Muscle Diseases

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[edit] Muscle Diseases

Timothy J. Benstead

[edit] PRESENTING SYMPTOMS OF MYOPATHY

Primary muscle diseases, or myopathies, include a broad range of disorders with many etiologies but with common presentation patterns. Most myopathic disorders affect only muscle fibers, producing symptoms and signs confined to the muscle. A few myopathies are accompanied by pathology of other tissues resulting in non-muscle manifestations. A good example of a myopathy with many non-muscle manifestations is myotonic dystrophy, which will be discussed later in this chapter.

The most frequently encountered manifestation of myopathy is weakness (Box 168-1). Weakness can occur because of failure of diseased muscle fibers to contract effectively, or in more severe processes the loss of muscle fibers. Some myopathies produce very little weakness and the manifestations may be restricted to other indicators of muscle fiber disease, such as myalgia, muscle cramps, and fatigue. Most myopathies produce symmetric symptoms and signs, unlike some nerve or motor neuron diseases, which can be highly asymmetric. There are a few exceptions to this rule, such as inclusion body myositis, but in general myopathies are highly symmetric. Myopathies also usually present with proximal muscle weakness and may remain confined to proximal muscles throughout the course of the illness. Again, not all myopathies follow this rule, but the majority do, and a disorder with distinctly proximal muscle weakness should always raise the concern for a myopathy.

The facial, palatal, cervical, and respiratory muscles are all quite proximal, and these muscle groups are often targets of muscle disease. Myasthenia gravis is not considered a primary muscle disease, although its pathologic process occurs at the acetylcholine receptor on the muscle fiber. Myasthenia gravis also usually affects proximal muscle most severely and will often be included in the differential diagnosis of a patient presenting with myopathic symptoms. Muscle fibers are the most distal aspect of the motor unit, which originates at the motor neuron and includes the nerve axon and neuromuscular junction. The muscle therefore is a component of the lower motor neuron complex. A lower motor neuron pattern of muscle weakness should be expected in muscle disease. In many ways this is true. Babinski's signs are absent in muscle diseases, and the muscle tone is often reduced. However, muscle stretch reflexes are usually not reduced as much as in peripheral nerve disease for the degree of weakness present. Also, muscle wasting is usually a later feature of myopathy than neuropathy. When sensory loss accompanies weakness this usually excludes myopathy as a possible etiology. These clinical features can be helpful in differentiating clinically between muscle and nerve disease, although a definite differentiation is not always clinically possible and laboratory evaluation is very important for establishing whether myopathy is the cause of a patient's weakness as well as determining the type of muscle disease.

[edit] LABORATORY INVESTIGATIONS FOR MYOPATHY

There are many investigations that may be helpful in accurately diagnosing a muscle disease, but the core investigations helpful for establishing whether a myopathy is present include measurement of serum muscle enzyme levels, electromyography, and muscle biopsy (Box 168-2). Many additional tests may be helpful in clarifying a more precise diagnosis, such as genetic analysis and evaluation of other organ systems, but the triad of investigations noted above remains the cornerstone of myopathy investigation.

The serum creatine kinase (CK) measurement is the most useful enzyme analysis in the diagnosis of muscle disease. Other serum enzymes that can be derived from skeletal muscle, such as lactate dehydrogenase (LD), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), may also be elevated in myopathy, but they do not increase as readily or dramatically as does CK in response to muscle pathology. It should be remembered that these serum enzymes can arise from other organs, and clinical acumen needs to be exercised to avoid attributing CK elevation to cardiac disease or LD, AST, and ALT elevation to liver disease when they may all be rising from skeletal muscle. Serum CK analysis is critical because isoenzyme analysis of CK can determine the source of the enzyme elevation and CK will not rise in response to liver disease.

In myopathy the CK elevation can range from mild to very severe. The degree of elevation tends to reflect the degree of muscle fiber necrosis that is occurring and the tempo of the disease. Disorders with widespread necrosis of muscle fibers, such as Duchenne's muscular dystrophy, have high CK levels. Disorders producing myoglobinuria, which have a very rapid onset of necrosis, will have the highest CK levels, often increasing to the many thousands. More slowly progressive disorders, such as some toxic myopathies, may have a CK elevation level in the hundreds. Many static muscle diseases, such as congenital myopathies, may have normal CK levels. If the disease process does not produce muscle fiber necrosis or some instability of muscle membrane, then CK levels do not usually increase. Elevated CK levels will sometimes occur in disorders affecting nerves. Usually this is in rapidly progressive disorders, such as amyotrophic lateral sclerosis (ALS) in which rapid denervation of many muscle fibers leads to enough muscle membrane leakage of CK to elevate the serum level. Usually this is a relatively minor CK elevation, unlike the much higher elevation that would be expected in a primary muscle disease of equivalent severity.

