What are the causes and treatment options for proximal muscle weakness in the lower limbs?

Proximal Muscle Weakness of Lower Limbs: Causes and Treatment

Immediate Diagnostic Priorities

Begin by assessing for life-threatening causes: check for respiratory muscle involvement, bulbar symptoms (dysphagia, dysarthria), and cardiac involvement, as these require urgent intervention and potential ICU admission. 1, 2, 3

Critical Red Flags to Identify First

• Checkpoint inhibitor-induced myositis carries 20% mortality risk due to concurrent myocarditis and requires immediate withdrawal of immunotherapy plus high-dose glucocorticoids, IVIG, and/or plasma exchange 3
• Respiratory muscle weakness represents a medical emergency requiring urgent high-dose methylprednisolone 2, 3
• Adult dermatomyositis mandates immediate comprehensive cancer screening including CT chest/abdomen/pelvis and age-appropriate tumor markers 2, 3

Systematic Diagnostic Approach

Initial Clinical Assessment

Look for objective symmetric weakness of proximal lower extremities, which scores 0.8 points (without biopsy) or 0.5 points (with biopsy) in the 2017 EULAR/ACR classification criteria for idiopathic inflammatory myopathies. 1

Key examination findings to document:

• Muscle weakness is more typical of myositis than pain - distinguish true weakness from pain-limited movement 1
• Check if proximal leg muscles are relatively weaker than distal muscles (scores 0.9-1.2 points in EULAR/ACR criteria) 1
• Assess neck flexor weakness relative to extensors (scores 1.6-1.9 points) 1
• Examine for pathognomonic skin findings: heliotrope rash (3.1-3.2 points), Gottron's papules (2.1-2.7 points), or Gottron's sign (3.3-3.7 points) 1, 2

Essential Initial Laboratory Tests

Order creatine kinase (CK), thyroid function tests (TSH, free T4), and inflammatory markers (ESR, CRP) as the first-line blood work. 1, 3, 4

Additional critical labs:

• CK elevation (≥3x upper limit of normal) scores 1.3-1.4 points and may also see elevated AST, ALT, LDH, and aldolase 1
• Troponin to evaluate myocardial involvement with echocardiogram as needed 1
• Anti-Jo-1 (anti-histidyl-tRNA synthetase) antibody scores 3.8-3.9 points when present 1, 2
• Myositis-specific antibody panels including anti-SRP for necrotizing myopathy 1, 2, 3

Advanced Diagnostic Testing

Consider EMG, MRI, and muscle biopsy when diagnosis is uncertain or when no toxic, metabolic, or endocrine cause is identified. 1, 3, 4

• EMG confirms myopathic process with polyphasic motor unit action potentials of short duration and low amplitude 1
• Muscle MRI identifies inflammation and guides biopsy site 3
• Muscle biopsy is the gold standard for confirming IIM diagnosis and distinguishing subtypes 1, 2, 3

Major Causes of Proximal Lower Limb Weakness

Drug-Induced and Toxic Myopathies

Statins are the most common drug cause, producing either statin-associated myopathy or immune-mediated necrotizing myopathy (IMNM). 3

• IMNM requires aggressive immunosuppression with high-dose corticosteroids, IVIG, and methotrexate - simply discontinuing statins is insufficient 2, 3, 5
• Other drug causes include corticosteroids, alcohol, and SGLT2 inhibitors 3

Endocrine and Metabolic Causes

Hyperthyroidism can present with isolated proximal lower limb weakness as the sole manifestation. 6

• Cushing's disease-related myopathy requires definitive treatment of hypercortisolism through transsphenoidal surgery 3
• Hypothyroidism and osteomalacia (vitamin D deficiency) are reversible causes 4

Idiopathic Inflammatory Myopathies (IIM)

The 2017 EULAR/ACR criteria require a score of ≥5.5 for probable IIM and ≥7.5 for definite IIM without muscle biopsy (or ≥6.7 and ≥8.7 respectively with biopsy). 2

Key IIM subtypes:

• Polymyositis: symmetric proximal weakness with CD8+ T cell invasion of muscle fibers on biopsy 3
• Dermatomyositis: proximal weakness with pathognomonic skin findings and elevated CK 2, 3
• Immune-mediated necrotizing myopathy: severe myopathy with minimal inflammatory infiltrate, triggered by statins, viral infections, or malignancy 2, 3, 5
• Inclusion body myositis: most prevalent acquired myopathy above age 50 with vacuolization 3

Hereditary Myopathies

Muscular dystrophy and mitochondrial myopathies should be included in the differential diagnosis when presenting with proximal weakness and elevated CK 1, 4

• Limb-girdle dystrophy (dysferlinopathies) can present in adult years 1
• Genetic testing for dystrophin gene is indicated when muscular dystrophy is suspected 1

Metabolic Storage Disorders

GSD III presents with proximal muscle weakness, elevated CK, hepatomegaly, and hypoglycemia in children. 1

• Distinguished from GSD I by higher hepatic transaminases (AST/ALT often >500 U/L) and normal lactate/uric acid 1
• Muscle weakness in GSD III can be both proximal and distal, unlike Pompe disease which is primarily truncal and proximal 1

Treatment Algorithms

For Idiopathic Inflammatory Myopathies

Initiate high-dose corticosteroids immediately, typically prednisone 1 mg/kg/day, concurrent with steroid-sparing agents such as methotrexate, azathioprine, or mycophenolate mofetil. 2, 3

Grade-based treatment approach:

• Grade 1 (mild symptoms): Complete diagnostic workup, analgesia with acetaminophen or NSAIDs if no contraindications 1
• Grade 2 (CK elevated ≥3x, muscle weakness present): Hold checkpoint inhibitors, initiate prednisone 0.5-1 mg/kg, refer to rheumatology/neurology 1
• Grade 3-4 (severe weakness): Permanently discontinue checkpoint inhibitors if myocardial involvement, consider hospitalization, initiate prednisone 1-2 mg/kg IV methylprednisolone or higher-dose bolus 1, 2, 3

Severe myositis requires high-dose methylprednisolone PLUS IVIG, cyclophosphamide, rituximab, or cyclosporine. 3

For Necrotizing Myopathy

Aggressive immunosuppression with high-dose corticosteroids (1 gram methylprednisolone IV followed by 1 mg/kg daily oral), IVIG (0.4 mg/kg/day for 5 days), and methotrexate is required. 2, 3, 5

• Plasmapheresis may be offered for severe cases 1
• Other immunosuppressants (azathioprine, mycophenolate mofetil) if no improvement after 4-6 weeks 1
• Rituximab should be used with caution given its long biologic duration 1

For Endocrine/Metabolic Causes

Correct the underlying abnormality: treat hyperthyroidism, replace vitamin D for osteomalacia, or perform transsphenoidal surgery for Cushing's disease. 3, 6

• Hyperthyroid myopathy recovers soon after medical treatment 6
• Post-remission growth hormone deficiency may contribute to persistent myopathy 3

For Drug-Induced Myopathy

Remove the offending agent, but for IMNM, aggressive immunosuppression is required in addition to drug discontinuation. 2, 3, 4

Critical Monitoring and Complications

During Corticosteroid Therapy

Corticosteroids cause major morbidity with primary adverse outcomes being osteoporosis, compression fractures, and avascular necrosis. 3

Preventive measures:

• Monitor bone health regularly 3
• Prescribe calcium and vitamin D supplements 3
• Add bisphosphonate if osteoporosis develops 3
• Test for viral hepatitis B, C, and latent/active TB prior to DMARD treatment 1

Important Caveats

Never use neuromuscular blocking agents in patients with necrotizing myopathy due to high risk of prolonged weakness and potential for Acute Quadriplegic Myopathy Syndrome. 2

Distinguish Pompe disease from GSD III: respiratory distress with diaphragm involvement is highly suggestive of Pompe disease, which does not present with hypoglycemia or hepatomegaly 1

Anti-SRP antibody indicates necrotizing myopathy with acute onset, dilated cardiomyopathy, and poor response to standard immunosuppression. 1