Corticosteroid-induced myopathy is the most common drug-induced myopathy and could appear during the treatment of diseases where corticosteroids are the mainstay of treatment. We present a clinical case of a patient treated with corticosteroids who presented with proximal muscle weakness, myalgias, marked elevation of muscle enzymes, and acute kidney injury due to rhabdomyolysis. The definitive diagnosis was only possible through a muscle biopsy.

Boxelder and sycamore maple contain hypoglycin A (HGA), the toxic metabolite of which, MCPA-CoA, inhibits fatty acid β-oxidation, causing seasonal pasture myopathy (SPM) or atypical myopathy (AM), respectively. White snakeroot and rayless goldenrod contain multiple benzofuran ketones (BFKs). The identity/toxicity of BFKs appear variable, possibly involving interactions between toxins/toxic metabolites, but ultimately inhibit cellular energy metabolism. Unthrifty horses grazing sparse pastures during the fall appear predisposed to these plant-associated, frequently fatal, toxic myopathies. Toxidromes are characterized by varying degrees of rhabdomyolysis and cardiac myonecrosis, with plant toxins remaining toxic in hay and being excreted in milk.

BACKGROUND: Hypoglycin A (HGA) intoxication after ingestion of Acer spp. tree material has never been confirmed in domesticated ruminants despite their similar grazing habitats.
OBJECTIVE: To investigate whether sheep have low HGA bioavailability caused by rumen HGA breakdown.
METHODS: Stomach and rumen fluid samples from 5 adult horses and 5 adult sheep respectively. Residual serum samples from 30 ewes and lambs.
METHODS: Experimental and retrospective cohort study. Hypoglycin A concentration was quantified in horse gastric and sheep ruminal samples after in vitro incubation with Acer pseudoplatanus seeds. Serum samples from grazing sheep (n = 20) and nursing lambs (n = 10) obtained before and after their release onto pastures with and without Sycamore seedlings were analyzed for HGA and methylenecyclopropyl-acetic acid carnitine, and serum biochemistry.
RESULTS: Neither ovine rumen nor equine gastric fluid affected HGA content in samples incubated for up to 2 hours. Despite HGA\'s detection in serum from sheep (n = 13/15; median, 23.71 ng/mL; range, 5.62-126.4 ng/mL) grazing contaminated pastures and in their nursing lambs (n = 2/5; median, 12.5 ng/mL; range, 8.82-15.67 ng/mL), there was no apparent clinical or subclinical disease.
CONCLUSIONS: Any reduced sensitivity to HGA intoxication in sheep seems unrelated to ruminal degradation. Serum HGA concentrations in sheep were similar to those of subclinically affected atypical myopathy horses. Any reduced sensitivity of sheep to HGA might be related to greater metabolic resistance rather than selective grazing habits or lower bioavailability. Hypoglycin A was found in nursing lambs, suggesting that HGA is excreted in milk.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been associated with muscle toxicity, mostly described as a proximal myopathy with evidence of lysosomal dysfunction on muscle biopsy. In this retrospective study, we aimed to define the clinical phenotype, laboratory features, and treatment outcomes of CQ/HCQ myopathy, as well as the safety profile of these drugs. We identified 13 patients seen between 2000 and 2019, with a median age at presentation of 66 years (range 53-89); 11 were females. At onset of symptoms, patients were on CQ or HCQ for a minimum of 6 months and up to 21 years. Diagnosis was often delayed by a median of 6 months (range 3-48). At presentation, 13 patients reported limb weakness, with five requiring assistance in walking. Ten reported dysphagia, often severe, resulting in marked weight loss or aspiration pneumonia. Nine reported respiratory symptoms, which were multifactorial in four, and four reported severe neck weakness. Myopathy clinical phenotype showed predominant involvement of one or more of the following: proximal limb muscle weakness (12 patients), dysphagia (9), axial weakness (4), and respiratory failure (5). Eleven patients had a cardiac evaluation showing prolonged QT interval in 10 and CQ/HCQ cardiomyopathy (CMP) in four. Ten out of 12 patients markedly improved after discontinuing the medication, but most were left with some residual weakness. Eleven patients had a muscle biopsy showing a myopathy with rimmed vacuoles and marked acid phosphatase reactivity. Nine had elevated creatine kinase level up to 1,199 U/L. Twelve patients had an electromyography (EMG), which showed myopathic motor unit potentials with fibrillation potentials in 11 and myotonic discharges in 3. Higher cumulative dose and longer exposure duration were associated with more severe disability and more common cardiac and swallow involvement, indicating a cumulative dose effect. Herein, we demonstrate that long-term exposure to CQ and HCQ may result in a myopathy with a wide spectrum of clinical presentation and predilection for swallowing, respiratory, and cardiac muscles, often with marked associated morbidity. Once accurately diagnosed and the drug is discontinued, patients usually improve but often fail to return to baseline.

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.

