Diseases of Muscle and the Neuromuscular Junction Part 4

Calcium channel disorders

Calcium channel disorders present as hypokalemic periodic paralysis (hypoKPP). This is an autosomal dominant disease localized to chromosome 1q31-q32 and caused by mutations in the di-hydropyridine-sensitive L-type calcium channel gene.70 HypoKPP presents as episodic paralytic attacks that begin in the first or second decade of life, usually during sleep. They are precipitated by high carbohydrate consumption, rest after exercise, and excitement. During attacks, the serum K+ concentration decreases and urinary retention of Na+ and water occurs. Between attacks, many patients develop a permanent, slowly progressive myopathy.

The disease should be distinguished from all the causes of secondary hypokalemias that can cause weakness, including diuretic use, kidney disease, hyperaldosteronism, licorice intoxication, laxative abuse, and potassium-losing GI diseases. In secondary hypokalemias, the paralytic attacks do not occur unless the K+ concentration falls below 3 mEq (usually below 2.5 mEq). In contrast, in hypoKPP the attacks occur even when the serum K+ concentration is closer to the normal level.

HypoKPP can be associated with thyrotoxicosis, especially in persons of Asian descent. In such cases, hypoKPP responds to propranolol or resolves after reversion of the patient to a euthy-roid state. Although hypoKPP is dominantly inherited, one third of patients may have sporadic disease. A provocation test, with insulin and glucose infusion under cardiac and respiratory monitoring, was necessary for the diagnosis until genetic identification became available. The frequency of the attacks and the inter-attack weakness respond to carbonic anhydrase inhibitor, aceta-zolamide, and dichlorphenamide.

Chloride channel disorders

Chloride channel disorders include autosomal dominant my-otonia congenita (Thomsen disease), which occurs in the first decade of life and is often associated with muscle hypertrophy, and autosomal recessive myotonia congenita (Becker-type my-otonia) (BMD), which comes later in life and can be more se-vere.67,68 Both of these diseases have been linked to distinct mutations on the chloride channel gene on chromosome 7q32, designated as the CLCN1 locus.6668 Patients with these disorders do not have periodic paralysis or weakness, although in Becker-type myotonia, transient but sometimes severe weakness may occur; such weakness improves with exercise. Typical percussion myotonia and generalized myotonia, experienced by the patient as stiffness and hypertrophy of the legs and buttocks, are characteristic findings. Myotonic stiffness improves with exercise (warm-up phenomenon). The myotonic symptoms may variably respond to phenytoin, mexiletine, or tocainide.

Isolated neuromyotonia (isaac disease)

Autoimmune acquired neuromyotonia occurs as an isolated neuromyotonia (also called Isaac disease) and as neuromyotonia associated with neuropathy, myasthenia gravis, and thymoma [see Neuromyotonia with K+ Channel Autoantibodies (Isaac Syndrome), below]. The isolated form of the disease is characterized by (1) myokymia, which is a rippling muscle twitching that occurs during rest; (2) impaired muscle relaxation and stiffness at rest; (3) painful cramps; and (4) increased sweating. It is caused by hyperactivity of the peripheral motor nerve endings, and it is correctly called neuromyotonia because the continuous muscle fiber activity is abolished by curare but not by proximal nerve block. Neuromyotonia occurs sporadically, but familial cases have occurred.73,74 Electromyography confirms the presence of neuromyotonia, and determination of K+ channel autoantibodies identifies the autoimmune nature of the disease.

Treatment is symptomatic (phenytoin, carbamazepine, and mexiletine are used); in resistant cases, immunotherapy with intravenous immunoglobulin or plasmapheresis may be necessary.

Drug-Induced Toxic Myopathies

Although drug-induced myopathies are not uncommon, their diagnosis may be elusive in clinical practice. The clinician should suspect a toxic myopathy in a patient who does not have a preexisting muscle disease, whose myopathy develops acutely or subacutely (sometimes slowly) with muscle pain and weakness, who manifests myoglobinuria after the administration of a known or putative myotoxic agent, or who improves upon withdrawal of a putative toxic drug [see Table 2].75,76 Myotoxic agents can cause myopathy by directly affecting a muscle organelle, such as the mitochondrion or thick filaments; by altering muscle antigens, thereby inducing an immunologic inflammatory reaction; or by inducing such secondary systemic effects as electrolyte disturbance, nutritional deprivation (e.g., the agent competes with vitamins), and malabsorption. Several drugs can be myotoxic either alone or in combination with other drugs. In addition to knowing which drugs are myotoxic, the clinician should always be alert to the potential myotoxicity of newly marketed drugs. The most common myotoxic drugs are discussed in the following sections.

