MYOPATHIES

MYOPATHIESDYSTROPHIESgroup of progressive hereditary degenerative diseases of skeletal muscles

The innervation of the affected muscles, in contrast to that of the neuropathic and spinal atrophies, is unaffected.

current clinical classification of the muscular dystrophies is based mainly on the distribution of the dominant muscle weaknessCLASSIC TYPES:Duchenne, Becker, Emery-Dreifuss, Landouzy-Dejerine, Miyoshi, Welander, Fazio-Londe, Bethlem

DUCHENNE MUSCULAR DYSTROPHYThis is the most frequent and best known of the early onset muscular dystrophies

begins in early childhood and runs a relatively rapid, progressive course

There is a strong familial liability as the disease is transmitted as an X-linked recessive trait, occurring almost exclusively in malesRarely, a severe proximal Duchenne-type muscular dystrophy occurs in young girls. This may have several explanations.

The female may have only one X chromosome, as occurs in the Turner (XO) syndrome, and that chromosome carries the Duchenne gene, or the Lyon principle may be operativeCLINICAL FEATS:usually recognized by the third year of life and almost always before the sixth year.

Nearly half of children show evidence of disease before beginning to walk

Many of them are slightly backward in other ways (mild mental retardation) and the muscle weakness may at first be overlooked.

A greatly elevated creatine kinase (CK) may be the clueIncreasing difficulty in walking, running, and climbing stairs, excessive lumbar lordosis, and waddling gait become more obvious as time passes.

The iliopsoas, quadriceps, and gluteal muscles are involved initially; then the pretibial muscles weaken (foot-drop and toe walking).

Enlargement of the calves and certain other muscles is progressive in the early stages The enlarged muscles have a firm, resilient ("rubbery") feel and are slightly weaker and more hypotonic than healthy ones. Thus the muscle enlargement is a pseudohypertrophy.

Rarely, all muscles are at first large and strong, even the facial muscles, as in one of Duchenne's cases (from the marble statue, Farnese Hercules); histologically, this is a true muscle hypertrophy.Muscles of the pelvic girdle, lumbosacral spine, and shoulders become weak and wasted

Weakness of abdominal and paravertebral muscles accounts for a lordotic posture and protuberant abdomen when standing and the rounded back when sitting.

Later, weakness and atrophy spread to the muscles of the legs and forearmsThe limbs are usually loose and slack, but as the disability progresses, fibrous contractures appear as a result of the limbs remaining in one position and the imbalance between agonists and antagonists.

Early in the ambulatory phase of the disease, the feet assume an equinovarus position as a result of shortening of the posterior calf musclesThe tendon reflexes are diminished and then lost as muscle fibers disappear, the ankle reflexes being the last to go.

The bones are thin and demineralized, and the appearance of ossification centers is delayed.

Smooth muscles are spared but the heart is affected by various types of arrhythmias. Death is usually the result of pulmonary infections and respiratory failure and sometimes, of cardiac decompensation.

Patients with Duchenne dystrophy usually survive until late adolescence but not more than 20 to 25 percent live beyond the twenty-fifth year.

The last years of life are spent in a wheelchair; finally the patient becomes bedfast.

Mild degrees of mental retardation, which is nonprogressive, are observed in many casesBECKER MUSCULAR DYSTROPHY

This milder dystrophy is closely related to the Duchenne type clinically, genetically, and ultrastructurally

It causes weakness and hypertrophy in the same muscles as Duchenne dystrophy but the onset is much later (mean age: 12 years; range: 5 to 45 years). While boys with Duchenne dystrophy are usually dependent on a wheelchair by early in the second decade, it is not uncommon for those with Becker dystrophy to walk well into adult life.

ETIOLOGY OF DUCHENE AND BECKER:mutation on the X chromosome and of its gene product, dystrophinThe protein is expressed in skeletal, cardiac, and smooth muscle, as well as in brainEMERY-DREIFUSS MUSCULAR DYSTROPHYThis genetically diverse group of disorders is another mainly X-linked muscular dystrophy characterized by the special feature of muscle contractures

The age of onset varies from childhood to late adolescence or adulthood. Weakness affects first the upper arm and pectoral girdle musculature and later the pelvic girdle and the distal muscles in the lower extremities.

The distinguishing feature of the disease is the early appearance of contractures in the flexors of the elbow, extensors of the neck, and posterior calf muscles.

Facial muscles are affected occasionally.

There is no hypertrophy or pseudohypertrophy, and mentation is unaffected. However, severe cardiomyopathy with variable sinoatrial and atrioventricular conduction defects is a common accompaniment.

Facioscapulohumeral Muscular Dystrophy (Landouzy-Dejerine Muscular Dystrophy)This is a slowly progressive dystrophy involving primarily the musculature of the face and shoulders, often with long periods of nearly complete arrest.

