Search

INTRODUCTION Sepsis-induced myopathy and critical illness myopathy are common causes of muscle weakness in intensive care patients. This study investigated the effect of different mean arterial blood pressure (MAP) levels on muscle membrane properties following experimental sepsis. METHODS Sepsis was induced with fecal peritonitis in 12 of 18 anesthetized and mechanically ventilated pigs. Seven were treated with a high (75-85 mmHg) and 5 were treated with a low (≥60 mmHg) MAP target for resuscitation. In septic animals, resuscitation was started 12 h after peritonitis induction, and muscle velocity recovery cycles were recorded 30 h later. RESULTS Muscles in the sepsis/high MAP group showed an increased relative refractory period and reduced early supernormality compared with the remaining septic animals and the control group, indicating membrane depolarization and/or sodium channel inactivation. The membrane abnormalities correlated positively with norepinephrine dose. DISCUSSION Norepinephrine may contribute to sepsis-induced abnormalities in muscle by impairing microcirculation. Muscle Nerve, 2017.

INTRODUCTION Myotonia in myotonic dystrophy types 1 (DM1) and 2 (DM2) is generally attributed to reduced chloride-channel conductance. We used muscle velocity recovery cycles (MVRCs) to investigate muscle membrane properties in DM1 and DM2, using comparisons with myotonia congenita (MC). METHODS MVRCs and responses to repetitive stimulation were compared between patients with DM1 (n = 18), DM2 (n = 5), MC (n = 18), and normal controls (n = 20). RESULTS Both DM1 and DM2 showed enhanced late supernormality after multiple conditioning stimuli, indicating delayed repolarization as in MC. Contrary to MC, however, DM1 showed reduced early supernormality after multiple conditioning stimuli, and weak DM1 patients also showed abnormally slow latency recovery after repetitive stimulation. CONCLUSIONS These findings support the presence of impaired chloride conductance in both DM1 and DM2. The early supernormality changes indicate that sodium currents were reduced in DM1, whereas the weakness-associated slow recovery after repetitive stimulation may provide an indication of reduced Na(+) /K(+) -ATPase activation. Muscle Nerve 54: 249-257, 2016.

INTRODUCTION Recording of muscle velocity recovery cycles (MVRCs) has been developed as a technique to investigate the pathophysiology of muscle diseases. MVRCs have been measured by direct muscle stimulation and concentric electromyographic needle recording. This study was undertaken to determine whether recordings can be made with surface electrodes. METHODS MVRCs with 1 and 2 conditioning stimuli were recorded simultaneously with concentric needle and surface electrodes from the brachioradialis muscle in 12 healthy volunteers. Muscle relative refractory period, early and late supernormality, and extra-late supernormality were compared between the recording techniques. RESULTS Surface recordings were possible in all subjects. The multifiber action potentials recorded with surface electrodes were smaller than those recorded with needles, but there was no significant difference between any of their MVRC properties. CONCLUSIONS MVRCs can be recorded with surface electrodes in healthy subjects. The use of surface electrodes may facilitate the technique of recording MVRCs. Muscle Nerve 53: 205-208, 2016.

Objective To examine the validity of multi-fiber muscle velocity recovery cycles (VRCs) recorded by direct muscle stimulation with submaximal stimuli. Methods VRCs were recorded from tibialis anterior muscle in normal volunteers with 1, 2 and 5 conditioning stimuli. Recordings were made with 6 different amplitudes of conditioning stimuli. Recordings were also made with two recording electrodes, at least 15 mm apart. Results Muscle VRCs in 6 subjects were not significantly different for conditioning stimuli between 80% and 150% of test stimulus amplitude. When recorded at two sites in 9 subjects, VRCs were similar when estimated over the shorter distance, the longer distance, and from the conduction time between the two electrodes. Conclusions Multi-fiber muscle VRCs can be reliably recorded with a single recording electrode and with equal amplitude conditioning and test stimuli. Significance Clinical neurophysiologists can be assured that this new method of testing muscle membrane properties provides valid and robust measurements on normal muscles.

