Myasthenia gravis is an autoimmune disease that causes muscle weakness that worsens with activity and improves with rest. Normally, the neurotransmitter acetylcholine stimulates muscular contractions. In most patients with myasthenia gravis, the immune system produces antibodies that block the acetylcholine receptor in muscle cells.

Some integrative therapeutics, such as vitamin D3, astragalus, and creatine may provide benefits or ease symptoms of myasthenia gravis.

Causes and Risk Factors

• Women are more likely than men to develop this autoimmune disease, and at a younger age.
• Ten to fifteen percent of people with myasthenia gravis have a thymic tumor, and 50% have an increased number of cells in the thymus.
• Infection with the Epstein-Barr virus and inflammation may contribute to the development of myasthenia gravis.

Signs and Symptoms

• Muscular weakness that progressively gets worse with prolonged exercise and is often more pronounced in the evening.
• First symptom is generally eye muscle weakness, which can affect up to 85% of affected individuals. In 15% of patients, the initial symptom is difficulty swallowing and slurred speech.
• Patients may also have blurred or double vision, drooping eyelids, or changes in facial expression and control.
  

Diagnosis

• Peek sign: The patient closes their eyes and, due to weakness of the eye muscles, the eyelids separate within 30 seconds to reveal the whites of the eye.
• Ice pack test: In patients with drooping eyelids, an ice pack is placed over the patient’s eye. If the patient has improvement in double vision or drooping eyelids after the ice pack is removed, they likely have myasthenia gravis.
• Physicians can perform analyses of blood samples to detect self-reacting antibodies.
  

Conventional Treatment

• The primary long-term treatment strategy for myasthenia gravis is suppression of the immune system, usually with corticosteroids and non-steroidal drugs.
• Acetylcholinesterase inhibitors, plasma exchange and intravenous immunoglobulin therapy are other therapies used for myasthenia gravis.

Note: Although rare, certain drugs may either induce symptoms of myasthenia gravis or aggravate existing symptoms, including penicillamine, intravenous magnesium, some antibiotics, and beta-blockers.

Novel and Emerging Strategies

• Several clinical trials have reported that rituximab, which is used for rheumatoid arthritis, may be effective for the treatment of myasthenia gravis.
• A phase II study showed that eculizumab, which inhibits a certain aspect of the immune system (the complement system), reduced symptoms of myasthenia gravis more than placebo.
• Granulocyte macrophage colony-stimulating factor (GM-CSF) may be an effective treatment option for myasthenia gravis as it can enhance the activity of regulatory T cells.

Dietary and Lifestyle Considerations

• As muscle fatigue can make eating a difficult task, doctors recommend eating during periods when patients have more strength and eating 5–6 small meals throughout the day.
• Several studies suggest exercise may improve muscle fatigue and weakness in patients with neuromuscular diseases, including myasthenia gravis. However, it is critical that those with myasthenia gravis do not over exercise, as this could exacerbate symptoms.

Integrative Interventions

• Vitamin D: A pilot study showed supplementation with vitamin D has beneficial effects on autoimmune response and may alleviate fatigue associated with myasthenia gravis.
• Astragalus: Astragalus was found to be as effective as prednisone for reducing symptoms of myasthenia gravis.
• Creatine: An analysis of six randomized controlled trials in muscle diseases reported that patients who supplemented with creatine had a significant improvement in muscle strength versus placebo-treated patients.
• White peony extract: Peony has been found to have immune-modulating properties, which may be helpful with the underlying pathology of myasthenia gravis.
• Fish oil: Due to its anti-inflammatory and immune-modulating properties, fish oil may help with the underlying pathology of myasthenia gravis.

