Clinical Approach to Muscle Diseases

Carlayne E. Jackson, M.D.


Semin Neurol. 2008;28(2):228-240. 

In This Article

Clinical Evaluation

Despite the tremendous increase in the number and sophistication of diagnostic tests, the most important element of evaluating a patient with a suspected muscle disease remains a thorough history and physical examination.[1] The history should allow the physician to make a reasonable preliminary diagnosis that places the patient into one of the categories in Table 1 . The findings on the physical examination, particularly the distribution of muscle weakness, should provide additional information in determining the correct diagnosis. Many muscle diseases have features so characteristic that they can be diagnosed with relative certainty at the bedside. The results of laboratory studies, including creatine kinase, electrodiagnostic studies, muscle biopsy, and/or molecular genetic studies should play a confirmatory diagnostic role rather than serving as a “fishing expedition.”

Although the basic components of the history are similar for patients with other medical conditions, certain features are unique to the patient with a suspected myopathy. Therefore, the first step is to ask six key questions based on specific symptoms and signs that may direct the clinician to the correct diagnosis.

Symptoms and signs of muscle disease ( Table 2 ) can be divided into “positive” complaints, such as myalgias, cramps, contractures, myoglobinuria, and muscle stiffness, and “negative” complaints, such as weakness, exercise intolerance, fatigue, and muscle atrophy. Myalgia, like fatigue, is a nonspecific symptom of some myopathies[2] ( Table 3 ). Diffuse myalgia may occur with viral infection or in association with polymyositis, dermatomyositis, toxic or infectious myopathies, and a few rare endocrine myopathies. Myalgias, which occur episodically in association with exercise, may suggest a metabolic myopathy. However, muscle pain is usually not associated with most other muscle diseases, and is more likely to be due to orthopedic, psychiatric, or rheumato-logical disorders. It is rare for a muscle disease to cause vague aches and muscle discomfort in the presence of a normal neuromuscular examination and laboratory studies.[3]

A specific type of muscle pain is the involuntary muscle cramp. Unlike contractures, cramps may occur at rest, last from seconds to minutes, and often be localized to a particular muscle region. They are typically benign, occurring frequently in normal individuals, and are seldom a feature of a primary myopathy. Cramps are characterized by rapidly firing motor unit discharges on needle electromyography similar to a maximal contraction.[4] Cramps can occur with dehydration, hyponatremia, azotemia, hypothyroidism, adrenal insufficiency, renal/hepatic failure, and pregnancy, as well as in peripheral neuropathies, radiculopathies, and motor neuron diseases.

Muscle contractures are uncommon but can superficially resemble a cramp. They are typically provoked by exercise in patients with glycolytic enzyme defects. Contractures differ from cramps in that they may persist for hours and are electrically silent with needle electromyography. Muscle disorders that are associated with contractures are listed in Table 4 .

Myotonia is a phenomenon of impaired relaxation of muscle after forceful voluntary contraction and most commonly involves the hands and eyelids. Myotonia is due to repetitive depolarization of the muscle membrane and is characterized on electrophysiological studies by waxing and waning rhythmical discharges. Patients may complain of muscle stiffness or tightness resulting in difficulty releasing their handgrip after a handshake, unscrewing a bottle top, or opening their eyelids if they forcefully shut their eyes. Myotonia classically improves with repeated exercise. In contrast, patients with paramyotonia congenita demonstrate “paradoxical myotonia” in that symptoms are typically worsened by exercise or repeated muscle contractions. Exposure to cold results in worsening of both myotonia and paramyotonia. The muscle disorders associated with muscle stiffness are listed in Table 5 .

Myoglobinuria is a relatively uncommon manifestation of muscle disease and is caused by the excessive release of myoglobin from muscle during periods of rapid muscle destruction (rhabdomyolysis). Severe myoglobinuria can result in renal failure due to acute tubular necrosis. Patients who complain of exercise-induced weakness and myalgias should be asked if their urine has ever turned coke-colored or red during or after these episodes. Recurrent myoglobinuria is usually due to an underlying metabolic myopathy ( Table 6 ), whereas isolated episodes, particularly those occurring after unaccustomed strenuous exercise, are frequently idiopathic.

