Corticosteroid-induced myopathy is a highly prevalent toxic noninflammatory myopathy, which occurs as an adverse effect of prolonged oral or intravenous glucocorticoid use. It was first described in 1932 by Harvey Cushing, as part of a constellation of symptoms seen in Cushing syndrome. With the broader use of corticosteroids as therapeutic tools in the 1950s, corticosteroid-induced myopathy became a more well-known entity. This toxic noninflammatory myopathy typically has an indolent presentation and predominantly affects pelvic girdle muscles, and is associated with muscle weakness, atrophy, without associated pain. Acute steroid-induced myopathy in the critical care setting is another presentation. Workup typically reveals normal creatine kinase and no other signs of inflammatory disease, with EMG studies unremarkable and biopsy showing atrophy of type 2b fast-twitch muscle fibers. The diagnosis requires a high index of suspicion and is confirmed when muscle weakness improves after 3 to 4 weeks of tapering steroids, although improvement may take months to a year. Other than steroid withdrawal, other options include switching from fluorinated to nonfluorinated glucocorticoids, or alternate day dosing. Additionally, physical therapy in the form of resistance and aerobic exercise has shown in some studies to prevent and treat steroid-induced myopathy. As such, a program of screening for steroid-induced myopathy should be implemented in the appropriate patient population, and patients should be prescribed physical therapy as a preventive and treatment modality for this condition.
Corticosteroid-induced myopathy is a toxic noninflammatory myopathy caused by exogenous corticosteroid administration. The condition typically develops with doses higher than 10 mg prednisone equivalents/day used for four weeks or longer. However, 2 to 3 weeks of higher doses (such as 40 to 60 mg prednisone/day) has been associated with more acute presentations. Oral and intravenous formulations are most associated with corticosteroid myopathy, although case reports exist regarding steroid myopathy following inhaled corticosteroids and epidural, intramuscular, or intra-articular injection. For patients in the intensive care setting undergoing mechanical ventilation and receiving curare-like paralytics, doses of methylprednisolone greater than 60 mg/day for 5 to 7 days are also associated with acute steroid myopathy.
Corticosteroid induced myopathy is the most common drug-induced myopathy, with an incidence of 50 to 60% among those using corticosteroids for a prolonged period. While any individual on chronic corticosteroids can be affected, elderly patients are most at risk due to lower baseline muscle mass, as are patients with oncologic diseases. Additional risk factors for corticosteroid-induced myopathy include patients with prior muscle disease or spinal cord injury, chronic respiratory illness, poor nutritional status, and sedentary lifestyle. Women are more prone to developing corticosteroid-induced myopathy, although the mechanism of this is unclear. In the acute illness setting, patients on mechanical ventilation who receive neuromuscular blockade with curare-like agents and receive high dose steroids are also at high risk for developing acute steroid-induced myopathy, which may take weeks to recover. Of note, case reports do exist of nonventilated patients experiencing acute early-onset steroid myopathy (defined as <2 weeks from the start of treatment) even with moderate steroid doses and unusual muscle involvement such as the vocal cords. Thus the epidemiology of the condition is highly variable.
Corticosteroid induced myopathy is believed to occur through both catabolic and anti-anabolic mechanisms. In terms of catabolic mechanisms, corticosteroids upregulate proteolytic systems such as the ubiquitin-proteasome system, cathepsins (lysosomes), and calpains (calcium-dependent systems). This increases the proteolysis of myofibrillar proteins by dissociating actin from myosin. Corticosteroids also induce myocyte apoptosis through receptor-based signaling pathways as well as mitochondrial-based signaling pathways involving cytochrome c and the caspase cascade. In terms of anti-anabolic mechanisms, corticosteroids inhibit amino acid transport into cells, inhibit muscle IGF-I production, and down-regulate differentiation of satellite cells into muscle fibers by blocking the transcription factor called myogenin, thus inhibiting protein synthesis and myogenesis. Additionally, corticosteroids with high mineralocorticoid activity lower serum potassium and phosphate, which may contribute to muscle weakness.
Muscle biopsy, if performed, reveals atrophy of type 2b or fast-twitch muscle fibers, with less impact on type 1 or slow-twitch muscle fibers, with variability in fiber size and centralization of nuclei, without evidence of inflammation or necrosis. The preferential atrophy of type 2b fibers, which have high glycolytic and low oxidative capacity supports the predominant involvement of extremity skeletal muscles rather than respiratory muscles.