Electromyography will aid investigation of myopathy in two ways. Electromyograms (EMGs) are very helpful in confirming the presence of disease of the motor unit. The technique will usually differentiate between disorders of nerve, muscle, and the neuromuscular junction. Once features of myopathy are detected on an EMG, the results will sometimes point to specific subtypes of myopathy. However, it should be remembered that the EMG changes of many myopathies overlap and are nonspecific. Other assessments will usually be required to firmly establish a diagnosis. The motor unit forms the core structure that is being assessed with EMG techniques. During EMG a recording needle electrode is inserted into a muscle and the electrical activity generated by muscle fibers adjacent to the needle is recorded. Because many myopathies affect muscles in variable degrees, needle EMGs entail a survey of several muscles. Through this approach, insight is obtained into the distribution of changes, enhancing the ability to diagnose neurologic disease through pattern recognition. With the EMG electrode in place in a muscle, motor unit potentials can be recorded by asking the patient to voluntarily contract the muscle. Muscle fibers within a motor unit are always activated as a group. Thus the electrode will record potentials that are the summated electrical discharges of several muscle fibers within a motor unit firing simultaneously. Many motor units will recruit with strong muscle contractions, but by asking for a graded muscle contraction the electromyographer is usually able to distinguish the features of individual motor unit potentials and compare them to expected normals. Myopathies affect muscle fibers in many motor units with indiscriminate selection of which motor units are affected. In this way, the number of effectively working muscle fibers within a motor unit will be reduced, leading to fewer summated responses in the motor unit potential. The recorded motor unit potentials in myopathy are usually smaller than normal, and this is the electromyographic hallmark of muscle disease. Similar changes do not occur in neuropathy or motor neuron disease. During the course of the disease there may be partial repair of muscle fibers within a motor unit, but the normal architecture of the motor unit is often not recovered and this can lead to other motor unit potential changes, such as an increased complexity or polyphasia. When muscle disease leads to muscle fiber necrosis, spontaneous discharges in the absence of voluntary contraction of the muscle called fibrillations can occur. Fibrillations are also seen in nerve and motor neuron disease, but in the presence of small motor unit potentials they imply a myopathy with active muscle fiber necrosis—a finding that has major implications for diagnosis. Diseases in which muscle fiber necrosis is a characteristic feature, such as polymyositis and muscular dystrophy, will almost always have fibrillations seen during an EMG. Alternatively, myopathies that usually do not produce muscle fiber necrosis, such as steroid myopathy, will usually be free of fibrillations.

The muscle biopsy is a critical aspect of precise diagnosis in myopathy. Because many myopathies have overlapping clinical and EMG findings, the biopsy is often the crucial diagnostic test. Choosing the appropriate muscle to biopsy is always important in improving diagnostic yield of this procedure. The clinical and EMG examinations can usually guide the choice of muscle. It is important to choose at least a moderately affected muscle and one easily accessible to the surgeon. A muscle with severe weakness and atrophy may yield only fatty replacement tissue on biopsy and therefore it is usually better to choose a lesser-affected muscle when end-stage disease is present in some muscles. A muscle that has recently been examined with a needle during EMG should be avoided because the needle track can produce microscopic changes in the muscle. The laboratory reviewing the biopsy should be experienced in the special preparation and evaluation techniques of muscle biopsy, including histochemical stains for fiber typing, mitochondria, glycogen, lipid and selected enzymes, and electron microscopic evaluation of muscle. Except for inflammatory muscle diseases and a few other selected myopathies, routine hematoxylin and eosin (H and E) staining alone will not be adequate to be certain of the pathologic diagnosis of the myopathy.

[edit] DIAGNOSING A MYOPATHY

The approach to myopathy diagnosis can be conducted systematically and will lead to an accurate diagnosis in most cases. The diagnostician must be aware of the many symptoms that can result from muscle disease and the broad range of disorders that produce myopathy. Myoglobinuria always indicates a pathologic muscle process. Weakness, myalgia, fatigue, and muscle cramps should trigger a suspicion of myopathy. These symptoms can occur in nonmyopathic neurologic disorders or as a general reaction to medical or psychiatric illness. Deciding which patients require a more thorough evaluation of possible myopathy can be difficult. In many patients, co-morbid conditions or indications of a psychologic disorder will eliminate the need for further muscle investigation. If the pattern of muscle weakness is proximal, then myopathy is more likely, although myasthenia gravis should be considered because it can produce a similar pattern of weakness. Evidence of sensory disturbance or upper motor neuron signs on neurologic examination will usually eliminate myopathy as a cause of weakness. Though some myopathies will not elevate the serum CK, it is increased in the majority, and this simple investigation should be performed as soon as myopathy is suspected. When muscle fatigue and myalgia are prominent symptoms, a serum lactate in the rested patient may be informative. If the examination and blood tests are suggestive of myopathy, then an EMG will be helpful in confirming the presence of myopathy and may provide information regarding the type of muscle disease.

Patients with confirmed myopathy should have several screening procedures (Box 168-3). A careful review of medications and toxic exposures should be performed. The patient's family history should be carefully reviewed for similar problems. The general medical history and examination should search for nonskeletal muscle stigmata of myopathies, such as cardiac disease, collagen-vascular disease manifestations, rashes, and evidence of an endocrinologic disorder. Patients should have blood screening for thyroid disease and collagen-vascular diseases. Additional blood screening can be directed toward evaluation of other clues apparent in the history and examination. If a specific inherited myopathy is apparent, then genetic testing may be possible. When a diagnosis cannot be made through less invasive means, a muscle biopsy should be strongly considered. Many myopathic disorders cannot be diagnosed properly without the aid of muscle biopsy. If a muscle biopsy is performed, then the laboratory analyzing the tissue should be experienced in performance and interpretation of the many special histochemical stains and electron microscopy necessary for a complete assessment of muscle tissue.

[edit] Referral to a Specialist

The primary care physician can perform much of the initial screening for myopathy. As noted earlier, the proper management of myopathy may only require the removal of a toxic substance or the treatment of an underlying medical disorder. The patient should be referred to a physician with specialized training in myopathy when initial evaluation fails to yield a specific diagnosis, or if the diagnosing physician is not experienced with the diagnosis and management of specific muscle disorders.

