Toxic Myopathy Research Articles

Increased autophagy accelerates colchicine-induced muscle toxicity

Colchicine treatment is associated with an autophagic vacuolar myopathy in human patients. The presumed mechanism of colchicine-induced myotoxicity is the destabilization of the microtubule system that leads to impaired autophagosome-lysosome fusion and the accumulation of autophagic vacuoles. Using the MTOR inhibitor rapamycin we augmented colchicine’s myotoxic effect by increasing the autophagic flux; this resulted in an acute myopathy with muscle necrosis. In contrast to myonecrosis induced by cardiotoxin, myonecrosis induced by a combination of rapamycin and colchicine was associated with accumulation of autophagic substrates such as LC3-II and SQSTM1; as a result, autophagic vacuoles accumulated in the center of myofibers, where LC3-positive autophagosomes failed to colocalize with the lysosomal protein marker LAMP2. A similar pattern of central LC3 accumulation and myonecrosis is seen in human patients with colchicine myopathy, many of whom have been treated with statins (HMGCR/HMG-CoA reductase inhibitors) in addition to colchicine. In mice, cotreatment with colchicine and simvastatin also led to muscle necrosis and LC3 accumulation, suggesting that, like rapamycin, simvastatin activates autophagy. Consistent with this, treatment of mice with four different statin medications enhanced autophagic flux in skeletal muscle in vivo. Polypharmacy is a known risk factor for toxic myopathies; our data suggest that some medication combinations may simultaneously activate upstream autophagy signaling pathways while inhibiting the degradation of these newly synthesized autophagosomes, resulting in myotoxicity.

Toxic myopathies.

This article reviews the most important muscle toxins, many of which are widely prescribed medications. Particular emphasis is placed on statins, which cause muscle symptoms in a relatively large proportion of the patients who take them. As with other toxic myopathies, most cases of statin-associated myotoxicity are self-limited and subside with discontinuation of the offending agent. Importantly, about 2% of the population is homozygous for a single nucleotide polymorphism, and these individuals have a dramatically increased risk of self-limited statin myopathy. Much more rarely, statins trigger a progressive autoimmune myopathy characterized by a necrotizing muscle biopsy and autoantibodies recognizing hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the pharmacologic target of statins. In most cases, toxic myopathies resolve after the toxic agent is stopped. Recognizing that statins can cause an autoimmune necrotizing myopathy is important because patients with this form of statin-triggered muscle disease usually require immunosuppressive therapy.

The spectrum of statin myopathy

This review discusses the spectrum of myopathies associated with statin use, with special attention given to a recently identified statin-associated autoimmune-necrotizing myopathy. The clinical characteristics of these patients, pathologic findings, associated autoantibody and immunogenetic risk factors are discussed. In the past several years, a novel form of autoimmunemyopathy associated with statin use has been described. Patients with this form of myositis have unique clinical, pathologic and pathophysiologic features when compared with those with self-limited statin toxic myopathy. An autoantibody directed against HMG-CoA reductase (HMGCR), the pharmacologic target of statins, characterizes the disease and can be used in clinical practice to identify these patients and direct therapy. Still, many questions remain to be answered regarding the pathogenic mechanisms at play, risk factors for developing the disease, long-term prognosis and effects of rechallenge with statins or other cholesterol-lowering drugs. Statins can cause a spectrum of muscle diseases, most of which are self-limited and improve with discontinuation of the offending agent. In a subgroup, an autoimmune necrotizing myopathy develops that persists after discontinuation of statins. Specific autoantibody testing can help identify these patients in clinical practice and determine the need for immunosuppressive therapy.