Weakness is by far the most common negative symptom reported by a patient with muscle disease. If the weakness involves the lower extremities, patients will complain of difficulty going up or down stairs, arising from a chair or toilet, arising from a squatted position, or getting off of the floor. When the upper extremities are involved, patients notice trouble lifting objects over their head, reaching to get things from top shelves, brushing teeth, shaving, dressing, and brushing their hair. These symptoms in the arms and legs indicate proximal muscle weakness, which is probably the most common site of weakness in a myopathic disorder (discussed later). Less commonly, patients with myopathies can complain of distal weakness manifested as difficulty opening jars, buttoning clothes, or turning a key in the ignition. Patients with distal lower extremity weakness may complain of tripping over curbs, difficulty walking on uneven ground or “foot slapping.” Some myopathies may also result in cranial muscle weakness resulting in complaints of dysarthria, dysphagia, or ptosis.

Fatigue is a much less useful negative symptom because it is nonspecific and may reflect a patient's cardiopulmonary status, level of conditioning, overall health, sleeping habits or emotional state.[4,5] Many patients who complain of diffuse global weakness or fatigue do not have a disorder of muscle, particularly if the neurological examination is normal. On the other hand, abnormal fatigability after exercise can result from certain metabolic and mitochondrial myopathies and neuromuscular junction disorders, and it is important to define the duration and intensity of exercise that provokes the fatigue.

A history of precipitating factors that might trigger or exacerbate symptoms of weakness or myotonia should be explored. It is important to ask the patient if there is any history of either illegal drug or prescription medication use that might produce a myopathy. A history of weakness, pain, and/or myoglobinuria, which is provoked by exercise, might suggest the possibility of a glycolytic pathway defect. Episodes of weakness, which occur in association with a fever, would be supportive of a diagnosis of carnitine palmityl transferase deficiency. Attacks of periodic paralysis are characteristically provoked by exercise and ingestion of a carbohydrate meal followed by a period of rest. Patients with paramyotonia congenita frequently report that cold exposure may precipitate their symptoms of muscle stiffness.

Because many myopathies are inherited, obtaining a thorough family history is obviously of great importance in making a correct diagnosis. A detailed family tree should be completed to look for evidence of autosomal-dominant, autosomal-recessive, and X-linked patterns of transmission. Questions regarding family members’ use of canes or wheelchairs, skeletal deformities, functional limitations, and associated medical conditions are usually more informative than vague questions such as, “Does any member of your family have a muscle disease?” Particularly in some autosomal-dominant disorders, such as myotonic dystrophy and facioscapulohumeral (FSH) dystrophy, phenotypic variability may be such that even affected parents can be asymptomatic. In this situation, examination of other family members may be necessary to distinguish an acquired from a hereditary disorder. Identifying a particular hereditary pattern cannot only help in correctly diagnosing the specific myopathy ( Table 7 ), but is also of tremendous importance in providing appropriate genetic counseling.

It is obviously important to determine the onset, duration, and evolution of the patient's symptoms and signs of muscle disease. Did the weakness (or other symptoms) first manifest at birth or was the onset in the first, second, third, or later decade ( Table 8 )? Identifying the age that symptoms began can provide crucial information leading to the correct diagnosis. For example, symptoms of Duchenne's muscular dystrophy usually are identified by 3 years of age, whereas most FSH and limb-girdle muscular dystrophies (LGMDs) begin in adolescence or later. Of the inflammatory myopathies, dermatomyositis occurs in children and adults, polymyositis rarely occurs in children but at any decade in the adult years, and inclusion body myositis occurs most commonly in the elderly.

