Overview
Lambert-Eaton Myasthenic Syndrome (LEMS)
1. Clinical Overview
Summary
Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction caused by antibodies against Voltage-Gated Calcium Channels (VGCCs) on the presynaptic nerve terminal. This impairs acetylcholine release, leading to proximal muscle weakness. The classic clinical triad is Proximal Weakness, Autonomic Dysfunction, and Areflexia that improves after brief exercise (Post-tetanic potentiation). Approximately 50-60% of LEMS cases are paraneoplastic, almost exclusively associated with Small Cell Lung Cancer (SCLC), and LEMS may precede cancer diagnosis by months to years. The remaining cases are autoimmune (Non-paraneoplastic). Diagnosis is confirmed by Anti-VGCC Antibodies and Repetitive Nerve Stimulation showing an Incremental Response (Opposite to Myasthenia Gravis). Treatment includes treating underlying malignancy (If present), 3,4-Diaminopyridine (3,4-DAP / Amifampridine), Immunotherapy (IVIG, Steroids, Azathioprine), and Pyridostigmine. [1,2,3]
Clinical Pearls
"Weakness that Gets Better with Exercise": Unlike MG, LEMS weakness may transiently improve after brief exertion (Post-tetanic potentiation).
"LEMS = Look for Lung Cancer": 50-60% of LEMS is paraneoplastic (SCLC). CT Chest mandatory. PET-CT if initial screening negative.
"Proximal > Distal, Legs > Arms": Difficulty rising from chair, Climbing stairs. Often starts in legs.
"Autonomic Features": Dry mouth is the most common. Also constipation, Erectile dysfunction, Postural hypotension.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Incidence | Rare: ~0.5 per million per year. |
| Age | Bimodal: 35-40 years (Autoimmune) and 55-65 years (Paraneoplastic/SCLC). |
| Sex | Male > Female (Especially paraneoplastic). Autoimmune LEMS = Equal. |
Aetiology
| Type | Notes |
|---|---|
| Paraneoplastic LEMS (~50-60%) | Associated with SCLC (>95% of paraneoplastic cases). SCLC cells express VGCCs → Immune response cross-reacts with nerve terminals. |
| Autoimmune LEMS (~40-50%) | No underlying malignancy. Often associated with other autoimmune conditions (Thyroid disease, Vitiligo, Pernicious anaemia). |
3. Pathophysiology
Neuromuscular Junction
- Normal: Action potential → Voltage-gated calcium channels (VGCCs) open → Calcium influx → Acetylcholine (ACh) release → Binds to postsynaptic receptors → Muscle contraction.
LEMS Mechanism
- Autoantibodies: IgG antibodies against P/Q-type VGCCs on presynaptic nerve terminal.
- VGCC Internalisation/Destruction: Reduced number of functional calcium channels.
- Impaired Calcium Influx: Less Ca²⁺ enters nerve terminal.
- Reduced ACh Release: Fewer ACh quanta released per action potential.
- Weakness: Insufficient postsynaptic depolarisation for muscle contraction.
Post-Tetanic Potentiation
- With repeated stimulation (Exercise), Calcium accumulates in nerve terminal.
- Temporarily overcomes the VGCC deficit → Increased ACh release → Transient improvement in strength.
- Explains why reflexes may appear after brief isometric contraction.
