Neuropharmacology & Neurotherapeutics
Gene therapy of muscular dystrophy
Aug. 24, 2021
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This article includes discussion of corticosteroid myopathies, acute quadriplegic myopathy, glucocorticoid myopathy, steroid myopathy, Addisonian myopathy, myopathy from ACTH excess, myopathy of Cushing disease, and myopathy of Cushing syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Exposure to endogenous or exogenous corticosteroids may produce myopathy. A particularly interesting entity is severe myopathy occurring in critically ill patients exposed to high-dose corticosteroids and neuromuscular blocking agents. In this updated article, the authors will refer to the common problem of distinguishing steroid myopathy from an underlying inflammatory muscle disease. When glucocorticoids are tapered in this situation, the patient must be monitored for a flare of the underlying condition (in particular, rise of CK) and for signs of evolving adrenal insufficiency. Improved strength within 3 to 4 weeks after corticosteroid tapering is a good indicator that the weakness was indeed due to the drug and not to the underlying inflammatory muscle disease.
• Patients treated with corticosteroids may develop myopathy months to years after initiation of therapy.
• Stopping the corticosteroid, lowering the dose, and switching to a nonfluorinated preparation are the mainstays of management.
• Critical illness myopathy is a severe, acute myopathy that may be triggered by high-dose corticosteroids and nondepolarizing neuromuscular blocking agents.
• Early mobilization of patients seems to be very effective in the management of critical illness myopathy.
The development of proximal muscle weakness and atrophy from excessive endogenous glucocorticoid production in patients with pituitary adenomas was first noted 75 years ago by Cushing (14). Subsequent studies confirmed that myopathy was a common complication of chronic exogenous corticosteroid administration. Dubois observed that profound weakness was the most serious adverse effect of triamcinolone, a new synthetic fluorinated corticosteroid (17).
High-dose corticosteroids may trigger critical illness myopathy, in particular, among patients with prolonged intensive care unit (ICU) stay, mechanical ventilation, or persistent systemic inflammation (35; 36). A severe, acute myopathy that prolongs ventilator dependence has been described in patients treated with high-dose corticosteroids, many of whom also received nondepolarizing neuromuscular blocking agents (25). The first patient reported with this acute form of steroid myopathy was a 24-year-old woman placed on large doses of intravenous hydrocortisone (up to 3 g a day) for status asthmaticus (40). After 8 days, her airway obstruction resolved, but she was unable to resist gravity in both proximal and distal muscles. She gradually improved and could walk unassisted after 3 weeks but continued to have distal leg weakness after 2 months. Since this initial description, many additional patients have been reported in the literature (25; 33; 34). However, most prospective studies could not identify corticosteroids as an independent risk factor for critical illness myopathy, as summarized in a Cochrane review (24). Similarly, ICU-acquired neuromyopathy was common (34%) among 128 survivors of persistent acute respiratory distress syndrome but was not significantly associated with methylprednisolone treatment (28). Differential diagnosis between critical illness myopathy and critical illness polyneuropathy is important, as prognosis is more favorable in critical illness myopathy (35; 36). Critical illness myopathy and critical illness polyneuropathy are discussed in detail in another MedLink summary.
Patients treated with corticosteroids may develop myopathy months to years after initiation of therapy. The myopathy produced by chronic steroid excess is characterized by various degrees of painless, proximal weakness with legs more involved than arms. The face, bulbar musculature, and sphincters are spared. Muscle wasting and myalgias may be prominent in the extremities. Reflexes are preserved. Other stigmata of corticosteroid toxicity, such as a Cushing appearance and fragile skin, invariably accompany the muscle weakness. Atrophy and weakness are accelerated in the setting of malnutrition, disuse, endocrinopathy, or debilitating illness.
Myopathy may be a complication of pituitary and adrenal adenomas, though modern reports of myopathy resulting from Cushing syndrome are rare (33). The myopathy in these patients resembles the clinical syndrome produced by exogenous steroids. The muscle weakness has been attributed to excess endogenous corticosteroid production, and the weakness usually reverses when glucocorticoid levels normalize. However, elevated levels of adrenocorticotropic hormone in Cushing disease may be the direct cause of myopathy (19; 29).
