MYOPATHIES

DYSTROPHIES
group 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 weakness

 CLASSIC TYPES:
Duchenne,
Becker,
Emery-Dreifuss,
Landouzy-Dejerine,
Miyoshi, Welander,
Fazio-Londe,
Bethlem

 DUCHENNE MUSCULAR DYSTROPHY

This 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 Xlinked recessive trait, occurring almost exclusively in males

 Rarely, 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 operative

 CLINICAL 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 clue

 Increasing 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
forearms

 The 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
muscles

 The 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 cases

 BECKER 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, dystrophin
The protein is expressed in skeletal, cardiac, and smooth muscle, as
well as in brain

 EMERY-DREIFUSS MUSCULAR DYSTROPHY

This 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 disease

 Limb-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 fortyfifth 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 cachexia

 Myotonic 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 parts

 The 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 usual

CONGENITAL MYOPATHIES
hypotonia 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 degrees

 In 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 dystrophy

METABOLIC MYOPATHIES
Three 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 deficiencies

 Acid 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, coughassist 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 cells

 TREATMENT:
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 Glycogenosis

type 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 acids

 Clinical 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 hyperammonemia

 A 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 betaoxidation 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.

 Treatment
A 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 alcoholic
nutritional 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
attacks

 Medium-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 Lcarnitine 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 betaoxidation 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 nonmembranebound.

ENDOCRINE MYOPATHIES
Thyroid 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 uremia

 Diseases of the Pituitary Gland

Proximal 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 MYOPATHIES
Included here are trichinosis, toxoplasmosis, parasitic and fungal
infections, and a number of viral infections
Trichinosis
This 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 daily

 Toxoplasmosis
This 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 addition

 Other 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 Muscle

HIV 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 MYOPATHIES
Polymyositis

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 weakness

 Dermatomyositis
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 daily

 Inclusion 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 muscle

 Eosinophilic 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
scleroderma

 Eosinophilic 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
eosinophils

 Eosinophilic 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 hypergammaglobulinemia

 Eosinophilia-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 shock

 Statin-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 <2 mEq/L).
The urinary excretion of potassium is not significantly increased, and
depletion is probably the result of vomiting and diarrhea. In addition,
serum levels of liver and muscle enzymes are markedly elevated.

 Biopsies from severely weakened muscles show single-fiber necrosis

and vacuolation. Treatment consists of the administration of
potassium chloride intravenously (about 120 mEq daily for several
days), after which oral administration suffices.
Strength returns gradually in 7 to 14 days, and enzyme levels return
to normal concomitantly.
A more dramatic myopathic syndrome, occurring acutely at the height
of a prolonged drinking bout, and appropriately termed acute
alcoholic myopathy, is manifest by severe pain, tenderness, and
edema of the muscles of the limbs and trunk, accompanied in severe
cases by renal damage.

 Hypokalemia is not implicated. The myonecrosis is generalized in

some patients, and remarkably focal in others. A swollen, painful,
tender limb or part of a limb may give the appearance of a deep
venous thrombosis or lymphatic obstruction