The pattern of inheritance is usually autosomal dominant.

As a rule, the first manifestations are difficulty in raising the arms above the head and winging of the scapulae, although bifacial weakness may have initially attracted attention, even in early childhood.

An interesting feature of this group of diseases is the occasional congenital absence of a muscle (one pectoral, brachioradialis, or biceps femoris) or part of a muscle in patients who later develop the typical features of the diseaseLimb-Girdle Muscular Dystrophies

(Scapulohumeral and Pelvifemoral Muscular Dystrophies, Erb Dystrophy)

now well-populated class of limb-girdle dystrophies are classified as LGMD1 for the autosomal dominant types and LGMD2 for the recessive types, and further subclassified based on the specific genotype.

Limb-Girdle Muscular Dystrophy 2I (Fukutin-Related Protein Mutation)

The defective FKRP gene is related in function to four other muscle genes in addition to fukutin (hence its name). All five of these genes are glycosyl transferases that attach sugar groups to proteins such as alpha-dystroglycan. The severity of the clinical phenotype is inversely related to the levels of glycosylation of alpha-dystroglycan. Defects in any of the 5 genes can cause developmental lesions in the brain in addition to muscle disease, although those associated with FKRP mutations are less common and less severe.

Severe Childhood Autosomal Recessive Muscular Dystrophy (Sarcoglycanopathy; LGMD 2C, D, E, and F)

Because of clinical similarities, there may be difficulty in distinguishing limb-girdle dystrophies (formerly termed severe childhood autosomal recessive muscular dystrophy [SCARMD]) from a dystrophinopathy (except that the former occur in females).

In addition to the difference in inheritance, they can be readily diagnosed by showing a loss of sarcolemmal immunostaining for any of the dystrophin-associated glycoproteins but with preservation of staining for dystrophin itself.

However, it is not possible on clinical grounds to distinguish one sarcoglycanopathy from another; this can be accomplished only by specific immunostaining.

Autosomal Recessive Muscular Dystrophy Linked to Chromosomes 15q and 2p (LGMD 2A and B; Calpain Mutation)

These forms of limb-girdle dystrophies have been described in large kindreds, in Indiana (among the Amish people), on the island of Runion in the Indian Ocean, in Brazil, and elsewhere, affecting males and females equally.

Both the shoulder and pelvic girdles are involved. The degree of weakness has varied considerably. In one form of the disease, called LGMD 2A, the abnormal gene codes for a calcium-activated neutral protease, or calpain Autosomal Dominant Limb-Girdle Dystrophies

LGMD 1B is a dominantly inherited disorder arising from mutations in the gene encoding the nuclear membrane protein lamin A/C.

The muscle disorders range from severe cases that mimic congenital muscular dystrophy to milder ones with features of limb girdle dystrophy or Emery-Dreifuss muscular dystrophy.

The diverse, nonmuscular manifestations of lamin A/C mutations include a cardiomyopathy, a form of lipodystrophy, a syndrome of accelerated aging (Hutchinson-Gilford progeria), and a recessively inherited axonal neuropathy.

Oculopharyngeal Dystrophy

Oculopharyngeal dystrophy is inherited as an autosomal dominant trait and is unique in respect to its late onset (usually after the forty-fifth year) and the restricted muscular weakness, manifest mainly as a bilateral ptosis and dysphagia

Difficulty in swallowing and change in voice are associated with slowly progressive ptosis. Swallowing becomes so difficult that food intake is limited, resulting in cachexiaMyotonic Dystrophy

There are two types of myotonic dystrophies (DM1 and DM2/PROMM).

Type I (DM1) is the most common adult muscular dystrophy

DM1 is distinguished by an autosomal dominant pattern of inheritance with a high level of penetrance, special topography of the muscle atrophy, associated obvious myotonia, and occurrence of dystrophic changes in nonmuscular tissues (lens of eye, testicle and other endocrine glands, skin, esophagus, heart, and, in some cases, the cerebrum).

Certain muscles, the levator palpebrae, facial, masseter, sternocleidomastoid, and forearm, hand, and pretibial muscles, are consistently involved in the dystrophic process.In the common early adult form of the disease, the small muscles of the hands along with the extensor muscles of the forearms are often the first to become atrophied

Pharyngeal and laryngeal weakness results in a weak, monotonous, nasal voice. The uterine muscle may be weakened, interfering with normal parturition, and the esophagus is often dilated because of loss of muscle fibers in the striated as well as smooth muscle partsThe disease progresses slowly, with gradual involvement of the proximal muscles of the limbs and muscles of the trunk. Tendon reflexes are lost or much reduced.

