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Am Fam Physician. 2020;101(2):95-108

Related letter: Differential Diagnosis of Muscle Weakness in Adults

Author disclosure: No relevant financial affiliations.

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

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

CauseWeaknessUpper or lower motor neuron signsPattern of onsetSystemic symptoms and findingsLaboratory or imagingCreatine kinase levelElectromyographyMuscle biopsy
Amyotrophic lateral sclerosisVariable, 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)BothGradualMuscle cramps, muscle atrophy (often in the hands); fasciculations, including in the tongue; spasticity; may exhibit pseudobulbar affectMRI of brain and spinal cord may help rule out other causes of weaknessNormal or elevatedReduced CMAP amplitude with normal sensory nerve amplitude; fibrillation potentials,* positive sharp wavesNot typically performed
Cerebral lesion (stroke, hemorrhage, mass)Variable depending on lesion location, often unilateralUpperAcute (stroke), subacute or gradual (mass, subdural hematoma)May present with headache, altered cognition, or altered sensoriumMRI may reveal etiologyNot typically obtainedNot typically performedNot typically performed
Compressive neuropathy of the peripheral nerve, (e.g., carpal tunnel syndrome, lumbar radiculopathy)Variable, unilateralLowerVariablePain, paresthesia; spinal nerve root compression may cause radicular symptomsUltrasonography may reveal nerve entrapmentNot typically obtainedFibrillation potentials,* positive sharp waves; reduced MUAP amplitude distal to offending lesionNot typically performed
Guillain-Barré syndromeSymmetric, bilateral; affects distal and proximal muscles; may progress to include respiratory and bulbar involvementLowerAcuteHistory 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 illnessNot typically obtainedMay be normal in first week of illness; later shows patchy demyelination findings of temporal dispersion of CMAPs; slowed motor conduction velocity and/or conduction blockNot typically performed
Lambert-Eaton syndromeProximal, caudocranial progression; initially improves with repetition; diminished tendon reflexesLowerVariableDysautonomia, impotence, hypotension, xerostomia; often develops as a paraneoplastic syndrome associated with small cell lung cancer but may be idiopathicAnti–voltage-gated calcium channel antibodyNormalLow CMAP amplitude with rest, improvement postexercise; fibrillation potentials*Not typically performed
Motor neuropathyDistal, eventually proximalLowerGradualMay have accompanying sensory neuropathy with paresthesia or numbness; toe deformities, foot ulcers; impaired balanceVarious genetic tests depending on suspected etiology; elevated serum glucose or A1C level if caused by diabetic neuropathy; muscle atrophy on MRINot typically obtainedLow CMAP amplitude in lower extremities; demyelination signs in upper extremitiesNot typically performed
Multiple sclerosisVariable depending on location, often unilateralUpperVariableMay present with bladder dysfunction, cognitive impairment, sensory changes, monocular vision loss due to optic neuritis, cerebellar ataxiaMRI may show characteristic white matter lesions of the brain or spinal cordNot typically obtainedNot typically performedNot typically performed
Myasthenia gravisProximal, cephalocaudal progression; worsens with repetition (fatigability); oculomotorLowerVariableWorsening of symptoms throughout the dayAnti–acetylcholine receptor antibody testing; anti–striated muscle antibody and anti–muscle specific tyrosine kinase antibody testing have less utilityNormalNormal 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 bilateralUpperAcute (stroke), gradual (mass)Back pain, bowel or bladder incontinenceMRI may reveal etiologyNot typically obtainedNot typically performedNot typically performed
DermatomyositisProximalAcute or subacuteViolaceous 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; dysphagiaElevated myoglobin; positive for antinuclear antibodies; may be positive for myositis autoantibodiesGreater than 10 times the normal elevationsActive and chronic myopathic unitsInflammatory infiltrate with myopathic changes and replacement by adipose and collagen
Inclusion body myositisDistal, especially forearm and hand; later stage may involve proximal weaknessGradualDysphagia (present in up to 80% of cases); extramuscular involvement not as commonElevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be presentElevatedActive and chronic myopathic unitsInflammatory infiltrate with vacuoles containing eosinophilic inclusions; ragged red or ragged blue fibers
Necrotizing myositisProximal, often profoundAcuteMay be associated with viral illness, malignancy, or statin use; dysphagiaAnti–signal recognition particle antibody; anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibodyMarkedly elevated (can be over 50 times normal limit)Active myopathic unitsScattered necrosis, deposits of complement may be noted on capillaries
PolymyositisProximalAcute or subacuteSimilar in presentation to dermatomyositis but without dermatologic signs; interstitial lung disease; disordered GI motility; dysphagiaElevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be presentGreater than 10 times normal elevationsActive and chronic myopathic unitsInflammatory infiltrate with myopathic changes and replacement by adipose and collagen
Adrenal insufficiency (Addison disease)GeneralizedVariableHypotension, hypoglycemia, bronzing of the skinHyponatremia, hyperkalemia; adrenocorticotropic hormone assay and stimulation testNormalMyotonic discharges§Diminished glycogen content
Elevated thyroid hormone (hyperthyroidism)Proximal, bulbarVariableWeight loss, tachycardia, increased perspiration, tremorElevated thyroxine (T4) and triiodothyronine (T3) hormones; thyroid-stimulating hormone variable depending on causeNormal or elevatedMyopathic MUAPs with or without fibrillation potentials*Usually normal
Endogenous glucocorticoid excess (Cushing syndrome)ProximalVariableBuffalo hump, purple striae, osteoporosisElevated urine-free cortisol, dexamethasone suppression, or corticotropin-releasing hormone stimulation testsNormal or lowMyopathic MUAPsSelective atrophy of type II muscle fibers, absent necrosis
Low/absent thyroid hormone (hypothyroidism)ProximalVariableMenorrhagia, bradycardia, goiter, delayed relaxation of deep tendon reflexesThyroid-stimulating hormoneElevatedWith or without myopathic MUAPs and fibrillation potentials*Myopathic changes, glycogen accumulation
Parathyroid hormone (secondary hyperparathyroidism)Proximal, lower extremity more than upper extremityVariableUsually has associated comorbidities (cardiovascular disease, diabetes mellitus); positive Chvostek or Trousseau signsHypocalcemia; uremiaNormalMyopathic MUAPsAtrophy of type II muscle fibers;increased lipofuscin beneath cell membrane; calcium deposits in muscle
Becker muscular dystrophyHip, proximal leg and armGradualIntellectual disability, cardiomyopathyVarious specific molecular genetic tests are availableElevatedMyopathic MUAPs with fibrillation potentials*Myopathic changes, decreased and patchy staining of dystrophin
Glycogen and lipid storage diseases, mitochondrial diseasesProximalVariableVariable; exercise intolerance and cardiomyopathy more commonSome glycogenoses associated with abnormal findings on forearm ischemic exercise testing**Variable, may increase with exerciseNormal 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 dystrophyVariable; usually proximal limb, pelvic, and shoulder girdle musclesGradualVariable, may have cardiac abnormalitiesVarious specific molecular genetic tests availableVariable, normal, or elevatedMyopathic MUAPs with or without fibrillation potentials*Myopathic changes, may demonstrate absence of specific protein on immunohistochemical staining
Myotonic dystrophy type 1Distal greater than proximal, foot drop, oropharyngeal, temporal and masseter wasting, difficulty opening hand after tight gripGradualCardiac conduction abnormalities, balding, intellectual disability, gonadal atrophy, cataracts, insulin resistance, scoliosisMolecular genetic testing may demonstrate unstable CTG trinucleotide repeat in the DMPK gene of chromosome 19Normal to minimally elevatedMyopathic MUAPs, myotonic discharges*Less necrosis and remodeling than in muscular dystrophy, atrophy of type I muscle fibers, ring fibers
FluoroquinolonesDistalAcute or subacuteTendon swelling or erythema, tendon rupture in severe casesUltrasonography or MRI may demonstrate tendon ruptureNot typically performedNot typically performed
GlucocorticoidsTypically affects proximal and postural musclesAcute, subacute, or gradualBuffalo hump, purple striaeNo reliable biomarkers; may have leukocytosisNormal or lowMyopathic MUAPsSelective atrophy of type II muscle fibers, absent necrosis
StatinProximal (may be distal)Acute or subacuteMyalgia 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 massNoneElevatedMyopathic MUAPsMyonecrosis in severe cases
Alcohol (myopathy or neuropathy)Proximal (may be distal)Alcoholic neuropathy: lower; alcoholic myopathy: —VariableChange in mental status, telangiectasia, peripheral neuropathyElevated transaminase and gamma-glutamyltransferase levels, anemia, decreased vitamin B levels12Normal to elevatedNormalMyopathic changes, selected atrophy of type II muscle fibers
Sarcopenia and frailtyVariable, slow gait speed, diminished grip strengthGradual onset in patients older than 65 yearsLoss of muscle mass, cachexiaNo specific biomarkers but may have low creatinine, decreased insulinlike growth factor 1, albumin, or vitamin D levels; may have elevated interleukin-6Normal or lowNot typically performedSample may be inadequate because of lack of muscle mass; fatty infiltration


