Lambert-Eaton Syndrome
Chapter notes (PDF)PDFAutoimmune disorder of the presynaptic neuromuscular junction caused by antibodies against voltage-gated calcium channels (VGCC). Characterised by proximal limb weakness that improves with repeated use, depressed reflexes, and autonomic dysfunction. ~60% associated with small cell lung cancer.
Key Facts
- Anti-VGCC antibodies target presynaptic voltage-gated calcium channels at the neuromuscular junction → reduced acetylcholine release
- ~60% paraneoplastic (small cell lung cancer - SCLC); ~40% autoimmune (non-paraneoplastic)
- Key feature: proximal weakness that IMPROVES with repeated use (opposite of MG); depressed/absent tendon reflexes that augment after brief exercise
- Autonomic dysfunction: dry mouth, constipation, erectile dysfunction, orthostatic hypotension
- Diagnosis: anti-VGCC antibodies; EMG: low CMAP at rest, >100% incremental response after brief exercise or high-frequency stimulation (20-50 Hz)
- Treatment: treat underlying malignancy; 3,4-diaminopyridine (amifampridine) 15-80 mg/day (NICE); immunosuppression if non-paraneoplastic
Overview
Key Facts
LEMS is a rare autoimmune channelopathy affecting presynaptic neuromuscular transmission. It is a paraneoplastic syndrome in ~60% (SCLC). Early cancer screening is essential.
Epidemiology
Rare: incidence ~0.5 per million/year. Prevalence ~2.5 per million. Paraneoplastic LEMS: older (>50 years), male predominance. Autoimmune LEMS: younger, female, associated with other autoimmune conditions.
Aetiology
- Paraneoplastic (~60%): SCLC expresses VGCC → immune response cross-reacts with NMJ; tumour usually found within 2 years of LEMS diagnosis
- Autoimmune (~40%): no underlying malignancy; associated with HLA-B8, other autoimmune diseases
- DELTA-P score: predicts cancer risk (Smoking, Age >50, Weight loss, Bulbar, Male, Karnofsky score)
Pathophysiology
Anti-VGCC (P/Q-type) antibodies bind presynaptic calcium channels at the NMJ
reduced calcium influx during depolarisation
reduced acetylcholine vesicle release
impaired neuromuscular transmission. Unlike MG (postsynaptic), the defect is presynaptic. With repeated stimulation, calcium accumulates presynaptically
improved ACh release
strength improves (facilitation).
Clinical Presentation
Motor Features
- Proximal limb weakness: legs > arms; difficulty rising from chair, climbing stairs
- Weakness IMPROVES with repeated use (post-exercise facilitation - opposite of MG)
- Depressed/absent tendon reflexes: characteristic; reflexes may augment after brief exercise (post-tetanic potentiation)
- Waddling gait
Autonomic Features
- Dry mouth (commonest autonomic symptom), constipation, erectile dysfunction, orthostatic hypotension, urinary retention
Bulbar and Ocular Features
- Less prominent than MG; mild ptosis, diplopia, dysarthria, dysphagia may occur but NOT the presenting feature
Red Flags
- Older male smoker with proximal weakness → SCLC until proven otherwise
- Weight loss, cough, haemoptysis (underlying SCLC)
- Rapid progression of weakness
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Myasthenia gravis | Fatigable weakness WORSE with use, ocular/bulbar predominant | Anti-AChR/MuSK, EMG (decrement) |
| Polymyositis | Proximal weakness, raised CK, no NMJ abnormality | CK, muscle biopsy, EMG |
| Motor neurone disease | UMN + LMN signs, fasciculations, wasting | EMG, clinical |
| Diabetic amyotrophy | Painful proximal leg weakness, weight loss, diabetes | NCS, clinical |
| Inclusion body myositis | Finger flexor/quad weakness, elderly, raised CK | Muscle biopsy |
| Botulism | Acute descending paralysis, dilated pupils | Toxin assay, EMG |
Diagnosis / Investigation
Serology
- Anti-VGCC antibodies (P/Q-type): positive in ~90% of LEMS; confirms diagnosis
- SOX1 antibodies: associated with paraneoplastic LEMS (SCLC)
Neurophysiology
- EMG: low compound muscle action potential (CMAP) amplitude at rest
- Repetitive nerve stimulation: decremental response at low-frequency (3 Hz) stimulation; >100% incremental response at high-frequency (20-50 Hz) stimulation or after 10 seconds of maximal voluntary contraction - diagnostic
Cancer Screening
- CT thorax (± CT abdomen/pelvis): SCLC screening; MANDATORY
- PET-CT: if CT negative but high clinical suspicion
- Repeat screening at 3-6 monthly intervals for 2 years if initially negative (cancer may present after LEMS)
Other
- DELTA-P score: risk stratification for underlying malignancy
Management
Treat Underlying Malignancy
- If SCLC: chemotherapy ± radiotherapy (LEMS often improves with tumour treatment)
Symptomatic
potassium channel blocker
prolongs presynaptic depolarisation
increases calcium influx
more ACh release; NICE recommended; side effects: perioral/digital paraesthesiae, seizures (high dose)
- Pyridostigmine 30-120 mg QDS: adjunct (less effective than in MG)
Immunosuppression (Non-paraneoplastic)
- Prednisolone + azathioprine: as per MG
- IVIg or plasma exchange: for acute worsening
- Rituximab: for refractory cases
Referral Criteria
- All suspected LEMS: neurology + cancer screening
- Oncology if SCLC confirmed
Prognosis
Paraneoplastic LEMS: prognosis determined by underlying SCLC (5-year survival ~5-10% for SCLC). Interestingly, SCLC patients with LEMS may have better tumour outcomes than SCLC without LEMS (immune surveillance effect). Autoimmune LEMS: good prognosis with immunosuppression; chronic relapsing course. 3,4-DAP provides significant symptomatic improvement in >80% of patients.
Other Relevant Information
LEMS vs Myasthenia Gravis Comparison
| Feature | LEMS | MG |
|---|---|---|
| Site of defect | Presynaptic | Postsynaptic |
| Antibody | Anti-VGCC | Anti-AChR/MuSK |
| Weakness pattern | Proximal limbs (legs) | Ocular/bulbar → limbs |
| Fatigability | Improves with use | Worsens with use |
| Reflexes | Depressed/absent | Normal |
| Autonomic | Yes (dry mouth, constipation) | No |
| EMG (high-freq RNS) | >100% increment | Decrement |
| Malignancy | SCLC (~60%) | Thymoma (10-15%) |