The phenomenon of myotonia, which expresses itself in prolonged idiomuscular contraction following brief percussion or electrical stimulation and in delay of relaxation after strong voluntary contraction, is the third striking attribute of the disease fourth major characteristic of the disease is the dystrophic change in nonmuscular tissues

The rarer and milder type 2 myotonic dystrophy (DM2) is caused by an expanded triplet repeat in the CNBP gene on chromosome 3

Onset was between 20 and 40 years of age, with intermittent myotonic symptoms of the hands and proximal leg muscles, followed by a mild, slowly progressive weakness of the proximal limb muscles without significant atrophy.

Myofibrillar Myopathy

Mutations of one of the proteins that relate to the Z-disc (the connection between adjacent sarcomeres, which are the structural units of the myofibril) of muscle seem to be the unifying feature

The diagnosis of myofibrillar myopathy is usually made in adult life by muscle biopsy. Men and women are equally affected. Slowly progressive weakness of the muscles of limbs and trunk is the main clinical feature.

Both proximal and distal muscles are affected, more in the legs than in the arms. Hyporeflexia is usualCONGENITAL MYOPATHIEShypotonia and facial diplegia at birth are the most prominent clinical features; myotonia, is notably absent

Drooping of the eyelids, the tented upper lip ("carp" mouth), and the open jaw impart a characteristic appearance, which allows immediate recognition of the disease in the newborn infant and child.

Difficulty in sucking and swallowing, bronchial aspiration, and respiratory distress are present in varying degreesIn surviving infants, delayed motor and speech development, swallowing difficulty, mild to moderately severe mental retardation, and talipes or generalized arthrogryposis are common.

Once adolescence is attained, the disease follows the same course as the later form

In the congenital form of this disease the affected parent is always the mother with type 1 (DM1) myotonic dystrophyMETABOLIC MYOPATHIESThree classes of metabolic diseases of muscle are recognizedone is traceable to a primary, or hereditary, metabolic abnormality of the muscle itself; another in which the myopathy is secondary to a disorder of endocrine function, i.e., to disease of the thyroid, parathyroid, pituitary, or adrenal gland; and a third group that is the result of a large variety of myotoxic drugs and other chemical agents. The latter two groups are relatively common and more likely to come initially to the attention of the internist than to the neurologist.

PRIMARY METABOLIC DISORDERS OF MUSCLE

Glycogen Storage Myopathies

An abnormal accumulation of glycogen in the liver and kidneys was described These enzymatic deficiencies alter the metabolism of many cells, but most strikingly those of the liver, heart, and skeletal muscle.

The most impressive and common of these glycogen storage diseases from the standpoint of the clinical neurologist are 1,4-glucosidase (acid maltase) and myophosphorylase deficienciesAcid Maltase Deficiency (Glycogenosis Type II; Pompe Disease and Related Disorders)

A deficiency of this enzyme takes three clinical forms, of which the first (Pompe disease) is the most serious.

Pompe disease typically develops in infancy, between 2 and 6 months; dyspnea and cyanosis call attention to enlargement of the heart, and the liver may be enlarged as well.

The skeletal muscles are weak and hypotonic, although their bulk may be increased. The tongue may be enlarged, giving the infant a cretinoid appearance.

Hepatomegaly, while often present, is not pronounced.

Exceptionally, the heart is normal in size and the central nervous system and muscles bear the brunt of the disorder. The clinical picture then resembles infantile spinal muscular atrophy (Werdnig-Hoffmann disease) and, to add to difficulty in differential diagnosis, there may be fasciculations. The disease is rapidly progressive and ends fatally in a few months.

In the second (childhood) form, onset is during the second year, with delay in walking and slowly progressive weakness of shoulder, pelvic girdle, and trunk muscles.

The toe walking, waddling gait, enlargement of calf muscles, and lumbar lordosis resemble those of Duchenne dystrophy.

Cardiomyopathy is exceptional, hepatomegaly is less frequent than in the infantile form, and mental retardation is present in a minority

Death occurs between 3 and 24 years of age, usually from ventilatory failure and recurrent pulmonary infections.

TREATMENT:The adult who is threatened by respiratory failure should be observed frequently with measurements of vital capacity and blood gases.

Respiratory support (rocking bed, nasal positive pressure, cough-assist devices, and negative-pressure cuirass) may prolong life.

Enzyme replacement therapy is available to treat Pompe disease. Recombinant acid alpha-glucosidase is injected intravenously at frequent intervals, and the results for prolonged survival are promising.

Myophosphorylase Deficiency (Type V Glycogenosis; Mcardle Disease) and Phosphofructokinase Deficiency (Type VII Glycogenosis; Tarui Disease)

These disorders are considered together because they are clinically virtually identical and both express themselves by the development of muscle cramps after exercise

In both diseases, an otherwise normal child, adolescent, or adult begins to complain of weakness and stiffness and sometimes pain on using the limbs.

Muscle contraction and relaxation are normal when the patient is in repose, but strenuous exercise, either isometric (carrying heavy weights) or dynamic (climbing stairs or walking uphill), causes the muscles to shorten (contracture), a result of their inability to relax.

