Fundamentals of Neurology: An Illustrated Guide

14. Diseases of Muscle (Myopathies)

Structure and Function of Muscle

General Symptomatology, Evaluation and Classification of Muscle Diseases

Muscular Dystrophies

Myotonic Syndromes and Periodic Paralysis Syndromes

Metabolic Myopathies


Other Diseases Affecting Muscle

Disturbances of Neuromuscular Transmission-Myasthenic Syndromes

Image  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.”


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

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 acetylcho-linesterase. Meanwhile, the sarcolemmal excitation is carried into the interior of the muscle fiber by way of numerous transverse invaginations of the cell mem


Fig. 14.2 Impulse transmission at the motor end plate. Acetyl-choline (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) reti-culum, 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.

Image  General Symptomatology, Evaluation, and Classification of Muscle Diseases

Muscle weakness can be either neurogenic or myo-genic. The causes and clinical features of neuro-genic 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

Table 14.1 Characteristics of myopathies


Characteristic findings

Onset and progression

usually progresses slowly (years); exceptions include myasthenia and polymyo


Appearance of muscles

usually atrophic, sometimes pseudohypertrophic (e. g., calf muscles)



Localization of atrophy and weakness

usually symmetrical; exceptions include myasthenia and, sometimes, polymyo

sitis; the weakness is usually proximal; exception, myasthenia (sometimes)


diminished or absent




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

origin; 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



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 autoimmunemyopathy. Prominent among them are polymyositis and dermato-myositis, 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:

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

Image physical examination, with particular attention to:

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

Image muscle atrophy,

Image fasciculations,

Image diminished or absent reflexes,

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

Image shortened muscles;

Image electromyography and electroneurography (p. 58);

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

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

Image muscle biopsy with conventional light-microscopic histopathological examination;

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

Image electron microscopy;

Image quantitative biochemical analysis of biopsy specimens;

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

Image 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.

Image  Muscular Dystrophies

The muscular dystrophies are genetically determined. They typically present with symmetric muscle weakness, which is at first either mainly proximal or mainly distal, and which slowly worsens over the years. The chronically progressive weakness is not accompanied by pain or by any sensory deficit. The muscles usually become atrophic, though this is masked, in some patients, by intramuscular deposition of fatty tissue (pseu-dohypertrophy). Connective tissue deposition can lead to muscle shortening and contractures. The reflexes are diminished or lost. Weakness produces characteristic postural abnormalities and deformities, e. g., to lumbar hyperlordosis (a common finding), Duchenne or Trendelenburg gait (p. 15), winging of the scapula, or scoliosis.

Table 14.3 provides an overview of the various types of muscular dystrophy. The major types are described in detail in the following paragraphs.




Fig. 14.3 Duchenne muscular dystrophy in a 10-year-old boy. a Lateral view: note the lumbar lordosis and pseudohypertrophic calves. b When the child walks, the trunk inclines to the side of the stationary leg (Duchenne limp). (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

Hereditary Muscular Dystrophies of X-chromosomal Inheritance-Dystrophinopathies

The diseases in this group are caused by a genetic defect on chromosome Xp21.2. They are, therefore, almost exclusively seen in boys whose mothers are (healthy) carriers. Dystrophin, a structural protein of the muscle fiber membrane that is also expressed in the brain, is present in reduced amounts or completely absent.

Duchenne Muscular Dystrophy

Clinical manifestations. Boys develop the first signs of the disease in the first decade of life, usually in the preschool years. The conspicuous abnormalities at first are difficulty climbing stairshyperlordosis of the lumbar spine, and waddling gait (Fig. 14.3). Over the next few years, weakness becomes progressively severe in the proximal muscles of the lower limbs and then of the upper limbs as well. The affected boys can stand up from a squatting position only by climbing up their own legs with their hands and arms (Gowers signFig. 14.4). Fat deposition leads to pseudohypertrophy of the calves. The waddling gait is due to bilateral hip adductor weakness (Duchenne or Trendelenburg gait, p. 15).

Diagnostic evaluation. The CK is markedly elevated in the initial stages of the disease. The absence of dystro-phin can be demonstrated by muscle biopsy with special tissue staining (Fig. 14.5).

Prognosis. The disease progresses relatively rapidly, rendering the affected boys unable to walk in the second decade of life. The scoliosis worsens and causes respiratory difficulty. The cardiac muscle is also affected, though usually not to any clinically evident extent. As dystrophin is expressed in the brain, most of the affected boys are mentally retarded. They usually die of respiratory insufficiency or secondary complications between the ages of 18 and 25.

Becker Muscular Dystrophy

This type of muscular dystrophy is about one-tenth as common as the Duchenne type. Dystrophin is not wholly absent, but is expressed in reduced amounts (Fig. 14.5). The affected boys show the first signs of the disease in the first or second decade; the progression is much slower than in the Duchenne type. Many patients are still able to walk after age 30, but most die in their fourth or fifth decade of life. The EMG and laboratory findings are similar to those of Duchenne muscular dystrophy.

