What is the diagnosis and management for a patient with leg muscle weakness and heaviness that improves with activity and has a normal Creatine Kinase (CK) level?

Diagnosis: Lambert-Eaton Myasthenic Syndrome (LEMS) or Myasthenia Gravis

The clinical presentation of leg muscle weakness and heaviness that improves with activity, combined with normal CK levels, is pathognomonic for a neuromuscular junction disorder, most likely Lambert-Eaton Myasthenic Syndrome (LEMS), which characteristically demonstrates post-exercise facilitation—the opposite pattern of typical myopathies.

Key Diagnostic Features

Pattern Recognition

• Weakness that improves with activity is the hallmark distinguishing feature of neuromuscular junction disorders from myopathies, which typically worsen with exertion 1, 2
• Normal CK definitively excludes inflammatory myopathies, muscular dystrophies, and rhabdomyolysis, which would show CK elevation (typically >3× ULN for pathological conditions) 3, 4
• The proximal leg distribution (weakness and heaviness) is consistent with LEMS, which predominantly affects proximal muscles initially 1

Critical Differentiating Points

• LEMS shows post-exercise facilitation: strength improves after brief exercise or sustained contraction, unlike myasthenia gravis where weakness worsens with repetitive activity 1, 2
• Myopathies are excluded by normal CK and the improvement with activity pattern 3, 4
• Peripheral arterial disease can cause leg heaviness but worsens with activity (claudication) rather than improves, making it incompatible with this presentation 3, 5

Diagnostic Workup

Essential Initial Testing

• Electromyography (EMG) with repetitive nerve stimulation: Look for incremental response (>100% increase in compound muscle action potential amplitude) with high-frequency (20-50 Hz) stimulation, which is diagnostic for LEMS 3, 1
• Anti-voltage-gated calcium channel (VGCC) antibodies: Positive in 85-90% of LEMS cases 1
• Anti-acetylcholine receptor (AChR) antibodies: To evaluate for myasthenia gravis as alternative diagnosis 3, 1

Secondary Evaluation

• Chest CT scan: Essential to screen for small cell lung cancer, as 50-60% of LEMS cases are paraneoplastic 3, 1
• Autoantibody panel: Including anti-striational antibodies if myasthenia gravis remains in differential 3
• Thyroid function tests: Thyroid disorders can cause weakness but would not show the activity-improvement pattern 2

Tests NOT Indicated

• Muscle biopsy is unnecessary given normal CK and characteristic clinical pattern 3, 4
• Inflammatory markers (ESR, CRP) are not helpful as this is not an inflammatory condition 3, 4
• Aldolase, AST, ALT, LDH are unnecessary with normal CK 3, 4

Management Algorithm

Immediate Management

1. Refer urgently to neurology for EMG confirmation and treatment initiation 3, 1
2. Screen for malignancy with chest CT, as paraneoplastic LEMS requires cancer treatment 3, 1
3. Avoid medications that worsen neuromuscular transmission: aminoglycosides, fluoroquinolones, beta-blockers, calcium channel blockers 1

Pharmacological Treatment

• 3,4-diaminopyridine (3,4-DAP): First-line treatment that enhances acetylcholine release by blocking presynaptic potassium channels 1
• Pyridostigmine: Acetylcholinesterase inhibitor, less effective than in myasthenia gravis but can provide symptomatic benefit 1
• Immunosuppression: Consider prednisone 0.5-1 mg/kg daily or other immunosuppressants (azathioprine, mycophenolate) if inadequate response to 3,4-DAP 3, 4
• IVIG or plasmapheresis: Reserved for severe cases or acute exacerbations 3, 4

Treatment of Underlying Malignancy

• Cancer treatment is paramount in paraneoplastic cases, as tumor removal often improves neurological symptoms 3, 1
• Continue symptomatic treatment with 3,4-DAP even during cancer therapy 1

Common Pitfalls to Avoid

Diagnostic Errors

• Do not attribute improvement with activity to "warming up" or exercise benefit—this pattern is pathognomonic for neuromuscular junction disorders, not musculoskeletal conditions 1, 2
• Do not dismiss normal CK as ruling out all neuromuscular disease—neuromuscular junction disorders characteristically have normal CK 3, 4, 1
• Do not confuse with polymyalgia rheumatica, which causes proximal pain and stiffness but has normal strength on formal testing and does not improve with activity 4

Management Errors

• Do not delay malignancy screening—50-60% of LEMS cases are paraneoplastic, and early cancer detection is critical 3, 1
• Do not start empiric corticosteroids before confirming diagnosis, as this may complicate interpretation of antibody testing 3, 4
• Do not prescribe medications that impair neuromuscular transmission, which can precipitate respiratory crisis 1

Prognosis and Monitoring

Expected Course

• Non-paraneoplastic LEMS: Generally responds well to 3,4-DAP with significant functional improvement 1
• Paraneoplastic LEMS: Prognosis depends on cancer treatment success; neurological symptoms may improve with tumor control 1
• Monitor for respiratory involvement: Though less common than in myasthenia gravis, respiratory muscle weakness can occur and requires urgent intervention 3, 1

Follow-up Strategy

• Reassess strength objectively using Medical Research Council scale at each visit 2
• Monitor for cancer development with periodic chest imaging if initial screening negative, as tumors may appear later 1
• Adjust immunosuppression based on symptom control and side effects 3, 4