Myasthenia gravis is an autoimmune disease that causes muscular weakness and fatigue, which is exacerbated by activity and improved with rest. Under normal circumstances antibodies are produced by the immune system largely to fight off infection. Myasthenia gravis causes the immune system to produce antibodies that target healthy cells, commonly affecting the cellular receptor in muscle cells for the neurotransmitter acetylcholine, which stimulates muscular contractions (Hoch 2001). The disease is characterized by fluctuating periods of muscular weakness, with easy fatigability representing a classic hallmark of the disease. Drooping eyelids, blurred vision, and difficulty chewing and swallowing are common symptoms. About 15–20% of people with myasthenia gravis develop severe, potentially life-threatening respiratory impairment, often within the first year of illness; this is a medical emergency called myasthenia crisis and necessitates mechanical ventilation (NINDS 2012; Juel 2004).

Myasthenia gravis affects an estimated 20 individuals per 100 000 people in the United States (Meriggioli 2012a; Jayam Trouth 2012). Women typically acquire the disease more frequently than men and at a younger age. Although initial signs of myasthenia gravis may emerge at any age, women most commonly develop symptoms under the age of 40, while symptoms among men usually develop after age 60 (NINDS 2012).

Scientists debate the predominant cause of the immune dysregulation associated with myasthenia gravis, though most theories agree that the thymus plays an important role in its development. The thymus is an organ behind the breastbone that produces certain immune cells called T cells (Rehan 2012). Approximately 10–15% of all people with myasthenia gravis have a thymic tumor and more than 50% have an increased number of cells (hyperplasia) in the thymus (Meriggioli 2012a). Recent, intriguing studies have suggested that inflammation and infection with the Epstein-Barr virus may also contribute to the development of this autoimmune disease (Cavalcante 2011).

Although the majority of patients with myasthenia gravis have antibodies that target muscle cell acetylcholine receptors, some researchers have discovered that some myasthenia gravis patients have antibodies against other proteins such as muscle-specific tyrosine kinase (MuSK) or the low-density lipoprotein receptor-related protein 4 (LRP4) (Zagoriti 2013).

Unfortunately, there is currently no cure for myasthenia gravis (MGFA 2010b). However, advances in treatment over the past few decades have enabled many myasthenia gravis patients to achieve prolonged remission with no signs or symptoms of the disease (Thanvi 2004). One of the most common treatments recommended for myasthenia gravis is removal of the thymus (Howard 2006; Ruckert 2011), but there is debate as to whether this procedure is effective in people who do not have thymic tumors (Diaz 2013; Spillane 2013; Corse 2014). Other common treatments include corticosteroids, which are used to inhibit the activity of immune cells short-term; acetylcholinesterase inhibitors, which allow the nerves to regain their ability to communicate with the muscles; and immunosuppressive drugs, which inhibit the body’s immune response long-term (Sathasivam 2011).

Physicians in the past believed that myasthenia gravis was a single disease, but now it has been suggested that it may represent several different clinical subtypes (Meriggioli 2012a; Meriggioli 2009). Clinicians are now able to test patients for the presence of different markers and tailor their treatments accordingly. Several recent clinical trials and laboratory experiments have suggested that agents used to treat other diseases, such as rituximab, which is used in the treatment of lymphomas and leukemias, may also be effective for the treatment of myasthenia gravis (Diaz-Manera 2012; Collongues 2012). Furthermore, additional studies have suggested that exercise and some integrative therapeutics, such as vitamin D3, astragalus extract, and creatine may also ease symptoms of myasthenia gravis (Askmark 2012; Stout 2001; Tu 1994).

In this protocol you will learn about the basics of myasthenia gravis and how it is typically treated by conventional medicine. A number of novel and emerging therapies for myasthenia gravis that have shown promise in clinical trials will be reviewed. Several dietary and lifestyle considerations that may mitigate myasthenia gravis symptoms will be presented, and a number of integrative, natural interventions that target some of the underlying mechanisms that contribute to myasthenia gravis will be outlined as well.

