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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. Muscle Nerve, 2007
Muscle weakness is common in the intensive care unit (ICU). The differential diagnosis includes critical illness myopathy (CIM) or polyneuropathy (CIP), demyelinating or axonal forms of Guillain–Barré syndrome, neuromuscular junction disorders, and central causes. The acquired neuromuscular disorders frequently present as difficulty in weaning from a ventilator and diffuse flaccid weakness. Clinical examination in the ICU is often a poor differentiator between myopathic and neurogenic causes, and both can be associated with spontaneous activity on needle electromyography (EMG) and reduced amplitude of the compound muscle action potential (CMAP) on motor nerve stimulation. Careful sensory examination is also often not possible and sensory nerve action potentials (SNAPs) may be difficult to obtain due to edema and other factors in the critically ill. Voluntary recruitment is often absent or limited, making motor unit potential analysis difficult or impossible. Furthermore, low-amplitude polyphasic motor unit potentials may be seen in both myopathy and early reinnervation.
Debate has continued with respect to the primary process in critical illness quadriplegia. Muscle-fiber inexcitability in CIM has been demonstrated in animal models and by means of direct muscle stimulation (DMS) in humans.32, 33 Although only semiquantitative, this technique has subsequently been used to distinguish between neuropathy and myopathy in the ICU in several studies.2, 25, 33, 43 It relies upon measuring the ratio of the CMAP amplitude obtained from nerve-mediated stimulation of a muscle and direct stimulation of the same muscle. However, this approach has potential pitfalls, one of them being that the ratio will diagnose a myopathy in normal muscle.
Bolton and others have noted a decline in amplitude and increase in duration of CMAPs in early CIM, suggesting primary dysfunction of the muscle-fiber membrane.5, 9, 31 Although not the main emphasis of the investigation, one previous study has reported evidence of slow muscle-fiber conduction velocity (MFCV) in CIM.43 The investigators did not draw particular attention to this finding, considering it secondary to fiber diameter reduction; however, they did demonstrate concurrent muscle inexcitability, by means of reduced DMS CMAP amplitudes. The interrelationships between CMAP parameters, particularly duration, MFCV, and individual muscle-fiber excitability in vivo, have not been studied previously.
The prime objective of this study was to determine whether there is dysfunction at the level of the muscle membrane in human CIM. We aimed to study the excitability characteristics of single muscle fibers in vivo as well as to correlate these with CMAP parameters and clinical findings.
PATIENTS AND METHODS
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- PATIENTS AND METHODS
We studied 32 patients with CIM, with an average age of 49 years. Patients were assessed clinically and underwent neurophysiological examination including nerve conduction studies, routine EMG, and repetitive nerve stimulation at ICU bedside.
Patients diagnosed with CIM fulfilled the following criteria: acute severe illness; acute quadriplegia or quadriparesis; and no evidence of alternative diagnosis. Electrophysiologically, patients had normal SNAPs and motor conduction velocities, small CMAP amplitudes, and EMG findings consistent with a myopathy or electrically inactive muscle. Patients with electrophysiological findings consistent with other disorders were excluded.
We had no histological data, so accordingly, where the clinical and electrophysiological findings were consistent with a probable diagnosis of CIM in line with the proposed criteria,22 we extended the examination, when possible, to study MFCV and muscle-fiber excitability. Lacomis et al. suggested that evidence of muscle inexcitability might replace histological evidence.22 Patients were classified broadly into two categories according to their overall muscle power, taken as an average. Patients who were able to move limbs against gravity at grade 3 or better on the Medical Research Council (MRC) scale were classified as having mild–moderate weakness. Those who had no movement of limbs or who could only move with gravity eliminated (MRC grade 2) were classified as having severe–very severe weakness.
We used the technique for calculation of muscle-fiber conduction velocity as described by Troni et al.45 DMS of tibialis anterior (TA) muscle fibers with a monopolar needle was performed in 7 patients (age 14–71 years) and in 5 control subjects (age 25–35 years) who had no known neuromuscular disease. This muscle was chosen specifically because of its size, accessibility, longitudinally orientated muscle fibers, and the eccentric location of the endplate in relation to the muscle belly. Other muscles were therefore not studied with this technique for these reasons.
