Muscle Weakness in Adults: Evaluation and Differential Diagnosis

 

Although the prevalence of muscle weakness in the general population is uncertain, it occurs in about 5% of U.S. adults 60 years and older. Determining the cause of muscle weakness can be challenging. True muscle weakness must first be differentiated from subjective fatigue or pain-related motor impairment with normal motor strength. Muscle weakness should then be graded objectively using a formal tool such as the Medical Research Council Manual Muscle Testing scale. The differential diagnosis of true muscle weakness is extensive, including neurologic, rheumatologic, endocrine, genetic, medication- or toxin-related, and infectious etiologies. A stepwise approach to narrowing this differential diagnosis relies on the history and physical examination combined with knowledge of the potential etiologies. Frailty and sarcopenia are clinical syndromes occurring in older people that can present with generalized weakness. Asymmetric weakness is more common in neurologic conditions, whereas pain is more common in neuropathies or radiculopathies. Identifying abnormal findings, such as Chvostek sign, Babinski reflex, hoarse voice, and muscle atrophy, will narrow the possible diagnoses. Laboratory testing, including electrolyte, thyroid-stimulating hormone, and creatine kinase measurements, may also be helpful. Magnetic resonance imaging is indicated if there is concern for acute neurologic conditions, such as stroke or cauda equina syndrome, and may also guide muscle biopsy. Electromyography is indicated when certain diagnoses are being considered, such as amyotrophic lateral sclerosis, myasthenia gravis, neuropathy, and radiculopathy, and may also guide biopsy. If the etiology remains unclear, specialist consultation or muscle biopsy may be necessary to reach a diagnosis.

Given its broad differential diagnosis, muscle weakness can be challenging to evaluate in primary care practice. Although its prevalence in the general population is not well described, muscle weakness occurs in 5% of U.S. adults 60 years and older.1 Physicians must distinguish true muscle weakness from subjective fatigue or pain-related motor impairment with normal motor strength. This requires a history and physical examination, which guide laboratory testing, imaging, electrodiagnostic testing, and muscle biopsy.25

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComment

History and physical examination findings should guide laboratory testing, imaging, electromyography, and muscle biopsy in patients with muscle weakness.25

C

Usual practice and expert opinion

A medication and toxin review should be completed in patients with muscle weakness.4,12,15,35

C

Usual practice and expert opinion

Electromyography should be performed in patients with muscle weakness if the diagnosis is unclear after a history, physical examination, and targeted laboratory evaluation.15,18,19,26

C

Expert opinion

Muscle biopsy should be considered to clarify the diagnosis in patients who have objective muscle weakness with elevated creatine kinase levels or abnormal findings on electromyography or muscle magnetic resonance imaging.20,21

C

Expert opinion


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComment

History and physical examination findings should guide laboratory testing, imaging, electromyography, and muscle biopsy in patients with muscle weakness.25

C

Usual practice and expert opinion

A medication and toxin review should be completed in patients with muscle weakness.4,12,15,35

C

Usual practice and expert opinion

Electromyography should be performed in patients with muscle weakness if the diagnosis is unclear after a history, physical examination, and targeted laboratory evaluation.15,18,19,26

C

Expert opinion

Muscle biopsy should be considered to clarify the diagnosis in patients who have objective muscle weakness with elevated creatine kinase levels or abnormal findings on electromyography or muscle magnetic resonance imaging.20,21

C

Expert opinion


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

Etiology and Differential Diagnosis

The differential diagnosis of muscle weakness in adults is extensive because it can occur when pathology affects any level of the neuromuscular pathway (upper or lower motor neurons, neuromuscular junction, and muscle fibers). Table 1 lists selected causes of muscle weakness and their clinical findings.522

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TABLE 1.

Selected Causes of Muscle Weakness in Adults

CauseWeaknessUpper or lower motor neuron signsPattern of onsetSystemic symptoms and findingsLaboratory or imagingCreatine kinase levelElectromyographyMuscle biopsy

Neurologic

Amyotrophic lateral sclerosis

Variable, typically starts unilaterally in one peripheral region of the body and progresses into others; may present with impairment of the ninth to 12th cranial nerves (bulbar palsy)

Both

Gradual

Muscle cramps, muscle atrophy (often in the hands); fasciculations, including in the tongue; spasticity; may exhibit pseudobulbar affect

MRI of brain and spinal cord may help rule out other causes of weakness

Normal or elevated

Reduced CMAP amplitude with normal sensory nerve amplitude; fibrillation potentials,* positive sharp waves

Not typically performed

Cerebral lesion (stroke, hemorrhage, mass)

Variable depending on lesion location, often unilateral

Upper

Acute (stroke), subacute or gradual (mass, subdural hematoma)

May present with headache, altered cognition, or altered sensorium

MRI may reveal etiology

Not typically obtained

Not typically performed

Not typically performed

Compressive neuropathy of the peripheral nerve, (e.g., carpal tunnel syndrome, lumbar radiculopathy)

Variable, unilateral

Lower

Variable

Pain, paresthesia; spinal nerve root compression may cause radicular symptoms

Ultrasonography may reveal nerve entrapment

Not typically obtained

Fibrillation potentials,* positive sharp waves; reduced MUAP amplitude distal to offending lesion

Not typically performed

Guillain-Barré syndrome

Symmetric, bilateral; affects distal and proximal muscles; may progress to include respiratory and bulbar involvement

Lower

Acute

History of recent Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, or mycoplasma infection; recent vaccination; may be associated with back pain and symmetric sensory changes (e.g., paresthesias)

Anti-GM1 antibody, anti-GD1a antibody; cerebrospinal fluid analysis may show increased protein and normal leukocytes after the first week of illness

Not typically obtained

May be normal in first week of illness; later shows patchy demyelination findings of temporal dispersion of CMAPs; slowed motor conduction velocity and/or conduction block

Not typically performed

Lambert-Eaton syndrome

Proximal, caudocranial progression; initially improves with repetition; diminished tendon reflexes

Lower

Variable

Dysautonomia, impotence, hypotension, xerostomia; often develops as a paraneoplastic syndrome associated with small cell lung cancer but may be idiopathic

Anti–voltage-gated calcium channel antibody

Normal

Low CMAP amplitude with rest, improvement postexercise; fibrillation potentials*

Not typically performed

Motor neuropathy

Distal, eventually proximal

Lower

Gradual

May have accompanying sensory neuropathy with paresthesia or numbness; toe deformities, foot ulcers; impaired balance

