- Research article
- Open Access
Voluntary activation failure is detectable in some myositis patients with persisting quadriceps femoris weakness: an observational study
Arthritis Research & Therapy volume 8, Article number: R67 (2006)
This cross-sectional, observational study was undertaken to examine whether voluntary activation failure could contribute to the persisting weakness observed in some patients with treated idiopathic inflammatory myositis. In 20 patients with myositis of more than six months' duration (5 males, 15 females; mean [± 1 SD] age 53  years) and 102 normal subjects (44 males, 58 females; mean age 32  years), isometric maximum voluntary contractions (MVCs) of the dominant quadriceps femoris (QF) were quantified. Absolute MVC results of normal subjects and patients were then normalised with respect to lean body mass (force per units of lean body mass), giving a result in Newtons per kilogram. Based on mass-normalised force data of normal subjects, patients were arbitrarily stratified into "weak" and "not weak" subgroups. During further MVC attempts, the "twitch interpolation" technique was used to assess whether the QF voluntary activation of patients was complete. This technique relies on the fact that, because muscle activation is incomplete during submaximal voluntary contractions, electrical stimulation of the muscle can induce force increments superimposed on the submaximal voluntary force being generated. No between-gender differences were seen in the mass-normalised MVC results of healthy subjects, so the gender-combined results of 6.6 (1.5) N/kg were used for patient stratification. No between-gender difference was found for mass-normalised MVCs in patients: males 5.4 (3.2) and females 3.0 (1.7) N/kg (p > 0.05). Mass-normalised MVCs of male patients were as great as those of normal subjects (p > 0.05), but mass-normalised MVCs of female patients were significantly smaller than those of the normal subjects (p < 0.001). Only one of the six "not weak" patients exhibited interpolated twitches during electrical stimulation, but six of the 14 "weak" patients did, the biggest twitches being seen in the weakest patient. That interpolated twitches can be induced in some myositis patients with ongoing QF weakness during supposed MVCs clearly suggests that voluntary activation failure does contribute to QF weakness in those patients.
Polymyositis (PM) and dermatomyositis (DM) are the idiopathic inflammatory myositis subtypes most often treated by rheumatologists [1, 2]. Corticosteroids and immunosuppressive drugs remain the mainstay of treatment , but the response to these agents is often disappointing, so chronic weakness and disability may persist despite treatment [3, 4]. In chronic, end-stage myositis, in which muscle wasting may be radiologically and even clinically obvious, weakness may be explained by loss of muscle mass which, once established, often appears irreversible. In the early acute phase of myositis, when muscle histology might demonstrate the characteristic infiltration by T cells and macrophages, with secondary muscle fibre damage and myonecrosis , weakness is often at its most severe. Because early weakness usually improves with treatment, albeit to a variable degree, it has traditionally been assumed that muscle weakness prior to treatment results from inflammatory processes, although the actual mechanisms responsible for inflammatory weakness induction remain unelucidated. In treated myositis, recovery of strength is often incomplete, even though radiological and histological evidence suggests that inflammation has been suppressed. Here, especially in the absence of obvious wasting, persisting weakness is harder to explain. Thus, it is also increasingly recognised in myositis that any correlation between the observed weakness of a muscle and the degree of its inflammatory cell infiltration at biopsy may be very poor [6, 7]. These discussions clearly suggest that mechanisms other than those related to inflammation are implicated in weakness induction in myositis . Indeed, many recent studies present compelling evidence that abnormalities of energy metabolism [9, 10], possibly due to disruption of local microcirculation , as well as cytokine dysfunction [12–14], are likely involved in weakness induction. More recently still, in murine and human myositis, activation of the endoplasmic reticulum stress response has been demonstrated as another, self sustaining, nonimmune mechanism capable of inducing skeletal muscle cell dysfunction and loss in myositis . These nonimmune myositis-induced abnormalities would all likely cause muscle weakness by disrupting contractile function.