The endplate zone of the muscle was identified using liminal surface stimulation, so this region was avoided. A monopolar stimulating needle electrode (26G, surface area 0.34 mm2; Teca, Oxford Instruments, Old Woking, UK) was placed approximately at the junction of the proximal two thirds with the distal one third of the TA muscle belly. A concentric recording needle electrode (26G; Teca, Oxford Instruments, Old Woking, UK) was then inserted 50 mm proximally. Both needles were inserted to a depth of about 20 mm perpendicular to the skin surface and maintained in a perpendicular position by taping the looped electrode leads to the skin surface. A surface ground electrode was placed between the needles and a surface anode electrode was placed 30 mm distal to the monopolar needle (Fig. 1). Fine needle manipulation and variation of the stimulus strength resulted in recording a complex of multiple single muscle-fiber action potentials (MFAPs) (Fig. 2). Responses earlier than 8 ms were likely to be conducted via intramuscular nerve twigs and were not included.11 Sequential sweeps were recorded to demonstrate that the responses were stimulus-induced, all-or-none, stable, and reproducible. The technique took approximately 20–60 minutes to perform. Responses were frequently acquired with stimulation at low intensity, typically between 1 and 3 mA (with stimulus duration of 0.1 ms). Muscle-fiber action potentials were recorded using filter settings between 500 HZ and 10 kHZ. The needle was repositioned along the 50-mm arc to exclude variable muscle-fiber alignment in case of lack of response. If still no response was seen at an interelectrode distance of 50 mm, the recording electrode was moved toward the stimulating electrode (to a measured distance between 20 and 30 mm). If after repositioning no responses were obtained, the muscle was assumed to be inexcitable. The latency to each muscle-fiber action potential was measured and MFCV calculated. The ratio of the fastest to the slowest MFCV was also determined. The ambient temperature in the ICU and the use of thermal blankets ensured that the limbs tested were warm. Hence, temperature was not measured routinely.
Figure 2. Multiple muscle-fiber action potentials obtained by DMS and recording with a concentric needle placed at a 50-mm distance.
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We assessed muscle-fiber excitability in 7 patients and 5 normal controls using a paired stimulus protocol to measure muscle-fiber absolute refractory period. We used the same electrode arrangement and further manipulated needle tip positions (by rotational and depth movements) and reduced stimulus intensity in order to obtain a single, stable, and well-defined muscle-fiber action potential. Paired stimuli were applied and the interstimulus interval (ISI) was then reduced in a stepwise fashion, to predetermined intervals of 20, 10, 8, 6, 5, 4, 3, and 2 ms. The effect on the second response was observed (Fig. 3). By a bracketing procedure, the refractory period was measured where possible to the nearest 0.1 ms.
Figure 3. Single muscle-fiber action potential response to paired stimuli. The top trace is the response to a single stimulus and below are responses to paired stimuli at intervals of 20, 10, 8, 6, 5, 4, 3, 2.5, and 2 ms, respectively. Note: The second action potential is absent at an ISI of 2 ms.
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CMAP duration in the abductor pollicis brevis (APB) and abductor hallucis (AH) muscles from supramaximal stimulation of the median and posterior tibial nerves, respectively, was measured as the interval between CMAP onset and the first zero crossing. CMAP parameters were measured in 26 patients and in 27 age-matched controls. Although care was taken to obtain data from these two chosen muscles, in 6 patients the CMAP data were not available for the aforementioned muscles. This was due either to inexcitability (2 patients) or inaccessibility (4 patients) due to dressings, vascular access, and other obstacles. Although it might have seemed prudent to measure CMAP parameters from TA, the considerable variability in normal responses and the often-present initial positive component would make such measurements unreliable. Furthermore, stimulation near the fibular head might inadvertently result in direct muscle stimulation, and more proximal stimulation of the peroneal nerve is unreliable.
We used unpaired t-tests to compare nerve conduction data and MFCVs. Non-parametric Mann–Whitney U-tests were used for comparing results of excitability studies.
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In this study we have demonstrated dysfunction at the level of the muscle-fiber membrane in CIM. We found a significant reduction in MFCV in CIM muscle, which correlates inversely with significant prolongation of the surface-recorded CMAP duration. We also found that muscle-fiber excitability is affected in CIM.