We sought to characterize the excitability properties of tibialis anterior (TA) and brachioradialis (BR) muscles at rest and during electrically induced muscle activation in normal subjects.

Non-invasive excitability studies of motor axons in patients with amyotrophic lateral sclerosis (ALS) have revealed a changing pattern of abnormal membrane properties with disease progression, but the heterogeneity of the changes has made it difficult to relate them to pathophysiology. The SOD1(G93A) mouse model of ALS displays more synchronous motoneuron pathology. Multiple excitability measures of caudal and sciatic nerves in mutant and wild-type mice were compared before onset of signs and during disease progression (4-19 weeks), and they were related to changes in muscle fiber histochemistry. Excitability differences indicated a modest membrane depolarization in SOD1(G93A) axons at about the time of symptom onset (8 weeks), possibly due to deficient energy supply. Previously described excitability changes in ALS patients, suggesting altered sodium and potassium conductances, were not seen in the mice. This suggests that those changes relate to features of the human disease that are not well represented in the animal model.

The value of various indexes to characterize the stimulus-response curve of human motor nerves was assessed in 40 healthy subjects recruited from four European centers of investigation (Créteil, Lausanne, Liège, Marseille). Stimulus-response curves were established by stimulating the right median and ulnar motor nerves at the wrist, with stimulus durations of 0.05 and 0.5 ms. The following parameters were studied: the threshold intensity of stimulation to obtain 10% (I 10), 50% (I 50), and 90% (I 90) of the maximal compound muscle action potential, the ratios I 10/I 50, I 90/I 50, (I 90 - I 10)/I 10, (I 90-I 50)/I 50, and (I 50 - I 10)/I 10, and the slopes of the stimulus-response curves with or without normalization to I 50. For each parameter, within-center variability and reproducibility (in a test-retest study) were assessed and between-center comparisons were made. For most of the parameters, the results varied significantly within and between the centers. Within the centers, only the ratios I 10/I 50 and I 90/I 50 were found constant and reproducible. Between the centers, the absolute intensity thresholds (I 10, I 50, I 90) and the ratio I 90/I 50 did not show significant differences at stimulus duration of 0.5 ms, whatever the stimulated nerve. The reduced variability and good reproducibility of the ratios I 10/I 50 and I 90/I 50 open perspectives in neurophysiological practice for the use of these indexes of the stimulus-response curve, a rapid and noninvasive test.

Objective To study neuromuscular excitability in patients with dystrophia myotonica type 1 (DM1). Methods The neuromuscular recovery cycle following motor nerve stimulation was assessed in 16 DM1 patients who had no sign of peripheral neuropathy or diabetes. Compound muscle action potentials were recorded from the adductor digiti minimi muscle to ulnar nerve stimulation at the wrist. Paired pulses were delivered, consisting of a conditioning stimulus of supramaximal intensity, followed by a submaximal test stimulus. Interstimuli intervals (ISIs) ranged between 1 and 8 ms. Durations of the absolute and relative refractory periods (ARP, RRP) and percentages of refractoriness and supernormality at ISIs of 2.6 and 7 ms, respectively, were computed using a subtraction method. The results obtained in the series of DM1 patients were compared to those obtained in six patients with other forms of myotonia and to normative values established in a series of age-matched healthy subjects. Correlations were made between excitability parameters, the number of cytosine–thymine–guanine (CTG) repeats, and the severity of myotonia, scored clinically. Results Compared to controls, DM1 patients presented prolonged durations of ARP and RRP, increased refractoriness and reduced supernormality. The decrease in refractoriness correlated with both the number of CTG repeats and the severity of myotonia. Conclusions Changes in the recovery cycle following supramaximal motor nerve stimulation revealed the existence of subtle alterations of neuromuscular excitability in DM1 patients. Significance Increase in refractoriness together with a reduced supernormality was consistent with a process of membrane depolarization. Such a depolarization may be related to the loss of chloride channels or to alterations in sodium conductance in the motor axon or the muscle fiber.