Various genetic tests depending on suspected etiology; elevated serum glucose or A1C level if caused by diabetic neuropathy; muscle atrophy on MRI

Not typically obtained

Low CMAP amplitude in lower extremities; demyelination signs in upper extremities

Not typically performed

Multiple sclerosis

Variable depending on location, often unilateral

Upper

Variable

May present with bladder dysfunction, cognitive impairment, sensory changes, monocular vision loss due to optic neuritis, cerebellar ataxia

MRI may show characteristic white matter lesions of the brain or spinal cord

Not typically obtained

Not typically performed

Not typically performed

Myasthenia gravis

Proximal, cephalocaudal progression; worsens with repetition (fatigability); oculomotor

Lower

Variable

Worsening of symptoms throughout the day

Anti–acetylcholine receptor antibody testing; anti–striated muscle antibody and anti–muscle specific tyrosine kinase antibody testing have less utility

Normal

Normal CMAP amplitude at rest, reduced CMAP amplitude with repetitive nerve stimulation; fibrillation potentials*

Not typically performed

Spinal cord lesion (stroke, hemorrhage, mass)

Variable depending on lesion location, may be unilateral or bilateral

Upper

Acute (stroke), gradual (mass)

Back pain, bowel or bladder incontinence

MRI may reveal etiology

Not typically obtained

Not typically performed

Not typically performed

Myositides

Dermatomyositis

Proximal

Acute or subacute

Violaceous rash on the knuckles and extensor surfaces of the upper extremities (Gottron papules [Figure 2]), violaceous rash on the eyelids and periorbital edema (heliotrope rash), violaceous rash on the upper chest and neck (V-sign) or back (shawl sign); calcinosis; interstitial lung disease; disordered GI motility; dysphagia

Elevated myoglobin; positive for antinuclear antibodies; may be positive for myositis autoantibodies

Greater than 10 times the normal elevations

Active and chronic myopathic units

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

Inclusion body myositis

Distal, especially forearm and hand; later stage may involve proximal weakness

Gradual

Dysphagia (present in up to 80% of cases); extramuscular involvement not as common

Elevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be present

Elevated

Active and chronic myopathic units

Inflammatory infiltrate with vacuoles containing eosinophilic inclusions; ragged red or ragged blue fibers

Necrotizing myositis

Proximal, often profound

Acute

May be associated with viral illness, malignancy, or statin use; dysphagia

Anti–signal recognition particle antibody; anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibody

Markedly elevated (can be over 50 times normal limit)

Active myopathic units

Scattered necrosis, deposits of complement may be noted on capillaries‡

Polymyositis

Proximal

Acute or subacute

Similar in presentation to dermatomyositis but without dermatologic signs; interstitial lung disease; disordered GI motility; dysphagia

Elevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be present

Greater than 10 times normal elevations

Active and chronic myopathic units

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

Endocrine

Adrenal insufficiency (Addison disease)

Generalized

Variable

Hypotension, hypoglycemia, bronzing of the skin

Hyponatremia, hyperkalemia; adrenocorticotropic hormone assay and stimulation test

Normal

Myotonic discharges§

Diminished glycogen content

Elevated thyroid hormone (hyperthyroidism)

Proximal, bulbar

Variable

Weight loss, tachycardia, increased perspiration, tremor

Elevated thyroxine (T4) and triiodothyronine (T3) hormones; thyroid-stimulating hormone variable depending on cause

Normal or elevated

Myopathic MUAPs‖ with or without fibrillation potentials*

Usually normal

Endogenous glucocorticoid excess (Cushing syndrome)

Proximal

Variable

Buffalo hump, purple striae, osteoporosis

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

Normal or low

Myopathic MUAPs‖

Selective atrophy of type II muscle fibers, absent necrosis

Low/absent thyroid hormone (hypothyroidism)

Proximal

Variable

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

Thyroid-stimulating hormone

Elevated

With or without myopathic MUAPs‖ and fibrillation potentials*

Myopathic changes,† glycogen accumulation

Parathyroid hormone (secondary hyperparathyroidism¶)

Proximal, lower extremity more than upper extremity

Variable

Usually has associated comorbidities (cardiovascular disease, diabetes mellitus); positive Chvostek or Trousseau signs

Hypocalcemia; uremia

Normal

Myopathic MUAPs‖

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

Genetic

Becker muscular dystrophy

Hip, proximal leg and arm

Gradual

Intellectual disability, cardiomyopathy

Various specific molecular genetic tests are available

Elevated

Myopathic MUAPs‖ with fibrillation potentials*

Myopathic changes,† decreased and patchy staining of dystrophin

Glycogen and lipid storage diseases, mitochondrial diseases

Proximal

Variable

Variable; exercise intolerance and cardiomyopathy more common

Some glycogenoses associated with abnormal findings on forearm ischemic exercise testing**

Variable, may increase with exercise

Normal or myopathic MUAPs‖ with or without fibrillation potentials*

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

Limb-girdle muscular dystrophy

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

Gradual

Variable, may have cardiac abnormalities

Various specific molecular genetic tests available

Variable, normal, or elevated

Myopathic MUAPs‖ with or without fibrillation potentials*

Myopathic changes,† may demonstrate absence of specific protein on immunohistochemical staining

Myotonic dystrophy type 1

Distal greater than proximal, foot drop, oropharyngeal, temporal and masseter wasting, difficulty opening hand after tight grip

Gradual

Cardiac conduction abnormalities, balding, intellectual disability, gonadal atrophy, cataracts, insulin resistance, scoliosis

Molecular genetic testing may demonstrate unstable CTG trinucleotide repeat in the DMPK gene of chromosome 19

Normal to minimally elevated

Myopathic MUAPs,‖ myotonic discharges*

Less necrosis and remodeling than in muscular dystrophy, atrophy of type I muscle fibers, ring fibers

Medications

Fluoroquinolones

Distal

Acute or subacute

Tendon swelling or erythema, tendon rupture in severe cases

Ultrasonography or MRI may demonstrate tendon rupture

Not typically performed

Not typically performed

Glucocorticoids

Typically affects proximal and postural muscles

Acute, subacute, or gradual

Buffalo hump, purple striae

No reliable biomarkers; may have leukocytosis

Normal or low

Myopathic MUAPs‖

Selective atrophy of type II muscle fibers, absent necrosis

Statin

Proximal (may be distal)

Acute or subacute

Myalgia often affecting bilateral large muscle groups, such as back, buttock, thigh, and shoulder girdle muscles; onset shortly after medication initiation; higher risk in females, older people, and those with lower muscle mass