Although the importance of these recent findings in terms of understanding nonimmune-mediated weakness induction in myositis is obvious, there are other mechanisms that may be important and that have not been investigated to date. Skeletal muscle weakness can result from a defect at any step in the neuromuscular command chain governing contraction . In general, however, weakness is termed "central" if due to a defect prior to the neuromuscular junction or "peripheral" if due to a defect beyond the junction . Applying such principles in myositis, inflammatory damage to the muscle membrane and contractile apparatus itself would obviously cause peripheral dysfunction. Abnormalities of the spinal cord, anterior horn cells, and peripheral nerves are not part of the usual clinical spectrum of myositis, so all appear unlikely causes of central dysfunction. However, other central factors such as insincerity of effort due to poor motivation/perceived illness, or pain inhibition due to myalgia, could theoretically contribute to weakness in myositis. In addition, reflex inhibition is a possibly relevant mechanism. It is well recognised clinically that acute knee joint pathologies cause rapid quadriceps femoris (QF) weakness and wasting. It has also been shown that acute iatrogenic knee joint effusions cause QF weakness [17, 18], which can be prevented if the joint is rendered insensate by local anaesthetic co-injected with the iatrogenic effusion . It was thus concluded that acute joint knee pathologies, including iatrogenic effusions, cause QF weakness by stimulating joint afferents, which reflexively inhibit anterior horn cell function and thereby reduce QF motor activation and cause "arthrogenous" QF weakness . In an analogous fashion, it seems theoretically plausible in myositis that inflammatory cell infiltrates could stimulate muscle afferents and similarly inhibit anterior horn cell function. The result would be "myogenous" weakness. The possibility that central activation failure from motivational problems and/or reflex inhibition could be responsible for weakness induction in myositis has never been assessed. This study of patients with myositis was therefore undertaken to examine the completeness of central activation during maximum voluntary contractions (MVCs) of QF.
Materials and methods
Patients with myositis
Twenty patients (15 females and 5 males) with adult (onset at or after 18 years) myositis, defined as definite according to the Bohan and Peter diagnostic criteria , were recruited into this observational, cross-sectional study, which was approved by the local ethics committee. Nine patients had PM, 5 had DM, and 6 had PM as part of a connective tissue disease overlap. Their mean age (± 1 SD) was 53 (11) years, and their mean myositis disease duration was 5.6 (3.9) years (Table 1). Current disease status of patients was assessed using the standard clinical tools available in the outpatient setting (that is, the results of "extended" manual muscle testing [MMT]  and circulating creatinine kinase [CK] and C-reactive protein [CRP] levels). Lower limb magnetic resonance imaging (MRI), QF muscle biopsy by conchotome , and needle electromyography (EMG) were not specifically used in this study to assess disease activity, but if any of these procedures had been undertaken for clinical reasons in the previous six months, their results were obviously used during disease assessments. According to the results of these clinical parameters, and based on "intention to treat" principles, patients' myositis disease activity and damage status was "guestimated" (Table 2). This simple scoring system was used because, although international efforts to develop comprehensive disease activity and damage assessment tools are in an advanced state of development [24, 25], work validating these tools is still ongoing [26, 27], and international consensus on their final versions is awaited. Patients' clinical details and disease activity and damage guestimates at the time of their recruitment are summarised in Tables 1 and 3. Patients suffering current QF myalgia were excluded because this could have caused weakness through pain inhibition. Patients with symptoms or signs of knee joint pathologies, such as osteoarthritis, that could cause arthrogenous QF weakness were also excluded.
Forty-four normal males (32.4 [7.9] years old) and 58 normal females (28.5 [6.8] years old) were recruited from hospital medical and nonmedical staff. Considerable efforts to age-match these subjects with the myositis patients were made, but older staff proved difficult to recruit; as a result, the normal subjects were significantly younger than the patients (p < 0.001). However, this age difference was not considered problematic, because it was known already from MMT results that many of the patients were weak, and the rationale for testing normal subjects was not to make direct comparisons with patients regarding QF force results. Instead, the aim of using normal data was to set a mass-normalised QF MVC limit below which patients' results could arbitrarily be defined as "weak" or "not weak." As with patients, normal subjects were excluded if they had any symptoms or signs of knee joint pathologies.