Symptoms of corticosteroid-induced myopathy consist of muscle weakness, typically in a symmetric distribution involving the proximal extremity muscles, with the hip girdle affected more and earlier than the shoulders. It is associated with long term muscle atrophy, notably with very minimal or no associated pain. Onset is typically insidious, with the range being weeks to months from initiation of corticosteroids. Patients often complain of difficulty rising from a seated position, climbing stairs, and trouble with overhead activities. History will invariably include ongoing oral or intravenous corticosteroid use, particularly prolonged fluorinated glucocorticoid exposure. It is important to observe that the higher doses are more likely to induce clinical myopathy. On physical exam, in one study, up to 20% of patients show objective signs of muscle weakness, although a subjective feeling of weakness occurs in 60%. The remainder of the physical exam can reveal decreased muscle stretch reflexes in the affected extremities; however, there are no sensory deficits and no neurological deficits that would point to a central nervous/spinal cord etiology and no cranial nerve involvement. Patients may have additional sequelae of chronic glucocorticoid administration, including Cushing syndrome stigmata, such as moon facies and fat redistribution. They may have metabolic complications, including obesity, diabetes, adrenal insufficiency, hyperlipidemia, hypertension, skin, and bone disorders, including osteoporosis and avascular necrosis. Other complications of chronic steroid use include increased susceptibility to infection, gastritis, cataracts, glaucoma, and mood/neurocognitive side effects. Thus patients may present with several complications of chronic steroid use.
Corticosteroid-induced myopathy is a clinical diagnosis that requires a high index of suspicion. Labwork including creatine kinase (CK), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and aldolase are typically normal, although these may be elevated very early in the disease process or acute steroid myopathy of critically ill patients. Muscle biopsy is not required for diagnosis, although, when performed, it may show nonspecific type 2b muscle fiber atrophy without inflammatory infiltrate, with variable fiber size and centrally located nuclei; necrosis is rare. The unremarkable lab and biopsy findings help differentiate corticosteroid-induced myopathy from other inflammatory myopathies. EMG findings are typically normal, with an occasional slight reduction in the amplitude of the motor unit potentials. This occurs as EMG measures both type 1 and type 2 fiber activity, and does not differentiate in the preferential atrophy of type 2b muscle fibers. Imaging, including MRI, is rarely performed for corticosteroid-induced myopathy, except when evaluating for alternate diagnoses. Sometimes, in patients on steroids for inflammatory myopathy, it is difficult to distinguish the muscle weakness arising from the worsening of the underlying myopathy to the symptoms arising from the newly developing corticosteroid-induced myopathy. Determination of corticosteroid-induced myopathy is ultimately tested and confirmed when symptoms improve with tapering or discontinuing corticosteroids.
Corticosteroid-induced myopathy is an often overlooked diagnosis, as symptoms are occasionally attributed to the primary illness that the corticosteroid is treating. This prolongs time to diagnosis and increases morbidity. Thus, a high index of suspicion must be maintained when patients present with muscle weakness in any muscle group (with particular emphasis on pelvic girdle) with any dose, route, or duration of steroids. Reduction or, ideally, discontinuation of the corticosteroid is the mainstay of treatment, with close monitoring for adrenal insufficiency and exacerbation of the primary illness during the discontinuation process. For patients unable to taper off steroids, replacement of fluorinated glucocorticoids with non-fluorinated glucocorticoids, such as dexamethasone with prednisone or hydrocortisone should be considered. Although the mechanism is not clear, fluorinated glucocorticoids are known to be much more potent than non-fluorinated glucocorticoids, and this may contribute to their higher toxicity. For patients with primary brain tumors on the fluorinated glucocorticoid dexamethasone, the anticonvulsant phenytoin has been used with dexamethasone to reduce the risk of developing corticosteroid-induced myopathy, as phenytoin is thought to help facilitate hepatic dexamethasone metabolism. Other options include non-daily dosing regimens. However, steroid-sparing treatments should be prioritized whenever possible. Diagnosis is confirmed when muscle strength improves within 3 to 4 weeks of tapering steroids, although recovery may take months to a year. In addition to steroid withdrawal, supportive management with an emphasis on physical therapy should be considered for both prevention and treatment. Physical therapy with aerobic and resistance exercises is effective at modulating muscle atrophy in patients who have corticosteroid-induced myopathy. Even for patients unable to taper off steroids, in a study of heart transplant recipients on chronic glucocorticoids (approximately 10 mg prednisone/daily), a 6-month regimen of monitored resistance training (with focus on low back and whole-body resistance exercises) successfully reversed corticosteroid-induced muscle atrophy and improved skeletal muscle strength 400% to 600% in the treatment versus the control group. Experimental agents such as exogenous IGF-I, branched-chain amino acids, creatine, androgens (testosterone, DHEA), glutamine have been investigated in animal models. However, they have not been conclusively evaluated in humans and are not currently recommended.
