Chronic Myopathy Research Articles

Acute pediatric rhabdomyolysis.

Rhabdomyolysis is a relatively common condition that may occur intermittently in chronic and inflammatory myopathy, muscular dystrophy, and metabolic myopathy. Rhabdomyolysis can also present acutely in otherwise healthy individuals. The list of etiologies for acute muscle cell lysis is enormous, with new causes described yearly. Series on acute pediatric rhabdomyolysis have not yet been published. This article describes a retrospective review of children admitted to the authors' institution during an 8-year period in whom rhabdomyolysis was recognized as a complication during their hospital stay. Patients with intermittent or relapsing rhabdomyolysis were excluded. Nineteen children were identified. Trauma (five cases), nonketotic hyperosmolar coma (two cases), viral myositis (two cases), dystonia (two cases), and malignant hyperthermia-related conditions (two cases) were the most common causes of rhabdomyolysis. Acute renal failure was the most frequent complication, occurring in 42% of cases. The mean age of renal failure patients was 13.9 years, compared to 8 years for non-renal failure children. Careful assessment of the initial urinalysis would have suggested a diagnosis of rhabdomyolysis in 9 of 16 patients tested.

Juvenile idiopathic inflammatory myopathies: the value of magnetic resonance imaging in the detection of muscle involvement

One of the major current challenges related to juvenile idiopathic inflammatory myopathy is the search for highly sensitive and specific non-invasive methods for diagnosis as well as for follow-up. The aim of our study was to describe typical magnetic resonance imaging findings and to investigate the usefulness of this method in detecting active muscle disease in juvenile dermatomyositis and juvenile systemic lupus erythematosus patients. Transverse study, blinded assessment. University referral unit (Pediatric Rheumatology section, Department of Pediatrics, Universidade Federal de São Paulo / Escola Paulista de Medicina). Thirteen patients (9 girls) with dermatomyositis, as well as 13 patients (12 girls) with juvenile systemic lupus erythematosus and 10 normal children (5 girls), were enrolled in the study. Qualitative and quantitative analyses of gluteus maximus, quadriceps, adductors and flexors were performed and evaluated by two radiologists, blinded to all clinical information. Spin-echo in T1, DP, T2 and IR was used in all MRI images. The different muscle groups presented non-uniform involvement in the patients. The patients with dermatomyositis presented acute and chronic muscular alterations, while those with lupus presented only chronic myopathy, especially atrophy. In the dermatomyositis group, the major alterations were found in the gluteus and flexor regions (signal intensity and fat replacement). The signal intensity was increased in all acute myopathies. The qualitative and quantitative resonance analyses are useful in detecting clinically active disease in patients with dermatomyositis.

Acute ethanol treatment decreases intracellular calcium-ion transients in mouse single skeletal muscle fibres in vitro.

Alcohol misuse frequently leads to muscle weakness, which may also occur in the setting of acute and chronic alcoholic myopathies. At the cellular level, ethanol has been found to interfere with signalling mechanisms in cardiac myocytes, skeletal myotubes, and smooth muscle cells. In this study, we focused on the effects of ethanol on the intracellular calcium ([Ca(2+)](i)) transients responsible for excitation-contraction (EC) coupling in isolated mouse skeletal fibres loaded with the fluorescent Ca(2+) indicator fura-2. Following electrical stimulation, ethanol caused a significant reversible dose-dependent reduction in [Ca(2+)](i) transient amplitude, already significant at 100 mM ethanol (P = 0.03), without modifying resting [Ca(2+)](i). Evaluating the potential loci for the effects of ethanol, we indirectly measured sarcolemmal Ca(2+) entry by monitoring Mn(2+)-quenching of intracellular fura-2 via the nitrendipine-sensitive Ca(2+) channels during electrical pacing. Ethanol at doses of 20 mM and greater caused a dose-dependent reduction in the rate of fura-2 quenching (all at P<0.05). Moreover, the intracellular pool of Ca(2+) releasable by caffeine was found to be reduced at a minimum of 300 mM ethanol (P = 0.05). We conclude that ethanol reduces the [Ca(2+)](i) transients underlying EC coupling in single mouse skeletal muscle fibres. This acute effect of ethanol was primarily due to an inhibitory effect of ethanol on sarcolemmal Ca(2+) influx via voltage-operated Ca(2+)-channels and, to a lesser extent, to a reduction in the Ca(2+) sarcoplasmic reticulum loading state. This inhibitory effect of ethanol may be implicated in the development of muscle weakness with alcohol consumption.