Measuring lean body mass, QF MVC, and mass-normalised MVC
In patients and normal subjects, lean body mass (LBM) was derived from skin-fold thickness measurements using well validated methods  before MVCs of their dominant QF muscle were measured on a standard isometric strain-gauge test-chair, based on the design of Edwards and Hyde [29, 30]. Because MVCs are rarely used during normal daily activities, patients and normal subjects were first familiarised with MVC force generation. To avoid subsequent fatigue effects on the test day results, this was undertaken 1 week prior to formal MVC testing. During MVC testing, subjects sat upright on the test chair, with knees and hips set at 90 degrees. An inextensible band, velcro-fastened securely around the ankle proximal to the malleoli, connected subjects to the force transducer. The transducer output was amplified and simultaneously recorded on a chart recorder, and a custom-built monitor displayed the attained force in Newtons. A restraining belt was also velcro-secured around test subjects' waists during their efforts to generate MVCs to minimise any test-induced change in hip angle. During MVCs, subjects received vigorous verbal encouragement to perform maximally, as well as visual feedback via the monitor displaying their attained force and the chart recorder output. Contraction attempts of 3–5 seconds were made, 1 minute apart, until MVCs were within 5% to 10% of each other, which is accepted as MVC in normal subjects under these conditions . With prior familiarisation and with verbal and visual feedback, all normal subjects attained their MVC within three attempts on the test day. The test technique and feedback given were identical for patients, none of whom complained of QF myalgia prior to, during, or after MVC testing.
Though a close relationship has been established between body mass (BM) and absolute QF MVC results, the expected force at any BM may range widely (for example, at 70 kg – the mean [± 1 SD] QF MVC force is 350  N) , thus making between-subject comparisons problematic. To overcome this problem, MVC results of normal subjects and patients were mass-normalised. Thus, once each normal subject's and patient's LBM had been determined, their absolute QF MVC force was divided by their LBM, giving a mass-normalised MVC result in Newtons per kilogram.
Whether or not a muscle is being maximally activated voluntarily can be assessed using the "twitch interpolation" technique [31–34]. The basis of this is that, if a muscle is being submaximally activated voluntarily, further activation is possible by superimposing electrical stimulation via surface electrodes applied over the motor nerve or over the muscle motor points. If voluntary activation is not complete, such stimulation will produce force increments over and above the submaximal voluntary force being generated  (Figure 1).
If interpolated twitches are detected during "supposed" MVCs (as has been observed, for instance, in chronic fatigue syndrome  and chronic fibromyalgia syndrome  patients), this confirms that voluntary activation is not complete.
It is known from previous use of the twitch interpolation technique that normal individuals, with prior familiarisation and visual feedback, can reliably attain MVCs [32, 37, 38], so interpolated twitches were not deemed necessary here to prove maximal voluntary QF activation in normal subjects. For twitch interpolation in patients, two flexible 16 × 12 cm carbon-impregnated silicon equine electrodes (Henleys Medical Supplies Ltd., Welwyn Garden City, Hertfordshire, UK) were applied proximally and distally to the lateral and medial thigh, respectively (that is, over the proximal and distal QF motor points). Electrical contact was optimised with a highly conductive electromedical gel (Dracard electrode gel; Crown Graphic Ltd., Totnes, Devon, UK). The electrode placements were secured by a bandage wrapped around the thigh, immediately prior to the patients' being seated on the MVC test-chair. Electrical stimulation (Devices 3072; Digitimer Ltd, Welwyn Garden City, Hertfordshire, UK) was computer-controlled (Amstrad PC1640; Amstrad Plc, Brentwood, Essex, UK) by specifically written software (Programmable Stimulator Controller, PULG10 Rev 1.2; Computer Allied Services, Queensland, Australia) and delivered at 1 Hz. In previous interpolated twitch studies in normal subjects, supramaximal stimulation voltages were usually used [33, 39, 40], but many of our patients with myositis appeared intolerant of such intense stimulation, so the voltages used instead were ones that were easily tolerated by them all. After familiarisation with twitches at clearly submaximal voltages, all patients eventually tolerated stimulation voltages of 90–100 V, and we were able to increase the square-wave pulse width from 50 to 500 μs at these voltages, which were then used during interpolation testing.
Having determined each patient's supposed MVC, stimulated twitches at test voltages were then delivered to the resting QF, for further familiarisation purposes. After a 60-second rest without stimulated twitches, these were restarted, and patients were asked to perform QF contractions at approximately 50% of their previously attained MVC, aided by visual feedback from their force traces, on which superimposed twitches were then visualised. After another 60-second rest without twitches, these were again restarted at rest and patients were then asked to produce another 3- to 5-second MVC, with full verbal and visual feedback, as already described. Voluntary QF activation was deemed incomplete if, during these supposed MVCs, interpolated twitch-induced force increments could be seen on the voluntary force trace.
