Myopathy

Holli A. Horak

Raul N. Mandler

Myopathy is an abnormality of the skeletal muscle in which striated muscle cells or connective tissue elements are affected. Myopathy can result from abnormalities of skeletal muscle proteins (Duchenne muscular dystrophy), alterations of the sarcolemmal ion channels (hyperkalemic periodic paralysis), mitochondrial alterations (mitochondrial myopathy), or cell-mediated autoimmune mechanisms (polymyositis), to name a few examples. Because of the myriad abnormal mechanisms, treatments vary from one condition to the next. Progress in molecular biology, genetics, and immunology has considerably expanded our understanding of these complicated diseases. This chapter emphasizes current therapeutic approaches to the care of patients with relatively common forms of myopathy.

I. IDIOPATHIC INFLAMMATORY MYOPATHY

Idiopathic inflammatory myopathies are autoimmune diseases characterized by muscle weakness, pain, and fatigue. Inflammatory damage of muscle fibers is the underlying pathology. Polymyositis can occur in isolation or accompany other connective tissue disorders or associated systemic autoimmune disorders. Dermatomyositis, inclusion body myositis (IBM), and polymyalgia rheumatica (PMR) are the other major categories of idiopathic inflammatory myopathy. The incidence of these diseases is approximately 1 case among 100,000 persons.

A. Natural history and prognosis.

1. Polymyositis

usually affects upper and lower girdle muscles in a symmetric pattern after the second decade of life. Patients with no family history of muscle weakness have subacute (weeks to months), progressive weakness of the deltoid, trapezius, neck flexor and extensor, biceps, triceps, iliopsoas, gluteus, quadriceps, and other muscles.

Patients characteristically have problems arising from a sitting position, washing their hair, or using stairs. Muscle pain may accompany the weakness. Pharyngeal muscle compromise can lead to dysphagia. The tongue, extraocular muscles, and facial muscles are usually spared. Sensation is not affected. Cardiac involvement can occur in as many as 40% of cases. Pulmonary involvement can result from primary weakness of respiratory muscles or from pulmonary interstitial fibrosis.

Polymyositis can occur in association with connective tissue and systemic autoimmune disorders. Polymyositis is not associated with an increased incidence of malignant disease. T-cell-mediated immunity plays a prominent role in the pathogenesis of polymyositis.

2. Dermatomyositis

is characterized by a rash that accompanies or precedes muscle weakness. The characteristic skin abnormality is a heliotrope rash over the orbits and zygomatic arch with erythema on the rest of the face, upper trunk, and knuckles (Gottren’s papules). Subcutaneous nodular calcifications and dilated capillaries in the nail beds occur.

In children, extramuscular manifestations are more frequent than they are in adults. Dermatomyositis usually occurs alone but may be associated with systemic sclerosis, mixed connective tissue disease, or malignant lesions. Ten percent of patients with dermatomyositis will be found to have an underlying malignancy. It is a humorally mediated microangiopathic disorder with vascular deposition of immunoglobulin G (IgG), C3, and membrane attack complex. This suggests that the primary immunologic event is generation of antibodies against antigens within the walls of intramuscular blood vessels.

3. IBM

involves distal and proximal muscles. Weakness and atrophy can be slightly asymmetric; quadriceps and finger flexors are commonly affected. It is a late-onset myopathy (sixth or seventh decade). It is treatment resistant. Occasionally, the diagnosis of IBM
is made retrospectively when a patient fails to respond to treatment for polymyositis. Hereditary forms of IBM have been described: an autosomal dominant variant, which has a younger age of onset and an autosomal recessive variant, caused by a mutation in the GNE gene, on chromosome 9.

4. PMR

affects elderly men and women with a peak incidence at 74 years of age. Patients describe diffuse muscle aching with neck and shoulder stiffness. Pain predominates over weakness or atrophy. Approximately 15% of the patients also have temporal arteritis. The erythrocyte sedimentation rate (ESR) is elevated to >40 mm per hour.

Noninfectious inflammatory myositis can also occur in the context of systemic lupus erythematosus, progressive systemic sclerosis, Sjögren’s syndrome, rheumatoid arthritis, mixed connective tissue disease, sarcoidosis, hypereosinophilic syndromes, and other disorders.

B. Diagnosis.

In addition to the clinical features, the diagnosis of inflammatory myopathy is supported by results of measurement of muscle enzymes, electromyography (EMG), and muscle biopsy.

