262

14 Diseases of Muscle (Myopathies)

Structure and Function of Muscle . . .		262		Metabolic Myopathies . . .		272
General Symptomatology, Evaluation				Myositis . . .	273
and Classification of Muscle Diseases . . .			263	Other Diseases Affecting Muscle . . .			274
Muscular Dystrophies . . .	265			Disturbances of Neuromuscular
Myotonic Syndromes and Periodic				Transmission−Myasthenic Syndromes . . .				275
Paralysis Syndromes . .	. 269

Structure and Function of Muscle

Microscopic anatomy of muscle. The most important structural components of striated skeletal muscle are the muscle fibers (Fig. 14.1). These cells contain contractile elements called myofibrils, which, in turn, are composed of interlacing actin and myosin molecules, which take the shape of filaments. The periodically repeating

pattern of molecular structures in skeletal muscle accounts for its characteristic, striped (“striated”) microscopic appearance (Fig. 14.1). The actin and myosin filaments are connected to each other by intermolecular “bridges.”

CM

N

NM

My

SR

Tr		T	Z	I
	G

H A

Z I

Mi

Fig. 14.1 Microstructure of skeletal muscle fibers (diagram of a	M.: Muskelkrankheiten, in Hornbostel H., Kaufmann W., Siegen-
frog preparation). CM, cell membrane. G, glycogen granule. Mi, mi-	thaler W.: Innere Medizin in Praxis und Klinik, vol. II, 4th edn, Thieme,
tochondrion. My, myofibrils. N, nucleus. NM, nuclear membrane.	Stuttgart 1992.)
SR, sarcoplasmic reticulum. T, tubular system. (After Mumenthaler,

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General Symptomatology, Evaluation, and Classification of Muscle Diseases

Physiology of muscle contraction. When a skeletal muscle contracts, the actin filaments pull the myosin filaments toward themselves. The myosin filaments slide over each other by a progressive ratcheting mechanism of the intermolecular bridges, resulting in a net shortening (contraction) of the muscle fiber. The energy for this process is derived from phosphate compounds, mainly adenosine triphosphate (ATP), but also creatine phosphate when the muscle is under acute stress. The regeneration of creatine phosphate after muscle contraction is catalyzed by the muscle-specific enzyme creatine phosphokinase (CK).

When a muscle is first set in contraction, glycogen within the muscle is anaerobically metabolized and lactic acid accumulates in the muscle for five to 10 minutes. After that, if the muscle continues to be contracted, a switch to aerobic metabolism occurs, with increasing consumption of fatty acids and lactic acid. Enzyme defects that interfere with these energy-liberating processes during muscle contraction can cause clinically apparent abnormalities of muscle function. Much of the aerobic energy metabolism in muscle tissue takes place in mitochondria (Fig. 14.1); thus, mitochondrial diseases, too, can impair muscle function.

Impulse transmission at the motor end plate and impulse conduction in the muscle fiber. Skeletal muscle is set in contraction by a nerve impulse arriving at the so-called motor end plate (Fig. 14.2) or neuromuscular junction. This “relay station” at the point where a nerve fiber and a muscle fiber meet consists of the presynaptic membrane, a specialized component of the terminal segment of the motor neuron; the synaptic cleft; and the postsynaptic membrane, a specialized component of the cell membrane (sarcolemma) of the muscle fiber.

An action potential arriving at the motor end plate induces the secretion of acetylcholine from the presynaptic membrane. The acetylcholine molecules then diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic membrane. This, in turn, leads to depolarization of the sarcolemma. Having accomplished their task, the acetylcholine molecules are now rapidly broken down within the synaptic cleft into acetate and choline, a step catalyzed by the enzyme acetylcholinesterase. Meanwhile, the sarcolemmal excitation is carried into the interior of the muscle fiber by way of numerous transverse invaginations of the cell mem-

	acetylase
		Ac-CoA
	ACh synthesis	Ac
		Ch
	ACh reserves
	available ACh	Ch
	ACh for immediate release

ACh-esterase

released ACh ACh receptor complex

Fig. 14.2 Impulse transmission at the motor end plate. Acetylcholine (ACh), the acetic acid ester of the aminoalcohol choline, is released into the synaptic cleft in response to a depolarizing stimulus and then binds to specific receptors on the postsynaptic membrane. Acetylcholine is inactivated by breakdown into its two components, choline (Ch) and acetate (Ac); this step is catalyzed by the enzyme acetylcholinesterase. Choline is taken back up into the presynaptic nerve terminal with the aid of specific transporters and then reacts again with the activated form of acetic acid (Ac-CoA) to form new acetylcholine molecules.

brane (the tubular system or T-system) and is then transmitted to the longitudinal system, a branched network of cisterns of the endoplasmic (sarcoplasmic) reticulum, which surrounds the individual myofibrils (Fig. 14.1). When the depolarizing stimulus arrives here, it induces the secretion of calcium ions from terminal cisterns and the intracellular calcium concentration accordingly rises. This, in turn, activates actomyosin ATPase, which is the final step in the initiation of muscle contraction.