The acute form of steroid myopathy is difficult to define on clinical grounds. Reports have varied widely in regard to the steroid preparation and dosages used, underlying medical conditions, and concomitant therapy, especially neuromuscular blocking agents. Despite these limitations, a few clinical observations have emerged. Approximately two thirds of patients were placed on high-dose corticosteroids for management of status asthmaticus (25). Another 20% to 25% had recent traumatic injuries. About 90% of patients also received nondepolarizing neuromuscular blocking agents for 4 to 21 days, usually pancuronium or vecuronium. Nearly all had received sedatives. Other associated factors include acidosis, elevated serum magnesium levels, hepatic or renal dysfunction, and aminoglycoside administration (20). In some reported cases, patients have received only corticosteroids (39; 47).
Most patients who develop the myopathy have received a cumulative equivalent dose exceeding 1000 mg of methylprednisolone (34). This form of myopathy may develop in critically ill patients without exposure to corticosteroids or neuromuscular blocking agents (15). Diffuse weakness developed as early as 4 days to 7 days after initiation of corticosteroids (25; 05). Complete flaccid quadriplegia develops in some patients, especially those receiving more than 80 mg total of vecuronium (34). In a series, distal limb and facial weakness were present in most patients (34). Extraocular muscles were involved in 1 of 14 patients. Sun and colleagues describe a patient presenting with acute flaccid hemiplegia, subsequently progressing to triplegia (58). The occurrence of a second episode of acute quadriplegic myopathy during a subsequent intensive care unit admission has been described (32; 39).
Up to half of patients with adrenal insufficiency (Addison disease) report generalized weakness (29). Similar symptoms are experienced by patients being withdrawn from exogenous corticosteroids, particularly after high-dose, long-term administration. These patients also may experience arthralgias, weight loss, skin changes, and fever. Muscle enzymes in serum and EMG are normal. The muscle biopsy is also normal except for diminished glycogen. The mild weakness and fatigue of Addison disease are rapidly corrected by hormone replacement. Similarly, slowing the taper will improve symptoms of steroid withdrawal.
Concurrent electrolyte imbalances or other endocrine disturbances are typically present with objective myopathic findings in patients with Addison disease. Therefore, severe weakness in a patient with Addison disease should prompt further investigation.
Hypotension, fasting hypoglycemia, and severe anorexia are frequent complications of Addison disease (29). Cardiovascular insufficiency, electrolyte and fluid imbalance, impaired carbohydrate metabolism, and poor nutritional status all contribute to the muscle weakness seen with adrenal insufficiency. The myopathy is rapidly corrected in most cases with glucocorticoid and mineralocorticoid replacement.
Generally, high dosages and long durations of therapy predispose patients to the development of corticosteroid myopathy. Patients receiving greater than 30 mg of prednisone a day are more likely to develop myopathy than those on lower doses or on alternate-day regimens (07). Patients receiving corticosteroids for less than 4 weeks rarely develop muscle weakness. However, individual sensitivity is an important factor, and the duration of therapy and steroid dose often correlate poorly with the degree of weakness.
All synthetic corticosteroid preparations used in clinical practice can produce myopathy. However, the risk of myopathy appears greater for the fluorinated corticosteroids: triamcinolone, betamethasone, and dexamethasone. In a review of 76 patients with corticosteroid myopathy, two thirds had been on triamcinolone or dexamethasone (02). Patients who develop myopathy on fluorinated agents may recover muscle strength when switched to equivalent doses of another corticosteroid.
Corticosteroids are proposed to cause myopathy through a variety of mechanisms. The main mechanism relates to impairment of protein and carbohydrate metabolism (29). Chronic low-dose corticosteroids induce protein catabolism primarily through diminished synthesis, but protein degradation dominates when higher doses are administered (59). Protein degradation has been associated with heightened skeletal muscle protease activity in some studies (42; 13). Protein catabolism is more prominent in type 2 fibers and is potentiated by sepsis and disuse. On the other hand, insulin induces an anabolic state on muscle, which may be antagonized by the insulin resistance produced by corticosteroids. The insulin-resistant state also alters carbohydrate metabolism, as shown by increased muscle glycogen deposition and marked reduction in glycolytic activity (18; 29). The significance of alterations in carbohydrate metabolism is unclear, as muscle ATP levels are not affected by corticosteroid treatment (54). Fibers with slow-twitch activity patterns and greater oxidative capacity, namely type 1, are considered more resistant to the effects of corticosteroids. Pathologically, type 2 muscle fiber atrophy is the hallmark of steroid myopathy.