Zidovudine myopathy and toxicity of other nucleoside analogues

The clinical features of zidovudine myopathy are proximal muscle weakness, myalgia (predominantly in the thighs and calves), fatigue, myopathic changes on EMG, and elevated serum CK levels, which often increase with exercise.61,77-79 Weight loss and elevation of the serum lactate level may herald the onset of zidovudine myopathy. Zidovudine can cause myopathic symptoms after 1 year of administration. Symptoms resolve 4 to 6 weeks after zidovudine is discontinued.

The unique histologic features of zidovudine myopathy are ragged-red fibers containing lipid accumulation and numerous cytochrome-c oxidase-negative fibers; both findings are suggestive of mitochondrial abnormalities.61,78,79 Zidovudine is a DNA-chain terminator that inhibits the y-DNA polymerase in the mito-chondrial matrix; termination of mtDNA synthesis then occurs, and as much as a 78% depletion of muscle mtDNA results.78,79 Among the other nucleoside analogues used in the treatment of AIDS, stavudine may also be myotoxic. The others, such as dideoxycytosine, dideoxyinosine, and lamivudine, cause a painful axonal neuropathy but not myopathy. A syndrome of lipodys-trophy, lactic acidosis, and myopathy has been seen with highly active antiretroviral therapy consisting of one of the newly introduced protease inhibitors in combination with two nucleoside analogues, especially stavudine (d4T).80

Myopathy caused by cholesterol-lowering agents

Several cholesterol-lowering drugs cause an often reversible myopathy that is characterized by proximal muscle weakness, myalgia, elevation of the serum CK level, and myo-pathic changes on EMG. Because cholesterol is the major sterol constituent of muscle membranes, reduction of the normal cholesterol pool available for membrane synthesis can increase membrane fluidity, leading to an unstable sarcolemma, myoton-ic discharges, and, in advanced cases, rhabdomyolysis. Statins also inhibit the production of ubiquinone, thereby interfering with mitochondrial ATP and energy metabolism within the my-ocyte. EMG findings include fibrillation potentials and myotonic or complex repetitive discharges.76,77,81,82 Gradual recovery can occur after withdrawal of the offending drug.

Although a transient increase in the serum CK level and myalgia is not unusual after treatment with statins, the drugs have been associated with clinically overt myopathic symptoms in fewer than 5% of treated patients. Coadministration of cyclosporine and lovastatin to patients with heart or kidney transplants and hyperlipidemia increased the incidence of myopathy with rhabdomyolysis. In a recent review, cerivas-tatin was the statin most commonly associated with myopath-ic symptoms; this was followed sequentially by lovastatin, flu-vastatin, atorvastatin, simvastatin, and pravastatin.81,82 The risk for statin-induced myopathy is increased with use of higher doses, statins that have a lipophilic action (which includes all except pravastatin and rosuvastatin), and concomitant therapy with drugs such as gemfibrozil, colchicine, or cyclosporine; elderly patients are at increased risk for myopathy when treated with statins.

Myopathy associated with critical illness

In patients with prolonged paralysis induced by such nonde-polarizing blocking agents as pancuronium, an acute myopathy may develop after mechanical ventilation is discontinued. Most of these patients received high doses of corticosteroids for status asthmaticus or another systemic illness for which artificial paralysis was induced to secure an aggressive pulmonary toilet.77,82,83 The combination of blocking agents and corticosteroids has been consistently implicated in the development of critical illness my- opathy, but sometimes patients have had only minimal exposure to one of these two agents.

Table 2 Myopathy-Inducing Agents

Prescribed Medications and Vitamins

Neuroleptics (in the absence of neuroleptic malignant syndrome)




e-Aminocaproic acid












Hypocholesterolemic drugs




Fibric acid derivatives









Vitamin E


Zidovudine (AZT)


Nonprescription Drugs Cocaine

3-Hydroxy-3-methylglu-taryl coenzyme A inhibitors





Phencyclidine (PCP)


Intramuscular Injections

Nicotinic acid (niacin)


Interferon alfa









The clinical presentation of myopathy associated with critical illness is characterized by severe generalized weakness of all extremities, failure to wean from mechanical ventilation, muscular atrophy, a normal or moderately elevated serum CK level, and myopathic changes on EMG. The weakness usually slowly im-proves.77,82-85 Blocking agent-corticosteroid myopathy may coexist with an axonal neuropathy, but the consensus now is that the paralytic disease is predominantly caused by a myopathy. The differential diagnosis should include neuromuscular transmission defects, such as myasthenia gravis; Guillain-Barre syndrome; inflammatory or acute necrotizing myopathy; and periodic paralysis. Muscle biopsy shows extensive morphologic abnormalities, which result from the selective loss of thick filaments without signs of necrosis, inflammation, or phagocytosis. With adenosine triphosphatase (ATPase) staining, striking areas of central pallor are seen in many fibers.77 Calpain expression is markedly enhanced, implicating an altered calcium homeostasis and enhanced proteolysis. Electron microscopy reveals selective and extensive loss of thick myofilaments; the thin myofilaments and Z disks are preserved.

