How LEMS Treatments Help
The purpose of this section is to provide a comprehensive overview of published and currently in-use treatments for Lambert-Eaton Myasthenic Syndrome (LEMS), to provide references to sources that provide further details, and to describe the experiences of some LEMS patients with these treatments.
This article does not provide medical advice, which should always be obtained from qualified medical professionals who know the patient.
The LEMS patients whose experiences are described in this article are a self-selected group that participates in monthly video conferences that are organized through the Lambert-Eaton LEMS Family Association and the Lambert-Eaton News site. About 5 to 15 patients participate in each of the video conferences.
We cannot claim that this group represents LEMS patients in general. We will refer to this group as the LEMS meeting group in the remainder of this article. The brief overview of the pathophysiology of LEMS in the following three paragraphs will help the reader understand the purpose of different LEMS treatments. Reference [1] in the list below gives further details on this topic.
Treatments for LEMS work in different ways to improve strength and reduce symptoms. Some drugs, like Firdapse® (amifampridine phosphate), help nerves release more signals to the muscles, while Mestinon® (pyridostigmine) slows the breakdown of those signals. Other options, like immunoglobulin infusions (IVIG/SCIG), immunosuppressive drugs, or plasmapheresis, can reduce the effect of the harmful antibodies that cause LEMS. Often, doctors combine treatments to give the best relief while managing side effects.
An Overview on LEMS Treatments from the Patient's Prospective
The following article provides resources and information on drugs that patients with LEMS have reported taken. This information should be used as a resources in the discussion with your doctor.
Below, you will find information on:
• amifampridine and amifampridine phosphate,
• pyridostigmine bromide, and
• guanidine
These drugs do not affect the production of LEMS-related autoantibodies. For a LEMS patient who can tolerate these drugs, they may provide sufficient treatment if the patient’s production of these autoantibodies is low enough. Otherwise, they may be used in combination with other treatments.
Amifampridine and Amifampridine phosphate
Amifampridine (also known as 3,4-Diaminopyridine or 3,4-DAP) and amifampridine phosphate are first-line treatments for LEMS. Both of these drugs extend the time that voltage-gated calcium channels in activated nerve endings stay open. This offsets, to some extent, the presence of the LEMS-related autoantibodies and causes the nerve endings to produce closer to a normal amount of neurotransmitter.
Amifampridine and amifampridine phosphate may be better known to many LEMS patients by the brand names of their commercialized versions, which are Ruzurgi® and Firdapse®, respectively. Ruzurgi® is a product of Jacobus Pharmaceuticals and Firdapse® is a product of Catalyst Pharmaceuticals.
Amifampridine phosphate is more chemically stable than amifampridine, so it has a longer shelf life and can be stored at room temperature.
Whether Ruzurgi®, Firdapse®, or non-commercialized formulations of amifampridine are available to a LEMS patient depends on which country the patient lives in. For example, at the time of writing, only Firdapse ® is available in the USA, both Firdapse ® and Ruzurgi ® are available in Canada, and a noncommercialized version of amifampridine is available in the United Kingdom.
The Catalyst Pharmaceuticals online information for Firdapse®, including dosing limits and side effects, is at firdapse.com. Similar online information appears to not be available for Ruzurgi®. Myaware, a registered charity in the United Kingdom, has information for amifampridine (referred to as 3,4 Diaminopyridine) at www.myaware.org.
Consistent with the Catalyst Pharmaceuticals online information for Fidapse®, most members of the LEMS meeting group (who mostly live in the USA) indicate that they take Firdapse® multiple times per 24 hour period. These LEMS patients generally report that doses are spaced at between 3 and 4 hours during waking hours. At least one of these LEMS patients takes a relatively low dose of Firdapse® at bedtime and once when rising during the night to use the washroom. Others of these LEMS patients avoid taking Firdapse® close to bedtime because they feel that it interferes with their sleep. Most of these LEMS patients take a dose of Firdapse® 20 minutes to an hour before rising in the morning. At least one of these LEMS patients cannot take Firdapse® because of a history of seizures (the Catalyst Pharmaceuticals information indicates a history of seizures to be a primary contraindication for Firdapse®). The published possible Firdapse® side effects that are experienced by these LEMS patients varies widely.
Pyridostigmine Bromide
Pyridostigmine bromide is commonly referred to as Mestinon®, a brand name for this drug. This drug is generically available from multiple manufacturers. Whereas amifampridine or amifampridine phosphate increases the amount of neurotransmitter that is released from an activated nerve ending, pyridostigmine bromide slows the breakdown of the produced neurotransmitter. This can also result in a noticeable increase in muscle strength.
Pyridostigmine bromide is frequently taken in combination with amifampridine or amifampridine phosphate by LEMS patients, who may report a greater benefit with this combination than with only one of the drugs, despite one clinical trial showing that the combination of pyridostigmine bromide and Firdapse® was not more effective than Firdapse® alone [5].
Individually, pyridostigmine bromide is generally not considered as effective for LEMS as amifampridine or amifampridine phosphate. Pyridostigmine bromide is more commonly recognized as a treatment for myasthenia gravis.
Pyridostigmine bromide is available in 60mg tablets and 180mg slow-release tablets. Either, or both, may be prescribed to a LEMS patient. One member of the LEMS meeting group takes 60mg tablets during the day in combination with Firdapse®, and an 180mg slow-release tablet at bedtime without Firdapse®.
Among LEMS meeting group members, the most frequently reported side effects of pyridostigmine bromide are abdominal cramping and diarrhea. These side effects have been more frequently reported by these patients than any of the Firdapse® side effects. For some of these members, these side effects are serious enough to have caused them to stop taking pyridostigmine bromide.
