Revisiting the compound muscle action potential (CMAP).

The compound muscle action potential (CMAP) is among the first recorded waveforms in clinical neurography and one of the most common in clinical use. It is derived from the summated muscle fiber action potentials recorded from a surface electrode overlying the studied muscle following stimulation of the relevant motor nerve fibres innervating the muscle. Surface recorded motor unit potentials (SMUPs) are the fundamental units comprising the CMAP. Because it is considered a basic, if not banal signal, what it represents is often underappreciated. In this review we discuss current concepts in the anatomy and physiology of the CMAP. These have evolved with advances in instrumentation and digitization of signals, affecting its quantitation and measurement. It is important to understand the basic technical and biological factors influencing the CMAP. If these influences are not recognized, then a suboptimal recording may result. The object is to obtain a high quality CMAP recording that is reproducible, whether the study is done for clinical or research purposes. The initial sections cover the relevant CMAP anatomy and physiology, followed by how these principles are applied to CMAP changes in neuromuscular disorders. The concluding section is a brief overview of CMAP research where advances in recording systems and computer-based analysis programs have opened new research applications. One such example is motor unit number estimation (MUNE) that is now being used as a surrogate marker in monitoring chronic neurogenic processes such as motor neuron diseases.

Motor unit recruitment and firing rate at low force of contraction.

INTRODUCTION/AIMS: A prevailing concept of motor unit (MU) recruitment used for calculating recruitment ratio (RR) suggests a progressive linear increase in firing rate (FR). The objective of this study is to assess its validity. METHODS: Concentric needle electromyography (EMG) recordings were made in normal muscle and abnormal muscle of patients with neurogenic findings. Signals recorded at low force were visually decomposed to study MU FR at onset, recruitment of a second MU, and recruitment of more MUs with further increases in force. RESULTS: We observed one to six MUs discharging at a rate < 15 Hz in normal muscles at low force. The MU FR was 5-8 Hz at onset. With increasing force, FR increased by 3-5 Hz and then idled at <15 Hz while other MUs were recruited. The recruitment frequency (RF) and RR had low sensitivity and were abnormal mainly in moderately to severely weak muscles. DISCUSSION: Our data are consistent with FR analysis results described by other investigators. It does not support a progressive linear increase in MU FR with recruitment. A revised model for MU recruitment at low effort during gradual increase in force is presented. On subjective assessment, the FR of the fastest firing MU can help detect MU loss in neurogenic processes.

Single fiber electromyography and measuring jitter with concentric needle electrodes.

This monograph contains descriptions of the single fiber electromyography (SFEMG) method and of the more recently implemented method of recording jitter with concentric needle electrodes (CNEs). SFEMG records action potentials from single muscle fibers (SFAPs), which permits measuring fiber density (FD), a sensitive measure of reinnervation, and jitter, a sensitive measure of abnormal neuromuscular transmission (NMT). With voluntary activation, jitter is measured between two SFAPs with acceptable amplitude and rise time. With activation by axon stimulation, jitter is measured between the stimulus and individual SFAPs. Pitfalls due to unstable triggers and inconstant firing rates during voluntary activation and subliminal stimulation during axon stimulation should be identified and avoided. In CNE recordings, spikes with shoulders or rising phases that are not parallel are produced by summation of SFAPS; these should be excluded and reference values for CNE jitter should be used. CNE and SFEMG have similar and very high sensitivity in detecting increased jitter, as in myasthenia gravis and other myasthenic conditions. However, jitter is also seen in ongoing reinnervation and some myopathic conditions. With SFEMG, these can be identified by increased FD; however, FD cannot be measured with CNE, and conventional electromyography should be performed in muscles with increased jitter to detect neurogenic or myogenic abnormalities. Jitter is abnormal after injections of botulinum toxin, even in muscles remote from the injection site, and can persist for 6 mo or more. This can complicate the detection or exclusion of abnormal NMT.

Single fiber EMG and measuring jitter with concentric needle electrodes.

