Toxic Myopathy Research Articles

581P Toxic autophagic vacuolar myopathies and the role of human leukocyte antigen class I molecules and membrane attack complex in its pathogenesis

581P Toxic autophagic vacuolar myopathies and the role of human leukocyte antigen class I molecules and membrane attack complex in its pathogenesis

Clinical and pathological aspects of toxic myopathies.

As the most frequent cause of acquired myopathy, toxic myopathies are characterised by clinicopathological features that vary depending on the mode of action of the drugs or toxins involved. Although a large number of substances can induce myotoxicity, the main culprits are statins, alcohol, and corticosteroids. A rigorous, well-organised diagnostic approach is necessary to obtain a rapid diagnosis. For early diagnosis and management, it is important for clinicians to be aware that most toxic myopathies are potentially reversible, and the goal of treatment should be to avoid serious muscle damage.

Statin-associated muscle symptoms: A comprehensive exploration of epidemiology, pathophysiology, diagnosis, and clinical management strategies.

Statins are the first line of treatment for both primary and secondary prevention of atherosclerotic cardiovascular disease. Despite the positive effects of statins on cardiovascular events, not all patients can use them at an optimized dose. The reason for this is the skeletal muscle side effects, termed statin-associated muscle symptoms (SAMS). Despite extensive research, the precise pathophysiology of SAMS remains unclear and multiple mechanisms may contribute to this phenomenon. Various therapeutic options are available for the management of SAMS, ranging from rechallenging with the same or a different statin to utilizing non-statin therapeutic alternatives in patients intolerant to statins. However, the lack of consensus on the definition of SAMS, the absence of a definitive diagnostic test, and lack of a universally accepted management algorithm pose a great challenge in dealing with this entity. This review aims to explore the various pathophysiological mechanisms involved in SAMS and understand the difference between self-limited toxic myopathy and immune-mediated myopathy requiring immunomodulatory therapy. The conundrum of statin withdrawal, tapering, and rechallenge in SAMS will also be explored in detail along with the newer non-statin therapies that are available.

Muscle ultrasound to identify prednisone-induced muscle damage in adults with nephrotic syndrome

Steroid myopathy is a non-inflammatory toxic myopathy that primarily affects the proximal muscles of the lower limbs. Due to its non-specific symptoms, it is often overshadowed by patients’ underlying conditions. Prolonged or high-dosage use of glucocorticoids leads to a gradual decline in muscle mass. There are no tools available to identify the course of steroid myopathy before the patient displays substantial clinical symptoms. In this study, we investigated individuals with nephrotic syndrome receiving prednisone who underwent muscle ultrasound to obtain cross-sectional and longitudinal pictures of three major proximal muscles in the lower limbs: the vastus lateralis, tibialis anterior, and medial gastrocnemius muscles. Our findings revealed that grip strength was impaired in the prednisolone group, creatine kinase levels were reduced within the normal range; echo intensity of the vastus lateralis and medial gastrocnemius muscles was enhanced, the pennation angle was reduced, and the tibialis anterior muscle exhibited increased echo intensity and decreased thickness. The total dose of prednisone and the total duration of treatment impacted the degree of muscle damage. Our findings indicate that muscle ultrasound effectively monitors muscle structure changes in steroid myopathy. Combining clinical symptoms, serum creatine kinase levels, and grip strength improves the accuracy of muscle injury evaluation.

Glucocorticoid-Induced Myopathy: Typology, Pathogenesis, Diagnosis, and Treatment.

Glucocorticoid-induced myopathy is a non-inflammatory toxic myopathy typified by proximal muscle weakness, muscle atrophy, fatigue, and easy fatigability. These vague symptoms coupled with underlying disorders may mask the signs of glucocorticoid-induced myopathy, leading to an underestimation of the disease's impact. This review briefly summarizes the classification, pathogenesis, and treatment options for glucocorticoid-induced muscle wasting. Additionally, we discuss current diagnostic measures in clinical research and routine care used for diagnosing and monitoring glucocorticoid-induced myopathy, which includes gait speed tests, muscle strength tests, hematologic tests, bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), electromyography, quantitative muscle ultrasound, histological examination, and genetic analysis. Continuous monitoring of patients receiving glucocorticoid therapy plays an important role in enabling early detection of glucocorticoid-induced myopathy, allowing physicians to modify treatment plans before significant clinical weakness arises.