Myopathie nécrosante auto-immune associée aux anticorps anti-hydroxy-méthyl-glutaryl-coenzyme A réductase

IntroductionStatins or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (HMGCR) are among the most commonly prescribed treatment in France. They may be responsible for muscular intolerance with variable severity. They have been recently involved in the occurrence of an acquired inflammatory myopathy associated with anti-HMGCR antibodies. This new type of toxic myopathy remains poorly known by clinicians. ObservationWe report a 61-year-old woman treated with a statin for many years who developed a lower and upper limb disabling myopathy with a rapid unfavourable course despite treatment withdrawal. Clinical history and investigations, especially including an assay for anti-HMGCR antibodies led to the diagnosis of autoimmune necrotizing myopathy with anti-HMGCR antibodies. Subsequent initiation of an immunosuppressive treatment by corticosteroids and methotrexate was effective. ConclusionStatins may unmask or cause an autoimmune necrotizing myopathy associated with the presence of anti-HMGCR antibodies. Their identification is now routinely available. An immunosuppressive treatment is necessary and justified by the autoimmune nature of the disease.

Diagnostic algorithm and case conundrums: patients presenting with proximal muscle weakness

In the last years it has been observed that enzyme replacement therapy is mostly effective when the treatment is started at an early stage of the disease, before advanced damage has occurred in muscle fibers; consequently, the timing of diagnosis has acquired an increasingly important role, both in children and in adults. We are now aware that some LOPD cases may show for years only a persistent mild hyperCKemia with no signs or symptoms. Often the finding of high serum CK levels in this group of asymptomatic patients is incidental (visit in the emergency room for chest pain, preoperative investigations, detection of increased serum transaminases) and their diagnosis may be very difficult. Different is the case of patients who are seen when they start to manifest weakness, usually with onset in the pelvic girdle muscles. They usually report fatigue, exertional dyspnea (eg, in climbing stairs), difficulties to get up from the ground or sitting: however, these are very common symptoms, shared by a large number of primary or secondary neuromuscular disorders. In the absence of a family history of Pompe disease or a biopsy with typical vacuolar changes, the diagnosis is easily missed, and this explains the broad diagnostic delay still now registered, with consequences on ERT efficacy. Neuromuscular diseases that may present with isolated proximal weakness include lower motor neuron diseases (eg, spinal muscular atrophy), disimmune motor neuropathies, neuromuscular junction disorders (pre-and post-synaptic), and a large number of genetically defined (eg, progressive muscular dystrophies due to altered sarcolemma proteins, congenital myopathies, channellopathies) or acquired myopathies (inflammatory myopathies, toxic myopathies). Differential diagnosis is often difficult and expensive, and can be completed only in specialized tertiary centers. A diagnostic algorithm aimed to facilitate the evaluation of patients with limb-girdle muscular weakness is presented, to target the use of specific tests that can be implemented even in non-specialized structures (eg, units of general neurology or rheumatology) and allow an early detection of Pompe disease. A series of clinical cases is presented, to stimulate a discussion and to prove the validity of the algorithm.

Noninflammatory Myopathies

The noninflammatory myopathies are a diverse group of diseases, some of which may mimic the autoimmune-mediated idiopathic inflammatory myopathies in their clinical presentation. They include certain metabolic, toxic, and infectious myopathies, as well as muscular dystrophies. In addition to muscle weakness, these forms of myopathy may present with exercise intolerance and muscle pain. Special testing techniques are often required to establish the diagnosis. This review focuses on those noninflammatory myopathies that should be included in the differential diagnosis of idiopathic inflammatory myopathy.

Statin-Associated Polymyositis Following Omeprazole Treatment

Statins are an extensively used class of drugs, and myopathy is an uncommon, but well-described side effect of statin therapy. Inflammatory myopathies, including polymyositis, dermatomyositis, and necrotizing autoimmune myopathy, are even more rare, but debilitating, side effects of statin therapy that are characterized by the persistence of symptoms even after discontinuation of the drug. It is important to differentiate statin-associated inflammatory myopathies from other self-limited myopathies, as the disease often requires multiple immunosuppressive therapies. Drug interactions increase the risk of statin-associated toxic myopathy, but no risk factors for statin-associated inflammatory myopathies have been established. Here we describe the case of a man, age 59 years, who had been treated with a combination of atorvastatin and gemfibrozil for approximately 5 years and developed polymyositis after treatment with omeprazole for 7 months. Symptoms did not resolve after discontinuation of the atorvastatin, gemfibrozil, and omeprazole. The patient was treated with prednisone and methotrexate followed by intravenous immunoglobulin, which resulted in normalization of creatinine kinase levels and resolution of symptoms after 14 weeks. It is unclear if polymyositis was triggered by interaction of the statin with omeprazole and/or gemfibrozil, or if it developed secondary to long-term use of atorvastatin only.