The primary abnormality in McArdle disease is a deficiency of myophosphorylase, which prevents the conversion of glycogen to glucose-6-phosphate.

Phosphofructokinase deficiency (Tarui disease) interferes with the conversion of glucose-6-phosphate to glucose-1-phosphate; the defect in the latter condition is also present in red blood cellsTREATMENT:

main treatment is a planned reduction and intermittency in physical activity.

Sucrose, taken as 75 g in a beverage, has been shown by Vissing and Haller to cause a short-lived improvement in exercise tolerance and they propose that exercise-induced rhabdomyolysis can be avoided by a well-timed drink.

Other Forms of Glycogenosistype III (debranching enzyme deficiency; Cori-Forbes disease) affects muscle but only inconsistently

The childhood form is characterized mainly by a benign hepatopathy, sometimes accompanied by diminished muscle strength and tone. An adult form beginning in the third and fourth decades presents with proximal and distal myopathy.

type IV glycogenosis (branching enzyme deficiency, or Andersen disease

This is a progressive disease of infancy and early childhood, characterized by cirrhosis and chronic hepatic failure, usually with death in the second or third year.

Hepatomegaly as a result of accumulation of an abnormal polysaccharide is a universal finding.

Muscle weakness and atrophy, hypotonia, and contractures occur less regularly and are overshadowed by the liver disease.

The diagnostic hallmark of the myopathy is the presence of basophilic, intensely PAS-positive polysaccharide granules in skin and muscle

Disorders of Lipid Metabolism Affecting Muscle (Lipid Myopathies)

progressive myopathy, lipid storage predominantly in type 1 muscle fibers, and a deficiency of muscle carnitine, a cofactor required for the oxidation of fatty acidsClinical Features of Disordered Fatty Acid Metabolism

Despite the many biochemical abnormalities that have been identified in the fatty acid metabolic pathways, there are essentially three clinical patterns by which these defects are expressed:

One constellation of symptoms referred to as the encephalopathic syndrome has its onset in infancy or early childhood. Its very first manifestation may be sudden death (sudden infant death syndrome [SIDS]), or there may be vomiting, lethargy and coma, hepatomegaly, cardiomegaly, muscular weakness, and hypoketotic hypoglycemia, with prominent hyperammonemiaA second (myopathic) syndrome appears in late infancy, childhood, or adult life and takes the form of a progressive myopathy, with or without cardiomyopathy. The myopathy may follow episodes of hypoketotic hypoglycemia or may develop de novo.

The third syndrome is one that usually begins in the second decade of life and is induced by a sustained period of physical activity or fasting. It is characterized by repeated episodes of rhabdomyolysis with or without myoglobinuria.

Primary Systemic Carnitine Deficiency

To date, this is the only form of carnitine deficiency that can be considered primary (see further on for discussion of the secondary types).

Its main clinical features are progressive lipid storage myopathy and cardiomyopathy, sometimes associated with the signs of hypoketotic hypoglycemia.

There is no dicarboxylic aciduria, in distinction to the secondary beta-oxidation defects, in all of which dicarboxylic aciduria is present. The cardiomyopathy, which is fatal if untreated, responds to oral administration of L-carnitine, 2 to 6 g/d.

This disorder is inherited as an autosomal recessive trait. In these families there is frequently a history of sudden unexplained death in siblings, so that early identification of affected children is essential

Carnitine Palmitoyltransferase Deficiency

There are three types, referred to as types I, IIA, and IIB. Type I is the most common.

It affects males predominantly, beginning in the second decade of life. Attacks of myalgia, cramps, and muscle weakness, "tightness," and stiffness are precipitated by sustained (although not necessarily intense) exercise and less often by a prolonged period of fasting.

Fever, anesthesia, drugs, emotional stress, and cold have been additional but rare precipitating events. In type I deficiency, necrosis of muscle fibers, particularly type I fibers, occurs during attacks, followed by regeneration.

Between attacks, the muscle appears normal.

In type IIA, lipid bodies accumulate in the liver, and in type IIB, excess lipid is detected in heart, liver, kidneys, and skeletal muscle.

TreatmentA high-carbohydrate, low-fat diet, ingestion of frequent meals, and additional carbohydrate before and during exercise appear to reduce the number of attacks.

Patients need to be instructed about the risks of prolonged exercise and skipped meals. Recently, the use of bezafibrate, a drug used for dyslipidemia, has been helpful in patients with mild CPT II.

Secondary Systemic Carnitine Deficiency

This is occasionally the result of severe dietary deprivation or impaired hepatic and renal function.

