Myopathies

What is a myopathy?

A myopathy is a disorder in which there is a primary functional or structural impairment of skeletal muscle.

What signs and symptoms are suggestive of a myopathy?

• Proximal symmetric weakness, which may be acute, subacute, or chronic

• Reduced, preserved, or enlarged muscle bulk

• Muscle pain or discomfort with palpation (myalgia)

• Muscle stiffness or cramps

• Fatigue

• Myoglobinuria

Define myoblast, myotube, myofiber, and myofibril.

A myoblast is a postmitotic, mononucleated cell capable of fusion and contractile protein synthesis. Myotubes are long, cylindrical, multinucleated (syncytial) cells formed from the fusion of myoblasts. When their central nuclei are shifted to a subsarcolemmal position in the later stages of development, they are called myofibers . The appearance of central nuclei within an otherwise normal adult muscle is a useful sign of muscle regeneration. Each adult myofiber is packed with numerous myofibrils, largely composed of hexagonal arrangements of thick and thin contractile filaments. Myosin is the major constituent of the thick filaments, whereas actin is the contractile protein of the thin filaments.

What is a motor unit?

A motor unit consists of a motor neuron, its single axon, the associated neuromuscular junctions and terminal axon branches, and the many muscle fibers that they supply. All muscle fibers belonging to a single motor unit are of the same histochemical and physiologic type.

What are the general categories of myopathies?

• Inflammatory myopathies (e.g., polymyositis [PM], dermatomyositis [DM], inclusion body myositis)

• Toxic myopathies (e.g., alcohol, zidovudine)

• Endocrine myopathies (e.g., hypothyroidism, hypoadrenalism)

• Infectious myopathies (e.g., trichinosis, AIDS)

• Muscular dystrophies (e.g., Duchenne, myotonic, limb-girdle)

• Congenital myopathies (e.g., central core, centronuclear myopathy)

• Metabolic myopathies (e.g., myophosphorylase deficiency, phosphofructokinase deficiency)

• Mitochondrial myopathies (e.g., Kearns–Sayre syndrome)

How do we grade functional weakness?

The most widely used system was developed by the Medical Research Council (MRC) of Great Britain. The MRC system grades strength from 0 to 5. The addition of a plus (+) or minus (−) further quantifies strength:

• 0.

  No movement

• 1.

  Trace movement

• 2.

  Able to move, but not against gravity

• 3.

  Able to move full range against gravity

• 4.

  Able to move against some resistance

• 5.

  Normal strength

In addition, the clinician may observe the patient performing the following maneuvers to look for subtle weakness:

• Arise from a chair with arms folded

• Walk the length of the examining room on toes, on heels, and tandem

  Medical Research Council: Aids to the Examination of the Peripheral Nervous System . London: W.B. Saunders, 2000.

• Hop on either foot

• Perform deep knee bends

• Climb a step

• Horizontally abduct arms and reach the vertex of the head

• Lift up the head from a table

• Arise from supine position with hands overhead

• Lift head and shoulders, and extend the neck while in a prone position

What is Gower’s sign?

This term describes the maneuver of rising from a supine position in the presence of marked proximal weakness. In order to rise to standing, the patient rolls to a prone position, pushes off the floor, locks the knees, and pushes the upper body upward by “climbing up” the legs with the hands. Although Gower’s sign is usually seen in children with myopathies, it may be present in any patient with marked proximal weakness ( Fig. 4-1 ).

What are the most common causes of muscle pain?

Most muscle pains are caused by a nonmuscular condition, such as vascular insufficiency, joint disease, or neuropathy. The vast majority of myopathies are painless. Myopathies that may be associated with pain include inflammatory myopathies, metabolic myopathies, mitochondrial myopathies, and some muscular dystrophies (limb-girdle, Becker muscular dystrophy [BMD]). In general, in patients with a normal exam and a normal serum creatine kinase (CK) level, muscle pain is usually not myopathic in origin.

What are the most valuable tests for evaluating patients with suspected muscle disease?

A diagnosis often can be established by supporting the clinical findings with results from three key tests: (1) serum CK levels, (2) electromyography (EMG), and (3) muscle biopsy.

Which myopathies are associated with elevated serum CK levels?

CK catalyzes the reversible reaction of adenosine triphosphate (ATP) and creatine to form adenosine diphosphate and phosphocreatine. It is elevated in many myopathies due to myofiber disruption or degeneration. Serum CK is especially high in limb-girdle muscular dystrophies (dysferlinopathies and sarcoglycanopathies), Duchenne and Becker muscular dystrophies, inflammatory myopathies, and rhabdomyolysis. However, CK levels may be normal in some patients with an ongoing myopathy. Examples include profound muscle wasting and selected conditions such as hyperthyroidism.

What is rhabdomyolysis?

