What are the causes and treatments of muscle weakness?

Causes of Muscle Weakness

Broad Categories of Muscle Weakness

Muscle weakness results from dysfunction at any level of the motor unit—from the anterior horn cell through the peripheral nerve, neuromuscular junction, to the muscle itself—and requires systematic evaluation to identify inflammatory versus noninflammatory causes, with particular attention to life-threatening etiologies. 1

Inflammatory Myopathies

• Dermatomyositis (DM) presents with symmetric proximal muscle weakness developing over weeks to months, coupled with characteristic skin findings (heliotrope rash, Gottron papules, periorbital edema) and elevated muscle enzymes 1
• Polymyositis (PM) causes proximal muscle weakness without the skin manifestations of DM, with inflammatory infiltrates on muscle biopsy 1
• Immune-mediated necrotizing myopathy (IMNM) presents with acute or subacute onset of severe proximal weakness, CK levels often exceeding 10 times normal, and minimal inflammatory infiltrate on biopsy; triggers include statins, viruses, and malignancy 1
• Inclusion body myositis affects patients over 50 years with insidious onset of asymmetric weakness involving both proximal and distal muscles, particularly forearm flexors, finger flexors, and quadriceps, with dysphagia as a prominent feature 1
• Immune checkpoint inhibitor-related myositis occurs in cancer patients receiving immunotherapy, requiring urgent recognition as it can rapidly progress to respiratory failure and myocarditis 1

Noninflammatory Myopathies

• Muscular dystrophies including late-onset limb-girdle dystrophy and dysferlinopathies present with proximal weakness and elevated CK; muscle biopsy shows dystrophin reduction/absence with degenerating fibers and fat/connective tissue replacement 1
• Mitochondrial myopathies demonstrate subsarcolemmal mitochondrial accumulation with "ragged red fibers" on Gomori trichrome stain and cytochrome c oxidase deficiency 1
• Pompe disease (glycogen storage disease type II) causes progressive proximal muscle weakness with respiratory impairment; infantile-onset presents with hypertrophic cardiomyopathy and massive cardiomegaly, while late-onset mimics limb-girdle dystrophy 1

Endocrine and Metabolic Causes

• Thyroid disorders (both hypothyroidism and hyperthyroidism) cause proximal muscle weakness with normal or mildly elevated CK 1
• Hyperparathyroidism produces proximal weakness through calcium dysregulation 1
• Hypophosphatemia directly causes respiratory muscle weakness through cellular ATP depletion, particularly in patients receiving continuous renal replacement therapy (CRRT) where prevalence reaches 60-80% 2
• Severe hypokalemia (below 2.5-3.0 mEq/L) causes respiratory muscle weakness affecting the diaphragm and accessory muscles, manifesting as reduced vital capacity and impaired cough 3

Neurologic Causes

• Amyotrophic lateral sclerosis (ALS) presents with progressive asymmetric weakness, muscle atrophy, fasciculations, and upper motor neuron signs 4
• Guillain-Barré syndrome causes acute ascending weakness evolving over hours to days with areflexia and potential respiratory failure 5, 4
• Myasthenia gravis produces fluctuating weakness with fatigability, typically affecting ocular, bulbar, and proximal muscles; concomitant use with anticholinesterase agents and corticosteroids can produce severe weakness 1, 6, 4
• Spinal muscular atrophy causes asymmetric muscle weakness with atrophy of voluntary muscles 1

Drug-Induced Myopathy

• Statin-induced necrotizing myopathy associated with anti-HMGCR antibodies causes severe weakness with markedly elevated CK that may persist after statin discontinuation 1
• Corticosteroid-induced myopathy occurs with high-dose or prolonged use, presenting as generalized weakness that may involve ocular and respiratory muscles with elevated creatinine kinase; acute myopathy is most common in patients with neuromuscular transmission disorders or those receiving neuromuscular blocking drugs 6
• Potassium-depleting agents (amphotericin B, diuretics) when combined with corticosteroids increase hypokalemia risk and associated weakness 6

Infectious and Toxic Causes

• Infectious myopathies from viral, bacterial, or parasitic organisms can cause acute or subacute weakness with elevated muscle enzymes 1
• Botulism produces descending paralysis with autonomic dysfunction evolving rapidly over hours to days 5