Potassium and phosphate depletion caused by glucocorticoids is not an important factor in the generation of myopathy, because sarcolemmal excitability and excitation-contraction coupling are not significantly affected by corticosteroids (55). In addition, there is little evidence for motor nerve or neuromuscular junction dysfunction in corticosteroid myopathy, and these structures appear normal on electron microscopy even in the setting of severe muscle atrophy (12).
Massa and colleagues have shown that glucocorticoids cause focal loss of myosin in denervated rat muscle and that this process is reversed by reinnervation (41). Furthermore, immobilization has been shown to increase the concentration of glucocorticoid receptors in rat muscle (16). Pharmacological denervation of muscle by neuromuscular blocking agents may, therefore, enhance the myopathic potential of corticosteroids, resulting in the severe weakness seen in patients with acute steroid myopathy. Furthermore, several nondepolarizing neuromuscular blocking agents, including pancuronium and vecuronium, are aminosteroids and may act in a direct, additive manner to structurally related corticosteroids (20; 34). Rich and colleagues demonstrated that muscle may completely lose its excitability in some patients with acute steroid myopathy (51). An animal model using denervated muscle subsequently exposed to high-dose corticosteroids suggests that this loss of excitability results from inactivation of sodium channels (50).
Apoptotic cell death of differentiated skeletal muscle has been reported in a rat model of steroid-induced myopathy (37). In another rat model of critical illness myopathy, apoptosis-associated processes were differentially regulated in muscles of different function and fiber type (04). These authors concluded that interventions combating apoptosis may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms.
In a human muscle transcriptomics approach from 5 major muscular diseases, a dysregulation of genes in forward membrane pathway, responsible for transmitting action potential from neural excitation, was found to be unique to acute quadriplegic myopathy, thus, providing a biomarker and functional insight into dysregulation in this muscular disease (22).
The myopathy seen in pituitary and adrenal disease is believed to result from excess endogenous glucocorticoid production. In addition, elevated adrenocorticotropic hormone levels in Cushing disease may be independently myotoxic, as suggested by the focal necrosis produced by adrenocorticotropic hormone administration in rabbit muscle (19). The extensive lipid deposition also observed after adrenocorticotropic hormone administration is not typical of corticosteroid myopathy, again suggesting that adrenocorticotropic hormone may have unique myotoxic actions independent of glucocorticoid excess, although the exact pathophysiologic mechanism remains to be elucidated.
The myopathy seen in Addison disease likely results from a variety of metabolic derangements that accompany adrenal insufficiency, including changes in carbohydrate, water, and electrolyte balance as well as muscle blood flow (29). Myopathy is not an expected complication of adrenal insufficiency; severe weakness in a patient with Addison disease should prompt further investigation.
In critically ill patients, controlled mechanical ventilation (CMV) may lead to a rapid and profound loss of diaphragm function, referred to as ventilator-induced diaphragm dysfunction. In contrast to CMV, assisted mechanical ventilation (AMV) maintains partial neural activation and mechanical loading of the diaphragm and preserves its function. Sassoon and colleagues found in a rabbit model that high-dose methylprednisolone had no additive effects on CMV-induced diaphragm dysfunction but had a negative impact on the diaphragm-sparing properties of AMV creating a CMV-like effect (56). Subject to confirmation in patients, these observations may have high clinical relevance.
Glucocorticoid excess also has major effects on muscle protein synthesis and degradation and myoblast proliferation (46).
In cultured myotubes, ß-hydroxy-ß-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, attenuated dexamethasone-induced damage such as protein degradation, decreased protein synthesis, and reduced myotube size (03), probably via MAP kinase and PI3K/Akt signaling pathways. Because HMB supplementation in humans is safe and has already been effective in clinical studies of muscle wasting due to cancer, AIDS, and aging, its effect in corticosteroid myopathy may be investigated in a randomized clinical trial.
Steroid myopathy is the most common form of endocrine muscle disease, a result of the widespread use of corticosteroids in clinical practice. Between 2.4% and 21% of patients receiving chronic corticosteroids develop significant myopathy. An even greater proportion of patients may develop some degree of muscle weakness. When quantitative strength testing is used, a majority of patients on chronic corticosteroid therapy will have reduced muscle peak torque and power (53). In contrast, glucocorticoid deficiency rarely causes myopathy (45). Corticosteroid myopathy has been reported in children and adults of all ages, with women and younger patients being more susceptible (09; 07). Cancer patients may be especially susceptible to corticosteroid myopathy, with 60% developing proximal weakness, typically during the first 2 weeks of therapy (06). Respiratory muscles are often affected in this population.
