Evaluation of the Patient with Muscle Weakness



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Am Fam Physician. 2005 Apr 1;71(7):1327-1336.

The online-only version of this article offers more detailed information on additional selected causes of muscle weakness.

Muscle weakness is a common complaint among patients presenting to family physicians. Diagnosis begins with a patient history distinguishing weakness from fatigue or asthenia, separate conditions with different etiologies that can coexist with, or be confused for, weakness. The pattern and severity of weakness, associated symptoms, medication use, and family history help the physician determine whether the cause of a patient’s weakness is infectious, neurologic, endocrine, inflammatory, rheumatologic, genetic, metabolic, electrolyte-induced, or drug-induced. In the physical examination, the physician should objectively document the patient’s loss of strength, conduct a neurologic survey, and search for patterns of weakness and extramuscular involvement. If a specific cause of weakness is suspected, the appropriate laboratory or radiologic studies should be performed. Otherwise, electromyography is indicated to confirm the presence of a myopathy or to evaluate for a neuropathy or a disease of the neuromuscular junction. If the diagnosis remains unclear, the examiner should pursue a tiered progression of laboratory studies. Physicians should begin with blood chemistries and a thyroid-stimulating hormone assay to evaluate for electrolyte and endocrine causes, then progress to creatine kinase level, erythrocyte sedimentation rate, and antinuclear antibody assays to evaluate for rheumatologic, inflammatory, genetic, and metabolic causes. Finally, many myopathies require a biopsy for diagnosis. Pathologic evaluation of the muscle tissue specimen focuses on histologic, histochemical, electron microscopic, biochemical, and genetic analyses; advances in technique have made a definitive diagnosis possible for many myopathies.

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.

Strength of Recommendations

Key clinical recommendation Label References

It is essential to consider depression as a possible diagnosis; several screening tools for depression have been validated for use in outpatient settings.

A

3,4

Primary muscle weakness must be distinguished from the more common conditions of fatigue and asthenia.

C

1

If the diagnosis is still inconclusive after the history, physical examination, and laboratory, radiologic, and electromyographic evaluation, a muscle biopsy is required for patients who have a suspected myopathy.

C

41


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, opinion, or case series. See page 1245 for more information.

Strength of Recommendations

View Table

Strength of Recommendations

Key clinical recommendation Label References

It is essential to consider depression as a possible diagnosis; several screening tools for depression have been validated for use in outpatient settings.

A

3,4

Primary muscle weakness must be distinguished from the more common conditions of fatigue and asthenia.

C

1

If the diagnosis is still inconclusive after the history, physical examination, and laboratory, radiologic, and electromyographic evaluation, a muscle biopsy is required for patients who have a suspected myopathy.

C

41


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, opinion, or case series. See page 1245 for more information.

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

TABLE 1

Causes of Asthenia and Fatigue

Addison’s disease

Anemia

Anxiety

Chemotherapy

Chronic fatigue syndrome

Chronic pain

Deconditioning/sedentary lifestyle

Dehydration and electrolyte disorders

Depression

Diabetes

Fibromyalgia

Heart disease

Hypothyroidism

Infections (such as influenza, Epstein-Barr virus, HIV, hepatitis C, tuberculosis)

Medications

Narcotics

Paraneoplastic syndrome

Pregnancy/postpartum

Pulmonary disease

Renal disease

Sleep disorders


HIV = human immunodeficiency virus.

Adapted with permission from Hinshaw DB, Carnahan JM, Johnson DL. Depression, anxiety, and asthenia in advanced illness. J Am Coll Surg 2002;195:276.

TABLE 1   Causes of Asthenia and Fatigue

View Table

TABLE 1

Causes of Asthenia and Fatigue

Addison’s disease

Anemia

Anxiety

Chemotherapy

Chronic fatigue syndrome

Chronic pain

Deconditioning/sedentary lifestyle

Dehydration and electrolyte disorders

Depression

Diabetes

Fibromyalgia

Heart disease

Hypothyroidism

Infections (such as influenza, Epstein-Barr virus, HIV, hepatitis C, tuberculosis)

Medications

Narcotics

Paraneoplastic syndrome

Pregnancy/postpartum

Pulmonary disease

Renal disease

Sleep disorders


HIV = human immunodeficiency virus.