Critical Illness-Related Weakness

• CRRT-associated weakness results primarily from hypophosphatemia (up to 80% prevalence), compounded by amino acid losses (10-15 g/day), protein losses (5-10 g/day), and electrolyte derangements including hypokalemia and hypomagnesemia 2
• Acute renal failure independently causes protein catabolism, insulin resistance, and altered amino acid metabolism predisposing to muscle weakness 2

Diagnostic Approach

Initial Laboratory Evaluation

• Creatine kinase (CK) is elevated in most inflammatory myopathies (highest in infantile Pompe disease and IMNM), muscular dystrophies, and some metabolic myopathies; approximately 95% of late-onset Pompe patients have elevated CK, though some adults may have normal levels 1
• Aldolase, AST, ALT, and LDH can be elevated, reflecting muscle enzyme release 1
• Thyroid-stimulating hormone (TSH) to exclude thyroid disorders 7
• Electrolytes including potassium, phosphate, magnesium, and calcium to identify metabolic causes; check phosphate at CRRT initiation and at least daily during treatment 2, 3
• Troponin and ECG to evaluate myocardial involvement, particularly in inflammatory myopathies 1
• Autoantibody testing for myositis-specific antibodies (anti-Jo-1, anti-SRP, anti-Mi2, anti-TIF1γ, anti-NXP2) and myasthenia gravis (anti-AChR, antistriational antibodies) 1
• Urinary glucose tetrasaccharide (Glc4) is a sensitive though nonspecific marker for Pompe disease and other glycogen storage diseases 1

Electrodiagnostic Testing

• EMG confirms myopathic process (polyphasic motor unit action potentials of short duration and low amplitude with increased insertional activity, fibrillation potentials, sharp waves) and targets muscle for biopsy 1
• EMG is indicated for suspected ALS, myasthenia gravis, neuropathy, and radiculopathy 7

Imaging

• MRI of proximal muscle groups using T1-weighted, T2-weighted, and fat suppression sequences identifies muscle inflammation, monitors treatment response, and can guide biopsy site selection 1
• Cardiac MRI evaluates myocardial involvement in inflammatory myopathies 1
• Brain/spine MRI is indicated for acute neurologic conditions (stroke, cauda equina syndrome) 7

Muscle Biopsy

• Muscle biopsy is the gold standard for confirming inflammatory myopathy diagnosis and differentiating inflammatory from noninflammatory causes; choose a weak muscle demonstrated by EMG abnormalities, biopsying the contralateral side 1
• Biopsy findings distinguish muscular dystrophy (dystrophin reduction/absence, fiber degeneration/regeneration, fat/connective tissue replacement), mitochondrial myopathy (ragged red fibers, cytochrome c oxidase deficiency), and inflammatory infiltrates characteristic of specific myositis subtypes 1

Genetic Testing

• Dystrophin gene testing for muscular dystrophy when biopsy suggests dystrophinopathy 1
• GAA enzyme activity measured in cultured fibroblasts, muscle biopsy, or purified lymphocytes confirms Pompe disease (virtually absent in infantile-onset, markedly reduced in late-onset) 1

Key Clinical Pitfalls

• Distinguishing true weakness from subjective fatigue requires objective grading using formal tools like the Medical Research Council Manual Muscle Testing scale; true weakness is defined as loss of power resulting in reduced motor function 7, 4
• Muscle weakness is more typical of myositis than pain; pain predominance suggests neuropathy or radiculopathy rather than primary muscle disease 1
• Respiratory muscle involvement can rapidly progress to life-threatening failure, particularly with severe hypokalemia (below 2.5 mEq/L), hypophosphatemia, Guillain-Barré syndrome, myasthenia gravis, and immune checkpoint inhibitor myositis; assess respiratory rate, work of breathing, oxygen saturation, and cough effectiveness immediately 2, 3, 5
• Corticosteroid-induced acute myopathy is most likely in patients with myasthenia gravis or those receiving neuromuscular blocking drugs; clinical improvement may require weeks to years after stopping corticosteroids 6
• Failing to correct magnesium deficiency makes potassium repletion ineffective in hypokalemic weakness 3
• Overlooking malignancy screening in adult dermatomyositis, where cancer association is well-established, though exhaustive evaluation is not warranted in children with juvenile dermatomyositis absent suggestive findings (hepatosplenomegaly, extensive lymphadenopathy) 1