Patients who acquire this problem may have been exposed to high doses of corticosteroids for only brief periods. Exceptional instances have been reported in which the myopathy was induced by doses as low as 60 mg prednisone administered for 5 days, but we have not encountered such a case. The degree and type of simultaneous exposure to neuromuscular blocking agents have varied, but the doses have generally also been quite high, falling in the range of a total dose of 500 to 4,000 mg of pancuronium or an equivalent, over several days.
The severe generalized muscle weakness usually becomes evident when the systemic illness subsides, often as attempts are made to wean the patient from the ventilator. The tendon reflexes are normal or diminished, and there may be confounding features of a “critical illness polyneuropathy,” which is discussed in Chap. 43. Most of our patients with acute myopathy have recovered over a period of 6 to 12 weeks after the corticosteroid agent has been greatly reduced in dose or withdrawn, but a few have remained weak for as long as a year.
Serum CK is elevated, at least early in the process. The EMG discloses the characteristic features of a myopathy; often there are fibrillations as well, theorized to be a result of separation of the motor endplate region from intact segments of muscle fibers. A concurrent polyneuropathy and any residual effects of neuromuscular blockade can be excluded by appropriate electrophysiologic studies. Muscle biopsy shows varying degrees of necrosis and vacuolation affecting mainly type 2 fibers. The identifying histologic feature is a striking loss of thick (myosin) filaments. Severe degrees of muscle necrosis occur and have been accompanied by massively elevated CK levels and by myoglobinuria with renal failure.
Several experimental observations may explain the apparent additive effect on muscle of corticosteroids and neuromuscular blocking agents. Animals exposed to high doses of steroids soon after experimental denervation of a muscle display a selective loss of myosin, the characteristic finding of acute steroid myopathy. Myosin depletion is reversed by reinnervation but not by withdrawal of the corticosteroids. Furthermore, denervation of muscle has been found to induce an increase in glucocorticoid receptors on the surface of the muscle. On this basis, Dubois and Almon have postulated that exposure to neuromuscular blocking agents creates a functional denervation, rendering the muscle fiber vulnerable to the damaging effects of steroids. It is curious that this myopathy has not been seen after high-dose corticosteroid administration for neurologic diseases such as multiple sclerosis, but the observation of Panegyres and colleagues of a patient with myasthenia who developed a severe, myosin-depleted myopathy following high doses of methylprednisolone supports such a dual action of denervation (at the postsynaptic membrane) and glucocorticoids. Whether it also explains the more common circumstance of clinical worsening of myasthenia gravis that sometimes accompanies the initial administration of corticosteroid treatment is also not clear.
Generalized weakness and fatigability are characteristic of adrenocortical insufficiency, whether primary in type, that is, because of Addison disease (infectious, neoplastic, or autoimmune destruction of the adrenal glands or adrenal hemorrhage), or secondary to a pituitary deficiency of adrenocorticotropic hormone (ACTH). The weakness and fatigability, however, are probably related to mostly water and electrolyte disturbances and hypotension, not to a primary disorder of muscle. Perhaps there is also an element of reduced central drive of motor activity. Biopsy has not disclosed any abnormalities of muscle and postmortem examination in one case showed no changes. Likewise, the EMG is normal, and the tendon reflexes are retained. Addisonian weakness responds (as does hyperkalemic paralysis) to glucocorticoid and mineralocorticoid replacement.