Autosomal Muscular Dystrophies

The genetic localization of the autosomal muscular dystrophies is known in most patients, though the gene products are not. We will only describe the more common forms here.


Fig. 14.4 Gowers sign in Duchenne muscular dystrophy. This 7-year-old boy stands up by climbing up his own thighs. (From: Mu-menthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

Facio-Scapulo-Humeral Type

This is a disease of autosomal dominant inheritance due to a genetic defect in the 4q35 region of chromosome 4, near the telomere. It begins in the second or third decade of life with weakness of the facial and shoulder girdle musculature (eye closure, whistling; raising the arms) (Fig. 14.6). Sensorineural deafness is often present as well. The muscles of the pelvic girdle and the distal muscles of the limbs are not affected until later decades. The life expectancy is normal.


Fig. 14.5 Dystrophin stain. a Normal skeletal muscle. Regular, ho- pressed to a varying extent on the individual muscle fibers, inmogeneous distribution of dystrophin on the inner surface of the diminished quantity and abnormal distribution; in some fibers, it issarcolemma of each muscle fiber (black contours). b Duchenne dys- not expressed at all. The presence of dystrophin—albeit in subnor-trophy. Dystrophin is absent. c Becker dystrophy. Dystrophin is ex- mal amounts—distinguishes Becker from Duchenne dystrophy.


Fig. 14.6 Facio-scapulo-humeral muscular dystrophy in a 37-year-old man. A photograph of the face (a), reveals weakness of the orbicularis oris m., because of which the patient cannot whistle. A rear view of the upper body (b), shows the protruding scapulae. The patient cannot raise his arms laterally above a horizontal line. (From Mumenthaler, M., in Hornbostel H., Kaufmann W., Siegenthaler W.: Innere Medizin in Praxis und Klinik, vol. II, 4th edn, Thieme, Stuttgart 1992, cf. Fig. 14.1)

Limb Girdle Types of Muscular Dystrophy

This is a genetically heterogeneous group of diseases: the inheritance pattern is autosomal dominant for some, autosomal recessive for others. Causative genetic defects have been found on chromosomes 5q, 13q, and 15q. The onset of disease can be in childhood or in adulthood. The first sign is always mainly proximal weakness of the muscles of either the shoulder girdle or the pelvic girdle; over time, the other limb girdle is affected as well (ascending vs. descending type). The prognosis is highly


Fig. 14.7 Steinert myotonic dystrophy in a 28-year-old man. Note the flaccid facial features and sunken temples (myopathic facies) and the predominantly distal muscle atrophy in the limbs, particularly the lower limbs. (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

variable: some patients experience rapid progression of the disease within one or two decades, while others live on into old age with hardly any impairment.

Myotonic Dystrophy of Curschmann-Steinert Type

Epidemiology. This is the most common myopathy of adulthood (see also Table 14.3).

Etiology. This is a disease of autosomal dominant inheritance due to an unstable CTG trinucleotide sequence expansion in a gene on chromosome 19q13.3. Clinical manifestations arise when the sequence contains more than the usual five to 30 trinucleotide repeats. The expansion lengthens from generation to generation when transmitted in the maternal line; this explains the onset of the disease at an earlier age in each successive generation (anticipation).

Clinical manifestations. Muscle involvement is the most prominent sign. Weakness of the facial and distal limb muscles usually becomes apparent in young adulthood. The face develops a typical “tired” appearance with sunken temples, mild ptosis, and loose folds around the often slightly open mouth (myopathic facies, cf. Fig. 14.7). Weakness and atrophy of the dorsiflexors of the feet produce a steppage gait. Myotonia is a striking phenomenon that may appear in a very early stage of the disease: after the patient firmly grips an object, he or she has difficulty letting it go. Delayed muscle relaxation can also be demonstrated after a sharp blow to a muscle (e. g., tongue, ball of the thumb). Other organs, too, are affected: early cataracts, dysphagia, sluggish bowel function, cardiomyopathy, pulmonary involvement, diabetes, testicular atrophy, and infertility are all possible manifestations of the disease.

Diagnosis. The diagnosis can be made tentatively based on the typical clinical features and thedemonstration of myotonic discharges in the EMG. It is confirmed by genetic testing.

Prognosis. The life expectancy is markedly lowered; most patients die around age 50.

Congenital Myotonic Dystrophy

This disease is due to a genetic defect involving a very large trinucleotide expansion (more than 2000 copies). It is usually passed on from mothers to their children, particularly when the mother already possesses a long expansion. The affected individuals suffer from birth onward from dysphagia and weakness of drinking, flaccid facial muscles, a high palate, mental retardation, and other signs like those of Curschmann-Steinertmyotonic dystrophy.

Rarer Types of Muscular Dystrophy

Congenital muscular dystrophies are a heterogeneous group of diseases characterized by dystrophic changes in muscle fibers that are present at birth and then either remain constant or slowly progress. Muscular dystrophy that has already exerted its effects in prenatal life presents in the newborn with arthrogryposis multiplex, i. e., fixed, abnormal positions of the joints.

