Motor unit number estimate of distal and proximal muscles in Charcot-Marie-Tooth disease

In order to determine the utility of motor unit number estimation (MUNE) in assessing axonal loss in chronic inherited neuropathies, we determined MUNEs in 54 patients with Charcot-Marie-Tooth (CMT) disease (29 patients with CMT-1A, 13 with CMT-X, and 12 with CMT-2) by using spike-triggered averaging (STA) of the ulnar-innervated abductor digiti minimi/hypothenar muscles (ADM) and the musculo-cutaneous innervated biceps/brachialis (BB) muscles. MUNEs were analyzed in relationship to the corresponding compound muscle action potential (CMAP) amplitudes as well as to clinical strength. Proximal muscles, which appeared strong clinically, had evidence of chronic denervation/reinnervation, although to a lesser extent than weak distal hand muscles, supporting the concept that axonal loss in CMT occurs in a length-dependent fashion. The reduction in ADM-MUNE strongly correlated with clinical weakness in the hand. Both the ADM-MUNE and BB-MUNE were abnormal more often than CMAP amplitude, probably reflecting extensive motor unit reconfiguration and enlargement that maintains CMAP amplitude despite severe motor unit loss. This study suggests that MUNE can assess motor unit loss in CMT and may better reflect axonal loss than CMAP amplitude. The STA technique of MUNE may be useful in longitudinal studies of proximal and distal motor unit changes in CMT.     

Assessment of axonal loss in Charcot-Marie-Tooth neuropathies

Sensory loss and weakness in Charcot-Marie-Tooth (CMT) neuropathy is due to axonal loss. However, the pattern and degree of axonal loss cannot be accurately determined from routine electrodiagnostic or strength testing due to collateral reinnervation. We sought to quantify axonal loss in two upper extremity muscles in CMT1A and CMT2 subjects using the electrophysiologic endpoint measure of motor unit number estimation (MUNE). Hypothenar and biceps-brachialis muscle groups were studied in 9 CMT1A, 9 CMT2, and 10 control subjects. The spike-triggered averaging (STA) technique was used to collect surface motor unit potentials for MUNE calculations, and a needle electrode was used to collect corresponding intramuscular data. Maximal voluntary hypothenar and handgrip strength was measured quantitatively, while biceps-brachialis strength was measured qualitatively. Compared to normal subjects, CMT1A and CMT2 subjects had significantly lower MUNE values in hypothenar muscles. Biceps-brachialis MUNE values were reduced in CMT2 but not in CMT1A subjects. In support of proximal axonal loss in CMT2 subjects, surface motor unit and intramuscular potential amplitudes were higher in biceps-brachialis muscles compared to controls. Correlations between quantitative strength and MUNE were significant for hypothenar but not for grip muscle groups. Axonal loss is demonstrated in distal muscles in CMT1A and CMT2 supporting a length-dependent axonopathy. Despite clinical findings of normal or near-normal strength and small reductions in compound muscle action potential (CMAP) amplitude, MUNE values were significantly lower in CMT2 subjects in proximal muscles, consistent with more diffuse denervation. These data indicate that subclinical axonal loss is present that cannot be appreciated using clinical examination or routine electrodiagnostic techniques.     

Counting motor units in chronic motor neuropathies

The degree of motor unit loss can not be accurately quantified in chronic motor neuropathies with routine electrodiagnostic testing or with pathologic examination. We used motor unit number estimation (MUNE), which is a unique electrophysiologic method that can estimate the number of surviving motor units innervating a muscle, to study axonal loss in spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) neuropathies. MUNE is based on the ratio of the maximal compound muscle action potential (CMAP) to the average surface-recorded motor unit potential (S-MUP). The hypothenar muscle group was studied in infant and older subjects with SMA, and the hypothenar and biceps-brachialis muscle groups were studied in adult CMT1A and CMT2 subjects. The multiple point stimulation MUNE technique was used in SMA subjects and the spike triggered averaging MUNE technique was used in CMT subjects. In SMA, motor unit loss was profound in types 1 and 2 subjects and more moderate in type 3 subjects. In CMT, motor unit loss was prominent in distal muscles in both CMT1A and 2 subjects, and present in proximal muscles in CMT2 subjects. MUNE is efficient in assessing the degree of motor unit loss in chronic motor neuropathies. SMA is considered to be a proximal muscle disorder, but loss was marked in distal muscles in all SMA types. In CMT1A, the demyelinating form, motor unit loss was marked in distal muscles, consistent with the idea that axonal loss and not slow conduction velocity is the important pathologic condition. The pattern of proximal motor unit loss differed between CMT1A and 2, suggesting differences in underlying axonal pathology.     