Cannabinoid Receptor Antagonist-Induced Striated Muscle Toxicity and Ethylmalonic-Adipic Aciduria in Beagle Dogs

Ibipinabant (IBI), a potent cannabinoid-1 receptor (CB1R) antagonist, previously in development for the treatment of obesity, causes skeletal and cardiac myopathy in beagle dogs. This toxicity was characterized by increases in muscle-derived enzyme activity in serum and microscopic striated muscle degeneration and accumulation of lipid droplets in myofibers. Additional changes in serum chemistry included decreases in glucose and increases in non-esterified fatty acids and cholesterol, and metabolic acidosis, consistent with disturbances in lipid and carbohydrate metabolism. No evidence of CB1R expression was detected in dog striated muscle as assessed by polymerase chain reaction, immunohistochemistry, Western blot analysis, and competitive radioligand binding. Investigative studies utilized metabonomic technology and demonstrated changes in several intermediates and metabolites of fatty acid metabolism including plasma acylcarnitines and urinary ethylmalonate, methylsuccinate, adipate, suberate, hexanoylglycine, sarcosine, dimethylglycine, isovalerylglycine, and 2-hydroxyglutarate. These results indicated that the toxic effect of IBI on striated muscle in beagle dogs is consistent with an inhibition of the mitochondrial flavin-containing enzymes including dimethyl glycine, sarcosine, isovaleryl-CoA, 2-hydroxyglutarate, and multiple acyl-CoA (short, medium, long, and very long chain) dehydrogenases. All of these enzymes converge at the level of electron transfer flavoprotein (ETF) and ETF oxidoreductase. Urinary ethylmalonate was shown to be a biomarker of IBI-induced striated muscle toxicity in dogs and could provide the ability to monitor potential IBI-induced toxic myopathy in humans. We propose that IBI-induced toxic myopathy in beagle dogs is not caused by direct antagonism of CB1R and could represent a model of ethylmalonic-adipic aciduria in humans.

Nerve, muscle and heart acute toxicity following oxaliplatin and capecitabine treatment

Capecitabine plus oxaliplatin combination (XELOX) is the first-line treatment in metastatic colorectal cancer. Here we report a case of acute, severe but substantially reversible, neuromuscular and cardiac toxicity following XELOX chemotherapy. Muscle biopsy findings were consistent with a toxic myopathy with necrotizing features and vacuolar changes; COX-negative fibers were also present. The time course could support a main role for capecitabine, which may have some neurotoxic effects (more frequently central), but a detrimental interaction between the two drugs cannot be ruled out and further studies are needed.

Inpatient EMG Studies. Do They Help with Patient Care? (P01.197)