Rhabdomyolysis is a condition of severe acute muscle injury causing myalgia, muscle weakness, muscle swelling, myoglobinuria, and very elevated CK levels (>5 times upper limit of normal), which develops over hours to days. Acute renal failure and its sequelae need to be treated. Then, the etiology needs to be determined. Causes include crush injuries, ischemia, alcohol/drugs/medications, metabolic disturbances, toxic exposures, infections, or myositis. If either an acquired cause is not clear or there are recurrent episodes, a muscle biopsy in search of metabolic or congenital myopathies or a muscular dystrophy may be indicated.

What conditions other than myopathies are associated with an elevated CK level?

Normal CK levels vary by race and gender with African American men having the highest values. HyperCKemia is defined as asymptomatic or paucisymptomatic elevations in CK level. Elevated CK could be a sign of a latent neuromuscular disease but there are many causes for this including:

• Exercise (especially if vigorous or unaccustomed)

• Increased muscle bulk

• Muscle trauma (needle injection, EMG, surgery, seizures, edema, or contusion)

• Viral illnesses

• Acute kidney disease

• Metabolic disturbances (hyponatremia, hypokalemia, hypophosphatemia)

• Drug use (including alcohol and cholesterol-lowering agents)

• Eating licorice

• Endocrine disorders (hypo/hyperthyroidism, hypoparathyroidism)

• Malignant hyperthermia

• Neurogenic disease (e.g., amyotrophic lateral sclerosis)

• Benign hereditary CK elevation

Typically CK levels are increased less than threefold in these conditions, whereas CK levels greater than fivefold often suggest an underlying myopathic etiology.

What is the approach to evaluating a persistent but incidental elevation of serum CK?

Perform an EMG if symptoms of weakness, myalgia, cramps, or tenderness are present. If the EMG findings are suggestive of a myopathy, a muscle biopsy may be considered. If the examination is normal, have the patient rest for 3 to 4 days and recheck serum CK early in the morning. If levels are still greater than 1.5 times the upper limit of normal for ethnicity and gender, an EMG and a muscle biopsy might be beneficial. If serum CK is within normal limits, then follow the patient clinically. A muscle biopsy in this setting rarely yields any useful information.

When is a muscle biopsy indicated? How is the muscle site chosen?

Muscle weakness with associated laboratory or electrophysiologic evidence of a myopathy is an indication to pursue a muscle biopsy. In general, the biceps or deltoid muscles in the upper extremity or the vastus lateralis muscle in the lower extremity are selected. Moderately affected muscles are better to biopsy than severely affected muscles because fibrosis and fatty replacement of the muscle, which are characteristic of end-stage muscle disease, may not provide adequate information. In addition, muscles affected by other conditions (e.g., radiculopathy or trauma) should be avoided if possible.

What morphologic features of a myopathy may be seen on biopsy?

Morphologic features of a myopathy include muscle fiber necrosis, phagocytosis and regeneration, increased central nuclei, fiber hypertrophy and rounding, variation in fiber size and shape, and increased endomysial connective tissue ( Fig. 4-2 ). Multiple stains can be used.

• Hematoxylin and eosin—general information about muscle structure/cellular details

• Modified Gomori trichrome—general information about the muscle structures and cellular details; ragged red fibers; rimmed vacuoles

• ATPase—histochemical fiber type

• Nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR)—differentiates type 1 and type 2 fibers, oxidative activity, cores

• Cytochrome oxidase (COX) and succinic dehydrogenase (SDH)—mitochondrial activity

• Congo red—rimmed vacuoles, amyloid deposits

• Other stains can look for glycolytic enzymes or storage materials.

How many fiber types are recognized by muscle histochemistry?

Type 1 fibers are slow-twitch, red fibers; type 2 fibers are fast-twitch, white fibers. The two major subtypes of type 2 fibers are types 2A and 2B. The histochemical and physiologic properties of each fiber type are determined by the anterior horn cell that innervates it.

What are ragged red fibers?

Ragged red fibers are muscle fibers with an accumulation of subsarcolemmal and intermyofibrillar material that stains red with modified Gomori trichrome stain ( Fig. 4-3 ). This red-stained material is actually mitochondria that are abnormal in number, size, and structure when viewed by electron microscopy. If there is mitochondrial dysfunction, muscle fibers with ragged red fibers also show excessive SDH staining and reduced or absent COX staining. Although ragged red fibers are typically seen in mitochondrial myopathies, they may occur in other conditions such as inclusion body myositis or could be normal.

Silvestri N and Wolfe GI: Asymptomatic/Pauci-symptomatic creatine kinase elevations (HyperCKemia). Muscle Nerve 47: 805–815, 2013.

How are inflammatory myopathies classified?

• Dermatomyositis

• Polymyositis

• Immune-mediated necrotizing myopathy

• Inclusion body myositis (IBM)

What are the clinical features of polymyositis (PM) and dermatomyositis (DM)?