Motor unit number index and compound muscle action potential amplitude

ObjectivesMUNIX (motor unit number index), derived from the compound muscle action potential (CMAP) and surface EMG interference pattern (SIP) has become popular as a substitute for motor unit number estimation (MUNE). This study was undertaken to determine why, in recent recordings from amyotrophic lateral sclerosis (ALS) patients and healthy controls, we found that MUNIX values resembled CMAP amplitudes more closely than MUNE values.MethodsThe relationship between MUNIX and CMAP and SIP amplitudes was investigated by a theoretical analysis and by reanalysing the data from the previous study.ResultsTheory indicates that when motor unit potentials overlap extensively, information about motor unit size and number is lost, and MUNIX depends only on CMAP area and power. Accordingly, MUNIX values were found to be sensitive to changes in CMAP amplitude but insensitive to changes in SIP amplitude. The reproducibility of MUNIX measurements in healthy controls was found to depend almost entirely on correlation with CMAP properties.ConclusionsMUNIX gives misleading information about motor unit numbers in healthy controls, and provides little information about loss of motor units in ALS patients beyond that given by simple CMAP amplitude measurements.SignificanceMUNIX should not be interpreted as a MUNE method.     

Longitudinal conduction studies in hereditary motor and sensory neuropathy type 1

Motor conduction studies were performed serially in 10 patients, ages 10-62 years, with clinical and electrophysiological criteria of hereditary motor and sensory neuropathy type 1 (HMSN-1) over periods of 11-19 years. Median nerve conduction velocity (MNCV) and distal motor latency showed no significant change on serial studies. Mean median compound muscle action potential (CMAP) amplitude values, however, decreased 66% in 8 patients. Observed clinical progression in HMSN-1, over prolonged periods of time, was not associated with MNCV slowing. However, CMAP amplitude reduction, reflecting progressive axonal loss, correlated with clinical deterioration.     

肯尼迪病患者自动递增刺激法运动单位估数的测定

目的研究肯尼迪病(KD)患者运动单位估数(MUNE)的变化并探讨其临床意义。方法收集KD患者20例和健康对照者30名,分别用自动递增磁刺激法检测受试者大、小鱼际肌MUNE数值及正中神经、尺神经最大复合肌肉动作电位(CMAP)波幅。比较KD组和对照组大小鱼际肌MUNE的差异;比较KD组患者大小鱼际肌MUNE异常率与正中神经、尺神经CMAP异常率的差异。同时,对KD患者病程与MUNE的相关性进行分析。结果与对照组比较,KD患者大、小鱼际肌MUNE数值降低(82.16±49.37比251.12±68.89,94.26±44.56比235.63±63.02,均P0.01)。KD患者大、小鱼际肌MUNE异常率分别为85.0%和80.0%,而正中神经、尺神经CMAP异常率均为15.0%,KD患者大小鱼际肌MUNE异常率与正中神经、尺神经CMAP异常率比较差异均有统计学意义(P0.01)。KD患者MUNE数值与病程呈负相关(P0.05)。结论 MUNE作为一种无创的电生理学技术,可能对早期及精确地判断KD患者下运动神经元受损情况有所帮助。     

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     

Diagnostic nerve ultrasound in Charcot–Marie–Tooth disease type 1B

Ultrasound is emerging as a useful tool for evaluation of neuromuscular conditions, because it can provide high‐resolution anatomic information to complement electrodiagnostic data. There have been few studies in which ultrasound was used to assess the peripheral nerves of individuals with Charcot–Marie–Tooth (CMT) disease and none involving CMT type 1B. In this study we compared nerve cross‐sectional area in individuals from a single large family with CMT 1B with normal, healthy controls. We also assessed for cranial nerve enlargement in those with CMT 1B with cranial neuropathies compared to those with CMT 1B without cranial neuropathies. Individuals with CMT 1B have significantly larger median and vagus nerves than healthy controls, but no difference was seen in cranial nerve size between those with versus those without cranial neuropathies. This is the first study to characterize the ultrasonographic findings in the peripheral nerves of individuals with CMT 1B. Muscle Nerve 40: 98–102, 2009     

Prognostic value of electrodiagnosis in the Dutch Guillain–Barré study

In the Dutch Guillain-Barré trial, three EMGs were performed according to a rigid protocol at early stages of the disease in 147 Guillain-Barré patients who were unable to walk independently. Independent locomotion 8 weeks and 6 months after entry were considered to be the outcome measures of most clinical value. Electrodiagnostic data obtained 1 week after entry were concluded to be most important for studying prognostic value. This has been attributed to the fact that 87% of the patients were in the nadir of their disease at that moment In univariate analysis, CMAP amplitudes of thenar and hypothenar muscles obtained after distal and proximal stimulation, as well as the recruitment pattern on maximal voluntary effort in these tested muscles, were significant predictors for outcome 8 weeks and 6 months after entry to the study. Motor nerve conduction velocity and distal motor latencies of ulnar and median nerves were weak predictors for outcome at 8 weeks after entry. In multivariate analysis the hypothenar CMAP amplitude on distal stimulation and recruitment pattern of abductor digiti minimi muscle both had an independent predictive value for independent locomotion 8 weeks after entry.     