Recording of muscle velocity recovery cycles (MVRCs) has been developed as a technique to investigate the pathophysiology of muscle diseases. MVRCs have been measured by direct muscle stimulation and concentric electromyographic needle recording. This study was undertaken to determine whether recordings can be made with surface electrodes.MVRCs with 1 and 2 conditioning stimuli were recorded simultaneously with concentric needle and surface electrodes from the brachioradialis muscle in 12 healthy volunteers. Muscle relative refractory period, early and late supernormality, and extra-late supernormality were compared between the recording techniques.Surface recordings were possible in all subjects. The multifiber action potentials recorded with surface electrodes were smaller than those recorded with needles, but there was no significant difference between any of their MVRC properties.MVRCs can be recorded with surface electrodes in healthy subjects. The use of surface electrodes may facilitate the technique of recording MVRCs.

Hyperkalemia is an important cause of membrane depolarization in renal failure. A recent theoretical model of axonal excitability explains the effects of potassium on threshold electrotonus, but predicts changes in superexcitability in the opposite direction to those observed. To resolve this contradiction we assessed the relationship between serum potassium and motor axon excitability properties in 38 volunteers with normal potassium levels. Most threshold electrotonus measures were strongly correlated with potassium, and superexcitability decreased at higher potassium levels (P = 0.016), contrary to the existing model. Improved modelling of potassium effects was achieved by making the potassium currents obey the constant-field theory, and by making the potassium permeabilities proportional to external potassium, as has been observed in vitro. This new model also accounted well for the changes in superexcitability and other excitability measures previously reported in renal failure. These results demonstrate the importance of taking potassium levels into account when assessing axonal membrane dysfunction by excitability testing, and provide evidence that potassium currents are activated by external potassium in vivo.

Schwartz-Jampel syndrome (SJS) is a recessive disorder with muscle hyperactivity that results from hypomorphic mutations in the perlecan gene, a basement membrane proteoglycan. Analyses done on a mouse model have suggested that SJS is a congenital form of distal peripheral nerve hyperexcitability resulting from synaptic acetylcholinesterase deficiency, nerve terminal instability with preterminal amyelination, and subtle peripheral nerve changes. We investigated one adult patient with SJS to study this statement in humans. Perlecan deficiency due to hypomorphic mutations was observed in the patient biological samples. Electroneuromyography showed normal nerve conduction, neuromuscular transmission, and compound nerve action potentials while multiple measures of peripheral nerve excitability along the nerve trunk did not detect changes. Needle electromyography detected complex repetitive discharges without any evidence for neuromuscular transmission failure. The study of muscle biopsies containing neuromuscular junctions showed well-formed post-synaptic element, synaptic acetylcholinesterase deficiency, denervation of synaptic gutters with reinnervation by terminal sprouting, and long nonmyelinated preterminal nerve segments. These data support the notion of peripheral nerve hyperexcitability in SJS, which would originate distally from synergistic actions of peripheral nerve and neuromuscular junction changes as a result of perlecan deficiency.

Myotonia congenita (MC) is caused by congenital defects in the muscle chloride channel CLC-1. This study used muscle velocity recovery cycles (MVRCs) to investigate how membrane function is affected.MVRCs and responses to repetitive stimulation were compared between 18 patients with genetically confirmed MC (13 recessive, 7 dominant) and 30 age-matched, normal controls.MC patients exhibited increased early supernormality, but this was prevented by treatment with sodium channel blockers. After multiple conditioning stimuli, late supernormality was enhanced in all MC patients, indicating delayed repolarization. These abnormalities were similar between the MC subtypes, but recessive patients showed a greater drop in amplitude during repetitive stimulation.MVRCs indicate that chloride conductance only becomes important when muscle fibers are depolarized. The differential responses to repetitive stimulation suggest that, in dominant MC, the affected chloride channels are activated by strong depolarization, consistent with a positive shift of the CLC-1 activation curve.