Oculopharyngeal dystrophy is a disease of autosomal dominant inheritance that first becomes evident in middle age. The initial signs are progressively severe ptosis and restriction of eye movements, without di-plopia. Later, dysphagia develops, which may be life threatening. Other muscle groups are sometimes paretic as well. This condition requires diagnostic differentiation from myasthenia gravis (p. 275) and Kearns-Sayre syndrome (p. 273).

Image  Myotonic Syndromes and Periodic Paralysis Syndromes

These inherited muscle diseases belong to the group of so-called channelopathies: they involve abnormalities of the chloride, sodium, or calcium channels in the muscle fiber membrane. They are caused by a variety of different genetic defects and manifest themselves clinically either with myo-tonia (delayed relaxation of muscle after active contraction) or with episodic paralysis.

Table 14.4 provides an overview of the major types of channelopathy. A selection of these will be discussed in the following paragraphs.




Fig. 14.8 Thomsen congenital myotonia in a 20-yxear-old man. The patient is of athletic build and has normal muscle strength, but active muscle contraction during the physical examination is followed by marked myotonia. (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

Diseases Mainly Causing Myotonia

Congenital Myotonia

Congenital myotonia has both dominant (Thomsen) and recessive (Becker) forms. Both are due to a genetic defect on chromosome 7q35 that impairs the transporting ability of chloride channels.

Clinical manifestations. The most prominent manifestation is myotonia, i. e., markedly slowed muscle relaxation after active contraction. A tightly grasped object can be let go again only after a delay. The patient cannot make any sudden movements, but the movements do become more fluid after a few attempts (the warming-up phenomenon). Raw muscle strength may be transiently diminished after a powerful contraction (=myotonic paralysis) but is otherwise normal. There is no atrophy; on the contrary, patients often have a markedly athletic habitus (Fig. 14.8). In the Becker form, the my-otonic manifestations are more severe and mild distal atrophy may be present in the late stage of the disease.

Diagnostic evaluation. Tonic muscle relaxation and transient indentations of muscle, the key features of myotonia, can be seen after a contraction induced by a tap or electrical stimulation of the muscle (Fig. 14.9). The diagnosis is confirmed by the typical electromyo-graphic findings (Fig. 14.10).

Treatment. Antiarrhythmic drugs such as procain-amide and mexitil, antiepileptic drugs such as pheny-toin, or acetazolamide can be used.

Prognosis. The prognosis is favorable, in that the severity of disease manifestations tends to lessen over the years and the life expectancy is normal.

Other Diseases with Myotonic Manifestations

Other diseases with myotonic manifestations are listed in Table 14.4. Curschmann-Steinert myotonic dystrophy is described above on p. 268; a few more rare diseases are described in the following paragraphs.

Proximal myotonic myopathy (PROMM). In this disease, mainly proximal muscle atrophy (particularly of the thigh muscles) is accompanied by mild myotonia. Cardiac arrhythmias and cataracts may also be present. The progression of the disease, and the impairment that it causes, are mild. The responsible gene is located on chromosome 3q.

Neuromyotonia is also known as the syndrome of continuous muscle fiber activity and as Isaacs syndrome. Its characteristic feature is continuous stiffness of the musculature, with myokymia. The patient's movements are correspondingly viscous. The EMG reveals continuous spontaneous muscle activity. This disease can arise at any age and is thought to be due to an autoimmune process. Antiepileptic drugs are an effective form of treatment, as is plasmapheresis in some patients.

“Stiff man” syndrome is also characterized by continuous muscle fiber activity, as revealed by EMG. The muscles are stiff and subject to painful spasms, which worsen in response to external stimuli and emotional stress. The disease manifestations progress slowly over months or years. Here, too, the pathogenesis is thought to be autoimmune. Effective treatments include diazepam, antiepileptic drugs, baclofen, and immunoglobulins.

Diseases Causing Periodic Paralysis

The genetically determined periodic paralyses are characterized by suddenly arising abnormalities of the serum potassium concentration leading to transient in-excitability of the muscle fiber membrane and therefore to muscle dysfunction. They share the following clinical features:

Image episodes of paralysis of sudden onset, of varying severity and duration, which may last for hours to days;

Image usually, sparing of the facial and respiratory muscles;

Image in some patients, permanent muscle weakness later on in the course of the disease.

There are normokalemichyperkalemic, and hypokalemic types (Fig. 14.4). We will describe only the last-named type here as a paradigmatic example.

Hypokalemic Periodic Paralysis

Pathogenesis. This is a disease of autosomal dominant inheritance caused by dysfunction of the dihydropy-ridine-sensitive calcium channels in the transverse tubular system of muscle fibers. These channels are encoded by a gene on chromosome 1q31-32. The disease has higher penetrance in men.