Such instances have been observed in patients with alcoholicnutritional diseases and kwashiorkor, in premature infants receiving parenteral nutrition, in patients with chronic renal failure undergoing dialysis, and rarely, as a complication of valproate therapy. Other Lipid Myopathies

Carnitine Acylcarnitine Translocase Deficiency

This condition causes muscular weakness, cardiomyopathy, hypoketotic hypoglycemia and hyperammonemia, which develop in early infancy and usually lead to death in the first month of life.

Long-Chain Acyl-CoA Dehydrogenase Deficiency

The presentation is in infancy, with recurrent episodes of fasting hypoglycemic coma, muscle weakness, and myoglobinuria, and sometimes sudden death.

Survivors may develop a progressive myopathy. Administration of carnitine improves the cardiac disorder and prevents metabolic attacksMedium-Chain Acyl-CoA Dehydrogenase Deficiency

This is a cause of SIDS and a Reye-like syndrome. About half of survivors develop a lipid-storage myopathy in childhood or adult life. The abnormal gene has been mapped to chromosome 1p31. Oral L-carnitine may be of therapeutic value.

Short-Chain Acyl-CoA Dehydrogenase Deficiency

This myopathy in a limb-girdle distribution may appear initially in older children and adults, or it may follow episodic metabolic disorders in infancy.

Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency

This is a disease of infancy marked by episodes of Reye-like syndrome, hypoketotic hypoglycemia, lipid storage myopathy, cardiomyopathy, and sometimes sudden death.

Short-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency

This presents as an episodic disorder such as the one described above, long-chain hydroxyacyl-CoA dehydrogenase deficiency (HAD), but its onset is in adolescence. Recurrent attacks may be associated with myoglobinuria.

Multiple Acyl-CoA Dehydrogenase Deficiency; Glutaric Aciduria Type II

Some cases are caused by a deficiency of electron transfer flavoprotein (ETF) and others by a deficiency of electron transfer flavoprotein-coenzyme Q oxidoreductase (ETF-QO).

In the severest form of multiple acyl-CoA dehydrogenase deficiency (MADD), infants are born prematurely and many die within the first week of life; added to the common metabolic abnormalities are multiple congenital defects and a characteristic "sweaty feet" odor.

Muscle Coenzyme Q10 Deficiency

This condition presents as a slowly progressive lipid storage myopathy from early childhood. The basic defect is in coenzyme Q10 in the respiratory chain of muscle mitochondria. The administration of coenzyme Q10 has improved the myopathic weakness.

Multisystem Triglyceride Storage Disease (Chanarin Disease)

This abnormality of lipid metabolism is distinct from the beta-oxidation defects. A progressive myopathy is combined with ichthyosis and neurologic manifestations, such as developmental delay, ataxia, neurosensory hearing loss, and microcephaly. The lipid material is stored in muscle as triglyceride droplets that are nonlysosomal and nonmembrane-bound.

ENDOCRINE MYOPATHIESThyroid Myopathies

Several myopathic diseases are related to alterations in thyroid function: (1) chronic thyrotoxic myopathy; (2) exophthalmic ophthalmoplegia (infiltrative orbital ophthalmopathy);

(3) myasthenia gravis associated with thyrotoxicosis; (4) periodic paralysis associated with thyrotoxicosis; (5) muscle hypertrophy and slow muscle contraction and relaxation associated with myxedema and cretinism

Chronic Thyrotoxic Myopathy

characterized by progressive weakness and wasting of the skeletal musculature, occurring in conjunction with overt or covert ("masked") hyperthyroidism.

The thyroid disease is usually chronic and the goiter is usually of the nodular rather than the diffuse type.

Exophthalmos and other classic signs of hyperthyroidism are often present but need not be. This complication of hyperthyroidism is most frequent in middle age, and men are more susceptible than women. Exophthalmic Ophthalmoplegia (Graves Ophthalmopathy)

This refers to the cooccurrence of weakness of the ocular muscles and exophthalmos in patients with Graves disease (pupillary and ciliary muscles are always spared).

The exophthalmos varies in degree, sometimes being absent at an early stage of the disease, and it is not in itself responsible for the muscle weakness.

Often there is some degree of orbital pain. Both the exophthalmos and the weakness of the extraocular muscles may precede the signs of hyperthyroidism, be associated with the other classic features of hyperthyroidism (tachycardia, weight loss, tremor), or may follow effective treatment of the disorder.

Thyrotoxic Hypokalemic Periodic Paralysis

consists of attacks of mild to severe weakness of the muscles of the trunk and limbs; usually the cranial muscles are spared.

The weakness develops over a period of a few minutes or hours and lasts for part of a day or longer. In some series of patients with periodic paralysis, as many as half have had hyperthyroidism and most of them have been Asian males.

Unlike the typical hypokalemic form, thyrotoxic periodic paralysis is not a familial disorder and its onset is usually in early adult life.Myasthenia Gravis with Hyperthyroidism

The weakness and atrophy of chronic thyrotoxic myopathy may be added to that of the myasthenia without appearing to affect the requirement for or response to anticholinesterase medications.