Andersen-Tawil syndrome (ATS) due to Kir2.1mutations typically manifests as periodic paralysis, cardiac arrhythmias and developmental abnormalities but is often difficult to diagnose clinically. This study was undertaken to determine whether sarcolemmal dysfunction could be identified with muscle velocity recovery cycles (MVRCs).Eleven genetically confirmed ATS patients and 20 normal controls were studied. MVRCs were recorded with 1, 2, and 5 conditioning stimuli and with single conditioning stimuli during intermittent repetitive stimulation at 20 Hz, in addition to the long exercise test.ATS patients had longer relative refractory periods (P0.0001) and less early supernormality, consistent with membrane depolarization. Patients had reduced enhancement of late supernormality with 5 conditioning stimuli (P0.0001), and less latency reduction during repetitive stimulation (P0.001). Patients were separated completely from controls by combining MVRC and repetitive stimulation.MVRCs combined with repetitive stimulation differentiated ATS patients from controls more effectively than the conventional long-exercise test.

We sought to characterize the excitability properties of tibialis anterior (TA) and brachioradialis (BR) muscles at rest and during electrically induced muscle activation in normal subjects.Two centers recruited 10 subjects each. Multi-fiber velocity recovery cycles (VRCs) were recorded from TA (both centers) and BR (one center). VRCs were assessed at rest and during repetitive stimulation (intermittent 20 Hz for 6 min). Changes in latency and peak amplitude of the muscle action potential induced by a frequency ramp to 30 Hz were also characterized.Excitability properties recorded from TA were very similar between centers. Repetitive stimulation generated marked excitability changes, which were similar between TA and BR.Standardized tests of muscle VRCs and responses to repetitive stimulation can provide consistent measures of membrane function and may encourage their wider use in clinical neurophysiology to investigate the pathophysiology of neuromuscular disorders.

This study was undertaken to develop a theoretical model of mouse motor nerve excitability, and to validate it by application to recordings from mouse axons with membrane potential altered by polarizing currents. Multiple excitability tests were performed on the caudal motor nerves of 12 mice. Membrane potential was artificially modified by injecting polarizing currents through the stimulating electrodes (±20% of threshold for 1 ms pulse). A human motor nerve model was adapted to the unpolarized mouse recordings by adjusting membrane parameters to optimize the fit. To evaluate the usefulness of the model, we then determined the parameter changes which best fitted the recordings from depolarized and hyperpolarized tail nerves. The recordings from the normal axons were well fitted by a model in which axons were hyperpolarized by 4 mV, and nodal sodium and slow potassium conductances were reduced by half, compared with human median nerve motor axons. The changes with polarizing currents were qualitatively similar to those in human axons, and modeling correctly identified a change in current as the best-fitting explanation for the altered excitability. We conclude that this new model should help identify changes in membrane potential and probably in other membrane parameters in mouse models of neurological disease.

Non-invasive excitability studies of motor axons in patients with amyotrophic lateral sclerosis (ALS) have revealed a changing pattern of abnormal membrane properties with disease progression, but the heterogeneity of the changes has made it difficult to relate them to pathophysiology. The SOD1(G93A) mouse model of ALS displays more synchronous motoneuron pathology. Multiple excitability measures of caudal and sciatic nerves in mutant and wild-type mice were compared before onset of signs and during disease progression (4-19 weeks), and they were related to changes in muscle fiber histochemistry. Excitability differences indicated a modest membrane depolarization in SOD1(G93A) axons at about the time of symptom onset (8 weeks), possibly due to deficient energy supply. Previously described excitability changes in ALS patients, suggesting altered sodium and potassium conductances, were not seen in the mice. This suggests that those changes relate to features of the human disease that are not well represented in the animal model.