Adapted with permission from Hinshaw DB, Carnahan JM, Johnson DL. Depression, anxiety, and asthenia in advanced illness. J Am Coll Surg 2002;195:276.

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 25,6), 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 36,912). 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-up6,1012  (Table 36,912).

TABLE 2

Medications and Narcotics that Can Cause Muscle Weakness

Amiodarone (Cordarone)

Antithyroid agents: methimazole (Tapazole); propylthiouracil

Antiretroviral medications: zidovudine (Retrovir); lamivudine (Epivir)

Chemotherapeutic agents

Cimetidine (Tagamet)

Cocaine

Corticosteroids

Fibric acid derivatives: gemfibrozil (Lopid)

Interferon

Leuprolide acetate (Lupron)

Nonsteroidal anti-inflammatory drugs

Penicillin

Sulfonamides

Statins


Information from references 5 and 6.

TABLE 2   Medications and Narcotics that Can Cause Muscle Weakness

View Table

TABLE 2

Medications and Narcotics that Can Cause Muscle Weakness

Amiodarone (Cordarone)

Antithyroid agents: methimazole (Tapazole); propylthiouracil

Antiretroviral medications: zidovudine (Retrovir); lamivudine (Epivir)

Chemotherapeutic agents

Cimetidine (Tagamet)

Cocaine

Corticosteroids

Fibric acid derivatives: gemfibrozil (Lopid)

Interferon

Leuprolide acetate (Lupron)

Nonsteroidal anti-inflammatory drugs

Penicillin

Sulfonamides

Statins


Information from references 5 and 6.

TABLE 3

Infectious and Neurologic Causes of Muscle Weakness

Infectious

Epstein-Barr virus

Human immunodeficiency virus

Influenza

Lyme disease

Meningitis (multiple agents)

Polio

Rabies

Syphilis

Toxoplasmosis

Neurologic

Amyotrophic lateral sclerosis

Cerebrovascular disease

Stroke

Subdural/epidural hematomas

Demyelinating disorders

Guillain-Barré syndrome

Multiple sclerosis

Neoplasm

Neuromuscular disorders

Botulism

Lambert-Eaton myasthenic syndrome

Myasthenia gravis

Organophosphate intoxication

Radiculopathies

Cervical spondylosis

Degenerative disc disease

Spinal cord injury

Spinal muscle atrophy


Information from references 6 and 9 through 12.

TABLE 3   Infectious and Neurologic Causes of Muscle Weakness

View Table

TABLE 3

Infectious and Neurologic Causes of Muscle Weakness

Infectious

Epstein-Barr virus

Human immunodeficiency virus

Influenza

Lyme disease

Meningitis (multiple agents)

Polio

Rabies

Syphilis

Toxoplasmosis

Neurologic

Amyotrophic lateral sclerosis

Cerebrovascular disease

Stroke

Subdural/epidural hematomas

Demyelinating disorders

Guillain-Barré syndrome

Multiple sclerosis

Neoplasm

Neuromuscular disorders

Botulism

Lambert-Eaton myasthenic syndrome

Myasthenia gravis

Organophosphate intoxication

Radiculopathies

Cervical spondylosis

Degenerative disc disease

Spinal cord injury

Spinal muscle atrophy


Information from references 6 and 9 through 12.

Less common myopathies include those caused by endocrine, inflammatory, rheumatologic, and electrolyte syndromes (Tables 458,1326 and 56,8,15,16,18,20,2438). 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.2123 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.13,2730

Rare causes of muscle weakness include genetic (muscular and myotonic dystrophies), metabolic (glycogenoses, lipidoses, and mitochondrial defects), and sarcoidand amyloid-associated myopathies2426,3438  (Tables 458,1326 and 56,8,15,16,18,20,2438).