Rare coexistence of spinal muscular atrophy with membranous nephropathy - A clinical conundrum with management dilemma.

A 48-year-old male presented with proximal muscle weakness of the shoulder with difficulty in lifting objects above the shoulder in July 2012. Electromyogram was suggestive of chronic motor axonal loss with a myogenic pattern, and a deltoid muscle biopsy revealed groups of atrophic muscle fibers and hypertrophic fibers with pan fascicular atrophy suggestive of adult-onset spinal muscular atrophy. He was managed conservatively and developed bilateral pedal edema in August 2022. He had nephrotic range proteinuria, and renal biopsy revealed capillary wall thickening of glomeruli with serum PLA2R antibody positivity suggestive of primary membranous nephropathy. He was managed with telmisartan for 6 months, and there was a reduction in proteinuria. In January 2023, he was given Injection Rituximab due to worsening proteinuria. He failed to have a clinical resolution. This case report describes the management dilemma in membranous nephropathy with SMA due to the risk of toxic myopathies associated with tacrolimus and steroids.

Monensin toxicosis in a dog with initial apparent recovery followed by severe relapse

AbstractThis case report describes successful intensive care management of a toxic myopathy in a 7‐month‐old, female, entire springer spaniel secondary to presumed monensin intoxication. The dog was seen chewing a monensin capsule, and was subsequently presented to the local veterinary practice with generalised weakness, ataxia, hypersalivation and pyrexia. Intravenous lipid emulsion‐activated charcoal and intensive fluid therapy were administered. Bloodwork identified a marked increase in serum creatine kinase activity (226,554 iu/L; reference range: 0–400 iu/L). The patient was discharged the following day after initial hospitalisation, with a complete resolution of clinical signs. Five days after exposure, a rapid deterioration required veterinary assessment at the referral hospital. The patient recovered and was discharged after 9 days of hospitalisation. This case report describes recurrence of clinical signs of monensin toxicosis after initial improvement. However, with aggressive emergency care, symptomatic therapy and intense monitoring, a positive outcome was achieved.

Natural and experimental salinomycin poisoning associated with the use of florfenicol in pigs

ABSTRACT: This study describes the spontaneous and experimental salinomycin poisoning associated with the use of florfenicol and warns about the effects of the administration of antibiotics to animals that receive ionophores in the feed as growth promoters. A batch with 1,200 finishing pigs fed a diet containing 30ppm of salinomycin received florfenicol (60ppm via feed) to control respiratory diseases. Twenty-seven pigs had difficulty walking, tip-toe walking, muscle tremors, and anorexia seven days after the start of treatment. Twenty-two animals died, 10 recovered, and two were sent to the Laboratory of Animal Pathology of CAV-UDESC to be necropsied. The experimental reproduction of the disease was carried out to clarify the possible influence of florfenicol on salinomycin poisoning using 12 pigs divided into four groups with three animals each, treated for 16 days with diets containing no additives (Group 1), 50ppm of salinomycin (Group 2), 40ppm of florfenicol (Group 3), and 50ppm of salinomycin and 40ppm of florfenicol (Group 4). Only animals in Group 4 became ill. The clinical disease was reproduced from the ingestion of 24.67mg/kg/LW of salinomycin and 19.74mg/kg/LW of florfenicol. Both natural and experimental salinomycin poisoning associated with the use of florfenicol caused a condition of myopathy characterized in histology by hyaline degeneration and floccular necrosis of skeletal fibers, with macrophage infiltrate, associated with the figures of regeneration in skeletal muscles and multifocal areas of the proliferation of fibroblasts, being more intense in the longissimus dorsi and semimembranosus muscles. Therefore, florfenicol can cause the accumulation of ionophore salinomycin in the animal organism, resulting in a condition of toxic myopathy.

Amphiphilic Myopathy Induced by Hydroxychloroquine Presenting with Dysarthria

Chloroquine and hydroxychloroquine (HCQ) are commonly used antimalarial agents as the treatment for a wide range of autoimmune disorders including dermatological, rheumatoid, and connective tissue diseases. These amphiphilic drugs can cause toxic myopathy in in patients which are commonly characterized as reversible proximal muscle weakness, dysphagia and dyspnea. Herein, we report a case of a patient on HCQ, who suffered from toxic myopathy presenting as proximal muscle weakness and dysarthria, which was fully recovered after the cessation.

Drug-induced Myopathies.

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.