Fig. 14.9 Myotonic reaction of the tongue musculature in Stein-ert myotonic dystrophy. Repeated tapping of the edge of the tongue (here, the left edge) produces a lasting indentation. (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)


Fig. 14.10 Electromyogram in a 29-year-old woman with Stein-ert myotonic dystrophy. Tapping on the thenar muscles evokes ong-lasting high-frequency electrical activity, whose amplitude dies down slowly.

Clinical manifestations. The initial paralytic attacks occur between the ages of five and 30, usually in the second decade of life. Their frequency is highly variable, ranging from daily attacks in some patients to a few attacks per year in others. Each attack lasts from a few hours to an entire day.

Diagnostic evaluation. The CK is usually normal. The EMG during an attack reveals only a few low-voltage potentials, or none at all. There are flat T and U waves in the ECG. Rare symptomatic (nonfamiliar) cases have been described in persons with hypothyroidism.

Treatment. The prognosis of each individual attack is good. The frequency of attacks can be reduced by a low-salt and low-carbohydrate diet, as well as by potassium supplementation. Intravenous administration of potassium shortens the duration of an attack.

Image  Metabolic Myopathies

Normal muscle function depends on an adequate supply and continuous regeneration of the energetic molecule ATP. ATP can be derived from a number of different sources; glycogen and lipid metabolism, and normal mitochondrial function, play a central role in these processes. Insufficient availability of energy to muscle tissue results in exercise-induced muscle weaknessmyalgias, and, in the later course of disease, contractures. The underlying metabolic disorder is usually due to an inherited enzyme defect. The major clinical entities of this type are the glycogenosescarnitine deficiency, and the group of mitochondrial (en-cephalo-)myopathies (with dysfunction either of the tricarbonic acid cycle, or of the respiratory chain and oxidative phosphorylation).

These metabolic diseases often do not become apparent until adolescence or young adulthood. The following findings suggest the presence of one of these conditions:

Image Muscle exercise is followed by muscle weakness, myalgias, and/or contractures. Rhabdomyolysis sometimes occurs, causing myoglobinuria and an elevated CK concentration.

Image Permanent muscle atrophy and weakness may develop over time.

Image The serum CK concentration is often elevated and sometimes the lactate concentration as well (particularly in mitochondrial diseases).

Image The EMG is usually normal; only in rare cases is there any evidence of myopathy.

Image Muscle exercise under ischemic conditions normally leads to a fourfold rise of the lactate concentration. This rise does not occur in persons suffering from one of the glycogenoses. If, on the other hand, an exaggerated rise is found after only mild exertion, a mitochondrial disease is probably present.

The individual types of metabolic myopathy are summarized in Table 14.5. In the following paragraphs, we will discuss only rhabdomyolysis and the mitochondrial encephalomyopathies in detail.

Acute Rhabdomyolysis

Rhabdomyolysis is the acute destruction of skeletal muscle tissue, resulting in the passage of myoglobin into the bloodstream and a marked rise of the serum CK concentration. There are both idiopathicforms, with an au-tosomal dominant inheritance pattern, and symptomatic forms of rhabdomyolysis, caused either by toxic in-fluences—e. g., the consumption of alcohol, heroin, or certain medications, such as statins—or by a disease of muscle metabolism, e.g., one of the glycogenoses. Rhabdomyolysis can thus be the symptomatic expression of a wide variety of pathological processes.

Clinical manifestations. The patient develops rapidly worsening muscle pain and weakness. Examination reveals loss of reflexes and often muscle swelling; urinaly-sis reveals myoglobinuria. There is no sensory deficit. The most feared complication is acute renal failure.

Treatment. If the patient has myoglobinuria, optimal hydration is given to prevent renal failure. If renal failure nevertheless occurs, dialysis is necessary.

Mitochondrial Encephalomyopathies

Mitochondrial function. Mitochondria are present in every cell of the body; they are the sites of pyruvate, fatty acid, and amino acid metabolism. These processes result in the production of ATP, an essential energy carrier for cellular metabolism and muscle contraction.


The mitochondrial genome. Mitochondria have two copies of the nuclear DNA (nDNA) at their disposal, but also multiple copies of their own mitochondrial DNA (mtDNA). Mitochondrial DNA is transmitted from generation to generation through the oocyte, independently of the nuclear genome. Thus, mitochondrial diseases caused by mtDNA defects are inherited in a maternal pattern.

General clinical manifestations of mitochondrial disease. Disturbances of mitochondrial metabolism impair the function of nearly all cells in the body. Muscle and brain cells are particularly strongly affected because of their high-energy requirements. Thus, mitochondrial diseases often express themselves clinically as an en-cephalomyopathy. The typical clinical features are summarized in Table 14.6.

Examples of Mitochondrial Myopathies

Progressive external ophthalmoplegia usually has its onset in adulthood and progresses very slowly. Its typical features are progressive ptosis and restriction of ocular motility, so that, in the end, all movements of the eyes are impossible. Skeletal muscle biopsy with Go-mori trichrome staining reveals accumulations of mitochondria in so-called “ragged red fibers.” The condition can appear as a familial disease of maternal inheritance or as a component of Kearns-Sayre syndrome (see below).

