What is the management and treatment of Lambert-Eaton Myasthenic Syndrome (LEMS)?

Management and Treatment of Lambert-Eaton Myasthenic Syndrome (LEMS)

3,4-diaminopyridine (amifampridine) is the first-line treatment for Lambert-Eaton Myasthenic Syndrome in adults and children 6 years and older, with strong evidence supporting its efficacy in improving muscle strength and neuromuscular transmission. 1

Disease Overview

Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare autoimmune presynaptic disorder of neuromuscular transmission characterized by:

• Antibodies against voltage-gated calcium channels (VGCCs) that reduce acetylcholine release at the neuromuscular junction 2
• Proximal muscle weakness, particularly affecting hip and shoulder muscles 3
• Reduced or absent muscle stretch reflexes that may increase after exercise 3
• Autonomic symptoms, particularly dry mouth 3, 2
• Association with small cell lung cancer (SCLC) in approximately 50-60% of cases (SCLC-LEMS) 2
• Non-tumor etiology associated with underlying autoimmune disease in the remaining cases (NT-LEMS) 2

Diagnostic Approach

Diagnosis of LEMS requires a three-pronged approach:

• Clinical features: proximal muscle weakness, reduced/absent reflexes, autonomic symptoms 2
• Electromyography: low-amplitude muscle responses that increase dramatically (>500%) after activation or high-frequency stimulation 2, 4
• Anti-VGCC antibody serology: positive in most patients 2

Treatment Algorithm

1. Initial Evaluation

• Conduct rigorous oncological screening, especially in older patients with smoking history 3, 2
• Search for small cell lung cancer as the most common associated malignancy 5, 2
• Evaluate for other potential malignancies (rarely vocal cord carcinoma has been reported) 4

2. First-Line Symptomatic Treatment

• Amifampridine (3,4-diaminopyridine) is FDA-approved for LEMS in adults and children 6 years and older 1
  • Mechanism: Potassium channel blocker that increases acetylcholine release at the presynaptic membrane 6
  • Dosing:
    • Adults and pediatric patients ≥45 kg: Start with 15-30 mg daily in 3-5 divided doses 1
    • Pediatric patients <45 kg: Start with 5-15 mg daily in divided doses 1
    • Increase by 5 mg daily every 3-4 days (2.5 mg for pediatric patients <45 kg) 1
    • Maximum single dose: 20 mg for adults/pediatric patients ≥45 kg; 10 mg for pediatric patients <45 kg 1
    • Maximum daily dose: 100 mg for adults/pediatric patients ≥45 kg; 50 mg for pediatric patients <45 kg 1
  • Efficacy: More than 85% of patients experience clinically significant benefit 3
  • Side effects: Primarily paresthesia around mouth, tongue, face, fingers, and toes 1, 6
  • Contraindications: History of seizures, hypersensitivity to amifampridine or other aminopyridines 1

3. Immunotherapy for Persistent Symptoms

• Intravenous Immunoglobulin (IVIg)

  • Provides transient improvement in muscle strength for up to eight weeks 7
  • Consider for patients with severe weakness despite amifampridine 3

• Plasma Exchange

  • May induce transient improvement but rarely normalizes function 3
  • Limited evidence from randomized controlled trials 7

• Immunosuppressive Therapy

  • Combinations of prednisone, azathioprine, or cyclosporine for persistent symptoms 3, 2
  • Improvement may take months and requires chronic administration 3
  • Consider for patients with NT-LEMS or those with persistent symptoms despite amifampridine 2

4. Treatment of Underlying Malignancy

• Successful treatment of underlying cancer leads to improvement in many patients 3
• Oncological treatment should take priority when malignancy is identified 2

Special Considerations

• Monitoring: Regular assessment of muscle strength, autonomic symptoms, and treatment side effects 2
• Seizure Risk: Amifampridine can cause seizures; discontinue or reduce dose if seizures occur 1
• Dose Adjustments: Lower starting doses for patients with renal or hepatic impairment and known N-acetyltransferase 2 (NAT2) poor metabolizers 1
• Drug Interactions: Avoid concomitant use with drugs that lower seizure threshold or have cholinergic effects 1

Prognosis

• Prognosis is primarily determined by the presence of cancer or other autoimmune disease 3
• SCLC-LEMS: Cause of death typically tumor progression 2
• NT-LEMS: Generally does not reduce life expectancy 2

Common Pitfalls and Caveats

• Delayed diagnosis due to symptom overlap with other myasthenic syndromes, particularly myasthenia gravis 2
• Inadequate oncological screening after LEMS diagnosis 2
• Failure to recognize LEMS as an early indicator of possible cancer 2
• Undertreatment of symptoms that significantly impact quality of life 2
• Overreliance on immunosuppression without adequate symptomatic treatment 3