The results are shown as the mean (± 1 SD). Between-group comparisons were performed using χ2 and Mann-Whitney U tests. Pearson coefficients (r) were derived for correlation analysis.
The patients with myositis were significantly older and heavier than the normal subjects: 53 (11) vs. 30 (8) years and 77.3 (13.2) vs. 70.5 (12.9) kg, respectively (p < 0.001 and < 0.02, respectively). As was expected from their larger masses, normal males were significantly stronger than normal females in absolute terms (that is, their MVCs were 388.5 (102.1) vs. 304.8 (82.5) N, p < 0.001). However, no between-gender differences were seen for mass-normalised MVC, with MVC/LBM results of 6.4 (1.3) and 6.8 (1.6) N/kg for normal males and females, respectively (p > 0.05). Thus, their gender-combined results of 6.6 (1.5) N/kg were used during subsequent patient stratification (see below). With an MVC/LBM of 5.4 (3.2) N/kg, male patients were, as a group, as strong as normal males (p > 0.05). With an MVC/LBM result of 3.0 (1.7) N/kg, female patients were as strong as male patients (p > 0.05) but significantly weaker than the gender-combined normals (p < 0.001).
Patients were then stratified as obviously "weak" or "not weak" according to their mass-normalised force results. For this purpose, "weak" was arbitrarily defined as a mass-normalised MVC lower than 1 SD below the mean of the gender-combined normal group (that is, below 5.1 N/kg), whereas "not weak" was arbitrarily defined as a mass-normalised MVC above 5.1 N/kg (Figure 2).
Of the 14 "weak" patients, 12 were female, but the individual with the lowest mass-normalised force was in fact male. When interpolated twitch-status was examined, seven of the 20 patients with myositis demonstrated twitches. Of the six patients stratified as "not weak", one demonstrated twitches, but six of the 14 patients stratified as "weak" demonstrated twitches (Table 3). The largest interpolated twitches were seen in the male individual with the lowest mass-normalised force result (Figure 3).
Of the six "weak" patients displaying interpolated twitches, five had disease designated as active, but the male subject with the largest twitches had disease designated as inactive. The disease duration of those "weak" patients with positive twitches was not significantly different to that of those "weak" patients without twitches, 7.3 (2.7) vs. 5.3 (5.5) years, respectively (p > 0.05). In two of the "weak" patients without twitches, QF biopsies had been undertaken during the preceding 6 months to investigate whether active disease was present and had demonstrated end-stage disease only, with marked fibre atrophy and with fatty and fibrosis replacement. Designated disease activity status did not influence normalised strength, with mass-normalised force results of 3.1 (1.8) vs. 4.3 (3.0) N/kg in active and inactive disease, respectively (p > 0.05). Not surprisingly, given that patients' CK results were used in assessing their disease activity status, there was a significant correlation between disease activity status and CK (r = 0.704, p < 0.01). There was, however, no correlation between CK and CRP (r = 0.1) or between disease activity and CRP (r = 0.13). In patients, the QF MMT results and those of formal physiological testing by quadriceps chair correlated poorly (for example, patients 6 and 20 both scored 4+ on MMT), but their mass-normalised force results were very different, whereas patients 11, 13, and 16 scored 5 on QF MMT, but all were clearly weak on formal physiological testing.
The detection of interpolated twitches during supposed MVCs in nearly half of the myositis patients designated as "weak" confirms that voluntary activation was incomplete in those subjects. Moreover, given the submaximal stimulation voltages used here, this result may represent an underestimate of the proportion of patients with myositis who do suffer with central activation problems. Given that current QF myalgia excluded patient participation, to minimise the possibility of pain-related inhibition of contraction, these results may suggest that voluntary activation failure had arisen through poor motivation, even though these patients had been pushed as intensely as normal subjects during MVC attempts, with respect to verbal encouragement and visual feedback, in order to maximise activation. Alternatively, twitches would also have been detectable if reflex inhibition of anterior horn cell function had given rise to myogenous weakness.
