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.

ALSUntangled #75: Portable neuromodulation stimulator therapy.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

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).

ALSUntangled #74: Withania Somnifera (Ashwagandha).

ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS (PALS) who ask about them. Here, we review withania somnifera (WS) commonly known as ashwagandha or winter cherry. WS has plausible mechanisms for slowing ALS progression because of its effects on inflammation, oxidative stress, autophagy, mitochondrial function, and apoptosis. Preclinical trials demonstrate that WS slows disease progression in multiple different animal models of ALS. Of the five individuals we found who described using WS for their ALS, two individuals reported moderate benefit while none reported experiencing any significant side effects. There is currently one clinical trial using WS to treat PALS; the results are not yet published. There are no serious side effects associated with WS and the associated cost of this treatment is low. Based on the above information, WS appears to us to be a good candidate for future ALS trials.

ALSUntangled #71: Nuedexta.

Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.

ALSUntangled #72: Insulin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.

ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

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.

ALSUntangled #70: caffeine.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.

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 # 69: astaxanthin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review astaxanthin which has plausible mechanisms for slowing ALS progression including antioxidant, anti-inflammatory, and anti-apoptotic effects. While there are no ALS-specific pre-clinical studies, one verified "ALS reversal" occurred in a person using a combination of alternative therapies which included astaxanthin. There have been no trials of astaxanthin in people living with ALS. Natural astaxanthin appears to be safe and inexpensive. Based on the above information, we support further pre-clinical and/or clinical trials of astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.

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.

ALSUntangled #68: ozone therapy.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.

ALSUntangled #67: rituximab.

ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS who ask about them. Here we review rituximab, a drug which specifically depletes B lymphocytes. We show a current lack of evidence for a role of these cells in ALS progression. The one patient we found who described using Rituximab for their ALS found no benefit. Given all this, and the known serious risks of rituximab, we advise against its use as an ALS treatment.

ALSUntangled #66: antimycobacterial antibiotics.

Several infections have been associated with motor neuron diseases resembling ALS, including species of viruses, bacteria, and parasites. Mycobacterium avium subspecies paratuberculosis (MAP), most known for its probable etiologic association with Crohn's disease, has been suggested as another possible infectious cause of motor neuron disease. Two published case reports describe the successful treatment of ALS-like symptoms with antimycobacterial antibiotics. Both cases had atypical features. Based on these, we believe it would be reasonable to begin performing chest imaging in PALS who have features of their history or exam that are atypical for ALS such as pain, fevers, or eye movement abnormalities. If the chest imaging is abnormal, more specific testing for mycobacteria may be indicated. Until there is more clear evidence of an association between mycobacteria and ALS, we cannot endorse the widespread use of potentially toxic antimycobacterial antibiotics for PALS.

ALSUntangled #65: glucocorticoid corticosteroids.

ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (PALS). Here we review glucocorticoids. Neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis, so some hypothesize that glucocorticoids might be an effective ALS therapy through their immunosuppressive effects. In this paper, we review the available evidence for glucocorticoids in ALS, including one pre-clinical study with a genetic mouse model of ALS, nine case reports (ranging from 1 to 26 patients each), and four clinical trials. We also review the possible side effects (including steroid myopathy) and the costs of therapy. We graded the level of evidence as follows: Mechanism, D; Pre-Clinical, F; Cases, B; Trials, F; Risks, C. Our review of the current evidence concludes that glucocorticoids do not offer clinical benefit in ALS and confer serious risks. Thus, ALSUntangled does not recommend glucocorticoids as a treatment for ALS.

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.