Skeletal muscle diseases, or myopathies, are disorders with structural changes or functional impairment of muscle. These conditions can be differentiated from other diseases of the motor unit (e.g., lower motor neuron or neuromuscular junction pathologies) by characteristic clinical and laboratory findings.
Myasthenia gravis and related disorders are discussed in Chap. 386; dermatomyositis, polymyositis, and inclusion body myositis are discussed in Chap. 388.
Most myopathies present with proximal, symmetric limb weakness (arms or legs) with preserved reflexes and sensation. However, asymmetric and predominantly distal weakness can be seen in some myopathies. An associated sensory loss suggests injury to peripheral nerve or the central nervous system (CNS) rather than myopathy. On occasion, disorders affecting the motor nerve cell bodies in the spinal cord (anterior horn cell disease), the neuromuscular junction, or peripheral nerves can mimic findings of myopathy.
Symptoms of muscle weakness can be either intermittent or persistent. Disorders causing intermittent weakness (Fig. 387-1) include myasthenia gravis, periodic paralyses (hypokalemic, hyperkalemic, and paramyotonia congenita), and metabolic energy deficiencies of glycolysis (especially myophosphorylase deficiency), fatty acid utilization (carnitine palmitoyltransferase deficiency), and some mitochondrial myopathies. The states of energy deficiency cause activity-related muscle breakdown accompanied by myoglobinuria, appearing as light-brown- to dark-brown-colored urine.
Diagnostic evaluation of intermittent weakness. AChR AB, acetylcholine receptor antibody; CPT, carnitine palmitoyltransferase; EOMs, extraocular muscles; MG, myasthenia gravis; PP, periodic paralysis.
Most muscle disorders cause persistent weakness (Fig. 387-2). In the majority of these, including most types of muscular dystrophy, polymyositis, and dermatomyositis, the proximal muscles are weaker than the distal and are symmetrically affected, and the facial muscles are spared, a pattern referred to as limb-girdle. The differential diagnosis is more restricted for other patterns of weakness. Facial weakness (difficulty with eye closure and impaired smile) and scapular winging (Fig. 387-3) are characteristic of facioscapulohumeral dystrophy (FSHD). Facial and distal limb weakness associated with hand grip myotonia is virtually diagnostic of myotonic dystrophy type 1. When other cranial nerve muscles are weak, causing ptosis or extraocular muscle weakness, the most important disorders to consider include neuromuscular junction disorders, oculopharyngeal muscular dystrophy, mitochondrial myopathies, or some of the congenital myopathies (Table 387-1). A pathognomonic pattern characteristic of inclusion body myositis is atrophy and weakness of the flexor forearm (e.g., wrist and finger flexors) and quadriceps muscles that is often asymmetric. Less frequently, but important diagnostically, is the presence of a dropped head syndrome indicative of selective neck extensor muscle weakness. The most important neuromuscular diseases associated with this pattern of weakness include myasthenia gravis, amyotrophic lateral sclerosis, late-onset nemaline myopathy, hyperparathyroidism, focal myositis, and some forms of inclusion body myopathy. A final pattern, recognized because of preferential distal extremity weakness, is typical of a unique category of muscular dystrophy, the distal myopathies.
Diagnostic evaluation of persistent weakness. Examination reveals one of seven patterns of weakness. The pattern of weakness in combination with the laboratory evaluation leads to a diagnosis. EOMs, extraocular muscles; OPMD, oculopharyngeal muscular dystrophy; FSHD, facioscapulohumeral dystrophy; IBM, inclusion body myositis; DM, dermatomyositis; PM, polymyositis; MG, myasthenia gravis; ALS, amyotrophic lateral sclerosis; CK, creatine kinase; EMG, electromyography.
Facioscapulohumeral dystrophy with prominent scapular winging.
Table 387-1 Neuromuscular Causes of Ptosis or Ophthalmoplegia |Favorite Table|Download (.pdf)
Table 387-1 Neuromuscular Causes of Ptosis or Ophthalmoplegia
|Progressive external ophthalmoplegia|
|Oculopharyngeal and oculopharyngodistal muscular dystrophy|
|Myotonic dystrophy (ptosis only)|
|Nemaline (ptosis only)|
|Hyperthyroidism/Graves' disease (ophthalmoplegia without ptosis)|
|Hereditary inclusion body myopathy type 3|
It is important to examine functional capabilities to help disclose certain patterns of weakness (Table 387-2). The Gowers' sign (Fig. 387-4) is particularly useful. Observing the gait of an individual may disclose a lordotic posture caused by combined trunk and hip weakness, frequently exaggerated by toe walking (Fig. 387-5). A waddling gait is caused by the inability of weak hip muscles to prevent hip drop or hip dip. Hyperextension of the knee (genu recurvatum or back-kneeing) is characteristic of quadriceps muscle weakness; and a steppage gait, due to footdrop, accompanies distal weakness.