Functional disturbances of these complex processes and structural changes of one or more elements of muscle or of the motor end plate cause various types of myopathy, which will be discussed from the clinical point of view in the remainder of this chapter.

General Symptomatology, Evaluation, and Classification

of Muscle Diseases

Muscle weakness can be either neurogenic or myogenic. The causes and clinical features of neurogenic muscle weakness were already discussed in earlier chapters. The present chapter concerns diseases involving a structural or functional defect of the muscle tissue itself, which are called myopathies. These, in turn, can be classified as either primary or symptomatic. Symptomatic myopathies are manifestations of muscle involvement

by some other underlying disease or condition— e. g., endocrine or toxic myopathy. Primary myopathies, in contrast, are due to a pathological process in the muscle itself. Most primary myopathies are genetically determined, e. g., the group of muscular dystrophies and the channelopathies

(functional disorders of the individual ion channels of the muscle fiber membrane), which express themselves clinically either as a myotonic syn-

ArgoOneBold

ThiemeArgoOne

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263

Diseases of Muscle

14

264	14 Diseases of Muscle (Myopathies)
		Table 14.1 Characteristics of myopathies
		Criterion	Characteristic findings
		Onset and progression	usually progresses slowly (years); exceptions include myasthenia and polymyo-
			sitis
		Appearance of muscles	usually atrophic, sometimes pseudohypertrophic (e. g., calf muscles)
		Strength	decreased
		Localization of atrophy and weakness	usually symmetrical; exceptions include myasthenia and, sometimes, polymyo-
			sitis; the weakness is usually proximal; exception, myasthenia (sometimes)
		Reflexes	diminished or absent
		Sensation	intact
		Contractures	usually develop over the course of time (years)
		Ancillary testing	pathological EMG, normal nerve conduction velocity, elevated serum creatine
			kinase concentration, typical biopsy findings
		Differential diagnosis	most importantly, spinal muscular atrophy; muscle weakness of metabolic ori-
			gin; functional pseudoparesis

Table 14.2 Classification of muscle diseases

Muscular dystrophies

Spinal muscular atrophy and other motor neuron diseases, cf. p. 154

Myotonias and periodic paralyses (“channelopathies”) Metabolic myopathies

Mitochondrial myopathies and encephalomyopathies Congenital myopathies

Infectious/inflammatory myopathies Myopathy due to endocrine disorders

Muscle involvement by electrolyte disturbances Toxic and iatrogenic myopathies

Disorders of neuromuscular transmission Tumors

Trauma

drome or as episodic paralysis. Most of the diseases caused by enzyme defects are also genetically determined (including, among others, the mitochondrial encephalomyopathies). There are also numerous types of autoimmune myopathy. Prominent among them are polymyositis and dermatomyositis, as well as myasthenia gravis, a disease of the motor end plate.

General clinical manifestations. Myopathies are traditionally considered part of the subject matter of neurology because their most prominent sign is motor weakness. The typical manifestations that are common to all myopathies as a class are summarized in Table 14.1.

General diagnostic considerations. The evaluation of myopathy comprises the following steps:

a complete and precise case history, including the family history;

physical examination, with particular attention to:

muscle weakness that is already present at rest, or that worsens or is exclusively present on exercise; the examiner should also specifically look for

muscle atrophy,

fasciculations,

diminished or absent reflexes,

myotonic reactions (p. 270) to a tap on a muscle, or on muscle contraction, and

shortened muscles;

electromyography and electroneurography (p. 58);

blood tests, particularly the serum concentration of creatine phosphokinase (CK);

and, as needed depending on the particular clinical situation, further special tests:

muscle biopsy with conventional light-micro- scopic histopathological examination;

special stains for the demonstration of abnormal lipid deposition, dystrophin, mitochondrial anomalies, enzyme defects, etc.;

electron microscopy;

quantitative biochemical analysis of biopsy specimens;

stress testing, e. g., measurement of the rise in lactate concentration after anaerobic muscle contraction;

genetic analyses.

Classification of muscle diseases. Myopathies can be classified by their etiology and pathophysiology, by their clinical phenomenology, or, as is now increasingly common, by their underlying genetic defects (Table 14.2). The genetically oriented classification of the myopathies is currently changing so rapidly that our listings in Tables 14.3, 14.4 must be regarded as provisional.

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