It is also imperative to determine the evolution and duration of the disease. Myopathies can present with either constant weakness (muscular dystrophies, inflammatory myopathies) or episodic periods of weakness with normal strength interictally (periodic paralysis, metabolic myopathies due to certain glycolytic pathway disorders). The episodic disorders have acute weakness that can return to normal strength within hours or days. Patients presenting with fluctuating weakness that is provoked by fatigue may also have a neuromuscular junction disorder. The tempo of the disorders with constant weakness can vary from: (1) acute or subacute progression in some inflammatory myopathies (dermatomyositis and polymyositis), (2) chronic slow progression over years (most muscular dystrophies), or (3) nonprogressive weakness with little change over decades (congenital myopathies). Finally, both constant and episodic myopathic disorders can have symptoms that may be monophasic or relapsing. For example, polymyositis can occasionally have an acute monophasic course with complete resolution of strength within weeks or months. Patients with periodic paralysis or metabolic myopathies can have recurrent attacks of weakness over many years, whereas a patient with acute rhabdomyolysis due to cocaine may have a single episode.

Involvement of organs or tissues other than muscle may also provide helpful clues in making the appropriate diagnosis. Respiratory failure may be the presenting symptom of myotonic dystrophy, centronuclear myopathy, nemaline myopathy, or acid maltase deficiency ( Table 9 ).[6,7,8] Eventually, most myopathies will affect respiratory muscle strength, highlighting the need for consistent monitoring of pulmonary function studies throughout the disease course. The earliest manifestations of hypoventilation usually result in frequent nocturnal arousals, morning headaches, excessive daytime sleepiness, and vivid dreams. Patients usually do not report dyspnea or orthopnea until the forced vital capacity falls below 50% of predicted. Once symptoms of hypoventilation are evident, supportive care with noninvasive positive pressure ventilation and assistive devices for clearance of upper airway secretions should be employed.

Cardiac disease, in the form of congestive heart failure or arrhythmias, is a common feature of many myopathies ( Table 10 ) including: myotonic dystrophy, Duchenne's or Becker's muscular dystrophies, LGMD 1B (laminopathy), LGMD 2I (fukutin-related protein [FKRP]), LGMD 2C-F (sarcoglycanopathies), LGMD 2G (telethoninopathy), Emery-Dreifuss muscular dystrophy, and Andersen's syndrome. It is critical to identify cardiac disease early because it may be amenable to therapy, including afterload reduction and pacemakers.

Hepatomegaly may be seen in myopathies associated with deficiencies in acid maltase, debranching enzyme, and carnitine. The presence of cataracts, frontal balding, and mental retardation strongly suggests the diagnosis of myotonic dystrophy. Optic atrophy and/or pigmentary retinopathy may be associated with a mitochondrial myopathy. The presence of a rash is extremely helpful in confirming the diagnosis of dermatomyositis and vasculitis, and multiple lipomas may lead to a diagnosis of a mitochondrial disorder. Musculoskeletal contractures can occur in many myopathies of longstanding duration. However, contractures developing early in the course of the disease, especially at the elbows, can be a clue to Emery-Dreifuss dystrophy, LGMD 1B (laminopathy), and Bethlem myopathy.

Central nervous system (CNS) involvement is frequently seen in the mitochondrial myopathies and may include strokelike episodes, headache, myoclonus, epilepsy, deafness, ataxia, and encephalopathy. CNS involvement in the form of a lower intelligence quotient occurs in some patients with Duchenne's dystrophy and in congenital myotonic dystrophy. Magnetic resonance imaging (MRI) in congenital muscular dystrophy with laminin α-2 chain deficiency shows hypomyelination, but patients rarely have intellectual impairment.[9] Peripheral nervous system (PNS) involvement can occur in some myopathies as well; in these rare situations, the differential diagnosis is rather limited ( Table 11 ) and includes alcohol abuse, amyloidosis, sarcoidosis, collagen vascular disorders, endocrine disorders, HIV infection, malnutrition, and mitochondrial myopathies.

