Toxic myopathy

Author(s): David Haustein, MD; Clinton Johnson, DO; Poonam Ochani, MD; and Mariko Kubinec, MD

Originally published:11/27/2012

Last updated:7/31/2017

1. DISEASE/DISORDER:

Definition

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 pathogenic pattern, which is often either purely necrotizing or vacuolar.

Etiology

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:

  1. Decreased ability to metabolize or excrete a drug and its metabolites
  2. Hepatic or renal failure
  3. Older adults
  4. Infants/children
  5. 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.

Statin myopathy

  • For statin users, as many as 20% experience mild musculoskeletal effects, such as myalgia or cramps.1 The precise frequency of toxic myopathy as a result of statin use is unknown, but rare, on the order of 1 in 10,000-20,000 person-years.  The incidence of  rhabdomyolysis  is even more rare, occurring at a rate of 0.44 per 10,000 patient-years.1,2  Higher rates of adverse effects among the statins are associated with atorvastatin, with intermediate risk with simvastatin, lovastatin, and pravastatin.3

Fibric acid derivatives

  • According to a 6-year cohort study, the risk for myopathy is greatest for fibrates rather than for statins.2

Colchicine myopathy

  • The primary risk factor for colchicine myopathy is chronic renal disease.2

Patho-anatomy/physiology

The pathophysiology of toxic myopathies is variable and not fully known. 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.2,3

Toxic myopathies may be classified by presumed pathogenic mechanisms:4,5,6

  1. Necrotizing myopathies and rhabdomyolysis: marked by the death of myocytes, with secondary inflammatory cells (macrophages) engulfing the dead myocytes.
    1. HMG CoA reductase inhibitors or statins
    2. Fibric acid derivatives
    3. Niacin
    4. Zidovudine (nucleoside analog reverse transcriptase inhibitor)
      1. Causes necrotizing myopathy, but also causes primary mitochondrial pathology in nonnecrotic muscle fibers
    5. Food/nutritional remedies:
      1. Edible mushroom (Tricholoma equestre)
      2. Red yeast rice ( Monascus purpureus)
  2. Antimicrotubular myopathies: vacuolation occurs in the absence of necrosis and is caused by the impairment of lysosomal trafficking on microtubules.
    1. Colchicine
    2. Vincristine
  3. Immunophilins:mechanism not fully known, may destabilize the lipophilic muscle membrane.
    1. Cyclosporine
    2. Tacrolimus
  4. Amphiphilic drugs: neuromyopathy because of amphiphilic drug interacting with anionic phospholipids of cell membranes and organelles.
    1. Chloroquine
    2. Hydroxychloroquine
    3. Amiodarone
  5. Drug-induced inflammatory myopathies
    1. L-tryptophan
    2. Toxic oil syndrome
    3. D-penicillamine
    4. Phenytoin sodium
    5. Procainamide
    6. Interferon-alpha
    7. Imatinib mesylate
  6. Other toxic myopathies
    1. Steroid myopathy
    2. Emetine
    3. Omeprazole
    4. Alcoholic myopathy
    5. Myopathies secondary to illicit drugs

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.7
  • 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.8
  • 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. 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.7

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.4
  • Kidney failure secondary to rhabdomyolysis.

2. ESSENTIALS OF ASSESSMENT

History

History typical for a toxic myopathy includes the following symptoms:

  1. Muscle cramps and myalgias. The timing of symptoms is important, because the most common causes are related to osteoarthritis, radiculopathy, or hypothyroidism.
  2. Proximal muscle weakness: difficulty ascending/descending stairs, arising from chair or floor, or reaching overhead.
  3. Lack of sensory complaints.

Physical examination

Physical exam findings consistent with a myopathy include:

  1. Proximal muscle weakness.
  2. Normal sensory exam.
  3. Decreased or absent deep tendon reflexes.
  4. Gait abnormalities to suggest proximal weakness, such as a Trendelenburg gait pattern.

Functional assessment

  • 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 and feeding self.

Laboratory studies

The diagnosis of a toxic myopathy is a diagnosis of exclusion.7

Creatine Kinase (CK)

  • 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.7
  • Symptomatic myopathy includes all statin-associated muscle complaints, such as myalgia, weakness, and cramps.
  • 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)8
  • Acute rhabdomyolysis may develop with serum CK as high as 2000 times the ULN and is associated with myoglobinuria7

Thyroid function

  • Thyroid function studies should be ordered to evaluate for hypothyroidism, which is a potential cause of an elevated CK level.3

Renal function

  • Monitor for acute renal insufficiency

Imaging

Imaging studies are not generally indicated.

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:

  1. Abnormal spontaneous activity (fibrillations and/or positive sharp waves) in proximal muscles.
  2. Motor unit configuration with small-amplitude, short-duration motor unit action potentials firing in an early recruitment pattern.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.

Early predictions of outcomes

For statin myopathies, most patients present with milder complaints, such as myalgia, weakness, cramps, and mild CK increases.8 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 only 8

Most statin myalgias resolve in 1-2 weeks but may take up to 2 months for complete resolution, according to the Predictor of Muscular Risk in Observational Conditions study.5

Symptoms that progress beyond 2 months following statin cessation may indicate a statin-associated immune-mediated necrotizing myopathy (SANAM) that often requires aggressive immunosuppressive therapy such as high-dose oral steroids, IV immunoglobulin (IVIg), and other steroid-sparing agent such as methotrexate.1

Professional Issues

  1. 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.8
  2. It is important to recognize that there is a high incidence of myalgias in both the placebo and toxic myopathy groups.

3. 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. 9

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

  1. 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.3
  2. 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.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

Areas of research for statin myopathy include:

  1. 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.1 Over 60% of statin myopathy cases had a C allele of the rx4149056 single nucleotide polymorphism of SLCO1B1.3
  2. Search for third generation statin drugs with less myotoxic potential.

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

The pathophysiology of the toxic myopathies is not fully understood. Further research to clarify the underlying mechanism is needed.

REFERENCES

  1. Mammen AL. Toxic myopathies. Continuum (Minneap Minn). 2013;19(6 Muscle Disease):1634-49
  2. Kuncl RW. Agents and mechanisms of toxic myopathy. Curr Opin Neurol. 2009;22:506-515.
  3. Mastaglia FL, Needham M. Update on toxic myopathies.Curr Neurol Neurosci Rep. 2012;12:54-61.
  4. Sieb JP, Gillessen T. Iatrogenic and toxic myopathies. Muscle Nerve. 2003;27:142-156.
  5. Walsh RJ, Amato AA. Toxic myopathies. Neurol Clin. 2005;23:397-428.
  6. Pasnoor M, Barohn RJ, Dimachkie, MM. Toxic Myopathies. Neurol Clin. 2014; 32(3): 647–670
  7. Valiyil R, Christopher-Stine L. Drug-related myopathies of which the clinician should be aware.Curr Rheumatol Rep. 2010:12:213-220.
  8. Siddiqi S, Thompson P. How do you treat patients with myalgia who take statins?Curr Atheroscler Rep. 2009,11:9-14.
  9. Anziska, Y., & Sternberg, A. (2013). Exercise in neuromuscular disease. Muscle & nerve48(1), 3-20.

Original Version of the Topic

Suzanne Woodbury, MD. Toxic myopathy. 11/27/2012.

Author Disclosure

David Haustein, MD
Nothing to Disclose

Clinton Johnson, DO
Nothing to Disclose

Poonam Ochani, MD
Nothing to Disclose

Mariko Kubinec, MD
Nothing to Disclose

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