1. Muscle enzymes. Creatine kinase (CK) is released from the sarcoplasm into the serum after muscle destruction, and the level may be elevated as much as 50-fold in polymyositis/dermatomyositis. Other muscle enzymes such as lactate dehydrogenase, aldolase, and aminotransferases are commonly elevated. In IBM, CK level may be elevated as much as 10-fold or remain normal. In childhood dermatomyositis and in patients with myopathy associated with connective tissue diseases, CK levels may be normal. ESR should be determined, especially for suspected PMR.

2. The main value of EMG resides in its ability to show that peripheral neuromuscular weakness originates from the muscle itself and not from denervation or from a defect in neuromuscular transmission. It can also help ascertain the presence of disease activity. The classic EMG findings include short-duration, small-amplitude motor unit potentials, and increased insertional activity. These findings should not be considered specific for inflammatory myopathy, because they can also be found in acute toxic or metabolic myopathy and in dystrophy.

3. Muscle biopsy helps establish the diagnosis.

In polymyositis, light microscopic examination displays intrafascicular inflammatory infiltrates, necrosis, atrophy and regeneration of muscle fibers, and increased amounts of connective tissue.
In dermatomyositis, the inflammatory infiltrates are present around the vessels or in the interfascicular septa, and perifascicular atrophy is characteristic. Small blood vessels with hyperplastic endothelia may be occluded.
IBM is characterized by basophilic granular inclusions around the edges of vacuoles (rimmed vacuoles).
Muscle biopsy has limitations. Because of sampling error, a biopsy sometimes fails to disclose abnormalities expected from the clinical presentation.

C. Therapy.

1. Prednisone.

Administration. High-dose prednisone is the initial line of therapy for polymyositis and dermatomyositis. For prednisone, the recommended dosage is 1.0 mg per kg a day in a single daily dose for 30 to 60 days. The total dose should not exceed 100 mg. Daily administration should be used until there is unquestionable improvement muscle strength with recovery of ambulation. Then the dosage can be slowly reduced over 10 weeks to 1 mg per kg every other day. If no deterioration occurs, the dose is further reduced by 5 to 10 mg every 3 to 4 weeks until the lowest dose that controls the disease is reached. The dose should not be reduced if strength decreases. If treatment is effective, strength should improve within 3 months. If after 3 months of therapy no improvement has been achieved, prednisone should be tapered off and another immunosuppressant medication begun.
Side effects. Patients need to become acquainted with the numerous side effects of long-term prednisone treatment. Infections, fluid retention, potassium depletion, hypertension, diabetes, osteoporosis, premature cataracts, peptic ulcer disease, and skin bruising are some of the side effects that can occur.

Prevention of osteoporosis requires supplemental calcium gluconate or carbonate (500 to 1,000 mg per day) and calcitriol (0.2 to 0.5 mg per day) as well as axial exercise and adequate passive range of motion maneuvers. Bisphosphonates (alendronate, risedronate among others) can be used. A baseline dual energy X-ray absorption densitometry scan to measure bone density should be obtained for every patient before steroid treatment is started. The scan should be repeated every 6 months.

Proton pump inhibitors should be used to prevent peptic ulcers. Periodic eye examinations are needed for diagnosis of incipient cataracts or glaucoma. Periodic laboratory tests for serum glucose and electrolytes are recommended. Steroid myopathy, a side effect of long-term steroid use, will be addressed later in this chapter.

Sometimes patients with dermatomyositis need separate therapy for the rash.

3. Azathioprine

is considered when complications preclude use of steroids, when the disease is not responding to adequate dosages of prednisone, or to add a steroid-sparing agent. A therapeutic response may take 3 to 6 months.

Administration. Azathioprine can be administered at 2 (up to 3) mg per kg a day. The initial dose should be approximately 50 mg per day, gradually increasing to BID dosing.
Side effects. The most common side effects of azathioprine are fever, nausea, rash. However, bone marrow suppression and liver toxicity can occur. CBC count with differential and platelets and liver function tests should be performed weekly for the first month and monthly thereafter. Patients with absent thiopurine S-methyltransferase (TPMT) enzyme activity are at high risk for azathioprine toxicity. TPMT testing is commercially available and may be considered before beginning treatment with azathioprine.

4. Mycophenylate mofetil

inhibits proliferation of T and B lymphocytes and can be used as an alternative to azathioprine. Doses typically start at 500 mg per day and are increased to 1,000 mg twice a day. Side effects include immunosuppression, gastrointestinal side effects, hepatotoxicity and bone marrow inhibition, possible reactivation of chronic infection such as tuberculosis, and remote risk of malignant disease.

5. Methotrexate

(15 to 25 mg per week by mouth) is used as another method to spare use of prednisone or if prednisone has not been effective. Hepatotoxicity, leukopenia, alopecia, stomatitis, and risk of neoplasia can occur. Methotrexate should not be used in patients with anti-Jo-1 antibodies and polymyositis because they are at increased risk for pulmonary fibrosis.

