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Lambert-Eaton Myasthenic Syndrome (LEMS)

Medical Management

There is no cure for Lambert-Eaton mysathenic syndrome (LEMS), as scientists have not yet figured out how to selectively stop the autoimmune attack on motor nerve terminal calcium channels and other nerve terminal proteins targeted by LEMS. Therefore, symptomatic treatments for neuromuscular weakness that results from LEMS are favored.

Potassium channel blockers

Potassium channel blockers allow the electrical activity that passes through the neuromuscular junction to continue for a longer period1, thereby increasing calcium influx into the nerve ending and the release of acetylcholine. Two potassium channel blockers are approved in the United States to treat LEMS.

Firdapse (also known as 3,4-diaminopyridine, 3,4-DAP) was approved by the FDA in November 2018 for the treatment of adults with LEMS and is commercialized by Catalyst Pharmaceuticals. Firdapse was tested in multiple clinical trials in adults living with LEMS. The studies measured the effect of Firdapse on the Quantitative Myasthenia Gravis score (a physician-rated scale used to assess muscle weakness) and the Subject Global Impression scale (a scale where patients rate their overall impression of the effects of the treatment). Patients receiving Firdapse showed a greater benefit on these measures as compared to those on placebo.2

Ruzurgi (amifampridine) was approved by the US Food and Drug Administration (FDA) in May 2019 for the treatment of LEMS in children 6 to 17 years of age and is commercialized by Jacobus Pharmaceutical Company. The approval of Ruzurgi was based on safety and efficacy data from a clinical trial of 32 adults with LEMS, safety data from pediatric patients, and pharmacokinetic modeling and simulation data. The efficacy study compared the time it takes a person to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause in patients who continued on Ruzurgi to those who switched to placebo. Patients who continued on Ruzurgi experienced less impairment than those on placebo; in addition, patients who switched to placebo perceived weakening.3

Firdapse and Ruzurgi have been known to cause seizures and should not be used in people who have a history of seizures. The most common side effects experienced in Firdapse clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension, and muscle spasms. The most common side effects seen in Ruzurgi trials were paresthesias, abdominal pain, indigestion, dizziness, and nausea.2,3

Cholinesterase inhibitors

The most commonly used cholinesterase inhibitor is pyridostigmine (Mestinon). These drugs slow the breakdown of acetylcholine.4

Cholinesterase inhibitors keep acetylcholine around longer at the neuromuscular junction but also in the autonomic nervous system (which controls involuntary bodily functions). Sometimes the drugs can cause diarrhea, abdominal cramps, and/or excessive saliva. At high doses, they can increase weakness. Imodium can be used to treat diarrhea caused by pyridostigmine.

Cholinesterase inhibitors are usually only mildly effective for LEMS, but in rare cases they can prove sufficient for managing the disease.

Additionally, cholinesterase inhibitors that are used in myasthenia gravis (MG) are also used in LEMS to help with symptoms by maintaining acetylcholine’s presence at the neuromuscular junction. Cholinesterase inhibitors block the action of acetylcholinesterase, the enzyme that breaks down acetylcholine.

Other approaches

Guanidine, a potassium channel blocker, is sometimes used in conjunction with pyridostigmine, but guanidine is mostly avoided because of toxicity that can involve kidney and bone marrow. If guanidine is used, doses should be low (5 to 10 mg/kg per day, given in three to four divided doses to start) and close monitoring of side effects is necessary.

Drugs that suppress the immune system can be used to attack the autoimmune nature of LEMS, but they have side effects and increase susceptibility to infections and, possibly, cancer.

Intravenous immunoglobulin (IVIG) therapy can be used to block the binding of antibodies.

These treatment options need to be considered carefully, and close follow-up is necessary. Your doctor or MDA Care Center physician can help you determine which treatments are appropriate for you.

In individuals with cancer, the primary malignancy is also treated.

Immune therapy

For individuals who need additional therapy, immunosuppression or immune modulation is usually the next step.

The treatment options are similar to those discussed for MG (see Myasthenia Gravis Medical Management), with prednisone and azathioprine most often being used. Mycophenolate mofetil may be a substitute for azathioprine.

Immune modulation options also include intravenous immunoglobulin (IVIG) and plasma exchange. Plasma exchange removes antibodies from the blood temporarily. IVIG is usually preferred, with benefits that peak at two to four weeks. IVIG therapy is essentially an injection of nonspecific antibody (immunoglobulin) that might work by dialing down the immune system's production of its own antibodies, much as warm air tells a thermostat to stop pumping out heat. It is also thought that IVIG blocks the binding of antibodies, such as calcium channel antibodies, from their targets. It probably also dilutes the antibodies and other immune system products that damage cells. IVIG can be given in combination with other immunotherapies and as a bridge while waiting for azathioprine to become effective.5

References

  1. Roden, D. M. Pharmacogenetics of potassium channel blockers. doi:10.1016/j.ccep.2016.02.003
  2. FIRDAPSE® (amifampridine) [Prescribing Information].Coral Gables, FL:Pharmaceuticals, Catalyst.
  3. RUZURGI (amifampridine) [prescribing information].Princeton, NJ:Jacobus Pharmaceutical Company. (2019).
  4. MESTINON (pyridostigmine bromide) [prescribing information].Philadelphia, PA: ICN Pharmaceuticals.
  5. Keogh, M., Sedehizadeh, S. & Maddison, P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst. Rev. (2011). doi:10.1002/14651858.cd003279.pub3

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