Table 387-2 Observations on Examination That Disclose Muscle Weakness |Favorite Table|Download (.pdf)
Table 387-2 Observations on Examination That Disclose Muscle Weakness
|Functional Impairment||Muscle Weakness|
|Inability to forcibly close eyes||Upper facial muscles|
|Impaired pucker||Lower facial muscles|
|Inability to raise head from prone position||Neck extensor muscles|
|Inability to raise head from supine position||Neck flexor muscles|
|Inability to raise arms above head||Proximal arm muscles (may be only scapular stabilizing muscles)|
|Inability to walk without hyperextending knee (back-kneeing or genu recurvatum)||Knee extensor muscles|
|Inability to walk with heels touching the floor (toe walking)||Shortening of the Achilles tendon|
|Inability to lift foot while walking (steppage gait or footdrop)||Anterior compartment of leg|
|Inability to walk without a waddling gait||Hip muscles|
|Inability to get up from the floor without climbing up the extremities (Gowers' sign)||Hip, thigh, and trunk muscles|
|Inability to get up from a chair without using arms||Hip muscles|
Gowers' sign showing a patient using arms to climb up the legs in attempting to get up from the floor.
Lordotic posture, exaggerated by standing on toes, associated with trunk and hip weakness.
Any disorder causing muscle weakness may be accompanied by fatigue, referring to an inability to maintain or sustain a force (pathologic fatigability). This condition must be differentiated from asthenia, a type of fatigue caused by excess tiredness or lack of energy. Associated symptoms may help differentiate asthenia and pathologic fatigability. Asthenia is often accompanied by a tendency to avoid physical activities, complaints of daytime sleepiness, necessity for frequent naps, and difficulty concentrating on activities such as reading. There may be feelings of overwhelming stress and depression. Thus, asthenia is not a myopathy. In contrast, pathologic fatigability occurs in disorders of neuromuscular transmission and in disorders altering energy production, including defects in glycolysis, lipid metabolism, or mitochondrial energy production. Pathologic fatigability also occurs in chronic myopathies because of difficulty accomplishing a task with less muscle. Pathologic fatigability is accompanied by abnormal clinical or laboratory findings. Fatigue without those supportive features almost never indicates a primary muscle disease.
Muscle Pain (Myalgias), Cramps, and Stiffness
Muscle pain can be associated with cramps, spasms, contractures, and stiff or rigid muscles. In distinction, true myalgia (muscle aching), which can be localized or generalized, may be accompanied by weakness, tenderness to palpation, or swelling. Certain drugs cause true myalgia (Table 387-3).
Table 387-3 Drugs That Cause True Myalgia
There are two painful muscle conditions of particular importance, neither of which is associated with muscle weakness. Fibromyalgia is a common, yet poorly understood, type of myofascial pain syndrome. Patients complain of severe muscle pain and tenderness and have specific painful trigger points, sleep disturbances, and easy fatigability. Serum creatine kinase (CK), erythrocyte sedimentation rate (ESR), electromyography (EMG), and muscle biopsy are normal (Chap. 335). Polymyalgia rheumatica occurs mainly in patients >50 years and is characterized by stiffness and pain in the shoulders, lower back, hips, and thighs (Chap. 326). The ESR is elevated, while serum CK, EMG, and muscle biopsy are normal. Temporal arteritis, an inflammatory disorder of medium- and large-sized arteries, usually involving one or more branches of the carotid artery, may accompany polymyalgia rheumatica. Vision is threatened by ischemic optic neuritis. Glucocorticoids can relieve the myalgias and protect against visual loss.
Localized muscle pain is most often traumatic. A common cause of sudden abrupt-onset pain is a ruptured tendon, which leaves the muscle belly appearing rounded and shorter in appearance compared to the normal side. The biceps brachii and Achilles tendons are particularly vulnerable to rupture. Infection or neoplastic infiltration of the muscle is a rare cause of localized muscle pain.
A muscle cramp or spasm is a painful, involuntary, localized, muscle contraction with a visible or palpable hardening of the muscle. Cramps are abrupt in onset, short in duration, and may cause abnormal posturing of the joint. The EMG shows firing of motor units, reflecting an origin from spontaneous neural discharge. Muscle cramps often occur in neurogenic disorders, especially motor neuron disease (Chap. 374), radiculopathies, and polyneuropathies (Chap. 384), but are not a feature of most primary muscle diseases. Duchenne's muscular dystrophy is an exception since calf muscle complaints are a common complaint. Muscle cramps are also common during pregnancy.