[edit] DIFFERENTIAL DIAGNOSIS OF MYOPATHY

Myopathy can be divided into several large categories of muscle disease, based on etiologic factors and clinical presentation. A complete discussion of myopathy is well beyond the scope of this chapter, but is presented elsewhere.^[1]Box 168-4 lists the major categories of muscle disease.

[edit] INHERITED MYOPATHIES

[edit] Congenital Myopathies

Several usually nonprogressive presumed inherited disorders of muscle exist, most of which are distinguishable primarily by the appearances of the muscle biopsy. As a group these myopathies are called the congenital myopathies, and they should be distinguished from the more clearly progressive muscular dystrophies. Children with congenital myopathy may present as floppy infants with mild feeding difficulty, but serious weakness and feeding or breathing problems would be uncharacteristic of most congenital myopathies. Some of the congenital myopathies may have marked variability of clinical expression and more severe infantile forms. Usually this would not be suspected until the specific muscle biopsy abnormalities were detected. Many patients with congenital myopathy present as thinly muscled, mildly weak children, with the problem often becoming apparent when walking begins or as the child begins to attempt more physically demanding tasks, such as climbing. It may be difficult sometimes to distinguish when this truly represents a pathologic process. Functional testing of muscles can be helpful in determining when the muscle is more likely to be abnormal. Difficulty in rising from the floor, climbing up on a chair, or a history of inability to perform common childhood physical activities should be clues that muscle disease is present. The weakness will be lifelong in congenital myopathy, but marked progression of weakness over time with loss of motor milestones should lead to consideration of a more progressive disorder.

On biopsy it may be possible to distinguish the subtypes of congenital myopathy, including central core disease, nemaline myopathy, centronuclear myopathy, multicore disease, and congenital fiber type disproportion. In some disorders dysmorphic physical features may be present, including elongated facies, kyphoscoliosis, congenital hip dislocation, and foot deformities. Central core disease was the first described congenital myopathy and in many ways is typical of the group. Small muscles and mild to moderate proximal muscle weakness are apparent usually in early childhood. The CK level is usually normal, or at most only mildly elevated, attesting to the relatively nonprogressive nature of the disorder. The family history may be positive for a similar disorder. On muscle biopsy the predominant feature is circular cores that are apparent running through the center of the long muscle fibers. The cores are densely packed myofilaments. Other features of muscle fiber necrosis are usually absent. The other congenital myopathies all have distinctive pathologic features, generally denoted by the myopathy name, but many have overlapping clinical features. An important distinguishing feature of central core disease is that this congenital myopathy also results in susceptibility to malignant hyperthermia. This susceptibility can be life threatening during anesthesia and is very important to identify for the patient.

[edit] Muscular Dystrophies

[edit] Duchenne's Muscular Dystrophy.

Many myopathies fall within the diverse category of muscular dystrophy. The clinical features, inheritance patterns, and prognosis vary widely within this group, but all have some common features. The dystrophies are all inherited primary muscle diseases that are progressive and have pathologic features of muscle fiber degeneration and attempted regeneration. The most dramatic condition within this group is Duchenne's muscular dystrophy (DMD), the most prominent of the muscle diseases with an inherited defect of dystrophin. Dystrophin is a muscle membrane protein essential for membrane integrity. With complete dystrophin deficiency, the full expression of DMD occurs. Inherited partial dystrophin deficiencies can produce a variety of more benign presentations, of which Becker's muscular dystrophy (BMD) is the most frequently encountered.

DMD is an X-linked recessive disorder. Male children with the abnormal gene express the disorder. Females who are carriers do not manifest DMD, although female carriers can sometimes demonstrate mild abnormalities such as an elevated CK level or minimal weakness. Most boys with DMD are first noted to be weak before the age of 3. Increased frequency of falling, difficulty climbing, or regression of motor milestones may indicate the first change. These children develop difficulty in rising from the ground early and adopt the Gowers' maneuver to accommodate (Fig. 168-1). With the Gowers' maneuver the child uses his hands to “climb” up the legs, allowing him to get his trunk into the upright position. Once upright, the child may need to swing the legs out at the hip to walk as opposed to a more normal stride. This gait has the appearance of waddling and is called a Trendelenburg gait. Most children with DMD have pseudohypertrophy of the calves. The calves appear disproportionately large compared to proximal leg muscles and have a rubbery, firm consistency. During the later half of the first decade of life, patients with DMD become progressively weaker, and most have lost the ability to ambulate by age 12. Joint contractures and scoliosis develop during this period and worsen as mobility declines. DMD frequently involves cardiac muscle and produces electrocardiographic and echocardiographic abnormalities early and may lead to heart failure late in the patient's disease. Some patients with DMD will have abnormalities of the brain, which will present as a static cognitive delay. The ultimate prognosis of DMD relates to the unrelenting skeletal muscle weakening, with eventual involvement of respiratory function or cardiac disease. Respiratory or cardiac failure are the most common causes of death in DMD. The mean age of survival is approximately 20 years.

Figure 168-1 Gowers' sign. Child must use his hands to rise from sitting position. (Redrawn from Siegel IM: Clinical management of muscle disease. In Canale: Campbell's Operative Orthopedics, ed 5, London, 1977, William Heinemann.)

