Critical illness myopathy: further evidence from muscle-fiber excitability studies of an acquired channelopathy

Recent studies have demonstrated acquired muscle inexcitability in critical illness myopathy (CIM) and have used direct muscle stimulation (DMS) techniques to distinguish neuropathy from myopathy as a cause of weakness in the critically ill. The mechanisms underlying weakness in CIM are incompletely understood and DMS is only semiquantitative. We report results from a series of 32 patients with CIM and demonstrate significant slowing of muscle-fiber conduction velocity (MFCV) and muscle-fiber conduction block during the acute phase of CIM, which correlates with prolonged compound muscle action potential (CMAP) duration, clinical severity, and course. We also used a paired stimulation technique to explore the excitability of individual muscle fibers in vivo. We demonstrate altered muscle-fiber excitability in CIM patients. Serial studies help define the course of these pathophysiological changes. Parallels are made between CIM and hypokalemic periodic paralysis. Our findings provide further evidence for muscle membrane dysfunction being the principal underlying abnormality in CIM.     

Correlation between compound muscle action potential amplitude and duration in axonal and demyelinating polyneuropathy

Objective

To get a better understanding of pathophysiology in polyneuropathies (PNPs) by correlating compound muscle action potential (CMAP) amplitude with duration.

Methods

A total of 145 motor nerve conduction studies (MNCS) in 53 axonal and 132 MNCS in 45 demyelinating PNPs were analyzed. Peroneal and tibial MNCS were done by surface stimulation while for median and ulnar nerves near nerve or surface stimulations were used. CMAP amplitude and duration were compared in axonal and demyelination PNPs. Relationships between amplitude and duration of distally and proximally evoked CMAP were examined using regression analysis.

Results

CMAP amplitude was lower and duration was increased in all examined nerves in demyelinating PNPs than in axonal PNPs. In demyelinating PNPs, an inverse linear correlation between amplitude and duration was seen in distally and proximally evoked CMAP in all examined nerves. In axonal PNPs, there was no correlation in any of the nerves neither in distally nor in proximally evoked CMAP.

Conclusions

Distal CMAP duration and the relationship between CMAP amplitude and duration show supplementary electrodiagnostic potential in demyelinating PNPs.

Significance

More knowledge about the relation between amplitude and duration in axonal lesions and demyelination may help to reveal the pathophysiology in PNPs. Significant correlation between amplitude and duration in demyelination may suggest that the severe decrease in amplitude in demyelinating PNPs is probably due to the increase in duration secondary to temporal dispersion.     

Utility of the distal compound muscle action potential duration for diagnosis of demyelinating neuropathies

To assess the significance of distal compound muscle action potential (CMAP) duration for diagnosis of demyelinating neuropathies, electrophysiologic data were reviewed from 471 subjects, including 145 normal controls, 60 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 205 with other neuropathy, and 61 with amyotrophic lateral sclerosis (ALS). The duration of distally evoked CMAP was measured in the median, ulnar, tibial, and peroneal nerves. Optimal cut-off values were calculated with receiver-operating characteristic (ROC) curves. In comparison of normal controls and CIDP patients, ROC analyses showed the sufficient area under the curves (82-93%). When the cut-off values in the detection of demyelination were determined as the point with 98% specificity vs. normal on the ROC curves (median, 6.6 ms; ulnar, 6.7 ms; peroneal, 7.6 ms; tibial, 8.8 ms), the sensitivity was 77% for CIDP, with a specificity of 90% vs. ALS and 95% vs. diabetic neuropathy. The distal CMAP duration is a useful index for the detection of distal demyelination. We suggest the above cut-off values for each nerve as one of the electrodiagnostic criteria for demyelinating neuropathies, preferentially affecting the distal nerve terminals, such as CIDP.     

A European multicentre reappraisal of distal compound muscle action potential duration in chronic inflammatory demyelinating polyneuropathy

Background: The electrodiagnostic value of distal compound muscle action potential duration (DCMAPD) has been studied rarely in chronic inflammatory demyelinating polyneuropathy (CIDP). Cut‐offs proposed have not been widely evaluated. The influence of low‐cut EMG filter settings ≤ 10 Hz as used in Europe is uncertain. Methods: We retrospectively reviewed records of 110 patients with typical, treatment‐responsive CIDP, from Leicester, U.K., Paris and Angers, France. All fulfilled revised European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) clinical and electrodiagnostic criteria for typical CIDP (2010), before consideration of DCMAPD prolongation. Results were compared with those of 110 controls with chronic sensory/sensory‐motor axonal neuropathy. We constructed receiver operating characteristic (ROC) curves for each nerve and derived cut‐offs for DCMAPD prolongation, offering specificity of ≥ 98% vs. controls. Results: DCMAPD was significantly greater in all nerves for CIDP patients, compared with controls (P < 0.001). ROC curves allowed derivation of cut‐offs of sensitivities ranging from 27.1% (ulnar nerve) to 60% (tibial nerve). Using these cut‐offs to define DCMAPD prolongation in any studied motor nerve offered a sensitivity of 69.1% for CIDP and specificity of 97.3% vs. controls. Conclusion: Cut‐offs for DCMAPD are dependent on EMG filter settings. DCMAPD prolongation in any motor nerve, using our derived cut‐offs, represents a sensitive and specific marker of CIDP in patients studied with EMG equipment with low‐cut filter settings ≤ 10 Hz. Appropriate use of this parameter appears an essential criterion to consider in assessing suspected CIDP, which may be helpful in limiting extensiveness and duration of electrophysiological testing, thereby reducing patient discomfort.     