Kearns-Sayre syndrome (KSS) is characterized by progressive external ophthalmoplegia combined with retinal pigment degeneration and an intracardiac conduction defect. There may be further clinical manifestations as well (cf. Table 14.6). KSS is usually familial and is due to a point mutation in the mitochondrial DNA.

MELAS syndrome consists of mitochondrial myopathy, encephalopathy, lactic acidosis, and “strokelike epi

Table 14.6 Clinical manifestations of mitochondrial diseases




myopathy with ragged red fibers

progressive external ophthalmoplegia

exercise intolerance

Nervous system

myoclonus and generalized seizures

stroke in younger individuals





optic neuropathy


basal ganglionic calcification

(Fahr syndrome)


elevated CSF protein concentration


retinitis pigmentosa cataract


cardiomyopathy conduction abnormalities

Gastrointestinal system

intestinal pseudoobstruction diarrhea

Endocrine system

short stature diabetes goiter hypogonadism


multiple lipomas ichthyosis

sodes.” It presents in childhood with transient cerebral ischemia, episodic vomiting, and often, later, dementia. The serum lactic acid concentration is elevated.

MERRF syndrome (myoclonus epilepsy with ragged red fibers) is a rare syndrome characterized by myoclonus, generalized epileptic seizures, myopathy, and dementia.

Image  Myositis

Myositis is an infectious or inflammatory disease

of muscle. The various types of myositis include:

Image autoimmune diseases affecting muscle, either as the major disease manifestation (as in polymyositis, which sometimes affects the skin as well=dermatomyositis) or as an accompanying manifestation in a larger syndrome;

Image muscle involvement by a primarysystemicnoninfectiouschronic inflammatory disease;

Image direct infection of muscle (infectious myositis).

The most important types of myositis are listed in Table 14.7.

General clinical manifestations. The common features of infectious and inflammatory myopathies are:

Image usually symmetrical muscle involvement;

Image usually very rapid progression, within a few months;

Image sometimes, local pain;

Image lack of a sensory deficit;

Image sometimes, very high serum CK concentration;

Image lack of a family history.

In this chapter, we will restrict ourselves to a description of polymyositis and dermatomyositis.

Polymyositis and Dermatomyositis

Epidemiology. The incidence of these conditions is low: they strike only five to 10 per 100 000 individuals per year. Women are more commonly affected. The disease usually appears either before puberty or around age 40.

Table 14.7 Infectious and inflammatory myopathies (myositi-des)

Autoimmune inflammatory


mainly affecting


dermatomyositis and polymyositis in adults

dermatomyositis and polymyositis in children

dermatomyositis and polymyositis ac

companying malignancy

inclusion body myositis myofasciitis

with macrophages



disorders affecting

muscle as well as

other organ systems


Sjögren syndrome

systemic lupus erythematosus

rheumatoid arthritis

mixed collagenosis (mixed connective

tissue disease, Sharp syndrome)

periarteritis nodosa

Behçet disease

Other noninfectious myositides

giant cell myositis

diffuse fasciitis with eosinophilia

eosinophilic polymyositis

polymyalgia rheumatica


myositis in Crohn disease

myositis ossificans


Infectious myositides

viral (e. g., influenza virus)






Pathogenesis. Humoral factors play a role in dermato-myositis, while cellular immune mechanisms are involved in pure polymyositis.

Clinical manifestations. The illness often begins with constitutional symptoms such as fatigue, myalgias, joint pain, and sometimes even fever. Thereafter, a usually symmetricalmainly proximal muscle weakness develops. Patients have difficulty rising from a squatting position, getting up from a chair, or raising the arms above the horizontal position. The muscles are often tender to pressure. The symptoms and signs progress rapidly over a few weeks or months. About one-third of patients suffer from dysphagia, which may result in aspiration pneumonia. If the skin is involved as well (dermatomyositis), it is discolored to a reddish-purple hue. The discoloration may involve the face in “butterfly” fashion (nose and both cheeks), or it may be visible on the chest, on the dorsum of the hand, or around the fingernails. Subcutaneous calcinosis, joint pain, joint effusions (rare), and Raynaud-like phenomena may also be present. The heart may be involved (extrasystole, heart failure). When polymyositis appears as a component of a collagenosis (Table 14.7) (“overlap syndrome”), other organs are affected as well. The only other disease affecting both the muscles and the skin is scleroderma.

Diagnostic evaluation. Ancillary testing is usually necessary. The serum CK concentration is elevated to 10 times the normal value or more, at least initially. The EMG reveals markedly shortened, low, polyphasic potentials, to a highly variable degree in different portions of the same muscle. Pathological spontaneous activity and denervation potentials are also present. Muscle biopsy typically reveals diffusely distributed muscle necrosis and inflammatory infiltrates.