Objective: To assess the usage and clinical impact of inpatient electromyography (IP-EMG) studies at a university-based hospital. Background Nerve conduction and electromyography studies are increasingly performed in the inpatient setting. Portable machines and dedicated teams have facilitated this increase. However, the impact of IP-EMG studies on patient care has not been studied. Design/Methods: We retrospectively reviewed the medical records of all patients who had IP-EMG between July 2009 and September 2011 by a single neuromuscular medicine-trained neurologist. Demographic data, results of the study, pre-study clinical impression and post-study diagnostic evaluation and management were analyzed. Results: During the study period, 122 patients underwent 137 IP-EMG studies. Mean age was 53 years and female: male ratio was 1.7:1. Thirteen studies were in patients in an intensive care unit; 6 had either critical illness neuropathy or myopathy. A predominant neurogenic etiology was found in 84 patients. Of these, 8 had acute inflammatory demyelinating polyneuropathy (AIDP) and 42 had chronic axonal neuropathy. Seven patients were newly diagnosed with motor neuron disease following IP-EMG. Twenty patients were classified as radiculopathy or plexopathy. Four patients were diagnosed with non-AIDP acute neuropathies and six patients were diagnosed with inflammatory or toxic myopathy. Twenty-nine IP-EMGs were normal. Seven of 8 AIDP patients had cerebrospinal fluid analysis; all were treated with IVIG and/or plasma exchange. All 6 patients with new onset myopathy had a muscle biopsy after IP-EMG. IP-EMG confirmed the pre-test clinical impression in 67 patients. In the majority of cases where IP-EMG was not confirmatory, the study helped to focus further diagnostic evaluation or led to the conclusion of a non-neurological cause of symptoms. The most common incidental finding judged unrelated to the clinical presentation was median mononeuropathy at the wrist. Conclusions: This study demonstrates that IP-EMG contributes value to clinical decision making for hospitalized patients suspected to have acute neuromuscular processes. Disclosure: Dr. Samuel has nothing to disclose. Dr. Muppidi has nothing to disclose. Dr. Wolfe has received personal compensation for activities with Eli Lilly & Company, Talecris and Genzyme Corporation as a speaker and/or participant on an advisory board.

Prognosis of Statin Myopathy (P04.090)

Objective: To characterize the prognosis of statin myopathy. Background Statin drugs cause myalgias, fatigue, weakness, and CK elevation, which often linger after discontinuing the drugs. The prognosis has not been well studied. Design/Methods: 143 patients with a diagnosis of toxic myopathy or myopathy and hyperlipidemia were identified from our patients9 database. 69/143 with muscle symptoms and/or CK elevation developed after initiating statin therapy without other identifiable causes were chosen for further studies by chart review. Results: Mean age at presentation was 62 years (range:37-91). 49 (71.0%) patients were men. Mean duration of statin use was 29.6 months (range:0.25-122). Myalgias was reported by 63 (91.3%), fatigue by 47 (68.1%), and weakness by 42 (60.9%). 18 (26.1%) patients had detectable muscle weakness. Mean CK level at presentation was 790 IU/L (range: 33-5091), normal in 17 (24.6%), mildly elevated ( 1,000) in 16 (23.2%). 32 (46.4%) patients had NCS/EMG, with myopathy diagnosed in 4 (12.5%). 16 (23.2%) patients underwent muscle biopsies, with non-specific myopathic changes seen in 4 (25.0%). Statin was discontinued in all patients. Mean duration of follow-up was 18.2 months (range: 1-120). Muscle symptoms completely resolved in 50 (72.5%), improved in 9 (13.0%), and unchanged in 10 (14.5%). Of those with symptoms resolved, 24.0% occurred within 1 month, 62.0% within 3 months, 90.0% within 6 months, and 96.0% within 1 year. 10/52 (19.2%) patients had their CK levels return to normal. Clinical improvement was not influenced by the presence of weakness, CK elevation, or myopathic changes on EMG or muscle biopsies. Conclusions: Majority of patients with statin myopathy are men and their disease is mild. Muscle symptoms can linger but rarely beyond 1 year. NCS/EMG and muscle biopsy, which can be useful to rule out other diseases, are not helpful to determine the prognosis. Disclosure: Dr. Armour has nothing to disclose. Dr. Zhou has nothing to disclose.

In Silico Models to Discriminate Compounds Inducing and Noninducing Toxic Myopathy.

Toxic myopathy is a muscular disease in which the muscle fibers do not function and which results in muscular weakness. Some drugs, such as lipid-lowering drugs and antihistamines, can cause toxic myopathy. In this work, a dataset containing 232 chemical compounds inducing toxic myopathy (IM-compounds) and 117 drugs not inducing toxic myopathy (notIM-compounds) was collected. The dataset was split into a training set (containing 270 compounds) and a test set (containing 79 compounds). A Kohonen's self-organizing map (SOM) and a support vector machine (SVM) were applied to develop classification models to differentiate IM-compounds and notIM-compounds. Polarizibity related descriptors, electronegativity related descriptors, atom charges related descriptors, H-bonding related descriptor, atom identity and molecular shape descriptors were used to build models. Using the SOM method, classification accuracies of 88.4 % for the training set and 88.2 % for the test set were achieved; using the SVM method, classification accuracies of 95.6 % for the training set and 86.1 % for the test set were achieved. In addition, extended connectivity fingerprints (ECFP_4) were calculated and analyzed to find important substructures of molecules relating to toxic myopathy.

