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.

Walter Eichler and his role in the development of electroneurography.

Walter Eichler (1904-1942) performed the first in situ nerve conduction studies in humans. Eichler's work has been largely overlooked and there have been no biographical accounts written of him. His 1937 paper, Über die Ableitung der Aktionspotentiale vom menschlichen Nerven in situ (On the recording of the action potentials from human nerves in situ) was translated and reviewed. Archival material was obtained on his career that was housed predominantly at the University of Freiburg im Breisgau. He had memberships in Nazi organizations but did not appear to be politically active. During his brief career, he constructed novel equipment and established seminal principles for performing nerve conductions on humans. The authors repeated his experiment in the ulnar nerve, which duplicated Eichler's findings. His recordings were quite remarkable given advances in technology. In summary, the Eichler paper is the first study in the development of in situ clinical electroneurography in humans. Many of his procedural observations are still fundamental in the current practice of electroneurography. As best can be determined, his study in humans did not appear ethically compromised. Although Eichler's personal background remains open to question, his paper is a seminal study in the history and development of clinical electroneurography.Abbreviations: AP: Action potential; C: Capacitor; CNP: Compound nerve potential; DC: Direct current; E1: Preferred term for active electrode; E2: Preferred term for reference electrode; NSDÄB: Nationalsozialistische Deutsche NSD-Ärtzebund (National Socialist German Doctors' League; NSDAP: Nationalsozialistische Deutsche Arbeiterpartei (National Socialist German Workers' Party/ Nazi Party); SS: Schutzstaffel (Protective Echelon or Squad of the Nazi party).

Serial electrodiagnostic studies in acute partial conduction block from cyclist's palsy.

INTRODUCTION/AIMS: To date, there is minimal literature in following resolution of partial conduction block (PCB) in compression neuropathy. We investigated a case of cyclist's palsy with PCB from compression using serial nerve conduction studies to monitor recovery. METHODS: Clinical recovery was monitored concomitant with compound muscle action potential (CMAP) amplitudes that were recorded from 3 ulnar-innervated muscles (first dorsal interosseous [FDI] 6 days post-onset, palmar interosseus [PI] 16 days post-onset, and abductor digiti minimi [ADM]) in both limbs. Sensory nerve conduction studies and needle electromyography were also performed. RESULTS: PCB was demonstrated in the FDI and PI with recordings done proximal and distal to the site of injury. Recovery in the FDI and PI occurred between week 2 and 3 post-onset but continued to improve until about 14 wk post-onset when the CMAP values on the affected side approximated the contralateral side. Sensory conduction studies were normal and symmetric. Needle EMG at 21 days post-injury showed no active denervation and a reduced number of normal-appearing motor unit potentials firing >16 Hz that reverted to a normal pattern on final study at 99 days post-onset. DISCUSSION: This study shows how rapidly PCB may initially resolve although full recovery takes longer. Criteria for defining PCB may be misleading when doing nerve conductions and comparing only the evoked responses below and above the block. To fully characterize PCB, it is important to optimize the position of the active recording electrode (E1) as well as compare results with the unaffected side.

Recording sensory nerve action potential using different electrode types.

INTRODUCTION/AIMS: Switching between different types of electrodes during motor and sensory nerve conduction studies adds time to a study. We investigated the use of disposable disc electrodes (DDE) used for motor nerve conduction studies to record the antidromic sensory nerve action potential (SNAP) in median, ulnar and radial sensory nerve conduction studies. METHODS: The SNAP was recorded using four different electrode types: reusable ring, reusable bar, disposable ring, and DDE in a random rotating order. Studies were performed in healthy subjects. Other than being an adult with no history of neuromuscular disease, there were no exclusion criteria. RESULTS: We studied 20 subjects (11 females, 9 males; age 41.1 ± 15.7 y). The SNAP waveforms recorded by all four electrode types were similar. There was no statistically significant difference in the onset latency, peak latency (PL), negative peak amplitude (NPA), peak to peak amplitude, or conduction velocity. In individual nerve recordings, the absolute PL difference between reusable ring electrodes (our current standard) and DDE was less than 0.2 ms in 58 of 60 (97%) nerves. The mean absolute NPA difference was 3.1 µV (standard deviation = 2.85 µV). Recordings with NPA difference >5 µV also had high NPA and/or had large artifacts. DISCUSSION: DDE may be used for performing motor and sensory nerve conduction studies. This can reduce the time required for electrodiagnostic testing.

