Corticosteroid-Induced Myopathy

Steroid myopathy may be more frequent with the use of fluorinated steroids, such as dexamethasone[11] or triamcinolone, than with nonfluorinated ones, such as prednisone or hydrocortisone.[12, 13] Although the exact mechanism of the muscle pathology is unclear, it may be related to decreased protein synthesis, increased protein degradation, alterations in carbohydrate metabolism, mitochondrial alterations, electrolyte disturbances, and/or decreased sarcolemmal excitability. Sedentary lifestyle may increase the risk of muscle weakness in a patient taking corticosteroids, since corticosteroids seem to affect less active muscles preferentially. Two distinct types of steroid myopathy exist, acute and chronic. The chronic (or classic) form occurs after prolonged use of corticosteroids and has a more insidious course. The acute form is less common, is associated with rhabdomyolysis, and occurs abruptly while the patient is receiving high-dose corticosteroids.

One study used skeletal muscle biopsy of the vastus lateralis and real-time polymerase chain reaction (PCR) assay to investigate the effects of dexamethasone on skeletal muscle. Twenty-four subjects were studied before and after the administration of dexamethasone 4 mg by mouth daily for 4 days. Following dexamethasone, all subjects (12 female and 12 male) demonstrated similar decreases in serum testosterone and transcription factor 4 (TCF4), an androgen-responsive transcription factor. Additionally, a significant decrease in skeletal muscle androgen receptor mRNA levels occurred following dexamethasone administration. Furthermore, plasma insulinlike growth factor-1 (IGF-1), produced by the liver, increased significantly following dexamethasone administration, whereas skeletal muscle IGF-1 mRNA levels decreased. Further studies are needed to investigate the significance of these findings.[14]

In a study performed by Levin et al, 60% of participants who used inhaled corticosteroids daily for a year or greater reported muscle weakness and 20% of that group showed objective signs of weakness. These researchers measured inhaled steroid–induced myopathy using a peripheral motor deficits scale, stepper test, ankle/wrist index, neuropathy disability score, and statistical analysis. Peripheral motor deficits scale was formulated to determine early stages of myopathy with physician's rating of the participant's weakness while (1) walking up and down stairs and (2) with difficulty in buttoning/unbuttoning, sewing, or picking up coins. Muscle atrophy measurements were made using an ankle/wrist index, in which the smallest circumference of the dominant leg above the ankle and that of the forearm above the wrist were compared. Neuropathy disability score was determined by evaluation of sensory functions and reflexes.[15]

A study by Minetto et al found that short-term glucocorticoid administration in healthy subjects produced the sorts of changes in muscle fibers that arise prior to the clinical appearance of myopathy in patients treated with glucocorticoids. In the study, in which dexamethasone was administered to five healthy males for 7 days, type 1 and type 2A muscle fibers demonstrated a reduction in cross-sectional area, myosin, and specific force.[16]

Similarly, a study by Nawata et al suggested that steroid therapy is associated with a reduction in muscle volume. The study, which included seven patients with myositis and eight controls, used computed tomography (CT) scanning to observe steroidal effects on a cross section of skeletal muscle at the caudal end of the third lumbar vertebra. The investigators found that in both groups, following treatment with high doses of steroids, the cross-sectional area of skeletal muscle was reduced, while the low muscle-attenuation rate was increased. Nonetheless, the patients with myositis experienced an increase in muscle strength, apparently due to factors other than muscle volume change.[17]

Frequency

United States

The exact incidence of steroid myopathy is unknown; sensitivity to particular medications varies among patients.

Mortality/Morbidity

The weakness seen with steroid myopathy typically resolves after the corticosteroid dose is reduced or discontinued, although recovery can take weeks or months. Case studies have reported a lack of full recovery, as well as difficulty weaning patients off of mechanical ventilation. Osteoporosis, which can occur as a comorbidity with steroid myopathy, can result from the corticosteroid or from decreased mobility and respiratory impairment.[6] Other comorbidities include joint contractures, pressure ulcers, and deep vein thrombi, although these can occur in any condition causing weakness and immobility. Mortality has not been described. Some case studies have reported patient mortalities, but they provided no indication that steroid myopathy was the cause.

Sex

For a given dose of steroid, women appear to be twice as likely as men to develop muscle weakness, although the reason is unclear.

Chronic (classic) steroid myopathy history findings are as follows:

• This form is the classic presentation of steroid myopathy.

• This condition can develop after prolonged administration of prednisone at a dose of 40-60 mg/d.[12, 13] Although there is no clear length of time, onset of weakness has been found to occur within weeks to years following initiation of corticosteroid administration.

