Lambert-Eaton Myasthenic Syndrome (LEMS)
Summary
Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction (NMJ). Unlike Myasthenia Gravis (Post-synaptic), LEMS is a Pre-synaptic defect caused by antibodies against Voltage-Gated Calcium Channels (VGCC). It presents with proximal Lower Limb weakness ("heavy legs"), autonomic dysfunction (dry mouth, erectile dysfunction), and hyporeflexia. A pathognomonic sign is Post-Tetanic Potentiation (reflexes and strength improve after brief exercise). Crucially, 60% of cases are Paraneoplastic, most commonly associated with Small Cell Lung Cancer (SCLC). In these cases, the tumour expresses VGCC, triggering the immune attack. Management involves treating the cancer (which can cure the LEMS) and symptomatic treatment with 3,4-Diaminopyridine (Amifampridine). [1,2]
Key Facts
- Mechanism: Antibodies to P/Q-type Voltage-Gated Calcium Channels (VGCC) on the presynaptic nerve terminal. This prevents Calcium entry -> prevents Acetylcholine release containing vesicles from fusing.
- The "Warm Up" Phenomenon: Rapid repeated stimulation allows calcium to accumulate in the terminal -> Massive ACh release -> Strength returns. This is the opposite of MG (Fatigability).
- Paraneoplastic Link: 90% of SCLC-associated LEMS cases present with the weakness before the cancer is found. It is an early warning system.
- Autonomic Features: Dry mouth (Xerostomia) is present in >80%. Constipation and ED are common.
- SOX1 Antibodies: A marker for the SCLC-associated form.
Clinical Pearls
"The Handshake Sign": Ask the patient to squeeze your hand hard. It starts weak. Ask them to "pulse" squeeze 10 times. The grip gets stronger! (Facilitation).
"Reflexes Return": Tap the knee jerk (Absent). Ask the patient to contract their quadriceps maximally for 10 seconds. Tap again. The reflex appears! (Post-tetanic potentiation).
"Metallic Taste": A side effect of LEMS (dysgeusia).
Incidence
- Rare: 100x rarer than current MG.
- Age: >50 years usually.
- Sex: Male predominance (reflecting smoking/SCLC risk).
The Presynaptic Defect
- Normal Physiology: Action Potential reaches nerve terminal -> VGCCs open -> Calcium influx -> Vesicles fuse -> ACh released.
- LEMS Physiology: Antibodies block/destroy VGCCs.
- Calcium cannot enter.
- Vesicles cannot fuse.
- Quantal Release is reduced (too few packets of ACh).
- The muscle End Plate Potential (EPP) fails to reach threshold. No contraction.
- Facilitation:
- High frequency firing (Exercise) keeps the few remaining channels open longer.
- Calcium builds up inside the terminal ("Calcium accumulation").
- Suddenly, massive release occurs.
The Cancer Connection
- SCLC: Neuroendocrine tumour. It expresses VGCCs on its surface.
- The immune system attacks the tumour (Good!) but cross-reacts with the nerve terminals (Bad!).
- Result: LEMS patients with SCLC actually survive longer than those without LEMS, because their immune system is aggressively fighting the cancer.
Motor (Weakness)
Autonomic (Cholinergic Blockade)
Reflexes
Neurophysiology (The Diagnostic Key)
- Repetitive Nerve Stimulation (RNS):
- Low Frequency (3Hz): Decrement (like MG).
- High Frequency (20-50Hz) or Post-Exercise: INCREMENT (>100% increase in CMAP amplitude). This is diagnostic.
- Single Fiber EMG: Increased jitter (sensitive but non-specific).
Serology
- Anti-VGCC (P/Q Type): Positive in 85-90% of LEMS (both paraneoplastic and idiopathic).
- Anti-SOX1: Highly specific for SCLC-LEMS.
Cancer Screening (Mandatory)
- CT Chest/Abdomen/Pelvis: Look for SCLC.
- PET-CT: If CT is negative but index of suspicion high (e.g. smoker).