DMD can be inherited from a female carrier or as a new mutation. Approximately one third of boys with the disease appear to have a new mutation. The diagnosis can be confirmed through DNA analysis in about 70% of carriers or affected patients. If DNA analysis is positive, prenatal diagnosis and counseling will be possible for future pregnancies or relatives at risk for carrying the abnormal gene. Even without positive DNA analysis, dystrophin staining of muscle will be absent. This is a highly reliable test to confirm diagnosis, but it is impractical for many aspects of potential carrier screening or prenatal diagnosis. Another useful tool to screen potential carriers is measurement of CK levels because elevations will be present in about 50%.

The management of DMD depends heavily on the utilization of physical therapies, bracing, and surgery. As the disease progresses the physical devices used to maintain ambulation progress from splints through walking aids. Passive stretching will slow contracture development. Surgery can help prevent contracture formation, but it may also be needed to relieve discomfort from progressive scoliosis. Alternate-day steroids have been shown to slow progression for at least a few years and are now a well-accepted management tool for this group.^[2] A number of experimental therapies have been evaluated, but none have significantly affected the prognosis of this severe myopathy.

[edit] Becker's Muscular Dystrophy.

Inherited disorders of dystrophin can present with conditions less severe than DMD. The most frequently encountered is BMD. In DMD dystrophin is completely absent from immunohistochemical staining of muscle tissue. Dystrophin staining is partially lost in BMD, and this partial disorder of dystrophin produces a clinical phenotype that has many similarities to DMD but presents at a later age and is less severe. Patients with BMD typically develop symptoms later than those with DMD. The mean age of first symptom is 12, but the range is marked and some patients will first note problems in later adult life. The inheritance is X-linked similar to DMD, and some of the clinical clues to the diagnosis are similar, such as calf hypertrophy. Although BMD is a less severe muscular dystrophy than DMD, it is still a disabling condition, with gradual progression and a high risk of loss of ambulatory ability. The diagnosis can be confirmed through appropriate histochemical staining of muscle tissue. Genetic counseling issues are important both for parents of patients with BMD and for the patients themselves because most will survive to reproductive age.

[edit] Myotonic Dystrophy.

For physicians with numerous subspecialty interests, knowledge of myotonic dystrophy is important. In addition to the muscle manifestations of myotonic dystrophy, a number of other body systems can be affected in this condition. Myotonic dystrophy is inherited as an autosommal dominant disorder with highly variable expression of the disease phenotype. The molecular abnormality is an expansion of a CTG nucleic acid triplet repeat sequence on the nineteenth chromosome.^[3] Similar to a number of other triplet repeat disorders, the longer the expansion of the repeating triplet sequence, the more profound the phenotypic expression of the disorder. Over generations there tends to be a progressive increase in the length of the expansion sequence, which accounts for the phenomenon of “anticipation” that results in the children of carriers expressing the disease more severely.

The muscle weakness of myotonic dystrophy can be quite mild in some patients, but it often produces marked facial weakness, ptosis, and greater distal extremity weakness than is often seen in other myopathies. The myotonic manifestations of the disorder are noted by the patient as a stiffness of muscles or a difficulty in releasing his or her hand grip. At the bedside, myotonia is best demonstrated either by watching the release of a firm hand grip or by percussion of the thenar eminence with a reflex hammer. Myotonia will appear as a slow release of the grip or a sustained contraction of the muscle after percussion.

The systemic manifestations of myotonic dystrophy can be key to the initial consideration of the diagnosis. Frontal balding is a frequent manifestation. It is usually more prominent in men but is also seen in women. A patient complaining of weakness and who has marked thinness of facial and neck muscles, ptosis, and balding has a high likelihood of having myotonic dystrophy. Some of the systemic manifestations have important health implications and are important to monitor. Premature cataracts will often occur, even in patients without very many muscle manifestations. Cardiac arrhythmias, diabetes, and testicular atrophy will also occur in this disorder. Follow-up of patients with myotonic dystrophy should include periodic electrocardiograms (ECGs), fasting glucose measurements, and ophthalmologic assessment.

Myotonia can be a disturbing symptom in some patients, but often it does not affect function. If the patient has disabling myotonia, quinine and phenytoin can be helpful. Mexiletine is more effective but should not be used if cardiac manifestations are present.

[edit] Limb-Girdle Muscular Dystrophy.

The molecular basis of many of the adult-onset muscular dystrophies has now been described. Limb-girdle muscular dystrophy (LGMD) often presents in adult life with slowly progressive weakness and wasting of proximal muscles of the legs and arms. The disorder can be autosomal dominant or recessive. Patients with LGMD can be severely disabled, but the prognosis is generally better than DMD. Molecular abnormalities have been described of the sarcoglycan complex, which is an important muscle membrane protein complex that interacts with dystrophin. Histochemical staining of the muscle biopsy will often lead to a specific diagnosis of the subtype of LGMD.

[edit] Inherited Channelopathies

[edit] Myotonia Congenita.

Muscle diseases that result from inherited dysfunction of muscle membrane ion channels produce two main varieties of muscle symptom: myotonia and periodic paralysis. The two symptoms are sometimes found in the same patient. Myotonic dystrophy differs from other myotonic disorders by the presence of weakness and the manifestations outside of the skeletal muscle. Myotonia congenita (Thomsen's disease) is inherited as an autosomal dominant condition. A recessive form (Becker myotonia) is usually more severe. Dominantly inherited myotonia congenita may lead to muscle hypertrophy caused by the frequent, excessive contraction of the muscle, producing a heavily muscled appearance although the patient is not usually excessively strong. Unlike myotonia in myotonic dystrophy, the symptom is often very bothersome to the patient, who may require pharmacologic management. Treatment is similar to the management of myotonia for myotonic dystrophy, although mexiletine is less likely to cause cardiac side effects. Myotonia congenita occurs because of an inherited defect of calcium channel function on the muscle membrane.