This monograph contains descriptions of the single-fiber electromyography (SFEMG) method and of the more recently implemented method of recording jitter with concentric needle electrodes (CNE). SFEMG records action potentials from single muscle fibers (SFAPs), which permits measuring fiber density (FD), a sensitive measure of reinnervation, and jitter, a sensitive measure of abnormal neuromuscular transmission (NMT). With voluntary activation, jitter is measured between two SFAPs with acceptable amplitude and rise time. With activation by axon stimulation, jitter is measured between the stimulus and individual SFAPs. Pitfalls due to unstable triggers and inconstant firing rates during voluntary activation and subliminal stimulation during axon stimulation should be identified and avoided. In CNE recordings, spikes with shoulders or rising phases that are not parallel are produced by summation of SFAPS; these should be excluded and reference values for CNE jitter should be used. CNE and SFEMG have similar and very high sensitivity in detecting increased jitter, as in myasthenia gravis and other myasthenic conditions. However, jitter is also seen in ongoing reinnervation and some myopathic conditions. With SFEMG, these can be identified by increased FD; however, FD cannot be measured with CNE, and conventional EMG should be performed in muscles with increased jitter to detect neurogenic or myogenic abnormalities. Jitter is abnormal after injections of botulinum toxin, even in muscles remote from the injection site, and can persist for 6 mo or more. This can complicate the detection or exclusion of abnormal NMT.

Analysis of the compound muscle action potential scan: Step index (STEPIX) and amplitude index (AMPIX).

OBJECTIVE: The compound muscle action potential (CMAP) scan is useful to study motor unit (MU) loss. It is of interest to develop simple measurements of the scan. METHODS: CMAP scan recordings were performed in the abductor pollicis brevis muscle of 20 control subjects and 26 patients with amyotrophic lateral sclerosis (ALS). They were analyzed using two new measurements called Step index (STEPIX) reflecting the number of steps, and Amplitude index (AMPIX) for amplitude of these steps. RESULTS: In control subjects, STEPIX ranged from 71 to 172 while AMPIX was 78-158 µV. In ALS patients STEPIX was reduced and AMPIX was increased. The degree of change in STEPIX and AMPIX varied among patients reflecting the success or failure of reinnervation. Follow up studies in 9 muscles demonstrated reduced STEPIX and increased AMPIX despite minimal change in the CMAP. CONCLUSIONS: STEPIX and AMPIX are deterministic measurements of the CMAP scan made using a spreadsheet program. STEPIX and AMPIX can be inferred as indices for the number of motor units and their size, and demonstrate the expected pattern in ALS patients. SIGNIFICANCE: The new algorithm for CMAP scan analysis may be useful to study disease progression in patients with ALS.

Marching band model for simulating a single muscle fiber action potential.

OBJECTIVE: We describe a mathematical model to calculate a single muscle fiber action potential (AP). Based on a marching band pattern, it is an enhancement to our previously described "modified line source" model. METHODS: Calculations were performed using an Excel spread sheet. AP was simulated for a 200 mm long muscle fiber with 60 µm diameter, propagation velocity of 4 m/s, and end-plate located at the center. Several different electrode locations were used to calculate the AP. RESULTS: The AP amplitude was highest at the end-plate where the waveform was biphasic with initial negativity. When the electrode was moved towards the tendon, the amplitude decreased for the first 1.5 mm. The AP was triphasic and its waveform was relatively constant at electrode positions beyond 1.5 mm from the end-plate. It matched the calculations using the modified line source model. When the electrode was near the tendon, the AP amplitude decreased asymmetrically and waveform became biphasic resembling a positive sharp wave. DISCUSSION: The model is conceptually and computationally simple. It simulated the expected AP shape at different electrode positions along the muscle fiber. The waveforms are similar to those obtained from mathematically complex volume conductor models. SIGNIFICANCE: The revised model can be useful for teaching and future simulation studies.

Experiment for teaching virtual cathode in nerve conduction studies.

INTRODUCTION/AIMS: The virtual cathode (VC) is a site near the anode where the nerve can be stimulated. Costimulation of neighboring nerves via the VC can affect recording and interpretation of responses. Hence, it is important to teach trainees the concept of the VC. The VC has been demonstrated previously with subtle changes in response latency, amplitude, and shape. Herein we describe an experiment that simply demonstrates a VC with its effects recognizable by gross changes in waveforms. METHODS: Compound muscle action potentials of the abductor pollicis brevis were recorded using various placements of the cathode and anode at different stimulus intensity levels. Studies were performed in nine healthy subjects. RESULTS: Three patterns were observed that demonstrated no stimulation, partial stimulation, and complete nerve stimulation by the VC. Partial stimulation yielded responses with long duration and low amplitude. Response patterns also depended on stimulus strength and proximity of the nerve from the skin surface. DISCUSSION: This experiment demonstrates that nerve stimulation can occur near the anode when high-intensity stimulus is used. It also illustrates collision of action potentials. This exercise can help trainees understand potential pitfalls in nerve conduction studies, especially at very proximal stimulation sites or when high stimulus intensity is used.