None

Elevated

Myopathic MUAPs‖

Myonecrosis in severe cases

Toxins

Alcohol (myopathy or neuropathy)

Proximal (may be distal)

Alcoholic neuropathy: lower; alcoholic myopathy: —

Variable

Change in mental status, telangiectasia, peripheral neuropathy

Elevated transaminase and gamma-glutamyltransferase levels, anemia, decreased vitamin B levels12

Normal to elevated

Normal

Myopathic changes,† selected atrophy of type II muscle fibers

Catabolic

Sarcopenia and frailty

Variable, slow gait speed, diminished grip strength

Gradual onset in patients older than 65 years

Loss of muscle mass, cachexia

No specific biomarkers but may have low creatinine, decreased insulinlike growth factor 1, albumin, or vitamin D levels; may have elevated interleukin-6

Normal or low

Not typically performed

Sample may be inadequate because of lack of muscle mass; fatty infiltration


CMAP = compound muscle action potential; GI = gastrointestinal; MRI = magnetic resonance imaging; MUAP = motor unit action potential.

*—Fibrillation potentials represent spontaneous activity of single muscle fibers (not usually noted with normal muscle).

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

‡—C3 and C4 are complement components.

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

‖—Myopathic MUAPs are shorter in duration, lower in amplitude, and polyphasic compared with MUAPs from normal muscle.

¶—Secondary hyperparathyroidism usually caused by renal failure.

**—Forearm ischemic exercise testing evaluates the rise of ammonia and lactate in the forearm during exertion.

Adapted with permission from Saguil A. Evaluation of the patient with muscle weakness. Am Fam Physician. 2005;71(7):1330–1331, with additional information from references 5 and 722.

TABLE 1.

Selected Causes of Muscle Weakness in Adults

CauseWeaknessUpper or lower motor neuron signsPattern of onsetSystemic symptoms and findingsLaboratory or imagingCreatine kinase levelElectromyographyMuscle biopsy

Neurologic

Amyotrophic lateral sclerosis

Variable, typically starts unilaterally in one peripheral region of the body and progresses into others; may present with impairment of the ninth to 12th cranial nerves (bulbar palsy)

Both

Gradual

Muscle cramps, muscle atrophy (often in the hands); fasciculations, including in the tongue; spasticity; may exhibit pseudobulbar affect

MRI of brain and spinal cord may help rule out other causes of weakness

Normal or elevated

Reduced CMAP amplitude with normal sensory nerve amplitude; fibrillation potentials,* positive sharp waves

Not typically performed

Cerebral lesion (stroke, hemorrhage, mass)

Variable depending on lesion location, often unilateral

Upper

Acute (stroke), subacute or gradual (mass, subdural hematoma)

May present with headache, altered cognition, or altered sensorium

MRI may reveal etiology

Not typically obtained

Not typically performed

Not typically performed

Compressive neuropathy of the peripheral nerve, (e.g., carpal tunnel syndrome, lumbar radiculopathy)

Variable, unilateral

Lower

Variable

Pain, paresthesia; spinal nerve root compression may cause radicular symptoms

Ultrasonography may reveal nerve entrapment

Not typically obtained

Fibrillation potentials,* positive sharp waves; reduced MUAP amplitude distal to offending lesion

Not typically performed

Guillain-Barré syndrome

Symmetric, bilateral; affects distal and proximal muscles; may progress to include respiratory and bulbar involvement

Lower

Acute

History of recent Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, or mycoplasma infection; recent vaccination; may be associated with back pain and symmetric sensory changes (e.g., paresthesias)

Anti-GM1 antibody, anti-GD1a antibody; cerebrospinal fluid analysis may show increased protein and normal leukocytes after the first week of illness

Not typically obtained

May be normal in first week of illness; later shows patchy demyelination findings of temporal dispersion of CMAPs; slowed motor conduction velocity and/or conduction block

Not typically performed

Lambert-Eaton syndrome

Proximal, caudocranial progression; initially improves with repetition; diminished tendon reflexes

Lower

Variable

Dysautonomia, impotence, hypotension, xerostomia; often develops as a paraneoplastic syndrome associated with small cell lung cancer but may be idiopathic

Anti–voltage-gated calcium channel antibody

Normal

Low CMAP amplitude with rest, improvement postexercise; fibrillation potentials*

Not typically performed

Motor neuropathy

Distal, eventually proximal

Lower

Gradual

May have accompanying sensory neuropathy with paresthesia or numbness; toe deformities, foot ulcers; impaired balance

Various genetic tests depending on suspected etiology; elevated serum glucose or A1C level if caused by diabetic neuropathy; muscle atrophy on MRI

Not typically obtained

Low CMAP amplitude in lower extremities; demyelination signs in upper extremities

Not typically performed

Multiple sclerosis

Variable depending on location, often unilateral

Upper

Variable

May present with bladder dysfunction, cognitive impairment, sensory changes, monocular vision loss due to optic neuritis, cerebellar ataxia

MRI may show characteristic white matter lesions of the brain or spinal cord

Not typically obtained

Not typically performed

Not typically performed

Myasthenia gravis

Proximal, cephalocaudal progression; worsens with repetition (fatigability); oculomotor

Lower

Variable

Worsening of symptoms throughout the day

Anti–acetylcholine receptor antibody testing; anti–striated muscle antibody and anti–muscle specific tyrosine kinase antibody testing have less utility

Normal

Normal CMAP amplitude at rest, reduced CMAP amplitude with repetitive nerve stimulation; fibrillation potentials*

Not typically performed

Spinal cord lesion (stroke, hemorrhage, mass)

Variable depending on lesion location, may be unilateral or bilateral

Upper

Acute (stroke), gradual (mass)

Back pain, bowel or bladder incontinence

MRI may reveal etiology

Not typically obtained

Not typically performed

Not typically performed

Myositides

Dermatomyositis

Proximal

Acute or subacute

Violaceous rash on the knuckles and extensor surfaces of the upper extremities (Gottron papules [Figure 2]), violaceous rash on the eyelids and periorbital edema (heliotrope rash), violaceous rash on the upper chest and neck (V-sign) or back (shawl sign); calcinosis; interstitial lung disease; disordered GI motility; dysphagia

Elevated myoglobin; positive for antinuclear antibodies; may be positive for myositis autoantibodies

