Toxic myopathies are a diverse group of muscle disorders caused by a variety of medications and toxins. These conditions may be classified by their presumed histo-pathological 4 pattern, which is observed on muscle biopsy. 4
Muscle tissue is highly sensitive to drugs and toxins because of its high metabolic activity. The exact pathophysiologic mechanisms are not fully known.
Epidemiology including risk factors and primary prevention
Baseline risk factors for toxic myopathy include:
- Decreased ability to metabolize or excrete a drug and its metabolites
- Hepatic or renal failure
- Older adults
- Concomitant use of statin drugs plus fibrates, macrolide antibiotics, azole antifungals, cyclosporine, amiodarone, verapamil, diltiazem, cimetidine, and/or other drugs sharing cytochrome P450 metabolism system.
- Lipid Lowering drugs (LLD) including Statin is the most commonly reported toxic agent associated with adverse effects of toxic myopathy.4, 8 For statin users, as many as 2-20% develop toxic myopathy. 7 The incidence of rhabdomyolysis is even more rare, occurring at a rate of 0.44 per 10,000 patient-years.9,13 Higher rates of adverse effects among the statins are associated with atorvastatin, with intermediate risk with simvastatin, lovastatin, and pravastatin.11
- Statin induced toxic myopathy symptoms resolved within 1 week to 3 months after stopping statins.4
- Many other drugs including other LLD (niacin and ezetimibe) and cyclosporine interact with statin and increase the risk of toxic myopathy.5
Fibric acid derivatives
- According to a 6-year cohort study, the risk for myopathy is greatest for fibrates rather than for statins.13
- The primary risk factor for colchicine myopathy is chronic renal disease.13
The pathophysiology of toxic myopathies is variable and poorly understood.5 Hypotheses being tested relate to the degree of lipophilicity, effects on ion channels in sarcolemma, intracellular calcium homeostasis, potential deficiency of ubiquinone, primary mitochondrial membrane pathology, organic anion transporters, and energy depletion.11,13
Toxic myopathies may be classified by presumed histo-pathological 4 mechanisms:
- Necrotizing myopathies and rhabdomyolysis: marked by the death of myocytes, with secondary inflammatory cells (macrophages) engulfing the dead myocytes.
- HMG CoA reductase inhibitors or statins
- Fibric acid derivatives
- Food/nutritional remedies:
- Edible mushroom (Tricholoma equestre)
- Red yeast rice (Monascus purpureus)
- Mitochondrial myopathy:4 Zidovudine (nucleoside analog reverse transcriptase inhibitor) anti-retroviral medication, causes primary mitochondrial pathology with chronic use.4 Pathogenic mechanism for Telbivudine, lamivudine, entecavir and other antiretrovirals for HIV and hepatitis B is poorly understood at present.5,6
- Antimicrotubular myopathies: Accumulation of vacuolation5 occurs in the absence of necrosis and is caused by the impairment of lysosomal trafficking on microtubules.
- Immunophilins: mechanism not fully known, may destabilize the lipophilic muscle membrane.
- Lysosomal storage myopathy:4 Amphiphilic drugs Cause neuromyopathy,5 as amphiphilic drugs interact with anionic phospholipids of cell membranes and organelles.
- Drug-induced inflammatory myopathies
- HMG-CoA reductase inhibitors (Statin)4
- Toxic oil syndrome
- Phenytoin sodium
- Imatinib mesylate
- Immune checkpoint inhibitors (ICIs) myopathy4,5 Cause inflammatory myopathy
- Other toxic myopathies
- Steroid myopathy
- Alcoholic myopathy
- Myopathies secondary to illicit drugs (cocaine, amphetamine etc.5)
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- The development of a toxic myopathy generally occurs weeks to months after regular exposure to the toxin or medication.12
- Symptoms are dose-related and include proximal weakness with muscle cramps and pain. In statin myopathies, the creatine kinase (CK) level may be normal or there may be asymptomatic CK increases.14
- With continued exposure to the toxin, the patient may develop severe weakness, fulminant rhabdomyolysis, and renal failure, which can be fatal.
- With withdrawal of the toxin and supportive treatment, gradual resolution of weakness typically occurs over weeks to months.5 Early recognition is important, with greater likelihood of full recovery with sooner diagnosis.
- In patients who fail to improve with drug withdrawal, a muscle biopsy should be considered to evaluate for an inflammatory or necrotizing autoimmune myopathy.4
Specific secondary or associated conditions and complications
Possible generalized complications of toxic myopathy include:
- Rhabdomyolysis, which is defined by the United States Food and Drug Administration’s voluntary Adverse Event Reporting System as CK levels greater than 50 times the upper limits of normal (ULN) with clinical features of organ damage, such as renal failure.15
- Kidney failure secondary to rhabdomyolysis.
Essentials of Assessment
History typical for a toxic myopathy includes the following symptoms:
- Muscle cramps and muscle pain:4 The timing of symptoms is important, because the most common causes are related to osteoarthritis, radiculopathy, or hypothyroidism.