One might predict that, if T cell infiltration can stimulate afferents to inhibit anterior horn cell function, such inhibition would be most marked where infiltration was greatest. This would fit with the clinical observation that weakness is often worse when infiltration would likely be greatest (that is, before treatment starts in new-onset disease and during disease relapses). It might therefore be speculated that interpolated twitches would more likely be detected in acute or relapsed disease, although this proposition has not been tested. If, however, only a small number of attacking T cells are required to induce reflex inhibition, this could explain the poor correlation observed between a muscle's strength deficit and the degree of its inflammatory cell infiltration at biopsy [6, 7]. This is because, in view of their shape, muscle cells have very large surface areas relative to the tiny fraction of which can be sampled at biopsy. Small numbers of T cells could thus be present and functionally relevant (that is, causing inhibition) yet missed at biopsy through simple sampling error. These discussions may, however, represent an oversimplification because, although the largest twitches seen in this study were demonstrated in the weakest patient, this patient's disease was clinically adjudged inactive. Although the twitch interpolation technique seems capable of detecting problems of central activation, it cannot discern between the relative contributions of motivational failure and reflex inhibition (that is, myogenous weakness due to reflex inhibition remains unproven).
If reflex inhibition was confirmed in myositis, what is the explanation for the absence of QF twitches in some "weak" patients with myositis? One possibility is that the inflammatory processes have been fully suppressed by treatment, so there is no inflammatory cell infiltrate to stimulate muscle afferents. Ongoing weakness in this situation would presumably then result from the nonimmune, myositis-induced defects already discussed. Another possibility is that inflammation-induced damage has disrupted the activation processes and/or the contractile apparatus, which thus cannot respond to excitation. That neuropathic EMG features occur in acute myositis [41–43] clearly suggests that coincidental terminal motor efferent, neuromuscular junction and muscle membrane damage can occur in myositis, which would explain excitation failure-induced weakness (that is, twitches would not be inducible if any these defects were present). However, EMGs undertaken in patients with more chronic myositis do not usually show neuropathic features. Where irreversible secondary damage to the contractile apparatus has occurred, including fibre atrophy and loss from fatty and/or fibrous replacement, the resulting contractile failure would also be insurmountable by superimposed twitches. In keeping with these discussions, three of the weak patients without twitches had muscle damage assessed as so severe that independent living was impossible, and two of these had had recent biopsies confirming the presence of end-stage damage, with severe atrophy and fatty and fibrous replacement. The absence of interpolated twitches in weak patients without obvious clinical muscle wasting is clearly in keeping with the growing body of evidence demonstrating that nonimmune mechanisms are involved in weakness induction in myositis  and that these mechanisms likely cause weakness by impairing contractile function.
If reflex inhibition does occur in myositis and it is due to afferent stimulation by inflammatory cells, what is the explanation for the detection of interpolated twitches in patients such as the one illustrated in Figure 3 (that is, in patients whose disease is thought inactive)? One possibility is that such disease is not in fact inactive, but the tools used to assess disease activity are simply too crude to detect low level disease. More sensitive tools would clearly be required to test this possibility. The ability to induce interpolated twitches, by surface stimulation over muscle motor points, requires intact function of terminal efferents, neuromuscular junctions, and muscle membranes. Thus, the finding of interpolated twitches in some patients seems to preclude in them the failure of any of these structures as a cause of the voluntary weakness. A potential alternative explanation for the finding of twitches in inactive myositis is that irreversible damage to the afferent apparatus (for example, muscle spindles and intrafusal fibres) occurred before the inflammation resolved. Such "desensitization" might reduce 1a afferent activity, thereby reducing stretch reflex gains and the excitability of the alpha motor neurones and so render descending motor impulses less effective. As long as the terminal efferents, and so on, are intact, muscle motor point stimulation would still induce interpolated twitches. Afferent dysfunction seems an attractive explanation here, if one considers the difficulty experienced by normal but MVC-naïve individuals when trying to produce MVCs without prior familiarisation/feedback. Contractions as vigorous as MVCs are rarely used on a day-to-day basis and so are infrequently perceived. In normal subjects, the MVC familiarisation process allows repeated perception of the sensation and effort of attaining MVCs, which can thereafter be reproduced reliably. In myositis patients with afferent damage, such familiarisation would clearly be more difficult.
