Myasthenia Gravis (MG)

Medical Management

Many drugs and procedures are available for treating myasthenia gravis (MG), each with distinct advantages and disadvantages.

Depending on the age of the patient, the severity of the disease, and the pace of progression, four basic therapies are used to treat MG:

• Symptomatic treatments (anticholinesterase agents)
• Chronic immunomodulating treatments (glucocorticoids and other immunosuppressive drugs)
• Rapid immunomodulating treatments (plasmapheresis and intravenous immunoglobulin)
• Surgical treatment (thymectomy)

Drugs known as cholinesterase inhibitors offer relief from symptoms by blocking the action of acetylcholinesterase and increasing the amount of acetylcholine at the neuromuscular junction. (For a more detailed explanation of how these drugs work, see Causes/Inheritance.)

Commonly used immunotherapeutic drugs in MG are prednisone, azathioprine, cyclosporine, and mycophenolate mofetil. In some circumstances, particularly in those with refractory MG, other agents such as rituximab, periodic intravenous immune globulin (IVIG), monthly pulse cyclophosphamide, and tacrolimus may be considered.

Plasmapheresis and IVIG are rapid immunotherapies that are usually reserved for certain situations, such as myasthenic crisis. They work quickly but have a short duration of action. They are used preoperatively before thymectomy, while initiating slower acting immunotherapies, or as an adjuvant to other immunotherapeutic medications in patients with refractory MG.

Thymectomy is beneficial for certain patients who are positive for the acetylcholine receptor antibody, however, thymus removal takes months to years to show benefits for MG patients. Immunosuppressant drugs can be used to attack the disease at its source, but they increase susceptibility to infectious diseases and most of them carry other potentially serious side effects.

The benefits and risks of these treatments must be weighed against each other and the needs of the patient. Your doctor or MDA Care Center director can help you determine which treatments are appropriate for you.

Cholinesterase inhibitors

These drugs, also known as anticholinesterases, have been used to treat MG since the early 1990s and can produce relief from symptoms within minutes. The one most commonly used is pyridostigmine bromide (Mestinon).

Cholinesterase inhibitors boost ACh levels not only 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. To minimize these side effects, your physician might lower the dose of cholinesterase inhibitors or prescribe atropine, which blocks the ACh receptors on nerve cells.

Patients with limb and bulbar symptoms typically respond better to pyridostigmine than those with ptosis and diplopia. In rare cases, cholinesterase inhibitors prove enough for managing MG, but most people also require immunosuppression treatment that restrains the actions of the immune system. The use of cholinesterase inhibitors in synergy with immunosuppressive drugs also allows a physician to reduce the dosage of immunosuppressive medications, something that can reduce side effects associated with it.

Drug warnings and other concerns

Many prescription drugs can unmask or worsen symptoms of MG. These include:

• Neuromuscular blocking agents used for anesthesia or intubation¹
• Aminoglycoside and quinolone antibiotics²
• Cardiac anti-arrhythmics, such as all beta blockers and procainamide
• Local anesthetics, such as lidocaine and procaine if injected intravenously 
• Magnesium salts
• Penicillamine used in other autoimmune diseases such as Wilson disease; it can induce MG³
• PD-1 inhibitors used as immunotherapy in certain cancers^{4, 5, 6}
• Central nervous system depressants and opioids
• Anticonvulsants such as antiepileptic or antiseizure drugs

Few reports show a connection between Statin treatments (a class of lipid lowering medications) and worsening of MG.^{7, 8, 9}

When taking a new prescription drug for the first time, it is essential to consult your doctor about its possible effects on MG. Also, you might want to keep a MedicAlert bracelet or card handy to inform emergency medical personnel that you have MG and that certain drugs can be harmful to you.

Aside from drugs, overexertion, emotional stress, infections (from tooth abscesses to the flu), menstruation, and pregnancy also can lead to increased weakness in MG.