By contrast, hypothyroidism, even of mild degree, seems to aggravate the weakness of myasthenia gravis, greatly increasing the need for pyridostigmine and at times inducing a myasthenic crisis.

In these cases, thyroxine is beneficial and, with respect to myasthenia, restores the patient to the status that existed before the onset of thyroid insufficiency.

The myasthenia should probably be regarded as an autoimmune disease independent of the thyroid disease and each must be treated separately.

Hypothyroid Myopathy

Abnormalities of skeletal muscle consisting of diffuse myalgia and increased volume, stiffness, and slowness of contraction and of relaxation are common manifestations of hypothyroidism, whether in the form of myxedema or cretinism.

These changes probably account for the relatively large tongue and dysarthria that one observes in myxedema.

Weakness, however, is not a prominent feature. The presence of action myospasm and myokymia (both of which are rare) and of percussion myoedema and slowness of both the contraction and relaxation phases of tendon reflexes assists the examiner in making a bedside diagnosis.

Corticosteroid and Cushing Disease Myopathy

The prolonged use of corticosteroids causes the proximal limb and girdle musculature to become weak to the point of causing difficulty in elevating the arms and arising from a sitting, squatting, or kneeling position; walking up stairs may also be hampered. Some individuals seem to be more susceptible than others.

There is a poor correlation between the total dose of corticosteroid administered and the severity of muscle weakness. Nevertheless, in patients who develop this type of myopathy, the corticosteroid dosage has usually been high and sustained over a period of months or years.

All corticosteroids may produce the disorder, although fluorinated ones, on uncertain evidence, are said to be more culpable than others. Discontinuation or reduction of corticosteroid administration leads to gradual improvement and recovery; alternate-day regimens may be helpful.

Acute Steroid Myopathy (Critical Illness Myopathy; Acute Quadriplegic Myopathy)

It was described initially with cases of severe asthma in patients who were exposed to high doses of steroids for treatment.

Subsequently this acute myopathy has been recognized with all types of critical systemic diseases and organ failure, again, in the context of with the administration of high doses of corticosteroids and, in a few cases, with sepsis and shock without exposure to this class of medication.

Adrenocortical Insufficiency

Generalized weakness and fatigability are characteristic of adrenocortical insufficiency, whether primary in type, i.e., because of Addison disease (infectious, neoplastic, or autoimmune destruction of the adrenal glands or adrenal hemorrhage), or secondary to a pituitary deficiency of adrenocorticotropic hormone (ACTH). The weakness and fatigability, however, are probably related to mostly water and electrolyte disturbances and hypotension, not to a primary disorder of muscle. Perhaps there is also an element of reduced central drive of motor activity

Primary Aldosteronism

Muscular weakness has been observed in 75 percent of the reported cases of hyperaldosteronism. In nearly half of those with mucle weakness there was either hypokalemic periodic paralysis or tetany.

Chronic potassium deficiency may express itself either by periodic weakness or by a chronic myopathic weakness. An associated severe alkalosis causes the tetany.

As in the weakness of Addison disease, there is no structural disorder of muscle, except perhaps for vacuolation, which is the result of severe hypokalemia.

Diseases of Parathyroid Glands and Vitamin D Deficiency

A proportion of patients with parathyroid adenomas complain of weakness and fatigability.

The tendon reflexes were retained. A few scattered muscle fibers had undergone degeneration but claims for a denervative muscle process are disputed. We have not been impressed with either a myopathy or neuropathy in this disease.In hypoparathyroidism, muscle cramping is prominent, but there are no other neuromuscular manifestations.

In both hypoparathyroidism and pseudohypoparathyroidismthe latter with characteristic skeletal abnormalities and, in some instances, mental slownessthe most important muscle abnormality is tetany. This is a result of low ionized serum calcium, which depolarizes axons more than muscle fibers

Osteomalacia, as a result of vitamin D deficiency and disorders of renal tubular absorption, often includes muscle weakness and pain as common complaints, similar to those in patients with primary hyperparathyroidism and with uremiaDiseases of the Pituitary GlandProximal muscle weakness and atrophy have been recorded as late developments in many acromegalic patients.

Formerly thought to be caused by neuropathy, these symptoms in acromegaly have been convincingly shown by Mastaglia and colleagues to be the result of a generalized myopathy. The serum CK is slightly elevated in some cases, and myopathic potentials are observed in the EMG.

Biopsy specimens have shown atrophy and reduced numbers of type 2 fibers, but necrosis of only a few fibers.

Treatment of the pituitary adenoma and correction of the hormonal changes restores strength.

A mild peripheral neuropathy of sensorimotor type has also been reported in a few patients with acromegaly, but is far less frequent than carpal tunnel syndrome and other focal entrapments in this disease.

