A study provided an overview of the use of amifampridine (brand names Firdapse and the recently approved Ruzurgi), along with other treatment choices for Lambert-Eaton myasthenic syndrome, including those for resistant muscle weakness.
The review study, “Recent Advances and Therapeutic Options in Lambert-Eaton Myasthenic Syndrome,” was published in the journal Cureus.
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular disorder caused by self-attacking antibodies that block the transmission of messages from nerve cells to muscles by attacking the neuromuscular junction.
Specifically, they disrupt voltage-gated calcium channels (VGCCs), which are located at the membrane of nerve cell terminals. Nerve impulses open VGCCs and this triggers the release of acetylcholine (ACh), a key neurotransmitter that conveys signals from nerve cells to muscles.
In people with LEMS, the disruption of this communication leads to weakening of muscles throughout the body.
First treatment choices
In the absence of malignancies, treatments mostly focus on alleviating symptoms, especially muscle weakness. The most effective are those that increase ACh release at the neuromuscular junction, prolonging the nerve signal.
To date, the only targeted therapy approved for LEMS is amifampridine (brand names Firdapse and Ruzurgi).
Amifampridine is an orally available potassium channel blocker that acts by making calcium channels stay open longer, which prolongs ACh release.
In Europe, amifampridine tablets (chemical name 3,4-Diaminopyridine, or 3,4-DAP) were approved in 2009 and recommended as a first-line symptomatic treatment for LEMS in 2010.
More recently, in 2018, a more stable salt formulation (amifampridine phosphate) was approved by the U.S. Food and Drug Administration (FDA) for treating adults with LEMS under the brand name Firdapse, by Catalyst Pharmaceuticals.
In May 2019, the FDA approved Ruzurgi, amifampridine tablets for children ages 6 to 17. With the decision, Ruzurgi, developed by Jacobus Pharmaceuticals, became the only targeted therapy approved for children with LEMS.
Many clinical trials have successfully shown the efficacy of amifampridine tablets in improving muscle strength, either measured by neurological disability score (NDS) or QMG score, and its benefits for muscle electrical activity, determined using the compound muscle action potential (CMAP).
Side effects of amifampridine are usually mild, including ‘pins and needles’ sensations around the mouth, tongue, face, fingers, toes, and other body parts, nausea, vomiting, and elevated liver enzymes in the blood.
Seizures can occur but the risk is low as the medicine has low brain penetration. However, at doses greater than 100 mg per day this risk is higher. The maximum daily dosage recommended is 100 mg for Ruzurgi and 80 mg for Firdapse.
Another potassium channel blocker, guanidine, was once recommended as a first-line treatment for LEMS, but its use has become limited given several side effects, such as kidney toxicity, gastrointestinal disturbances (anorexia, diarrhea, gastric irritation), and bone marrow suppression.
If amifampridine is not available or tolerated, low-doses of guanidine (1,000 mg/day), alone or in combination with pyridostigmine, can be recommended.
Pyridostigmine is sold as Mestinon and approved by the FDA to treat muscle weakness in people with myasthenia gravis (MG), but it also is used off-label to treat muscle weakness in LEMS. It is an acetylcholinesterase inhibitor that works by inhibiting ACh breakdown so the ACh stays in the neuromuscular junction longer, strengthening muscle stimulation.
Pyridostigmine has a better tolerance compared to other medicines in the same class. Recommended doses for LEMS go from 30 mg to 180 mg. The side effects are mild and include nausea, abdominal cramping, and diarrhea.
Muscle weakness resistant to treatment
When muscle weakness is refractory, that is, symptoms are not controlled by normal treatment, the use of immunomodulators (treatment that modulates the immune system) are recommended.
Intravenous immune globulin (IVIG) is considered a first-line treatment option in these cases. It consists of injections into the veins (intravenous) of a mixture of antibodies collected from human plasma. In LEMS, the mechanism of action of IVIG is unknown but it is believed to act by neutralizing autoantibodies and by regulating the immune system.
Infusions are effective for two to five days, with maintenance therapy for up to 12 weeks also proven beneficial in some patients. It takes two to four weeks of treatment to see improvements in weakness. Complications and side effects are usually minor and include laboratory changes, rash, and headache. There have been rare cases of deep venous thrombosis (DVT, a blood clot in a deep vein in the body).
Rituximab is a monoclonal antibody that binds to a specific protein — CD20– present on the surface of B-cells, the immune cells that produce antibodies. By binding to CD20, rituximab triggers the killing of B-cells, decreasing the production of harmful autoantibodies. It also may prevent other immune cells, called T- cells, from attacking the neuromuscular junction.
For LEMS, the standard dose is 375 mg/m2 given as intravenous injections, once weekly for four weeks, and then each month for two months. The side effects include heart problems, as well as anaphylaxis (a life-threatening allergic reaction), other allergic reactions, nausea, and vomiting.
Plasma exchange “has limited advantages” for LEMS patients, but may be beneficial to some patients in combination with other immunosuppressive agents. The protocol suggested for LEMS is the same recommended for MG — five exchanges over the course of seven to 14 days.
Patients’ outlook largely depends on the association of LEMS with cancer. About 60% of LEMS cases are associated with small cell lung cancer (SCLC), an aggressive form of lung cancer. Other types of tumors may be present in about 10 percent of patients. These malignancies can shorten patients’ survival. Conversely, in patients without cancer, life expectancy is the same or close to that of healthy people.