- Limb-Girdle (Symmetrical Proximal leg and arm muscle) weakness: difficulty ascending/descending stairs, rising from chair or floor, combing hair, or lifting/reaching overhead objects.4
- Lack of sensory complaints.
Physical exam findings consistent with a myopathy include:
- Proximal muscle weakness.
- Normal sensory exam.
- Decreased or absent deep tendon reflexes.
- Gait abnormalities to suggest proximal weakness, such as a Trendelenburg gait pattern.
- Mobility may be affected if there is significant proximal weakness. There may be difficulty ascending/descending stairs or walking with severe proximal weakness.
- Self-care may be affected by proximal upper extremity weakness and may include difficulty performing grooming, dressing and feeding self.4
The diagnosis of a toxic myopathy is a diagnosis of exclusion.12
Creatine Kinase (CK) MM subtype4
- It is helpful to have a baseline CK for comparison, because normative ranges for CK are broad, and it is possible for a patient to have muscle injury with a result that is within the reference range.12
- Symptomatic myopathy includes all statin-associated muscle complaints, such as muscle pain in proximal large muscle groups, weakness, and cramps in small muscles in the hands and feet.1, 5
- CK levels are typically normal in the early stages. For statin myopathy, the National Lipid Association has proposed definitions based on the presence of muscle symptoms and degree of CK elevation:
- mild (>normal to <10 the ULN)
- moderate (>10 but <50 times the ULN)
- marked (>50 times the ULN)14
- Acute rhabdomyolysis may develop with serum CK as high as 2000 times the ULN and is associated with myoglobinuria4, 12
Anti-HMG-CoA reductase antibody test5,7
- Thyroid function studies should be ordered to evaluate for hypothyroidism, which is a potential cause of an elevated CK level.11
- Monitor for acute renal insufficiency
Imaging studies are not generally indicated. However, ultrasound, proximal muscle MRI and muscle biopsy are useful to complement complex clinical assessment in the cases for differential and definitive diagnosis, where symptoms get worse despite discontinuation of possible toxic agent.4
Supplemental assessment tools
Electromyography (EMG) can be helpful to confirm a myopathic process if symptoms do not resolve with discontinuance of the suspected toxin. Abnormal findings on an EMG suggestive of a myopathy include:
- Non-specific finding: Abnormal spontaneous activity (fibrillations, positive sharp waves and/or complex repetitive discharges) in proximal muscles.4,5
- Specific findings: Motor unit configuration with low-amplitude, short-duration motor unit action potentials (MUAP) firing in an early recruitment pattern in weak muscles.4,5
Steroid myopathy preferentially affects type 2 muscle fibers. Given an EMG records type 1 muscle fibers, the EMG will be normal in the setting of steroid myopathy. Muscle biopsy may be needed if the patient’s symptoms do not respond to drug withdrawal.
Muscle biopsy: Not generally indicated, however useful when non-invasive workup fails to diagnose the cause of toxic myopathy. Hallmarks of different toxic myopathy on muscle biopsy include necrosis, muscle atrophy, inflammation, vacuoles or red ragged fibers.4,7
Early predictions of outcomes
Prompt recognition based on history and physical exam, timely stopping offending toxic agents will help with improvement and resolution of symptoms in most cases,5 reduce further muscle damage and improve quality of life.4
For statin myopathies, most patients present with milder complaints, such as myalgia, weakness, cramps, and mild CK increases.14 A treatment algorithm proposed includes:
- Patient with intolerable symptoms or with CK levels greater than 10 times the ULN should stop the statin.
- CK levels between 5-10 times the ULN, CK should be monitored monthly and the patients should be watched for symptom escalation
- CK less than 5 times the ULN, monitor symptoms only14
Most statin myalgias symptoms in early stages are reversible4,7symptoms resolve in 1-2 weeks but may take up to 3 months for complete resolution.
Symptoms that progress beyond 3 months following statin cessation may indicate a statin-associated immune-mediated necrotizing myopathy (SANAM) also called anti-HMG-CoA reductase myopathy5, often requires aggressive immunosuppressive therapy such as high-dose oral steroids, IV immunoglobulin (IVIg), and other steroid-sparing agent such as methotrexate.5,7
- After resolution of toxic myopathy, a decision may be made to rechallenge the patient with a lower dose of medication or a similar agent. This will require consideration of the associated risks/benefits.14
- It is important to recognize that there is a high incidence of myalgias in both the placebo and toxic myopathy groups.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Rehabilitation management of a patient with toxic myopathy includes supportive physical and occupational therapy for passive range of motion to prevent contractures, strengthening as the patient’s CK level normalizes, and providing adaptive devices when appropriate.
Under a physician’s guidance, patients with myopathies can begin gradual and gentle strength training and submaximal aerobic exercise on alternating days. Patients should be informed that if severe muscle pain and/or myoglobinuria occurs, exercise should be decreased. When symptoms resolve, exercise can gradually be resumed.10
Coordination of care
Consultation with the patient’s primary care physician or other specialist for alternative therapeutic agents is recommended.