CIM and CIP were both first described over 20 years ago.13, 28 Both have been reported with a relatively high incidence in ICU patients.8, 14, 17, 21, 49, 51 In a series of 92 patients with neuromuscular disorders in the ICU, a myopathy consistent with CIM was three times as common as axonal polyneuropathy (42% vs. 13%).21 Severe illness in itself can cause acute quadriplegic myopathy.40 Neither sepsis nor multiorgan failure is a prerequisite to developing CIM.19 Mortality rates of 50% have been reported.8 In our series, mortality was 38%, usually as a consequence of the underlying illness. When biopsies are performed, CIM patients have clear histological evidence of myopathy, in the presence of normal nerves.25, 38 It is possible that some patients have a “neuromyopathy.” Differentiating muscle disease from a pure motor neuropathy is challenging and relies on direct demonstration of muscle dysfunction. There is dispute over which are the most useful tests to distinguish CIM and CIP.44
Nerve and muscle biopsy, including electron microscopy, can aid in the differentiation of CIP from CIM, revealing normal peripheral and intramuscular nerves and selective loss of myosin in CIM.20, 21, 23, 24, 29, 38 However, this is frequently neither available nor practical in most ICUs. Myosin loss in itself cannot explain muscle inexcitability, and myosin loss itself lags behind the development of weakness.40, 50 Calpains may increase degradation of myosin filaments and show enhanced expression in CIM muscle biopsies.40 Additionally, severe illness, sepsis, glucocorticoid therapy, and paralysis also stimulate muscle protein catabolism.37 Weakness in CIM can develop very rapidly but can also show rapid improvement. Despite rapid early improvement, however, recovery can be prolonged. Severe CIM paralysis may result in greater muscle protein loss, and regaining ambulation after CIM may take several months,8 presumably in part due to secondary muscle atrophy. Atrophy is a likely consequence of the systemic illness but cannot account for the sudden onset of paralysis or the electrical inexcitability of the muscles. Secondary atrophy, however, is likely and is commensurate with the delayed recovery and chronically reduced MFCV, reflecting the now smaller muscle-fiber diameter.
Although serum CK may be elevated, it is frequently normal or only mildly increased in CIM. In the recent study by Lefaucheur et al.,25 when the single patient with a serum CK of 12,000 IU/L was excluded, most patients with pure or predominant myopathy had an average CK of 127 IU/L, with a range of 17–700 IU/L. It appears that an elevated serum CK should be considered a supportive but not a major diagnostic finding.22 Coexistent scattered necrosis has been noted in CIM muscle biopsies.8, 24 It is likely that this causes the increased serum CK observed in some CIM cases. This, in turn, is probably related to critical illness as opposed to primary muscle pathology. In the present series, the serum CK elevation was disproportionately low relative to the degree of weakness. This further supports the notion that weakness is due to muscle-fiber membrane dysfunction and not to structural muscle changes at onset. Subsequent structural changes may occur due to changes at the level of the muscle-fiber membrane and other factors.
Some investigators suggested that myopathic-appearing motor units, associated with an often nearly normal serum CK, could be due to a distal axonopathy,50 an argument potentially supported by abnormal single-fiber EMG findings.39 These findings, however, could also be explained by abnormalities of the postsynaptic membrane. Normal intramuscular nerves have been demonstrated on biopsy.22 MUP duration analysis in CIM has indicated myopathic changes, whereas mean MUP amplitudes, quantitative electromyography, and motor unit number estimates were within normal limits in one study.43 In common with other acquired muscle disorders, the pathology is likely to be diffuse, affecting most skeletal muscles, but patchy in any given muscle. This would explain why some fibers are nearly normal but others are very abnormal with respect to MFCV and excitability.
Direct intramuscular stimulation of muscle fibers is not a new technique.6, 32, 41, 45, 53 Rich et al. reported that the motor nerve stimulation (MNS)/DMS ratio was useful in distinguishing myopathy and neuropathy in ICU quadriplegia.33 A ratio of >0.5 was associated with myopathy. Others have also used the DMS technique to distinguish myopathy and neuropathy.2, 25, 43 However, there are potential disadvantages to DMS. The whole muscle is not necessarily stimulated and the CMAP amplitudes used in the calculation are likely derived from unequal or different muscle-fiber populations. The results are semiquantitative, only indirectly demonstrating dysfunction of muscle. DMS also has limited utility in mildly affected patients, as only large changes in amplitude can be detected and there is a lack of normative data in ICU controls. A high ratio will not distinguish between abnormal and normal muscle.