Salinomycin intoxication in pigs associated with the use of tiamulin in the State of Santa Catarina, Brazil

This paper describes a spontaneous outbreak of toxic myopathy in finishing pigs due to the ingestion of feed with salinomycin associated with tiamulin and addresses the control methods performed during the outbreak to minimize economic losses resulting from the intoxication. A lot of 940 pigs fed feed containing 30 ppm salinomycin received 100 ppm tiamulin (via water) to control recurrent respiratory diseases on the farm. After ingesting tiamulin, some animals manifested clinical signs of motor incoordination, stiff gait, reluctance to move, muscle weakness and tremors, dyspnea, depression, and decubitus, remaining in “sitting-dog position” or with the abduction of the pelvic limbs, and rested on tip-toes when in a standing position. Two animals were euthanized for macro-and microscopic evaluation. The other sick animals received supportive anti-inflammatory treatment. The most relevant macroscopic finding observed during necropsy was the slight pallor of the pelvic limb muscles. The main histopathological findings consisted of multifocal areas of hyaline degeneration and marked necrosis of skeletal myofibers, with macrophage infiltrate associated with cell regeneration and skeletal fiber phagocytosis. These lesions were more intense in the longissimus dorsi, diaphragm, and masseter muscles. The definitive diagnosis was based on epidemiological aspects and clinical lesional conditions compatible with toxic myopathy secondary to ionophore intoxication.

Challenges in diagnosing hydroxychloroquine myopathy during the COVID-19 pandemic.

Hydroxychloroquine is being used for COVID-19 symptoms and in clinical trials, but can cause a toxic myopathy that leads to muscle weakness. A review of skeletal muscle biopsies from patients with hydroxychloroquine myopathy gives pointers of steps that can be taken to diagnose this toxic myopathy early and help differentiate it from COVID-19-related muscle weakness.

Outbreak of botulism type A in dairy cows detected by MALDI-TOF mass spectrometry

Twenty-eight lactating dairy cattle in New York State were exposed to botulism toxin; 12 died and 16 recovered but never returned to full productivity. Pieces of a raccoon carcass were found in the total mixed ration on the first day of the outbreak. Clinical signs included anorexia, decreased milk production, decreased tongue tone, profound weakness, and recumbency. Clostridium botulinum type A (BoNT/A) was detected in rumen contents from 2 deceased cows via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In addition, C. botulinum type C was cultured from the liver of a third cow, and C. botulinum neurotoxin-producing type C gene (bont/C) was detected via real-time PCR. On postmortem examination, 4 cows had findings suggestive of toxic myopathy, but the cause and significance of these lesions is unknown given that botulism is typically not associated with gross or histologic lesions. This outbreak of BoNT/A in cattle in North America was diagnosed via MALDI-TOF MS, a rapid and sensitive modality for detection of botulinum preformed neurotoxin.

"STATINS KALEIDOSCOPE". MYOPATHY FROM STATINS

Statins are medications that inhibit the 3-hydroxy-3-methylglutaryl-CoA reductase enzyme, thus inhibiting cholesterol biosynthesis. Statins reduce cardiovascular risk and morbidity in patients with coronaropathia, however, without forgetting their side effect in muscle toxicity. Clinically, patients with myopathy caused by statins are divided into four main groups: those with rhabdomyolysis, myalgia / hyper CPK, toxic myopathy limited by statins and myositis (necrotizing myopathy mediated by immune complexes with anti-HMGCR antibodies, IMNM).

