Lambert-Eaton Myasthenic Syndrome (LEMS) Treatment & Management

Individually tailor therapy for Lambert-Eaton myasthenic syndrome (LEMS) on the basis of severity of weakness, underlying disease(s), life expectancy, and response to previous treatment. Therapy is best coordinated with the primary care physician and appropriate consultants.

If an underlying neoplasm is present (eg, small cell lung cancer [SCLC]), initial treatment should be aimed at the neoplasm because weakness frequently improves with effective cancer therapy. No further LEMS treatment may be necessary in some patients. Typical treatments for patients with SCLC as the cause of their LEMS would include combination therapy with cisplatin and etoposide. Through both tumor modulation and its direct immunosuppressive properties, chemotherapy does seem to improve the symptoms of LEMS.

In patients with LEMS who do not have cancer, aggressive immunotherapy should be considered.

Therapy seldom is started in the emergency department (ED). In general, before medical therapy begins, myasthenia gravis (MG) must be excluded. If the diagnosis is in any doubt, further workup or therapy for MG should be considered.

In the ED setting, the most serious threat to life in these patients is the rare cases of respiratory failure. In such cases, treat as in any other patient: initiate supplemental oxygen; secure intravenous (IV) access; and intubate, if indicated. If intubation proves necessary, the use of neuromuscular blocking agents may further exacerbate the weakness and have prolonged effects (see Avoidance of weakness-exacerbating drugs).

Patients experiencing acute exacerbations of weakness should be admitted for further testing and therapy that is best completed on an in-patient basis. Medical therapy, to include immunosuppression and plasmapheresis, may be indicated (see Pharmacologic Therapy and Plasma Exchange).

Avoidance of weakness-exacerbating drugs

Drugs that compromise neuromuscular transmission frequently exacerbate weakness in LEMS. Competitive neuromuscular blocking agents, such as d-tubocurarine and pancuronium, have an exaggerated and prolonged effect in patients with LEMS.

Initial signs of possible LEMS include prolonged weakness or apnea following administration of neuromuscular blocking agents during anesthesia.

Some antibiotics, particularly aminoglycosides, fluoroquinolones (eg, ciprofloxacin), and erythromycin, have significant neuromuscular blocking effects. Some antiarrhythmics (eg, quinine, quinidine, procainamide) and beta-adrenergic blocking drugs also worsen myasthenic weakness.

Exacerbation of LEMS after administration of any of several other agents, including magnesium and IV iodinated radiographic contrast agents, has been reported in isolated cases. In general, patients with LEMS should be observed for clinical worsening after initiating any new medication.

Unless absolutely necessary, avoid drugs that are known to impair neuromuscular transmission. In such cases, a thorough knowledge of their potential deleterious effects is required.

In patients with cancer, LEMS is usually not the major therapeutic concern: the primary concern is the cancer. Accordingly, when the diagnosis of LEMS is confirmed, perform an extensive search for an underlying malignancy with radiography and computed tomography (CT) of the chest, bronchoscopy, and possibly positron emission tomography (PET) scanning.

If no tumor is found, periodically search again for occult malignancy. Frequency of these evaluations is determined by the patient’s risk of cancer.

Patients younger than 50 years without history of long-term smoking have a low risk of associated malignancy, especially if evidence of coexisting autoimmune disease is present. Extensive surveillance for cancer may not be necessary for such patients. Patients older than 50 years with a history of long-term smoking almost certainly have underlying SCLC.

Initial treatment should be aimed at the neoplasm because weakness frequently improves with effective cancer therapy. No further LEMS treatment may be necessary in some patients.

Immunotherapy of LEMS without effective treatment of the underlying cancer usually produces little or no improvement in strength. A theoretical concern is that the immunosuppression may reduce immunologic suppression of tumor growth.

In patients with LEMS who do not have cancer, aggressive immunotherapy should be considered (see Pharmacologic Therapy and Plasma Exchange).

Amifampridine phosphate (Firdapse), a voltage-dependent potassium channel blocker, was approved by the FDA for LEMS in December 2018. Approval was based on two phase 3 placebo-controlled trials. Efficacy was assessed on the basis of scores on the Quantitative Myasthenia Gravis test (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression scale (a 7-point scale on which patients rate their overall impression of the effects of the study treatment on their physical well-being). ^[8]

A trial evaluating maintenance of strength showed patients who were randomized to continuous amifampridine did not show greater than 30% deterioration in triple timed up-and-go (3TUG) times, whereas 72% of those who tapered to placebo had more than 30% deterioration (p < 0.0001). ^[9]

Amifampridine (Ruzurgi) was approved by the FDA in May 2019 for LEMS in children aged 6-17 years. Approval was supported by safety data in children and pharmacokinetic data in adults, pharmacokinetic modeling, and simulation to identify the dosing regimen in pediatric patients. ^[10]

Recent studies have introduced a Ca²⁺ channel agonist (GV-58) as a potential therapeutic alternative for LEMS. In addition, in a mouse model, GV-58 and 3,4-DAP were shown to interact in a supra-additive manner to restore the magnitude of neurotransmitter release at the neuromuscular junctions. ^{[2, 11]}

The initial pharmacotherapy for LEMS is with agents that increase the transmission of acetylcholine (ACh) across the neuromuscular junction, either by increasing the release of ACh (eg, DAP ^[12] ) or by decreasing the action of acetylcholinesterase (eg, pyridostigmine). Treatment of the associated cancer may also decrease the weakness and other symptoms.

If these treatments are not effective and the patient has relatively mild weakness, determine if aggressive immunotherapy is justified. When such therapy is warranted, plasma exchange (PEX) or high-dose IVIg may be used initially to induce rapid, albeit transitory, improvement. Immunosuppressants should be added for more sustained improvement, although a theoretical concern exists that immunologic suppression of tumor growth may thereby be reduced in paraneoplastic LEMS.

Prednisone and azathioprine, the most frequently used immunosuppressants, can be used alone or in combination. Cyclosporine may benefit patients with LEMS who are candidates for immunosuppression but cannot take or do not respond well to azathioprine. Improvement may be seen within 1-2 month after initiation of cyclosporine, with the maximum response usually observed in 3-4 months.

PEX produces improvement in many patients with LEMS. Improvement is temporary unless the patient is also receiving immunosuppression. Response to PEX is often more gradual in patients with LEMS than in those with MG. Maximal response may take several weeks. Repeated courses of PEX may be necessary to maintain improvement. PEX may be performed 4-6 times over 7-10 days, as described in standard protocols. Potential complications include autonomic instability, hypercalcemia, and bleeding due to depletion of clotting factors.

IVIg, given in a course of 2 g/kg over 2-5 days, also induces clinically significant temporary improvement in many patients. ^[13] The frequency of improvement in response to repeated courses of treatment has not been determined.

In patients with chronic weakness, consultation with a neurologist may be indicated for electromyography (EMG), further workup, and initiation of pharmacotherapy. The diagnosis of LEMS may be suspected clinically but must be confirmed by electrodiagnostic testing. In addition, many of the medications and therapies that have been shown to produce clinical improvement are not appropriate for the ED. Most notably, in addition to pharmacotherapy, IVIG has been shown to have significant results. ^[13]

Other appropriate consultations may include an oncologist and a physical medicine specialist.

Ideally, the patient’s neurologist or primary care physician should coordinate all tests and procedures ordered on an outpatient basis.

Physical therapy and exercise are important parts of the outpatient regimen to help maintain muscle tone and strength. Weakness of LEMS may be worse when the ambient temperature increases or when the patient is febrile. Patients should avoid hot showers or baths. Systemic illness of any sort may cause transient worsening of weakness.