Patient & family education
The patient should always be counseled on the potential toxic side effects of medications and potential drug interactions at the time the medications are prescribed.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
- It is recommended to obtain a baseline CK level prior to initiation of a statin drug. This will help identify patients with asymptomatic elevation of a CK level prior to drug initiation.11
- Cramps and myalgias are common complaints in the general population and are more commonly caused by osteoarthritis or cervical or lumbar radiculopathy than toxic myopathy.
Cutting Edge/ Emerging and Unique Concepts and Practice
Cutting edge concepts and practice
Areas of research for statin myopathy include:
- Zebrafish has recently been used as a research animal model. Zebrafish mevalonate pathway, distrubed in statin induced myotoxicity in-vivo systems, closely mimic human condition. Zebrafish may become a valid research model in future to study further on preclinical trials of new safer and more effective LLD mechanisms and understanding details about drugs adverse effects such as statin induced myopathy mechanism.1
- There have been numerous case reports in coronavirus disease 2019 (COVID-9) critically ill patients caused by SARS CoV-2, having neuromuscular presentation such as myopathies, critical illness myopathy (CIM), intensive care unit (ICU) acquired weakness (ICUAW) and Rhabdomyolysis 2, 3. However, given the fact that is COVID-19 is a relatively new fatal disease with multi-organ systemic presentation, multiple variants, limited data, lacking long term data. Also as these patients requires prolong hospitalization including intubation and ICU stay, treated with steroid medication due to respiratory failure or given experimental anti-malarial medication (Chloroquine) or may be already taking LLD at time of presenting with COVID-19 symptoms, further large scale, long term observational research studies will help us to understand; if neuromuscular involvement in COVID-19 patients is due to CIM, medication induced toxic myopathy or separate unknown entity of COVID-19 induced post-viral myopathy.
- Genetic susceptibility testing to identify individuals at greater risk of developing toxic myopathy with statin use and screening. A genome-wide study identified a genetic variant in the SLCO1B1 gene that encodes the organic anion-transporting polypeptide hepatic transporter for statins. Around 2% of the general population have this variant and it is estimated that about 15% of these patients would develop a myopathy within the first year of using simvastatin at a high dose of 80 mg/day.9 Over 60% of statin myopathy cases had a C allele of the rx4149056 single nucleotide polymorphism of SLCO1B1.11
- Search for third generation statin drugs with less myotoxic potential.
Gaps in the Evidence- Based Knowledge
The pathophysiology of the toxic myopathies is not fully understood yet. Further research to clarify the underlying mechanism is needed.
- Magda Dubińska-Magiera. Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies, Int J Mol Sci. 2021 Jun; 22(11): 5654.
- Julie Byler, Rebecca Harrison. Rhabdomyolysis Following Recovery from Severe COVID-19: A Case Report, Am J Case Rep 2021 May 8;22:e931616
- Lidia Cabañes-Martínez. Neuromuscular involvement in COVID-19 critically ill patients. Clin Neurophysiol. 2020 Dec;131(12):2809-2816
- Lando Janssen, Silvie Timmers. Muscle toxicity of drugs: When Drugs turn physiology into pathophysiology. Physiological Reviews. 2020 Apr 1;100(2):633-672.
- Christopher T. Doughty, Anthony Amato. Toxic myopathies. Continuum (Minneap Minn). 2019 Dec;25(6, Muscle and Neuromuscular Junction Disorders):1712-1731
- Takayuki Fujii, Kei-ichiro Takase, Jun-ichi Kira. Toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B: A case study. 07 March 2019 https://doi.org/10.1111/neup.12548 (Japanese Society of Neuropathology)
- Salik Nazir, Saroj Lohani. Statin-Associated Autoimmune Myopathy: A Systematic Review of 100 Cases. J Clin Rheumatol. 2017 Apr;23(3):149-154
- Hans Katzberg, Charles Kassardjian. Toxic and Endocrine Myopathies. Continuum (Minneap Minn). 2016 Dec;22(6, Muscle and Neuromuscular Junction Disorders):1815-1828
- Mammen AL. Toxic myopathies. Continuum (Minneap Minn). 2013;19(6 Muscle Disease):1634-49
- Anziska, Y., & Sternberg, A. (2013). Exercise in neuromuscular disease. Muscle & nerve, 48(1), 3-20.
- Mastaglia FL, Needham M. Update on toxic myopathies.Curr Neurol Neurosci Rep. 2012;12:54-61.
- Valiyil R, Christopher-Stine L. Drug-related myopathies of which the clinician should be aware. Curr Rheumatol Rep. 2010:12:213-220.
- Kuncl RW. Agents and mechanisms of toxic myopathy. Curr Opin Neurol. 2009;22:506-515.
- Siddiqi S, Thompson P. How do you treat patients with myalgia who take statins? Curr Atheroscler Rep. 2009,11:9-14.
- Sieb JP, Gillessen T. Iatrogenic and toxic myopathies. Muscle Nerve. 2003;27:142-156.
Original Version of the Topic
Suzanne Woodbury, MD. Toxic myopathy. 11/27/2012.
Previous Revision(s) of the Topic
David Haustein, MD; Clinton Johnson, DO; Poonam Ochani, MD; and Mariko Kubinec, MD. Toxic myopathy. 7/31/2017
Poonam Ochani, MD
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