Myasthenia gravis causes defects in cellular communication between nerve and muscle cells. Under normal circumstances, an impulse travels along a nerve to the nerve ending, and the nerve sends a messenger called acetylcholine to the muscle cell. Acetylcholine binds to the acetylcholine receptor on muscle cells, resulting in muscular contraction. In myasthenia gravis, the body produces antibodies against its own acetylcholine receptors and blocks them from binding acetylcholine. Individual receptors are also destroyed by antibodies, complement fixation, and by inducing the muscle cell to eliminate the receptors via endocytosis; this results in a decreased number of acetylcholine receptors. These phenomena lead to a reduced ability of the muscle cell to respond to nerve impulses (Jayam Trouth 2012; Howard 2006; NINDS 2012).

It is generally accepted that the thymus plays an important role in the development of myasthenia gravis, though the precise mechanism is still unclear. Over 50% of all people with myasthenia gravis have hyperplasia within the thymus and 10–15% of patients have a tumor of the thymus – called a thymoma (Meriggioli 2009; Meriggioli 2012a). The thymus produces different types of T cells that identify foreign invaders in the body and help eliminate them (Takahama 2006). Regulatory T cells (T_reg) monitor the activity of other T cells. T_reg maintain tolerance and prevent an autoimmune response as they have the ability to recognize proteins that are normally present in the cells of the body. T helper (T_H) cells, on the other hand, help combat the attack of foreign pathogens by different mechanisms. There are several types of T helper cells; some of them produce proteins called cytokines, which regulate inflammation, while others communicate with other immune cells, including B cells, to participate in immune responses against various types of pathogens. B cells produce specific ‘antibodies,’ specialized molecules that target the specific pathogen or ‘antigen’ (NIAID 2014).

In myasthenia gravis, certain T helper cells begin to react against self-proteins and cause B cells to produce antibodies against self-proteins (Jayam Trouth 2012). Defects in T regulatory cells’ ability to recognize normal proteins in the body also play a role in this process (Thiruppathi, Rowin, Ganesh 2012). These combined events result in the circulation of self-reacting antibodies and an inflammatory environment.

The majority of patients with myasthenia gravis (about 85%) have antibodies against the acetylcholine receptor on muscle cells. In approximately 7–8% of patients, antibodies against muscle-specific tyrosine kinase (MuSK) are detected (Meriggioli 2012a). The remaining patients may have antibodies against lipoprotein-related protein 4 (LRP4) or other muscle-associated proteins (Zhang 2012; Meriggioli 2012a). Some patients may be considered seronegative (no detectable antibodies against acetylcholine receptors). Patients with no detectable antibodies to MuSK or acetylcholine receptors are referred to as ‘double seronegative.’ However, patients may be ‘falsely seronegative’ due to immunosuppression or if the test is performed early in the disease course. Furthermore, the number of ‘true seronegative’ patients may be very low due to a simple inability of currently available screening tests to detect levels of some antibodies (Meriggioli 2012a).

A theory published in 2012 suggested that an impaired ability of the immune system to control the Epstein-Barr virus (EBV) could be involved in producing autoantibodies that could be responsible for a number of autoimmune diseases, including myasthenia gravis. Based on this theory, B cells infected with EBV are not eliminated by the immune system. Under normal circumstances, when B cells become infected with EBV, they are killed by a type of T cells known as CD8+. However, since patients with myasthenia gravis (and other immune diseases) have low numbers of these CD8+ T cells, the EBV-infected B cells, instead of being destroyed by the immune system, multiply and enter the thymus where they produce antibodies against self-proteins (Pender 2012). Interestingly, females generally have lower numbers of CD8+ cells than males (Cavalcante 2011; Amadori 1995). Scientists have shown that levels of CD4+ and CD8+ T cells may be regulated by hormone levels — higher levels of serum estrogen correlate with an increase in the ratio of CD4+/CD8+ T cells (Ho 1991). This discovery may indicate why myasthenia gravis tends to affect women at a younger age than men: higher levels of estrogen in females under the age of 40 coupled with a higher ratio of CD4+/CD8+ T cells may predispose this population of women to the disease.