Intravenous immunoglobulin (IVIg) infusions may provide clinical benefits in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). The short delay in the clinical response to IVIg therapy is not consistent with a process of remyelination or axonal regeneration. We assessed whether or not the efficacy of IVIg infusions in MMN and CIDP could reflect changes in axonal membrane properties and nerve excitability. Ulnar motor nerve excitability was studied before and after three to five consecutive days of IVIg infusions (0.4 g/kg/day) in 10 patients with MMN, 10 patients with CIDP, and 10 neurological controls (CTRLs). Excitability recovery cycle, stimulus-response and strength-duration properties were investigated. The recovery cycle parameters (absolute and relative refractory period durations, refractoriness and supernormality) were similar in all groups and did not change after IVIg infusions. At baseline, patients with CIDP, but not with MMN, showed a reduced strength-duration time constant (chronaxie) and increased rheobase when compared to CTRLs. After IVIg infusions, strength-duration time constant remained stable in CTRLs, but decreased in patients with MMN or CIDP. Rheobase increased in the three groups after treatment. The decreased strength-duration time constant after IVIg infusions in patients with MMN or CIDP could reflect a reduction of persistent Na(+) current, able to limit intraaxonal Na(+) accumulation and then to produce neuroprotective effects. However, this could also reflect compensatory mechanisms that did not directly underlie the therapeutic effect. Whatever the underlying process, this result revealed that IVIgs were able to produce early nerve excitability changes.

Non-invasive excitability tests have been developed to appraise axonal membrane properties in peripheral nerves and are contributing to our understanding of neuropathies and neuronopathies. These techniques have been adapted to in vivo and in vitro rat models, but little data are available on mice, although mice provide more transgenic models of neurological disorders. This study was therefore undertaken to assess the suitability of mice to model human nerve excitability measurements and to document changes during maturation. Female mice, aged 4-19 weeks, were recorded under isoflurane anesthesia. Electrical stimuli were applied via surface electrodes to the caudal motor nerve and compound muscle action potentials (CMAPs) recorded from the tail with needle electrodes. Then, the sciatic nerve was stimulated above the ankle and CMAPs recorded from plantar muscles. The method was only minimally invasive, enabling the same animal to be tested up to eight times at weekly intervals. As in human studies, the multiple excitability program recorded stimulus-response, strength-duration, and current-threshold relationships; threshold electrotonus; and recovery cycle. The response waveforms were qualitatively similar to those from human axons. This resemblance was closer for the caudal nerve, which also showed more marked changes with age. Early hyperpolarizing electrotonus fell sharply from weeks 4 to 13 (p < 0.0001), while a progressive increase in superexcitability occurred throughout the period studied (p < 0.001). We conclude that multiple measures of nerve excitability can be performed reliably in mice in vivo, preferentially on the tail, and are suitable for longitudinal studies, but age matching is critical for younger animals.

Epub on http://www.sfet.asso.fr

Inflammatory demyelinating neuropathies can be classified according to the topography of the nervous lesion. Acute and chronic polyradiculoneuritis are characterized by diffuse and multifocal, but predominantly proximal lesions, multifocal motor and sensory-motor neuropathies with persistent conduction blocks are restricted to some nerve trunks, while neuropathies due to monoclonal IgM with anti-MAG (Myelin Associated Glycoprotein) activity show distal and symmetric distribution. The clinical characteristics of inflammatory demyelinating neuropathies vary according to the type of neuropathy. Their course can be remittent or progressive but is especially marked by the risk of definitive axonal lesions, source of permanent neurological deficits. These neuropathies correspond to various mechanisms, which can be differentiated according to the antigenic target, the type of immunological disorder (with respect to cellular or humoral predominance), and the adapted therapeutic strategy. The inflammatory process is accompanied by energetic failure, leading to Na+/K+ pump impairment and intra-axonal Na+ accumulation. This failure results in Na+/Ca2+ exchanger activation, provoking neuronal Ca2+ influx, enzymatic proteolysis and axonal degeneration.