Value of distal compound muscle action potential duration prolongation in acute inflammatory demyelinating polyneuropathy: a European perspective

Introduction: The value of distal compound muscle action potential duration (DCMAPD) has not been widely studied in acute inflammatory demyelinating polyneuropathy (AIDP) with electromyography (EMG) equipment at low‐cut filter settings <10 Hz, as used in Europe. Methods: We retrospectively reviewed the records of 40 patients with AIDP and 40 controls with axonal neuropathy, from Leicester, UK, and Angers, France. Results: The best combination of sensitivity/specificity for AIDP using DCMAPD prolongation in any one nerve was offered by cut‐offs from two other studies (sensitivity: 90% and 87.5%, respectively; specificity: 92.5% for both). Independent DCMAPD prolongation in any one nerve was better than, or equivalent to, other criteria. Conclusions: DCMAPD prolongation in any one nerve, at cut‐offs suggested by prior studies, represents a sensitive and specific marker to aid/simplify electrodiagnosis of AIDP in patients studied with EMG equipment with low‐cut filter settings of <10 Hz. Muscle Nerve, 2011     

Far-field potentials in the compound muscle action potential

It has long been believed that the compound muscle action potential (CMAP) in motor-nerve conduction studies (MCSs) records the action potential beneath the active electrode over the muscle belly. However, recent studies have revealed the contribution of the reference electrode to the CMAP, most prominent in the tibial nerve, followed by the ulnar nerve. This “reference electrode potential” is recorded when the conventional reference electrode distal to the muscle belly is connected to a proximal reference. It must be a far-field potential (FFP) considering its distribution, although the precise mechanism of its generation has not been clarified. The conventional theory of termination of the action potential at the muscle-tendon junction is insufficient. Regarding the ulnar CMAP, interosseous muscles mostly contribute to the FFPs. New understanding of CMAP based on the FFP theory may provide new insights into the interpretation of MCSs and related techniques, including motor unit number estimation.     

Influence of reference electrode position on the compound muscle action potential

ObjectiveWhen 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.MethodsThe 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.ResultsThe 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.ConclusionA 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.SignificanceThe proposed ‘Proximal E2’ montage may be better suited to assess pathology.     

Anatomical and electrophysiological determinants of the human thenar compound muscle action potential

Clinical interpretation of the compound muscle action potential (CMAP) requires a precise understanding of its underlying mechanisms. We recorded normal thenar CMAPs and motor unit action potentials using different electrode configurations and different thumb positions. Computer simulations show that the CMAP has four parts: rising edge, negative phase, positive phase, and tail, which correspond to four distinct stages of electrical activity in the muscle: initiation at the end-plate, propagation, termination at the muscle/tendon junctions, and slow repolarization. The shapes of volume-conducted signals recorded beyond the muscle are also explained by these four stages. Changes in CMAP shape associated with thumb abduction are due to changes in termination times resulting from changes in muscle-fiber lengths. These findings demonstrate that the negative and positive phases of the CMAP are due to different mechanisms, and that anatomical factors, particularly muscle-fiber lengths, play an important role in determining CMAP shape. © 1996 John Wiley & Sons, Inc.     

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. Muscle Nerve 53 : 555–563, 2016     

Critical illness myopathy serum fractions affect membrane excitability and intracellular calcium release in mammalian skeletal muscle

Abstract. The pathogenesis of myopathies occurring in critically ill patients (critical illness myopathy, CIM) is poorly understood. Both local and systemic responses to sepsis and other severe insults to the body are presumed to be involved but the precise mechanisms by which muscle function is impaired are far from clear. To elucidate such mechanisms we investigated the effects of blood serum fractions (5 kDa to 100 kDa molecular weight cut-off, MWCO) from patients with CIM and from control persons on membrane and contractile functions in intact mammalian single skeletal muscle fibres and chemically skinned fibre bundles. In intact fibres, resting membrane potentials were less negative when exposed to CIM serum fractions compared with control serum fractions. Half-width and maximum rise time of action potentials (AP) were smaller in CIM serum low MWCO fractions vs. control serum. Peak amplitudes of fast inward sodium currents (I_Na) were increased by low MWCO-CIM fractions compared with control sera fractions. Additionally, voltage dependent inactivation of I_Na was shifted towards more positive potentials by high MWCO fractions of CIM sera. In skinned fibres, pCa-force relations were similar in CIM and control serum fractions but peak force of Ca²⁺ induced force transients was decreased by low MWCO-CIM vs. control serum fractions. Our results (i) provide the first evidence that serum from CIM patients affects membrane excitability and the excitation-contraction coupling process at the level of the sarcoplasmic reticulum Ca²⁺ release of mammalian muscle fibres and (ii) also show that even control serum fractions per se alter the response to important physiological membrane and contractility parameters compared with physiological saline.     