In a series of 27 consecutive patients treated with steroids and neuromuscular blocking agents for status asthmaticus, 4 (15%) developed severe quadriplegia (01). Creatine kinase levels were elevated in the 3 patients tested. However, the true incidence of this complication is still unknown. Hyperthyroidism may predispose to corticosteroid-induced myopathy (52).
An observational study of 36 patients with respiratory diseases (mostly asthma) showed that 65% of patients using corticosteroids daily over more than 1 year reported weakness in legs, and 20% of these patients demonstrated objective signs of muscle weakness. As the majority of patients in this study had been using inhaled steroids, the results do not support the view that inhaled steroids are safer than oral steroids (38).
Avoiding the use of fluorinated preparations may prevent corticosteroid myopathy. In addition, an exercise program may reduce or even reverse corticosteroid-induced muscle atrophy and weakness (27). One randomized study showed that resistance exercise can prevent corticosteroid-induced myopathy in heart transplant recipients (08). Inspiratory muscle training can prevent the impairment of respiratory muscle function seen in patients receiving corticosteroids (61). Attention to pain management may allow patients to remain active, avoid immobilization, and thereby minimize their risk of corticosteroid myopathy. Judicious use of neuromuscular blocking agents in patients receiving high doses of intravenous corticosteroids may reduce the likelihood of acute quadriplegic myopathy.
Diagnosing steroid myopathy is straightforward in patients receiving corticosteroids for disorders not characterized by muscle weakness. However, the diagnosis is more difficult in patients treated with glucocorticoids for disorders that themselves produce weakness. For instance, clinical deterioration in a patient receiving prednisone for inflammatory myopathy may result from corticosteroid myopathy or from a disease exacerbation. The inflammatory myopathy is more likely to be responsible if weakness occurs early in the course of corticosteroid therapy or if there are no other stigmata of glucocorticoid toxicity (29). Creatine kinase elevations also suggest that a flare of the inflammatory myopathy is the underlying cause. On the other hand, a predominance of lactic dehydrogenase 1, 2, and 3 isoenzymes in serum is indicative of corticosteroid myopathy (30) because this isoenzyme shift is not observed in inflammatory myopathy. EMG may be helpful in distinguishing drug toxicity from disease flares in that fibrillations are more common in inflammatory myopathy. Although type 2 atrophy in a muscle biopsy is nonspecific, persistence or progression of inflammation would suggest myositis.
Changes in creatine excretion may help distinguish the cause of deterioration (29) but only when a baseline is known. If the weakness is from corticosteroid toxicity, a dose reduction will lower creatine excretion. If the patient is experiencing a flare of the inflammatory process, a dose reduction will cause an increase in creatine excretion and further deterioration of muscle strength. The level of creatinuria has not been found to correlate with either the steroid dose or the degree of weakness (07).
Clinical, laboratory, and electrophysiologic data help distinguish acute steroid myopathy from other common causes of acute flaccid weakness in the intensive care setting, such as Guillain-Barré syndrome, myasthenia gravis, and critical illness polyneuropathy. Direct muscle stimulation may be particularly helpful in this clinical setting (51). Inexcitable muscle would predict that an acute quadriplegic myopathy is the cause of weakness.
Serum creatine kinase levels are typically normal in chronic corticosteroid myopathy, whereas elevated urinary creatine excretion is commonplace (02). In most patients, creatine kinase is elevated early in the course of acute steroid myopathy, up to 400 times control levels (25). Early monitoring of creatine kinase levels in patients at risk may alert physicians to an evolving myopathy and the need to lower or discontinue corticosteroids and neuromuscular blocking agents (34).
EMG findings in corticosteroid myopathy are variable. Insertional activity is normal and, except for scattered reports of fibrillation potentials, abnormal spontaneous activity is usually absent (29). Fibrillations and complex repetitive discharges may occur in the myopathy of Cushing syndrome (33). Myopathic motor units are usually absent; however, they are rarely reported, especially in the setting of marked weakness or the acute form of steroid myopathy (31).
Selective atrophy of fast-twitch glycolytic fibers (type 2b) is the classic histologic feature on muscle biopsy in myopathy from either exogenous corticosteroid toxicity or Cushing disease (29). Increased glycogen may be noted in type 2 fibers. Ultrastructural abnormalities include initial proliferation and aggregation of mitochondria followed by degeneration and mitochondrial loss. Muscle biopsies from some patients with acute steroid myopathy and quadriplegia show a selective loss of myosin filaments followed by degeneration of muscle fibers (60; 05). Type 2 myofiber atrophy with fiber necrosis and regeneration are the principal findings in other reports (23; 34). The distinctive loss of thick filaments may not be seen in biopsy specimens obtained in the first 2 weeks after corticosteroids are initiated (34).