12. When is inflammatory myositis not inflammatory myositis?

IntroductionA 52-year-old man presented with extensive bilateral inflammatory myositis of the quadriceps on a background of pyrexia of unknown origin (PUO). He had markedly elevated acute phase reactants but had a normal CK and did not develop muscle weakness. This was a transient phenomenon which resolved spontaneously over 10 weeks. There was not an infective process identified and he was not treated with glucocorticoids or other immunosuppressants. This case highlights the importance of careful consideration of steroid treatment in atypical presentations without a clear diagnosis and the value of multidisciplinary involvement in patient care.Case descriptionThe patient presented with a 2-week history of acute onset bilateral thigh pain, stiffness and persistent fevers following an episode of alcohol intake although symptoms may have preceded this. Myalgia was a prominent feature however he maintained full power of the hip flexors and all other proximal and distal muscle groups. No skin changes, swallow or respiratory symptoms.CK was normal at presentation and remained low. Acute phase reactants were elevated including CRP 405mg/L, ESR 110mm/hr. Platelets 1000x109/L, WCC 17.7x109/L. Urinalysis and renal function normal. ALT raised at 136U/L. AST normal, other liver parameters raised in keeping with acute phase response. No previous episodes, no preceding travel, infection, bites, illicit drugs or family history of muscle disorders. He was taking a statin which was discontinued.PUO work up including cultures, viral titres, echocardiogram and CT imaging did not identify a source. Empiric antibiotics were trialled without improvement.ANA, ANCA and myositis panels were negative. MRI of thighs reported extensive inflammatory myositis involving the quadriceps bilaterally with mild involvement of biceps femoris. There were no features of an infected collection or rhabdomyolysis. Muscle biopsy showed a lymphocytic myositis with neurogenic atrophy. Differential included idiopathic inflammatory myositis (IIM) spectrum with viral myositis felt less likely. Clinically he remained sore but improving and mobilising. Daily pyrexias persisted but he remained fully strong with a low normal CK and a downward trend in inflammatory markers. Investigations for occult malignancy including CTPET and bone marrow biopsy were negative.Steroid treatment was not instigated. A watchful waiting approach was taken and his symptoms and blood investigations gradually improved. He embarked on a physiotherapist guided exercise programme. Follow up MRI at 10 weeks showed complete resolution of the inflammatory features.DiscussionThis is a case of an acute onset myositis with systemic inflammatory features which resolved spontaneously. Differential diagnoses including inherited, metabolic and toxic myopathies were considered and discounted. Although alcohol had been taken and he had been taking a statin prior to onset, the clinical picture, normal CK and biopsy findings did not support these as likely culprits. Extensive viral and serology infective tests were negative and the exact cause was not identified.The clinical features strongly mimicked an idiopathic inflammatory myositis (IIM) however atypical features including normal CK and lack of objective weakness led to continued doubt of an autoimmune aetiology. Additionally there were no upper limb or neck flexor symptoms and no extra-muscular manifestations. Applying the ACR/EULAR 2017 criteria for IIM to this case the probability of this diagnosis is 5% although this does not take into account the radiological findings.With evidence of inflammatory myositis and a dramatic acute phase response including persistent pyrexia there was a strong temptation to begin steroid therapy. His case was discussed with radiology, pathology and neurology and ultimately the decision to withhold was justified.In this case improvement would have occurred with steroid which would likely have led to an incorrect diagnosis of IIM and the patient would have been unnecessarily treated with prolonged high dose steroid and disease modifying drugs with the associated side effects and long term sequelae.Key learning pointsThis case highlights the importance of confirming a diagnosis prior to initiating steroid therapy particularly if there are atypical features. Glucocorticoids would undoubtedly have led to a clinical improvement however this would have given rise to a misdiagnosis and unnecessary long term immunosuppression.There were many positive test results for inflammation including blood, imaging and muscle tissue but ultimately the clinical examination findings, particularly the absence of weakness, were consistent and the basis of the rationale to withhold steroid treatment. As clinical improvement progressed with supportive management this decision was justified. This demonstrates the importance of patient centred care and the value of the clinical examination.This was an unusual case therefore input and advice was sought from colleagues in neurology, neuropathology, rheumatology and radiology. This was vital to clinical care decisions and emphasizes the importance of a multidisciplinary approach in complex cases.Despite extensive investigations no cause was identified for this transient inflammatory myositis. This highlights the unknown elements within this spectrum of disease and the need for ongoing reporting of atypical cases.Conflicts of interestThe authors have declared no conflicts of interest.

Untargeted metabolic profiling of dogs with a suspected toxic mitochondrial myopathy using liquid chromatography-mass spectrometry

‘Go Slow myopathy’ (GSM) is a suspected toxic myopathy in dogs that primarily occurs in the North Island of New Zealand, and affected dogs usually have a history of consuming meat, offal or bones from wild pigs (including previously frozen and/or cooked meat). Previous epidemiological and pathological studies on GSM have demonstrated that changes in mitochondrial structure and function are most likely caused by an environmental toxin that dogs are exposed to through the ingestion of wild pig. The disease has clinical, histological and biochemical similarities to poisoning in people and animals from the plant Ageratina altissima (white snakeroot). Aqueous and lipid extracts were prepared from liver samples of 24 clinically normal dogs and 15 dogs with GSM for untargeted liquid chromatography-mass spectrometry. Group-wise comparisons of mass spectral data revealed 38 features that were significantly different (FDR<0.05) between normal dogs and those with GSM in aqueous extracts, and 316 significantly different features in lipid extracts. No definitive cause of the myopathy was identified, but alkaloids derived from several plant species were among the possible identities of features that were more abundant in liver samples from affected dogs compared to normal dogs. Mass spectral data also revealed that dogs with GSM have reduced hepatic phospholipid and sphingolipid concentrations relative to normal dogs. In addition, affected dogs had changes in the abundance of kynurenic acid, various dicarboxylic acids and N-acetylated branch chain amino acids, suggestive of mitochondrial dysfunction.