[edit] Paramyotonia Congenita.

Paramyotonia congenita can lead to both myotonic symptoms and periodic paralysis. The myotonia is different in paramyotonia congenita in that it worsens the more a muscle is used, which is the opposite of other myotonic disorders. Patients with paramyotonia congenita also have cold-sensitive symptoms (e.g., in the cold they experience paralysis of muscles). The genetic defect is on the same chromosome as hyperkalemic periodic paralysis and affects the function of K⁺ ion channels in muscle membrane.

[edit] Periodic Paralysis

Periodic paralysis episodically results in severe weakness of extremity and trunk muscle, but it usually spares respiratory and bulbar muscles. The subtypes of periodic paralysis include hypokalemic, hyperkalemic, and normokalemic periodic paralysis. These patients do not have sensory manifestations and are often mistaken for patients with conversion reaction. Large meals or exercise in patients with the hypokalemic form can trigger the episodes of weakness. A positive family history is extremely helpful for suspecting the diagnosis. The serum K⁺ levels should be measured during attacks to facilitate diagnosis. The hypokalemic form can be diagnosed through provocative tests using glucose loading with or without additional insulin to promote hypokalemia. This test needs to be performed under carefully controlled circumstances to recognize hypoglycemia and treat it promptly if it occurs. The EMG in hyperkalemic periodic paralysis will often demonstrate myotonia, which will be a clue to the diagnosis. Acetazolamide is useful as a prophylactic agent for hypokalemic and hyperkalemic periodic paralysis, although dietary manipulation can also help avoid attacks. Potassium supplementation with a low-carbohydrate diet may prevent attacks in hypokalemic periodic paralysis. Eating a carbohydrate-rich substance may abort milder hyperkalemic periodic paralysis attacks. If periodic paralysis first occurs in adult life, then a secondary form should be considered, such as thyrotoxic periodic paralysis or periodic paralysis caused by loss of K⁺ from the kidneys or gastrointestinal tract from medication or disease.

[edit] Inherited Metabolic Myopathies

The inherited metabolic myopathies are a large and diverse group of disorders, each of which is due to an abnormality of muscle energy metabolism. The two primary sources of energy in muscle are sugars and fats. Thus the two major categories of inherited metabolic myopathy are disorders of glycolysis and lipid metabolism. Lipid metabolism leads to oxidative phosphorylation to produce ATP for high-energy utilizing tissues such as muscle. Oxidative phosphorylation occurs within mitochondria; therefore mitochondrial disorders are a subtype of lipid metabolism disorders that lead to muscle manifestations.

[edit] Myoglobinuria.

The most dramatic presentation of an inherited metabolic myopathy is with myoglobinuria, which develops when massive muscle fiber necrosis, or rhabdomyolysis, occurs very quickly and muscle fiber contents are spilled into the blood stream in large amounts. The serum CK level is always markedly elevated in patients with myoglobinuria. Myoglobin is filtered through the kidney and appears as a tea-colored discoloration of the urine. The large protein load on the kidneys induced by myoglobinuria can lead to acute renal failure and needs to be promptly managed.

Disorders of glycolytic and lipid metabolism can lead to myoglobinuria. McArdle's disease is caused by a deficiency of myophosphorylase and is a good example of a disease of glycolysis. Myophosphorylase deficiency impairs the ability of the muscle to metabolize glycogen as an energy source. This is particularly important during anaerobic muscle activity, when oxidative phosphorylation cannot be depended on because of reduced oxygen delivery to the muscle tissue. Exercise-induced myalgia is the most frequent symptom of patients with McArdle's disease. The exercise intolerance is most noticeable during the beginning stages of muscle activity or when isometric exercise is performed. In both situations glycolytic pathways are more important as an energy source for the muscle. Most patients with McArdle's disease describe a “second wind” phenomenon. If symptoms develop after a brief exercise and patients stop exercising briefly, when they restart the exercise they usually perform better. During exercise the muscle normally switches from being glycolytic pathway dependent to oxidative phosphorylation dependent for its energy source. “Second wind” represents that transition (i.e., the patient with McArdle's disease functions much better when oxidative phosphorylation is the predominant source of muscle energy). If McArdle's disease is suspected, the ischemic forearm test will provide strong evidence of the disorder. With a blood pressure cuff on the upper arm inflated above systolic blood pressure, the patient exercises forearm muscles by repeatedly squeezing the hand. Blood is drawn to evaluate the serum lactate level before the exercise and several times after its completion. Normally, at least a threefold increase in serum lactate levels is detected immediately after the exercise and lasts for several minutes. In McArdle's disease, the lactate fails to rise because of the inability of muscle to utilize glycolytic pathways even under ischemic conditions. Myophosphorylase staining of the muscle biopsy will confirm the diagnosis. Currently, no effective treatment is available for McArdle's disease, but accurate diagnosis is important to appropriately counsel patients regarding the need for prompt treatment of episodes of myoglobinuria.

Myoglobinuria will also occur with carnitine palmityl transferase (CPT) deficiency, which is an enzyme deficiency impairing transport of free fatty acids across the membrane of the muscle mitochondria. Because oxidative phosphorylation is the metabolic pathway altered in CPT deficiency, the exercise intolerance tends to occur after a longer duration of aerobic exercise than was encountered in McArdle's disease. The manifestations of myoglobinuria and the importance of prompt treatment are the same regardless of the underlying diagnosis.