- Bronchoscopy: If nodes enlarged.
- Surveillance: If negative initially, repeat screening every 6 months for 2 years (DELTA-P Score predicts risk).
Management Algorithm
DIAGNOSIS CONFIRMED
↓
┌───────────────────────┐
SEARCH FOR CANCER SYMPTOM CONTROL
↓ ↓
Found SCLC? 3,4-DAP
│ │ (Amifampridine)
Yes No ↓
│ └─> Review q6m Immunosuppression
↓ (Pred / IVIg)
CHEMO / RADIO
(Treating cancer often
cures LEMS)
1. Symptomatic Treatment
- 3,4-Diaminopyridine (Amifampridine):
- Mechanism: Blocks Voltage-Gated Potassium Channels (VGKC). This prolongs the Action Potential duration, keeping VGCCs open longer -> More Calcium -> More ACh.
- Efficacy: Excellent.
- Side Effects: Paraesthesia (tingling), Seizures (dose dependent). EGC monitoring required (QT prolongation).
- Pyridostigmine: Less effective than in MG.
2. Immunotherapy
- Used if no cancer found or symptoms persist despite cancer Tx.
- Prednisolone + Azathioprine.
- IVIg / Plasma Exchange (for acute severe weakness).
3. Oncological
- Chemotherapy (Platinum/Etoposide) for SCLC.
- Successful tumour regression leads to clinical improvement in LEMS.
"Potassium Blockade for Calcium Gain."
- The Problem: Lack of Calcium entry.
- The Trick: We can't easily open Calcium channels that are destroyed. But we can stop the nerve from resetting.
- Action: Blocking Voltage-Gated Potassium Channels (VGKC) prevents repolarization. The nerve terminal stays depolarized (positive) for milliseconds longer.
- Result: The few remaining Calcium channels have more time to let Calcium in.
- Safety: Historically, compounded 3,4-DAP was unstable. Now "Firdapse" (Amifampridine Phosphate) is the licensed, stable salt form.
| Feature | Myasthenia Gravis (MG) | Lambert-Eaton (LEMS) |
|---|---|---|
| Site | Post-synaptic (AChR) | Pre-synaptic (VGCC) |
| Weakness | Ocular/Bulbar first | Leg/Proximal first |
| Fatigability | Worsens with exercise | Improves with exercise (briefly) |
| Reflexes | Normal | Absent/Depressed |
| Autonomic | Absent | Present (Dry mouth) |
| Cancer | Thymoma (10%) | SCLC (60%) |
| RNS | Decrement | Increment |
- Paraneoplastic: Prognosis depends on the SCLC. (Median survival < 1 year). LEMS confers a slightly better survival due to immune surveillance.
- Non-Paraneoplastic (Idiopathic): Normal life expectancy. Chronic autoimmune course. Good response to 3,4-DAP.
What is LEMS?
It is a condition where the nerves cannot "talk" to the muscles. The signal arrives, but the chemical messenger is not released.
Why do I have it?
In many cases (about half), it is triggered by an underlying lung condition (tumour). The body attacks the tumour but accidentally attacks the nerve endings too. We need to screen you carefully for this.
Will the strength come back?
With treatment (Amifampridine), yes. If we find and treat a tumour, the weakness often goes away completely.
The "Warm Up"
You might notice that you are stiff when you first stand up, but after a few steps, you walk better. This is classic for LEMS.
- Titulaer MJ, et al. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011.
- Kesner VG, et al. Lambert-Eaton Myasthenic Syndrome. Neurol Clin. 2018.
Common Exam Questions
1. Pathology:
- Q: What is the target antigen in LEMS?
- A: P/Q-type Voltage-Gated Calcium Channels (VGCC).
2. Signs:
- Q: How do you demonstrate post-tetanic potentiation?
- A: Test absent reflex -> Maximal contraction 10s -> Retest reflex (Present).
3. Oncology:
- Q: What is the most common associated malignancy?
- A: Small Cell Lung Cancer.
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