It is known that exposure to sunlight can increase the number of CD8+ cells (Hersey, Bradley, 1983; Hersey, Haran, 1983). Scientists believe that this may be due to the production of vitamin D, as vitamin D can increase the number of CD8+ T cells (Zofkova 1997), and people who are deficient in vitamin D have lower levels of CD8+ T cells (Pender 2012). Scientists have hypothesized that the high prevalence of autoimmune diseases in populations living at high latitudes may in part be due to lack of sunlight and vitamin D (Pender 2012).

Myasthenia gravis, like other autoimmune diseases, is a complex disease and a combination of different factors appear to contribute to its development, including environmental factors, smoking history, sex hormones, and exposure to certain viruses. Studies of identical twins have shown that some people have genetic risk factors that predispose them to acquiring the disease. Individuals with certain versions (alleles) of HLA genes are more likely to develop the disease. HLA genes encode proteins that present ‘antigens’ or foreign objects on the surface of cells, which are recognized by cells of the immune system (T cells) (Beisswanger 2007). Scientists discovered associations between the presence of certain HLA alleles and early-onset myasthenia gravis, late-onset myasthenia gravis, and thymic abnormalities. Other gene alleles have also been shown to be associated with myasthenia gravis, including PTPN22, CHRNA1, and CTLA-4 (Zagoriti 2013). It is hoped that by identifying possible genetic risk factors for myasthenia gravis, more effective treatment options or preventive therapies can be discovered.

Symptoms of myasthenia gravis vary from person to person and differences in the age of onset, gender, presence of thymic abnormalities, and the type of self-antibodies present allow the characterization of myasthenia gravis into different subtypes (Meriggioli 2009). The predominant characteristic of myasthenia gravis is easy fatigability, muscular weakness that progressively gets worse with prolonged exercise and is often more pronounced in the evening compared to earlier in the day (Corse 2014; Albertini 2011). Commonly, the first symptom that patients notice is eye muscle weakness, which can affect up to 85% of affected individuals. In 15% of patients, the initial symptom is difficulty swallowing and slurred speech (Meriggioli 2009; NINDS 2012). Disease symptoms usually progress within the first two years, with patients reporting more generalized muscular weakness (Meriggioli 2009). Patients may also have blurred or double vision, drooping eyelids, changes in facial expression and control, difficulty swallowing, and impaired speech (NINDS 2012). As the disease progresses, patients’ arms and legs may also be affected, resulting in difficulty walking. A serious complication of myasthenia gravis called myasthenia crisis may occur in which patients are unable to breathe adequately and may develop respiratory failure requiring mechanical ventilation (Meriggioli 2009).

Patients with muscle-specific tyrosine kinase positive (MuSK+) myasthenia gravis have different symptoms than acetylcholine receptor positive patients. MuSK+ disease primarily affects middle-aged women and muscle weakness is rarely limited to the eye; rather, muscle weakness is also typically found in the face, neck, mouth, and pharynx. Additionally, the thymus is usually normal or very slightly affected in this patient subset. MuSK+ patients are at a higher risk of developing myasthenia crisis and have a lower chance of achieving stable remission (Sieb 2014).

There are several frequently overlooked non-motor symptoms of myasthenia gravis in patients who have thymoma. Pure red cell aplasia (a defect in red blood cell production), weakened immune system, and hair loss are due to CD8+ T cell-induced cell death of white and red blood cell precursors. Spontaneous muscular activity, brain inflammation, heart muscle inflammation, and taste disorders are caused by antibodies to self-proteins. Neurological and cardiac problems are reported in some myasthenia gravis patients with thymoma (Suzuki 2013). Myasthenia gravis can also negatively affect a patient’s quality of life, leading to symptoms of anxiety, depression, and sleeplessness (Basta 2012; Martinez De Lapiscina 2012).

