What are the differences between Lambert-Eaton Syndrome (LES) and Myasthenia Gravis (MG)?

Lambert-Eaton Syndrome vs Myasthenia Gravis: Key Differences

Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG) are both autoimmune neuromuscular junction disorders but differ fundamentally in their site of antibody attack, clinical presentation, associated malignancies, and electrophysiologic findings.

Pathophysiology: Different Antibody Targets

• LEMS involves presynaptic antibodies directed against P/Q-type voltage-gated calcium channels (VGCC) on the presynaptic cholinergic nerve terminals, which impairs acetylcholine release from the nerve terminal 1
• MG involves postsynaptic antibodies against acetylcholine receptors (AChR) on the postsynaptic muscle membrane, blocking neurotransmission to muscle fibers 2
• This fundamental difference in antibody location explains the distinct clinical and electrophysiologic patterns between the two conditions 1

Clinical Presentation: Proximal vs Ocular/Bulbar

• LEMS typically presents with proximal leg weakness that improves with repeated muscle use (facilitation), along with autonomic dysfunction (dry mouth, constipation, erectile dysfunction) 1, 3
• MG characteristically presents with fluctuating weakness affecting ocular muscles (ptosis, diplopia), bulbar muscles (dysphagia, dysarthria), and limb muscles that worsens with repetitive use (fatigability) 4, 3
• The pattern of muscle involvement differs: LEMS predominantly affects proximal lower extremities first, while MG often begins with ocular and bulbar symptoms 3

Malignancy Association: Critical Distinction

• LEMS has a strong paraneoplastic association, most commonly with small cell lung carcinoma (SCLC), requiring cancer screening for up to two years after diagnosis 5, 1
• MG is associated with thymic pathology (thymoma or thymic hyperplasia) rather than lung cancer, and thymectomy is a treatment consideration in AChR-positive generalized MG 4
• When LEMS is paraneoplastic, treating the underlying cancer often improves the myasthenic symptoms 5, 1

Electrophysiologic Testing: Opposite Patterns

• LEMS shows low baseline compound muscle action potential (CMAP) amplitudes that increase significantly (>100%) with high-frequency repetitive nerve stimulation (RNS) or post-exercise facilitation 3
• MG demonstrates decremental response (>10% decline) in CMAP amplitude with low-frequency (2-3 Hz) repetitive nerve stimulation, reflecting postsynaptic receptor blockade 2
• Single-fiber EMG shows increased jitter in both conditions, but the RNS pattern is the key distinguishing feature 2

Symptomatic Treatment: Different First-Line Agents

• 3,4-diaminopyridine is first-line symptomatic treatment for LEMS, augmenting acetylcholine release by blocking presynaptic potassium channels, with proven efficacy in improving muscle strength and CMAP amplitudes 5, 6
• Pyridostigmine (acetylcholinesterase inhibitor) is first-line for MG, preventing acetylcholine breakdown at the synapse, though it can be used in both conditions 5, 4
• Pyridostigmine alone is often insufficient in LEMS but may be adequate in mild MG, particularly in AChR-positive patients 5

Immunotherapy Approach: Shared but Context-Dependent

• Both conditions respond to immunosuppression with corticosteroids, azathioprine, and other immunosuppressants, though the urgency and approach differ based on disease activity 5, 4
• For highly active AChR-positive MG, complement inhibitors (eculizumab, ravulizumab) or neonatal Fc receptor modulators (efgartigimod) are now recommended 4
• For MuSK-antibody positive MG, rituximab is specifically recommended, while LEMS treatment focuses on 3,4-diaminopyridine first with immunosuppression added as needed 5, 4
• Plasma exchange and IVIG provide rapid but temporary improvement in both conditions, reserved for severe exacerbations or myasthenic crisis 5, 6

Diagnostic Differentiation: Essential Clinical Algorithm

• The American Academy of Neurology recommends distinguishing LEMS from MG through comprehensive evaluation including antibody testing, electrophysiology, and cancer screening 7
• Obtain AChR antibodies and MuSK antibodies for suspected MG; obtain VGCC antibodies for suspected LEMS 1, 3
• Perform RNS testing: decremental response at low frequency suggests MG, while incremental response at high frequency or post-exercise facilitation suggests LEMS 3
• In LEMS, always search for malignancy with chest CT and continued screening, while in MG, obtain chest imaging to evaluate for thymoma 5, 4

Important Clinical Caveats

• Both conditions show fatigable weakness, but the temporal pattern differs: LEMS may show initial improvement with activity before fatigue sets in, while MG consistently worsens with use 3
• Patients with LEMS have altered sensitivity to neuromuscular blocking agents used in anesthesia, requiring special perioperative considerations 7
• Autonomic symptoms are prominent in LEMS but rare in MG, providing an important clinical clue 1