TABLE 4

Selected Causes of Primary Muscle Weakness

Cause Weakness Age of onset/diagnosis Systemic symptoms and findings Laboratory abnormalities Creatine kinase Electromyogram Muscle biopsy

Drugs

Alcohol

Proximal (may be distal)

Variable

Change in mental status; telangiectasia; peripheral neuropathy

Elevated transaminase and GGT levels; anemia; decreased vitamin B12

Normal to elevated

Normal

Myopathic changes*; selected atrophy of type II muscle fibers

Endocrine

Adrenal insufficiency

Generalized

Variable

Hypotension; hypoglycemia; bronzing of the skin

Hyponatremia; hyperkalemia; ACTH assay; ACTH stimulation test

Normal

Myotonic discharges†

Diminished glycogen content

Glucocorticoid excess

Proximal

Variable

Buffalo hump; striae; osteoporosis

Elevated urine-free cortisol, dexamethasone suppression, or corticotropin-releasing hormone stimulation tests

Normal

Myopathic MUAPs‡

Selective atrophy of type II muscle fibers

Parathyroid hormone (secondary hyperparathyroidism§)

Proximal, lower extremity more than upper extremity

Variable, older adult

Usually has associated comorbidities (cardiovascular disease, diabetes)

Hypocalcemia; uremia

Normal

Myopathic MUAPs‡

Atrophy of type II muscle fibers; increased lipofuscin beneath cell membrane; calcium deposits in muscle

Thyroid hormone (hyperthyroidism)

Proximal, bulbar

40 to 49 years

Weight loss; tachycardia; increased perspiration; tremor

Elevated T4 and T3; TSH variable, depending on cause

Normal or elevated

Myopathic MUAPs‡ with or without fibrillation potentials∥

Usually normal

Thyroid hormone (hypothyroidism)

Proximal

30 to 49 years

Menorrhagia; bradycardia; goiter; delayed relaxation of deep tendon reflexes

TSH

Elevated

With or without myopathic MUAPs‡ and fibrillation potentials∥

Myopathic changes*; glycogen accumulation

Inflammatory

Dermatomyositis

Proximal

Variable, increased incidence with age

Gottron papules; heliotrope rash; calcinosis; interstitial lung disease; disordered GI motility

Elevated myoglobin; ANA positive; myositis autoantibodies may be present

Greater than 10 times normal elevations

Myopathic MUAPs‡ with fibrillation potentials∥

Inflammatory infiltrate with myopathic changes* and replacement by adipose and collagen

Inclusion body myositis

Distal, especially forearm and hand

At least 50 years (younger than 50 years: rare)

Dysphagia; extramuscular involvement not as common

Elevated myoglobin; positive ANA less common; myositis autoantibodies may be present

Elevated

Myopathic MUAPs‡ with fibrillation potentials∥

Inflammatory infiltrate with vacuoles containing eosinophilic inclusions

Polymyositis

Proximal

Variable, increased incidence with age

Interstitial lung disease, disordered GI motility; overlap with rheumatologic diseases more common

Elevated myoglobin; ANA positive; myositis autoantibodies may be present

Greater than 10 times normal elevations

Myopathic MUAPs‡ with fibrillation potentials∥

Inflammatory infiltrate with myopathic changes* and replacement by adipose and collagen

Rheumatologic

Rheumatoid arthritis

Focal, periarticular, or diffuse

Adult

Symmetric joint inflammation (especially MCP, PIP joints); dry eyes and mouth

Elevated rheumatoid factor

Normal or elevated

No data

Atrophy of type II muscle fibers; may have overlap syndrome with polymyositis

Systemic lupus erythematosus

Proximal

Adult

Malar rash; nephritis; arthritis

ANA, anti-DNA antibodies, depressed C3 and C4

Normal to elevated

No data

Type II fiber atrophy; lymphocytic vasculitis; myositis

Genetic

Becker muscular dystrophy

Hip; proximal leg and arm

Late childhood to adulthood

Mental retardation; cardiomyopathy

None

Elevated

Myopathic MUAPs‡ with fibrillation potentials∥

Myopathic changes*; decreased and patchy staining of dystrophin

Limb-girdle muscular dystrophies**

Variable, usually proximal limb, pelvic, and shoulder girdle muscles

Variable

Variable, may have cardiac abnormalities

None

Variable, normal, or elevated

Myopathic MUAPs‡ +/– fibrillation potentials∥

Myopathic changes*; may demonstrate absence of specific protein on immunohistochemical staining