For some LEMS patients, pyridostigmine bromide is the first LEMS-related drug that they were prescribed. Their preliminary medical exam produced evidence of some type of myasthenic syndrome (a group of disorders that includes LEMS and myasthenia gravis), but was not conclusive specifically for LEMS. In these cases, pyridostigmine bromide was readily available, inexpensive, and provided some symptom relief early in the diagnostic process.
Guanidine
Guanidine works similarly to amifampridine but has more serious side effects, which makes it a less preferred as a treatment for LEMS. To the author’s knowledge, no member the LEMS meeting group has ever reported using guanidine.
Intravenous and Subcutaneous Immunoglobulin Infusion (IVIG or SCIG)
An immunoglobulin (IgG) infusion product is a liquid that contain immunoglobulins (antibodies), mainly of the class IgG, that are taken from the plasma of many human donors. This product is injected into the body of a patient in order to treat an immune deficiency or an autoimmune disorder. The injection may be intravenous or subcutaneous. The intravenous and subcutaneous forms may be referred to as IVIG and SCIG, respectively.
IVIG or SCIG infusions are sometimes used to treat LEMS when drugs that act only on the neuromuscular junction provide insufficient relief or are not tolerated. They may also be used in combination with these drugs and with immunosuppressive drugs. IVIG may be used short-term while waiting for immunosuppressive drugs to become effective, or IVIG/SCIG may be used as a long-term maintenance treatment.
In one formal study involving nine LEMS patients, IVIG therapy was shown to result in improved muscle strength and a lowered concentration of of LEMS related autoantibodies [6]. Exactly how IVIG can do this is not completely understood.
When starting IVIG therapy a LEMS patient will receive infusions over two to five consecutive days. After that, the patient will typically receive infusions every every two to six weeks. A LEMS patient may not experience the full benefit of the treatment until weeks or even months from the first infusion. Many patients tolerate IVIG well, but some experience significant negative side effects. When these side effects of IVIG are intolerable, the patient may be able to instead tolerate the side effects of SCIG and obtain good clinical results from it. Reference [7] describes one example of this for a LEMS patient.
Some members of the LEMS meeting group who take IVIG every three to four weeks describe worsening LEMS symptoms during a period of several days or even a week before their next IVIG dose. Some members have also described difficulties with with vein access. One LEMS patient has written about how a switch from IVIG to SCIG has eliminated these problems and has also resulted in a reduction of negative side effects.
There is anecdotal evidence that IVIG or SCIG is not equally effective for all LEMS patients. Several members of the LEMS meeting group who take Firdapse® also rely on long-term IVIG use as an essential part of their treatment. However, one member of this group has reported that over a five month trial of IVIG in combination with Firdapse® and pyridostigmine bromide no benefit was experienced over that which was experienced by taking Firdapse® and pyridostigmine bromide alone.
Plasmapheresis
Plasmapheresis, or plasma exchange, is a mechanical process for the treatment of autoimmune diseases, including LEMS, in which the patient’s blood is circulated through a machine that separates the plasma from the cellular components of the blood. The plasma contains the antibodies, including autoantibodies that cause the autoimmune disease. The cellular components are then returned to the patient’s body along with replacement plasma that excludes the autoantibodies. Plasmapheresis may provide rapid and significant relief of LEMS symptoms without immunosuppression, but the effect is short-lived (e.g., lasting a week after a single round of plasmapheresis). Plasmapheresis is a relatively rarely used treatment for LEMS. It is mostly used when other treatments are insufficient, or as part of an emergency response to a serious flare-up of symptoms [9].
Immunosuppressive Drugs
An immunosuppressive drug weakens certain parts of the patient’s immune system. This is useful for preventing the rejection of transplanted organs or for reducing the immune system activity that causes an autoimmune disorder such as LEMS.
An ideal immunosuppressive drug for LEMS would prevent the production of the LEMS-related autoantibodies and have no other effect on the patient’s immune system. However, such a drug does not exist, and any available immunosuppressive drug has the side effect of additionally suppressing some normally functioning parts of the immune system. This means that the patient will be more susceptible to infections or malignancies that the suppressed parts normally fight. Immunosuppressive drugs generally also have other potential side effects.
In contrast, IVIG and SCIG modulates the patient’s immune system without suppressing it. Drugs that only act on the neuromuscular junction also do not suppress the patient’s immune system. However, for some LEMS patients these treatments do not provide adequate relief, even in combination, or their side effects may be prohibitive. In these cases, the addition of a tolerated immunosuppressive drug to the patient’s treatment may result in improved relief that justifies associated side effects and greater patient monitoring requirements.
The following are immunosuppressive drugs that are commonly used to treat LEMS patients:
- prednisone
- azathioprine
- mycophenolate
- rituximap
- Cyclosporin has also been mentioned in the literature as a LEMS treatment [8], but much less frequently than the drugs listed above.
None of these drugs were developed specifically to treat LEMS patients.
Members of the LEMS meeting group who are long-term immunosuppressive drug users generally use mycophenolate (commonly referred to by the brand name CellCept®) or rituximab (commonly referred to by the brand name Rituxan®).
One member of the LEMS meeting group uses both rituximab and IVIG and has stated that the purpose of IVIG in this case is to restore the normal IgG group of antibodies (i.e., excluding LEMS-related autoantibodies) that have been intentionally depleted along with the LEMS-related autoantibodies by the rituximab use, and thus avoid the greater risk to infection that would result from rituximap use alone. This synergy of rituximab and IVIG for autoimmune disease treatment is a subject of recent medical research.