Comparison of CMT1A and CMT2: similarities and differences

To evaluate the clinical and electrophysiological similarities and differences between two large groups of patients with Charcot-Marie-Tooth disease, i.e. CMT1A and CMT2, we performed a post hoc comparison of clinical and electrophysiological data.Most CMT1A and CMT2 patients had the classical CMT phenotype. Age of onset was significantly later in CMT2. Total areflexia was present in approximately half of the CMT1A patients whereas it was rare in CMT2. Foot deformities and weakness of knee extensor and foot dorsal flexor muscles were more frequent in CMT1A. Median nerve motor nerve conduction velocities (MNCV) were always less than 38 m/s in CMT1A patients, whereas this was also the case in 16% of the CMT2 patients. Sensory nerve conduction velocities showed less overlap. In both CMT1A and CMT2 CMAP and SNAP amplitudes were often reduced or not obtainable in the legs. In CMT1A, SNAP amplitude was more reduced and SNAP duration more prolonged than in CMT2.We conclude that there are no robust clinical signs or symptoms that differentiate between CMT1A and CMT2 patients. Electrodiagnostical studies show a length-dependent motor and sensory axonal dysfunction in both CMT-types. Additional SNAP and SNCV evaluation may be helpful in focusing molecular genetic analysis in the occasional case of CMT2 showing slow motor nerve conduction velocities overlapping with CMT1A values. The reduction of CMAP and SNAP amplitudes in CMT1A is probably a combined effect of demyelination and axonal dysfunction.     

Evaluation of spinal and bulbar muscular atrophy by the clustering index method

Introduction: A reliable electrophysiological marker for clinical trials is increasingly needed in spinal and bulbar muscular atrophy (SBMA). We previously developed a quantitative analysis method for surface electromyography (SEMG), the clustering index (CI) method. Our purpose was to test the utility of the CI method for evaluating lower motor neuron involvement in SBMA patients. Methods: Subjects included 29 SBMA patients and 27 healthy controls. The recording electrode was placed over the abductor digiti minimi (ADM) muscle with a proximal reference. The Z‐score, based on the CI method, was compared with compound muscle action potential (CMAP) amplitude and motor unit number estimation (MUNE), with regard to sensitivity. Results: The Z‐scores of the CI method, CMAP amplitude, and MUNE were abnormal in 100%, 72%, and 93% of the patients, respectively. Interrater reliability of the CI method was sufficiently high. Conclusion: The CI method is promising as a non‐invasive electrophysiological marker in SBMA. Muscle Nerve, 2011     

Motor unit number estimation in facial paralysis

The value of motor unit number estimation (MUNE) in determining the prognosis of acute peripheral facial paralysis (PFP) was evaluated in 89 patients with PFP on days 6, 8, 11, 14, 20, and 30 of PFP and repeated once per month until complete recovery or the end of the first year. The symptomatic/asymptomatic side ratios of the compound muscle action potential (CMAP) amplitudes recorded from nasalis muscles and MUNEs studied using the incremental method by recording from the same muscle were assessed with regard to three outcome groups (Group I, complete recovery; Group II, mild dysfunction; Group III, moderate-moderately severe dysfunction). CMAP and MUNE ratios were parallel to each other in all patient groups throughout the observation period with lower values in the more severe groups. However, CMAP amplitude loss was significantly greater than the MUNE loss in the first 3 weeks of PFP. The MUNE method is not superior to CMAP size in determining prognosis in PFP. However, the significant disparity between the CMAP and MUNE ratios in the early period may have some physiological relevance with regard to the pathophysiology of the Wallerian degeneration process and deserves further research into its potential sources.     

Clinical disease severity and axonal dysfunction in hereditary motor and sensory neuropathy Ia

Abstract Background Hereditary motor and sensory neuropathy type Ia (HMSN Ia) is known as a primarily demyelinating peripheral nerve disease. Evidence is accumulating that axonal involvement determines the course of the disease process. Methods Fifty-one patients were investigated. Physical disability and impairments were scored. Nerve conduction velocities (NCVs) were used as indirect measures for myelination status and compound muscle/sensory nerve action potential (CMAP/SNAP) amplitudes served as indirect measures for axonal function. Results Median age was 39 years (range 6–69).Muscle weakness and sensory dysfunction was more severe in the legs than in the arms and distally more than proximally. However, more than 40% of the patients had proximal muscle weakness in the legs. Three point grip was used as representative of combined distal arm muscle groups. CMAP amplitude was the most important independent variable in a multiple linear regression model (forward selection) to explain the relation between three point grip strength and four different features, i. e., CMAP amplitude of the abductor pollicis brevis, median nerve MNCV, gender, and duration of signs and symptoms. The severity of axonal dysfunction was nerve length-dependent and was related to the myelination status. The mild physical disability due to both muscle weakness and sensory dysfunction was also related to axonal dysfunction. Conclusions In HMSN Ia, clinical disease severity at the impairment and disability levels is related to the severity of axonal dysfunction. Our data support the hypothesis that the myelination status is one of the factors that determine the extent of axonal dysfunction later in life. Proximal weakness of the legs is encountered in a considerable proportion of our patients.     

