What is the initial diagnostic approach and treatment plan for a patient presenting with weakness?

Initial Diagnostic Approach to Weakness

Begin by clarifying what the patient means by "weakness" through direct questioning, as patients often use this term to describe fatigue, asthenia, or other conditions rather than true loss of motor strength—this distinction fundamentally changes the diagnostic pathway. 1, 2

History: Critical Elements to Elicit

• Onset and tempo: Acute (hours to days) versus subacute/chronic; sudden onset suggests vascular, toxic, or metabolic causes, while gradual progression points toward neuromuscular disorders 3, 4

• Pattern of weakness: Proximal versus distal, symmetric versus asymmetric, focal versus generalized—this localizes the lesion along the neuraxis from brain to muscle 3, 2

• Associated symptoms:

  • Respiratory difficulty or dysphagia suggests myasthenia gravis, Guillain-Barré, or severe myositis requiring urgent intervention 5
  • Cranial nerve involvement (diplopia, ptosis, facial weakness) points to myasthenia gravis or brainstem pathology 6
  • Sensory deficits indicate peripheral neuropathy or spinal cord lesions rather than primary muscle disease 5, 2

• Medication history: Specifically ask about statins, corticosteroids, immune checkpoint inhibitors, chemotherapy agents, and illicit drugs 5

• Family history: Inherited myopathies, periodic paralysis, or muscular dystrophies 5, 2

Physical Examination: Objective Documentation Required

Perform manual muscle testing (MMT) using the Medical Research Council (MRC) 6-point scale across 12 muscle groups bilaterally—this provides objective quantification and an MRC sum score <48 defines clinically significant weakness. 5, 7

• Observe for Gower maneuver: Inability to rise from floor without pushing up with arms indicates proximal muscle weakness, classic for muscular dystrophy 5

• Assess muscle bulk and texture: Atrophy suggests chronic denervation or disuse; calf hypertrophy in a weak child suggests Duchenne muscular dystrophy 5

• Deep tendon reflexes: Diminished/absent reflexes indicate lower motor neuron or peripheral nerve disease; hyperreflexia with upgoing plantar responses indicates upper motor neuron pathology 5, 2

• Respiratory assessment: Measure vital capacity if any suggestion of respiratory muscle involvement—this is critical for myasthenia gravis, Guillain-Barré, or severe myositis 5

• Cranial nerve examination: Test extraocular movements, facial strength, palatal elevation, and tongue strength 6, 2

Initial Laboratory Testing

Order creatine kinase (CK), thyroid-stimulating hormone (TSH), and basic metabolic panel as first-line tests—these identify the most common and treatable causes of weakness. 5, 2

Tier 1 (Obtain immediately):

• CK level: Markedly elevated (>1000 U/L) indicates rhabdomyolysis, muscular dystrophy, or severe myositis requiring urgent management 5
• Electrolytes including calcium and magnesium: Hypokalemia, hypercalcemia, and hypomagnesemia cause reversible weakness 5, 6
• TSH: Hypothyroidism and hyperthyroidism both cause weakness 5, 2
• Troponin if CK elevated: Myocarditis can accompany myositis, particularly with immune checkpoint inhibitors 5

Tier 2 (If Tier 1 normal and weakness persists):

• Complete blood count, comprehensive metabolic panel, liver function tests 5
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP): Elevated in inflammatory myopathies 5, 2
• Fasting glucose and hemoglobin A1c: Diabetic neuropathy or myopathy 5

Tier 3 (Guided by clinical suspicion):

• Autoantibody panel: ANA, anti-Jo-1, anti-acetylcholine receptor antibodies if myositis or myasthenia gravis suspected 5, 2
• Aldolase, LDH, AST, ALT: Additional muscle enzyme markers 5

Electrodiagnostic Testing

If the diagnosis remains unclear after initial laboratory testing, proceed to electromyography (EMG) and nerve conduction studies (NCS)—these distinguish myopathy from neuropathy from neuromuscular junction disorders. 5, 2

• EMG/NCS should be performed early (Days 2-10) in uncooperative ICU patients, but can be delayed in cooperative patients to see if abnormalities persist 5
• The positive predictive value of early ICU EMG for final weakness diagnosis is only 50%, but negative predictive value is 89% 5

Critical Red Flags Requiring Urgent Intervention

Immediately assess for these life-threatening conditions:

• Respiratory muscle weakness: Measure vital capacity; intubation may be needed for myasthenia crisis, Guillain-Barré, or severe myositis 5
• Dysphagia: Aspiration risk requires NPO status and swallow evaluation 5
• Rhabdomyolysis: Check urinalysis for myoglobinuria; CK >5000 U/L with renal dysfunction requires aggressive IV hydration 5
• Hypokalemia <2.5 mEq/L: Can cause life-threatening arrhythmias and paralysis requiring urgent potassium replacement 6

Treatment Approach Based on Etiology

For Immune-Mediated Myositis (Grade 3-4):

Hold any immune checkpoint inhibitors permanently and initiate methylprednisolone 1-2 mg/kg IV; consider plasmapheresis for severe cases with respiratory compromise or dysphagia. 5

• Hospitalize patients with severe weakness limiting mobility, respiratory involvement, or rhabdomyolysis 5
• Urgent rheumatology and neurology consultation 5
• IVIG is an alternative but has slower onset than plasmapheresis 5

For Suspected Myasthenia Gravis:

• Edrophonium test (2 mg IV) produces rapid but transient improvement if positive 6
• Anti-acetylcholine receptor antibodies confirm diagnosis 5
• Initiate pyridostigmine; severe cases require plasmapheresis or IVIG 6

For Muscular Dystrophy (Elevated CK in child):

• Genetic testing for DMD gene mutations confirms Duchenne/Becker muscular dystrophy 5
• Refer to neuromuscular specialist for disease-modifying therapies 5

Common Pitfalls to Avoid

• Mistaking fatigue or deconditioning for true weakness: Always objectively document loss of strength with MMT 1, 2
• Overlooking medication-induced myopathy: Statins are a frequent culprit and should be held during evaluation 5
• Delaying respiratory assessment: Vital capacity measurement is simple and identifies patients at risk for respiratory failure 5
• Assuming normal CK excludes myopathy: Some myopathies (mitochondrial, congenital myasthenia) have normal CK 5, 2
• Failing to check potassium in acute weakness: Hypokalemic periodic paralysis is easily treated but can recur without prophylaxis 6