INFECTIOUS MYOPATHIESIncluded here are trichinosis, toxoplasmosis, parasitic and fungal infections, and a number of viral infections

TrichinosisThis parasitic disease is caused by the nematode Trichinella spiralis

Often, there is conjunctival, orbital, and facial edema, sometimes accompanied by subconjunctival and subungual splinter hemorrhages. As the trichinae become encysted over a period of a few weeks, the symptoms subside and recovery is complete

Treatment: No treatment is required in most cases. In patients with severe weakness and pain, a combination of thiabendazole, 25 to 50 mg/kg daily in divided doses for 5 to 10 days, and prednisone, 40 to 60 mg/d, is recommended. Albendazole, in a single oral dose of 400 mg dailyToxoplasmosisThis is an acute or subacute systemic infection caused by the encephalitozoon Toxoplasma gondii

occurs with variable fever, lymphopenia, and failure of other organs, consists of weakness, wasting, myalgia, and elevated CK levels

Sulfadiazine in combination with pyrimethamine or trisulfapyrimidine, which act synergistically against the toxoplasmic trophozoites, improves the muscle symptoms and reduces serum CK. Folic acid is given in additionOther Parasitic and Fungal Infections of Muscle:Echinococcosis, cysticercosis, trypanosomiasis (Chagas disease), sparganosis, toxocariasis, and actinomycosis have all been known to affect skeletal muscle on occasion

Viral Infections of MuscleHIV and Human T-Lymphotropic Virus Type I Myositis

An inflammatory, and presumed infectious, myopathy may develop early in the course of HIV infection but is rarely the initial manifestation. The pattern is like that of idiopathic polymyositis with painless weakness of the girdle and proximal limb muscles. Reflexes are diminished in most cases, but this is difficult to interpret in view of the high incidence of concomitant polyneuropathy.

Serum CK is elevated and the EMG shows an active myopathy with fibrillations, brief polyphasic motor units, and complex repetitive discharges.

INFLAMMATORY MYOPATHIESPolymyositis

This is an idiopathic subacute or chronic and symmetrical weakness of proximal limb and trunk muscles without dermatitis.

The onset is usually insidious and the course progressive over a period of several weeks or months. It may develop at almost any age and in either sex; however, the majority of patients are 30 to 60 years of age, and a smaller group shows a peak incidence at 15 years of age; women predominate in all age groups.

A febrile illness or benign infection may precede the weakness, but in most patients the first symptoms develop in the absence of these or other apparent initiating events.

The usual mode of onset is with mainly painless weakness of the proximal limb muscles, especially of the hips and thighs and to a lesser extent the shoulder girdle and neck muscles. Often, the patient cannot easily determine the time of onset of weaknessDermatomyositis

The presentation of muscle weakness is similar to that of polymyositis but the denominative feature is a rash.

Most often, the skin changes precede the muscle syndrome and take the form of a localized or diffuse erythema, maculopapular eruption, scaling eczematoid dermatitis, or exfoliative dermatitis.

Sometimes, skin and muscle changes evolve together over a period of 3 weeks or less. A characteristic form of the skin lesions are patches of a scaly roughness over the extensor surfaces of joints (elbows, knuckles, and knees) with varying degrees of pink-purple coloration.

Red, raised papules may be present over exposed surfaces such as the elbows, knuckles, and distal and proximal interphalangeal joints (Gottron papules); these are particularly prominent in DM of childhood

Treatment:

Most clinicians agree that corticosteroids (prednisone, 1 mg/kg, as a single daily dose orally, or intravenously) are the first line of therapy for both PM and DM. The response to treatment is monitored by careful testing of strength and measurement of CK (not by following the erythrocyte sedimentation rate [ESR]).

In patients who respond, the serum CK decreases before the weakness subsides; with relapse, the serum CK rises before weakness returns. Once the CK level normalizes and strength improves, typically several weeks or longer, the dosage may be reduced graduallyby no more than 5 mg every 2 weekstoward 20 mg dailyInclusion Body Myopathy

Inclusion body myositis, or myopathy, is the third major form of idiopathic inflammatory myopathy and, depending on the care taken with histologic diagnosis, is the most common inflammatory myopathy in patients older than 50 years of age

characterized by a steadily progressive, painless muscular weakness and modest atrophy, which may be generalized or affect limbs selectively and often asymmetrically

Other Inflammatory Myopathies

(1) eosinophilic myositis, fasciitis, and myalgia syndrome, (2) orbital myositis(3) sarcoidosis of muscleEosinophilic Myositis and Fasciitis

This term has been applied to four overlapping clinical entities: (1) eosinophilic fasciitis, (2) eosinophilic monomyositis (sometimes multiplex), (3) eosinophilic PM (4) the eosinophilia-myalgia syndrome

Eosinophilic Fasciitis

scleroderma-like appearance of the skin and flexion contractures at the knees and elbows associated with hyperglobulinemia, elevated sedimentation rate, and eosinophilia.