Comparison: LEMS vs Myasthenia Gravis
| Feature | LEMS | Myasthenia Gravis |
|---|---|---|
| Antibody Target | Presynaptic VGCCs | Postsynaptic AChRs (Or MuSK) |
| Location of Defect | Presynaptic | Postsynaptic |
| ACh Release | Reduced | Normal |
| Weakness Distribution | Proximal (Legs > Arms) | Ocular, Bulbar, Generalised |
| Effect of Exercise | May improve (Briefly) | Worsens (Fatigable) |
| Reflexes | Reduced/Absent (May improve after exercise) | Normal |
| Autonomic Features | Common (Dry mouth) | Rare |
| Malignancy Association | SCLC (~50-60%) | Thymoma (~15%) |
| RNS Pattern | Increment (>100% at high frequency) | Decrement (At low frequency) |
4. Clinical Presentation
Motor Symptoms
| Symptom | Notes |
|---|---|
| Proximal Leg Weakness | Most common. Difficulty rising from chair, Climbing stairs, Walking. |
| Proximal Arm Weakness | Later. Difficulty lifting arms above head. |
| Gait Disturbance | Waddling gait. |
| Reduced/Absent Reflexes | Areflexia or Hyporeflexia. May transiently improve after brief isometric contraction (Lambert's Sign). |
| Cranial Nerve Involvement (Less Common) | Mild ptosis, Diplopia (Less prominent than MG). Dysarthria, Dysphagia (Rare). |
Autonomic Symptoms
| Symptom | Frequency |
|---|---|
| Dry Mouth (Xerostomia) | ~80%. Most common autonomic feature. |
| Constipation | Common. |
| Erectile Dysfunction | Males. |
| Postural Hypotension | May cause dizziness on standing. |
| Blurred Vision | Impaired pupil constriction. |
| Reduced Sweating |
Examination Findings
| Finding | Notes |
|---|---|
| Proximal Muscle Weakness | MRC grading. Legs > Arms. |
| Hyporeflexia/Areflexia | Deep tendon reflexes reduced or absent (Especially in legs). |
| Post-Tetanic Potentiation | After brief isometric contraction (e.g., Fist clenching for 10 seconds), Re-test reflexes or strength → May transiently improve. |
| Mild Ptosis | May be present but less prominent than MG. |
5. Investigations
Serology
| Test | Notes |
|---|---|
| Anti-VGCC Antibodies (P/Q-type) | Positive in ~85-90% of LEMS. Confirms diagnosis. |
| Anti-SOX1 Antibodies | Marker for paraneoplastic LEMS (Associated with SCLC). If positive, High likelihood of underlying cancer. |
Electrophysiology
| Test | Findings |
|---|---|
| Repetitive Nerve Stimulation (RNS) | Low-frequency (2-3 Hz): Decrement (Similar to MG). High-frequency (20-50 Hz) or Post-Exercise: Incremental Response (>100% increase in CMAP amplitude). Diagnostic. |
| Single Fibre EMG | Increased jitter (But less specific than RNS for LEMS). |
Cancer Screening (Essential)
| Investigation | Notes |
|---|---|
| CT Chest | First-line. Look for SCLC. |
| PET-CT | If CT negative but high suspicion. More sensitive for small tumours. |
| Repeat Imaging | If initial screening negative, Repeat every 6-12 months for 2 years (Cancer may emerge later). |
DELTA-P Score (Predict Paraneoplastic LEMS)
| Factor | Points |
|---|---|
| Dysarthria/Dysphagia | -2 |
| Erectile dysfunction (Males) | +1 |
| Loss of weight (>5%) | +1 |
| Tobacco use (Current/Recent) | +3 |
| Age at onset >50 | +1 |
| Karnofsky Performance score less than 70 | +1 |
| Score ≥3 | High probability of SCLC. |
6. Management
Management Algorithm
SUSPECTED LEMS
(Proximal weakness, Areflexia, Autonomic symptoms)
↓
CONFIRM DIAGNOSIS
- Anti-VGCC antibodies (P/Q-type)
- Repetitive Nerve Stimulation (Increment at high frequency)
↓
CANCER SCREENING (MANDATORY)
- CT Chest (SCLC)
- PET-CT if CT negative and high suspicion
- SOX1 antibodies (Paraneoplastic marker)
- Repeat imaging 6-12 monthly if negative
┌────────────────┴────────────────┐
PARANEOPLASTIC (SCLC) NON-PARANEOPLASTIC (Autoimmune)
↓ ↓
**TREAT CANCER** SYMPTOMATIC + IMMUNOTHERAPY
(Chemotherapy, RT, Surgery)
Improvement expected with
cancer treatment
↓
SYMPTOMATIC TREATMENT
┌──────────────────────────────────────────────────────────┐
│ **3,4-Diaminopyridine (Amifampridine)** │
│ - Blocks K+ channels → Prolongs action potential │
│ - Increases Ca2+ influx and ACh release │
│ - First-line symptomatic treatment │
│ - 10-20mg TDS-QDS (Max 80mg/day) │
│ - Side effects: Perioral tingling, Seizures (High dose) │
│ │
│ **Pyridostigmine** │
│ - Acetylcholinesterase inhibitor │
│ - Modestly helpful. Often used as adjunct. │
└──────────────────────────────────────────────────────────┘
↓
IMMUNOTHERAPY
┌──────────────────────────────────────────────────────────┐
│ **IVIG** │
│ - Rapid effect. Used for exacerbations. │
│ │
│ **Prednisolone** │