Although PM is an adult disease, DM occurs in both children and adults. Patients with PM or DM develop symmetric proximal muscle weakness progressive over weeks to months. Pharyngeal or diaphragmatic weakness is common. EMG shows low-amplitude, small myopathic units with evidence of fibrillation potentials and/or positive sharp waves. CK is usually markedly elevated. Magnetic resonance imaging of affected muscles can show increased T2 signal secondary to edema, inflammation, or fibrotic replacement.

Unique to DM are cutaneous manifestations that typically present at the same time as the weakness. A purplish discoloration involving the eyelids, cheeks and nose (heliotrope rash), or an erythematous rash often seen on the knuckles (Gottron’s papules), are both pathognomonic for DM. A rash on the neck and upper chest (V sign), shoulders (shawl sign), or extensor surfaces of elbows, knees, hips, and medial malleoli (Gottron’s sign) can also be seen. The rash often worsens with exposure to sunlight. Skin may become scaly and atrophic, and the nail beds may appear shiny and red. Subcutaneous calcification over pressure points is more common in juvenile-onset DM.

Patients can develop symptomatic systemic involvement, including fever, weight loss, cardiac arrhythmias and conduction abnormalities, interstitial lung disease (10% to 20%), conjunctivitis/uveitis, calcinosis, and gastrointestinal (GI) abnormalities. Myositis-specific autoantibodies ( Table 4-1 ), found in 60% to 80% of patients with autoimmune myopathies, can help diagnose as well as predict systemic involvement. The most common is antisynthetase syndrome, most associated with the presence of anti-Jo-1 antibody. These patients have a constellation of clinical symptoms including autoimmune myopathy, interstitial lung disease (ILD), nonerosive arthritis, fever, and “mechanic’s hands,” hyperkeratotic lesions on the palmar fingers.

Both PM and DM also have been associated with malignancies, in particular lung, GI, breast, and ovarian cancers. All patients with DM or PM should be screened for malignancy.

Mammen AL: Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis. Nat Rev Neurol 7, 343–354, 2011.

What are the major pathologic changes on light microscopy in the muscle biopsies of patients with PM and DM?

Both PM and DM have the following ( Figs 4-4 and 4-5 ):

• Variation and rounding of muscle fibers; occasional angular and atrophic fibers

• Fiber necrosis, phagocytosis

• Inflammatory infiltrate:

  • In DM, perivascular and perimysial inflammation composed of macrophages, B cells, and CD4 ⁺ dendritic cells

  • In PM, nonnecrotic endomysial inflammation composed of CD8 ⁺ T cells and macrophages

What does the muscle biopsy in Fig. 4-5 signify?

This is the typical finding of perifascicular atrophy. The muscle fibers at the periphery of the muscle fascicles are smaller, whereas the fibers in the deepest part of the fascicle are of normal size. This type of atrophy is suggestive of DM. Even in the absence of inflammation, this biopsy is characteristic.

How are DM and PM treated?

Corticosteroids are considered first-line treatment usually starting with 1 mg/kg/day followed by a taper 4 weeks to several months after initiation. If there is either no improvement with steroids or the steroids cannot be tapered, treatment with a second-line agent, usually intravenous immunoglobulin (IVIG), azathioprine, or methotrexate should be started. Mycophenolate mofetil, tacrolimus, rituximab, cyclosporine, and cyclophosphamide can be used as well. The choice often depends on extramuscular involvement as well as side effects.

What is inclusion body myositis (IBM)?

IBM is the most common cause of acquired chronic myopathy in patients age 50 years and older. Characteristically, there is insidious onset of painless weakness and atrophy involving the quadriceps, finger flexors, and foot dorsiflexors. Dysphagia is common. There is early loss of patellar reflexes, and a mild neuropathy may be present. CK levels are either normal or only mildly elevated. Electrodiagnostic evaluation reveals mixed myopathic and neurogenic changes. Muscle biopsy shows invasion of nonnecrotic fibers by mononuclear cells, cytoplasmic “rimmed” vacuoles and eosinophilic inclusion bodies, and small angular atrophic and denervated fibers sometimes with mitochondrial dysfunction ( Fig. 4-6 ). Despite the evident inflammation, IBM is resistant to conventional immunotherapies and is felt to be more likely a myodegenerative condition. One-third of cases appear stable or show improvement for periods of 6 months or more. Cricopharyngeal myotomy might be beneficial in cases of dysphagia and might delay the need for a percutaneous endoscopic gastrostomy.

What is immune-mediated necrotizing myopathy?

Patients present with acute or subacute proximal weakness and myalgia with markedly elevated CK and scattered necrotic muscle fibers with only sparse inflammatory cell infiltration on muscle biopsy. The myopathy may be secondary to an underlying connective tissue disease (most commonly scleroderma or mixed connective tissue disease) or cancer but most are likely triggered by statin use. These patients require treatment with immunosuppressive agents.