Biopsy revealed greatly thickened fascia, extending from the subcutaneous tissue to the muscle and infiltrated with plasma cells, lymphocytes, and many eosinophils; the muscle itself appeared normal and the skin lacked the characteristic histologic changes of sclerodermaEosinophilic Monomyositis

Painful swelling of a calf muscle or, less frequently, some other muscle has been the chief characteristic of this disorder.

Biopsy discloses inflammatory necrosis and edema of the interstitial tissues; the infiltrates contain large but variable numbers of eosinophilsEosinophilic Polymyositis

The features of the muscle disorder were typical of PM except that the inflammatory infiltration was predominantly eosinophilic and the muscles were swollen and painful.

Moreover, the muscle disorder was part of a widespread systemic illness typical of the hypereosinophilic syndrome.

The systemic manifestations included a striking eosinophilia (20 to 55 percent of the white blood cells), cardiac involvement (conduction disturbances and congestive failure), vascular disorder (Raynaud phenomenon, subungual hemorrhages), pulmonary infiltrates, strokes, anemia, neuropathy, and hypergammaglobulinemiaEosinophilia-Myalgia Syndrome

The onset of the muscular illness was relatively acute, with fatigue, low-grade fever, and eosinophilia (>1,000 cells/mm3).

Muscle pain and tenderness, cramps, weakness, paresthesias of the extremities, and induration of the skin were the main clinical features.

A severe axonal neuropathy with slow and incomplete recovery was associated in some cases.

Biopsies of the skin fascia, muscle, and peripheral nerve disclosed a microangiopathy and an inflammatory reaction in connective tissue structures; changes like those observed in scleroderma, eosinophilic fasciitis, and in the toxic oil syndrome

Acute Orbital Myositis

The abrupt onset of orbital pain that is made worse by eye motion, redness of the conjunctiva adjacent to the muscle insertions, diplopia caused by restrictions of ocular movements, lid edema, and mild proptosis are the main clinical features and, admittedly, the distinctions from orbital pseudotumor are not clear.

It may spread from one orbit to the other. TOXIC MYOPATHIES

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.

Necrotizing Myopathy (Rhabdomyolysis)

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.

Regardless of the cause of the rhabdomyolysis, the affected muscles become painful and tender within a few hours and their power of contraction is diminished.

Sometimes the skin and subcutaneous tissues overlying the affected muscles (nearly always of the limbs and sometimes of the trunk) are swollen and congested.

There is a marked elevation of CK in the serum and there may be a low-grade fever and a reactive leukocytosis.

If myoglobinuria is mild, recovery occurs within a few days and there is only a residual albuminuria. When severe, renal damage may ensue and lead to anuric renal failure requiring dialysis.

The mechanism of the renal damage is not entirely clear; it is not simply a mechanical obstruction of tubules by precipitated myoglobin (although this does occur).

Treatment of Myoglobinuria:

Alkalinization of the urine by ingestion or infusion of sodium bicarbonate is said to protect the kidneys by preventing myoglobin casts, but in severe cases it is of doubtful value and the sodium may actually be harmful if anuria has already developed.

Diuresis induced by mannitol or by loop diuretics such as furosemide and by the administration of intravenous fluids reduces the chances of anuric renal failure if given in time. Therapy is much the same as for the anuria that follows shockStatin-Induced Myopathy

With the widespread use of these lipid-lowering medications, myotoxicity has become a well-described but possibly overrated idiosyncratic problem.

Symptoms range in severity from mild muscular aches with slightly elevated CK concentrations in the serum to a rare but potentially fatal rhabdomyolytic syndrome.

The first generation of these drugs were fungal metabolites (lovastatin, pravastatin, simvastatin) and were infrequently implicated in muscle damage, but the newer synthetic ones (atorvastatin, fluvastatin, cerivastatin) are more frequently toxic, especially when given with gemfibrozil

Colchicine Myoneuropathy

This condition is included here as much for its curious histopathologic features as for its clinical interest. The drug, used widely in the treatment of gout, often gives rise to a mild subacute proximal muscular weakness but has also produced an acute necrotizing myopathy.

Most instances of the latter have occurred in patients with a degree of renal failure, which allows accumulation of the drug

The mechanism of the muscle damage is unknown but is probably attributable to the drug's interference with tubulin, a protein required for the polymerization of microtubules in muscle and nerve.

Weakness resolves in a matter of days or weeks when the drug is discontinued, but the neuropathic features may remain.

Alcoholic Toxic Myopathy

Several forms of muscle weakness have been ascribed to alcoholism. In one type, a painless and predominantly proximal weakness develops over a period of several days or weeks in the course of a prolonged drinking bout and is associated with severe degrees of hypokalemia (serum levels