Volume conduction: Extracellular waveform generation in theory and practice.

The extracellular waveform manifestations of the intracellular action potential are the quintessential diagnostic foundation of electrodiagnostic medicine, and clinical neurophysiology in general. Volume conduction is the extracellular current flow and associated voltage distributions in an ionic conducting media, such as occurs in the human body. Both surface and intramuscular electrodes, in association with contemporary digital electromyographic systems, permit very sensitive detection and visualization of this extracellular spontaneous, voluntary, and evoked nerve/muscle electrical activity. Waveform configuration, with its associated discharge rate/rhythm, permits the identification of normal and abnormal waveforms, thereby assisting in the diagnosis of nerve and muscle pathology. This monograph utilizes a simple model to explain the various waveforms that may be encountered. There are a limited number of waveforms capable of being generated in excitable tissues which conform to well-known volume conductor concepts. Using these principles, such waveforms can be quickly identified in real time during clinical studies.

Defective E2 electrode lead gives low-amplitude compound muscle action potential.

INTRODUCTION/AIMS: Low-amplitude compound muscle action potential (CMAP) suggests a neuromuscular pathology. Low amplitude will also result from a defective E1 electrode or its lead, that is, a technical artifact. The aim of this study was to investigate the effect of a defective E2 electrode lead on the CMAP. METHODS: The CMAP was recorded using standard nerve conduction methodology and all electrode leads connected properly. Signals were then recorded when either the E1 or the E2 electrode lead was disconnected from the amplifier. This simulated a defective electrode lead. Studies were performed in four nerves of a healthy subject. RESULTS: CMAP amplitude was reduced as expected when E1 was disconnected. Surprisingly, the amplitude fell by more than 65% when the E2 lead was disconnected, although E1 was properly connected. DISCUSSION: E1 and E2 electrodes contribute to the CMAP. A defective recording electrode lead to E1 or E2 results in a low-amplitude CMAP. The amplitude drop observed with a disconnected E2 lead was far greater than the signal recorded by the E2 electrode. This occurs due to the amplifier's inherent property to reduce the voltage difference between the E1 and E2 inputs. When E2 lead is defective, the CMAP will be an attenuated version of the signal recorded by the E1 electrode, and vice versa. When low-amplitude CMAP amplitude is observed in all conduction studies, technical artifact should be considered before exploring the pathological basis for the abnormal results.

ALSUntangled #63: ketogenic diets.

ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

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.

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.

Reinnervation as measured by the motor unit size index is associated with preservation of muscle strength in amyotrophic lateral sclerosis, but not all muscles reinnervate.

INTRODUCTION/AIMS: The motor unit size index (MUSIX) may provide insight into reinnervation patterns in diseases such as amyotrophic lateral sclerosis (ALS). However, it is not known whether MUSIX detects clinically relevant changes in reinnervation, or if all muscles manifest changes in MUSIX in response to reinnervation after motor unit loss. METHODS: Fifty-seven patients with ALS were assessed at 3-month intervals for 12 months in four centers. Muscles examined were abductor pollicis brevis, abductor digiti minimi, biceps brachii, and tibialis anterior. Results were split into two groups: muscles with increases in MUSIX and those without increases. Longitudinal changes in MUSIX, motor unit number index (MUNIX), compound muscle action potential amplitude, and Medical Research Council strength score were investigated. RESULTS: One hundred thirty-three muscles were examined. Fifty-nine percent of the muscles exhibited an increase in MUSIX during the study. Muscles with MUSIX increases lost more motor units (58% decline in MUNIX at 12 months, P < .001) than muscles that did not increase MUSIX (34.6% decline in MUNIX at 12 months, P < .001). However, longitudinal changes in muscle strength were similar. When motor unit loss was similar, the absence of a MUSIX increase was associated with a significantly greater loss of muscle strength (P = .002). DISCUSSION: MUSIX increases are associated with greater motor unit loss but relative preservation of muscle strength. Thus, MUSIX appears to be measuring a clinically relevant response that can provide a quantitative outcome measure of reinnervation in clinical trials. Furthermore, MUSIX suggests that reinnervation may play a major role in determining the progression of weakness.