│ - Oral steroids. Useful for long-term control. │
│ │
│ **Azathioprine / Mycophenolate** │
│ - Steroid-sparing agents. Maintenance therapy. │
│ │
│ **Rituximab** │
│ - For refractory cases. │
│ │
│ **Plasma Exchange** │
│ - Rapid effect. Short duration. Crisis management. │
└──────────────────────────────────────────────────────────┘
↓
CAUTIONS
- Avoid drugs that impair neuromuscular transmission:
Aminoglycosides, Magnesium, Muscle relaxants
- Anaesthetic precautions
Treatment Summary
| Treatment | Mechanism | Use |
|---|---|---|
| 3,4-DAP (Amifampridine) | Prolongs presynaptic depolarisation → More ACh release. | First-line symptomatic. |
| Pyridostigmine | Inhibits AChE → More ACh at synapse. | Adjunct. |
| IVIG | Immunomodulation. | Acute exacerbations. |
| Steroids + Azathioprine | Immunosuppression. | Long-term autoimmune LEMS. |
| Treat SCLC | Removes source of antigen. | Paraneoplastic LEMS. |
7. Complications
| Complication | Notes |
|---|---|
| Respiratory Failure | Rare but can occur. Diaphragm weakness. |
| Aspiration | If bulbar involvement (Rare). |
| Falls | Due to proximal weakness and hypotension. |
| SCLC Progression | If paraneoplastic. |
8. Prognosis and Outcomes
| Factor | Notes |
|---|---|
| Paraneoplastic LEMS | Prognosis tied to SCLC. Treating cancer often improves LEMS. |
| Autoimmune LEMS | Chronic condition. Good symptom control with treatment. Normal lifespan if no malignancy. |
| Response to Treatment | 3,4-DAP very effective. Immunotherapy improves function. |
9. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| LEMS | NICE / ABN | Diagnosis with anti-VGCC + RNS. Cancer screening mandatory. 3,4-DAP first-line. |
| Paraneoplastic Syndromes | EFNS | Repeat cancer screening if initial negative. |
Evidence Points
- 3,4-DAP (Amifampridine): Cochrane review supports efficacy in LEMS.
- Cancer Association: SCLC in ~50-60%. Treat cancer to improve LEMS.
10. Patient and Layperson Explanation
What is LEMS?
Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare condition where your immune system attacks the nerve endings that control your muscles. This makes your muscles weak, especially in the upper legs and arms.
What are the symptoms?
- Weakness in legs and arms – Difficulty standing up from a chair, Climbing stairs, Lifting arms.
- Dry mouth – Very common.
- Tiredness.
- Reflexes are reduced – May temporarily get better with exercise.
Is it linked to cancer?
About half of people with LEMS have an underlying lung cancer (Small cell lung cancer). Finding and treating this cancer is very important. You will need scans to check for this.
What is the treatment?
- A medication called 3,4-DAP (Amifampridine) – Helps nerves work better.
- Immunotherapy – Steroids, IVIG, or other medications to calm the immune system.
- Treat the cancer (If present) – This often improves the LEMS.
What is the outlook?
With treatment, most people with LEMS can improve their strength and quality of life. If associated with cancer, treating the cancer is crucial.
11. References
Primary Sources
- Titulaer MJ, et al. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10(12):1098-1107. PMID: 22094130.
- Wirtz PW, et al. The epidemiology of myasthenia gravis, Lambert-Eaton myasthenic syndrome and their associated tumours in the northern part of the province of South Holland. J Neurol. 2003;250(6):698-701. PMID: 12796831.
- Kesner VG, et al. Lambert-Eaton Myasthenic Syndrome. Neurol Clin. 2018;36(2):379-394. PMID: 29655456.
12. Examination Focus
Common Exam Questions
- Antibody Target: "What is the antibody target in LEMS?"
- Answer: Voltage-Gated Calcium Channels (VGCCs) (P/Q-type) on the presynaptic nerve terminal.
- Malignancy Association: "What malignancy is most commonly associated with LEMS?"
- Answer: Small Cell Lung Cancer (SCLC).
- RNS Finding: "What is the characteristic finding on Repetitive Nerve Stimulation?"
- Answer: Incremental Response (>100% increase in CMAP amplitude) at high-frequency stimulation or post-exercise.
- First-Line Symptomatic Treatment: "What is the first-line drug for LEMS?"
- Answer: 3,4-Diaminopyridine (Amifampridine).
Viva Points
- Presynaptic vs Postsynaptic: LEMS = Presynaptic (VGCCs). MG = Postsynaptic (AChRs).
- Post-Tetanic Potentiation: Strength/Reflexes transiently improve after brief exertion.
- Autonomic Features: Dry mouth, Constipation, ED – Common in LEMS, Rare in MG.
- SOX1 Antibodies: Marker for paraneoplastic LEMS.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.