Chronic immunotherapies

The second therapeutic modality in MG is the administration of immunomodulating agents called corticosteroids. These drugs (which include prednisone and prednisolone) reproduce the actions of corticosteroid hormones, which are made by the outer layer of the adrenal gland. They have broad anti-immune and anti-inflammatory effects, making them powerful treatments for MG.

They are not as fast-acting as cholinesterase inhibitors, but they are faster than some other immunosuppressants, producing improvement within weeks to months. They are also relatively inexpensive.

A disadvantage of corticosteroids is that they can produce many side effects — some of them potentially serious — including osteoporosis (weakening of bones), mood disturbances, gastrointestinal problems, weight gain, high blood pressure, cataracts, and stunted growth (in children). For many people, these side effects can be managed with other therapies; for example, bisphosphonate drugs can be used to prevent osteoporosis.

For others, corticosteroids are used as a first-line defense against MG, then gradually tapered off and supplemented or replaced with slower-acting immunosuppressants that have fewer side effects. Most of these other drugs were developed to prevent the rejection of transplanted organs but have since been co-opted for use against MG and other autoimmune diseases.

Azathioprine (Imuran) was the first non-steroid immunosuppressant to come into widespread use, in the 1970s, against MG. The drug inhibits the synthesis of nucleic acids and interferes with the proliferation of adaptive immune cells. It is found that the ACh receptor antibody count is reduced with azathioprine treatment. Dosage starts at 50mg daily and can be increased at 50mg increments every two to four weeks until a maintenance dose of 2mg to 3 mg per kilogram of total body weight is reached. Monthly monitoring of one’s complete blood count and liver function is needed every six months. Checks can be less frequent once blood count and liver function stabilizes. Azathioprine acts more slowly than corticosteroids, producing improvement after six to 12 months, and usually has few side effects. Occasionally, however, it can produce serious side effects including inflammation of the pancreas, liver toxicity, bone marrow suppression, and possibly an increased risk of cancer.

Mycophenylate mofetil (CellCept) is a relatively new immunosuppressant but so far it has shown promising results against MG in clinical trials. In two small trials completed in 2001, about 65% of MG patients experienced gains in strength or a reduced need for prednisone after taking CellCept for several months. More recent analyses have shown that some people take longer to respond to the drug but that nearly 75% eventually show improvement, with occasional relatively nonserious side effects such as nausea and diarrhea.

Cyclosporine (Neoral, Sandimmune) is a useful, relatively fast-acting treatment for MG and improves MG symptoms in 90% of patients. However, cyclosporine may have side effects including increased blood pressure, abnormal kidney function, unwanted body hair, and stomach upset.

Cyclophosphamide (Cytoxan, Neosar) is considered effective against MG, but because it has many potentially serious side effects, it’s often reserved for use only when other drugs fail. It’s reserved for only severe cases of MG.

Tacrolimus is less nephrotoxic (toxic to the kidneys) than cyclosporine, however it has clinically significant side effects, such as hyperglycemia (high blood sugar), hypomagnesemia (Low Magnesium), tremor, and paresthesias (“pins and needles” sensation).

Methotrexate is an immunosuppressant agent that decreases purine and pyrimidine synthesis (the components that build DNA). Based on results from a study, methotrexate has been suggested as a second line immunosuppressant agent for treating MG.

Soliris approved to treat generalized MG

Alexion Pharmaceuticals announced on Oct. 23, 2017, that the US Food and Drug Administration (FDA) has approved eculizumab (brand name Soliris) as a treatment for adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor antibody-positive. Soliris is the first in a new class of drugs to be approved for MG in the U.S.

Soliris was tested in clinical trials in people who previously did not respond to immunosuppressive treatment and continued to experience significant unresolved disease symptoms such as difficulties seeing, walking, talking, swallowing, and breathing. Participants taking Soliris had improved scores on scales designed to assess quality of life and symptom burden including double vision, ptosis (drooping of the eyelids), and difficulty swallowing, speaking, breathing, and using the arms and legs.