Treatment. Children tend to respond well to treatment with corticosteroids. Adults often require treatment with other immunosuppressive drugs, usually azathioprine. Immunoglobulins are beneficial in the initial stage of treatment but must always be supplemented with corti-costeroids or immune suppressants over the course of time.

Image  Other Diseases Affecting Muscle

Myopathies Due to Systemic Disease

A variety of general medical conditions cause muscle weakness, among them certain endocrinopathies (hypo- and hyperthyroidism, hyper- and hypoparathy-roidism, Cushing disease, Addison disease). Paraneo-plastic syndromescausing muscle weakness include paraneoplastic poly- and dermatomyositis, as well as Lambert-Eaton syndrome, in which neuromuscular transmission is impaired (p. 277). Among the electrolyte disorders, hyper- and hypokalemia (not of genetic origin) can cause muscle weakness, as can medications such as colchicine, chloroquine, fluorocortisone, and antilipemic agents. Toxic substances such as gasoline vapor and toluene can produce rhabdomyolysis (be aware of recreational sniffing as a possible cause!), while alcohol can produce an acute alcoholic myopathy. Malnutrition, e.g., in prison camps, can lead to my-astheniform disturbances, and vitamin E deficiency can lead to severe myopathy.

Congenital Myopathies

A number of types of congenital myopathy have been described and the genetic basis of some of them is now known. Their common features are:

Image markedly reduced muscle tone from infancy onward;

Image delayed motor development;

Image later, mainly proximal muscle weakness;

Image often, generally diminished muscle bulk;

Image often, a narrow head with a raised, “Gothic” palate and possibly other skeletal deformities;

Image slow progression, or none;

Image sometimes, cardiomyopathy and/or dementia.

Table 14.8 contains a list of congenital myopathies classified by the histopathological findings of muscle biopsy.

Table 14.8 Congenital myopathies

Central core myopathy

Nemaline (rod) myopathy

Centronuclear myopathy

Multicore myopathy

Fingerprint body myopathy

Sarcotubular myopathy

Hyaline body myopathy (=myopathy with disintegration of

myofibrils in type I fibers)

Image  Disturbances of Neuromuscular Transmission-Myasthenic Syndromes

The myasthenic syndromes are characterized by abnormal fatigability of muscle. The weakness may affect individual muscle groups in more or less isolated fashion, or, alternatively, all of the muscles of the body. Pathophysiologically speaking, these conditions are due to a disturbance of impulse transmission at the motor end plate, usually because of an underlying autoimmune disorder. For example, the most common myasthenic syndrome, myasthenia gravis, is due to the destruction of acetylcholine receptors on the postsynaptic membrane by cross-reacting autoantibodies.

The cellular processes involved in impulse transmission at the motor end plate are discussed on p. 263 and shown pictorially in Fig. 14.2. Theoretically speaking, these processes were impaired in a number of different ways:

Image inadequate synthesis of acetylcholine, or defective storage of acetylcholine in axon terminals;

Image inadequate release of acetylcholine from axon terminals;

Image impaired transport of acetylcholine in the synaptic cleft;

Image impaired binding of acetylcholine to its specific receptors on the postsynaptic membrane.

The last-named mechanism is at work in the commonest and clinically most important type of myasthenia, namely, myasthenia gravis. In Lambert-Eaton syndrome (p. 277), on the other hand, the underlying problem is inadequate release of acetylcholine from the presynaptic membrane.

Myasthenia Gravis

Epidemiology. The incidence of this disorder is one to four per 100 000 individuals per year; its prevalence in the general population is 140 per million. Women are more commonly affected, in a female-to-male ratio of 3:2. The onset of the disease is usually in the second through fourth decade of life in women, but in the sixth decade in men. In principle, however, myasthenia gravis can appear at any age.

It is not uncommon for myasthenia gravis to be accompanied by certain other diseases: thymoma occurs in about 15% of patients with the disease, hyperthyroid-ism in 5%, hypothyroidism likewise in 5%, and polyarthritis in 4 %.

Pathophysiology. Three-quarters of all patients with myasthenia gravis have hyperplasia of the thymus and 15% harbor a thymoma. Antibodies are generated against the myoid cells of the thymus; owing to a misdirection of the immune response, these antibodies also attack the acetylcholine receptors of the motor end plate. Acetylcholine receptor antibodies are present in the serum in elevated concentration in a large majority of patients with generalized myasthenia. If the serum of an affected patient is injected into an experimental animal, the animal develops a myasthenic syndrome. The antibodies can be transmitted across the placenta from a myasthenic mother to her child (see below). They are highly heterogeneous and bind to the acetylcholine receptor at a number of different locations.

Clinical manifestations. The clinical features of my-asthenia are summarized in Table 14.9. The most prominent manifestation is abnormal fatigability of muscle. Initially, the muscles most obviously affected are those that carry out very fine movements and that accordingly contain unusually small motor units. These are the muscles that react most strongly to a decline in acetyl-choline receptor density, i. e., the extraocular muscles, the levator palpebrae m., and the muscles of mastication and deglutition. Thus, the early manifestations of my-asthenia gravis often include diplopiaptosisdysphagia with frequent aspiration, and difficulty chewing food. Nevertheless, practically any other muscle group can be involved, even at the onset of the disease. The disease manifestations worsen over the course of the day and are worst in the evening. Repeated activation of an affected muscle group leads to rapidly worsening weakness. This phenomenon forms the basis of a number of clinical diagnostic tests.