Other medications known to cause a drug-induced myopathy include colchicine, antimalarials, and antiretrovirals. Drug-induced myopathy should be considered mainly for patients taking two myopathic agents such as hydroxychloroquine and glucocorticoids for inflammatory disorders. Statins have been known to cause a myopathy, which typically presents with myalgias and evidence of muscle inflammation on labwork; an autoimmune necrotic myopathy in the setting of statin use has been reported in the literature. Other toxic substances, such as alcohol and cocaine, can also cause myopathy. Organic causes of myopathy should be ruled out and include inflammatory diseases such as polymyositis and dermatomyositis.
In contrast to corticosteroid-induced myopathy, these present with elevated muscle enzymes, worsening muscle weakness with discontinuation of steroids, systemic signs of muscle breakdown and inflammation, and characteristic "early recruitment" findings on EMG. On biopsy, inflammatory myopathies show endomysial or perivascular inflammation and perifascicular atrophy, whereas corticosteroid-induced myopathy shows predominantly type 2b muscle fiber atrophy without inflammation.
Additionally, myositis may present as a manifestation of systemic lupus erythematosus, Sjögren syndrome, scleroderma, and rheumatoid arthritis; these organic causes of myopathy should be considered when diagnosing corticosteroid-induced myopathy. Given the increased risk for malignancy in dermatomyositis, paraneoplastic syndromes can be on the differential. More broadly, endocrine disorders (thyroid, adrenals, or pituitary), electrolyte abnormalities (potassium, calcium), and nutrient deficiencies (such as low vitamin D) can cause muscle weakness. Metabolic myopathies related to carbohydrate, lipid, and purine metabolism and congenital myopathies are more rare causes of muscle weakness and have distinct patterns of presentation. Thus, a broad differential exists, and each patient should be evaluated in their clinical context.
Corticosteroid-induced myopathy is reversible, with improvement in myopathy within 3 to 4 weeks of tapering corticosteroids, although recovery can take months to a year. Other than withdrawing corticosteroids, there are no known pharmacotherapies to accelerate recovery. Switching from fluorinated glucocorticoids like dexamethasone to nonfluorinated glucocorticoids such as prednisone can sometimes help. It should be recognized that many of the patients on the chronic steroid therapy would need to be weaned off slowly from their steroid regimen to avoid adrenal insufficiency or exacerbation of the disease process for which they have been on long term steroids. Physical therapy, with both resistance and endurance exercise, taking into account baseline functional status, is recommended to help prevent and treat glucocorticoid-induced myopathy.
Complications of corticosteroid-induced myopathy include the morbidity and subsequent mortality associated with chronic muscle weakness. Patients experience decreased quality of life through the inability to perform activities of daily living and are at increased risk for falls and injury. In patients with treatment-resistant asthma on chronic corticosteroids, corticosteroid-induced myopathy should be entertained as a contributing factor to uncontrolled asthma and chronic respiratory failure.
Patients should routinely be educated on the risk versus benefit profile of corticosteroids, including the risk of corticosteroid-induced myopathy. Patients should be advised to contact their provider if they notice weakness developing. Patients should be informed that physical activity can help prevent and mitigate the effects of corticosteroid-induced myopathy, and should be prescribed physical therapy as part of a preventive and treatment regimen.
Given the high incidence of corticosteroid-induced myopathy in patients receiving glucocorticoid therapy for a wide range of clinical indications, interdisciplinary teams should implement systematic clinical screening for corticosteroid-induced myopathy in the appropriate patient populations. Since Primary care physicians are the most frequently and consistently involved specialty in taking care of such patients, they should maintain a high degree of suspicion for this diagnosis. Additionally, providers and team members should systematically recommend and prescribe physical therapy to prevent and treat corticosteroid-induced myopathy.
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