Cause	Weakness	Upper or lower motor neuron signs	Pattern of onset	Systemic symptoms and findings	Laboratory or imaging	Creatine kinase level	Electromyography	Muscle 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