Diseases of Muscle (Myopathies)

15.1 Structure and Function of Muscle

15.2 General Symptomatology

15.3 Muscular Dystrophies

15.4 Myotonic Syndromes and Periodic Paralysis Syndromes

15.5 Metabolic Myopathies

15.6 Myositis

15.7 Other Diseases Affecting Muscle

15.8 Disturbances of Neuromuscular Transmission—Myasthenic Syndromes

Going Weak

An 81-year-old man with longstanding hypertension and diabetes sustained a myocardial infarction. Coronary angiography revealed stenosis of three coronary vessels, which were recanalized with stents. His clinical condition improved rapidly; after 4 days in the hospital, he was transferred to a rehabilitation center. His doctors in the hospital had optimized his antihypertensive and antidiabetic drug regimen and added a statin (atorvastatin 80 mg orally daily) to treat an elevated cholesterol level.

His condition stabilized in rehabilitation, and he was discharged without symptoms 3 weeks later.

He had barely arrived home when he began to feel diffuse pain in all four limbs, which steadily worsened. He also noted increasing weakness of his entire body, which he interpreted, at first, as fatigue. Ultimately, the pain and weakness bothered him so much that he consulted his family doctor. His urine had also become unusually dark.

The family physician’s examination revealed generalized muscle weakness with diminished intrinsic muscle reflexes. The urine was dark brown, and a test strip disclosed high protein content (myoglobin). The serum creatine kinase (CK) concentration was markedly elevated.

These findings clearly indicate rhabdomyolysis, a rapidly progressive loss of striated muscle fibers accompanied by the appearance of myoglobin, creatine, and other muscle enzymes in the blood. This patient’s rhabdomyolysis was presumably due to statin treatment: it is known that antilipemic agents (fibrates more often than statins) can, rarely, produce CK elevation, rhabdomyolysis, and toxic myopathy. Elderly patients are at increased risk, as are patients with renal failure or alcoholism. The main symptoms are back pain and muscle pain. If myopathy and rhabdomyolysis are recognized early, the prognosis after discontinuation of the offending drug is good.

A dreaded complication of rhabdomyolysis is acute renal failure: freely circulating myoglobin, a large protein molecule, can obstruct the renal tubules. Forced diuresis is urgently indicated.

The patient was immediately hospitalized and treated with forced diuresis. The statin drug was discontinued. Within a few days, his urine became clear again, and the serum enzymes and renal function tests returned to normal. Acute renal failure was successfully prevented. He was given ezetimibe (a resorption inhibitor) instead of a statin to lower his cholesterol level.

15.1 Structure and Function of Muscle

15.1.1 Microscopic Anatomy of Muscle

The most important structural components of striated skeletal muscle are the muscle fibers ( ▶ Fig. 15.1). The muscle fibers contain contractile elements called myofibrils; these, 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. 15.1). The actin and myosin filaments are connected to each other by intermolecular bridges.

Fig. 15.1 Microstructure of the sarcomere of a skeletal muscle fiber. (Reproduced from Aumüller G, Engele J, Kirsch J, et al. Duale Reihe Anatomie. Stuttgart: Thieme; 2014.)

15.1.2 Physiology of Muscle Contraction

When a skeletal muscle contracts, the actin filaments and myosin filaments slide over each other (the sliding filament theory). The connecting bridges between the actin and myosin filaments are disconnected and then reconnected in a ratcheting mechanism, and a net shortening (contraction) of the muscle fiber results. 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 CK, the muscle-specific enzyme.

When a muscle is first set in contraction, glycogen within the muscle is anaerobically metabolized, and lactic acid accumulates in the muscle for 5 to 10 minutes. After that, if contraction continues, 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 manifest abnormalities of muscle function. Much of the aerobic energy metabolism in muscle tissue takes place in mitochondria ( ▶ Fig. 15.1); thus, mitochondrial diseases, too, can impair muscle function.

