Myasthenia Gravis vs Lambert-Eaton Syndrome: How to Tell Them Apart
Both are autoimmune disorders of the neuromuscular junction that produce fatigable weakness with no sensory loss. The core axis is anatomical: myasthenia gravis is a postsynaptic problem (antibodies destroy or block acetylcholine receptors), while Lambert-Eaton is a presynaptic problem (antibodies against voltage-gated calcium channels reduce acetylcholine release). This single distinction drives their opposite behavior on repetitive use, their reflexes, and their cancer associations.
How to tell them apart
| Feature | Myasthenia gravis | Lambert-Eaton myasthenic syndrome |
|---|---|---|
| Site of lesion | Postsynaptic — antibodies against acetylcholine receptors block ACh binding, increase receptor degradation, and cause complement-mediated destruction of the postsynaptic membrane | Presynaptic — antibodies against voltage-gated calcium channels reduce ACh vesicle release |
| Effect of repeated/sustained activity | Weakness worsens with activity; classically worse in the evening, better in the morning and with rest | Weakness improves (facilitates) with activity due to calcium build-up enhancing ACh release |
| Deep tendon reflexes | Normal (the reflex arc is intact at rest) | Depressed at baseline but potentiate after ~10 seconds of maximal contraction/exercise |
| Distribution of weakness | Prominent ocular (ptosis, diplopia) and bulbar (dysphagia, nasal/slurred speech, fatigable chewing) symptoms; ocular is most common at onset | Proximal limb weakness, legs greater than arms |
| Autonomic symptoms | Absent | Present — dry mouth, constipation |
| Antibodies | Anti-AChR (test first), then anti-MuSK if negative, then anti-LRP4; ~10% seronegative | Anti-VGCC (voltage-gated calcium channel) antibodies |
| Associated malignancy | Thymoma (10-15% of patients); all MG patients need chest imaging | Small cell lung cancer (50-60%); occurs classically in heavy smokers, requires chest CT at diagnosis and repeat screening |
| Repetitive nerve stimulation | Decremental response with repetitive (low-frequency) stimulation | Low-amplitude CMAP at baseline with an incremental response after high-frequency stimulation or exercise |
The reasoning
Start by recognizing the shared anchor: fatigable weakness without sensory loss localizes to the neuromuscular junction. Then arbitrate on three points. First, examine reflexes and the effect of exertion — normal reflexes and weakness that worsens with use point to MG, whereas depressed reflexes that potentiate after sustained contraction and weakness that improves with activity point to LEMS. Second, look at distribution and autonomic features — ocular/bulbar predominance argues for MG, while proximal leg weakness with dry mouth and constipation argues for LEMS. Third, confirm with the right antibody (AChR vs VGCC) and matching electrodiagnostics (decrement vs increment), and always hunt for the associated tumor (thymoma vs small cell lung cancer).
Key tests
- Antibody panel: AChR antibodies (positive in ~85% of generalized MG; if negative test MuSK, then LRP4) confirm MG, whereas anti-VGCC antibodies confirm LEMS.
- Repetitive nerve stimulation: MG shows a decremental response, while LEMS shows a low baseline CMAP with an incremental (facilitating) response at high-frequency stimulation or after exercise. Single-fiber EMG is the most sensitive study in MG (shows jitter).
- Chest imaging: order CT/MRI of the chest in MG to evaluate for thymoma; screen for small cell lung cancer with chest CT in LEMS (repeat every 6 months for 2 years if initial screening is negative).
What they share
- Fatigable weakness that is the signature of a neuromuscular junction disorder
- No sensory involvement (the NMJ is pure motor)
- Autoimmune, antibody-mediated pathophysiology
- Association with an underlying malignancy that mandates chest imaging (thymoma in MG, small cell lung cancer in LEMS)
- Diagnosis supported by antibody testing and electrodiagnostic (repetitive nerve stimulation) studies
Pitfalls
- Assuming all NMJ weakness worsens with use — LEMS characteristically facilitates, with strength and reflexes improving after brief exercise.
- Being reassured by normal reflexes: they are normal in MG but depressed in LEMS, so the reflex exam is a key discriminator, not a screening test to exclude NMJ disease.
- Forgetting to screen for cancer: MG requires chest imaging for thymoma, and LEMS demands aggressive small cell lung cancer screening, including repeat scans if the first is negative.
- Ordering a single antibody and stopping: in MG, a negative AChR test should prompt MuSK and then LRP4 testing, and ~10% remain seronegative.
- Overlooking dangerous medications in MG — aminoglycosides, fluoroquinolones, magnesium, and beta-blockers can worsen weakness.
Practice this the way the exam tests it — on branching cases where your decisions shape the patient.