Myotonic dystrophy type 1

Distal greater than proximal; foot drop; temporal and masseter wasting

Adolescence to adulthood

Conduction abnormalities; mental retardation; cataracts; insulin resistance

None

Normal to minimally elevated

Myopathic MUAPs‡; myotonic discharges∥

Less necrosis and remodeling than in muscular dystrophies; atrophy of type I muscle fibers; ring fibers

Metabolic

Glycogen and lipid storage diseases; mitochondrial dis ease

Proximal

Variable

Variable; exercise intolerance and cardiomyopathy more common

Some glycogenoses associated with abnormal FIET††

Variable, may increase with exercise

Normal or myopathic MUAPs‡ +/– fibrillation potentials∥

Myopathic changes* with glycogen deposits, lipid deposits, or ragged red fibers (for glycogen, lipid, or mitochondrial disease, respectively)


GGT = gamma-glutamyltransferase; ACTH = adrenocorticotropin hormone; MUAPs = motor unit action potentials; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; GI = gastrointestinal; ANA = antinuclear antibodies; MCP = metacarpophalangeal; PIP = proximal interphalangeal; EMG = electromyogram; FIET = forearm ischemic exercise testing.

*—Myopathic changes are nonspecific and include atrophy, degeneration, and regeneration of muscle fibers.

†—Myotonic discharges are a type of prolonged burst of activity seen on insertion of the EMG needle.

‡—Myopathic MUAPs are shorter in duration, lower in amplitude, and polyphasic when compared to MUAPs from normal muscle.

∮—Secondary hyperparathyroidism usually caused by renal failure.

∥—Fibrillation potentials represent spontaneous activity on the part of single muscle fibers (not usually noted with nondiseased muscle).

¶—C3 and C4 are complement components.

**—Including facioscapulohumeral dystrophy.

††—FIET evaluates the rise of ammonia and lactate in the forearm during exertion.

Information from references 5 though 8 and 13 through 26.

TABLE 4   Selected Causes of Primary Muscle Weakness

View Table

TABLE 4

Selected Causes of Primary Muscle Weakness

Cause Weakness Age of onset/diagnosis Systemic symptoms and findings Laboratory abnormalities Creatine kinase Electromyogram Muscle biopsy

Drugs

Alcohol

Proximal (may be distal)

Variable

Change in mental status; telangiectasia; peripheral neuropathy

Elevated transaminase and GGT levels; anemia; decreased vitamin B12

Normal to elevated

Normal

Myopathic changes*; selected atrophy of type II muscle fibers

Endocrine

Adrenal insufficiency

Generalized

Variable

Hypotension; hypoglycemia; bronzing of the skin

Hyponatremia; hyperkalemia; ACTH assay; ACTH stimulation test

Normal

Myotonic discharges†

Diminished glycogen content

Glucocorticoid excess

Proximal

Variable

Buffalo hump; striae; osteoporosis

Elevated urine-free cortisol, dexamethasone suppression, or corticotropin-releasing hormone stimulation tests

Normal

Myopathic MUAPs‡

Selective atrophy of type II muscle fibers

Parathyroid hormone (secondary hyperparathyroidism§)

Proximal, lower extremity more than upper extremity

Variable, older adult

Usually has associated comorbidities (cardiovascular disease, diabetes)

Hypocalcemia; uremia

Normal

Myopathic MUAPs‡

Atrophy of type II muscle fibers; increased lipofuscin beneath cell membrane; calcium deposits in muscle

Thyroid hormone (hyperthyroidism)

Proximal, bulbar

40 to 49 years

Weight loss; tachycardia; increased perspiration; tremor

Elevated T4 and T3; TSH variable, depending on cause

Normal or elevated

Myopathic MUAPs‡ with or without fibrillation potentials∥

Usually normal

Thyroid hormone (hypothyroidism)