The distribution of weakness is in many respects the most essential information to be determined from the history and physical examination, as it provides critical clues to the diagnosis. To determine the distribution of muscle weakness, it is important to know which muscles to test and how to grade their power. Muscle strength can be tested by manual testing and from observation of functional activity ( Table 12 ). Functional testing is particularly informative in young children, who cannot usually cooperate with formal manual muscle testing, and in adults with “give-way” weakness who present with complaints of muscle pain.[10]

In performing manual muscle testing of the upper extremities, it is necessary to assess shoulder abduction, external and internal rotation; elbow flexion and extension; wrist flexion and extension; and finger and thumb extension, flexion, and abduction. Muscle groups that should be tested in the lower extremities include hip flexion, extension, and abduction; knee flexion and extension; ankle dorsiflexion, plantar flexion, inversion, and eversion; and toe extension and flexion. All muscle groups should be tested bilaterally, and preferably against gravity. Neck flexors should be assessed in the supine position and neck extensors in the prone position. Knee extension and hip flexion should be tested in the seated position, knee flexion should be tested prone, and hip abduction should be tested in the lateral decubitus position. If testing against gravity is not done, the presence of significant muscle weakness can escape recognition. Assessment of muscle strength is usually based on the expanded MRC (Medical Research Council of Great Britain) grading scale of 0 to 5 ( Table 13 ).[11]

Finally, cranial nerve muscles such as the orbicularis oculi and oris, extraocular muscles, tongue, mass-eters, and palate should be examined. These may be best tested by observation of functional activities such as asking the patient to whistle, suck from a straw, and smile broadly. Mild ptosis may be subtle and difficult to detect on examination, and some patients may tilt their head backward, raise their eyebrows or wrinkle their foreheads in an attempt to compensate. When assessing ptosis and extraocular muscle function, it is also critical to check for fatigability. Evaluating the patient's speech is also an excellent method for assessing palatal and tongue strength. Palatal weakness produces speech that is nasal, with difficulty pronouncing sounds such as k and the hard g. In contrast, tongue weakness produces slurred speech, and patients have difficulty with sounds such as d, l, n, and t. Swallowing can be assessed by timing how long it takes to swallow a certain amount of fluid or by documenting the number of swallows taken.

In addition to manual muscle testing and functional testing, muscles should be inspected for evidence of atrophy or hypertrophy. Atrophy of proximal limb muscles is common in most chronic myopathies. However, certain myopathies may demonstrate atrophy in specific groups that correspond to severe weakness in those muscles and provide additional diagnostic clues. For example, atrophy of the parascapular muscles associated with scapular winging is characteristic of FSH dystrophy. Scapular winging is also seen in patients with LGMD 1B (laminopathy), LGMD 2A (calpainopathy), and LGMD 2C-F (sarcoglycanopathies). Selective atrophy of the quadriceps muscles and forearm flexor muscles is highly suggestive of inclusion body myositis. Distal myopathies may have profound atrophy of the anterior or posterior lower extremity compartments. On the other hand, muscles can show evidence of hyper-trophy in some myotonic conditions such as myotonia congenita and neuromyotonia. Muscle hypertrophy is also characteristic of disorders including amyloidosis, sarcoidosis, debrancher enzyme deficiency, and hypothyroid myopathy. In Duchenne's and Becker's dystrophy, the calf muscles demonstrate “pseudohypertrophy” due to replacement with connective tissue and fat. Calf muscle hypertrophy is also characteristically seen in LGMD 2C-F (sarcoglycanopathies) and LGMD 2I (FKRP). In LGMD 2G (telethoninopathy), 50% of patients will show calf hypertrophy and 50% will have calf atrophy.[12] Focal muscle enlargement can also be due to a neoplastic or inflammatory process, ectopic ossification, tendon rupture, or partial denervation.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.