There are no neurophysiologic features characteristic of “axonal” Guillain–Barré syndrome

Classical views hold Guillain–Barré syndrome (GBS) as a primary inflammatory-demyelinating neuropathy in which secondary axonal degeneration may occur, particularly when inflammatory lesions are severe. Feasby and colleagues proposed that primary axonal degeneration can also cause GBS characterized by inexcitable motor nerves and poor outcome. This hypothesis rests largely on the results of a single autopsy in which no inflammation or demyelination were found. Using an illustrative case report confirming earlier studies, we point out that inexcitable motor nerves (or low amplitude compound muscle action potentials [CMAPs]) are of ambiguous significance and may reflect distal demyelination, causing conduction block between distal stimulation sites and target muscles, a pattern not uncommon in GBS. Recovery from such lesions may occur within weeks with restoration of CMAP amplitudes. The recognition of a yet unproven axonal variant of GBS cannot be based solely on documentation of inexcitable motor nerves in the context of rapidly developing weakness. © 1994 John Wiley & Sons, Inc.     

The motor neuron response to SMN1 deficiency in spinal muscular atrophy

Introduction: The purpose of this study was to measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA). Methods: Sixty‐two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE. Results: Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (?6.32 μV/year, P = 0.10), and stable CMAP amplitude. Conclusions: The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology. Muscle Nerve 49 : 636–644, 2014     

Motor unit number estimation by spatial-temporal summation of single motor unit potentials

Current techniques for motor unit number estimation (MUNE) rely on the amplitude of the compound muscle action potential (CMAP) evoked by supramaximal stimulation and mean amplitude of single motor unit potentials (SMUPs). The phase cancellation during summation is not considered. We developed a technique to address this issue. Slow and fast types of motor unit potentials were collected from 5 normal subjects from their abductor pollicis brevis muscles by low-level voluntary contractions, and near-threshold nerve stimulation, respectively. Two of each type of SMUPs were used as templates for reconstructing the best fitted CMAP using a feed-forward neural network. The total number of SMUPs simulated from the four templates during the reconstruction served as MUNE. The mean MUNE was 222 ± 98. The technique is simple and noninvasive, and may be applied in the future for MUNE in patients. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 461–468, 1997     

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.     

Progressive motor unit loss in the G93A mouse model of amyotrophic lateral sclerosis is unaffected by gender

We examined whether there are gender differences in the progressive loss of functional motor units in SOD1^G93A transgenic mice. Isometric muscle and motor unit twitch contractions were recorded in fast‐ and slow‐twitch muscles in response to stimulation of the sciatic nerve. Using a modified motor unit number estimation technique (ITS‐MUNE), we found that motor unit numbers declined rapidly from 40 to 90 days of age during the asymptomatic phase of ALS in fast‐ but not slow‐twitch hindlimb muscles of both male and female mice. There was a corresponding decline in twitch and tetanic contractile forces of the fast‐twitch muscles. Gender did not affect the progressive loss of motor units and associated decline in force production. We conclude that gender does not alter progressive, muscle‐specific motor unit loss in ALS, even though gender does influence disease onset. Muscle Nerve 39: 318–327, 2009     

Anterior tibialis cmap amplitude correlations with impairment in CMT1A

Introduction: CMT1A is the most common form of Charcot‐Marie‐Tooth disease (CMT), a slowly progressive neuropathy in which impairment is length dependent. Fibular nerve conduction studies to the anterior tibialis muscle (AT) may serve as a physiological marker of disease progression in patients with CMT1A. The objective of this study is to determine whether the AT compound muscle action potential (CMAP) amplitude correlates with impairment in patients with CMT1A. Methods: We correlated AT CMAP amplitudes and impairment measured by the CMT Neuropathy Score (CMTNS) in a cross‐section of 121 patients with CMT1A and a subset of 27 patients with longitudinal data. Results: AT CMAP amplitudes correlated with impairment as measured by the CMTNS in cross sectional analysis. Longitudinal changes in the AT CMAP showed a strong inverse correlation with leg strength but not other components of the CMTNS. Conclusions: AT CMAP amplitude may serve as a useful outcome measure for physiological changes in natural history studies and clinical trials for patients with CMT1A. Muscle Nerve, 2013     

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.