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


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


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


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


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


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

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
Gemfibrozil (Lopid)
Glucocorticoids (systemic)
HMG-CoA reductase inhibitors (statins)Hydroxychloroquine (Plaquenil)
Interferon alfa*
Local anesthetics
Omeprazole (Prilosec)*
Penicillamine (Cuprimine)*
Phenytoin (Dilantin)*
Silicone gel (ruptured breast implant)*


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


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


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


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).

Key findingsSuggested diagnoses
Diplopia, blurry visionMyasthenia gravis (intermittent), diabetic neuropathy (permanent)
DysphagiaInflammatory 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, rashInflammatory or infectious myopathy
Monocular vision loss, bladder dysfunctionMultiple sclerosis
PainNerve compression, rhabdomyolysis, inflammatory myopathy, inflammatory neuropathy (e.g., Parsonage-Turner syndrome), muscle damage due to toxins or medications (e.g., statins, fluoroquinolones)
ParesthesiaHereditary sensorimotor disorders (e.g., Charcot-Marie-Tooth disease), nerve compression, nerve damage due to toxins, multiple sclerosis
Raynaud phenomenonInflammatory myopathy
Tendon ruptureFluoroquinolone use
Physical examination
Cardiac arrhythmiasInflammatory myopathy, genetic disorders, electrolyte imbalances
Cholinergic toxidromeOrganophosphate poisoning
Chvostek sign,* Trousseau sign, tetanyHypocalcemia
Cushingoid appearance (buffalo hump, purple striae)Glucocorticoid excess (endogenous [Cushing syndrome] vs. exogenous [long-term glucocorticoid use])
Fatigable weakness, ptosisMyasthenia gravis
HyperreflexiaUpper motor neuron lesion, hyperthyroidism, hypercalcemia
HyporeflexiaHypothyroidism, lower motor neuron lesion
Muscle atrophyLower motor neuron pathology, frailty/sarcopenia
Skin bronzingHypoaldosteronism (Addison disease)
Third cranial nerve (oculomotor nerve) palsyDiabetic 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

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).

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


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 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


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.

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