Greater than 10 times the normal elevations

Active and chronic myopathic units

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

Inclusion body myositis

Distal, especially forearm and hand; later stage may involve proximal weakness

Gradual

Dysphagia (present in up to 80% of cases); extramuscular involvement not as common

Elevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be present

Elevated

Active and chronic myopathic units

Inflammatory infiltrate with vacuoles containing eosinophilic inclusions; ragged red or ragged blue fibers

Necrotizing myositis

Proximal, often profound

Acute

May be associated with viral illness, malignancy, or statin use; dysphagia

Anti–signal recognition particle antibody; anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibody

Markedly elevated (can be over 50 times normal limit)

Active myopathic units

Scattered necrosis, deposits of complement may be noted on capillaries‡

Polymyositis

Proximal

Acute or subacute

Similar in presentation to dermatomyositis but without dermatologic signs; interstitial lung disease; disordered GI motility; dysphagia

Elevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be present

Greater than 10 times normal elevations

Active and chronic myopathic units

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

Endocrine

Adrenal insufficiency (Addison disease)

Generalized

Variable

Hypotension, hypoglycemia, bronzing of the skin

Hyponatremia, hyperkalemia; adrenocorticotropic hormone assay and stimulation test

Normal

Myotonic discharges§

Diminished glycogen content

Elevated thyroid hormone (hyperthyroidism)

Proximal, bulbar

Variable

Weight loss, tachycardia, increased perspiration, tremor

Elevated thyroxine (T4) and triiodothyronine (T3) hormones; thyroid-stimulating hormone variable depending on cause

Normal or elevated

Myopathic MUAPs‖ with or without fibrillation potentials*

Usually normal

Endogenous glucocorticoid excess (Cushing syndrome)

Proximal

Variable

Buffalo hump, purple striae, osteoporosis

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

Normal or low

Myopathic MUAPs‖

Selective atrophy of type II muscle fibers, absent necrosis

Low/absent thyroid hormone (hypothyroidism)

Proximal

Variable

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

Thyroid-stimulating hormone

Elevated

With or without myopathic MUAPs‖ and fibrillation potentials*

Myopathic changes,† glycogen accumulation

Parathyroid hormone (secondary hyperparathyroidism¶)

Proximal, lower extremity more than upper extremity

Variable

Usually has associated comorbidities (cardiovascular disease, diabetes mellitus); positive Chvostek or Trousseau signs

Hypocalcemia; uremia

Normal

Myopathic MUAPs‖

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

Genetic

Becker muscular dystrophy

Hip, proximal leg and arm

Gradual

Intellectual disability, cardiomyopathy

Various specific molecular genetic tests are available

Elevated

Myopathic MUAPs‖ with fibrillation potentials*

Myopathic changes,† decreased and patchy staining of dystrophin

Glycogen and lipid storage diseases, mitochondrial diseases

Proximal

Variable

Variable; exercise intolerance and cardiomyopathy more common

Some glycogenoses associated with abnormal findings on forearm ischemic exercise testing**

Variable, may increase with exercise

Normal or myopathic MUAPs‖ with or without fibrillation potentials*

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

Limb-girdle muscular dystrophy

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

Gradual

Variable, may have cardiac abnormalities

Various specific molecular genetic tests available

Variable, normal, or elevated

Myopathic MUAPs‖ with or without fibrillation potentials*

Myopathic changes,† may demonstrate absence of specific protein on immunohistochemical staining

Myotonic dystrophy type 1

Distal greater than proximal, foot drop, oropharyngeal, temporal and masseter wasting, difficulty opening hand after tight grip

Gradual

Cardiac conduction abnormalities, balding, intellectual disability, gonadal atrophy, cataracts, insulin resistance, scoliosis

Molecular genetic testing may demonstrate unstable CTG trinucleotide repeat in the DMPK gene of chromosome 19

Normal to minimally elevated

Myopathic MUAPs,‖ myotonic discharges*

Less necrosis and remodeling than in muscular dystrophy, atrophy of type I muscle fibers, ring fibers

Medications

Fluoroquinolones

Distal

Acute or subacute

Tendon swelling or erythema, tendon rupture in severe cases

Ultrasonography or MRI may demonstrate tendon rupture

Not typically performed

Not typically performed

Glucocorticoids

Typically affects proximal and postural muscles

Acute, subacute, or gradual

Buffalo hump, purple striae

No reliable biomarkers; may have leukocytosis

Normal or low

Myopathic MUAPs‖

Selective atrophy of type II muscle fibers, absent necrosis

Statin

Proximal (may be distal)

Acute or subacute

Myalgia often affecting bilateral large muscle groups, such as back, buttock, thigh, and shoulder girdle muscles; onset shortly after medication initiation; higher risk in females, older people, and those with lower muscle mass

None

Elevated

Myopathic MUAPs‖

Myonecrosis in severe cases

Toxins

Alcohol (myopathy or neuropathy)

Proximal (may be distal)

Alcoholic neuropathy: lower; alcoholic myopathy: —

Variable

Change in mental status, telangiectasia, peripheral neuropathy

Elevated transaminase and gamma-glutamyltransferase levels, anemia, decreased vitamin B levels12

Normal to elevated

Normal

Myopathic changes,† selected atrophy of type II muscle fibers

Catabolic

Sarcopenia and frailty

Variable, slow gait speed, diminished grip strength

Gradual onset in patients older than 65 years

Loss of muscle mass, cachexia

No specific biomarkers but may have low creatinine, decreased insulinlike growth factor 1, albumin, or vitamin D levels; may have elevated interleukin-6

Normal or low

Not typically performed

Sample may be inadequate because of lack of muscle mass; fatty infiltration


CMAP = compound muscle action potential; GI = gastrointestinal; MRI = magnetic resonance imaging; MUAP = motor unit action potential.

*—Fibrillation potentials represent spontaneous activity of single muscle fibers (not usually noted with normal muscle).

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

‡—C3 and C4 are complement components.

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

‖—Myopathic MUAPs are shorter in duration, lower in amplitude, and polyphasic compared with MUAPs from normal muscle.

¶—Secondary hyperparathyroidism usually caused by renal failure.

**—Forearm ischemic exercise testing evaluates the rise of ammonia and lactate in the forearm during exertion.

Adapted with permission from Saguil A. Evaluation of the patient with muscle weakness. Am Fam Physician. 2005;71(7):1330–1331, with additional information from references 5 and 722.