Patients with myasthenia gravis are at an increased risk of developing other autoimmune diseases, including thyroiditis (thyroid inflammation), rheumatoid arthritis, and lupus erythematosus. More recently, clinicians have found a strong association between myasthenia gravis and neuromyelitis optica spectrum disorder (NMOSD) (Sieb 2014). NMOSD causes inflammation of the optic nerves and spinal cord, leading to pain and vision loss, muscle weakness, and occasionally varying degrees of paralysis in the arms and legs (NINDS 2014; Matsumoto 2014). Myasthenia gravis and NMOSD typically occur together in young women. Myasthenia gravis patients also have an increased risk of developing myocarditis (inflammation of the heart) with symptoms including heart failure and arrhythmias (Sieb 2014).

If an individual displays any of the symptoms described in the previous section, a physician will run an initial evaluation for possible signs of myasthenia gravis. If the physician suspects the patient has the disease, a number of different diagnostic tests may be performed. Some of the tests include the following.

Peek Sign

In this test the patient simply closes their eyes. A normal response entails the eyelids remaining closed. In myasthenia gravis patients, the fatigable weakness of the eye muscles causes the eyelid to begin to open revealing the whites of the eye (Tavee 2010).

Ice Pack Test

An ice pack test is another simple, non-intrusive test. It is recommended for patients who have drooping eyelids and is not effective in those patients who do not display this symptom. A physician places an ice pack over a patient’s eye for two to five minutes. If the patient has improvement in double vision or drooping eyelids after the ice pack is removed, the patient likely has myasthenia gravis (Jayam Trouth 2012; Kearsey 2010). It is thought that reducing the temperature of the tissue causes a decrease in acetylcholinesterase activity. The ice pack test is fairly sensitive considering its simplistic nature, and one study indicated it is able to correctly diagnose myasthenia gravis in approximately 77% of patients (Kearsey 2010).

Tensilon (Edrophonium Chloride) Test

Myasthenia gravis can be caused by antibodies that disrupt the interaction between acetylcholine and its receptor on muscle cells. Therefore, agents that promote communication through this receptor can be used to provide diagnostic insight. Edrophonium chloride is an inhibitor of acetylcholinesterase. It prevents the breakdown of acetylcholine and allows it to work for longer periods of time at nerve-muscle junctions, resulting in improvement of muscle strength (NINDS 2012). It is administered intravenously and the patient is monitored for improvement in drooping eyelids or eye muscle function. If the patient displays temporary improvement in any affected muscle group, the patient most likely has myasthenia gravis. The tensilon test typically works better in people presenting with eye muscle weakness (Howard 2006). It is important to note that the tensilon test is not effective in cases of MuSK+ myasthenia gravis (Sieb 2014).

The tensilon test can also be used to monitor myasthenia gravis patients’ medication and determine if they have overdosed on acetylcholinesterase inhibitor drugs. When there is an overdose of acetylcholine in the body, tensilon makes the person even weaker. This suggests that their acetylcholinesterase inhibitor dosage is too high and their treatment medication should be adjusted accordingly (Jasmin 2014).

Immunoanalysis of Blood

The majority of myasthenia gravis patients (about 85%) have antibodies against the acetylcholine receptor. Approximately 8% of patients have antibodies against MuSK (Meriggioli 2012a). Physicians can perform immunoanalyses of blood samples to detect these self-reacting antibodies (NINDS 2012). It is important to note that the presence and concentration of anti-acetylcholine receptor antibodies in the blood does not predict severity of disease (Jayam Trouth 2012; Evoli 2003). It is possible that a patient tests negative for both of these antibodies, yet may still have the disease. As mentioned previously, these patients are called double seronegative (NINDS 2012; Howard 2006). Several other muscle-specific self-antibodies may also be detected through blood analysis, including antibodies to titin, myosin, actin, and ryanodine receptors. The presence of these antibodies usually indicates that the individual has myasthenia gravis with involvement of the thymus, or a thymic tumor without myasthenia gravis (Jayam Trouth 2012).