Estimation of MFCV using methods based on voluntary contraction will be biased toward the slowest fibers, which are recruited first.1 However, invasive MFCV study is a relatively easy technique to perform, provides objective, quantitative results, and has been found to be more sensitive than surface EMG measurement in hypokalemic periodic paralysis (HPP) carriers.48 Using an invasive method, Troni et al. found normal values of MFCV to be 3.53–4.24 m/s (male) and 2.96–3.74 m/s (female).45 Also, using an invasive technique, normal values of 2.6–5.3 m/s (mean 3.7) were reported specifically for the TA muscle.1 Our normal control data agree, providing a mean of 4.0 m/s, with a range of 3.0–5.5 m/s. Trojaborg et al. used an invasive DMS technique to measure the MFCV and the evoked response amplitude. MFCV was 30% lower in 5 CIM patients compared with controls (4.5 ± 0.2 m/s vs. 6.4 ± 0.3 m/s).43 Although their study showed a relative difference between these two groups, the absolute MFCV values were higher than those reported by us and others for controls and by us for CIM patients. This may reflect technical differences in measurement and possibly differences in the spectrum of CIM severity assessed.
The technique used could introduce error in the form of interelectrode distance variation. Although inserted at a measured distance (usually 50 mm), needle angulation within the tissues could result in the needle tips being closer together or further apart than the surface measurement. We estimated that, on visual inspection, a 5-degree angle of the needle could be missed and not corrected by re-placement. This would result in a 4% shortening of the distance (4% of 50 mm) with needle insertion to a depth of 20 mm. If both needles were angulated their relative separation would be reduced or exaggerated by approximately 8%. If it was assumed that this effect overestimated MFCV by 8% for all control subjects and underestimated the MFCV by 8% for all patients, we calculated that the new mean for controls would be 3.84 m/s (SD 0.23) and for patients would be 2.56 m/s (SD 1.17). This difference would still reach a statistically significant level (P = 0.0278). This scenario is, however, unlikely as we took care to maintain perpendicular needle positions during the studies.
Reduced MFCV values can be obtained from histologically normal muscle, such as in HPP.11, 46 Small atrophic fibers would be expected to show a reduced MFCV,3 but the commonly observed rapid deterioration and resolution as seen in CIM would not be expected if atrophy were the cause. Furthermore, the degree of slowing is greater than that found in other myopathies, which is further evidence of sarcolemmal dysfunction. Inaccuracy of MFCV calculation could result from uncertainty regarding the site of muscle-fiber activation. However, evidence suggests that, with weak stimulation, muscle fibers are activated at discrete low-threshold sites close to the needle tip.47 In the presence of a normal nerve and neuromuscular junction, the amplitude of MUPs can be affected by dispersion between action potentials of fibers in single motor units, amplitude decline of a single fiber action potential due to a decrease in MFCV, and blocking of action potentials.13 We believe that all three of these mechanisms may play a role in CIM. We found in several patients that muscle fibers were unable to conduct action potentials over the standard 50-mm distance. They were, however, able to conduct action potentials over shorter distances, albeit at reduced velocities, suggesting that there might be conduction block along muscle fibers. This finding has not been described prior to our study, at least to our knowledge.
With respect to the excitability of normal human muscle fibers, a few studies have found a mean absolute refractory period of 4.12 ms (range 2.69–8.13 ms) and a relative refractory period of 5.99 ms (2.88–12.40 ms).30 Our data fall within these limits, with our mean normal absolute refractory period being 2.5 ms and that for patients tending to be higher at 4.7 ms, notably above the normal mean for the other studies. The method used by us is likely to stimulate the fibers close to the stimulating electrode with the lowest threshold for activation. This technique may therefore underestimate the degree of inexcitability of muscle fibers in close proximity to the needle tip, as the most inexcitable fibers may simply not be activated.
Trojaborg et al. recently highlighted previous studies showing CMAP prolongation in CIM.44 One patient with histologically confirmed CIM had normal intramuscular nerves and marked CMAP prolongation. The smoothly outlined but prolonged CMAPs were thought to be due to slowing of MFCV, as a result of impairment or blockade of voltage-gated ion channels, although this was not demonstrated.9 Another study of 9 possible CIM cases revealed prolonged CMAP duration, again with smooth and synchronous waveforms. The investigators suggested that this observation might be useful as a simple diagnostic test.31 However, those findings could not be replicated in a subsequent study,43 perhaps reflecting milder CIM severity. As we have shown, abnormalities in CIM, namely reduced MFCV and prolonged CMAP duration, are inversely correlated and related to the clinical severity and clinical phase of the illness.