• Several studies have suggested that the risk for steroid-induced myopathy is greater in severely asthmatic patients who use oral steroids.[18] One study, however, found no significant difference in the prevalence of myopathy in oral steroid users and inhaled steroid users.

• A report by Stanton et al indicated that in 43 patients with asthma, a statistically significant association existed between inhaled corticosteroid dose and patient voice scores obtained using the GRBAS (grade-roughness-breathiness-asthenia-strain) system.[19] Despite this apparent relationship, however, evidence of steroid-induced myopathy was found in only 2 of the 43 patients.

• Fluorinated steroids seem to produce weakness and myopathy more frequently than do nonfluorinated ones.

• The insidious onset of proximal muscle weakness of the upper and lower limbs is a prominent clinical feature.

• Progressive proximal muscle weakness of the upper and lower limbs is reported.

• Patients typically complain of a progressive inability to rise from chairs, climb stairs, and perform overhead activities.

• Patients initially note little difficulty with hand strength.

• The facial and sphincter muscles usually are spared.

• Myalgias can become a prominent feature with time.

• Contrary to previous beliefs, several studies have shown involvement of the respiratory muscles (eg, the diaphragm); thus, pulmonary symptoms may be present.[6]

Acute steroid myopathy history findings are as follows:

• This form is encountered less frequently than is the chronic type.

• Acute, generalized weakness, including weakness of the respiratory muscles, typically occurs 5-7 days after the onset of treatment with high-dose corticosteroids.[6] Some case reports describe the development of muscle weakness after the administration of a single dose of corticosteroid.

• One study indicates a possible correlation between the occurrence of acute steroid myopathy and the total dose of steroid administered; acute atrophy was encountered with total doses of greater than 5.4 g of hydrocortisone in 6 days, whereas no signs of myopathy were noted with total doses of less than 4 g.

• Previous systemic corticosteroid use does not appear to contribute to the development of myopathy.

• An unexpectedly short time may pass from initial steroid administration to the onset of clinical myopathy. A study performed by Haran et al reviewed published reports of myopathy developing within 14 days of initiating corticosteroid treatment, as well as their own experiences with four patients. There were cases that began within just 1 hour of administration and other cases that began within just 1-3 days. The study also reported cases in which comparatively low doses, or even a single dose, of corticosteroid led to the onset of myopathic signs and symptoms. In addition, acute myopathy was reported to occur after various administration routes for the steroids, including intravenous, oral, intramuscular, epidural, and inhalation.[5]

Chronic (classic) steroid myopathy physical findings are as follows:

• Proximal muscle weakness is more pronounced than is distal muscle weakness; however, severe relative weakness of the anterior tibialis muscle can be found.

• Pelvic girdle muscles usually are affected more severely and earlier than are pectoral girdle muscles.

• Muscle bulk typically is normal, but muscle atrophy can occur.

• Muscle stretch reflexes typically are normal.

• Sensory examination should be normal.

Acute steroid myopathy physical findings are as follows:

• Generalized muscle weakness, not limited to a more proximal distribution, is noted.

• Involvement of bulbar and respiratory muscles can occur ^[5]

• Muscle stretch reflexes typically are normal.

• Sensory examination should be normal.

In chronic (classic) steroid myopathy, serum levels of creatine kinase typically are within the reference range. Creatinine excretion in the urine increases dramatically and can precede the clinical appearance of myopathy by several days.[1]  Myoglobinuria and rhabdomyolysis are absent.

In acute steroid myopathy, patients can have high levels of serum creatine kinase as well as associated myoglobinuria. According to Haran et al, however, muscle enzymes are often normal in acute, early onset myopathy associated with glucocorticoid treatment.[5]

Moreover, although circulating muscle proteins such as creatine kinase and myoglobin can be increased in acute steroid myopathy, glucocorticoid down-regulation of protein synthesis may lead to decreased levels of these proteins in chronic steroid myopathy.

A randomized, placebo-controlled study aimed to determine the effects of dexamethasone on circulating levels of muscle protein. Following 1 week of dexamethasone 8 mg by mouth daily, the 10 subjects in the experimental group all had significantly decreased serum creatine kinase levels, 4 of which fell below the lower limit of normal. Serum myoglobin was also decreased in all 10 subjects; however, there was a trend of greater decrease in creatine kinase than myoglobin, which corresponds to the greater expression of creatine kinase in type II muscle fibers. As mentioned previously, corticosteroid-induced myopathy causes preferential atrophy of type II muscle fibers.[20]

Muscle biopsy in chronic (classic) steroid myopathy

Muscle biopsy shows preferential atrophy of type II fibers, particularly the fast-twitch glycolytic fibers (type IIB).[6, 7] Some atrophy of other type II fibers and, to a small degree, type I muscle fibers can occur. Increased variation in the diameter of muscle fibers occurs. A lack of evidence of muscle fiber inflammation is reported. There is a distinct lack of necrosis or regeneration of muscle. Less active muscles appear to be affected preferentially.[21]

Muscle biopsy in acute steroid myopathy

Muscle biopsy shows focal and diffuse necrosis of all fiber types, without predilection for type II fibers.

