Muscle weakness is a common complaint among patients presenting to the family physician’s office. Although the cause of weakness occasionally may be apparent, often it is unclear, puzzling the physician and frustrating the patient. A comprehensive evaluation of these patients includes a thorough examination and coordination of appropriate laboratory, radiologic, electrodiagnostic, and pathologic studies.

Definitions

Determining the cause of muscle weakness involves distinguishing primary weakness from fatigue or asthenia, common conditions that differ from, but often overlap with, muscle weakness.¹ Fatigue describes the inability to continue performing a task after multiple repetitions; in contrast, a patient with primary weakness is unable to perform the first repetition of the task. Asthenia is a sense of weariness or exhaustion in the absence of muscle weakness. This condition is common in people who have chronic fatigue syndrome, sleep disorders, depression, or chronic heart, lung, and kidney disease.¹ Because these conditions are prevalent in the ambulatory population, family physicians can expect to encounter patients with asthenia and fatigue more frequently than those with intrinsic muscle weakness.¹ Selected causes of asthenia and fatigue are listed in Table 1.¹

Unfortunately, the distinction between asthenia, fatigue, and primary weakness often is unclear. Patients frequently confuse the terms, and the medical literature sometimes uses them interchangeably.² In addition, a patient’s condition may cause progression from one syndrome to another; for example, asthenia in a patient with heart failure may progress to true muscle weakness through deconditioning. Further, asthenia and fatigue can coexist with weakness, such as in patients with multiple sclerosis and concomitant depression. Because depression is so prevalent, it is essential to consider it as a possible cause of a patient’s symptoms; diagnosis can be facilitated by using one of the several validated screening tools designed for the outpatient setting.^3,4 This article discusses only intrinsic muscle weakness in adults.

Differential Diagnosis

Conditions that result in intrinsic weakness can be divided into several main categories: infectious, neurologic, endocrine, inflammatory, rheumatologic, genetic, metabolic, electrolyte-induced, or drug-induced.

In adults, medications (Table 2^5,6), infections, and neurologic disorders are common causes of muscle weakness. The use of alcohol or steroids can cause proximal weakness with characteristic physical and laboratory findings.^5,7,8 Infectious agents that are most commonly associated with muscle weakness include influenza and Epstein-Barr virus (Table 3^6,9–12). Human immunodeficiency virus (HIV) is a less common cause of muscle weakness but should be considered in patients with associated risk factors or symptoms.^6,9 Neurologic conditions that can cause weakness include cerebrovascular disease (i.e., stroke, subdural/epidural hematomas), demyelinating disorders (i.e., multiple sclerosis, Guillain-Barré syndrome), and neuromuscular disorders (i.e., myasthenia gravis, botulism). Localizing neurologic deficits can help the physician focus the diagnostic work-up^6,10–12 (Table 3^6,9–12).

Less common myopathies include those caused by endocrine, inflammatory, rheumatologic, and electrolyte syndromes (Tables 4^{5–8,13–26} and5^{6,8,15,16,18,20,24–38}). Of the endocrine diseases, thyroid disease is common, but thyroid-related myopathy is uncommon; parathyroid-related myopathy should be suspected in a patient with muscle weakness and chronic renal failure.^14,15,32 Inflammatory diseases typically affect older adults and include both proximal (polymyositis and dermatomyositis) and distal myopathies (inclusion body myositis); the proximal inflammatory myopathies respond to steroids.^21–23 Rheumatologic disorders causing weakness, such as systemic lupus and rheumatoid arthritis, can occur in young and elderly persons.^17,18 Disorders of potassium balance are among the more common electrolyte myopathies and may be primary (such as in hypokalemic or hyperkalemic periodic paralysis) or secondary (such as in renal disease or angiotensin-converting enzyme inhibitor toxicity). Patients in whom these disturbances are suspected should have electrocardiography to screen for cardiac sequelae.^13,27–30

Rare causes of muscle weakness include genetic (muscular and myotonic dystrophies), metabolic (glycogenoses, lipidoses, and mitochondrial defects), and sarcoidand amyloid-associated myopathies^{24–26,34–38} (Tables 4^{5–8,13–26} and5^{6,8,15,16,18,20,24–38}).

