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.     

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.     

Origin of surface motor unit potentials in hypothenar motor unit number estimation

Introduction: Far‐field potentials (FFPs) from muscles other than the abductor digiti minimi (ADM) may interfere with motor unit number estimation (MUNE) from that muscle. Methods: We identified the origin of each surface motor unit potential (SMUP) during hypothenar MUNE using the multiple point stimulation method in 20 control subjects by recording from individual ulnar‐innervated muscles with a common proximal reference (pref). Results: ADM SMUPs comprised 39.0% of the accepted SMUPs, followed by those from the fourth dorsal interosseous muscle (14.0%), the fourth lumbrical muscle (9.2%), and the second and third palmar interosseous muscles (8.8% each). The percentage of ADM SMUPs varied from 18% to 73% of accepted SMUPs among individual subjects. Accepted non‐ADM SMUPs were usually much smaller than ADM SMUPs, and many more non‐ADM SMUPs were excluded due to their small size. Conclusions: A large contribution from non‐ADM or non‐hypothenar SMUPs obscures the meaning of the MUNE value. Muscle Nerve, 48: 185–190, 2013     

Age‐related changes in motor unit number estimates in adult patients with Charcot–Marie–Tooth type 1A

Background: Charcot–Marie–Tooth disease type 1A (CMT1A) is known as a demyelinating hereditary neuropathy. Secondary axonal dysfunction is the most important determinant of disease severity. In adult patients, clinical progression may be because of further axonal deterioration as was shown with compound muscle action potential (CMAP) amplitude reductions over time. The motor unit number estimation (MUNE) technique may be more accurate to determine the number of axons as it is not disturbed by the effect of reinnervation. The purpose of this study was to investigate the number and size of motor units in relation to age in patients and controls. Methods: In a cross‐sectional design, we assessed arm and hand strength and performed electrophysiological examinations, including CMAP amplitudes and MUNE of the thenar muscles using high‐density surface EMG in 69 adult patients with CMT1A and 55 age‐matched healthy controls. Results: In patients, lower CMAP amplitudes and MUNE values were related to hand weakness. The CMAP amplitude and MUNE value of the thenar muscles were significantly lower in patients than in controls. CMAP amplitudes declined with age in controls, but not in patients. MUNE values declined with age in both patients and controls. Conclusions: The age‐dependent decrease in the number of motor units was not significantly different between patients with CMT1A and controls, indicating that loss of motor units in adult patients is limited.     

Multiple point electrical stimulation of ulnar and median nerves.

A computer-assisted method of isolating single motor units (MUs) by multiple point stimulation (MPS) of peripheral nerves is described. MPS was used to isolate 10-30 single MUs from thenar and hypothenar muscles of normal subjects and patients with entrapment neuropathies, with the original purpose of obtaining a more representative mean motor unit potential for estimating the number of MUs in a muscle. The two important results that evolved from MPS however, were: (1) in the absence of 'alternation' MUs were recruited in an orderly pattern from small to large, and from longer to shorter latencies by graded electrical stimulation in both normal and pathological cases, (2) a comparison of the sizes of MUs recruited by stimulation proximal and distal to the elbow suggested that axonal branching can occur in the forearm 200 mm or more proximal to the motor point in intrinsic hand muscles.     

Differentiation between axonal and demyelinating neuropathies: Identical segments recorded from proximal and distal muscles

The presence of significant slowing of motor nerve conduction velocity is considered one of the electrodiagnostic hallmarks of demyelinating neuropathies; however, slowing of conduction velocity may also accompany severe axonal loss. When compound muscle action potential (CMAP) amplitudes are markedly reduced, it is frequently difficult to determine if conduction velocity slowing is due to axonal loss with dropout of the fastest conducting fibers or demyelination. To evaluate the relationship between conduction velocity and axonal dropout, we compared conduction velocities through the same segment of nerve recording from distal and proximal peroneal muscles in patients with chronic neuropathies, in patients with motor neuron disease, and in control subjects. In controls and patients with motor neuron disease, conduction velocities were normal with no significant difference between proximal and distal sites. In patients with axonal neuropathies, conduction velocities were preferentially slowed when recording from distal muscles and relatively normal when recording from proximal sites. Patients with demyelinating neuropathies showed marked slowing of conduction at both sites. We conclude that comparing conduction velocity obtained from proximal versus distal muscle recordings provides a simple, reliable aid for differentiating between chronic axonal and demyelinating polyneuropathies, especially in cases with conduction velocity slowing and low CMAP amplitudes. © 1995 John Wiley & Sons, Inc.     