A muscle contracture is different from a muscle cramp. In both conditions, the muscle becomes hard, but a contracture is associated with energy failure in glycolytic disorders. The muscle is unable to relax after an active muscle contraction. The EMG shows electrical silence. Confusion is created because contracture also refers to a muscle that cannot be passively stretched to its proper length (fixed contracture) because of fibrosis. In some muscle disorders, especially in Emery-Dreifuss muscular dystrophy and Bethlem's myopathy, fixed contractures occur early and represent distinctive features of the disease.
Muscle stiffness can refer to different phenomena. Some patients with inflammation of joints and periarticular surfaces feel stiff. This condition is different from the disorders of hyperexcitable motor nerves causing stiff or rigid muscles. In stiff-person syndrome, spontaneous discharges of the motor neurons of the spinal cord cause involuntary muscle contractions mainly involving the axial (trunk) and proximal lower extremity muscles. The gait becomes stiff and labored, with hyperlordosis of the lumbar spine. Superimposed episodic muscle spasms are precipitated by sudden movements, unexpected noises, and emotional upset. The muscles relax during sleep. Serum antibodies against glutamic acid decarboxylase are present in approximately two-thirds of cases. In neuromyotonia (Isaac's syndrome) there is hyperexcitability of the peripheral nerves manifesting as continuous muscle fiber activity. Myokymia (groups of fasciculations associated with continuous undulations of muscle) and impaired muscle relaxation are the result. Muscles of the leg are stiff, and the constant contractions of the muscle cause increased sweating of the extremities. This peripheral nerve hyperexcitability is mediated by antibodies that target voltage-gated potassium channels. The site of origin of the spontaneous nerve discharges is principally in the distal portion of the motor nerves.
Myotonia is a condition of prolonged muscle contraction followed by slow muscle relaxation. It always follows muscle activation (action myotonia), usually voluntary, but may be elicited by mechanical stimulation (percussion myotonia) of the muscle. Myotonia typically causes difficulty in releasing objects after a firm grasp. In myotonic muscular dystrophy type 1 (DM1), distal weakness usually accompanies myotonia, whereas in DM2 proximal muscles are more affected; thus the related term proximal myotonic myopathy (PROMM) is used to describe this condition. Myotonia also occurs with myotonia congenita (a chloride channel disorder), but in this condition muscle weakness is not prominent. Myotonia may also be seen in individuals with sodium channel mutations (hyperkalemic periodic paralysis or potassium-sensitive myotonia). Another sodium channelopathy, paramyotonia congenita, also is associated with muscle stiffness. In contrast to other disorders associated with myotonia in which the myotonia is eased by repetitive activity, paramyotonia congenita is named for a paradoxical phenomenon whereby the myotonia worsens with repetitive activity.
Muscle Enlargement and Atrophy
In most myopathies muscle tissue is replaced by fat and connective tissue, but the size of the muscle is usually not affected. However, in many limb-girdle muscular dystrophies (and particularly the dystrophinopathies) enlarged calf muscles are typical. The enlargement represents true muscle hypertrophy, thus the term pseudohypertrophy should be avoided when referring to these patients. The calf muscles remain very strong even late in the course of these disorders. Muscle enlargement can also result from infiltration by sarcoid granulomas, amyloid deposits, bacterial and parasitic infections, and focal myositis. In contrast, muscle atrophy is characteristic of other myopathies. In dysferlinopathies (LGMD2B), there is a predilection for early atrophy of the gastrocnemius muscles, particularly the medial aspect. Atrophy of the humeral muscles is characteristic of facioscapulohumeral dystrophy (FSHD).
A limited battery of tests can be used to evaluate a suspected myopathy. Nearly all patients require serum enzyme level measurements and electrodiagnostic studies as screening tools to differentiate muscle disorders from other motor unit diseases. The other tests described—DNA studies, the forearm exercise test, and muscle biopsy—are used to diagnose specific types of myopathies.
CK is the preferred muscle enzyme to measure in the evaluation of myopathies. Damage to muscle causes the CK to leak from the muscle fiber to the serum. The MM isoenzyme predominates in skeletal muscle, while creatine kinase-myocardial bound (CK-MB) is the marker for cardiac muscle. Serum CK can be elevated in normal individuals without provocation, presumably on a genetic basis or after strenuous activity, minor trauma (including the EMG needle), a prolonged muscle cramp, or a generalized seizure. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), aldolase, and lactic dehydrogenase (LDH) are enzymes sharing an origin in both muscle and liver. Problems arise when the levels of these enzymes are found to be elevated in a routine screening battery, leading to the erroneous assumption that liver disease is present when in fact muscle could be the cause. An elevated γ-glutamyl transferase (GGT) helps to establish a liver origin since this enzyme is not found in muscle.