History

Once muscle weakness has been differentiated from asthenia and fatigue, the physician should ask the patient about disease onset and progression. Acute onset may indicate infection or stroke. Subacute onset may implicate drugs, electrolytes, or inflammatory or rheumatologic disease. Chronic progressive weakness is the classic presentation in genetic and metabolic myopathies. Despite these generalizations, there is considerable variation in the time courses of different classes of myopathy, and even within the individual disorders. For instance, although typically subacute, myasthenia gravis may present with rapid, generalized weakness or remain confined to a single muscle group for years (as in ocular myasthenia).¹²

Because of this variability, the pattern of muscle weakness is crucial in differentiating the etiology. The physician should establish whether the loss of strength is global (e.g., bilateral; may be proximal, distal, or both) or focal. Focal processes (those that are unilateral or involve specific nerve distributions or intracranial vascular areas) tend to be neurologic—although not all neurologic processes are focal—and may require a different approach than that used with global strength loss.

In patients with diffuse weakness, the physician should determine whether the loss of function is proximal or distal by noting which physical activities muscle weakness limits. If the patient has difficulty rising from a chair (hip muscles) or combing his or her hair (shoulder girdle), the weakness is proximal; if the patient has difficulty standing on his or her toes (gastrocnemius/soleus) or doing fine work with the hands (intrinsics), the muscle weakness is distal. Although many myopathies are associated with proximal weakness, a small number are associated predominantly with distal weakness; these include myotonic dystrophy, inclusion body myositis, and the genetic distal myopathies.^21,34 Patients with statin or alcohol toxicity can present with either proximal or distal weakness.^5,7,39

Other areas to address in the patient’s history are associated symptoms, family history, and pharmaceutical use. Common drugs associated with muscle weakness are listed in Table 2.^5,6 Associated symptoms are found in many myopathies and can be especially helpful in narrowing the differential diagnosis among endocrine, rheumatologic, and inflammatory disorders. For example, dysphagia may accompany weakness in inclusion body myositis and systemic sclerosis, whereas menorrhagia may attend the weakness that occurs in hypothyroidism. A family history, which almost always is present in genetic myopathies, may also be present in other causes of weakness, including lupus, rheumatoid arthritis, dermatomyositis, polymyositis, and the potassium-related paralyses²⁷ (Table 6^{5,7–15,17,18,21,24–27,34,36,38}).

Physical Examination

The physical examination begins with an objective confirmation of the subjective severity and distribution of muscle weakness. In addition to individual muscles, the physician should survey functional activities such as standing and writing to determine whether the weakness is proximal, distal, or both.

Next, a thorough neurologic survey should accompany motor testing. The physician should note patterns and relations among defects and narrow the differential by determining whether the deficits are referable to the central or peripheral nervous system. The pattern is important. A neurologic examination that shows deficits in a single nerve or radicular distribution indicates a possible mononeuritis, entrapment neuropathy, or radiculopathy, and calls for a different workup than that required for a limb paresis in a patient with cerebrovascular risk factors.

If the neurologic examination is unrevealing, a more general physical examination, searching for extramuscular signs, is warranted (Table 6^{5,7–15,17,18,21,24–27,34,36,38}). Mental status testing may reveal changes suggestive of a myopathy-inducing electrolyte disorder (calcium or magnesium) or an arrest of mental development as occurs in genetic myopathies.^25,29 The cardiovascular assessment may elicit changes consistent with a cardiomyopathy—a nonspecific consequence of many myopathy-inducing disorders—or a pericarditis, as occurs with some of the infectious and rheumatologic causes of muscle weakness.^{5,7,8,9,18,21,24,25,29,36,38}

Pulmonary testing may reveal the crackles of a restrictive lung defect, found in some inflammatory and rheumatologic myopathies.^17,21 Gastrointestinal examination may reveal hepatomegaly, associated with metabolic storage diseases and amyloidosis.^24,38 Skin findings are possible in multiple categories of disease (e.g., skin bronzing in adrenal insufficiency; Gottron’s papules and heliotrope rash in dermatomyositis; and erythema nodosum in sarcoidosis). The skeletal examination may reveal the leg bowing and pseudofractures of osteomalacia or the symmetric joint swelling of lupus and rheumatoid arthritis.^{8,17,18,21,25,35}

Laboratory and Radiologic Evaluation

The sequence and timing of the ancillary investigations varies with the clinical scenario. In a patient whose muscle weakness is suggestive of neurologic disease, early neuroimaging (for suspected cerebrovascular disease) or lumbar puncture (for possible meningitis, encephalitis, or multiple sclerosis) is indicated. If infectious disease is suspected, appropriate titers or cultures should be obtained. When a specific class or type of myopathy is suspected, appropriate testing should be performed.