NEUROLOGIC

Upper motor neurons, which are located in the cerebral cortex, brainstem, and corticospinal tracts, may be injured from stroke, multiple sclerosis, and spinal cord or brain masses. Lower motor neurons, which are located in the anterior horn of the spinal cord, nerve roots, and peripheral nerves, may be damaged by infections, Guillain-Barré syndrome, hereditary sensorimotor disorders (e.g., Charcot-Marie-Tooth disease), compressive neuropathy (e.g., carpal tunnel syndrome), radiculopathy from intervertebral disk herniation, inflammation, spinal muscular atrophy type IV, or amyloid infiltration.2,2325

Upper and lower motor neurons are involved in amyotrophic lateral sclerosis.24 The neuromuscular junction is the site of pathology in myasthenia gravis and Lambert-Eaton syndrome, which are rare autoimmune-mediated disorders.7,8

MYOSITIDES

Weakness is the predominant feature of primary muscle disorders, or myositides. Some of these disorders, such as dermatomyositis, polymyositis, and necrotizing myositis, present with acute or subacute proximal weakness and may be associated with malignancy or connective tissue disorders. Conversely, inclusion body myositis, which tends to occur in older adults, has a gradual course, affecting distal muscles early and progressing in an asymmetric pattern.9,10,26,27

ENDOCRINE

Some endocrine disorders can cause weakness. These include hyperthyroidism and hypothyroidism, adrenal insufficiency (Addison disease), endogenous glucocorticoid excess (Cushing syndrome), acromegaly, and primary hyperaldosteronism (Conn syndrome).3 Diabetic neuropathy may affect motor neurons, including the oculomotor nerve.28

ELECTROLYTE DISTURBANCES

Numerous electrolyte imbalances are linked to muscle weakness, including disturbances in calcium, phosphate, potassium, and sodium. Hypokalemia is particularly common and can be caused by medications, such as diuretics; Gitelman syndrome (hypokalemic periodic paralysis); renal tubular acidosis; primary hyperaldosteronism; thyrotoxicosis; or infections, such as dengue fever.3,4,2931

GENETIC

Muscular dystrophy usually presents during childhood or adolescence, but certain subtypes (e.g., Becker muscular dystrophy, myotonic dystrophy) can present during adulthood.11 Disorders of lipid and glycogen metabolism and disorders of mitochondria can also cause weakness, myopathy, and rhabdomyolysis; these disorders may be exacerbated by exercise or febrile illnesses and rarely present in adults.32,33

MEDICATIONS

Numerous medications have been reported to cause muscle weakness (Table 24,1214,34), including several commonly used medications. For example, statins are well known to cause myopathy and rhabdomyolysis, although the mechanism is unclear.12,13 Fluoroquinolones are linked to tendinopathies, rhabdomyolysis, and tendon ruptures.12 Glucocorticoids can cause a noninflammatory myopathy, primarily affecting postural muscles.12,14 A medication review is thus essential in the evaluation of muscle weakness.4,12,35

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TABLE 2.

Medications that Can Cause Muscle Weakness

Amiodarone Antimicrotubular medications (colchicine, vincristine) Antiretroviral medications (nucleoside reverse transcriptase inhibitors, such as zidovudine [Retrovir], stavudine, and lamivudine [Epivir]; protease inhibitors, such as indinavir [Crixivan], saquinavir [Invirase], and ritonavir [Norvir]) Any medication causing hypocalcemia/hypercalcemia or hypokalemia/hyperkalemia Fibrates* Fluoroquinolones Gemfibrozil (Lopid) Glucocorticoids (systemic) HMG-CoA reductase inhibitors (statins)†Hydroxychloroquine (Plaquenil) Hydroxyurea Interferon alfa* Local anesthetics Omeprazole (Prilosec)* Penicillamine (Cuprimine)* Phenytoin (Dilantin)* Silicone gel (ruptured breast implant)*


CYP3A4 = cytochrome P450 3A4.

*—Can cause weakness via drug-induced dermatomyositis.

†—Concurrent use of statins and CYP3A4 inhibitors increases the likelihood of statin toxicity. Select CYP3A4 inhibitors include amiodarone, calcium channel blockers (e.g., amlodipine [Norvasc], diltiazem, verapamil), certain anti-HIV agents (e.g., ritonavir, saquinavir), certain antidepressants (e.g., fluoxetine [Prozac], fluvoxamine), certain antifungals (e.g., fluconazole [Diflucan], itraconazole [Sporanox], ketoconazole, miconazole), tamoxifen, and grapefruit juice.

Information from references 4, 1214, and 34.

TABLE 2.

Medications that Can Cause Muscle Weakness

Amiodarone Antimicrotubular medications (colchicine, vincristine) Antiretroviral medications (nucleoside reverse transcriptase inhibitors, such as zidovudine [Retrovir], stavudine, and lamivudine [Epivir]; protease inhibitors, such as indinavir [Crixivan], saquinavir [Invirase], and ritonavir [Norvir]) Any medication causing hypocalcemia/hypercalcemia or hypokalemia/hyperkalemia Fibrates* Fluoroquinolones Gemfibrozil (Lopid) Glucocorticoids (systemic) HMG-CoA reductase inhibitors (statins)†Hydroxychloroquine (Plaquenil) Hydroxyurea Interferon alfa* Local anesthetics Omeprazole (Prilosec)* Penicillamine (Cuprimine)* Phenytoin (Dilantin)* Silicone gel (ruptured breast implant)*


CYP3A4 = cytochrome P450 3A4.

*—Can cause weakness via drug-induced dermatomyositis.

†—Concurrent use of statins and CYP3A4 inhibitors increases the likelihood of statin toxicity. Select CYP3A4 inhibitors include amiodarone, calcium channel blockers (e.g., amlodipine [Norvasc], diltiazem, verapamil), certain anti-HIV agents (e.g., ritonavir, saquinavir), certain antidepressants (e.g., fluoxetine [Prozac], fluvoxamine), certain antifungals (e.g., fluconazole [Diflucan], itraconazole [Sporanox], ketoconazole, miconazole), tamoxifen, and grapefruit juice.

Information from references 4, 1214, and 34.