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.

Atypical fibrillation and fasciculation potentials: An exercise in waveform identification and analysis.

No consensus criteria exist for recording and analyzing waveforms in clinical electromyography (EMG). There have been significant technical improvements in recent decades that are under-used in both routine practice and research. In current practice, disciplined techniques in acquisition and analysis of signals are required to appropriately define them. As an example, we describe such an exercise in acquisition and analysis. During a routine study, atypical spontaneous activity was encountered. High-quality digital recordings were stored for off-line analysis. These revealed waveforms that could be isolated and quantitatively defined using basic instrumentation available on most modern EMG systems: "slow" firing fibrillation potentials and a repeating fasciculation potential. Subjective analysis alone could not have identified them. To improve accuracy in identification and understanding of these waveforms, we propose criteria for data collection and signal analysis. This is critical for quality in routine practice, education, and proper reporting of electrophysiological signals.

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.

ALSUntangled 59: Tamoxifen.

Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

Skill, confidence and support: conceptual elements of a child/youth caregiver training program in amyotrophic lateral sclerosis - the YCare protocol.

Aim: Pilot study of a novel caregiving training and support intervention for children and youth <19 years, who provide care for person living with amyotrophic lateral sclerosis. Materials & methods: Youth (n = 19) between the ages of 8-19 years, participated in skills training and support program (basic care, feeding/communication, assistive devices and social support). Results: Participants reported significant increase in confidence in tasks, including communication systems and respiratory equipment. Participants identified goal setting and creating behaviors to reach those goals. Benefits of training included that the day changed their perceptions of care and meeting 'like' peers. Conclusion: Results of the pilot YCare intervention underscores the need to assess how young caregivers feel and respond to new tasks when receiving support from developmentally similar peers.

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.

US data on children and youth caregivers in amyotrophic lateral sclerosis.

OBJECTIVE: An estimated 1.4 million young caregivers (<19 years of age) in the United States provide care to ill family members yet remain hidden from state and national caregiving programs and services, including amyotrophic lateral sclerosis (ALS) caregiving services. Given the intensive care needs and acuity of ALS, appreciation of the young caregiver experience within the family context may have a significant impact on patient and family quality of life. This article seeks to identify family and youth caregiver characteristics and perceptions of care through interviews with 38 youth caregivers and their families with ALS. METHODS: Online adult surveys and follow-up youth interviews were conducted with families with ALS across the United States in this cross-sectional study. Participants were accessed through chapters of the ALS Association. Both thematic content analysis and descriptive statistics were used. RESULTS: Youth caregivers (n = 38) ranged in age from 8 to 18 years and spent an average of 5 h/d providing care for an average of 12 tasks. Persons with ALS relied on youth primarily due to cost and identified complex feelings about relying on youth caregivers, including feeling like a failure, guilty, but proud. CONCLUSION: Youth are intricately involved in all areas of caregiving in ALS. They are isolated and have little training or guidance in care, yet they are able to identify ways to manage their care burden. Results provide clear implications for health care professionals in designing best care and support practices for persons with ALS and their young caregivers.

Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.

Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis.

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (-0.80 vs. -0.84 T40, -0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

Influence of reference electrode position on the compound muscle action potential.

OBJECTIVE: When the compound muscle action potential (CMAP) is recorded in motor nerve conduction studies, the reference (E2) electrode can make a significant contribution to the CMAP. This study investigates the E2 recorded signal and its effect on CMAP measurements when E2 electrode is placed at different sites. METHODS: The CMAP was recorded using the active electrode on the muscle belly and 4 different E2 electrodes placed at distal and proximal sites. The signal recorded by each electrode was also measured using a reference electrode on the contralateral limb. Signals were recorded from the abductor pollicis brevis, abductor digiti minimi, tibialis anterior and biceps muscles. RESULTS: The E2 recorded a smaller signal when it was placed near or off the proximal tendon or muscle origin. This affected CMAP latency, duration for tibialis anterior. Contrary to expectation, initial upward deflection was noted for E2 signal. CONCLUSION: A proximal E2 position records a lower volume conducted signal and yields a CMAP that is more representative of the muscle over which the E1 (active) electrode is placed. SIGNIFICANCE: The proposed 'Proximal E2' montage may be better suited to assess pathology.