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Physiological Reviews Jul 2015Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term... (Review)
Review
Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.
Topics: Animals; Biomechanical Phenomena; Critical Illness; Disease Models, Animal; Energy Metabolism; Excitation Contraction Coupling; Humans; Inflammation Mediators; Intensive Care Units; Ion Channels; Mechanotransduction, Cellular; Molecular Motor Proteins; Muscle Weakness; Muscle, Skeletal; Muscular Diseases; Polyneuropathies; Predictive Value of Tests; Risk Factors
PubMed: 26133937
DOI: 10.1152/physrev.00028.2014 -
Seminars in Arthritis and Rheumatism Feb 2021The aim of the study was to summarize current knowledge on antisynthetase syndrome (ASS), including its epidemiology, pathogenesis, proposed so far diagnostic criteria,... (Review)
Review
The aim of the study was to summarize current knowledge on antisynthetase syndrome (ASS), including its epidemiology, pathogenesis, proposed so far diagnostic criteria, heterogeneity of clinical manifestations, prognostic factors and therapeutic possibilities. PubMed database was screened for "antisynthetase syndrome" OR "antisynthetase antibodies" between February and April 2020. Aminoacyl-tRNA synthetases participate in the immune system activation as antigens, but also serve chemoattractive and cytokine-resembling roles, initiating innate and adaptive pathways. Exposure to various inhaled antigens may induce the autoimmune cascade leading to ASS. NK cells with its impaired INF-y production as well as formation of NETs by neutrophils contribute to pathogenesis. The prevalence of symptoms vary significantly depending on the study with muscular, articular and pulmonary involvement being the most frequently observed. Although classified as subtype of idiopathic inflammatory myopathies, myositis may not necessarily be the prominent manifestation. Since clinical presentation is heterogeneous and symptoms can emerge gradually, ASS could be considered as a heterogeneous spectrum rather than a homogenous disease entity. The currently available classification criteria do not fully correspond with the clinical patterns of the disease. Therapy is based on glucocorticosteroids and other immunosuppressive agents. Randomized controlled trials, dedicated for patients with ASS, are needed to form treatment algorithms.
Topics: Amino Acyl-tRNA Synthetases; Autoantibodies; Humans; Muscular Diseases; Myositis
PubMed: 33360231
DOI: 10.1016/j.semarthrit.2020.09.020 -
Neurologic Clinics Aug 2014Myopathies are a heterogeneous group of disorders that can be challenging to diagnose. This review provides a diagnostic approach based predominantly on the clinical... (Review)
Review
Myopathies are a heterogeneous group of disorders that can be challenging to diagnose. This review provides a diagnostic approach based predominantly on the clinical history and neurologic examination. Laboratory testing that can be used to confirm the suspected diagnosis based on this pattern recognition approach is also discussed. Careful consideration of the distribution of muscle weakness and attention to common patterns of involvement in the context of other aspects of the neurologic examination and laboratory evaluation should assist the clinician in making a timely and accurate diagnosis and can sometimes minimize the expense of further testing.
Topics: Humans; Medical History Taking; Muscular Diseases; Neurologic Examination
PubMed: 25037080
DOI: 10.1016/j.ncl.2014.04.008 -
Journal of Clinical Neurophysiology :... May 2020Critical illness myopathy (CIM) is a primary myopathy associated with increased mortality and morbidity, which frequently develops in severely ill patients. Several risk... (Review)
Review
Critical illness myopathy (CIM) is a primary myopathy associated with increased mortality and morbidity, which frequently develops in severely ill patients. Several risk factors have been suggested for the development of critical illness myopathy. However, neither the exact etiology nor the underlying mechanisms are known in detail. Although for definite diagnosis muscle biopsy is needed, electrophysiological tests are crucial for the diagnosis of probable critical illness myopathy and differential diagnosis. In this review, conventional electrophysiological tests such as nerve conduction studies, needle electromyography, direct muscle stimulation, and repetitive stimulation for diagnosis of critical illness myopathy are summarized. Moreover, studies using the novel method of recording muscle velocity recovery cycles are addressed.
Topics: Critical Care; Critical Illness; Electromyography; Humans; Muscular Diseases; Risk Factors
PubMed: 32358245
DOI: 10.1097/WNP.0000000000000652 -
Zeitschrift Fur Orthopadie Und... Apr 2023Differential diagnosis of muscle pain and weakness is extensive, including neurological, vertebral, arthrogenic, vascular, traumatic, immunological, endocrine, genetic...