Acid maltase deficiency is also a disorder of glycolysis and can present in childhood or adult life. The key clinical clue is the early and severe involvement of respiratory muscles in this disorder, often leading to the need for assisted ventilation. Management may be aided by biphasic positive airway pressure (BIPAP) or continuous positive airway pressure (CPAP) at night, but these patients often need to consider the possibility of long-term home ventilation.

[edit] Mitochondrial Myopathy.

Muscle is dependent on mitochondria to produce adenosine triphosphate (ATP) through oxidative phosphorylation. Many defects of mitochondrial function have been detected and most are associated with muscle disease, although other body tissues may also be affected. Several muscle syndromes are associated with mitochondrial dysfunction. The mitochondrial syndromes can include progressive external ophthalmoplegia, progressive extremity weakness often associated with exercise-induced myalgia, or a combination of myopathy and neuropathy. Other neurologic manifestations can occur in mitochondrial disorders, such as stroke at a young age, myoclonic seizures, migraine, sensorineural hearing loss, ataxia, and dementia.^[4] Nonneurologic manifestations of mitochondrial disorders can include lactic acidosis, diabetes mellitus, pigmentary retinopathy, cardiac conduction disorders, short stature, and Fanconi's syndrome. Several syndromes have been described that combine groups of manifestations of mitochondrial disease. The MELAS syndrome consists of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. MERRF refers to myoclonic epilepsy with ragged red fibers. The muscle biopsy of mitochondrial myopathy often demonstrates an excessive accumulation of mitochondria, forming clumps adjacent to the muscle membrane. The mitochondria likely proliferate in an attempt to compensate for abnormal function. Using a Gomori's trichrome stain, these mitochondria appear as red granular deposits leading to the ragged red muscle fiber description. Ragged red fibers are a pathologic feature common to many of the mitochondrial myopathies. The genetic defects of some mitochondrial syndromes have been described, facilitating diagnosis in some patients. Muscle can also be evaluated for the components of oxidative phosphorylation, allowing detection of the specific defect of energy metabolism in some patients. No effective treatment is yet available for mitochondrial diseases, although some manifestations may be effectively managed, such as diabetes, cardiac conduction defects, migraine, and others.

[edit] ACQUIRED MYOPATHIES

[edit] Inflammatory Myopathies

The inflammatory myopathies are an important treatable group of muscle diseases. There are several inflammatory myopathy syndromes with different treatment options for each. This subject is discussed in detail in Chapter 131 . It is always important to consider the diagnosis of an inflammatory myopathy in a newly acquired myopathy, but it is equally important to recognize the differential diagnosis as outlined in this chapter to ensure the management plan for the patient with myopathy is correct.

[edit] Acquired Metabolic Myopathies

[edit] Endocrine Myopathies.

Myopathy is common in many endocrine disorders, although the severity and clinical significance of the myopathy will vary according to the endocrine disorder. Box 168-5 lists endocrine causes of myopathy.

[edit] Thyroid Myopathy.

Evidence of myopathy is commonly found with hyperthyroidism and hypothyroidism, although the muscle disease is often subclinical or only mildly symptomatic. Patients with hypothyroidism commonly have a striking elevation of serum CK levels, with only mild weakness or fatigue and myalgia. The delayed tendon reflexes found in hypothyroidism reflect a slowness of muscle relaxation. Weakness is typically proximal and slowly improves with thyroid hormone replacement.

Although the serum CK levels in hyperthyroid myopathy are often only mildly increased or normal, weakness is frequently much greater than encountered in the hypothyroid state. In thyrotoxicosis, weakness can develop abruptly and can be severe, but the usual course is a gradual worsening of weakness over several months. Thyrotoxicosis is also a secondary cause of periodic paralysis and is described later. Hyperthyroid myopathy produces proximal weakness, and fatigue can be a prominent symptom. The differential diagnosis of myopathy in the presence of thyroid disease includes myasthenia gravis, which has a strong association with autoimmune thyroid diseases. Myasthenia produces fatigable muscle weakness, and bulbar muscles are more commonly affected in myasthenia gravis. The distinction between hyperthyroid myopathy and myasthenia gravis associated with hyperthyroidism can be difficult on clinical grounds alone and investigations such as EMG, measurement of serum CK levels and acetylcholine receptor antibodies. The Tensilon test is often required to clarify the diagnosis. Serum CK levels will be elevated in most myopathies, and acetylcholine receptor antibodies will be present in most patients with myasthenia gravis. Repetitive nerve stimulation during EMG will demonstrate decrement of the motor response in many myasthenia patients. Intravenous injection of 10 mg of Tensilon will temporarily correct the weakness in myasthenia gravis. The Tensilon test should be performed cautiously because of the potential for bradycardia and syncope. In addition, the subjective nature of the test can result in false interpretation. Dependence on the more objective investigations is recommended.

[edit] Thyroid Ophthalmopathy.

Thyroid eye disease is most commonly associated with hyperthyroidism but will occur in hypothyroid or, occasionally, in euthyroid patients (see Chapter 97 ). The most frequent manifestation is lid lag as the patient looks down and eyelid retraction, giving the impression of protuberant eyes. This is almost always associated with thyrotoxicosis. In a small number of patients with thyroid disease the extraocular muscles and soft tissues of the orbit gradually swell, producing proptosis, diplopia, and abnormalities of extraocular movement on examination. The swelling can increase intraorbital pressure, which has the potential to damage vision. Because the eye disease is likely related to the autoimmune process associated with thyroid disease, inducing a euthyroid state will not always correct the eye problem. Treating the underlying thyroid disease may help the eye disease, but some patients will require surgical decompression of the eye and steroid treatment.

