What are the possible causes of leg weakness?

Causes of Leg Weakness

Leg weakness arises from a broad spectrum of etiologies spanning neurologic, muscular, endocrine, vascular, rheumatologic, infectious, and toxic causes, requiring systematic evaluation to identify the underlying pathology and prevent progression to irreversible disability.

Neurologic Causes

Central Nervous System

• Spinal cord pathology including tethered cord syndrome presents with progressive leg weakness, gait disturbances, and sensorimotor deficits that worsen over time, particularly in children who may regress from previously normal ambulation 1
• Lumbar spinal stenosis causes bilateral buttock and posterior leg pain with weakness that worsens with standing or spinal extension and improves with sitting or lumbar flexion, predominantly affecting middle-aged and older adults 2, 3
• Stroke requires immediate imaging evaluation when acute asymmetric weakness develops 4
• Cauda equina syndrome presents with bilateral motor weakness, saddle anesthesia, and urinary retention, constituting a surgical emergency 3

Peripheral Nervous System

• Guillain-Barré syndrome manifests as rapidly progressive bilateral weakness starting distally in the legs and ascending to arms and cranial muscles, with decreased or absent reflexes and a monophasic course reaching maximum disability within 2 weeks 1
• Radiculopathy causes sharp, lancinating pain radiating down specific dermatomal distributions with associated weakness in the affected nerve root distribution 2, 5
• Peripheral neuropathy presents with distal weakness, sensory loss, and pain, often asymmetric in distribution 4
• Leg amyotrophic diplegia is a lower motor neuron disease variant with weakness confined to legs for at least 2 years, showing an asymmetric pelviperoneal pattern (sparing knee extension and/or ankle plantar flexion) with mean survival of 87 months 6

Muscular Causes

Inflammatory Myopathies

• Polymyositis, dermatomyositis, and inclusion body myositis cause moderate to severe proximal muscle weakness, with inclusion body myositis being the most prevalent acquired myopathy above age 50 7
• Immune checkpoint inhibitor-related myositis presents with muscle weakness (more typical than pain), elevated creatine kinase and aldolase, and requires urgent evaluation for myocardial involvement 1

Metabolic and Toxic Myopathies

• Medication-induced myopathy from statins, corticosteroids, SGLT2 inhibitors, and antimalarials causes proximal weakness with elevated creatine kinase 7
• Alcohol-related myopathy produces generalized proximal weakness 7
• Glycogen storage diseases such as McArdle disease cause rapid exhaustion, myalgia, and cramping in working muscles 7

Hereditary Myopathies

• Muscular dystrophies including limb girdle, facioscapulohumeral, Duchenne, and Becker types present with progressive proximal weakness 7
• Lipid deposition myopathies cause lipid accumulation in skeletal muscle fibers leading to degeneration 7

Endocrine and Metabolic Causes

• Adrenal dysfunction including both Cushing's syndrome and adrenal insufficiency causes proximal myopathy and can present with rapid progressive leg weakness, particularly when iatrogenic 7, 8
• Thyroid disorders (both hyperthyroidism and hypothyroidism) directly contribute to muscle weakness 7
• Parathyroid disorders and pituitary dysfunction indirectly cause myopathy 7

Vascular Causes

• Peripheral artery disease with claudication causes leg pain and weakness that occurs predictably with walking a specific distance and resolves within 10 minutes of rest, confirmed by ankle-brachial index ≤0.90 2, 5
• Critical limb ischemia presents with rest pain, non-healing wounds, or tissue loss and constitutes a vascular emergency requiring immediate specialist evaluation 5

Rheumatologic Causes

• Systemic lupus erythematosus, Sjögren's syndrome, and overlap syndromes manifest with moderate to severe muscle weakness 7
• Sarcoidosis can present with muscle weakness and myalgia 7

Infectious Causes

• Viral myositis from HIV, dengue, influenza, hepatitis B and C, and SARS-CoV-2 causes muscle weakness 7

Age-Related Syndromes

• Sarcopenia and frailty in older adults (≥60 years) present with generalized weakness, occurring in approximately 5% of this population 4
• COPD-related skeletal muscle dysfunction shows decreased oxidative enzyme capacity, altered fiber type distribution, and reduced capillarization leading to leg fatigue and exercise intolerance 1

Critical Diagnostic Pitfalls

• Do not assume vascular disease without ankle-brachial index testing, as bilateral leg symptoms frequently mimic peripheral artery disease but may be neurogenic, particularly when relieved by lumbar flexion rather than simple rest 2, 3
• Distinguish true muscle weakness from subjective fatigue or pain-related motor impairment by objective grading using the Medical Research Council Manual Muscle Testing scale 4
• Recognize atypical presentations in young children who may present with refusal to bear weight, irritability, or unsteady gait rather than classic weakness 1
• Evaluate for myocardial involvement in suspected myositis by checking troponin, ECG, and echocardiogram, as cardiac complications significantly impact mortality 1
• Consider combined pathology in elderly patients, as lumbar spinal stenosis may coexist with endocrine, vascular, or other medical conditions that contribute to rapid weakness progression 8
• Assess psychosocial factors including depression and passive coping strategies, which predict poorer outcomes in chronic weakness conditions 3