Lambert-Eaton Syndrome
Autoimmune 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
- 3,4-Diaminopyridine (amifampridine) 15-80 mg/day in 3-4 divided doses: 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%) |