Low-dose ethanol consumption allows strength recovery in chronic alcoholic myopathy.

Chronic skeletal myopathy may affect one third of chronic alcohol misusers. It is generally accepted that abstinence allows partial recovery, and that continued high-dose ethanol consumption progressively deteriorates muscle function. However, the effect of low-dose ethanol consumption in alcoholic myopathy has not been studied. We studied 58 chronic alcoholic male patients with biopsy-proven chronic alcoholic myopathy over 5 years. We evaluated ethanol intake, biochemical and nutritional parameters, and assessed muscle strength. Eighteen patients who remained abstinent showed marked improvement in muscle strength. As expected, the 19 patients who persisted in high-dose ethanol consumption further diminished in their muscle strength. In the 11 patients who maintained low-dose (</=60 g ethanol/day) 'controlled' drinking, muscle strength improved (p=0.003), despite no change in nutritional and exercise status. There is a dose-dependent recovery in muscle strength according to the degree of ethanol consumption, and moderate controlled drinking of up to 60 g ethanol/day still allows improvement in muscle strength.

Molecular mechanisms of coxsackievirus persistence in chronic inflammatory myopathy: viral RNA persists through formation of a double-stranded complex without associated genomic mutations or evolution.

Enterovirus infection and persistence have been implicated in the pathogenesis of certain chronic muscle diseases. In vitro studies suggest that persistent enteroviruses mutate, evolving into forms that are less lytic and display altered tropism, but it is less clear whether these mechanisms operate in vivo. In this study, persistent coxsackievirus RNA from the muscle of mice afflicted with chronic inflammatory myopathy (CIM) was characterized and compared with RNA from a virus that had established a persistent infection of G8 mouse myoblasts for 30 passages in vitro. Competitive strand-specific reverse transcription-PCR and susceptibility to RNase I treatment revealed that plus- and minus-strand viral RNAs were present at nearly equivalent levels in muscle and that they persisted in a double-stranded conformation. All regions of the viral genome persisted and were amplified as a series of seven overlapping fragments. Restriction endonuclease fingerprinting coupled with sequencing indicated that there was no evolution of the viral genome associated with its persistence in muscle. This contrasted with the productive persistent infection that was established in myoblast cultures, where plus-strand RNA predominated and persistent virus developed distinct mutations. In vitro persistence proceeded by a carrier culture mechanism and was completely dependent on production of infectious virus, since persistent viral RNA was not detected in cultures subjected to antibody-mediated curing. These experiments demonstrate that persistence of coxsackievirus RNA in muscle is not facilitated by distinct genetic changes in the virus that give rise to replication-defective forms but occurs primarily through production of stable double-stranded RNA that is produced as the acute viral infection resolves. The data suggest a mechanism for coxsackievirus persistence in myofibers and perhaps other nondividing cells whereby cells that survive infection could harbor persistent viral RNA for extended times without producing detectable levels of infectious virus.

Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines.

This review summarizes the current status of intravenous immunoglobulin (IVIg) in the treatment of autoimmune neuromuscular disorders and the possible mechanisms of action of the drug based on work in vivo, in vitro, and in animal models. Supply of idiotypic antibodies, suppression of antibody production, or acceleration of catabolism of immunoglobulin G (IgG) are relevant in explaining the efficacy of IVIg in myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and antibody-mediated neuropathies. Suppression of pathogenic cytokines has putative relevance in inflammatory myopathies and demyelinating neuropathies. Inhibition of complement binding and prevention of membranolytic attack complex (MAC) formation are relevant in dermatomyositis (DM), Guillain-Barré syndrome (GBS), and MG. Modulation of Fc receptors or T-cell function is relevant in chronic inflammatory demyelinating polyneuropathy (CIDP), GBS, and inflammatory myopathies. The clinical efficacy of IVIg, based on controlled clinical trials conducted in patients with GBS, CIDP, multifocal motor neuropathy (MMN), DM, MG, LEMS, paraproteinemic IgM anti-myelin-associated glycoprotein (anti-MAG) demyelinating polyneuropathies, and inclusion body myositis is summarized and practical issues related to each disorder are addressed. The present role of IVIg therapy in other disorders based on small controlled or uncontrolled trials is also summarized. Finally, safety issues, risk factors, adverse reactions, spurious results or serological tests, and practical guidelines associated with the administration of IVIg in the treatment of neuromuscular disorders are presented.

A Case of Chronic Thyrotoxic Myopathy Associated with Myelopathy.