Update on Toxic Myopathies

The toxic myopathies are a clinically and pathologically diverse group of disorders that can be caused by a variety of therapeutic agents used in clinical practice, as well as various venoms and other biological toxins. The most important iatrogenic causes are the statin and fibrate cholesterol-lowering agents that can cause a severe necrotizing myopathy and acute rhabdomyolysis and myoglobinuria. The current update focuses on the mechanisms of statin myotoxicity and the importance of genetic predisposing factors for statin myopathy, as well as the recently described form of necrotizing autoimmune myopathy, which is associated with antibodies to the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme and is responsive to aggressive immunotherapy. Mitochondrial myopathies associated with antiretroviral agents and the pyrimidine nucleoside analogue clevudine, and recent reports of myopathies caused by ingestion of red yeast rice and toxic species of mushrooms are also discussed.

Steroid myopathy: Some unresolved issues

Steroid myopathy is a non-inflammatory toxic myopathy that occurs as side effect of exogenous and endogenous glucocorticoid excess. The purpose of this review is to examine issues that limit our understanding of this myopathy with respect to nosology, etiopathogenesis, conditioning factors, and muscle fiber selectivity. We suggest that if more data were available on these issues, the understanding of steroid myopathy would be enhanced substantially, thus allowing an early detection of its occurrence (before the appearance of clinical or laboratory signs) and a proper treatment of the patients.

Myopathies in the elderly: A hospital-based study

Population in western countries is ageing, and myopathies are likely to be more frequently found in elderly patients. We analyzed the files of 270 consecutive adult patients (age >18 years) with newly diagnosed biopsy-proven myopathy in the 2003–2009 interval. Fifty patients (18%) were aged with more than 70 years. In this group of elderly patients, 50% had inflammatory myopathy, 32% had genetically-determined myopathy, 16% had myopathy of unspecified cause, and 2% had toxic myopathy. When considering muscle weakness and serum creatine kinase activity, there was no statistical difference between elderly patients and younger patients. In contrast, elderly patients more frequently presented with myalgia, inflammatory myopathy, and cancer. Myopathies in the elderly are frequent in developed countries, representing a significant proportion of adult myopathies in our series. Muscle pain was a prominent symptom and inflammatory myopathies, often associated with cancer, were the most frequent cause of myopathy. Clinicians should be aware of the existence of geriatric myopathies, an emerging entity with important implications for management, treatment, and genetic counseling.

Drug-related Myopathies of Which the Clinician Should Be Aware

Many drugs used for therapeutic interventions can cause unanticipated toxicity in muscle tissue, often leading to considerable morbidity. A drug-induced, or toxic, myopathy is defined as the acute or subacute manifestation of myopathic symptoms such as muscle weakness, myalgia, creatine kinase elevation, or myoglobinuria that can occur in patients without muscle disease when they are exposed to certain drugs. A brief review of agents with a known association with myotoxicity and the proposed mechanisms linked to that toxicity is outlined; however, the purpose of this review is to highlight recent discoveries and advances in the field of toxic myopathies that have practical implications for practicing physicians. Because many drug-related myopathies are potentially reversible at early stages, it is important for clinicians to recognize toxic myopathies early in their course to determine when to discontinue therapy and potentially prevent irreversible muscle damage.