MeRef: Multivariable extrapolated reference values in motor nerve conduction studies.

INTRODUCTION: In this study we describe a method called "multivariable extrapolated reference values" (MeRef) that derives reference values (RVs) using patient data and includes the dependence of these variables on multiple patient demographic variables, such as age and height. METHODS: Computer simulations were used to generate "normal" and "patient" nerve conduction data. Median, ulnar, and tibial motor nerve conduction data from 500 patients studied were tabulated. Data were analyzed using the MeRef method. RESULTS: The simulations showed great similarity between RVs obtained from MeRef of "patient" data and traditional analysis of "normal" data. In the real patient data, MeRef gave RVs as regression equations based on patient age and/or height. DISCUSSION: MeRef can provide RVs by including patient demographic data and does not require subject grouping. It provides parameters of multivariable linear regression and standard deviation, and requires a few hundred patient studies to define reference values.

Neurogenic vs. Myogenic Origin of Acquired Muscle Paralysis in Intensive Care Unit (ICU) Patients: Evaluation of Different Diagnostic Methods.

Introduction. The acquired muscle paralysis associated with modern critical care can be of neurogenic or myogenic origin, yet the distinction between these origins is hampered by the precision of current diagnostic methods. This has resulted in the pooling of all acquired muscle paralyses, independent of their origin, into the term Intensive Care Unit Acquired Muscle Weakness (ICUAW). This is unfortunate since the acquired neuropathy (critical illness polyneuropathy, CIP) has a slower recovery than the myopathy (critical illness myopathy, CIM); therapies need to target underlying mechanisms and every patient deserves as accurate a diagnosis as possible. This study aims at evaluating different diagnostic methods in the diagnosis of CIP and CIM in critically ill, immobilized and mechanically ventilated intensive care unit (ICU) patients. Methods. ICU patients with acquired quadriplegia in response to critical care were included in the study. A total of 142 patients were examined with routine electrophysiological methods, together with biochemical analyses of myosin:actin (M:A) ratios of muscle biopsies. In addition, comparisons of evoked electromyographic (EMG) responses in direct vs. indirect muscle stimulation and histopathological analyses of muscle biopsies were performed in a subset of the patients. Results. ICU patients with quadriplegia were stratified into five groups based on the hallmark of CIM, i.e., preferential myosin loss (myosin:actin ratio, M:A) and classified as severe (M:A < 0.5; n = 12), moderate (0.5 ≤ M:A < 1; n = 40), mildly moderate (1 ≤ M:A < 1.5; n = 49), mild (1.5 ≤ M:A < 1.7; n = 24) and normal (1.7 ≤ M:A; n = 19). Identical M:A ratios were obtained in the small (4-15 mg) muscle samples, using a disposable semiautomatic microbiopsy needle instrument, and the larger (>80 mg) samples, obtained with a conchotome instrument. Compound muscle action potential (CMAP) duration was increased and amplitude decreased in patients with preferential myosin loss, but deviations from this relationship were observed in numerous patients, resulting in only weak correlations between CMAP properties and M:A. Advanced electrophysiological methods measuring refractoriness and comparing CMAP amplitude after indirect nerve vs. direct muscle stimulation are time consuming and did not increase precision compared with conventional electrophysiological measurements in the diagnosis of CIM. Low CMAP amplitude upon indirect vs. direct stimulation strongly suggest a neurogenic lesion, i.e., CIP, but this was rarely observed among the patients in this study. Histopathological diagnosis of CIM/CIP based on enzyme histochemical mATPase stainings were hampered by poor quantitative precision of myosin loss and the impact of pathological findings unrelated to acute quadriplegia. Conclusion. Conventional electrophysiological methods are valuable in identifying the peripheral origin of quadriplegia in ICU patients, but do not reliably separate between neurogenic vs. myogenic origins of paralysis. The hallmark of CIM, preferential myosin loss, can be reliably evaluated in the small samples obtained with the microbiopsy instrument. The major advantage of this method is that it is less invasive than conventional muscle biopsies, reducing the risk of bleeding in ICU patients, who are frequently receiving anticoagulant treatment, and it can be repeated multiple times during follow up for monitoring purposes.