Differential diagnosis of muscle pain and weakness is extensive, including neurological, vertebral, arthrogenic, vascular, traumatic, immunological, endocrine, genetic and infectious aetiologies, as well as medication or toxin-related causes. Muscles are highly sensitive to a large number of drugs, especially with high doses. Although many drug classes can cause toxic myopathy, a significant number of cases are caused by lipid-lowering drugs, long-term use of corticosteroids, and, most often, alcohol misuse. Some drug interactions, e.g. those that are metabolised via the enzyme CYP3A4, can increase the serum levels of the drugs and drug-induced toxicity. A careful history of patient's drug and alcohol consumption is therefore vital. Clinical symptoms depend on the drug, dosage and patient's sensitivity. They can vary from asymptomatic increase in serum levels of creatine kinase, mild myalgia and cramps to muscle weakness, rhabdomyolysis, kidney failure and even death. The pathogenesis is often only partially known and multifactorial. Toxic myopathy is often reversible once the drug is discontinued, alternative drug therapy is started or a different dosage regimen is chosen. Complications such as acute kidney failure must be avoided, and analgesic therapy may be indicated.
Topics: Humans; Muscular Diseases; Myotoxicity; Rhabdomyolysis; Ethanol
PubMed: 34320661
DOI: 10.1055/a-1488-6912 -
Nature Communications Feb 2020Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle...
Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote FAP senescence or resistance against tumor necrosis factor-mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses FAP apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of FAP senescence after exercise leads to muscle degeneration with FAP accumulation. FAP-targeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy.
Topics: Aging; Animals; Apoptosis; Exercise Therapy; Female; Humans; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Diseases; Regeneration
PubMed: 32060352
DOI: 10.1038/s41467-020-14734-x -
Neurologic Clinics Aug 2020Healthy muscle relies on a complex and interdependent network that includes, but is not limited to, proteins, ion channels, and the production and utilization of ATP.... (Review)
Review
Healthy muscle relies on a complex and interdependent network that includes, but is not limited to, proteins, ion channels, and the production and utilization of ATP. Disruptions to the system can occur for a number of reasons (genetic mutations, toxins, systemic disease, inflammation), yet they clinically present with symptoms that are nonspecific and common to myopathies: weakness, muscle pain, cramping, hypotonia. This article uses a case-based format to review the clinical reasoning and diagnostic tools that guide the accurate diagnosis of myopathies. We specifically focus on toxic, metabolic, mitochondrial, and late-onset congenital myopathies.
Topics: Adult; Female; Humans; Male; Middle Aged; Mitochondrial Myopathies; Muscle Weakness; Muscular Diseases; Mutation; Myalgia
PubMed: 32703473
DOI: 10.1016/j.ncl.2020.04.002 -
Neuromuscular Disorders : NMD Jan 2018
Topics: Animals; Biomarkers; Humans; Immune System Diseases; Muscular Diseases; Necrosis; Netherlands
PubMed: 29221629
DOI: 10.1016/j.nmd.2017.09.016 -
Brain and Nerve = Shinkei Kenkyu No... Aug 2020Muscular sarcoidosis is a granulomatous myopathy of unknown etiology characterized by the presence of non-caseating granulomas associated with sarcoidosis. Asymptomatic...
Muscular sarcoidosis is a granulomatous myopathy of unknown etiology characterized by the presence of non-caseating granulomas associated with sarcoidosis. Asymptomatic muscle involvement is revealed by imaging findings in majority of the patients with muscular sarcoidosis. Symptomatic muscular sarcoidosis, namely sarcoid myopathy, is a rare condition, and three distinct clinical types are recognized: nodular myopathy, acute myopathy, and chronic myopathy. Patients often present with myalgia, progressive weakness, and atrophy of the proximal muscles of the extremities. In order to confirm a diagnosis of sarcoid myopathy and distinguish it from other muscle disorders, muscle biopsy is the most effective and useful method even in the absence of weakness or myalgia. In addition, magnetic resonance imaging, gallium-67 citrate scintigraphy, and fluorodeoxyglucose-positron emission tomography provide significant information for diagnosis. Immunomodulatory therapy, including corticosteroids, plays an important role in preventing progression. However, effective therapeutic strategies for sarcoid myopathy have not been established yet and need to be explored in the future.
Topics: Humans; Magnetic Resonance Imaging; Muscular Diseases; Myositis; Positron-Emission Tomography; Sarcoidosis
PubMed: 32741767
DOI: 10.11477/mf.1416201611 -
Human Mutation Dec 2014A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types...
A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (∼7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease.
Topics: Alternative Splicing; Animals; Chromosomes, Human, Pair 2; Databases, Genetic; Exons; Genotype; Humans; Models, Animal; Muscle Proteins; Muscular Diseases; Mutation; Phenotype
PubMed: 25205138
DOI: 10.1002/humu.22693