We present a 52-year-old woman with Graves' disease, who was characterized by having both chronic thyrotoxic myopathy and posterolateral myelopathy. Both symptoms began and progressed concomitantly. After the administration of methimazole for treatment of Graves' disease, myopathy improved, while myelopathy remained unchanged. Various possible disorders to cause myelopathy were sought. However roentgenographic findings of entire spine X ray, myelogram, magnetic resonance imaging and cerebrospinal fluid examinations were all with negative results. The present data imply that rare manifestations associated with myelopathy in this patient may be due to thyrotoxicosis which is strongly linked to an abnormality in autoimmune mechanisms.

Natural History of Alcoholic Myopathy: A 5‐Year Study

Chronic myopathy is a common complication of alcoholism, but its natural history has not been well described. We, therefore, studied muscle structure and function in a 5-year study of 30 chronic alcoholics who became abstinent and 20 who relapsed, and 40 control subjects. The mean strength of the abstaining alcoholics increased from 18.6 to 23.2 kg; but, after 5 years, they were still substantially weaker than controls. In a subset who showed histological myopathy, the strength of half of the patients remained two standard deviations below that of controls. Alcoholics who relapsed tended to become progressively weaker (21.7 kg vs. 18.2 kg) and develop histological evidence of myopathy. Thus, continued alcohol abuse was generally reflected in deterioration of muscle strength and the appearance of histological injury to muscle. Importantly, almost half of the sober patients did not recover to normal levels, indicating that alcoholic myopathy is only partially reversible. We also unexpectedly found that, in some alcoholics, a substantial reduction in the amount of alcohol consumed may be as effective as complete abstinence in improving muscle strength or preventing its deterioration.

Rigid spine syndrome: case report

We describe a patient who had difficulty in walking since toddling stage and presented proximal upper and lower member weakness which have evolved to a progressive limitation of neck and trunk flexure, compatible with rigid spine syndrome. The serum muscle enzymes were somewhat elevated and the electromyography showed a myopatic change. The muscle biopsy demonstrated an active and chronic myopathy. The DNA analysis through PCR did not display any abnormality for dystrophin gene. The dystrophin by immunofluorescence was present in all fibers, but some interruptions were found in the plasma membrane giving it the appearance of a rosary. The test for merosin was normal.

Extramuscular manifestations in idiopathic inflammatory myopathies.

The major syndromes of chronic inflammatory myopathy (dermatomyositis and polymyositis) may have in certain instances extramuscular manifestations including pulmonary, cardiac, gastrointestinal, and of course, in the first instance, dermatological involvement. Here we review recent literature addressing these associated clinical areas of involvement. Malignancies, which may affect as many as 20% to 30% of adults with dermatomyositis, will not be addressed in this review.

Normal in vivo skeletal muscle oxidative metabolism in sporadic inclusion body myositis assessed by 31P-magnetic resonance spectroscopy.

Sporadic inclusion body myositis (s-IBM) is a chronic inflammatory myopathy of unknown pathogenesis. The common findings of ragged red fibres, cytochrome c oxidase-negative fibres and multiple mitochondrial DNA deletions in the muscle of patients with s-IBM have suggested that a deficit of energy metabolism may be of pathogenic relevance. To test this hypothesis we used 31P magnetic resonance spectroscopy to assess in vivo skeletal muscle mitochondrial function in the calf muscles of 12 patients with definite s-IBM. Eleven patients showed multiple mitochondrial DNA deletions in skeletal muscle and 67% showed ragged red fibres and/or cytochrome c oxidase-negative fibres. T1-weighted MR images showed increased signal intensity in the calf muscle of all patients except one. The involvement of calf muscle was confirmed by 31P magnetic resonance spectroscopy of resting muscle, which disclosed abnormalities in metabolite ratios in all patients. However, muscle oxidative metabolism assessed during recovery from exercise was normal in patients with s-IBM, as maximum rates of mitochondrial ATP production and post-exercise ADP recovery rates were within the normal range in all cases. We conclude that muscle mitochondrial abnormalities are a secondary process and unlikely to play a significant role in the pathogenesis of s-IBM.