15.1.3 Impulse Transmission at the Motor End Plate and Impulse Conduction in the Muscle Fiber

Skeletal muscle is set in contraction when a nerve impulse arrives at the so-called motor end plate ( ▶ Fig. 15.2) or neuromuscular junction. This “relay station” at the point where a nerve fiber and a muscle fiber meet consists of the following:

The presynaptic membrane, a specialized part of the terminal segment of the motor neuron.
The synaptic cleft.
The postsynaptic membrane, a specialized part of the cell membrane (sarcolemma) of the muscle fiber.

Fig. 15.2 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.

An action potential arriving at the motor end plate induces the release of acetylcholine from the presynaptic membrane. The acetylcholine molecules 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 membrane (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. 15.1). When the depolarizing stimulus arrives here, it induces the secretion of calcium ions from terminal cisterns, and the intracellular calcium concentration rises. This, in turn, activates actomyosin ATPase, leading to 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.

15.2 General Symptomatology

Key Point

Muscle weakness can be either neurogenic or myogenic. The causes and clinical features of neurogenic muscle weakness have already been 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 are classified as either primary or symptomatic. Primary myopathies are due to a pathologic process in the muscle itself; symptomatic myopathies are manifestations of muscle involvement by some other underlying disease or condition— for example, an endocrine or toxic disorder.

General etiology Most primary myopathies are genetically determined, for example, the group of muscular dystrophies, which express themselves clinically as progressive weakness, and the channelopathies (functional disorders of individual ion channels of the muscle fiber membrane), which express themselves either as a myotonic syndrome or as episodic paralysis. Most of the diseases caused by enzyme defects are genetically determined (including, among others, the mitochondrial encephalomyopathies). There are also many kinds of autoimmune myopathy; prominent among them are polymyositis and dermatomyositis, as well as myasthenia gravis, a disease of the motor end plate.

General clinical features 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 15.1.

**Table 15.1** Characteristics of myopathies
Criterion	Typical findings
Onset and progression	Usually progresses slowly (years); exceptions include myasthenia and inflammatory, toxic, and endocrine myopathies
Appearance of muscles	Usually atrophic Sometimes pseudohypertrophic (e.g., calf muscles)
Strength	Decreased
Localization of atrophy and weakness	Usually symmetric; exceptions include myasthenia and, sometimes, polymyositis The weakness is usually proximal; exceptions include myotonic dystrophy and myasthenia (sometimes)
Reflexes	Diminished or absent
Sensation	Intact
Contractures	Usually develop over the course of time (years)
Ancillary testing	Pathologic EMG Normal nerve conduction velocity Elevated serum creatine kinase concentration Typical biopsy findings
Differential diagnosis	Mainly spinal muscular atrophy Muscle weakness of metabolic origin Functional pseudoparesis
Abbreviation: EMG, electromyogram.

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 the following:
- Muscle weakness that is already present at rest, or that worsens or is exclusively present on exertion.
- Muscle atrophy.
- Fasciculations.
- Diminished or absent reflexes.
- Myotonic reactions (see section ▶ 15.4) to a tap on a muscle or on muscle contraction.
- Shortened muscles.
Electromyogram (EMG) and electroneurography (see sections ▶ 4.3.4 and ▶ 4.3.5).
Blood tests, particularly the serum concentration of CK.
Further special tests, as needed in particular clinical situations:
- Magnetic resonance imaging (MRI) of muscle.
- Muscle biopsy with conventional light-microscopic histopathologic examination.
- Special stains for abnormal lipid deposition, dystrophin, mitochondrial anomalies, enzyme defects, etc.
- Electron microscopy.
- Quantitative biochemical analysis of biopsy specimens.
- Stress testing, for example, measurement of the rise in lactate concentration after anaerobic exercise.
- Genetic analysis.

The classification of muscle diseases This is based partly on etiology and pathophysiology, partly on clinical manifestations, and increasingly also on genetic criteria: