What initial laboratory tests are recommended for a patient presenting with lower extremity muscle weakness?

Initial Laboratory Workup for Lower Extremity Muscle Weakness

For a patient presenting with lower extremity muscle weakness, begin with creatine kinase (CK) and thyroid-stimulating hormone (TSH) levels as your initial laboratory tests, followed by a complete blood count (CBC), comprehensive metabolic panel (CMP), and inflammatory markers if the diagnosis remains unclear. 1, 2

Primary Initial Tests

Creatine Kinase (CK) and Aldolase

• CK is the single most important initial test when muscle weakness is accompanied by low to normal tone, as it screens for muscular dystrophies and myositis 1
• CK levels >1000 U/L are significantly elevated and suggest Duchenne muscular dystrophy (DMD), which can present with lower extremity weakness starting at 2-4 years of age but may show signs earlier 1
• Aldolase provides additional confirmation of muscle inflammation and should be measured alongside CK 1
• Transaminases (AST and ALT) and LDH can also be elevated in myositis and provide supporting evidence 1

Thyroid-Stimulating Hormone (TSH)

• TSH should be measured early to exclude endocrine causes of weakness, as thyroid dysfunction is a common and treatable cause 1, 2

Secondary Laboratory Tests

Complete Blood Count (CBC)

• Order CBC to evaluate for anemia, which can present with fatigue and weakness 2
• Look for signs of systemic inflammation or infection that may contribute to weakness 2

Comprehensive Metabolic Panel (CMP)

• Evaluate electrolyte abnormalities (particularly potassium, calcium, magnesium) that can cause weakness 2
• Assess renal function with creatinine, as chronic kidney disease can be associated with weakness 2
• Check glucose levels to evaluate for diabetes-related complications 2

Inflammatory Markers

• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) help identify inflammatory or rheumatologic causes 1, 2
• These are particularly important if autoimmune myositis is suspected 1

Specialized Testing Based on Clinical Context

For Suspected Myositis or Immune-Related Causes

• Troponin levels to evaluate for myocardial involvement, as myositis can affect the heart 1
• Autoantibody testing including anti-acetylcholine receptor (anti-AChR) and antistriational antibodies to evaluate for myasthenia gravis 1
• Paraneoplastic autoantibody panel (anti-TIF1γ, anti-NXP2) if muscle symptoms preceded any immunotherapy or if paraneoplastic syndrome is suspected 1
• Urinalysis to check for myoglobinuria and rhabdomyolysis 1

For Suspected Duchenne Muscular Dystrophy

• If CK is significantly elevated (>1000 U/L), proceed directly to DMD gene molecular sequencing for confirmation 1
• Family history of affected males on the maternal side supports this diagnosis, though one-third of cases are new mutations 1

Clinical Examination Priorities

Key Physical Findings to Document

• Gower maneuver: inability to rise from the floor without using arms to push up, which is pathognomonic for proximal muscle weakness 1
• Muscle bulk and texture: look for calf hypertrophy (suggests DMD) or atrophy 1
• Deep tendon reflexes: diminished or absent reflexes suggest lower motor neuron disorders, while increased reflexes with abnormal plantar reflex suggest upper motor neuron dysfunction 1
• Tone assessment: distinguish between high, normal, or low tone, as this guides the differential diagnosis 1

Common Pitfalls to Avoid

• Do not delay CK testing in children or young adults with weakness and low tone, as early diagnosis of DMD is critical for management and genetic counseling 1
• Do not assume normal CK excludes all myopathies, as some muscular dystrophies and metabolic myopathies may have normal or only mildly elevated CK 2
• Do not confuse weakness with fatigue or asthenia, which have different etiologies and require different workups 2
• Do not overlook medication history, as statins and other drugs can cause drug-induced myopathy 1
• Consider holding statins if CK is elevated and myopathy is suspected 1

When to Proceed Beyond Initial Labs

If initial laboratory tests (CK, TSH, CBC, CMP, ESR/CRP) are unrevealing:

• Consider electromyography (EMG) to confirm myopathy versus neuropathy versus neuromuscular junction disease 2
• MRI imaging of affected muscles can identify inflammation or structural abnormalities when diagnosis is uncertain 1
• Muscle biopsy may be required for definitive diagnosis of many myopathies, with analysis including histologic, histochemical, electron microscopic, biochemical, and genetic studies 2
• Urgent referral to neurology or rheumatology is indicated for grade 2 or higher weakness (moderate weakness limiting instrumental activities of daily living) 1