Electrophysiological Tests

There are two electrostimulatory tests commonly performed to diagnose myasthenia gravis: repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG). In RNS, a physician stimulates a patient’s nerve cells repeatedly with small pulses of electricity. If the patient has progressively weaker muscle responses during the test, myasthenia gravis is suspected (Jayam Trouth 2012; NINDS 2012). RNS is not a specific diagnostic test for myasthenia gravis and can only detect the disease in approximately 60% of patients (Howard 2006). In SFEMG, individual muscle fibers are stimulated with small electrical pulses. In the muscle fibers of patients with myasthenia gravis, there is more variability in the time that it takes the action potentials to be transmitted along a nerve and to reach the muscle fibers that it innervates, unlike muscle fibers of healthy individuals in which there is hardly any variability in the transmission time of action potentials along a nerve (Jayam Trouth 2012; NINDS 2012; Selvan 2011; Tanhehco 2003). SFEMG is more sensitive than RNS and almost all patients with myasthenia gravis can be diagnosed with this neuromuscular stimulation test (Howard 2006).

Diagnostic Imaging

Approximately 10–15% of patients with myasthenia gravis have a thymic tumor, which is generally benign, but may become malignant in some cases. Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest are performed to detect the presence of these abnormalities (Jayam Trouth 2012; NINDS 2012).

Thyroid Testing

People who have myasthenia gravis are often diagnosed with overactive or underactive thyroid disease (Mayo Clinic 2013). In overactive thyroid disease (hyperthyroidism), the thyroid produces excessive amounts of thyroid hormones leading to symptoms including weight loss, increased appetite, rapid and irregular heartbeat, anxiety, and sensitivity to heat. People with an underactive thyroid (hypothyroidism) have low amounts of hormones produced by the thyroid and experience symptoms including weight gain, fatigue, sensitivity to cold, constipation, and joint or muscle pain. Blood tests and radioactive iodine uptake tests are used to measure levels of thyroid hormone to diagnose hypothyroidism or hyperthyroidism. In the radioactive iodine uptake test, a patient swallows a liquid or capsule containing a small amount of radioactive iodine. The thyroid uses the iodine to make thyroid hormones that exhibit radioactivity and can be detected by a probe that is placed over the thyroid. Low levels of radioactivity suggest hypothyroidism, while high levels of radioactivity suggest hyperthyroidism (Jonklass 2012).

Fortunately, the majority of patients who have myasthenia gravis are able to be treated successfully and live normal lives. In some patients, temporary or permanent remission is possible and medications can be discontinued (MGFA 2010b). The choice of therapy depends on the type and severity of symptoms that the patient has and includes the following:

Acetylcholinesterase Inhibitors

Myasthenia gravis patients’ muscles are not able to respond properly to acetylcholine that is released from nerve cells. Therefore, treatments such as acetylcholinesterase inhibitors that increase levels of acetylcholine allow the muscle cells more time to respond to nerve impulses. Acetylcholinesterase inhibitors temporarily relieve symptoms, but will not block progression of the disease (Jayam Trouth 2012). They are usually used in patients with mild disease who present frequent symptoms and in patients with moderate disease in combination with immunosuppressant medication (Corse 2014). The most commonly prescribed acetylcholinesterase inhibitor is pyridostigmine bromide (Mestinon®, Regonol®); its side effects include diarrhea and stomach cramps. Drug overdose can lead to increased salivation, low heart rate, increased sweating, increased secretion of tears, and excessive pupil constriction (Meriggioli 2009). In patients who have antibodies to MuSK, acetylcholinesterase inhibitor treatment is typically less effective and may even result in worsening of symptoms (Corse 2014).

Plasma Exchange and Intravenous Immunoglobulin Therapy

Plasma is the liquid portion of the blood that transports blood cells and numerous other biomolecules. In plasma exchange, a patient’s plasma that contains self-antibodies is separated and removed from the remaining components of the blood. The removed plasma containing self-antibodies is usually replaced with plasma from donor individuals or a combination of albumin and saline (MGFA 2010a; Winters 2012). Plasma exchange can result in a rapid decrease in symptoms and is an important modality in the treatment of acute exacerbations; however, results are temporary. Side effects include decreased blood pressure, blood clots, infection, and an increased risk of bleeding (Jayam Trouth 2012).