[edit] Pituitary and Adrenal Disease

[edit] Steroid Myopathy.

Cushing's syndrome refers to a variety of conditions in which excessive corticosteroid activity produces clinical manifestations. The syndrome can occur because of Cushing's disease (see Chapter 98 ). The myopathies caused by the various forms of Cushing's syndrome are similar. Steroid myopathy is the most important toxic myopathy and the most common cause of myopathy. Steroid myopathy usually occurs in the presence of long-term, high-dose steroid treatment, but it can also develop with lower doses during long-term treatment or as a complication of very-high-dose acute treatment in critically ill patients. Most steroid myopathies produce proximal muscle weakness and should always be considered in patients on steroids who complain of new weakness. Unlike many other myopathies, steroid myopathy is usually not accompanied by an elevated serum CK level and the EMG usually has relatively little change. In particular, there is usually an absence of fibrillations on EMG. The muscle pathology in steroid myopathy is a type 2 muscle fiber atrophy without evidence of muscle fiber necrosis or loss of muscle membrane integrity, which explains the lack of CK elevation and fibrillation on EMG. The diagnosis can be particularly difficult in patients being treated with steroids for polymyositis or dermatomyositis and who appear to have a late deterioration in their condition. A normal serum CK level and absence of evidence of active muscle fiber necrosis on EMG will point to steroid myopathy as a complication of management and will be helpful in guiding therapeutic decisions. Steroid myopathy improves readily with withdrawal of the steroid treatment. Because muscle fiber necrosis has usually not occurred, the recovery is generally complete and reasonably prompt. In patients who cannot have steroids withdrawn, myopathy can be minimized by using the smallest possible dose of steroid, treating with alternate-day steroids, avoiding protein deprivation in the diet, and increasing physical activity. Myopathy related to Cushing's syndrome other than that due to steroid treatment should be suspected if the myopathy is accompanied by a cushingoid facial appearance, truncal weight distribution, or other physical features of corticosteroid excess.

[edit] Intensive Care Unit-n-Associated Myopathy.

Critically ill patients are at risk for developing a variety of neuromuscular problems. The polyneuropathy of critical illness is associated with multiorgan failure. The mechanism of intensive care unit (ICU)–associated myopathy is still incompletely understood, although high-dose steroid treatment—often in the presence of paralyzing agents—is usually associated with the disorder.^[5] Patients with ICU-associated myopathy develop a fulminant paralyzing illness, usually equally affecting distal and proximal muscles. These patients cannot be weaned from the ventilator because of the muscle weakness. Pathology studies have improved our understanding of the pathogenesis of ICU-associated myopathy. Some patients will have inflammatory changes, but the usual pathologic abnormality is an absence of myosin (or thick filaments) in the muscle fiber. Myosin is part of the structure that contracts to shorten muscle; thus without myosin the muscle fiber will fail to work even in the absence of fiber necrosis. Electromyography is an essential component of investigation of ICU patients with apparent neuromuscular weakness because polyneuropathy, myopathy, and other causes of weakness can usually be distinguished by an EMG. If the EMG suggests myopathy, muscle biopsy will confirm the disorder. Myosin filament loss is reversible. Patients with ICU-associated myopathy should be appropriately supported while the disorder corrects itself.

[edit] Other Pituitary and Adrenal Disorders.

Adrenal insufficiency, acromegaly, and primary aldosteronism can all cause weakness in the pattern of a myopathy. The serum CK level in these disorders is usually normal or only minimally increased and each disorder usually corrects with the appropriate endocrine treatment.

[edit] Parathyroid Diseases.

The most frequently encountered myopathy related to parathyroid dysfunction occurs in patients with chronic renal failure who develop secondary hyperparathyroidism. The myopathy in this disorder is similar to primary hyperparathyroidism caused by parathyroid adenoma. Patients complain of muscle weakness and stiffness, which is more marked in the lower extremities. Serum CK levels are usually normal, but the EMG will demonstrate myopathic motor unit potential changes. Primary hyperparathyroidism myopathy will correct with parathyroidectomy, but in patients with secondary hyperparathyroidism myopathy does not respond well to intervention other than renal transplantation.

Myopathic weakness is only rarely associated with hypoparathyroidism, but hypocalcemia associated with hypoparathyroidism will lead to muscle tetany. Myopathy can also occur in other parathyroid-related conditions, such as osteomalacia.

[edit] Toxic Myopathies

As pharmacologic management of disease advances, the list of agents capable of producing muscle disease is constantly growing. Some agents have a greater impact on modern medical management because of the frequency the agent is used. For example, although steroid myopathy only occurs in a small percentage of patients taking steroids, the broad list of indications for oral steroid treatment leads to the disorder being encountered by physicians with many different interests. Box 168-6 lists several agents that can provoke myopathy. Some of these are used in the treatment of diseases and some result from poisoning or ingestion of recreational agents toxic to muscle.

Box 168-6 is only a partial list of agents capable of producing a toxic reaction in muscle. The agents listed are examples of muscle syndromes associated with toxic agents and are those that may be more frequently encountered or appear to have a particularly potent reaction on muscle. Many other drugs and toxins have been associated with muscle disease, and if a patient develops evidence of muscle disease the adverse reaction profile of agents taken by the patient should be carefully reviewed. Details of some toxic myopathies are outlined below.