Proximal

30 to 49 years

Menorrhagia; bradycardia; goiter; delayed relaxation of deep tendon reflexes

TSH

Elevated

With or without myopathic MUAPs‡ and fibrillation potentials∥

Myopathic changes*; glycogen accumulation

Inflammatory

Dermatomyositis

Proximal

Variable, increased incidence with age

Gottron papules; heliotrope rash; calcinosis; interstitial lung disease; disordered GI motility

Elevated myoglobin; ANA positive; myositis autoantibodies may be present

Greater than 10 times normal elevations

Myopathic MUAPs‡ with fibrillation potentials∥

Inflammatory infiltrate with myopathic changes* and replacement by adipose and collagen

Inclusion body myositis

Distal, especially forearm and hand

At least 50 years (younger than 50 years: rare)

Dysphagia; extramuscular involvement not as common

Elevated myoglobin; positive ANA less common; myositis autoantibodies may be present

Elevated

Myopathic MUAPs‡ with fibrillation potentials∥

Inflammatory infiltrate with vacuoles containing eosinophilic inclusions

Polymyositis

Proximal

Variable, increased incidence with age

Interstitial lung disease, disordered GI motility; overlap with rheumatologic diseases more common

Elevated myoglobin; ANA positive; myositis autoantibodies may be present

Greater than 10 times normal elevations

Myopathic MUAPs‡ with fibrillation potentials∥

Inflammatory infiltrate with myopathic changes* and replacement by adipose and collagen

Rheumatologic

Rheumatoid arthritis

Focal, periarticular, or diffuse

Adult

Symmetric joint inflammation (especially MCP, PIP joints); dry eyes and mouth

Elevated rheumatoid factor

Normal or elevated

No data

Atrophy of type II muscle fibers; may have overlap syndrome with polymyositis

Systemic lupus erythematosus

Proximal

Adult

Malar rash; nephritis; arthritis

ANA, anti-DNA antibodies, depressed C3 and C4

Normal to elevated

No data

Type II fiber atrophy; lymphocytic vasculitis; myositis

Genetic

Becker muscular dystrophy

Hip; proximal leg and arm

Late childhood to adulthood

Mental retardation; cardiomyopathy

None

Elevated

Myopathic MUAPs‡ with fibrillation potentials∥

Myopathic changes*; decreased and patchy staining of dystrophin

Limb-girdle muscular dystrophies**

Variable, usually proximal limb, pelvic, and shoulder girdle muscles

Variable

Variable, may have cardiac abnormalities

None

Variable, normal, or elevated

Myopathic MUAPs‡ +/– fibrillation potentials∥

Myopathic changes*; may demonstrate absence of specific protein on immunohistochemical staining

Myotonic dystrophy type 1

Distal greater than proximal; foot drop; temporal and masseter wasting

Adolescence to adulthood

Conduction abnormalities; mental retardation; cataracts; insulin resistance

None

Normal to minimally elevated

Myopathic MUAPs‡; myotonic discharges∥

Less necrosis and remodeling than in muscular dystrophies; atrophy of type I muscle fibers; ring fibers

Metabolic

Glycogen and lipid storage diseases; mitochondrial dis ease

Proximal

Variable

Variable; exercise intolerance and cardiomyopathy more common

Some glycogenoses associated with abnormal FIET††

Variable, may increase with exercise

Normal or myopathic MUAPs‡ +/– fibrillation potentials∥

Myopathic changes* with glycogen deposits, lipid deposits, or ragged red fibers (for glycogen, lipid, or mitochondrial disease, respectively)


GGT = gamma-glutamyltransferase; ACTH = adrenocorticotropin hormone; MUAPs = motor unit action potentials; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; GI = gastrointestinal; ANA = antinuclear antibodies; MCP = metacarpophalangeal; PIP = proximal interphalangeal; EMG = electromyogram; FIET = forearm ischemic exercise testing.

*—Myopathic changes are nonspecific and include atrophy, degeneration, and regeneration of muscle fibers.

†—Myotonic discharges are a type of prolonged burst of activity seen on insertion of the EMG needle.

‡—Myopathic MUAPs are shorter in duration, lower in amplitude, and polyphasic when compared to MUAPs from normal muscle.