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。     

Relation between maximum discharge rates on electromyography and motor unit number estimates

To improve quantitative assessment of motor unit recruitment by standard concentric needle electromyography (CNEMG), hypothenar muscles of 22 healthy subjects, 18 with denervation, and 10 with a myopathy were studied. Discharge rates of motor units were measured in CNEMG recordings comprising action potentials of, at most, 4 motor units. Motor unit number estimation (MUNE) was done using the manual incremental method. In controls, the upper 95% limit of the discharge rate was 16.2/s. In all subjects, a strong nonlinear correlation between the number of motor units and the maximal discharge rate was found (r = 0.88, P < 0.0001). Increased discharge rates were found in all but one of the paretic muscles with denervation, but in none of the myopathic muscles. Measurement of the discharge rate is a simple and reliable procedure. If the discharge rate is high in a hypothenar muscle, loss of motor units can be inferred. Moreover, the discharge rate value gives an estimate of the number of motor units in that muscle. Thus, we suggest that maximal discharge rate be included in electromyographic reports.     

Early surgery improves peripheral motor axonal dysfunction in acute traumatic central cord syndrome: A prospective cohort study

ObjectiveTo investigate the impact of early vs. delayed surgical decompression on peripheral motor axonal dysfunction following acute traumatic central cord syndrome (ATCCS).MethodsBoth axonal excitability testing and motor unit number estimation (MUNE) were performed in 30 ATCCS patients (early- vs. delayed-surgical treatment: 12 vs. 18) before operation and 28 healthy subjects. Axonal excitability testing was repeated 3–5 days and 1-year after operation, and MUNE was re-evaluated 1-year after operation.ResultsPreoperatively, an obvious modification in membrane potentials was observed in ATCCS patients that mostly coincided with depolarization-like features, and MUNE further revealed reduced motor units in tested muscles (P < 0.05). Unlike delayed-surgical cases, early-surgical cases showed recoveries of most measurements of axonal excitabilities soon after operation (P < 0.05). Postoperative one-year follow-up demonstrated that greater motor unit numbers in tested muscles were obtained in early-surgical cases than in delayed-surgical cases (P < 0.05).ConclusionsATCCS has adverse downstream effects on peripheral nervous system, even in the early stage of ATCCS. Early surgical treatment can ameliorate both excitability abnormalities and motor unit loss in distal motor axons.SignificanceOptimizing axonal excitability in the early phases of ATCCS may alleviate peripheral nerve injury secondary to lesions of upper motor neuron and improve clinical outcomes.     

Dissociated small hand muscle involvement in amyotrophic lateral sclerosis detected by motor unit number estimates.

In some patients with amyotrophic lateral sclerosis (ALS), the thenar hand is more severely affected than the hypothenar hand. To quantify the dissociated involvement, we examined the motor unit number estimate (MUNE) of both the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles in 23 patients with ALS. Whereas ALS patients had significantly smaller MUNEs than normal subjects in both muscles, the extent of motor unit loss was significantly greater in the APB than ADM. Moreover, a simple comparison of the amplitude of compound muscle action potentials (CMAPs) showed that ALS patients had significantly smaller APB/ADM ratios than normal subjects and patients with cervical spondylotic amyotrophy, bulbospinal muscular atrophy, or peripheral neuropathy. The more severe involvement of the APB probably reflects the specific pathophysiology in ALS, and possible mechanisms for the dissociated involvement are discussed.     

Reduction in the motor unit number estimate (MUNE) after cerebral infarction

Background: The mechanism of the decrease in motor unit number estimates (MUNEs) after cerebral infarction has not been studied systematically. We examined the relationship between the degree to which MUNEs decreased and the other clinical features of patients with the infarction. Methods: Using a multiple point stimulation technique, we obtained the MUNE of the hypothenar muscle group in 13 age-matched control subjects and 30 patients with cerebral infarction. In all patients, we obtained the Japan Stroke Scale (JSS) and head MR images. In eight patients with acute cerebral infarction, admitted within 24 h after onset, we also obtained head MR angiograms and single-photon emission CT. Findings: There was a decrease in the MUNE of the hypothenar muscle group on the affected side of 24 patients with cerebral infarction and hand weakness. The decrease in the MUNE started from 4 to 30 h after the infarction, when T1-weighted MR images of the brain involved were normal. The degree to which the MUNE decreased correlated with the part of the JSS showing the upper extremity weakness. Interpretations: A decrease in the MUNE of the hypothenar muscle group within 30 h after cerebral infarction may be due to trans-synaptic inhibition of the spinal alpha motor neurons innervating this muscle.     