Agents and mechanisms of toxic myopathy

Mechanistic-based research has made possible a more pathophysiologic approach to certain drug-induced muscle disorders, especially those caused by the lipid-lowering statin family of drugs, but also myopathies caused by antimicrotubule drugs, mitochondrial toxins, foods, and purported nutriceutical remedies. This is a critical review of those syndromes that are most well founded on evidence of challenge/de-challenge/re-challenge, case-controls, or experimental controls. Statins are well tolerated drugs with very high safety windows in skeletal muscle, and third-generation statins now under development offer the hope of even less risk of toxic myopathy. Toxicity is dose-related and time-related, and is due to intramyofiber cascades downstream from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG Co-A) reductase inhibition. A robust pathophysiologic animal model shows that statins decrease strength and increase cytosolic Ca2+ by increasing both mitochondrial Ca2+ permeability and Ca2+ release from sarcoplasmic reticulum. As a result, the earliest pathologic change in statin myotoxicity is compatible with simple necrosis and intracellular membrane accumulation. Genome-wide searching has yielded a single nucleotide polymorphism in the SLCO1B1 gene for the organic anion-transporting polypeptide that regulates statin uptake. Drug-drug interactions dominate recent reports of all toxic myopathies. The peculiar mitochondrial pathology of zidovudine-induced mitochondrial DNA depletion, cytochrome oxidase depletion, and mitochondrial proliferation has been confirmed in a rigorous animal model. Finally, recent interest has been piqued by putative lipid-lowering neutraceuticals like red yeast rice (Monascus purpureus) and edible mushrooms that can clearly cause toxic myopathy. A principled approach to the diagnosis of toxic myopathies, based on the consideration of currently known pathophysiologic mechanisms, biopsy pathology, the characteristic clearance properties of creatine kinase, the time course of muscle fiber regeneration, drug challenge/de-challenge/re-challenge, and differential diagnoses, rather than on mere temporal association, will reduce the healthcare costs of common diagnostic error.

The accuracy of discharge diagnosis coding for Amyotrophic Lateral Sclerosis in a large teaching hospital

To evaluate the accuracy of hospital discharge data as a source of Amyotrophic Lateral Sclerosis (ALS) cases for epidemiological studies or disease registries, a validation study was performed. All records of patients discharged in 2005 and 2006 with principal or secondary International Classification of Diseases, 9th rev., Clinical Modification (ICD 9 CM) diagnosis code of ALS (335.20), other anterior horn cell disease (335), spinal cord disease (336), hereditary and idiopathic peripheral neuropathy (356), inflammatory and toxic neuropathy (357), myoneural disorders (358), muscular dystrophies and myopathies (359), were selected from the electronic archive of discharge data of the University Hospital of Udine, Friuli Venezia Giulia Region, North East Italy. Corresponding clinical documentation was reviewed to ascertain the presence of El Escorial criteria, the gold standard. Sensitivity of the ICD 9 CM discharge code 335.20 was 93% (95%CI: 82-99%) and decreased to 91% (95%CI: 77-98%) when suspect ALS was excluded. Specificity was 99% (95%CI: 97-99%). The ICD 9 CM discharge code 335.20 can identify a high percentage of hospitalizations of patients truly affected by ALS and of patients with no ALS, among selected neurological diagnostic codes. To ensure complete ALS case ascertainment, prospective population-based registries or epidemiologic studies require active prospective surveillance and use of multiple sources, among them hospital discharge archives can provide accurate information.

Kongenitale und andere Myopathien

The myopathies presented here fall into two groups: Congenital myopathies and protein aggregate myopathies. These genetic conditions often require all modern diagnostic investigations, including histology, enzyme histochemistry, immunohistochemistry and electron microscopy to pave the way to an adequate individual molecular analysis and diagnosis. This is necessary to provide the patient and his or her family information about disease-characteristics or even disease-specific features. Distal myopathies, although caused by mutations in different genes, and toxic myopathies as acquired neuromuscular conditions largely provide non-specific morphological features a correct nosological interpretation of which only succeeds with additional non-morphological data.

Toxic and drug-induced myopathies

Drugs used for therapeutic interventions either alone or in combination may sometimes cause unexpected toxicity to the muscles, resulting in a varying degree of symptomatology, from mild discomfort and inconvenience...