High doses of steroids should be used with caution in patients receiving paralytic agents for prolonged periods. The myopathy improves slowly with intense rehabilitation.

Vitamin e intoxication

A necrotizing myopathy with proximal muscle weakness and elevation of the serum CK level has been reported to occur in patients self-medicated with high doses of vitamin E.75,76,86 This condition is very rare and has not been clearly substantiated.

Chloroquine myopathy

The antimalarial drug chloroquine is often used by rheumatolo-gists for the treatment of various collagen vascular diseases. It can cause macular and corneal degeneration, peripheral neuropathy, and myopathy. The myopathy is seen with long-term administration of high doses of chloroquine (500 mg daily). The myopathy has interesting morphologic features that resemble those that occur with acid maltase deficiency: multiple vacuoles with acid phos-phatase-positive material, myeloid bodies within the vacuoles, and enlarged lysosomes with increased lysosomal enzyme activity.75

Colchicine myopathy

Colchicine interferes with the growth of microtubules, thereby affecting mitosis. After long-term use, colchicine causes a vac-uolar myopathy and an axonal neuropathy, often in patients who are between 50 and 70 years of age and who have gout and a mild, chronic renal insufficiency.87 The concomitant use of statins increases the risk of myopathy. Symptoms include proximal muscle weakness, elevation of the serum CK level, distal sensory involvement, and areflexia. Symptoms resolve 4 to 6 weeks after discontinuance of the drug.

Steroid-induced myopathy

Patients with hyperadrenocorticism (i.e., Cushing syndrome) may develop weakness. Similar changes can occur during long-term administration of prednisone (usually at dosages greater than 20 mg daily) or dexamethasone, especially in poorly mobilized patients. The steroid-induced myopathic weakness is mild, spares the neck flexor muscles,77 and may aggravate the weakness caused by the underlying immune disease or malignancy for which steroids are administered. Lowering the dose of the drug reverses the myopathy. The serum CK level is normal, the muscle biopsy shows only type II fiber atrophy, and the EMG is not informative.

Myopathy associated with alcoholism

Patients with alcoholism most often develop an axonal peripheral neuropathy and, occasionally, an acute or chronic myopathy. The acute myopathy presents with tightly swollen, painful, and tender muscles; it occurs in chronic alcoholics, frequently after a heavy bout of drinking. Acute myopathy can be localized (resembling thrombophlebitis) or generalized and severe (presenting as rhabdomyolysis and myoglobinuria).75,82 It can recur if the patient resumes drinking. Acute myopathy in patients with alcoholism may also be related to hypokalemia when the serum K+ concentration is below 2.5 mEq. This myopathy is painless, not accompanied by muscle swelling, and quickly reversible.

Proximal muscle weakness in patients with long-term alcoholism is often multifactorial and not necessarily a primary toxic effect of alcohol to the muscle; for example, poor nutrition, inactivity, or neurogenic disease may be involved.58 Histologically, type II fiber atrophy is most common. Some long-term drinkers may experience an asymptomatic elevation of the serum CK level—as much as 20 times higher than normal levels—that is aggravated by physical activity.

Drug-induced inflammatory myopathy

Patients with Wilson disease, rheumatoid arthritis, or progressive systemic sclerosis can develop polymyositis or myas-thenia gravis during treatment with D-penicillamine. The disease responds to discontinuance of the drug or the administration of steroids. In single, unconfirmed reports, procainamide, propyl-thiouracil, and cimetidine have been reported to cause a poly-myositis-like disease.

Contaminated L-tryptophan was responsible for an outbreak of a syndrome of eosinophilic fasciitis, myositis, thickening of the skin, axonal neuropathy, and other systemic manifestations. An immune process against fibroblasts in the extracellular matrix triggered by the contaminant was implicated in the cause of this syndrome, called the eosinophilia-myalgia syndrome.88 The disease has left several patients with residual skin thickening, myalgia, and fatigue. Macrophagic myofasciitis is an entity encountered in France and resulting from aluminum-containing vaccines. Patients present with myalgia and fatigue. Biopsy at the sites of vaccines shows accumulation of macrophages in the epimysium, perimysium, and endomysium.

Interferon alfa (IFN-a), now commonly used for certain malignancies and hepatitis, causes fatigue, arthralgias, and, at times, myalgia. The exact mechanism of the muscle fatigue and myalgia is unknown, but rare cases of myositis and myasthenia-like disease have been noted. The cytokine interleukin-2, used for renal cell carcinoma, can exacerbate preexisting polymyositis or dermatomyositis.

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