∮—Secondary hyperparathyroidism usually caused by renal failure.

∥—Fibrillation potentials represent spontaneous activity on the part of single muscle fibers (not usually noted with nondiseased muscle).

¶—C3 and C4 are complement components.

**—Including facioscapulohumeral dystrophy.

††—FIET evaluates the rise of ammonia and lactate in the forearm during exertion.

Information from references 5 though 8 and 13 through 26.

TABLE 5

Additional Selected Causes of Muscle Weakness

Electrolyte

Hypercalcemia

Hyperkalemia/hypokalemia

Hypermagnesemia/hypomagnesemia

Endocrine

Acromegaly

Primary hyperparathyroidism

Hypopituitarism

Vitamin D deficiency (osteomalacia)

Rheumatologic

Polymyalgia rheumatica

Systemic sclerosis/scleroderma

Genetic

Distal myopathies

Oculopharyngeal muscular dystrophy

Myotonic dystrophy type 2 (proximal myotonic myopathy)

Metabolic

Glycogenoses

Acid maltase deficiency

Aldolase A deficiency

Brancher enzyme deficiency

Myophosphorylase deficiency

Phosphofructokinase deficiency

Lipidoses

Carnitine deficiency

Carnitine palmitoyltransferase II deficiency

Trifunctional protein deficiency

Mitochondrial defects

Miscellaneous

Amyloidosis

Sarcoidosis


Information from references 6, 8, 15, 16, 18, 20, and 24 through 38.

TABLE 5   Additional Selected Causes of Muscle Weakness

View Table

TABLE 5

Additional Selected Causes of Muscle Weakness

Electrolyte

Hypercalcemia

Hyperkalemia/hypokalemia

Hypermagnesemia/hypomagnesemia

Endocrine

Acromegaly

Primary hyperparathyroidism

Hypopituitarism

Vitamin D deficiency (osteomalacia)

Rheumatologic

Polymyalgia rheumatica

Systemic sclerosis/scleroderma

Genetic

Distal myopathies

Oculopharyngeal muscular dystrophy

Myotonic dystrophy type 2 (proximal myotonic myopathy)

Metabolic

Glycogenoses

Acid maltase deficiency

Aldolase A deficiency

Brancher enzyme deficiency

Myophosphorylase deficiency

Phosphofructokinase deficiency

Lipidoses

Carnitine deficiency

Carnitine palmitoyltransferase II deficiency

Trifunctional protein deficiency

Mitochondrial defects

Miscellaneous

Amyloidosis

Sarcoidosis


Information from references 6, 8, 15, 16, 18, 20, and 24 through 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 65,715,17,18,21,2427,34,36,38).

TABLE 6

Diagnostic Clues for Muscle Weakness

Finding Suggested diagnoses

History

Abdominal pain; excessive urination; renal stones

Hypercalcemia; hyperparathyroidism

Acute weakness with neurologic deficit(s)

Spinal cord injury; stroke

Arthralgia; malaise; myalgia; respiratory symptoms

Epstein-Barr virus; HIV; influenza

Chronic neck or back pain, with or without sharp shooting pains

Cervical spondylosis; degenerative disc disease

Distal weakness

Genetic distal myopathies; inclusion body myositis

Dysphagia; rash around eyelids; shortness of breath

Dermatomyositis

Easy bruising; emotional lability; obesity

Glucocorticoid excess; steroid-induced myopathy

Exercise-provoked weakness

Glycogen and lipid storage diseases; mitochondrial myopathies; myasthenia gravis

Family history of myopathy

Hyper- or hypokalemic periodic paralysis; inflammatory disease; muscular dystrophies; rheumatologic disease

Heat-induced symptoms; multiple neurologic deficits spread over space and time

Multiple sclerosis

Legal problems; memory loss; repeated trauma; sexual dysfunction

Alcoholism

Positive medication history

Medication-induced myopathy (esp. anti-retrovirals, statins, steroids)