Possible role for nitric oxide dysregulation in critical illness myopathy

Muscle fiber inexcitability and myosin loss underlie weakness in critical illness myopathy (CIM). Nitric oxide (NO) takes part in the maintenance of muscle fiber resting potential and, in pathological conditions accompanied by oxidative stress, may damage proteins through peroxynitrite generation. Sepsis and other conditions associated with CIM may differentially affect expression of NO synthases (NOSs), so that both downregulation and upregulation with excessive peroxynitrite production can be hypothesized. In six patients with CIM we studied NOS1, NOS2, and NOS3 protein expression by immunohistochemistry and Western blot. To investigate peroxynitrite production, we performed immunohistochemistry for nitrotyrosine and measured nitrotyrosine levels by enzyme-linked immunosorbent assay. In three patients, sarcolemmal staining for NOS1 was selectively absent. In the others, it was absent in atrophic fibers and absent or reduced in non-atrophic fibers. Total NOS1 protein content was reduced by 41% in patients compared to controls, whereas no significant changes were found in levels and localization of NOS2, NOS3, and nitrotyrosine. Further studies are warranted to determine whether NOS1 loss plays a role in the pathophysiology of CIM, possibly reducing the release of NO at the sarcolemma and affecting muscle fiber excitability.     

Contribution of reference electrode to the compound muscle action potential

In compound muscle action potential (CMAP) recording, the contribution by the reference electrode is considered to be much smaller than that of the active electrode. We tested this assumption by making quantitative measurements of the signals recorded individually by the active and reference electrodes. In the thenar (median nerve) and extensor digitorum brevis (peroneal nerve) muscles, the reference electrode did contribute less. In the hypothenar muscle (ulnar nerve), however, the signals recorded by active and reference electrodes were of similar amplitude. In tibial nerve conduction studies (NCS), the CMAP from the abductor hallucis (AH) muscle was recorded mainly by the reference electrode; the large-amplitude signal recorded by the reference electrode is attributed to volume-conducted activity from other muscles stimulated during the study. The onset latency of the potential recorded by the active and reference electrodes was similar despite significantly different distances from the stimulating site. Hence, the merits of using anatomic landmarks for defining the distal stimulation site are assessed. When the reference electrode makes a large contribution, the CMAP amplitude may not decrease commensurate with any wasting of the muscle under the active recording electrode, and the need to use another muscle for recording the CMAP for that nerve should be considered.     

Comparison of single-fiber and macro electrode recordings: Relationship to motor unit action potential duration

The factors contributing to the duration of a motor unit action potential (MUAP) are believed to be well known, with both manual measurements and computer simulations agreeing with respect to MUAP durations approaching 10 ms. In this investigation, it is clearly demonstrated that use of a wide-open amplifier bandpass combined with signal-to-noise ratio enhancement results in MUAP durations approaching 30 ms recorded with either a macro or single-fiber electrode. Why the clinically recorded MUAP duration differs significantly from these physiologic durations is discussed. A hypothesis is presented whereby the major contributing factor toward MUAP duration is the total time of action potential transmembrane current flow along the muscle fiber from end-plate zone to musculotendinous junction. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1381–1388, 1997     

Neuromuscular manifestations of critical illness

Critical illness, more precisely defined as the systemic inflammatory response syndrome (SIRS), occurs in 20%-50% of patients who have been on mechanical ventilation for more than 1 week in an intensive care unit. Critical illness polyneuropathy (CIP) and myopathy (CIM), singly or in combination, occur commonly in these patients and present as limb weakness and difficulty in weaning from the ventilator. Critical illness myopathy can be subdivided into thick-filament (myosin) loss, cachectic myopathy, acute rhabdomyolysis, and acute necrotizing myopathy of intensive care. SIRS is the predominant underlying factor in CIP and is likely a factor in CIM even though the effects of neuromuscular blocking agents and steroids predominate in CIM. Identification and characterization of the polyneuropathy and myopathy depend upon neurological examination, electrophysiological studies, measurement of serum creatine kinase, and, if features suggest a myopathy, muscle biopsy. The information is valuable in deciding treatment and prognosis.