Soliris is designed to prevent destruction of the NMJ

Soliris is a terminal complement inhibitor that targets a part of the immune system called the complement system, which is responsible for helping antibodies clear damaged cells and potentially toxic microbes that could cause infections. In MG, antibodies whose job it is to target these toxic pathogens instead inappropriately recruit the complement system and target the space across which nerve fibers transmit signals to muscle fibers, called the neuromuscular junction (NMJ).

In people with anti-acetylcholine receptor antibody-positive MG, the body’s own immune system turns on itself to produce antibodies against the acetylcholine receptors located on muscle cells at the NMJ. The inappropriate binding of antibodies to acetylcholine receptors activates the complement system, which leads to a localized destruction of the NMJ. As a result, the communication between nerve and muscle is impaired, which in turn leads to a loss of normal muscle function.

Soliris is thought to work in MG by inhibiting the complement pathway to prevent destruction of the NMJ.

Treatment with Soliris will not cure generalized MG, but it may improve disease symptoms, the ability to carry out activities of daily living, and quality of life.

Myasthenic crisis

Especially in people with bulbar or respiratory symptoms, MG can sometimes worsen to the point of myasthenic crisis, a life-threatening condition involving an extreme episode of weakness that culminates in respiratory failure and the need for mechanical ventilation. In some cases, the respiratory muscles themselves give out, and in others, weakness in the throat muscles causes the airway to collapse.

When MG is properly treated, crisis is very rare, with a 2% to 3% risk for MG patients. And when crisis does occur, it has a good rate of recovery thanks to the wide range of treatments for MG and the quality of respiratory care at most hospitals. Most cases of myasthenic crisis take place within the first few years after diagnosis.

Sometimes, myasthenic crisis can occur without warning, but it often has an identifiable trigger, such as fever, respiratory infection, traumatic injury, stress, or ingestion of one of the drug types mentioned on this page. If you have MG, you should have these conditions monitored by a physician, and if you experience labored breathing or unusual weakness, you should seek immediate medical attention.

Evaluation and management of myasthenic crisis:

• Admission to intensive care unit
• Frequent monitoring of respiratory muscle strength
• Elective intubation if clinical evaluation suggests impending respiratory failure (hospital staff will temporarily stop anticholinesterase medications for intubated patients)
• Initiation of rapid therapy with plasma exchange or intravenous immune globulin (IVIG)
• Initiation of immunomodulating therapy with high-dose glucocorticoids; healthcare providers will consider azathioprine, mycophenolate mofetil, or cyclosporine if glucocorticoids are contraindicated or were previously ineffective
• Weaning from mechanical ventilation when respiratory muscle strength is improving, but only after starting treatment with plasma exchange or IVIG

Plasmapheresis and intravenous immunoglobulin (IVIG)

In plasmapheresis, also known asplasma exchange, an intravenous line is used to remove antibodies from the blood. IVIG therapy is essentially an injection of a nonspecific antibody (immunoglobulin) that might dial down the immune system’s production of its own antibodies, much as warm air tells a thermostat to stop pumping out heat.

These treatments bring about fast but short-lived relief from MG, and are mostly used until other medications take effect, prior to surgery or for myasthenic crisis. However, some people receive regular plasmapheresis or IVIG as a supplement to immunosuppressant drugs.

Plasmapheresis is not commonly used as a long-term treatment as each treatment requires five plasma exchanges over the course of one or two weeks. This need for repeated exchanges often leads to issues with venous access.

Pregnancy

In rare cases, pregnancy appears to trigger the onset of MG. In women who already have MG, pregnancy can cause a worsening of symptoms (usually after birth but sometimes during the first trimester). These trends are not consistent from one pregnancy to the next.

Some medications for MG are safe to use during pregnancy and nursing, but some others are not recommended. If you are planning to become pregnant, you should consult your physician, and if you are a nursing mother, consult your child’s pediatrician.

Between 10% and 20% of babies born to mothers with MG develop transient neonatal MG because the antibodies that cause MG can pass through the placenta. Symptoms (such as feeble cry, feeding difficulties, or general and respiratory weakness) often are detected within hours to days after birth, and decreased movement may be detected inside the womb.