The sole aim of the current study was to establish whether central activation failure occurs in patients with myositis. To better understand the detected inability of some patients to produce maximum force with voluntary activation and to better understand the origin(s) of this deficit(s) will require further, detailed neurophysiological investigations using well established techniques. These include the use of H-responses to examine afferent function and transcranial magnetic stimulation to test anterior horn cell excitability. At whatever neurophysiological level such investigations confirm the problem to be, the demonstration that central factors can contribute to weakness induction in myositis is not at odds with the other proposed nonimmune mechanisms already outlined [8–15]. These overall discussions highlight that multifactorial contributions could be made from peripheral and central mechanisms and could have an immune or nonimmune origin. Until more is learnt about the mechanisms of weakness induction in myositis, designing therapies to improve strength and performance will continue to be problematic, a situation compounded by the limitations of the tools currently available for assessing disease activity and damage. The disparity between the results of MMT and formal physiological testing in patients highlights such limitations.
Potential criticisms of this study include the age differences of normal subjects and patients and the relatively small number of patients studied. As pointed out in Materials and methods, the rationale for having a normal group was not to make direct comparisons with patients but instead to generate normative mass-normalised QF MVC results from which patients could arbitrarily be stratified as "weak" or "not weak." The normal subject/patient age difference is also conceded, but it has not impaired the ability to test the study hypothesis. Indeed, if only patients' results had been presented here, proof of hypothesis would still have been provided. The inclusion of normal subjects has, however, improved our ability to discuss the potential cause(s) of the detected central activation problem. With respect to the patient numbers used, the Salford myositis database contains approximately 45 patients with myositis (that is, more than many UK rheumatology units). Even so, some of these patients are old and frail, and some were unable or unwilling to help. Others have coexisting knee joint pathologies precluding their participation, whereas others who agreed to participate were subsequently intolerant of surface stimulation, even at the submaximal voltages used. It is because of the small patient numbers studied that, although central activation failure has been demonstrated, the results presented must be regarded as preliminary and as posing many unanswered neurophysiological questions. Another problem is that no attention has been paid here to the phenomenon of fatigue, which is very common in myositis. All central and peripheral causes of weakness could potentially also cause problems with fatigue, so this is a valid criticism. However, the issue of fatigue was not a study aim, so this issue will have to be addressed in future studies.
This is the first study to demonstrate that voluntary activation failure does contribute to ongoing muscle weakness in some treated myositis patients. However, myositis-induced weakness appears a multifactorial problem, comprising central activation and peripheral contractile failures and perhaps afferent failure. Large, multicentre studies correlating clinical, neurophysiological, MRI, and histological parameters are now needed to further elucidate the complex issues of weakness induction and fatigue induction in myositis. Such studies will need to include prospective assessments in new-onset patients, if treatment-induced changes in the physiological variables are to be assessed. Improving the treatment of myositis-induced weakness and fatigue will depend on the outcome of such studies.
= body mass
= creatinine kinase
= C-reactive protein
= lean body mass
= manual muscle testing
= magnetic resonance imaging
= maximum voluntary contraction
= quadriceps femoris
Targoff I: Polymyositis and Dermatomyositis in Adults 5.9.1. Oxford Textbook of Rheumatology. Edited by: Maddison PJ ID, Woo P, Glass DN. 1998, Oxford: Oxford Med Pub, 2: 1249-1287. 2
Karpati G, Hilton-Jones D: Disorders of Voluntary Muscle. 2001, Cambridge: Cambridge University Press, 7
Harris-Love M: Physical activity and disablement in the idiopathic inflammatory myopathies. Curr Opin Rheumatol. 2003, 15: 679-690. 10.1097/00002281-200311000-00002.
Sultan S, Ioannou Y, Moss K, Isenberg D: Outcomes in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology. 2002, 41: 22-26. 10.1093/rheumatology/41.1.22.
Engel A, Arahata K: Mononuclear cells in myopathies: quantitation of functionally-distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies. Hum Pathol. 1986, 17: 704-721.
Plotz P: NIH Conference. Current concepts in the Idiopathic Inflammatory Myopathies: Polymyositis, Dermatomyositis, and related disorders. Ann Intern Med. 1989, 111: 143-157.
Olsen N, Park J: Inflammatory myopathies: issues in diagnosis and management. Arthritis Care Res. 1997, 10: 200-207.
Lundberg I: Clinical symptoms in patients with myositis – an acquired metabolic myopathy?. Curr Opin Rheumatol. 2003, 15: 675-678. 10.1097/00002281-200311000-00001.