Electromyography (EMG) and nerve conduction studies (NCSs) in chronic (classic) steroid myopathy

Motor and sensory NCS results typically are normal. Repetitive stimulation studies do not reveal significant decrement or increment. EMG studies reveal normal insertional activity with little abnormal spontaneous activity (positive sharp waves and fibrillation potentials). EMG may reveal a mild decrease in motor unit action-potential amplitude during maximal recruitment. In moderate-to-severe cases, studies may show an early recruitment pattern.[22]

EMG and NCS in acute steroid myopathy

Some case reports have indicated abnormal needle EMG findings, including abnormal spontaneous activity (positive sharp waves and fibrillation potentials), early recruitment, and small, polyphasic motor units. In addition, decreased amplitude of muscle action potential may occur.[5]  There have also been findings suggestive of the development of associated neuropathy following high-dose corticosteroid treatment.[23, 24]

Diagnostic muscle ultrasonography for myopathy

Ultrasonography can be used to visualize details such as muscle echogenicity, muscle size, and the presence or absence of muscle movement. The thickness and overall appearance of the intermuscular/intramuscular fascia can also be assessed using ultrasonography. Myopathic disorders often display ultrasonographic abnormalities, which can vary between different types of myopathies.[8]

Using ultrasonography, Minetto et al found echo intensity and thickness of the lower limb muscles to be significantly greater in patients with active Cushing disease than in those with remitted disease. Thus, in patients with steroid-induced myopathy, ultrasonography may help with diagnosis of the condition and assessment of disease progression.[25]

Muscle biopsy typically shows a preferential atrophy of type II fibers, particularly the fast-twitch glycolytic fibers (type IIB), with some atrophy of other fiber types.[6, 7] There is a distinct lack of necrosis or regeneration of muscle. Some studies, however, have reported focal and diffuse necrosis of all fiber types, without predilection for type II fibers. In acute steroid myopathy, the histologic study of muscle biopsy is not diagnostically helpful.[5]

Physical Therapy

Some literature suggests that aerobic exercises and resistance training may help to prevent weakness or reduce its severity. Although there are no definitive recommendations regarding therapy for steroid myopathy, it would seem reasonable to direct therapy to address the weakness and resulting impaired mobility. Range-of-motion exercises (either passive, active-assisted, or active, depending on the degree of weakness) and stretching exercises should be performed to prevent joint contractures. As a general rule, resistance exercises should be limited to muscles with greater than antigravity strength. Bed mobility, balance activities, transfer training, and gait training should be included to address decreased mobility. However, high-intensity exercise should be avoided because, according to some preliminary animal research models, it may be harmful.[9]

Occupational Therapy

Occupational therapy may focus on maximizing the patient's ability to independently perform activities of daily living. Training may include the use of assistive devices to enhance the patient's performance of self-care tasks, such as a balanced forearm orthosis to allow positioning of the upper arm in a manner that permits more independent feeding. Other adaptive equipment may include a raised toilet seat and similar devices that allow the patient to rise from a sitting position, and/or a motorized lift for ascending stairs.

Any adjustment of a patient's corticosteroid medications should be coordinated with the physician who has been prescribing those agents. Given reports of respiratory muscle weakness causing respiratory impairments,[6, 10] consider consultation with a pulmonologist. Consultation with a neurologist can be considered for assistance with diagnosis and for the exclusion of other potential causes of weakness. A physiatrist can also be consulted for assistance with diagnosis and with the management of a therapy program.

There is a risk of chronic and irreversible changes with acute steroid myopathy. Therefore, the corticosteroid dose should generally be reduced or discontinued completely when possible.[5]

In cases of myopathy caused by long-term corticosteroid use, decreasing the corticosteroid dose to below a 30 mg/d threshold may result in resolution of muscle weakness. In patients in whom myopathy has resulted from a short course of high-dose corticosteroid use, partial or complete recovery has been reported following the discontinuation of steroid administration.[10]  Eddelien et al, for example, reported on a patient who, following 10 days of treatment in the intensive care unit (ICU) with methylprednisolone 240 mg/d for severe respiratory failure due to bronchospasm, awoke from sedation with quadriplegia. With glucocorticoid-induced myopathy suspected, glucocorticoid treatment was tapered; within a few months, complete recovery from quadriplegia had been attained.[26]