In immunoglobulin therapy, a patient suffering from myasthenia gravis is infused intravenously with antibodies isolated from human donors. The mechanism by which immunoglobulin therapy works is unclear, but it is believed that the infused antibodies block the activity of a number of different types of immune cells, including B cells, T cells, and macrophages. This is also a short-lived therapy, but it is highly effective at reducing symptoms of myasthenia gravis during exacerbation. Side effects are rare, but include blood clots (Jayam Trouth 2012).

Plasma exchange and immunoglobulin therapy produce similar results and have similar side effects. However, the cost of immunoglobulin therapy is significantly greater than the cost of plasma exchange (Jayam Trouth 2012).

Immunosuppressants

The primary long-term treatment strategy for myasthenia gravis is suppression of the immune system, also known as immunosuppression (Sanders 2010). There are two classes of immunosuppressive agents commonly used: corticosteroids and non-steroidal drugs. Many myasthenia gravis patients must take immunosuppressive drugs indefinitely (Sieb 2014).

Corticosteroids. Corticosteroids are the most common immunosuppressive agents used to treat myasthenia gravis. They work extremely well to decrease symptoms; however, they only work for short periods of time and are associated with significant side effects (Sathasivam 2011). Prednisone is a steroidal drug typically used in patients with symptoms that cannot be controlled by acetylcholinesterase inhibitors (Meriggioli 2009). Approximately one-third of patients who take high doses of prednisone develop worsening of symptoms 7–10 days after the first administration. These symptoms can last for several days (Sathasivam 2011; UIC 2007; Meriggioli 2009). To prevent this complication, steroids should first be administered at low doses, on alternate days, and gradually increased over time.Alternatively, acetylcholinesterase inhibitors, plasma exchange, or immunoglobulin can also be used to treat these exacerbations (Meriggioli 2009). Side effects of corticosteroid use include high blood pressure, diabetes, osteoporosis, infection, psychiatric disorders, insomnia, and increased white blood cell count (Sathasivam 2011).

Non-steroidal agents. There are several different types of non-steroidal drugs used to treat myasthenia gravis.

• Azathioprine (Imuran®, Azasan®) is effective in 70–90% of patients; however, benefits are not immediate and reductions in symptoms are often delayed by as long as 12 months. Azathioprine works by blocking T cells and B cells from dividing. It is often combined with prednisone in treatment strategies. Azathioprine has several severe side effects, including liver toxicity and a decrease in white blood cells. Fortunately, these side effects are reversible if drug concentration is reduced or treatment suspended. Azathioprine treatment can also increase the risk of developing different types of cancer (Meriggioli 2009). Azathioprine is generally the first choice agent for long-term immunosuppression in myasthenia gravis patients (Sieb 2014).

• Cyclosporine (eg, Sandimmune®) works by blocking T cells from dividing. Cyclosporine side effects include tremors, anemia, hypertension, and kidney toxicity. It can also lead to an increased risk of developing cancer. A similar drug, Tacrolimus (Prograf®), also blocks T cells from increasing in number and has similar side effects as cyclosporine; however, it is associated with less kidney toxicity and the increase in blood pressure was less pronounced (Sakuma 2000; Mihatsch 1998; Meriggioli 2009; Thoms 2011).