EMG, repetitive nerve stimulation, and nerve conduction studies (Chap. e45) are essential methods for evaluation of the patient with suspected muscle disease. In combination, they provide the information necessary to differentiate myopathies from neuropathies and neuromuscular junction diseases. Routine nerve conduction studies are typically normal in myopathies but reduced amplitudes of compound muscle action potentials may be seen in atrophied muscles. The needle EMG may reveal irritability on needle placement suggestive of a necrotizing myopathy (inflammatory myopathies, dystrophies, toxic myopathies, myotonic myopathies), whereas a lack of irritability is characteristic of long-standing myopathic disorders (muscular dystrophies, endocrine myopathies, disuse atrophy, and many of the metabolic myopathies). In addition, the EMG may demonstrate myotonic discharges that will narrow the differential diagnosis (Table 387-4). Another important EMG finding is the presence of short-duration, small-amplitude, polyphasic motor unit action potentials (MUAPs). Such MUAPs can be seen in both myopathic and neuropathic disorders; however, the recruitment or firing pattern is different. In myopathies, the MUAPs fire early but at a normal rate to compensate for the loss of individual muscle fibers, whereas in neurogenic disorders the MUAPs fire faster. The EMG is usually normal in steroid or disuse myopathy, both of which are associated with type 2 fiber atrophy; this is because the EMG preferentially assesses the physiologic function of type 1 fibers. The EMG can also be invaluable in helping to choose an appropriately affected muscle to sample for biopsy.
Table 387-4 Myotonic Disorders |Favorite Table|Download (.pdf)
Table 387-4 Myotonic Disorders
|Myotonic dystrophy type 1|
|Myotonic dystrophy type 2/proximal myotonic myopathy|
|Hyperkalemic periodic paralysis|
|Chondrodystrophic myotonia (Schwartz-Jampel syndrome)|
|Cholesterol-lowering agents (statin medications, fibrates)|
|Glycogen storage disordersa (Pompe's disease, debrancher deficiency, branching enzyme deficiency)|
This serves as an important tool for the definitive diagnosis of many muscle disorders. Nevertheless, there are a number of limitations in currently available molecular diagnostics. For example, in Duchenne's and Becker's dystrophies, two-thirds of patients have deletion or duplication mutations that are easy to detect, while the remainder have point mutations that are much more difficult to find. For patients without identifiable gene defects, the muscle biopsy remains the main diagnostic tool.
In myopathies with intermittent symptoms, and especially those associated with myoglobinuria, there may be a defect in glycolysis. Many variations of the forearm exercise test exist. For safety, the test should not be performed under ischemic conditions to avoid an unnecessary insult to the muscle, causing rhabdomyolysis. The test is performed by placing a small indwelling catheter into an antecubital vein. A baseline blood sample is obtained for lactic acid and ammonia. The forearm muscles are exercised by asking the patient to vigorously open and close the hand for 1 minute. Blood is then obtained at intervals of 1, 2, 4, 6, and 10 minutes for comparison with the baseline sample. A three- to fourfold rise of lactic acid is typical. The simultaneous measurement of ammonia serves as a control, since it should also rise with exercise. In patients with myophosphorylase deficiency or other glycolytic defects, the lactic acid rise will be absent or below normal, while the rise in ammonia will reach control values. If there is lack of effort, neither lactic acid nor ammonia will rise. Patients with selective failure to increase ammonia may have myoadenylate deaminase deficiency. This condition has been reported to be a cause of myoglobinuria, but deficiency of this enzyme in asymptomatic individuals makes interpretation controversial.
Muscle biopsy is an important step in establishing the diagnosis of a suspected myopathy. The biopsy is usually obtained from a quadriceps or biceps brachii muscle, less commonly from a deltoid muscle. Evaluation includes a combination of techniques—light microscopy, histochemistry, immunocytochemistry with a battery of antibodies, and electron microscopy. Not all techniques are needed for every case. A specific diagnosis can be established in many disorders. Endomysial inflammatory cells surrounding and invading muscle fibers are seen in polymyositis; similar endomysial infiltrates associated with muscle fibers containing rimmed vacuoles, amyloid deposits within fibers, and TDP-43 inclusions are characteristic of inclusion body myositis; while perivascular, perimysial inflammation associated with perifascicular atrophy are features of dermatomyositis. In addition, the congenital myopathies have distinctive light and electron microscopy features essential for diagnosis. Mitochondrial and metabolic (e.g., glycogen and lipid storage diseases) myopathies also demonstrate distinctive histochemical and electron-microscopic profiles. Biopsied muscle tissue can be sent for metabolic enzyme or mitochondrial DNA analyses. A battery of antibodies is available for the identification of missing components of the dystrophin-glycoprotein complex and related proteins to help diagnose specific types of muscular dystrophies. Western blot analysis on muscle specimens can be performed to determine whether specific muscle proteins are reduced in quantity or are of abnormal size.