TOXINS

Exposure to heavy metals, such as arsenic, lead, thallium, and mercury, can cause motor neuropathy; therefore, a toxin review should be completed in patients with muscle weakness.4,35 Organophosphate poisoning causes weakness at the level of the neuromuscular junction, with severe cholinergic effects (toxidrome). Alcohol and certain recreational drugs (e.g., “glue sniffing,” cocaine, amphetamines, opioids) can also cause muscle weakness. Alcohol is neurotoxic and myotoxic at high doses and can cause acute muscle weakness in individuals who binge drink.15

Envenomation, including from tick bites (tick paralysis) and certain venomous snake bites, may cause weakness. Exposure to Clostridium botulinum toxin from eating contaminated or undercooked food causes acute paralysis by blocking release of acetylcholine into the neuromuscular junction.4,11,35

INFECTIONS

Certain infections are linked to muscle weakness. These include West Nile virus infection, HIV infection, Lyme disease, diphtheria, dengue fever, neurocysticercosis, trichinosis, Chagas disease, rabies, botulism, herpes zoster, cytomegalovirus infection, hepatitis C, and herpes simplex virus 1 infection. Lyme disease, herpes zoster, and potentially herpes simplex virus 1 infection can cause facial nerve palsy (Bell palsy). Poliomyelitis was historically a significant cause of flaccid paralysis but now rarely occurs because of worldwide vaccination efforts.3,23,24,29,30,36,37

SARCOPENIA AND FRAILTY

When evaluating generalized weakness in older adults, sarcopenia and frailty should be considered in the differential diagnosis. Sarcopenia and frailty are common multifactorial syndromes that typically do not occur in younger people. They are associated with increased morbidity, disability, institutionalization, and mortality. Sarcopenia is thought to be catabolic age-related loss of muscle mass and strength and can be evaluated by measuring grip strength, gait speed, and muscle mass.38,39 Frailty, which often coexists with sarcopenia, can be defined as the presence of three or more of the following: grip weakness, slow gait speed, unintentional weight loss, subjective exhaustion, and low physical activity.40

History

Physicians should inquire about onset, duration, and progression of symptoms. Acute onset of weakness (hours to days) should prompt timely evaluation, because it may indicate vascular, infectious, inflammatory, metabolic, or toxin-mediated disorders. Subacute presentation (days to weeks) may suggest electrolyte, inflammatory, or rheumatologic disorders. More gradual progressive weakness often suggests neurologic, genetic, or metabolic disorders or inclusion body myositis.2,9,11,29

The history should be guided by knowledge of the potential diagnoses and proceed in a stepwise approach (Figure 125,724,2633,3538,4144). Specific elements of the history may provide diagnostic clues (Table 324,711,13,2224,2628,31,35,43,44).

FIGURE 1.

Evaluation of muscle weakness in adults.

AChR = anti–acetylcholine receptor; ANA = antinuclear antibodies; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; LMN = lower motor neuron; MRI = magnetic resonance imaging; UMN = upper motor neuron; VGCC = voltage-gated calcium channel.

Information from references 25, 724, 2633, 3538, and 4144.


FIGURE 1.

Evaluation of muscle weakness in adults.

AChR = anti–acetylcholine receptor; ANA = antinuclear antibodies; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; LMN = lower motor neuron; MRI = magnetic resonance imaging; UMN = upper motor neuron; VGCC = voltage-gated calcium channel.

Information from references 25, 724, 2633, 3538, and 4144.

 Enlarge     Print

TABLE 3.

Diagnostic Clues in the Evaluation of Muscle Weakness

Key findingsSuggested diagnoses

History

Diplopia, blurry vision

Myasthenia gravis (intermittent), diabetic neuropathy (permanent)

Dysphagia

Inflammatory myopathy, motor neuron disease, myasthenia gravis, muscular dystrophy, botulism

Facial nerve paralysis (Bell palsy)

Lyme disease, herpes zoster (Ramsay Hunt syndrome), herpes simplex virus 1 infection

Fevers, arthralgias, rash

Inflammatory or infectious myopathy

Monocular vision loss, bladder dysfunction

Multiple sclerosis

Pain

Nerve compression, rhabdomyolysis, inflammatory myopathy, inflammatory neuropathy (e.g., Parsonage-Turner syndrome), muscle damage due to toxins or medications (e.g., statins, fluoroquinolones)

Paresthesia

Hereditary sensorimotor disorders (e.g., Charcot-Marie-Tooth disease), nerve compression, nerve damage due to toxins, multiple sclerosis

Raynaud phenomenon

Inflammatory myopathy

Tendon rupture

Fluoroquinolone use

Physical examination

Cardiac arrhythmias

Inflammatory myopathy, genetic disorders, electrolyte imbalances

Cholinergic toxidrome

Organophosphate poisoning

Chvostek sign,* Trousseau sign,† tetany

Hypocalcemia

Cushingoid appearance (buffalo hump, purple striae)

Glucocorticoid excess (endogenous [Cushing syndrome] vs. exogenous [long-term glucocorticoid use])

Fatigable weakness, ptosis

Myasthenia gravis

Hyperreflexia

Upper motor neuron lesion, hyperthyroidism, hypercalcemia

Hyporeflexia

Hypothyroidism, lower motor neuron lesion

Muscle atrophy

Lower motor neuron pathology, frailty/sarcopenia

Skin bronzing

Hypoaldosteronism (Addison disease)

Third cranial nerve (oculomotor nerve) palsy

Diabetic neuropathy

Violaceous rash on the knuckles and extensor surfaces of upper extremities (Gottron papules [Figure 2]), violaceous rash on the eyelids and periorbital edema (heliotrope rash), violaceous rash on the upper chest and neck (V-sign) or back (shawl sign)

Dermatomyositis


*—Tapping the facial nerve anterior to the earlobe and inferior to the zygomatic arch elicits ipsilateral facial nerve spasm.

†—Inflating a brachial blood pressure cuff induces distal carpopedal spasm.

Information from references 24, 711, 13, 2224, 2628, 31, 35, 43, and 44.

TABLE 3.