Ethanol Acutely Decreases Calcium Transients in Cultured Human Myotubes

Ethanol consumption frequently leads to a number of skeletal muscle disorders, including acute and chronic alcoholic myopathy. Ethanol has been found to interfere with signal transduction mechanisms in cardiac and smooth muscle cells. We studied the effects of ethanol on the intracellular calcium ([Ca2+]i) transients responsible for excitation-contraction coupling in human myotubes from chronic alcoholic patients and healthy controls. Cultured myotubes were loaded with the fluorescent Ca2+ indicator fura-2 and evaluated on a single-cell basis. Following electrical stimulation, ethanol caused a significant reversible dose-dependent reduction in [Ca2+]i transient amplitude, achieving a mean decrease of 36+/-5% at 300 mM ethanol (p < 0.01), without modifying the basal [Ca2+]i. This acute effect of ethanol was similar in myotubes obtained from chronic alcoholics and controls. Similarly, ethanol caused a dose-dependent reduction of [Ca2+]i transient amplitude in control samples when depolarization was elicited by 100 mM KCl (p < 0.01). Several potential mechanisms of ethanol action were studied in control muscle samples. Sarcolemmal Ca2+ entry was measured indirectly by monitoring Mn2+-quenching of intracellular fura-2 via the nitrendipine-sensitive Ca2+ channels during electrical pacing. Ethanol at doses of 100 mM and greater caused a dose-dependent reduction in the rate of quench (p < 0.01). In addition, the intracellular pool of Ca2+ releasable by caffeine was found to be reduced at 300 mM ethanol (p < 0.05). We conclude that ethanol reduces the [Ca2+]i transients underlying excitation-contraction coupling in human myotubes, and that this occurs to a similar extent in cells obtained from chronic alcoholics and controls. This acute effect of ethanol was primarily due to an inhibitory effect of ethanol on sarcolemmal Ca2+ influx via voltage-operated Ca2+ channels, although there may also be an effect on the Ca2+ sarcoplasmic reticulum loading state.

Antirapsyn Antibodies in Chronic Procainamide‐associated Myopathy (CPAM)

Antirapsyn Antibodies in Chronic Procainamide‐associated Myopathy (CPAM)

Serum and Muscle Levels of α‐Tocopherol, Ascorbic Acid, and Retinol Are Normal in Chronic Alcoholic Myopathy

Some authors have suggested a possible loss of antioxidant factors in alcoholic skeletal myopathy. To assess the relationship between ethanol consumption and serum and muscle levels of alpha-tocopherol, ascorbic acid, and retinol in chronic alcoholics with and without skeletal myopathy, a prospective cross-sectional study was performed in the Alcohol Unit of a 1000-bed university hospital. Twenty-five chronic male alcoholic patients (10 with skeletal myopathy) and 15 male controls of similar age were included. Evaluation of daily and lifetime ethanol consumption, assessment of anthropometric and protein nutritional parameters, and open biopsy of the left deltoid muscle were performed, as well as determinations of serum and muscle levels of retinol, alpha-tocopherol, and ascorbic acid by HPLC analysis. Ten of the 25 chronic alcoholic patients presented histological criteria of skeletal myopathy. Four alcoholics presented caloric malnutrition and three protein malnutrition. All of the muscle biopsies of the control group were entirely normal, as were their nutritional studies. The serum and muscular levels of alpha-tocopherol, ascorbic acid, and retinol were normal and were similar in both alcoholics and controls. Except for serum retinol, these values were also similar in alcoholic patients with or without skeletal myopathy. In the univariate analysis, we identified the total lifetime dose of ethanol (p < 0.003), the muscle arm area (p < 0.05), and serum levels of prealbumin (p < 0.03) and retinol-binding protein (p < 0.05) as factors influencing the development of alcoholic myopathy. However, in multivariate analysis, the total lifetime dose of ethanol was the only independent factor in relation to alcoholic myopathy (p < 0.003). Serum and muscle levels of the antioxidants alpha-tocopherol, ascorbic acid, and retinol do not influence the presence of skeletal myopathy in chronic alcoholic patients.

Serum and Muscle Levels of alpha-Tocopherol, Ascorbic Acid, and Retinol Are Normal in Chronic Alcoholic Myopathy

Serum and Muscle Levels of alpha-Tocopherol, Ascorbic Acid, and Retinol Are Normal in Chronic Alcoholic Myopathy

Coxsackievirus-Induced Chronic Inflammatory Myopathy: Virus Variants Distinguish between Acute Cytopathic Effects and Pathogenesis of Chronic Disease

