Approach
The first priority in treating patients with Lambert-Eaton myasthenic syndrome (LEMS) is to thoroughly evaluate for underlying cancer and to treat the cancer appropriately. Treatment of the underlying cancer can often result in substantial clinical improvement in LEMS in association with an underlying cancer (CA-LEMS). See Small Cell Lung Cancer (Management).
Symptomatic therapy
Both CA-LEMS and non-cancer-associated LEMS (NCA-LEMS; as part of a more general autoimmune state) subtypes benefit from symptomatic treatment.
First-line therapies focus on symptomatic improvement by augmenting neuromuscular transmission. Agents include amifampridine (also known as 3,4-diaminopyridine [3,4-DAP]), pyridostigmine, and combinations of these agents.[9][39]
Amifampridine is approved by the US Food and Drug Administration (FDA) for the treatment of LEMS in adults. In clinical trials, patients randomised to amifampridine experienced significantly greater improvement (per the Quantitative Myasthenia Gravis score, a 13-item physician-rated categorical scale assessing muscle weakness) than those receiving placebo.[40] Amifampridine can rarely cause seizures and the risk increases with use of higher doses. Therefore it is contraindicated in patients with a history of seizure disorders. Paraesthesia, headache, and nausea are among the most commonly reported adverse effects.
Although pyridostigmine does not usually produce significant improvement in LEMS-related neuromuscular weakness, as monotherapy or additive improvement in combination with amifampridine, it may improve dry mouth and taste dysfunction, and so may be used in conjunction with amifampridine therapy.[41]
Supportive care
Supportive care includes deep vein thrombosis and peptic ulcer prophylaxis, adequate nutrition and hydration, appropriate surveillance and treatment of infections, and avoiding medications that impair neuromuscular transmission. The most common medications on this list include antibiotics (macrolides, aminoglycosides, fluoroquinolones) and beta-blockers. Other medications that impair neuromuscular transmission include magnesium, lithium, quinidine, calcium-channel blockers, procainamide, and immune checkpoint inhibitors.[42] Intravascular contrast agents containing ionic or chelating agents should be avoided, as use has resulted in exacerbation of weakness.[43] Neuromuscular blocking agents, such as vecuronium and curare, should be used cautiously, as use may result in prolonged neuromuscular blockade. A complete reference of drugs impairing neuromuscular transmission is available. MGFA: medications and myasthenia gravis Opens in new window
Treatment-refractory patients
If initial therapy with amifampridine is not effective and weakness is relatively mild, the decision to pursue more aggressive therapy with immunomodulators and immunosuppressants should be made judiciously. Prednisone (prednisolone) is the most frequently used immunosuppressant; concomitant use of azathioprine often enables lower doses of corticosteroids to be used.[18][44] Although no randomised controlled studies have been performed, data from observational studies suggest efficacy.[9][44] A serious idiosyncratic allergic reaction that includes rash, fever, nausea, vomiting, and abdominal pain occurs in 10% to 15% of patients within the first 3 weeks of treatment.[45][46] The reaction resolves within 24 hours of stopping azathioprine and recurs with rechallenge. By analogy to myasthenia gravis, mycophenolate and ciclosporin may also be used, although evidence of benefit is limited to case reports and small case series.[9][18] Due to a favourable adverse-effect profile, mycophenolate is preferred over ciclosporin. Substantial and continuing doses of immunosuppressive medications may be required. However, in CA-LEMS, prolonged immunosuppression should be avoided in light of impaired immune surveillance and risk of worsening or relapse of cancer.
When weakness is severe, plasma exchange or high-dose intravenous immunoglobulin (IVIG) may be used to induce relatively rapid but transient improvement.[47][48] An observational study showed that treatment with plasma exchange may result in short-term improvement, although repeated courses may be necessary to sustain improvement.[48] One small randomised controlled trial demonstrated short-term improvement for IVIG (up to 8 weeks), although it is unclear whether scheduled infusions produce sustained improvement.[17][39] Maximum improvement is noted at 2 to 4 weeks following infusion, with associated decline in serum voltage-gated calcium-channel (VGCC) antibody titres.[17] IVIG should be used with caution in patients with suspected malignancy due to the increased risk of thrombosis.
Severe respiratory or bulbar weakness
Severe respiratory or bulbar weakness is a neurological emergency. Severe weakness may be provoked by infections, medications, surgery, or trauma, although this is uncommon in LEMS and should prompt evaluation for an alternative aetiology such as a myasthenia gravis/LEMS overlap syndrome.
Serial measurements of FVC and negative inspiratory force should be taken using an appropriate interface for patients with severe bulbar weakness. Indication for mechanical ventilation includes FVC of ≤15 mL/kg and negative inspiratory force of ≤20 cm H₂O. Neither abnormal ABGs nor pulse oxygenation reflects the degree of respiratory weakness because abnormalities in either occur late in the course after clinical decompensation.
Therapy focuses on providing ventilatory support, removing the provoking factors, providing general supportive measures, and instituting either plasma exchange or IVIG to rapidly improve neuromuscular function.
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