Sexually transmitted disease

HIV; syphilis

Physical examination

Arthritis; malar rash; nephritis

Systemic lupus erythematosus

Cardiomyopathy

Alcohol; amyloid; glycogen storage disease; inflammatory myopathies; muscular dystrophies; sarcoid

Dry eyes and mouth; joint inflammation (especially MCP, PIP joints)

Rheumatoid arthritis

Facial weakness; fatigable weakness; ptosis

Myasthenia gravis

Neurologic deficits

Focal

Central

Multiple sclerosis; stroke

Peripheral

Peripheral neuropathy; radiculopathy

Diffuse

Central

Amyotrophic lateral sclerosis

Peripheral

Guillain-Barré syndrome; polyneuropathy

Orthostatic hypotension; skin bronzing

Hypoadrenalism


HIV = human immunodeficiency virus; MCP = metacarpophalangeal; PIP = proximal interphalangeal.

Information from references 5, 7 through 15, 17, 18, 21, 24 through 27, 34, 36, and 38.

TABLE 6   Diagnostic Clues for Muscle Weakness

View Table

TABLE 6

Diagnostic Clues for Muscle Weakness

Finding Suggested diagnoses

History

Abdominal pain; excessive urination; renal stones

Hypercalcemia; hyperparathyroidism

Acute weakness with neurologic deficit(s)

Spinal cord injury; stroke

Arthralgia; malaise; myalgia; respiratory symptoms

Epstein-Barr virus; HIV; influenza

Chronic neck or back pain, with or without sharp shooting pains

Cervical spondylosis; degenerative disc disease

Distal weakness

Genetic distal myopathies; inclusion body myositis

Dysphagia; rash around eyelids; shortness of breath

Dermatomyositis

Easy bruising; emotional lability; obesity

Glucocorticoid excess; steroid-induced myopathy

Exercise-provoked weakness

Glycogen and lipid storage diseases; mitochondrial myopathies; myasthenia gravis

Family history of myopathy

Hyper- or hypokalemic periodic paralysis; inflammatory disease; muscular dystrophies; rheumatologic disease

Heat-induced symptoms; multiple neurologic deficits spread over space and time

Multiple sclerosis

Legal problems; memory loss; repeated trauma; sexual dysfunction

Alcoholism

Positive medication history

Medication-induced myopathy (esp. anti-retrovirals, statins, steroids)

Sexually transmitted disease

HIV; syphilis

Physical examination

Arthritis; malar rash; nephritis

Systemic lupus erythematosus

Cardiomyopathy

Alcohol; amyloid; glycogen storage disease; inflammatory myopathies; muscular dystrophies; sarcoid

Dry eyes and mouth; joint inflammation (especially MCP, PIP joints)

Rheumatoid arthritis

Facial weakness; fatigable weakness; ptosis

Myasthenia gravis

Neurologic deficits

Focal

Central

Multiple sclerosis; stroke

Peripheral

Peripheral neuropathy; radiculopathy

Diffuse

Central

Amyotrophic lateral sclerosis

Peripheral

Guillain-Barré syndrome; polyneuropathy

Orthostatic hypotension; skin bronzing

Hypoadrenalism


HIV = human immunodeficiency virus; MCP = metacarpophalangeal; PIP = proximal interphalangeal.

Information from references 5, 7 through 15, 17, 18, 21, 24 through 27, 34, 36, and 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 65,715,17,18,21,2427,34,36,38). 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).8,1315,28,29,32

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).1719 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.7,1820,21,24,25,27,28,35,37

The Author

AARON SAGUIL, CPT (P), MC, USA, is a faculty development fellow in the Department of Family Medicine at the Madigan Army Medical Center, Tacoma, Wash. Dr. Saguil received his medical degree from the University of Florida College of Medicine, Gainesville. He completed a family practice residency at DeWitt Army Community Hospital, Fort Belvoir, Va.

Address correspondence to Aaron Saguil, CPT (P), MC, USA, Department of Family Medicine, Madigan Army Medical Center, Tacoma, WA 98431 (e-mail: aaron.saguil@us.army.mil). Reprints are not available from the author.

The author does not have any conflicts of interest. Sources of funding: none reported.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department or the U.S. Army Service at large.

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