Favorable Outcome of Severe Poisoning by Snake Green Mamba (&lt;i&gt;Dendroaspis viridis&lt;/i&gt;) Clinical Case

This clinical case of acute poisoning due to bite of snake Dendroaspis viridis seems interesting to share because of its rare incidence inRussiaand management peculiarities: the critical care was conducted without specific antidote therapy due to absence of the antidote.The prevailing clinical presentation included signs of toxic myopathy combined with paresis of skeletal and breathing muscles that led to development of acute respiratory failure and metabolic disorders. The processes described were induced by the action of snake poison dendrotoxins featuring the activities of potassium channel blockers and acetyl cholinesterase inhibitors.The proper critical care included conduct of syndrome therapy aimed at maintaining life support systems adequately to condition (replacement of the breathing and circulation functions), antibiotic therapy and desensitizing treatment and metabolic care by administration of drugs characterized by antihypoxant/antioxidant mechanism of action.The comprehensive therapy applied has resulted in a favorable outcome of acute poisoning by snake green mamba without development of possible complications even when the specific antidote drug has not been included into the treatment protocol.

Proximal muscle weakness

A 38-year-old woman gave a 1-year history of difficulties climbing stairs and walking long distances, needing a wheelchair at times. More recently, she had also experienced weakness of her arms...

Myositis associated with carbon monoxide poisoning

Carbon monoxide (CO) poisoning causes hypoxia and inflammation, which could adversely affect muscle. We could find no published information about CO poisoning causing myositis. A 53-year-old previously healthy female semi truck driver had CO poisoning from a faulty diesel engine exhaust intermittently over three months, culminating in an episode of acute CO poisoning, with syncope after exiting the truck at the end of the three-month period. Neuropsychological symptoms immediately after the acute poisoning event were followed by the development of fatigue, weakness and myalgias within two months and a diagnosis of "polymyositis" within four months. C-reactive protein and creatine kinase were elevated. Electromyogram showed pure myopathy without sensory abnormalities. Occult malignancy was ruled out. Thigh muscle biopsy revealed severe inflammatory myopathy and myonecrosis. Muscle specialist pathologists interpreted the biopsy as toxic or viral inflammatory myopathy, not polymyositis, with CO poisoning as the likely etiology. She received steroids and mycophenolate. Nineteen months later, a repeat biopsy was negative for inflammation or myopathic process. Alternative diagnoses were ruled out by clinical investigation and her course over the next five years. This patient's presentation and clinical course support a diagnosis of myositis from CO poisoning, although it is possible that the myositis was either idiopathic or post-viral (without evidence of a causative virus).

Toxic myopathies.

Our aim is to highlight major advances reported in the last few years in drug-induced muscle toxicity. Our focus is on myopathies induced by statins and immune checkpoint inhibitors with a brief overview of rare steroid myopathies. Statin muscle injury is frequently because of direct toxicity rather than an autoimmune mechanism. Laboratory testing and muscle pathologic features distinguish these two conditions. Statin-associated necrotizing autoimmune myopathy (SANAM) is associated with an autoantibody in 66% of cases targeting the HMGCR enzyme. The later autoantibody is a marker for necrotizing autoimmune myopathy, regardless of statin exposure. In SANAM, MHC-I antigens are expressed on the surface of intact muscle fibers. Genetic HLA loci predispose patients exposed to statins to immunologic toxicity. SANAM requires long-term therapy with multiple immunosuppressive therapies. Immune checkpoint inhibitors are powerful emerging therapies for advanced cancer that pause a novel therapeutic challenge. This review is focused on statins, the most prevalent myotoxic drug class. In addition, we examine the accumulating body of evidence of muscle injury and its management with immune checkpoint inhibitors. We anticipate the reader to become more knowledgeable in recent discoveries related to these myotoxic drugs, and their mechanisms of action and management.