Introduction: This Perspective reassesses the consensus opinion that statin-associated muscle symptoms (SAMS) occur in <1% of users and associated myopathic proximal muscle weakness is even more rare.Areas covered: Of the over 180,000 participants in clinical trials and large registries of statin users, only a few studies have included a standard manual muscle test (MMT), dynamometry or a focused questionnaire to assess for proximal weakness and related disability in daily and recreational activities. Formal strength testing suggests, however, that weakness can be demonstrated in at least 10% of users.Expert opinion: Reporting inaccuracies about SAMS, confirmation bias among experts and physicians, absence of a standard questionnaire regarding the potential consequences of weakness on physical capacity, and the failure to routinely perform an objective assessment of strength may have led to under-diagnosis of statin-induced myopathy. A brief MMT before cholesterol-lowering agents are started and at follow-up visits, a 12-week withdrawal of the statin in the presence of new paresis without an alternative cause, and the exam finding that strength recovers off the statin are necessary to assess the incidence of drug-induced proximal weakness and inform alternative therapeutic strategies.

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.

BACKGROUND: Several pasture management strategies have been proposed to avoid hypoglycin A (HGA) intoxication in horses, but their efficacy has never been investigated.
OBJECTIVE: To evaluate the effect of mowing and herbicidal spraying on HGA content of sycamore seedlings and the presence of HGA in seeds and seedlings processed within haylage and silage.
METHODS: Experimental study.
METHODS: Groups of seedlings were mowed (n = 6), sprayed with a dimethylamine-based (n = 2) or a picolinic acid-based herbicide (n = 1). Seedlings were collected before intervention, and at 48 h, 1 and 2 weeks after. Cut grass in the vicinity of mowed seedlings was collected pre-cutting and after 1 week. Seeds and seedling (n = 6) samples processed within haylage and silage were collected. HGA concentration in samples was measured using a validated LC-MS-based method.
RESULTS: There was no significant decline in HGA content in either mowed or sprayed seedlings; indeed, mowing induced a temporary significant rise in HGA content of seedlings. HGA concentration increased significantly (albeit to low levels) in grass cut with the seedlings by 1 week. HGA was still present in sycamore material after 6-8 months storage within either hay or silage.
CONCLUSIONS: Restricted number of herbicide compounds tested.
CONCLUSIONS: Neither mowing nor herbicidal spraying reduces HGA concentration in sycamore seedlings up to 2 weeks after intervention. Cross contamination is possible between grass and sycamore seedlings when mowed together. Mowing followed by collection of sycamore seedlings seems the current best option to avoid HGA toxicity in horses grazing contaminated pasture. Pastures contaminated with sycamore material should not be used to produce processed hay or silage as both seedlings and seeds present in the bales still pose a risk of intoxication.

The goal of this article is to provide physiatrists, neurologists, and neuromuscular medicine physicians a framework that can be easily used in the process of evaluating, identifying, and treating patients with toxic myopathies. This review attempts to classify these rare but potentially deadly conditions in clinical patterns and distinguishes the cellular mechanisms in which the offending agents tend to impact the structure and function of myocytes.

Nrf2 (nuclear factor [erythroid-derived 2]-like 2; the transcriptional master regulator of the antioxidant stress response) is regulated through interaction with its cytoplasmic inhibitor Keap1 (Kelch-like ECH-associated protein 1), which under basal conditions targets Nrf2 for proteasomal degradation. Sequestosome 1 (SQSTM1)/p62-a multifunctional adapter protein that accumulates following autophagy inhibition and can serve as a diagnostic marker for human autophagic vacuolar myopathies (AVMs)-was recently shown to compete with Nrf2 for Keap1 binding, resulting in activation of the Nrf2 pathway. In this study, we used 55 human muscle biopsies divided into five groups [normal control, hydroxychloroquine- or colchicine-treated non-AVM control, hydroxychloroquine- or colchicine-induced toxic AVM, polymyositis, and inclusion body myositis (IBM)] to evaluate whether Keap1-SQSTM1 interaction led to increased Nrf2 signaling in human AVMs. In toxic AVMs and IBM, but not in control muscle groups or polymyositis, Keap1 antibody labeled sarcoplasmic protein aggregates that can be used as an alternate diagnostic marker for both AVM types; these Keap1-positive aggregates were co-labeled with the antibody against SQSTM1 but not with the antibody against autophagosome marker LC3 (microtubule-associated protein 1 light chain 3). In human AVM muscle, sequestration of Keap1 into the SQSTM1-positive protein aggregates was accompanied by an increase in mRNA and protein levels of Nrf2 target genes; similarly, treatment of differentiated C2C12 myotubes with autophagy inhibitor chloroquine led to an increase in the nuclear Nrf2 protein level and an increase in expression of the Nrf2-regulated genes. Taken together, our findings demonstrate that Nrf2 signaling is upregulated in autophagic muscle disorders and raise the possibility that autophagy disruption in skeletal muscle leads to dysregulation of cellular redox homeostasis.