Endocrine, Toxic, and Critical Illness Myopathies

Hypothyroid Myopathy. Most patients with myxedema (chronic hypothyroidism) complain of weakness; 25% have objective proximal muscle weakness. Myoedema, an electrically silent mounding of percussed muscle, occurs in one third of patients. The relaxation phase of muscle stretch reflexes is delayed. In childhood, hypothyroid myopathy presents with hypertrophic muscles that slowly contract and relax. In adults, fatigue is associated with muscular spasms and cramps. Serum CK is mildly elevated. EMG may be normal, but in long-standing hypothyroidism, increased insertional activity, complex repetitive discharges, and myopathic motor unit potentials are seen. Judicious thyroid replacement restores function.

Hyperthyroid Myopathy. Muscle weakness is common in hyperthyroidism, often affecting the shoulder and pelvic-girdle muscles. Rarely, hyperthyroid patients have very brisk muscle stretch reflexes, muscle wasting, and fasciculations mimicking motor neuron disease. CK is normal. Muscle strength and bulk improves as the euthyroid state is restored.

Hyperparathyroid Myopathy. Weakness and fatigability frequently occur as presenting symptoms of primary hyperparathyroidism. Pelvic-girdle and leg muscles are involved before upper extremities. Some patients have unexplained osteomalacia associated with myopathy. Serum parathormone levels are elevated. CK is normal. Patients improve after parathyroidectomy.

Hypoparathyroid Myopathy. Muscle aching, spasm, twitching, and tremor may occur, but true myopathy in hypoparathyroidism is extremely rare. CK elevations result from muscle damage sustained during prolonged hypocalcemia-induced cramping.

Acromegalic Myopathy. Proximal muscle weakness, developing many years after the onset of acromegaly, occurs about 50% of the time. CK and muscle biopsy are normal. The pathogenesis may relate to sustained high levels of growth hormone effects on muscle metabolism. After hypophysectomy, slow improvement occurs unrelated to postoperative growth hormone level decline.

Toxic Myopathy. Numerous drugs lead to potentially reversible myopathies. Renal insufficiency predisposes because of reduced drug clearance. Cholesterol–lowering agents (e.g., hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) cause myopathies characterized by muscle cramping, sometimes proximal muscle weakness; and often increased serum CK. Myopathic potentials with myotonia are seen on EMG and muscle fiber necrosis with biopsy. This myopathic syndrome usually resolves with drug discontinuation. Occasionally, these drugs trigger an immune-mediated myopathy with necrosis and without inflammation that responds to corticosteroids

Chloroquine causes a vacuolar myopathy with insidious onset of slowly progressive proximal weakness. Electron microscopy discloses autophagic vacuoles containing lamellar or myeloid lipid-containing inclusions and curvilinear bodies. Colchicine induces both an axonal neuropathy and myopathy with vacuolar degeneration, almost always with associated renal insufficiency. Azidothymidine (AZT) is associated with a myopathy and abnormal mitochondria on muscle biopsy. On rare occasions, penicillamine, cimetidine, and procainamide produce an inflammatory myopathy. Alcohol occasionally leads to chronic myopathies difficult to identify in patients with concomitant neuropathy and malnutrition complications. Acute alcoholic myopathies occur with episodic rhabdomyolysis, acute myalgia, muscle swelling, and weakness.

Critical Illness Myopathy (CIM). Exposure to intravenous corticosteroids and neuromuscular blocking agents are major CIM risks; this also develops with severe systemic illness, multiorgan failure, and sepsis in an intensive care unit (ICU) setting. Weakness is typically diffuse—a flaccid quadriparesis with proximal greater than distal distribution—and sometimes affects the diaphragm, causing failure to wean. Muscle stretch reflexes are depressed or absent. Early in the disease course, serum CK is elevated in 50% of patients. Nerve conduction studies demonstrate low-amplitude motor responses but preserved sensory responses. EMG reveals fibrillation potentials with myopathic MUPs. Muscle biopsy typically demonstrates selective myosin loss, type II fiber muscle fiber atrophy, and occasional mild fiber necrosis. The pathogenesis is myosin thick filament loss secondary to muscle apoptosis, calpain upregulation, and a transforming growth factor beta/mitogen-activated protein kinase pathway. Inexcitable muscle results from inactivation of sodium channels at the resting membrane potential. Treatment is symptomatic. Intensive insulin therapy (targeting blood glucose concentrations of 80 to 110 mg/dL) may lower the incidence of critical illness myopathy. Most patients recover over weeks to months; residual paresis may occur, depending upon severity and duration of weakness.

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