The genetic aspects of mitochondrial diseases and the diverse and overlapping clinical syndromes that constitute this category—including the myopathic ones—are discussed in Chap. 37. The histologic change termed ragged red fibers reflects the mitochondrial changes of this class of diseases and is common to many of them, even without manifest symptoms of muscle disease.
MYOPATHIES CAUSED BY DRUGS AND TOXINS; RHABDOMYOLYSIS (SEE CHAP. 41)
A vast number of drugs and other chemical agents have been identified as myotoxic. In 1989, Curry and colleagues found reports (in the English literature alone) of approximately 100 drugs that had caused rhabdomyolysis and myoglobinuria, mostly acting in an idiosyncratic manner, and the list continues to grow. Additional myotoxic agents that can be expected to appear as new drugs are introduced. Because it is impractical to describe all the implicated drugs and toxins individually, they are broadly categorized and their main features listed in Chap. 41.
Exogenous agents may produce myopathic changes in several ways. They may act directly on muscle cells, either diffusely or locally, as occurs with intramuscular injections, or the muscle damage can be a result of diverse secondary factors—electrolyte disturbances (hypokalemia), renal failure, excessive energy requirements of muscle (as occur with drug-induced seizures and malignant hyperthermia), or inadequate delivery of oxygen and nutrients. Of course, there is a derivative category of drug-induced coma with compressive-ischemic injury to muscle. However, the most important group is that of direct toxic effects on the muscle membrane on the internal apparatus of the cell.
Several clinical features mark a myopathy as toxic in nature: lack of preexisting muscular symptoms; a predictable delay in onset of symptoms after exposure to a putative toxin; the lack of any other cause for the myopathy; and often, complete or partial resolution of symptoms after withdrawal of the toxic agent. Pathologically, this group of disorders is characterized by nonspecific myopathic changes, which in most severe degrees take the form of myonecrosis (rhabdomyolysis) and resultant myoglobinuria. This necrotizing muscle syndrome is the most frequent and serious myotoxic syndrome.
In any disease that results in rapid destruction of striated muscle fibers (rhabdomyolysis), myoglobin and other muscle proteins enter the bloodstream and appear in the urine. The latter is “cola”-colored (burgundy red or brown), much like the urine in hemoglobinuria. In hemoglobinuria, however, the serum is pink, because hemoglobin (but not myoglobin) is bound to haptoglobin, and this complex is not excreted in the urine as readily as myoglobin; also in addition, the hemoglobin molecule is three times as large as the myoglobin molecule. (The hemoglobin–haptoglobin complex is removed from the blood plasma over a period of hours and haptoglobin may be depleted, so that hemoglobinuria is present without grossly evident hemoglobinemia.) Differentiation of the two pigments in urine is difficult; both are guaiac-positive and may be detected by the “dipstick” test that can be used to advantage at the bedside in appropriate circumstances. Only small differences are seen on spectroscopic examination. The most sensitive means of detecting myoglobin is by radioimmunoassay. It should be mentioned that porphyrins are another cause of discoloration of the urine. The clinical picture in porphyria is one of a polyneuropathy and not a myopathy.