Lambert-Eaton Myasthenic Syndrome (LEMS): Diagnosis and Treatment

Immediate Diagnostic Approach

LEMS should be suspected in any patient presenting with proximal leg-predominant weakness, reduced or absent muscle stretch reflexes, and dry mouth, particularly in smokers over age 40. 1

Clinical Features to Identify

Proximal muscle weakness starting in hips and shoulders, with potential spread to ocular and oropharyngeal muscles 1
Reduced or absent deep tendon reflexes that may improve after brief exercise 2
Autonomic symptoms including dry mouth (most common), erectile dysfunction, constipation, and orthostatic hypotension 3, 2
Cranial nerve involvement with diplopia, ptosis, and bulbar weakness in more severe cases 3
Fatigue that is often profound and disproportionate to weakness 3

Three-Pronged Diagnostic Confirmation

The diagnosis requires a threefold approach: clinical features, electromyography, and anti-VGCC antibody testing. 3

1. Electromyography (EMG) Findings

Low-amplitude compound muscle action potentials (CMAPs) at rest 1, 2
Dramatic increment (>100%) in CMAP amplitude after 10 seconds of maximal voluntary contraction or high-frequency (20-50 Hz) repetitive nerve stimulation 2
Decremental response at low-frequency (2-5 Hz) repetitive nerve stimulation 2

2. Serological Testing

Anti-voltage-gated calcium channel (VGCC) antibodies, specifically P/Q-type, are present in >90% of LEMS patients 4, 3
These antibodies are pathogenic and directly cause disease by impairing acetylcholine release at the neuromuscular junction 4

3. Cancer Screening (Critical)

A LEMS diagnosis should immediately trigger rigorous oncological screening, as 50-60% of cases are paraneoplastic, most commonly associated with small cell lung cancer (SCLC). 3, 2

CT chest with contrast is the initial screening modality 3
PET-CT scan if initial CT is negative, particularly in patients >40 years with smoking history 3
Repeat screening every 3-6 months for at least 2 years if initial workup is negative, as tumors may be occult at presentation 3
Risk factors for paraneoplastic LEMS: age >40, smoking history, rapid symptom onset, severe bulbar weakness 1, 3

Treatment Algorithm

Step 1: Symptomatic Treatment with 3,4-Diaminopyridine (Amifampridine)

3,4-diaminopyridine (3,4-DAP/amifampridine) is the first-line symptomatic treatment, providing clinically significant benefit in >85% of patients. 1, 5

FDA-Approved Dosing (FIRDAPSE®)

For adults and pediatric patients ≥45 kg: 6

Starting dose: 15-30 mg daily in 3-5 divided doses
Titration: Increase by 5 mg every 3-4 days based on response
Maximum single dose: 20 mg
Maximum daily dose: 100 mg

For pediatric patients <45 kg: 6

Starting dose: 5-15 mg daily in 3-5 divided doses
Titration: Increase by 2.5 mg every 3-4 days
Maximum single dose: 10 mg
Maximum daily dose: 50 mg

Special Populations Requiring Lower Starting Doses

Renal impairment (CrCl 15-90 mL/min): Start at lowest recommended dose (15 mg for adults/pediatric ≥45 kg; 5 mg for pediatric <45 kg) 6
Any degree of hepatic impairment: Start at lowest recommended dose 6
Known NAT2 poor metabolizers: Start at lowest recommended dose 6

Critical Safety Considerations

Contraindicated in patients with history of seizures 6
Contraindicated in hypersensitivity to amifampridine or aminopyridines 6
Monitor for seizure risk, especially with concomitant medications that lower seizure threshold 6

Step 2: Add Immunotherapy for Inadequate Response

If weakness persists despite optimal 3,4-DAP dosing, add immunosuppressive therapy. 4, 1

First-Line Immunotherapy

Intravenous immunoglobulin (IVIg): Most effective when administered within 1 month of symptom onset 7, 4
- Provides transient improvement lasting up to 8 weeks 5
- Demonstrated significant improvement in limb strength in controlled trials 5
Plasma exchange: Leads to clear clinical benefit with transient improvement 4, 1, 5

Second-Line Immunotherapy (if no improvement after 2-4 weeks)

Prednisone plus azathioprine (most commonly used combination) 1, 3
Alternative agents: Cyclosporine, mycophenolate, rituximab, or cyclophosphamide 7, 1
Important caveat: Improvement occurs only after many months and requires chronic administration at significant doses 1

Step 3: Treat Underlying Malignancy (If Present)

For paraneoplastic LEMS associated with SCLC, tumor therapy is the first priority and essential. 4, 1

Successful treatment of underlying cancer leads to improvement in many patients 1
Response to cancer therapy favorably affects the course of LEMS 4
Oncological treatment should take priority over immunotherapy in tumor-associated cases 3

Prognosis and Long-Term Management

Non-Tumor LEMS (NT-LEMS)

Life expectancy is normal 3, 2
Complete remission is uncommon; most patients require ongoing symptomatic treatment 2
Often associated with other autoimmune diseases 1, 3

Tumor-Associated LEMS (SCLC-LEMS)

Prognosis determined by tumor progression 8, 1, 2
Paradoxically, SCLC patients with LEMS have better prognosis than SCLC without LEMS 2
Performance status at LEMS diagnosis is the most important prognostic factor 8

Critical Perioperative Consideration

Patients with LEMS have altered sensitivity to neuromuscular blocking agents used in anesthesia, requiring special attention during surgical procedures 8

Common Pitfalls to Avoid

Misdiagnosis as myasthenia gravis: LEMS has overlapping symptoms but distinct EMG findings (increment vs. decrement) and different antibody profiles 3, 9
Inadequate cancer screening: Failure to perform thorough and repeated oncological surveillance, particularly in older smokers 3
Delaying symptomatic treatment: 3,4-DAP should be initiated promptly as >85% of patients benefit significantly 1, 5
Expecting rapid immunotherapy response: Chronic immunosuppression requires months to show benefit, unlike the immediate effect of 3,4-DAP 1
Using 3,4-DAP in patients with seizure history: This is an absolute contraindication 6

What is the diagnosis and treatment for a patient with Lambert-Eaton Myasthenic Syndrome (LEMS)?

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