Eaton-Lambert syndrome

PATHOPHYSIOLOGY: IgG autoantibodies target presynaptic P/Q-type voltage-gated calcium channels (VGCC) on motor nerve terminals (and autonomic nerve terminals). Impaired Ca2+ influx leads to decreased ACh vesicle release, so end-plate potentials are small. About 50-60% of cases are paraneoplastic, most commonly small cell lung cancer (SCLC, ~50-60% of paraneoplastic cases), because tumor cells express VGCCs and trigger molecular mimicry. The remainder are idiopathic autoimmune and associated with other autoimmune disease (HLA-DR3-B8 association).

CLINICAL FEATURES: - Proximal muscle weakness, especially lower limbs (difficulty climbing stairs, rising from a chair), with waddling gait. - Weakness IMPROVES with repeated or sustained effort (post-exercise facilitation) because repetitive stimulation causes Ca2+ accumulation in the terminal and more ACh release. Strength may worsen again with prolonged activity. - Hyporeflexia or areflexia, which transiently improves after brief exercise. - Autonomic dysfunction: dry mouth (most common), constipation, erectile dysfunction, orthostatic hypotension. - Ocular and bulbar involvement is mild and less prominent than in myasthenia gravis (MG). Ptosis and diplopia can occur but are uncommon early. - Neurologic symptoms may precede the cancer diagnosis by months to years (up to ~2 years).

DIAGNOSIS: - Electrodiagnostics: low-amplitude compound muscle action potential (CMAP) at rest. Low-frequency (2-3 Hz) repetitive nerve stimulation gives a decremental response. High-frequency (20-50 Hz) stimulation or brief maximal voluntary exercise gives an incremental response (>100% increase in CMAP amplitude, classically), which is the hallmark. - Serum anti-P/Q-type VGCC antibodies (~85-95% sensitive). - Screen for malignancy: chest CT, then PET/CT if negative, with repeat surveillance (e.g., every 6 months for ~2 years) in high-risk patients (smokers, older age).

TREATMENT: - Treat the underlying cancer (this often improves symptoms). - First-line symptomatic therapy: 3,4-diaminopyridine (amifampridine), a K+ channel blocker that prolongs presynaptic depolarization, keeps VGCCs open longer, and increases ACh release. Seizures are a key adverse effect. - Pyridostigmine (acetylcholinesterase inhibitor) is adjunctive and only modestly effective. - Immunotherapy for refractory disease: IVIG, plasmapheresis, corticosteroids, azathioprine.

KEY COMPARISON, LEMS vs MYASTHENIA GRAVIS: - Target: LEMS = presynaptic VGCC. MG = postsynaptic nicotinic ACh receptor (or MuSK). - Strength with use: LEMS improves. MG worsens (fatigability). - Distribution: LEMS = proximal limbs, with mild ocular involvement. MG = ocular and bulbar prominent (ptosis, diplopia). - Reflexes: LEMS = reduced. MG = normal. - Autonomic features: LEMS = present. MG = absent. - Cancer: LEMS = SCLC. MG = thymoma or thymic hyperplasia. - RNS: LEMS = incremental response at high frequency. MG = decremental response at low frequency. - Edrophonium (Tensilon) test: LEMS = poor response. MG = good response.

HIGH-YIELD PEARLS: Think LEMS when a smoker has proximal weakness, dry mouth, and absent reflexes that improve with exercise. It is the classic paraneoplastic syndrome of SCLC, along with SIADH, ACTH production (Cushing syndrome), and anti-Hu (paraneoplastic encephalomyelitis and sensory neuronopathy). SCLC also has neuroendocrine features (Kulchitsky cells, central location). The related botulinum toxin also blocks presynaptic ACh release (by cleaving SNARE proteins), but it causes descending flaccid paralysis with prominent cranial nerve and autonomic involvement, and it shows an incremental response on high-frequency RNS.