Diagnostic Clues in the Evaluation of Muscle Weakness

Key findingsSuggested diagnoses

History

Diplopia, blurry vision

Myasthenia gravis (intermittent), diabetic neuropathy (permanent)

Dysphagia

Inflammatory myopathy, motor neuron disease, myasthenia gravis, muscular dystrophy, botulism

Facial nerve paralysis (Bell palsy)

Lyme disease, herpes zoster (Ramsay Hunt syndrome), herpes simplex virus 1 infection

Fevers, arthralgias, rash

Inflammatory or infectious myopathy

Monocular vision loss, bladder dysfunction

Multiple sclerosis

Pain

Nerve compression, rhabdomyolysis, inflammatory myopathy, inflammatory neuropathy (e.g., Parsonage-Turner syndrome), muscle damage due to toxins or medications (e.g., statins, fluoroquinolones)

Paresthesia

Hereditary sensorimotor disorders (e.g., Charcot-Marie-Tooth disease), nerve compression, nerve damage due to toxins, multiple sclerosis

Raynaud phenomenon

Inflammatory myopathy

Tendon rupture

Fluoroquinolone use

Physical examination

Cardiac arrhythmias

Inflammatory myopathy, genetic disorders, electrolyte imbalances

Cholinergic toxidrome

Organophosphate poisoning

Chvostek sign,* Trousseau sign,† tetany

Hypocalcemia

Cushingoid appearance (buffalo hump, purple striae)

Glucocorticoid excess (endogenous [Cushing syndrome] vs. exogenous [long-term glucocorticoid use])

Fatigable weakness, ptosis

Myasthenia gravis

Hyperreflexia

Upper motor neuron lesion, hyperthyroidism, hypercalcemia

Hyporeflexia

Hypothyroidism, lower motor neuron lesion

Muscle atrophy

Lower motor neuron pathology, frailty/sarcopenia

Skin bronzing

Hypoaldosteronism (Addison disease)

Third cranial nerve (oculomotor nerve) palsy

Diabetic neuropathy

Violaceous rash on the knuckles and extensor surfaces of upper extremities (Gottron papules [Figure 2]), violaceous rash on the eyelids and periorbital edema (heliotrope rash), violaceous rash on the upper chest and neck (V-sign) or back (shawl sign)

Dermatomyositis


*—Tapping the facial nerve anterior to the earlobe and inferior to the zygomatic arch elicits ipsilateral facial nerve spasm.

†—Inflating a brachial blood pressure cuff induces distal carpopedal spasm.

Information from references 24, 711, 13, 2224, 2628, 31, 35, 43, and 44.

In particular, identifying the distribution of weakness helps narrow the broad differential diagnosis. Patients with proximal (limb-girdle) weakness may have difficulty rising from a chair, climbing stairs, or lifting their arms overhead to perform activities of daily living (e.g., combing hair).2,26 Proximal weakness is more common in myopathies. Patients with distal weakness may have difficulty opening jars or may drop objects or have foot drop. Distal weakness is more typically caused by certain toxins (e.g., organophosphates), hereditary motor neuropathy, or early inclusion body myositis.3,9,16,41 Simultaneous proximal and distal weakness may result from inclusion body myositis or Guillain-Barré syndrome.

Asymmetric weakness is typically neurologic and may be due to central nervous system lesions or peripheral nerve inflammation or compression. The physician should also inquire about the presence of oropharyngeal symptoms (e.g., dysphagia, dysarthria), vision loss, or diplopia, which can be indicative of inflammatory myopathy, multiple sclerosis, or myasthenia gravis, respectively.2,911,27

The presence of accompanying sensory symptoms suggests a neuropathic etiology from intrinsic or extrinsic factors. For example, pain in the same distribution as the weakness suggests nerve compression, inflammatory neuropathy or myopathy, or muscle damage due to toxins or medications. History of fevers, arthralgias, rash, or Raynaud phenomenon suggests inflammatory etiologies. Fever also suggests infectious etiologies. All types of inflammatory myopathy can present with pain and muscle tenderness.3,10,26

Patients with myasthenia gravis often present with intermittent blurry vision or diplopia and less commonly with more generalized weakness. In addition, symptoms of myasthenia gravis often fluctuate, worsen throughout the day, and may be exacerbated by elevated temperatures.7

A family history may help identify hereditary causes of muscle weakness.2,11,17 A medication review and screening for substance use should always be performed in patients with muscle weakness.15,35

Physical Examination

Physical examination is crucial to diagnosing the cause of muscle weakness. Weakness should be formally graded and documented with a tool such as the Medical Research Council Manual Muscle Testing scale (Table 445).

 Enlarge     Print

TABLE 4.

Medical Research Council Manual Muscle Testing Scale for Assessing Muscle Strength

5: Muscle movement/activation against examiner's full resistance

4: Muscle strength is reduced but movement/activation against some resistance is possible

3: Muscle movement/activation against gravity (e.g., raising leg or arm) but not against resistance

2: Muscle movement/activation only when not moving against gravity (e.g., not lifting leg or raising arm)

1: Trace muscle movement/activation (e.g., a twitch)

0: No muscle movement/activation


Note: The patient's strength is graded from 0 (no movement) to 5 (full strength).

Adapted with permission from Naqvi U, Sherman AI. Muscle strength grading. StatPearls. February 17, 2019. https://www.ncbi.nlm.nih.gov/books/NBK436008/

TABLE 4.

Medical Research Council Manual Muscle Testing Scale for Assessing Muscle Strength

5: Muscle movement/activation against examiner's full resistance

4: Muscle strength is reduced but movement/activation against some resistance is possible

3: Muscle movement/activation against gravity (e.g., raising leg or arm) but not against resistance

2: Muscle movement/activation only when not moving against gravity (e.g., not lifting leg or raising arm)

1: Trace muscle movement/activation (e.g., a twitch)

0: No muscle movement/activation


Note: The patient's strength is graded from 0 (no movement) to 5 (full strength).

Adapted with permission from Naqvi U, Sherman AI. Muscle strength grading. StatPearls. February 17, 2019. https://www.ncbi.nlm.nih.gov/books/NBK436008/

NEUROLOGIC EXAMINATION

A neurologic examination should be performed in patients with muscle weakness to observe signs of upper motor neuron vs. lower motor neuron pathology. Upper motor neuron findings include spasticity (e.g., spastic gait), hyperreflexia, upgoing-toe plantar reflexes (positive Babinski reflex), dysarthria, clonus, and poor coordination. Lower motor neuron findings include diminished or absent reflexes, hypotonia, muscle atrophy (e.g., hoarse voice from laryngeal muscle atrophy), and fasciculations. Visual inspection of the muscles with attention to bulk, involuntary movements, and symmetry is also important.

Hyperreflexia can occur with upper motor neuron lesions, hyperthyroidism, and hypercalcemia. Hypocalcemia is suggested with tetany, Chvostek sign (tapping the facial nerve anterior to the earlobe and inferior to the zygomatic arch elicits ipsilateral facial nerve spasm), and Trousseau sign (inflation of a brachial blood pressure cuff induces distal carpopedal spasm). Up to 94% of patients with hypocalcemia present with Trousseau sign, although Chvostek sign is neither sensitive nor specific for hypocalcemia.43,44

Cranial nerve examination can reveal facial nerve weakness suggesting Lyme disease, herpes simplex virus 1 infection, or herpes zoster (Ramsay Hunt syndrome).37 Ptosis or diplopia may suggest myasthenia gravis. Motor strength worsens with repetition in patients with myasthenia gravis, whereas strength and reflexes may transiently improve after repetitive muscle contraction in patients with Lambert-Eaton syndrome.7,8

The distribution of weakness elicited in the history should be confirmed on physical examination with careful attention to proximal vs. distal strength and symmetric vs. asymmetric strength.