Diagnostic evaluation. Myasthenic ptosis worsens visibly over the course of a single minute if the patient rapidly and repeatedly closes and opens the eyes, or looks upward for a prolonged period (the Simpson testFig. 14.11).

Table 14.9 Clinical features of myasthenia

Image Progressive weakness of individual muscles

Image The weakness increases on rapid, repeated contraction of the affected muscles

Image Recovery within minutes, or a fraction of an hour, at rest

Image The weakness usually worsens toward evening

Image The eye muscles are often affected first (ptosis, diplopia), or

else the pharyngeal muscles (dysphagia, nasal speech)

Image Variably severe weakness of muscles belonging to different motor units

Image Occasionally, crises with sudden deterioration of muscle strength

Image No atrophy or fasciculations

Image More or less complete resolution of disease manifestations

after the administration of a cholinesterase inhibitor, e.g., test

injection of edrophonium chloride I.V. (Tensilon test)

Image Usually, elevated serum titer of antibodies against the acetylcholine receptor (though this is a rare finding in ocular myasthenia)

Further diagnostic tests serve to confirm the clinical diagnosis. In the Tensilon test, 10 mg of the acetylcho-linesterase inhibitor edrophonium chloride are injected intravenously over 10 seconds. This drug inhibits the breakdown of acetylcholine in the synaptic cleft, so that acetylcholine is available to its receptors on the muscle cell membrane for a longer time and the deleterious effect of diminished receptor density is counteracted. An improvement is seen within 30 seconds and lasts for about three minutes. A marked ptosis, for example, can transiently disappear.

When a motor nerve is repeatedly stimulated, the electromyogram recorded from the corresponding muscle through a surface electrode reveals a progressive fall-off (decrement) in the amplitude of the muscle potential (Fig. 14.12).

Antibodies against the acetylcholine receptor are demonstrable in the serum of 85% of patients with my-asthenia gravis. They are not found, however, in 50% of patients with the purely ocular form, as well as in about


Fig. 14.11 Myasthenia of the extraocular muscles and a Simpson test in a 23-year-old man. The left ptosis (a), becomes increasingly evident on looking up repeatedly in rapid succession—this is a maneuver that activates the levator palpebrae muscle (b). (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

15% of patients with generalized myasthenia (see below). A chest CT or MRI must be performed to disclose or rule out a thymoma. Other diseases that can mimic or accompany myasthenia must be sought and excluded as well (see below).


Fig. 14.12 Electromyogram of a 59-year-old man with ocular myasthenia. Electrical activity is recorded from the nasalis m. on repetitive stimulation of the facial n. in the stylomastoid fossa (frequency of stimulation, 3 Hz). The EMG tracing is shown in a. In b, the same curve is shown on an expanded time scale, and the responses to successive stimuli are superimposed. The summed muscle potential diminishes from one stimulus to the next; the response to the fifth stimulus is 54 % smaller than the initial response. Normally there should be no more than a 10% diminution in amplitude.

Classification. Myasthenia can be subdivided into a number of stages depending on the extent and severity of muscle involvement. Ossermann classification has four main stages and is reproduced in Table 14.10.

Spontaneous course. The severity of the disease manifestations fluctuates markedly without treatment, even over longer periods. Spontaneous remissions may be long lasting, but true spontaneous cures are rare. The eyes are initially affected in 50 % of patients and are eventually affected at some point in 90%. Myasthenic manifestations remain confined to the eyes in 16% (ocular myasthenia). Generalization of manifestations from the eyes to the rest of the body, if it occurs, usually occurs within three years of onset. Transient neonatal my-asthenia, caused by placental transmission of antibodies from a myasthenic mother to her child, rarely lasts longer than two weeks.

Treatment. Cholinesterase inhibitors improve the disease manifestations by delaying the breakdown of acetylcholine and thereby prolonging its effect on the remaining functional acetylcholine receptors of the muscle fiber membrane. Pyridostigmine is given several times a day in individual doses of 10 to 60 mg.

Immune therapies with short-lasting effect are used to treat acute exacerbations of myasthenia gravis with impending respiratory failure (myasthenic crises). These include plasmapheresis and intravenous immuno-globulins. Corticosteroids and other immune suppressants, e. g., azathioprine, are given chronically to influence the disease process in the long term. Most patients with myasthenia gravis need these drugs. Steroid treatment can transiently worsen the manifestations of disease and should therefore be initiated very slowly or during an in-patient hospitalization. It usually takes two to four weeks for the positive effect to appear.