[edit] Alcoholic Myopathy.

Alcohol can affect muscle in many ways. Chronic alcoholism with associated protein-calorie malnutrition can produce muscle wasting and weakness, which is often attributed to neuropathy, but muscle biopsy also demonstrates primary muscle degeneration. Alcohol is likely toxic to muscle through many mechanisms, including the production of toxic metabolites such as acetaldehyde and impairment of muscle metabolism. Acute severe alcohol intoxication can produce widespread necrosis of muscle associated with myoglobinuria and the associated complications of myoglobinuria. Dehydration and compression injury to muscle in obtunded patients will contribute to rhabdomyolysis secondary to alcohol intoxication. Abstention from alcohol and proper nutrition will reverse the muscle damage in this disorder.

[edit] Antiretroviral Agent-n-Associated Myopathy.

Myopathy is a less commonly occurring complication of antiretroviral therapy than neuropathy and is most often detected in patients taking zidovudine (AZT). Myopathy related to AZT therapy of the human immunodeficiency virus (HIV) can be difficult to differentiate from the wasting and weakness associated with acquired immunodeficiency syndrome (AIDS) but it should be considered when myopathic symptoms are prominent. Patients with AZT-related myopathy develop a steadily progressive, painful muscle weakness. The muscle biopsy demonstrates mitochondrial abnormalities, suggesting a toxic disruption of oxidative metabolism in the muscle. AZT-related myopathy may improve after withdrawal of the drug, but if the myopathy worsens, the muscle disease may be more likely related to the HIV infection.

[edit] HMG-CoA Reductase Inhibitors (Statin-Type Lipid-Lowering Agents).

HMG-CoA reductase inhibitors used in the treatment of hyperlipidemia increase serum CK levels in approximately 0.5% to 1.0% of patients on long-term therapy. Most of these patients will not have significant clinical symptoms of myopathy. However, if the chronic CK elevation has not been documented, confusion can arise if the patient is assessed for chest pain with enzyme testing. The CK elevation caused by statin drugs is skeletal muscle in origin. Isoenzyme testing should clarify the origin of the muscle enzyme elevation.

Much less commonly statin drugs will produce myalgias and weakness. Occasionally, rhabdomyolysis will develop. Concurrent use of some medications, including cyclosporine and gemfibrozil, increases the incidence of severe myopathy associated with statin drugs. Patients presenting with muscle pain or weakness should be evaluated promptly for evidence of myopathy because withdrawal of the medication will be necessary if there is evidence of muscle fiber necrosis.

[edit] Malignant Hyperthermia.

Malignant hyperthermia is a potentially fatal reaction to anesthetic agents. Succinylcholine, halothane, and other agents used during general anesthesia can induce the disorder. The condition begins shortly after induction of anesthesia, with severe contraction of jaw and extremity muscles. The heat production from massive muscle fiber activity elevates the body temperature. Acidosis, hypertension, and cardiac arrhythmias will develop quickly. Untreated, the mortality rate is about 70%. Intravenous dantrolene started early in the development of malignant hyperthermia will relax muscles adequately in most patients to reverse the process. Malignant hyperthermia is an inherited disorder with autosommal dominant inheritance. The gene locus responsible for malignant hyperthermia in some families is on chromosome 19. Determining susceptibility can be difficult. Patients at risk because of family history should be counseled regarding the potential for this life-threatening disorder, and treating physicians need to be aware of the risk because some anesthetic agents will be safer to use in susceptible patients. CK testing can help determine risk. A patient with elevated CK levels who is genetically at risk for the disorder should follow all of the precautions for patients with known susceptibility to the disorder. If the CK level is normal, a special evaluation of the muscle biopsy by performing the contracture test will assess risk. This test is only available in selected muscle biopsy centers.

[edit] Neuroleptic Malignant Syndrome.

Several features of neuroleptic malignant syndrome are similar to malignant hyperthermia. This disorder occurs sporadically in patients treated with neuroleptic agents, such as haloperidol and chlorpromazine. Patients develop muscle rigidity, elevated body temperature, tachycardia, and elevated CK levels. The disorder begins gradually over a few weeks and is not inherited. As the disorder progresses, the patient may develop dehydration related to reduced intake and greater loss of fluids from the hyperthermia. Withdrawal of the neuroleptic, general medical support, bromocriptine, and dantrolene will improve the condition, but it may take several weeks to completely reverse.

[edit] Cocaine and Other Abused Drugs.

Cocaine and less frequently heroin and amphetamines have been associated with episodes of rhabdomyolysis, sometimes producing myoglobinuria. With all of these agents, coma and prolonged pressure from lying on muscle can lead to muscle fiber necrosis. Cocaine also may damage muscle through vascular injury. A chronic myopathy may occur because of repeated injury from chronic use of cocaine.

[edit] Eosinophilic Myalgia Syndrome (l-Tryptophan).

l-Tryptophan has been used as a dietary supplement and is sold without prescription. l-Tryptophan–induced eosinophilic myalgia syndrome is an example of the effects of widespread contamination of a dietary product.^[6] The condition was first detected in the early 1980s but increased dramatically in incidence in 1989. A similar event occurred in 1981 when thousands of people in Spain developed an eosinophilic myalgia syndrome related to the ingestion of contaminated rapeseed oil. The l-tryptophan contamination resulted in a gradual onset of fatigue, muscle pain, fever, and skin rash. Skin and muscle biopsies demonstrated inflammatory infiltrates. Some patients died from the illness, and the offending product has now been withdrawn.

[edit] REFERENCES