EXTRANEUROLOGIC FINDINGS

Extraneurologic findings may help narrow the diagnosis in patients with muscle weakness. As noted earlier, fever suggests inflammatory or infectious myopathy. Cushingoid appearance (buffalo hump, purple striae) suggests endogenous or exogenous glucocorticoid excess. A violaceous rash on the knuckles and extensor surfaces of the upper extremities (Gottron papules; Figure 246), a heliotrope rash, the V-sign (violaceous rash on the upper chest and neck), and the shawl sign (violaceous rash on the back) occur with dermatomyositis. Cardiac arrhythmias may occur with inflammatory myopathy, genetic disorders, and electrolyte imbalances.3,9,10,14,26

FIGURE 2.

Gottron papules.

Reprinted with permission from Kim HS, Kim SM, Lee JD. Erythematous papules on dorsum of both hands. Am Fam Physician. 2017;95(12):803.


FIGURE 2.

Gottron papules.

Reprinted with permission from Kim HS, Kim SM, Lee JD. Erythematous papules on dorsum of both hands. Am Fam Physician. 2017;95(12):803.

SARCOPENIA AND FRAILTY

Numerous screening tools are available to evaluate weakness in older patients if sarcopenia or frailty is suspected. They include the Fried frailty index, FRAIL (fatigue, resistance, ambulation, illnesses, loss of weight) scale, grip strength analysis, and gait speed analysis.47 Grip strength can be measured objectively with a dynamometer, and gait speed can be measured by timing a patient's usual walking gait to the examination room or by using the Timed Up and Go test.48 Age-specific normative values for grip strength and gait speed are available.38,39

Laboratory Evaluation

Depending on clinical findings and suspected diagnosis, focused or expansive laboratory testing may be indicated in patients with muscle weakness.

Creatine kinase elevation is nonspecific but can help narrow the differential diagnosis and confirm myopathy.26 Creatine kinase levels should not be checked immediately after electrodiagnostic testing because they may be transiently elevated.5,18 Myoglobinuria may also indicate myopathy.3

Because metabolic abnormalities may contribute to weakness, an electrolyte panel should be considered to determine levels of calcium, potassium, sodium, phosphate, and magnesium. Thyroid function testing and cortisol measurement should also be considered.

Serum testing for infectious etiologies, including HIV infection, Lyme disease, West Nile virus infection, and dengue fever, may be indicated if a pathogen is suspected. Lumbar puncture may be indicated if central nervous system infection is suspected.

Anti–acetylcholine receptor antibodies are present in 80% to 90% of patients with generalized myasthenia gravis but in only 50% to 55% of patients with isolated ocular myasthenia gravis.7,11 If clinical suspicion is high despite negative findings on serum anti–acetylcholine receptor antibody testing, the patient should be referred to a neurologist.4,7,11

Specific serum molecular genetic testing may be performed if there is concern for genetic disorders, although this testing is typically ordered by a specialist (e.g., neurologist, rheumatologist, geneticist).

Imaging and Electrodiagnostic Testing

Timely neuroimaging is critical in the evaluation of suspected stroke and cauda equina syndrome. If other neurologic diagnoses (e.g., multiple sclerosis, spinal stenosis, stroke) are suspected, appropriate imaging should be performed. Magnetic resonance imaging and ultrasonography of muscle tissue may be used in the diagnosis of inflammatory myopathy.5

Electromyography should be performed in patients with muscle weakness if the diagnosis is unclear after a history, physical examination, and targeted laboratory evaluation.5,18,19,26 Electromyography assists in localizing the cause of weakness to the motor neuron, neuromuscular junction, or muscle.3 Although electromyography complements the neurologic examination, the findings are not pathognomonic for specific diseases. Abnormal findings on electromyography, with or without muscle imaging, may help localize a suitable site for muscle biopsy.5,18,19

Muscle Biopsy

Muscle biopsy is considered the definitive test for diagnosing myopathies; however, it is invasive and used sparingly. Muscle biopsy should be considered to clarify the diagnosis in patients who have objective weakness with elevated creatine kinase levels or abnormal findings on electromyography or on muscle magnetic resonance imaging.20,21 Biopsy may also be necessary in cases of suspected inflammatory myopathy if the skin findings of dermatomyositis are absent.9,10

Muscle biopsy is generally performed as an outpatient procedure by a surgical consultant. The ideal biopsy site is a muscle that exhibits mild-to-moderate clinical weakness. Severely weak muscles should be avoided, because biopsy of a muscle in an advanced stage of myopathy often shows signs of fibrosis or fatty infiltration, yielding nondiagnostic results.5,9 Muscle biopsy in older patients with significant sarcopenia is unlikely to be diagnostic.5 Complications of muscle biopsy are uncommon but include pain, stiffness, bleeding, and infection.5,21

This article updates a previous article on this topic by Saguil.6

Data Sources: We searched PubMed, the Cochrane database, and Essential Evidence Plus for the terms muscle weakness, muscle weakness evaluation, myopathy, motor neuropathy, muscle biopsy, neurologic weakness, electrodiagnostic testing weakness, myasthenia gravis, Lambert Eaton, inflammatory myopathy, sarcopenia, frailty, Guillain Barré, Parsonage Turner, hypocalcemia, Chvostek, Trousseau calcium, and multiple sclerosis. Search dates: January 12 to June 13, 2019, and September 22, 2019.

The Authors

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SCOTT T. LARSON, MD, is a clinical assistant professor in the Department of Family Medicine at the University of Iowa Hospitals and Clinics, Iowa City....

JASON WILBUR, MD, is the director of the Geriatric Medicine Fellowship Program, associate director of the Family Medicine Residency Program, and a clinical professor in the Department of Family Medicine at the University of Iowa Carver College of Medicine, Iowa City.

Address correspondence to Jason Wilbur, MD, University of Iowa Carver College of Medicine, 200 Hawkins Dr., Iowa City, IA 52242 (email: jason-wilbur@uiowa.edu). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

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show all references

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