A study by Meduri et al indicated that the advantages of low to moderate glucocorticoid doses in the treatment of ICU patients with sepsis and acute respiratory distress syndrome (ARDS) outweigh concerns about glucocorticoid-associated ICU-acquired weakness (ICUAW). The report states that prolonged use of low to moderate doses of glucocorticoid in these patients decreases nuclear factor (NF)-ĸB DNA binding, reduces inflammatory cytokine transcription, helps to resolve systemic and pulmonary inflammation, and reduces mortality. The investigators also reported that meta-analyses of randomized, controlled trials involving cases of severe sepsis and ARDS indicated that low to moderate glucocorticoid doses do not increase the risk of ICUAW.[27]

Preliminary studies on rats suggest that creatine plays a part in the prophylaxis of steroid-induced myopathy. Further studies are needed to explore this possible treatment/prevention option.[28]

Other experimental treatments include IGF-I, branched-chain amino acids, glutamine, and androgens such as testosterone and DHEA. Further studies are needed to correlate the benefits of such treatment.[29] One study demonstrated that the concomitant injection of branched-chain amino acids with dexamethasone seemed to reverse the reduction of total protein concentration induced by the steroid in rat muscles.[30]

Banerjee et al described the successful use of the glucocorticoid-receptor antagonist mifepristone in a pediatric patient with Cushing syndrome, with effects including a significant improvement in myopathy.[31]

Various medications, including potassium supplements, phenytoin, vitamin E, and anabolic steroids, have been tried as potential treatments for steroid myopathy.[12] None have been clearly shown to prevent or reverse muscle weakness induced by steroid myopathy. The main treatment recommendations for steroid myopathy are a decrease in the dose of steroid to below a threshold level or the discontinuation of the corticosteroid's use. Alternate-day dosing could also be considered.[32] Another recommendation is that the currently administered steroid be exchanged for one that is not fluorinated.

Consider the judicious use of steroids.

Although prior studies have reported full motor recovery, some patients may be left with varying degrees of residual weakness.

In chronic (classic) steroid myopathy, recovery from weakness may take weeks to months following discontinuation or dose reduction of the corticosteroid.

In acute steroid myopathy, recovery may be prolonged (>6 mo). The course can be relatively mild, with an insidious onset and a fair prognosis, or it can be severe and life-threatening. However, even the less severe course can be followed by chronic and irreversible changes if steroids are continued.[5]

Inform patients of the potential of development of myopathy when starting high-dose or long-term corticosteroid therapy.

The main potential pitfall in diagnosing steroid myopathy relates to patients with polymyositis/dermatomyositis, which typically is treated with corticosteroids. The main symptom of polymyositis/dermatomyositis is proximal upper and lower extremity weakness. When these patients, while being treated with corticosteroids, develop increasing weakness, it can be difficult to determine whether the weakness is secondary to the polymyositis or to steroid myopathy.

Laboratory studies can aid in differentiating between the 2 conditions. Creatine kinase typically is elevated significantly in polymyositis/dermatomyositis. In steroid myopathy, it typically has been described that, although there is elevated urinary creatinine excretion, the serum creatine kinase is not significantly elevated.[1, 24] However, some studies have reported elevations of creatine kinase in some cases of the previously described acute form of steroid myopathy.

On electrodiagnostic study, polymyositis typically demonstrates normal NCS results, as, commonly, does steroid myopathy. On EMG study, however, polymyositis demonstrates abnormal spontaneous activity and increased polyphasic waveforms with short durations. The classic form of steroid myopathy has been described as not demonstrating significantly abnormal EMG findings. Again, some studies have described an acute form of steroid myopathy that can demonstrate abnormal spontaneous activity, an early recruitment pattern, and small, polyphasic waveforms.[22, 24]

The initial recommendation is to decrease or discontinue the use of the corticosteroid.[10] If the weakness improves, then steroid myopathy is the most likely diagnosis. If the weakness persists or worsens, then the most likely diagnosis is worsening of the polymyositis.

Overall, when reading the published medical literature, there are significant challenges when trying to assess whether various steroid treatments are actually associated with steroid myopathy and how frequently this occurs. For example, in patients with asthma, long-term steroid based therapy reportedly causes a side effect of steroid-induced myopathy in some patients. 

However, Wu et al, in a systematic review of nine studies, looked at whether steroid treatments cause myopathy in asthmatic persons and concluded that standardized methods used to establish the diagnosis of myopathy are lacking, as is a clear definition of myopathy in functional terms. The investigators highlighted a need to ascertain myopathy side-effect rates for fluorinated versus non fluorinated steroids and for different administration routes and dosages.[33]