A modified multiple point stimulation method for motor unit number estimation of the hypothenar muscles

Introduction: The goal of this study is to test the hypothesis that single motor unit action potentials (SMUPs) originating from other ulnar nerve–innervated intrinsic hand muscles can inflate the motor unit number estimation (MUNE) of the hypothenar muscles. Methods: Using the multiple point stimulation method, SMUPs recorded over the hypothenar muscles from distant origins were characterized through multichannel recordings. The MUNE calculated using only the hypothenar SMUPs was compared with estimations based on the whole ensemble. Results: Of the 41 studies performed, distant SMUPs represented 17 ± 9.5% (mean ± SD) of the overall sample. MUNE calculated using only hypothenar SMUPs was 423 ± 204, compared with 537 ± 290 if all SMUPs were included (P < 0.05). The extent of increase in MUNE was highly correlated with the proportion of distant SMUPs found (r = 0.89, P < 0.05). Discussion: Erroneous inclusion of SMUPs from distant muscles can significantly distort the MUNE results. Muscle Nerve 59 :337–341, 2019     

Motor unit number estimation in infants and children with spinal muscular atrophy

Spinal muscular atrophy (SMA) is a disease of lower motor neurons. Motor unit number estimation (MUNE) is an electrophysiologic method to estimate the number of motor neurons innervating a muscle group. We applied the multiple point stimulation technique to the ulnar nerve--hypothenar muscle group to study lower motor neuron loss in 14 SMA subjects, including those presymptomatic, and varying from newborn through 45 years of age. Preliminary data support the value of MUNE to help understand the time course of motor neuron loss in SMA.     

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.     

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.     

Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis: Evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset

Objective

To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS.

Methods

In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution.

Results

The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset.

Conclusions

The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease.

Significance

This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS.     

Depletion and sizes of motor units in spinal muscular atrophy

Motor unit number estimation (MUNE) was applied to the biceps brachii muscles of 13 young patients (age 5--24 years) with spinal muscular atrophy (SMA) and the results compared with those of healthy control subjects matched for age and gender. In the SMA patients, all motor unit (MU) estimates fell below the control range, and there was good correspondence between the values for the two arms in the same subject. No correlation could be found between the MUNEs and the severity of the weakness. This unexpected result was attributed to the presence of small and normal-sized MUs in the muscles of patients, in addition to MUs that appeared to be considerably enlarged. The threefold mean increase in MU potential size was insufficient to compensate for the MU loss. In addition, the study confirmed that there are, on average, approximately 130 MUs in the healthy biceps brachii muscle.     

Updating motor unit number estimation (MUNE).

Motor unit number estimation (MUNE) is a unique electrophysiologic technique that can provide a numeric estimate of the number of axons innervating a muscle or group of muscles. The first technique was first described in 1971, and since then different techniques have been developed to address specific methodologic issues. The field was reviewed in this journal in 2001, and this update covers new information and uses of MUNE over the past five years. These include models of muscles that allow evaluation of MUNE techniques and comparisons between techniques. There have been further investigations of specific technical aspects of MUNE. Modifications to MUNE techniques have been offered that permit more rapid acquisition of data. MUNE has been used in clinical situations to elucidate the pathophysiology features of axonal loss in a number of disorders. There is now more experience with MUNE as endpoint measures in clinical trials.     

Use of the collision technique to improve the accuracy of motor unit number estimation.

OBJECTIVE: To evaluate the risk of stimulating the same motor axon at different points along the median nerve when using the multiple point stimulation (MPS) technique and how this affects the accuracy of the motor unit number estimate (MUNE). METHODS: Using the MPS technique, MUNE in the median innervated intrinsic hand muscles was done on two normal subjects, a patient with carpal tunnel syndrome and one with prior poliomyelitis. The collision technique was then used to confirm whether two motor unit action potentials (MUAPs) with similar configurations and sizes were generated by the same motor unit. A new MUNE was recalculated after the repeated inclusion of the same motor unit had been excluded. RESULTS: While the risk of stimulating the same motor axon at widely separate locations of the median nerve was negligible in normal subjects, this risk was much higher in patients with a depleted motor neuron pool. This resulted in marked distortion of the calculated size of the average single MUAP and, consequently, inaccuracy of the MUNE. CONCLUSIONS: The inadvertent inclusion of the same motor units, if not recognized, can markedly affect the accuracy of the MUNE. The collision technique can be useful in minimizing this risk.     

Mechanisms of early and late recovery in acute motor axonal neuropathy

Motor unit number estimate (MUNE) of the abductor pollicis brevis (APB) was sequentially performed in seven patients with acute motor axonal neuropathy (AMAN). The MUNE markedly decreased (mean, 11) at the peak of the illness. Clinical recovery of APB strength began during week 4, with an increase in amplitude of distal compound muscle action potentials. The MUNE did not change significantly in this early recovery phase and increased slowly with time. The main mechanism for early recovery in AMAN may be collateral reinnervation, with nerve regeneration developing later.