Form factor analysis of the surface electromyographic interference pattern.

INTRODUCTION: In contrast to needle electromyography (EMG), surface EMG recordings are painless. It is of interest to develop methods to analyze surface EMG for diagnostic purposes. METHODS: Surface EMG interference pattern (SIP) recordings from the abductor pollicis brevis muscle of healthy subjects and subjects with amyotrophic lateral sclerosis (ALS) were analyzed by measuring root-mean-square (RMS) voltage, mean rectified voltage, form factor (FF), and the clustering index (CI). The FF vs SIP area plot was used for analysis. RESULTS: The SIP FF was increased and abnormal in ALS subjects, especially when SIP area was less than 200 mVms. Power regression showed a faster FF decline with SIP area in ALS patients than in healthy subjects. The CI and FF showed a strong correlation. DISCUSSION: FF is easy to calculate and demonstrates abnormalities in ALS patients.

Motor unit number index: Guidelines for recording signals and their analysis.

INTRODUCTION: This study proposes guidelines for motor unit number index (MUNIX) recording and analysis. METHODS: MUNIX was measured in control participants and in patients with amyotrophic lateral sclerosis. Changes in MUNIX values due to E1 electrode position, number of surface electromyography interference pattern (SIP) epochs, SIP epoch duration, force of contraction, and outlier data points were investigated. RESULTS: MUNIX depends on optimized compound muscle action potential (CMAP) amplitude. Individual muscles showed variations when the number of epochs was low or when the SIP duration was short. Longer SIP duration allowed better recognition of artifacts. MUNIX results were affected by SIP values at all force levels but was more affected when SIP area was low. DISCUSSION: We recommend changing the E1 electrode position to maximize CMAP amplitude. Twenty or more SIP signals of 500-ms duration should be recorded by using force levels ranging from slight to maximum. Traces should be reviewed to identify and exclude signals with tremor or solitary spikes. Muscle Nerve 58: 374-380, 2018.

The extrapolated reference values procedure: Theory, algorithm, and results in patients and control subjects.

INTRODUCTION: Reference values (RVs) are required to separate normal from abnormal values obtained in electrodiagnostic (EDx) testing. However, it is frequently impractical to perform studies on control subjects to obtain RVs. The Extrapolated Reference Values (E-Ref) procedure extracts RVs from data obtained during clinically indicated EDx testing. We compared the E-Ref results with established RVs in several sets of EDx data. METHODS: The mathematical basis for E-Ref was explored to develop an algorithm for the E-Ref procedure. To test the validity of this algorithm, it was applied to simulated and real jitter measurements from control subjects and patients with myasthenia gravis, and to nerve conduction studies from patients with various conditions referred for EDx studies. RESULTS: There was good concordance between E-Ref and RVs for all evaluated data sets. DISCUSSION: E-Ref is a promising method to develop RVs. Muscle Nerve 57: 90-95, 2018.

Optimizing testing methods and collection of reference data for differentiating critical illness polyneuropathy from critical illness MYOPATHIES.

INTRODUCTION: In severe acute quadriplegic myopathy in intensive care unit (ICU) patients, muscle fibers are electrically inexcitable; in critical illness polyneuropathy, the excitability remains normal. Conventional electrodiagnostic methods do not provide the means to adequately differentiate between them. In this study we aimed to further optimize the methodology for the study of critically ill ICU patients and to create a reference database in healthy controls. METHODS: Different electrophysiologic protocols were tested to find sufficiently robust and reproducible techniques for clinical diagnostic applications. RESULTS: Many parameters show large test-retest variability within the same healthy subject. Reference values have been collected and described as a basis for studies of weakness in critical illness. CONCLUSIONS: Using the ratio of neCMAP/dmCMAP (response from nerve and direct muscle stimulation), refractory period, and stimulus-response curves may optimize the electrodiagnostic differentiation of patients with critical illness myopathy from those with critical illness polyneuropathy.

Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5-year follow-up study.

The purpose of this study was to evaluate progression of diabetic polyneuropathy and differences in the spectrum and evolution of large- and small-fiber involvement in patients with diabetes type 1 and 2 over 5 years. Fifty-nine patients (35 type 1 and 24 type 2) were included. Nerve conduction studies (NCS), quantitative sensory testing, skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), symptom scoring and clinical evaluations were performed. Z-scores were calculated to adjust for the physiologic effects of age and height/gender. Neuropathic symptoms were not significantly more frequent in type 2 than in type 1 diabetic patients at follow-up (54% vs. 37%). The overall mean NCS Z-score remained within the normal range, but there was a small significant decline after 5 years in both groups: type 1 (p = 0.004) and type 2 (p = 0.02). Mean IENFD Z-scores changed from normal to abnormal in both groups, but only significantly in those with type 2 diabetes (reduction from 7.9 ± 4.8 to 4.3 ± 2.8 fibers/mm, p = 0.006). Cold perception threshold became more abnormal only in those with type 2 diabetes (p = 0.049). There was a minimal progression of large fiber neuropathy in both groups. Reduction of small fibers predominated and progressed more rapidly in those with type 2 diabetes.

Painful cramps and giant myotonic discharges in a family with the Nav1.4-G1306A mutation.

INTRODUCTION: Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation. METHODS: Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied. RESULTS: A G1306A mutation in the Nav1.4 voltage-gated sodium channel of skeletal muscle was identified. This mutation is known to cause myotonia fluctuans. No giant myotonic discharges or painful muscle cramps were found in the other G1306A families. CONCLUSIONS: Ephaptic transmission between neighboring muscle fibers may not only cause the unusual size of the myotonic discharges in this family, but also a more severe type of potassium-aggravated myotonia than myotonia fluctuans.

Cumulative motor index: an index to study progression of amyotrophic lateral sclerosis.

PURPOSE: To study disease progression in patients with amyotrophic lateral sclerosis (ALS), we have developed the "cumulative motor index (CMI)" using the compound muscle action potential amplitude recorded in multiple upper and lower limb muscles. METHODS: To study its reproducibility, CMI was measured by 2 operators in 10 healthy subjects on 2 occasions. In 15 patients with ALS, CMI and ALS functional rating score (revised) were measured at 3- to 6-month interval for 12 months or longer. RESULTS: The CMI had good reproducibility in healthy subjects. In one patient with ALS, CMI and ALS functional rating score (revised) remained relatively unchanged. In all remaining 14 patients with disease progression, CMI decreased in a relatively monotonic manner. At 1 year after baseline study, CMI was reduced more than ALS functional rating score (revised) in 10 patients. CMI measurements were possible for longer time period, than analysis from a single distal muscle recording. CONCLUSIONS: The CMI can be measured using standard equipment and software available in most electrodiagnostic laboratories. This may be a simple measurement that can be used for clinical studies of ALS progression over longer time periods.

Concentric needle jitter on voluntary activated frontalis in 20 healthy subjects.

INTRODUCTION: Normative data for jitter parameters using a disposable concentric needle have been described in a few studies. METHODS: Jitter, expressed as the mean consecutive difference (MCD), was measured in the frontalis muscle in 20 subjects by voluntary contraction. RESULTS: Mean MCD for individual studies (20, gaussian), all potentials (400, non-gaussian), and 18th highest value (20, gaussian) were 19.9 ± 2.9 µs, 19.9 ± 6.6 µs, and 26.9 ± 4.4 µs, respectively. CONCLUSION: The suggested upper normal limit for mean MCD is 26 µs and for outliers is 36 µs.

Concentric needle jitter in stimulated frontalis in 20 healthy subjects.

Normative data for jitter parameters using a disposable concentric needle have been presented in a few studies. Jitter, expressed as the mean consecutive difference (MCD), was measured in the frontalis muscle in 20 subjects by percutaneous bar stimulation of the temporal nerve branch. The mean MCD for individual studies (20) and for all potentials (600) were 16.05 ± 2.73 µs and 16.05 ± 5.96 µs, respectively. The suggested limit for mean MCD is 22 µs and for outliers is 28 µs.