A motor nerve conduction block is defined as a reduction of either amplitude or area of the compound motor action potential elicited by proximal vs. distal motor nerve stimulation. The pathophysiological mechanisms leading to a figure of conduction block include segmental demyelination, recent axonal interruption, or various axonal excitability abnormalities due to ion channel dysfunction or membrane potential changes. These processes can be related to compressive, ischemic or dysimmune inflammatory causes. The etiologic diagnosis is established on the combination of clinical, electrophysiological, and biological data. Among the neuropathies that feature nerve conduction blocks, there is a group of particular dysimmune multifocal neuropathies characterized by long-term persistent conduction blocks, including pure motor forms and sensori-motor forms. The clinical, electrophysiological, biological, and therapeutic specificities of these two types of neuropathy will be discussed.

Objective To study peripheral motor nerve excitability in patients with multiple sclerosis (MS). Methods Twenty MS patients with normal nerve conduction parameters and no predisposing factors for peripheral neuropathy were included. Compound muscle action potentials were recorded from the abductor digiti minimi muscle to paired-pulse stimulation of the ulnar nerve at the wrist, with various interstimuli intervals (ISIs) ranging from 1 to 7 ms. The motor nerve recovery cycle was studied using a subtraction method. We measured the durations of the absolute and relative refractory periods (ARP, RRP) and the percentages of refractoriness and supernormality at 2.6 and 7 ms ISIs. The results obtained in MS patients were compared to normative values established in 20 age-matched healthy subjects. Correlations were made between excitability parameters and MS type (relapsing-remitting or progressive), EDSS score, disease duration, and motor evoked potential (MEP) abnormalities. Results Supernormality was extremely reduced, refractoriness was increased and both ARP and RRP were prolonged in MS patients vs. healthy controls. These alterations did not correlate to clinical features or to the presence of MEP abnormalities. Conclusions Changes in motor nerve recovery cycle revealed the existence of subtle impairment in the peripheral nervous system of MS patients, mainly characterized by a reduced supernormality. Significance Peripheral nerve excitability alterations in MS may be due to axoglial paranodal dysjunction or juxtaparanodal dysfunction.

Objective To compare various techniques of stimulation and methods of analysis to estimate absolute (ARP) and relative (RRP) refractory periods in motor nerve trunks of humans. Methods Double collision (DC) technique and two types of paired pulse (PP) technique, with test stimulation of supramaximal (PP supra ) or submaximal (PP sub ) intensity, were applied to 32 healthy subjects. The ulnar nerve was stimulated either at a single site (wrist) for the PP techniques or at two sites (wrist and elbow) for the DC technique, with various distal interstimuli intervals (ISIs). The elicited compound muscle action potentials (CMAPs) were recorded from the abductor digitorum minimi muscle. The DC technique provided estimates of minimal and maximal ARPs, whereas maximal RRP values were obtained with the PP techniques. Data were analyzed using three methods: a visual reading of the raw ISI–CMAP curves and two computer-aided analyses of the regression curve fitting the ISI–CMAP plots. Pain induced by each technique was assessed on a 0–10 visual analogue scale. A test-retest study was performed with the PP techniques in 12 subjects. Results RP estimates varied with both the stimulation technique and the analysis method. The DC technique was more painful than the PP techniques, but provided shorter and more accurate ARP values, whereas the PP sub technique provided longer, but valid RRP values. Computer-aided methods of data analysis gave the lowest coefficients of test-retest variation. Conclusions Compared to the PP techniques, the DC technique allowed the evaluation of the whole distribution of ARP estimates, not distorted by muscle fiber RPs. For RRP estimation, the PP sub technique can be preferred to the PP supra technique. Finally, computer-aided methods are preferable to analyze ISI–CMAP curves. Significance The distribution of RP estimates can be easily and reliably assessed in whole motor nerve trunks of humans, providing valuable information to assess peripheral nerve excitability.