Thymectomy should be considered for every patient with myasthenia: the operation brings cures, or at least substantially improves, of myasthenia in 80% of operated patients, after a latency period of several months or years. There is little controversy regarding the indication for thymectomy in patients below age 60, except for those with the mild ocular form of the disease. Good results have also been obtained in older patients. A thymoma, if present, must be surgically removed whatever the age of the patient. Adjuvant radiotherapy must be given if the resection is subtotal, because 25% of these tumors undergo malignant degeneration. The operative approach should be chosen to allow the surgeon to inspect the mediastinum thoroughly, so that the thymus or thymoma can be completely resected.

Complications. Patients in the midst of a myasthenic crisis may require such high doses of cholinesterase inhibitors that they develop toxic manifestations such as nausea, diaphoresis, abdominal cramps, excessive tra-cheobronchial secretions, agitation, and anxiety. This syndrome is referred to, somewhat simplistically, as a cholinergic crisis. Long-term immunosuppressive therapy can also cause complications, including leukopenia, increased susceptibility to infections, etc.

Table 14.10 Ossermann classification of myasthenia


Ocular myasthenia, i. e., limited to the eye muscles


Mild generalized myasthenia


Moderately severe generalized myasthenia, not involving

muscles of respiration


Acute, rapidly progressive myasthenia, beginning abruptly

and progressing to involve

the muscles of respiration within 6 months of onset


Chronic, severe myasthenia; may develop from previous

Class I or Class II disease after two years of a relatively

stable course


Patients in Classes III and IV are subject to higher mortality

and suffer more frequently from thymoma

Seronegative myasthenia gravis and anti-MuSK antibodies. About 70% of “seronegative” myasthenia gravis patients have antibodies to muscle-specific receptor typrosine kinase (MuSK). These patients are typically women under age 40 at disease onset in whom the cranial and bulbar muscles are severely affected. They often suffer from respiratory crises. Anticholinesterase drugs often yield no useful benefit and may even worsen the manifestations of disease. Thymectomy is also of no benefit. Immunosuppressive therapy, however, is usually effective, just as it is in seropositive myasthenia gravis.

Lambert-Eaton Syndrome

Etiology and pathogenesis. The clinical manifestations of this disease are caused by antibodies against voltage-sensitive calcium channels in the motor nerve terminals at the motor end plate. Inactivation of these channels lessens the calcium influx induced by an incoming action potential and therefore results in the release of inadequate amounts of acetylcholine from the nerve terminal. The impairment of neuromuscular transmission in Lambert-Eaton syndrome is therefore located in the pre-synaptic cell (unlike myasthenia gravis). The underlying etiology in two-thirds of patients is a small-cell carcinoma of the lung: voltage-sensitive calcium channels on the cell membranes of the carcinoma cells initiate a misdirected autoimmune response. In cases of nonneoplas-tic origin, Lambert-Eaton syndrome is often seen in combination with other autoimmune conditions, such as pernicious anemia, hypo- or hyperthyroidism, my-asthenia gravis, Sjögren syndrome, and others. The thy-mus is not enlarged.

Clinical manifestations. The hallmark of this condition is weakness and, above all, abnormal fatigability of the muscles, predominantly in the pelvic girdle and lower limbs. The extraocular muscles and the levator palpe-brae m. are sometimes mildly affected. Muscular strength transiently increases, at first, with exercise. The intrinsic muscle reflexes are often absent and many patients complain of dry mouth or other autonomic manifestations (orthostatic hypotension, impotence).

Diagnostic evaluation. In the electromyogram, the first few muscle action potentials on repeated stimulation are low, and the subsequent ones are larger. This is particularly evident with high-frequency stimulation.

Treatment. The weakness and fatigability of muscle respond to immunoglobulins and plasmapheresis, and, in the long term, to corticosteroids and azathioprine. Cho-linesterase inhibitors are not very effective.

Rare Myasthenia-like Syndromes

Hereditary myasthenic syndromes are usually of au-tosomal recessive inheritance. These genetic diseases may be due to either pre- or postsynaptic disturbances of neuromuscular transmission. Clinically, they are characterized by ocular manifestations and generalized muscle weakness. Cholinesterase inhibitors are ther-apeutically effective, as is 3,4-diaminopyridine in rare cases. Congenital myasthenia gravisand familial infantile myasthenia are hereditary syndromes whose manifestations are present over the patient's entire lifetime. The last-named disease can cause potentially lethal episodes of respiratory insufficiency in affected children, but its severity tends to lessen in later life.

“Slow channel” syndrome is of autosomal dominant inheritance. It usually becomes clinically evident in young adulthood. The underlying abnormality of neu-romuscular transmission is that the cation channels of the acetylcholine receptors open too slowly. In addition to exercise-dependent muscle weakness, patients suffer from muscle atrophy. The usual treatments for my-asthenia are ineffective in this disease.

Myasthenic weakness can be produced by a number of different substances, including organophosphates and penicillamine. Other substances can worsen myasthenia that is already present, such as aminoglycosides, quinine, antiarrhythmic drugs, and anticonvulsants.