Infection with the Tucson strain of coxsackievirus B1 (CVB1T) causes the development of chronic inflammatory myopathy (CIM) and hind limb weakness in susceptible strains of mice. In this study, a panel of six plaque-purified viruses exhibiting either small or large plaque phenotypes was derived from parental CVB1Tand parental CVB1Tthat had been passaged through monkey kidney cells. All six variants caused similar acute histopathology in muscle, but three of four passaged viruses (AMP1, AMP2, and AMP3) did not induce CIM while the fourth (MP3) caused some hind limb weakness but without associated muscle inflammation. In contrast, both viruses (MP1 and MP2) isolated directly from the parental CVB1Tstock were myopathic. Large plaque MP2 caused higher mortality and more rapid inhibition of host cell biosynthesis, but both MP1 and MP2 induced CIM that was comparable to that induced by parental CVB1T. Plaque size was a stable characteristic of the variants but did not correlate with their ability to induce CIM. Five of the six variants showed equivalent levels of replication in muscle, monkey kidney cells, and G8 myoblasts while one, AMP3, was selectively impaired for replication. Receptor binding and virus-induced inhibition of host cell transcription and translation were not linked to myopathogenicity. Thus, most of the passaged variants are robust infectious viruses, suggesting that viral induction of CIM does not depend solely on cytopathogenicity during the acute infection.

GREATER PERIPHERAL THAN CENTRAL ADAPTATION TO AEROBIC TRAINING IN MITOCHONDRIAL MYOPATHIES 186

In theory, limited aerobic capacity in patients with mitochondrial myopathies (MM) could be secondary to the primary disease process or effects of chronic deconditioning. The objectives of this study were to determine 1) whether patients with MM could respond to aerobic training and 2) their ability to adapt centrally versus peripherally relative to patients with other chronic non-metabolic myopathies (NM). 10 patients with MM, 6 patients with NM, and 5 sedentary healthy control subjects were evaluated before and after undergoing a similar aerobic training regimen for 8 weeks. Aerobic capacity(METs) was estimated from performance on a graded exercise test to 85% HRmax. Heart rate for an identical submaximal exercise workload was used as an index of central adaptation. Blood lactate at rest and after a constant submaximal workload, and muscle oxidative ATP resynthesis after ischemic exercise (as reflected by the ADP recovery half time [T1/2] estimated by phosphorus magnetic resonance spectroscopy) were used as indices of peripheral muscle oxidative capacity. The mean initial fitness level was similar in MM and NM, and significantly lower than that of healthy controls(p<.01). Training resulted in a significant improvement in aerobic capacity in all groups, but MM improved 20% more than NM and 27% more than controls. Decreases in HR were detected in both patient groups (p<.01) but only MM showed significant improvement (p<.01) in blood lactate concentrations(50%) and ADP T1/2 (over 2-fold) after training. Thus, both MM and NM benefit from aerobic training, but MM benefit even more than NM. The difference appears to be due to greater peripheral adaptation in MM and supports the hypothesis that partially reversible limitation at the muscle level dominates the training response in patients with mitochondrial myopathy.

Long-term management of acute respiratory failure in metabolic myopathy.

To describe how patients cope with the proposal of treatment with intermittent artificial ventilation after acute respiratory failure due to progressive respiratory muscle weakness. Case series, follow-up study. Neurological intensive care unit (ICU). 7 consecutive patients with metabolic myopathy treated for acute respiratory failure between 1983 and 1992. Intermittent positive pressure ventilation (IPPV) via tracheostomy. Symptoms of chronic hypoventilation preceded acute respiratory failure for months. With one exception, patients were mainly disabled from respiratory muscle weakness and sleep-related breathing disorders. IPPV was recommended to prevent recurrent respiratory failure. Two of three patients who accepted home IPPV returned to full-time jobs. One patient, who decided against IPPV, died from CO2 narcosis several months after discharge. All patients adhered to the respiratory regimen once instituted. Acute respiratory failure in chronic myopathy is heralded by daytime drowsiness. IPPV, or at least regular monitoring of waking and sleeping partial pressure of carbon dioxide, is highly recommended even if weaning is successful. IPPV improved quality of life. The treatment strategy at discharge from the ICU should be optimal, as patients are reluctant to modify regimens.

Discrepant results for cardiac troponin T and troponin I in chronic myopathy, depending on instrument and assay generation

Discrepant results for cardiac troponin T and troponin I in chronic myopathy, depending on instrument and assay generation

Infectious agents associated with myopathies.

Several infectious agents can cause chronic or acute myopathy. Most current investigations into possible infectious causes of the idiopathic inflammatory myopathies have focused on retroviruses, including HIV and human T-cell leukemia-lymphoma virus type I. In both cases, viruses likely do not directly infect muscle fibers but instead induce an immunologically mediated myositis. Other interest has focused on enteroviruses as potential etiologic agents of idiopathic inflammatory myopathy, but their relationship to human myositis is less clear. In addition to chronic muscle disease, several infectious agents can cause acute myositis, including pyomyositis, which is being recognized in temperate climates with increasing frequency, and rhabdomyolysis.