When Cushing syndrome is suspected, a dexamethasone suppression test and urinary free cortisol are recommended to confirm the diagnosis (33). Diffuse fibrillations and myopathic motor units were seen in 80% to 90% of patients with the acute form of steroid myopathy (34). Patients were unable to activate motor unit potentials in severely affected muscles. On nerve conduction studies, motor amplitudes were typically reduced out of proportion to any reduction in sensory nerve action potentials, helping to distinguish these patients from those with critical illness polyneuropathy.
Utilization of ultrasonography of the muscle is helpful to monitor the progression of the disease and the early response to treatment. Change in muscles echogenicity can precede noticeable change in muscle strength examination. Echo intensity of the proximal lower limb muscle is increased in patients with Cushing syndrome, and a quantitative measurement can assess the changes induced by corticosteroid in muscle mass and structure (44).
Stopping the corticosteroid, lowering the dose, and switching to a nonfluorinated preparation are the mainstays of management (29). Converting to an alternate-day dosing schedule may also improve muscle strength. Even with these measures, however, recovery may take months. Reducing endogenous glucocorticoid synthesis is the goal of treatment in patients with pituitary or adrenal hyperfunction. Muscle atrophy and weakness from Cushing disease resolve when corticosteroid levels normalize.
When glucocorticoids are tapered in the case of an underlying inflammatory muscle disease, the patient must be monitored for a flare of the underlying condition (in particular, rise of CK) and for signs of evolving adrenal insufficiency (11). Improved strength within 3 to 4 weeks after corticosteroid tapering is a good indicator that the weakness was indeed due to the drug and not to the underlying inflammatory muscle disease (49).
Although dietary supplementation in patients with adequate protein intake is not beneficial, exercise may partially protect muscle from glucocorticoid-induced atrophy. Immobilization has been shown to increase the concentration of glucocorticoid receptors in rat muscle (16), suggesting that inactivity may place patients at greater risk to develop corticosteroid myopathy. Furthermore, isokinetic physical training was found to reverse muscle atrophy and normalize strength in renal transplant patients receiving low to moderate doses of prednisone (27). Therefore, physical therapy may play an important role in the management of patients receiving chronic glucocorticoids.
A variety of medications including potassium supplements, phenytoin, vitamin E, and anabolic steroids have not proved effective in the prevention or management of corticosteroid myopathy (26). In rats, creatine supplementation attenuated corticosteroid-induced muscle wasting and impairment of exercise performance (43).
In general, corticosteroid myopathy is fully reversible when the steroid dosage is reduced below a threshold of prednisone 30 mg/day. Most promising for management of critical illness myopathy has been the demonstration of the feasibility and benefits of early, targeted physiotherapy, even while patients are undergoing life- and organ-support interventions (48). Mobilization of critically ill patients is safe and can be facilitated with modest additions of staff and equipment to the ICU. In a randomized controlled trial, investigators reported that early physical and occupational therapy, coupled with a sedative holiday, resulted in a reduction in the duration of mechanical ventilation, a reduction in days in the ICU, and near doubling of the fraction of patients who achieved independent functional status (57). Another randomized controlled trial showed that in addition to standard physiotherapy, patients who had initially passive and then active daily cycling exercises in the ICU had an improved 6-minute walking distance and physical satisfaction score at hospital discharge (10). If these benefits can be sustained and the results of these seminal trials confirmed in larger trials, early mobilization of patients may become a standard approach in critical illness myopathy (21).
Chronic corticosteroid myopathy is fully reversible when the medication is stopped or lowered below an equivalent of prednisone 30 mg a day (26). The prognosis is favorable in most patients with acute steroid myopathy. In a review, nearly 90% of patients improved, although only one half regained normal motor function (25). In both the acute and chronic forms, the recovery period may persist for months to years. Similarly, myopathy from increased endogenous production resolves when glucocorticoid levels normalize.
Nondepolarizing neuromuscular blocking agents may potentiate the development of acute steroid myopathy and should be used with caution and moderation in patients also receiving high-dose corticosteroids.
Aravindhan Veerapandiyan MD
Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.See Profile
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