What is the appropriate diagnostic work-up and treatment approach for a patient presenting with muscle weakness?

Muscle Weakness Work-Up

Begin by distinguishing true muscle weakness (loss of motor power) from subjective fatigue or pain-related impairment, then grade the weakness objectively using the Medical Research Council Manual Muscle Testing scale, as this distinction fundamentally changes your diagnostic and management approach. 1, 2

Initial Clinical Assessment

History - Key Elements to Elicit

• Pattern of weakness: Determine if proximal versus distal, symmetric versus asymmetric, as asymmetric weakness strongly suggests neurologic conditions while symmetric proximal weakness suggests myopathy 2
• Temporal course: Acute onset (hours to days) suggests Guillain-Barré syndrome, myasthenia gravis, or stroke; subacute (weeks) suggests inflammatory myopathy; chronic (months to years) suggests genetic or endocrine causes 1, 2
• Associated symptoms: Presence of dysphagia, dysarthria, facial weakness, or respiratory symptoms are red flags requiring urgent evaluation 3, 4
• Medication history: Specifically ask about statins, immune checkpoint inhibitors, corticosteroids, and other potentially myotoxic drugs 5, 6
• Fever, rash, or joint symptoms: These suggest inflammatory or autoimmune etiology 5, 4

Physical Examination - Critical Findings

• Objective strength testing: Use Medical Research Council scale (0-5) to document specific muscle groups; functional testing alone is insufficient 2
• Deep tendon reflexes: Absent or reduced reflexes suggest Guillain-Barré syndrome or neuropathy; hyperreflexia with Babinski sign suggests upper motor neuron disease 3, 2
• Muscle atrophy: Presence suggests chronic denervation or disuse 2
• Extramuscular signs: Examine for ptosis and extraocular movement abnormalities (myasthenia gravis), skin rash (dermatomyositis), hoarse voice (bulbar involvement) 3, 4, 2

Laboratory Work-Up

First-Tier Testing (Order Immediately)

• Creatine kinase (CK): Primary marker of muscle inflammation; CK >10× upper limit of normal with symptoms suggests severe myopathy requiring urgent intervention 5, 6
• Electrolytes including calcium and magnesium: Hypocalcemia (check for Chvostek sign), hypokalemia, and hypomagnesemia can cause weakness 2
• Thyroid-stimulating hormone (TSH): Hypothyroidism and hyperthyroidism both cause weakness 1, 2
• Comprehensive metabolic panel: Assess renal function and liver enzymes 4, 6
• Complete blood count: Evaluate for infection or anemia 4

Second-Tier Testing (Based on Initial Results)

• Additional muscle enzymes: Aldolase, AST, ALT, LDH if CK is elevated or inflammatory myopathy suspected 5, 4, 6
• Inflammatory markers: ESR and CRP to assess systemic inflammation 5, 4
• Troponin and ECG: Mandatory if myositis suspected, as myocardial involvement can be life-threatening 5, 4, 6
• Autoimmune panel: ANA, rheumatoid factor, anti-CCP if inflammatory disease suspected 4
• Acetylcholine receptor (AChR) antibodies: If myasthenia gravis suspected; if negative, check muscle-specific kinase and LRP4 antibodies 3

Advanced Testing (When Diagnosis Remains Unclear)

• Electromyography (EMG) with nerve conduction studies: Indicated to distinguish myopathy from neuropathy or neuromuscular junction disorders; include repetitive stimulation testing if myasthenia gravis suspected 3, 1, 2
• MRI of affected muscles: Provides objective evidence of inflammation and guides biopsy site selection 4, 2
• Lumbar puncture: If Guillain-Barré syndrome suspected (elevated protein with or without elevated WBCs); send cytology in cancer patients 3
• Muscle biopsy: Required for definitive diagnosis of many myopathies when other testing is inconclusive 4, 1, 2

Management Algorithm Based on Severity

Grade 1: Mild Weakness Without Functional Limitation

• Continue normal activities and monitor symptoms 5
• If CK elevated with documented weakness: Offer oral prednisone 0.5 mg/kg/day 4
• For pain management: Use acetaminophen 500-1000 mg every 6-8 hours as first-line 5
• Hold potentially causative medications (especially statins if CK >5× upper limit of normal) 6
• Repeat CK, ESR, CRP in 1-2 weeks to monitor for progression 6

Grade 2: Moderate Weakness Interfering With Activities of Daily Living

• Hold potentially causative medications immediately 5, 6
• Refer to rheumatology or neurology early - do not delay specialist consultation 4
• Initiate prednisone 0.5-1 mg/kg/day if inflammatory myopathy suspected 4, 6
• For myasthenia gravis: Start pyridostigmine 30 mg orally three times daily, gradually increase to maximum 120 mg four times daily; add prednisone 1-1.5 mg/kg/day 3
• Order complete autoimmune workup, EMG, and MRI 4

Grade 3-4: Severe Weakness, Dysphagia, Respiratory Involvement, or Rapidly Progressive

• Hospitalize immediately with capability for ICU-level monitoring 3
• Permanently discontinue immune checkpoint inhibitors if this is the cause 3
• Initiate high-dose corticosteroids: Methylprednisolone 1-2 mg/kg IV daily or prednisone 1 mg/kg/day 3, 4
• For myasthenia gravis or Guillain-Barré syndrome: Add IVIG 0.4 g/kg/day for 5 days (total 2 g/kg) or plasmapheresis for 5 days 3
• Urgent neurology consultation 3
• Frequent pulmonary function testing with negative inspiratory force and vital capacity monitoring 3
• Daily neurologic assessments 3

Special Clinical Scenarios

ICU-Acquired Weakness

• Risk factors: Severe sepsis, prolonged mechanical ventilation, difficulty with ventilator liberation 3
• Physical rehabilitation improves outcomes in heterogeneous ICU populations, though specific benefit in ICUAW requires more research 3
• Consider early mobilization in at-risk patients 3

Immune Checkpoint Inhibitor-Related Myositis

• Hold therapy if CK ≥3× upper limit of normal with symptoms 6
• May resume only when: Symptoms resolve, CK normalizes, and prednisone dose <10 mg daily 6
• Permanently discontinue if any myocardial involvement detected - this is life-threatening 3, 4, 6
• Can present with concurrent myasthenia gravis and/or myocarditis - maintain high index of suspicion 3

Statin-Associated Myopathy

• Discontinue statin if CK >10× upper limit of normal with symptoms to prevent progression to rhabdomyolysis 6
• After 2-4 week washout and symptom resolution: Consider re-challenge with lower dose alternative statin or alternate-day dosing 6

Critical Pitfalls to Avoid

• Do not attribute CK elevation solely to exercise without excluding pathological causes, even in athletes 6
• Do not delay specialist referral in moderate to severe cases - early intervention improves outcomes 4
• Do not overlook myocardial involvement - always check troponin and ECG when myositis suspected, as cardiac involvement can be fatal 5, 4, 6
• Do not continue statins when CK >10× upper limit of normal with symptoms - this risks rhabdomyolysis 6
• Avoid medications that worsen myasthenia gravis: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, macrolides 3
• Do not perform reflex kidney biopsy in suspected immune-mediated nephritis until corticosteroid treatment attempted 3

Monitoring Parameters

• Serial CK, ESR, CRP every 1-2 weeks initially to assess treatment response 5, 6
• Reassess for development or progression of weakness at each visit 6
• For patients on immunosuppression: Monitor for infections and medication side effects 5, 4
• Taper corticosteroids over 4-6 weeks once symptoms resolve and CK normalizes 3, 5, 6