The smooth contour of the markedly prolonged CMAP probably reflects the synchronous depolarization of muscle fibers, which are not only slowed but also have a wider-than-normal distribution of MFCV. Another feature seen in these patients is that the positive phase of the CMAP is often prolonged or even replaced by a long “tail” of the negative phase. This is probably the effect of the few muscle fibers within the diseased muscle with markedly slowed conduction velocities (Fig. 4). However, altered membrane repolarization dynamics, as part of the overall membrane dysfunction, may also contribute. CMAP measurements represent the whole muscle and, although the MFCV studies sample only a very small proportion of fibers within a single muscle, it is logical that these findings are complementary.
In vitro studies have shown that serum fractions from patients with CIM affect the excitability of intact muscle-fiber membranes and calcium release from the sarcoplasmic reticulum.15 Rich and Pinter demonstrated that depolarization of the resting membrane potential and a hyperpolarizing shift in the voltage dependence of sodium-channel gating is the principal factor underlying inexcitability in an animal model of CIM. In their model, depolarization of the resting membrane potential following denervation was one of the most important factors because it increased inactivation of sodium channels.35, 36 In the critically ill, denervation may not be a prerequisite, as the resting membrane potential may be reduced (depolarized) due to raised intracellular sodium, possibly due to a generalized cellular dysfunction related to critical illness.10 In vitro intracellular recording of individual muscle fibers by Rich and Pinter showed failure of muscle fibers to generate action potentials when stimulated electrically, possibly due to reduced sodium current.34 Sodium-channel dysfunction in the muscle-fiber membrane can lead to inexcitability and is well known in type 2 HPP, which is associated with SCNA4 mutations.7, 42 These mutations also result in enhanced inactivation and reduced current through the muscle sodium channel.18
Drawing parallels between CIM and HPP may help to define the pathophysiology of CIM and also offer common therapeutic opportunities. In HPP, surface recordings between attacks revealed reduced MFCV.52 Sensory and motor nerve studies between attacks are normal as are needle EMG findings, although chronically some may develop myopathic changes.16 During a paralytic attack the CMAP amplitude declines secondary to muscle-membrane inexcitability52 and invasive recordings show low MFCVs (mean 2.0, range 0.9–3.0 m/s), which improves within hours to days.27 Early during an attack, fibrillation potentials are evident, indicating depolarized muscle membranes.16 Single-fiber EMG during an attack shows an increase in jitter and occasional potential blocking, but there is no jitter between attacks.12, 52 Troni et al. reported that DMS in one patient was not possible for a long period during recovery from paralysis. Muscle showed near electrical silence during paralysis. When power increased to MRC grade 3 in biceps, the MFCV was still slow at 1.7 m/s.46 In HPP, paralysis is caused by membrane depolarization triggering sodium-channel inactivation, rendering the muscle membrane inexcitable.26 In CIM, a similar shift in membrane potential, due to critical illness and perhaps serum factors,15 may contribute to sodium-channel inactivation and a similar pattern of pathophysiology. Depolarization of the muscle membrane initially gives rise to spontaneous activity, and slowed MFCV; as this progresses, conduction block ensues, and finally the fibers become inexcitable.
“Synchronized dispersion” of the CMAP, in contrast to the well-known asynchronous dispersion seen in demyelinating neuropathy is, we suggest, a characteristic feature of CIM. We agree with previous studies that monitoring of this is simple to perform and may be useful for diagnosis. It may also predict recovery but requires further systematic study. The techniques used for MFCV and excitability measurement are technically demanding. They are powerful research tools but are unlikely to become standard diagnostic testing techniques. Our experience suggests that CIM is more common than CIP and that there is a spectrum of severity within CIM. Some patients are moderately weak, have characteristic neurophysiological changes, and improve quickly. Other patients have more profound weakness, which requires a longer recovery period. These patients have inexcitable muscles, reduced MFCV, and predictable CMAP abnormalities. In CIM, changes at the level of the muscle-fiber membrane correlate with CMAP parameters and the clinical phases.