If the cause of muscle weakness is unclear, serum chemistries (electrolytes, calcium, phosphate, magnesium, glucose) should be obtained, as well as a thyroid-stimulating hormone assay to evaluate for electrolyte and endocrine myopathies. If an endocrinopathy is suspected, more specific assays can be performed based on clinical suspicion (e.g., 24-hour urine cortisol testing to rule out Cushing’s disease; oral glucose load/growth hormone assay to rule out acromegaly; vitamin D assay to rule out osteomalacia).^{8,13–15,28,29,32}

Next, investigations looking for inflammatory, rheumatologic, or genetic myopathies can be performed sequentially or concurrently. Although nonspecific, the creatine kinase (CK) level usually is normal in the electrolyte and endocrine myopathies (notable exceptions are thyroid and potassium disorder myopathies).^8,16,28,29 However, the CK level may be highly elevated (10 to 100 times normal) in the inflammatory myopathies and can be moderately to highly elevated in the muscular dystrophies.^16,23,25 Other conditions that can be associated with elevated CK levels include sarcoidosis, infections, alcoholism, and adverse reactions to medications. Metabolic (storage) myopathies tend to be associated with only mild to moderate elevations in CK levels.^7,16

In addition to CK, an erythrocyte sedimentation rate (ESR) and an antinuclear antibody assay (ANA) may help determine if a rheumatologic myopathy exists. If either ESR or ANA assay is positive, additional studies may be obtained, including rheumatoid factor (rheumatoid arthritis); anti–double-stranded DNA or antiphospholipid antibodies (lupus); or anticentromere antibodies (scleroderma).^17–19 Patients with idiopathic inflammatory myopathies also tend to have elevated ESR and ANA levels; many of these same patients have overlap syndromes, in which an inflammatory myopathy and a rheumatologic disease coexist. An antisynthetase antibody, when positive, may help confirm the presence of an inflammatory myopathy.²³

Electromyography

If the presence of myopathy is uncertain, electromyography may be indicated. Although changes seen on electromyography are not pathognomonic for any specific disease process, an abnormal electromyogram can indicate if a neuropathy or neuromuscular disease is present or can help solidify the diagnosis of a primary myopathy.

Electromyography assesses several components of muscle electrical activity: the muscle’s spontaneous activity; its response to the insertion of a probe; the character of the muscle’s individual motor unit action potentials; and the rapidity with which additional motor units are recruited in response to an electrical signal. Muscle inflammation, atrophy, necrosis, denervation, or neuromuscular disease can alter these components, giving rise to patterns that may help illuminate the underlying pathology. Although the procedure can cause minor discomfort, most patients tolerate it well.^16,24,40

Muscle Biopsy

If the diagnosis is still inconclusive after the history, physical examination, and laboratory, radiologic, and electromyographic evaluations, a muscle biopsy is required for patients who have a suspected myopathy.⁴¹ The technology of this method, especially regarding the use of genetic markers, is advancing rapidly, making a definitive diagnosis possible for a wider range of myopathies.^24,25

The biopsy site should be an affected muscle that is not diseased to the point of necrosis. Common biopsy sites are the vastus lateralis of the quadriceps for proximal myopathies and the gastrocnemius for distal myopathies; in patients without involvement of these muscles, an affected group is chosen.²⁴ The muscle biopsy can be accomplished as an outpatient procedure and carries the attendant risks of pain, bleeding, infection, and sensory loss. As with electromyography, patients should avoid using anticoagulants before the procedure, and the site chosen for biopsy should be free of overlying infection.

The pathologic analysis of biopsy specimens focuses on the histologic, histochemical, electron microscopic, genetic, and biochemical changes that are found in the affected muscle. Histology may show atrophic, degenerating, and regenerating muscle fibers (general findings referred to as myopathic changes), or it may show more specific findings such as accumulations of glycogen (glycogen storage diseases), ragged red fibers (mitochondrial myopathies), noncaseating granulomas (sarcoidosis), and amyloid deposits (amyloidosis). Histochemical techniques assay for specific enzymes and proteins, and may reveal deficiencies as in disorders of carbohydrate or fatty acid metabolism or the muscular dystrophies. Electron microscopy and biochemical assays may help to uncover subtle changes not detectable by other techniques, further aiding in the diagnosis of metabolic and protein-deficiency myopathies.^{7,18–20,21,24,25,27,28,35,37}