As the name implies, transient neonatal MG is only temporary. Most babies require medication and supportive care but usually recover completely within a few weeks after birth. Permanent weakness or recurrence of MG later in life is extremely rare.¹⁰

Thymectomy

Thymectomy — surgical removal of the thymus gland — is recommended for thymoma and for most cases of generalized MG. It is believed to be the only therapy capable of producing long-term, drug-free remission from MG, but most data regarding its use have come from case studies rather than clinical trials.

Thymectomy initially was estimated to produce one-year remission from MG in less than 20% of people, but in the last seven to 10 years the remission rate has increased to up to 50%.^{11, 12, 13} Thymectomy is also known to increase strength or reduce the need for medication in an additional 50% of patients who receive it. These improvements may take several months to several years after surgery to occur.

Thymectomy usually has the most favorable outcomes in people who are younger than age 60. Also, thymectomy is recommended when symptoms are sufficiently controlled. Because the thymus is required for immune system development, most doctors prefer not to perform the surgery on prepubescent children. The surgery is also not usually recommended for patients older than 60 unless thymoma is present. However, the procedure can still be done depending on a patient’s overall health and if they really wish to undergo the surgery.¹⁴

For more about MG management, see:

• Managing Myasthenia
• Keeping Your Focus: Eye Care in Neuromuscular Disorders
• Not Always Smooth Sailing: Charting a corticosteroid course
• Coping with Anesthesia

References

1. Dillon, F. X. Anesthesia issues in the perioperative management of myasthenia gravis. Seminars in Neurology (2004). doi:10.1055/s-2004-829587
2. Jones, S. C., Sorbello, A. & Boucher, R. M. Fluoroquinolone-Associated Myasthenia Gravis Exacerbation. Drug Saf. (2011). doi:10.2165/11593110-000000000-00000
3. Komal Kumar, R. N. et al. Effect of D-penicillamine on neuromuscular junction in patients with Wilson disease. Neurology (2004). doi:10.1212/01.WNL.0000137021.90567.37
4. Zhu, J. & Li, Y. Myasthenia gravis exacerbation associated with pembrolizumab. Muscle and Nerve (2016). doi:10.1002/mus.25055
5. Lau, K. H. V., Kumar, A., Yang, I. H. & Nowak, R. J. Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle and Nerve (2016). doi:10.1002/mus.25141
6. Polat, P. & Donofrio, P. D. Myasthenia gravis induced by nivolumab therapy in a patient with non–small-cell lung cancer. Muscle and Nerve (2016). doi:10.1002/mus.25163
7. Parmar, B., Francis, P. J. & Ragge, N. K. Statins, fibrates, and ocular myasthenia [2]. Lancet (2002). doi:10.1016/S0140-6736(02)09846-X
8. Engel, W. K. Reversible ocular myasthenia gravis or mitochondrial myopathy from statins? [15]. Lancet (2003). doi:10.1016/S0140-6736(03)12152-6
9. Oh, S. J. et al. Statins may aggravate myasthenia gravis. Muscle and Nerve (2008). doi:10.1002/mus.21074
10. Morel, E. et al. Neonatal myasthenia gravis: a new clinical and immunologic appraisal on 30 cases. Neurology (1988).
11. Shrager, J. B. et al. Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy. Ann. Thorac. Surg. (2002). doi:10.1016/S0003-4975(02)03722-0
12. Saperstein, D. S. & Barohn, R. J. Management of myasthenia gravis. Seminars in Neurology (2004). doi:10.1055/s-2004-829586
13. Jaretzki, A., Steinglass, K. M. & Sonett, J. R. Thymectomy in the management of myasthenia gravis. Seminars in Neurology (2004). doi:10.1055/s-2004-829596
14. Skeie, G. O. et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. European Journal of Neurology (2010). doi:10.1111/j.1468-1331.2010.03019.x