What is the treatment for Lambert-Eaton Myasthenic Syndrome (LEMS)?

Treatment of Lambert-Eaton Myasthenic Syndrome (LEMS)

3,4-diaminopyridine (amifampridine) is the first-line symptomatic treatment for LEMS, with FDA approval for adults and pediatric patients 6 years and older. 1

Initial Diagnostic Considerations

Before initiating treatment, screen thoroughly for underlying small cell lung cancer (SCLC), as more than 50% of LEMS cases are paraneoplastic. 2, 3 The prevalence of LEMS in SCLC is 1% to 1.6%, and anti-voltage-gated calcium channel (VGCC) antibodies are present in more than 90% of LEMS patients. 2

First-Line Symptomatic Treatment: 3,4-Diaminopyridine (Amifampridine)

3,4-DAP is the most effective symptomatic treatment for LEMS, recommended as first-line therapy by the European Federation of Neurological Societies. 3, 4

Mechanism of Action

3,4-DAP blocks presynaptic potassium channels, prolonging the action potential and increasing presynaptic calcium concentrations, which increases the quantal release of acetylcholine at the neuromuscular junction. 4, 5

Dosing Protocol

For adults and pediatric patients ≥45 kg: 1

• Start with 15-30 mg daily in divided doses (3-5 times daily)
• Increase by 5 mg daily every 3-4 days as tolerated
• Maximum single dose: 20 mg
• Maximum daily dose: 100 mg

For pediatric patients <45 kg: 1

• Start with 5-15 mg daily in divided doses (3-5 times daily)
• Increase by 2.5 mg daily every 3-4 days as tolerated
• Maximum single dose: 10 mg
• Maximum daily dose: 50 mg

For patients with renal impairment, hepatic impairment, or known NAT2 poor metabolizers: Start with the lowest recommended initial daily dosage. 1

Monitoring Treatment Response

Use electrophysiological repetitive nerve stimulation studies recording the amplitude of initial compound muscle action potential (CMAP) in thenar muscles, which correlates excellently with clinical myasthenic muscle power. 6 This approach is more reliable than repetitive clinical muscle power tests, which are complicated by painful myalgia and activation potentiation. 6

Efficacy Evidence

Four placebo-controlled trials demonstrated that 3,4-DAP effectively increases muscle strength and resting compound muscle action potentials. 4 Studies involving 208 patients in eight randomized trials confirmed amifampridine as the most effective symptomatic drug for LEMS. 5

Safety Profile

Common side effects (>10%): 1

• Paresthesias (tingling around mouth, tongue, face, fingers, toes)
• Upper respiratory tract infection
• Abdominal pain, nausea, diarrhea
• Headache
• Elevated liver enzymes
• Back pain
• Hypertension
• Muscle spasms

Serious adverse events: 1, 4

• Seizures (most common serious adverse event)
• Anaphylaxis and hypersensitivity reactions

Absolute Contraindications

Do not use 3,4-DAP in patients with: 1

• History of seizures
• Hypersensitivity to amifampridine or another aminopyridine

If a seizure occurs during treatment, discontinue or reduce the dose immediately. 1

Adjunctive Symptomatic Treatment

Acetylcholinesterase Inhibitors

Pyridostigmine can be combined with 3,4-DAP when monotherapy provides insufficient benefit. 6 However, 3,4-DAP alone has been shown to be more effective than acetylcholinesterase inhibitors as monotherapy. 4

Immunomodulating Therapy

Initiate immunomodulating or immunosuppressive treatments when symptomatic treatments (3,4-DAP ± pyridostigmine) do not provide satisfactory improvement. 2, 3

Intravenous Immunoglobulin (IVIg)

One randomized controlled trial demonstrated that IVIg improves LEMS symptoms. 2, 3 Limited experience suggests that immunosuppressive therapy with a combination of IVIg, methylprednisolone, and cyclophosphamide may stabilize paraneoplastic neurological syndromes transiently, but these treatments cannot improve symptoms over the long term. 2

Treatment of Underlying Malignancy

For paraneoplastic LEMS associated with SCLC, anti-tumor treatment is essential and favorably affects the course of the syndrome. 2, 3 Concomitant immunotherapy does not adversely affect malignancy outcomes. 2

Long-Term Management

Patients have been successfully treated with 3,4-DAP for up to 10 years with acceptable tolerability. 6 The individual drug response varies, and no standard doses exist; therefore, titrate dosing based on clinical response and electrophysiological monitoring. 6

Drug Interactions to Avoid

Do not use 3,4-DAP concomitantly with: 1

• Drugs that lower seizure threshold (increased risk of seizures)
• Drugs with cholinergic effects, including direct or indirect cholinesterase inhibitors (may increase cholinergic effects and risk of adverse reactions)