6. High-dose intravenous (IV) gamma globulin

is effective in the management of polymyositis and in dermatomyositis. The recommended dosage is 0.5 mg per kg IV for 4 days, repeating each month as needed. Side effects include headaches, hypertension, acute renal failure, and hyperviscosity. Aseptic meningitis can occur and may respond to prednisone treatment. IgA-depleted preparations reduce the risk of reactions related to anti-IgA antibodies. Treatments are expensive. Despite these reservations, highdosage IV gamma globulin might benefit patients who have been unresponsive to other medications.

In refractory cases, or if interstitial lung disease occurs, cyclophosphamide (1 to 2 g per m² a month IV) may be considered. Side effects include nausea, vomiting, alopecia, hemorrhagic cystitis, teratogenicity, bone marrow suppression, carcinogenesis, and pulmonary fibrosis. Cyclophosphamide can also be used orally at doses of 1 to 2 mg per kg a day.

8. Rituximab,

a CD20 monoclonal antibody that depletes B cells, is being investigated for use in resistant disease. It is administered at a dose of 375 mg per m² every week for a month, with possible repeat courses in 6 months or 1 year. Opportunistic infections have occurred with this medication.

In PMR, prednisone rapidly provides benefits. Duration of treatment and dosage have to be individualized. In general, a starting dosage of 1 mg per kg a day should be appropriate. In patients suffering from temporal arteritis, corticosteroid treatment needs to be initiated immediately.

D. Prognosis.

Dermatomyositis and, to a lesser degree, polymyositis are responsive to treatment, whereas IBM is usually resistant. Patients with interstitial lung disease have a higher mortality rate. When management of polymyositis is unsuccessful, the patient should be reevaluated and the muscle biopsy specimen reexamined to exclude
IBM or muscular dystrophy of the limb-girdle type. Finally, it is important to emphasize the need to evaluate the patient’s strength and activities of daily living as measures of improvement, rather than simply adjusting treatment on the basis of CK levels alone.

II. VIRAL INFLAMMATORY MYOPATHY

Viruses and retroviruses can cause acute or subacute inflammatory myopathy.

A. Reye’s syndrome

is acute encephalopathy with fatty degeneration of the liver that develops after varicella or influenza infections. This rare condition that affects children and adolescents begins with repeated vomiting and continues with confusion, lethargy, and coma. The mortality is high. There is acute liver dysfunction. The level of CK MM isoenzyme derived from skeletal muscle may be increased 300-fold. The level of CK correlates with prognosis. Salicylates may precipitate the syndrome. Treatment is supportive. The incidence of this syndrome has decreased precipitously over the years because aspirin is no longer being used to treat children with flu-like symptoms.

B. HIV

may cause subacute or chronic myopathy early or late in relation to the infection. Proximal, symmetric involvement of lower or upper limbs manifests as weakness with or without atrophy. Serum CK levels may be elevated 10 to 15 times. The syndrome is almost identical to polymyositis. Thus, in the evaluation of patients with polymyositis, evaluation for HIV is recommended.

III. PARASITIC INFLAMMATORY MYOPATHY

In North America, trichinosis, cysticercosis, and toxoplasmosis are rarely the cause of a myopathy. These causes may need to be considered in an acute-subacute onset myopathy in an immunocompromised patient or one who has been in an endemic area or has had possible exposure to the parasite.

IV. PERIODIC PARALYSES

Periodic paralyses are disorders characterized by episodes of flaccid muscle weakness that can evolve into paralysis. Attacks usually last hours. Periodic paralysis is either a primary autosomal dominant disorder or a secondary disorder. The inherited forms of these diseases are caused by channelopathies, or defects in genes coding for muscle membrane ion channels (Table 47.1).

A. Natural history and prognosis.

1. Primary hypokalemic periodic paralysis

affects young and middle-aged persons. Attacks usually occur at night or after strenuous exercise. On awakening, patients may be paralyzed and unable to get out of bed. The flaccid paralysis usually spares the respiratory and cranial muscles. During attacks, serum potassium level decreases. An ECG may reveal hypokalemic changes, including progressive flattening of T waves, depression of the ST segment, and appearance of U waves. Some patients eventually develop a progressive myopathy.

Seventy percent of patients with this disorder have a defect in the calcium channel gene: CACNA1S, which is located on chromosome 1q31. A small percentage of patients, however, have a sodium channel defect (SCN 4A). For approximately 20% of patients the gene defect is yet to be identified.

2. Secondary hypokalemic periodic paralysis.