduction velocities and F-wave latencies were also abnormal. Conduction block was never observed and sensory potentials were normal. An "ALS neurophysiological index" was derived from these ulnar nerve studies and consisted of the expression: (CMAP amplitude/DML) x F frequency -, where F frequency was expressed as the number of F responses recorded in 20 trials. This index was strongly correlated with ADM weakness (r = 0.74, P < 0.001). Neurophysiological studies restricted to a single nerve-muscle system, the ulnar nerve/ADM, appear potentially useful in objectively assessing change in ALS.     

Revised statistical motor unit number estimation in the Celecoxib/ALS trial

Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. As amyotrophic lateral sclerosis (ALS) is characterized by progressive motor unit loss, this disease offers an ideal setting for the use of MUNE. Statistical MUNE was employed in a recent multicenter trial of creatine in ALS, and was shown to be reliable, reproducible, and to decline with disease progression. However, motor unit amplitude stayed constant over 7 months, a finding believed to reflect an artifact of the method. The statistical method was revised to reflect more accurately the presence of larger motor units and employed in a 12-month study of Celecoxib in ALS. MUNE declined by 49% in 12 months; however, motor unit amplitude again stayed constant over the same period. Statistical MUNE estimates motor unit number based on the variability of response to a repeated stimulus of constant strength, with an underlying assumption that this variability is due solely to the number of motor units responding in an intermittent manner. Based on studies showing that single motor units in ALS display excessive amplitude variability when stimulated repeatedly, we show that response variability in ALS patients is in large part due to single unit changes. Thus, we conclude that the statistical method is not an appropriate measure of motor unit number in any disease associated with motor unit instability.     

Reproducibility of statistical motor unit number estimates in amyotrophic lateral sclerosis: comparisons between size- and number-weighted modifications

Motor unit number estimations (MUNEs) can directly assess motor unit populations in muscle and quantify the degree of physiological or pathological motor unit degeneration. A high degree of reproducibility and reliability is required of any effective quantitative tool. MUNE is being increasingly applied clinically, and statistical MUNE has several advantages over alternative techniques. Nevertheless, the optimal method of applying statistical MUNE with respect to its reproducibility has not been established. We performed statistical MUNE by selecting the most compensated compound muscle action potential (CMAP) area as a test area and modified the results obtained by using the weighted mean surface-recorded motor unit potential (SMUP). MUNE measurements made in patients with amyotrophic lateral sclerosis (ALS) showed better reproducibility after incorporating the size-weighted modification. Therefore, we suggest that the size-weighted MUNE in combination with the selection of testing "neurogenically compensated" CMAP areas is a more reliable method of statistical MUNE analysis in ALS patients.     

Stratifying disease stages with different progression rates determined by electrophysiological tests in patients with amyotrophic lateral sclerosis

By determining the usefulness of motor unit number estimate (MUNE) and compound muscle action potential (CMAP) amplitude in patients with amyotrophic lateral sclerosis (ALS), we tried to find an effective way to stratify the disease stages. In all, 112 consecutive ALS patients were enrolled, among whom 73 were elicited in a longitudinal study. MUNE by the standard incremental technique, the average CMAP amplitude, total Medical Research Council (MRC) score, ALS‐functional rating score (ALS‐FRS), Appel ALS rating scale (AARS), and forced vital capacity (FVC) were performed at baseline and months 3, 6, and 12 after study entry. We found MUNE correlated with CMAP amplitude (P < 0.01) as well as MRC score (P < 0.01) in regionally concordant distal muscles. Both MUNE and CMAP amplitude correlated significantly with ALS‐FRS (P < 0.05) and AARS (P < 0.01). A MUNE decrease was observed at months 3, 6, and 12 compared with baseline, and the rate of change at month 3 was 50.47%. The decrease in MUNE over the first 3 months was significantly greater than other measurements. We arbitrarily divided the patients into three stages: (1) rapid progression: the rate of change of MUNE and CMAP amplitude during the first 3 months exceeded 50%; (2) moderate progression: the rate of change of MUNE was greater than 50% but CMAP amplitude was less than 50%; (3) slow progression: the rate of change of both MUNE and CMAP amplitude were less than 50%. Comparing the rate of ALS‐FRS descent per year using one‐way ANOVA showed a significant difference among the three groups (P < 0.01). Muscle Nerve 39: 304–309, 2009     

Clinical neurophysiology of ALS

The neurophysiology of amyotrophic lateral sclerosis is important not only in relation to diagnosis, but also in the development of methods to follow progress, and the effects of putative therapies, in the disease. Quantitative techniques can be applied to the measurement of reinnervation using needle electromyogram. The methodology of motor unit number estimation may be useful in measuring loss of functioning motor units in groups of patients but variability in the measurement using current methods limits its sensitivity in the evaluation of individual patients. Conventional neurophysiological measurements, expressed as a multimetric index, may be useful in assessing progress. The cortical and upper motor neuron system can be assessed using transcortical magnetic stimulation protocols, and cortical excitability may be measured by the peristimulus histogram method. In this review the advantages, limitations and promise of these various methods is discussed, in order to indicate the direction for further neurophysiological studies in this disorder.