Newman E, Kurland R: P-31 magnetic resonance spectroscopy in polymyositis and dermatomyositis. Altered energy utilisation during exercise. Arthritis Rheum. 1992, 35: 199-203.
Pfleiderer B, Lange J, Loske K-D, Sunderkotter C: Metabolic disturbances during short exercises in dermatomyositis revealed by real-time functional 31P magnetic resonance spectroscopy. Rheumatology. 2004, 43: 696-703. 10.1093/rheumatology/keh182.
Cea G, Bendahan D, Manners D, Hilton-Jones D, Lodi R, Styles P, Taylor D: Reduced oxidative phosphorylation and proton efflux suggest reduced capillary blood supply in skeletal muscle of patients with dermatomyositis and polymyositis: a quantitative 31P-magnetic resonance spectroscopy and MRI study. Brain. 2002, 125: 1635-1645. 10.1093/brain/awf163.
Lundberg I, Ulfgren A, Nyberg P, Andersson U, Klareskog L: Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum. 1997, 40: 865-874.
Lundberg I, Kratz A, Alexanderson H, Patarroyo M: Decreased expression of IL-1a and ß, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis. Arthritis Rheum. 2000, 43: 336-348. 10.1002/1529-0131(200002)43:2<336::AID-ANR13>3.0.CO;2-V.
Nyberg P, Wikman A, Nennessmo I, Lundberg I: Increased expression of interleukin-1 alpha and MHC Class I molecules in muscle tissue of patients with chronic, inactive polymyositis and dermatomyositis. J Rheumatol. 2000, 27: 940-948.
Nagaraju K, Casciola-Rosen L, Lundberg I, Rawat R, Cutting S, Tahpliyal R, Chang J, Dwivedi S, Mitsak M, Chen Y-W, et al: Activation of the endoplasmic reticulum stress response in autoimmune myositis. Arthritis Rheum. 2005, 52: 1824-1835. 10.1002/art.21103.
Bigland-Ritchie B, Jones D, Hosking G, Edwards R: Central and peripheral fatigue in sustained maximum voluntary contractions of the human quadriceps muscle. Clin Sci Mol Med. 1978, 54: 609-614.
de Andrade J, Grant C, Dixon A: Joint distension and reflex inhibition in the knee. J Bone Joint Surg Am. 1965, 47: 313-322.
Harding B: An investigation into the cause of arthritic muscular atrophy. Lancet. 1929, i: 433-434.
Jayson M, Dixon A: Intra-articular pressure in rheumatoid arthritis of the knee. III. Pressure changes during joint use. Ann Rheum Dis. 1970, 29: 401-408.
Stokes M, Young A: The contribution of reflex inhibition to arthrogenous muscle weakness. Clin Sci. 1984, 67: 7-14.
Bohan A, Peter J: Polymyositis and dermatomyositis. N Engl J Med. 1975, 292: 344-347.
Kendall F, McCreary E, Provance P: Muscle strength: testing and function. Muscle Strength: Testing and Function. Edited by: Kendall F. 1993, Baltimore: Williams and Wilkins, 1: 4
Henricksson K: 'Semi-open' muscle biopsy technique: a simple outpatient procedure. Acta Neurol Scand. 1979, 59: 317-323.
Miller F, Rider L, Chung Y-L, Cooper R, Danko K, Farewell V, Lundberg I, Morrison C, Oakley L, Oakley I, et al: Proposed preliminary core set measures for disease outcome assessment in adult and juvenile inflammatory myopathies. Rheumatology (Oxford). 2001, 40: 1262-1273. 10.1093/rheumatology/40.11.1262.
Isenberg D, Allen E, Farewell V, Ehrenstein M, Hanna M, Lundberg I, Oddis C, Pilkington C, Plotz P, Scott D, et al: International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology. 2004, 43: 49-54. 10.1093/rheumatology/keg427.
Sultan S, Allen E, Kiely P, Cooper R, Oddis C, Vencovsky J, Lundberg I, Dalmachi M, Hanna M, Isenberg D: Inter-rater reliability and validity of two disease activity assessment tools in patients with idiopathic inflammatory myositis (IIM). Rheumatology. 2005, 44: S335-
Sultan S, Allen E, Cooper R, Agarwal S, Oddis C, Vencovsky J, Lundberg I, Kiely P, Hanna M, Isenberg D: Inter-rater reliability of a new damage assessment tool in patients with idiopathic inflammatory myositis (IIM). Rheumatology. 2005, 44: S332-10.1093/rheumatology/keh505.
Durnin J, Rahman M: The assessment of the amount of fat in the human body from the measurement of skin fold thickness. Br J Nutr. 1967, 21: 681-688. 10.1079/BJN19670070.
Edwards R, Young A, Hosking G, Jones D: Human skeletal muscle and function: description of tests and normal values. Clin Sci Mol Med. 1977, 52: 283-290.
Tornvall G: Assessment of the physical capabilities with special reference to the evaluation of maximal voluntary isometric muscle strength and maximal working capacity. Acta Physiologica Scandinavica. 1963, 58: S201-
Merton P: Voluntary strength and fatigue. J Physiol. 1954, 123: 553-564.
Chapman S, Edwards R, Greig C, Rutherford O: Practical application of the twitch interpolation technique for the study of voluntary contraction of the quadriceps muscle in man. J Physiol. 1984, 353: 3P-
Rutherford O, Jones D, Newham D: Clinical and experimental application of the percutaneous twitch superimposition technique for the study of human muscle activation. J Neurol Neurosurg Psychiatry. 1986, 49: 1288-1291.
Cooper R, Edwards R, Gibson H, Stokes M: Human muscle fatigue: frequency dependence of excitation and force generation. J Physiol. 1988, 397: 585-599.
Stokes M, Cooper R, Edwards R: Normal muscle strength and fatiguability in patients with 'effort syndromes'. BMJ. 1988, 297: 1014-1017.
Jacobsen S, Wildschiodtz G, Danneskiold-Samsoe B: Isokinetic and isometric muscle structure combined with transcutaneous electrical muscle stimulation in primary fibromyalgia syndrome. J Rheumatol. 1991, 18: 1390-1393.
Bellemare F, Woods J, Johansson R, Bigland-Ritchie B: Motor-unit discharge rates in maximal voluntary contractions of three human muscles. J Neurophysiol. 1983, 50: 1380-1392.
Bigland-Ritchie B, Furbush F, Woods J: Fatigue of intermittent submaximal voluntary contractions: central and peripheral factors. J Appl Physiol. 1986, 61: 421-429.
Behm D, St Pierre D, Perez D: Muscle inactivation: assessment of interpolated twitch technique. J Appl Physiol. 1996, 81: 2267-2273.
Kent-Braun J, Le Blanc R: Quantitation of central activation failure during maximal voluntary contractions in humans. Muscle Nerve. 1996, 19: 861-869. 10.1002/(SICI)1097-4598(199607)19:7<861::AID-MUS8>3.0.CO;2-7.
Johns T, Crowley W, Miller J, Campa J: The syndrome of myasthenia and polymyositis with comments on therapy. Ann N Y Acad Sci. 1971, 183: 64-71.
Vasilescu C, Bucur G, Petrovici A, Florescu A: Myasthenia in patients with dermatomyositis: clinical, electrophysiological and ultrastructural studies. J Neurol Sci. 1978, 38: 129-144. 10.1016/0022-510X(78)90060-6.
Vogelsegang S, Gutierrez J, Klipple G, Katona I: Polyneuropathy in juvenile dermatomyositis. J Rheumatol. 1995, 22: 1369-1372.
The Saudi Arabian Government sponsored the work of AOAO, and the Myositis Support Group UK purchased some of the equipment.
The authors declare that they have no competing interests.
CBM carried out testing of individuals with myositis and the analysis of results and drafted the manuscript. AOAO carried out testing on the normal controls. KTE coordinated the logistics of the experiments. RGC conceived the study, its design and coordination, carried out the experiments with CBM, and helped draft the manuscript. All authors read and approved the final manuscript.
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Molloy, C.B., Al-Omar, A.O., Edge, K.T. et al. Voluntary activation failure is detectable in some myositis patients with persisting quadriceps femoris weakness: an observational study. Arthritis Res Ther 8, R67 (2006) doi:10.1186/ar1935
- Chronic Fatigue Syndrome
- Quadriceps Femoris
- Weakness Induction
- Reflex Inhibition