• Mycophenolate mofetil (CellCept®) is used to treat myasthenia gravis in some patients; however, efficacy has not been conclusively determined in large-scale, randomized controlled studies (Tavee 2010). Similar to azathioprine, mycophenolate mofetil works by blocking T and B cell multiplication (Meriggioli 2009). Despite many studies reporting that mycophenolate mofetil is effective in the treatment of myasthenia gravis (Sathasivam 2011), several clinical trials show that it is not more effective than prednisone in decreasing symptoms (Meriggioli 2009). Furthermore, a large clinical trial reported that treatment with mycophenolate mofetil has similar efficacy to treatment with a placebo (Sanders 2008). Common side effects associated with its use include headache, nausea, and diarrhea. Serious side effects may also occur such as infection, decreased white blood cell development, and liver toxicity (Sathasivam 2011).

• Cyclophosphamide (eg, Cytoxan®) is a non-steroidal immunosuppressive agent that targets DNA and inhibits cell division (Johnson 2012). It is commonly used to treat different types of cancer including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), ovarian cancer, and breast cancer (MedlinePlus 2011). Clinical trials have found that cyclophosphamide is effective at improving symptoms of myasthenia gravis (Sanders 2010). A randomized, controlled trial in myasthenia gravis patients who failed other treatment options showed that prednisolone plus cyclophosphamide treatment resulted in significantly improved muscle strength at 12 months, but marginally at 6 months. The patients also were able to decrease their dosage of corticosteroid drugs at 6 and 12 months (De Feo 2002). Unfortunately, side effects of cyclophosphamide are severe because it is a non-specific agent and can damage normal dividing cells including those in the immune system, reproductive system, and gastrointestinal tract (Abarikwu 2012). Potential side effects include hair loss, nausea, vomiting, abdominal pain, and diarrhea (Jimenez 1992; RxList 2014). Cyclophosphamide treatment can also lead to severe side effects such as inhibition of immune function, bladder inflammation and bleeding, and an increased risk of infection and cancer (Sathasivam 2011; Sanders 2010). Due to these side effects, cyclophosphamide is only used in patients with severe myasthenia gravis who have shown no improvement with other treatment options (Sanders 2010).

Thymectomy

Thymectomy, the surgical removal of the thymus, is a common treatment procedure for myasthenia gravis patients who have moderate to severe disease (Corse 2014). It is often performed in patients who have thymic tumors or hyperplasia, but is also performed in those who do not. Patients who have their thymus removed are more likely to achieve remission and become symptom free without medication than those who don’t. However, there is considerable debate about whether thymectomy is an effective and necessary option for patients without a thymoma (non-thymomatous). The remission rate for patients with non-thymomatous myasthenia gravis who undergo a thymectomy ranges from 38–72% (Diaz 2013). The first phase III randomized trial to determine if thymectomy is an effective treatment option in non-thymomatous myasthenia gravis patients is ongoing as of the time of this writing and preliminary results are expected in late 2015 (Cutter 2013). Removing the thymus gland may significantly impair one’s long term immune function (Bains 2013; Gerli 1999; Sauce 2009). Life Extension® suggests thymectomy be considered as a last resort.

Rituximab

Rituximab (Rituxan®) is a drug that targets a protein expressed on the surface of B cells called CD20; it leads to destruction of B cells. Rituximab is approved by the Food and Drug Administration (FDA) for the treatment of certain variants of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis (Schuna 2007; Genentech 2013; Harrison 2014; Bryan 2010). Several small clinical trials have reported that rituximab may also be effective for the treatment of myasthenia gravis (Collongues 2012; Lebrun 2009; Sathasivam 2011). One study showed that rituximab worked better in patients who had MuSK antibodies than patients with acetylcholine receptor antibodies. All MuSK+ patients had improvements in symptoms and immunosuppressant drugs were reduced or withdrawn, whereas 6 of 11 patients with acetylcholine receptor antibodies needed further treatment (Diaz-Manera 2012). Side effects associated with rituximab include fever, chills, nausea, vomiting, flushing, and bronchospasms. Severe side effects include infection, low neutrophil count, and the risk of leukoencephalopathy, which affects the white matter of brain (Sathasivam 2011). Additional studies are needed to confirm the possible benefit of rituximab in myasthenia gravis, and results of clinical trials are pending as of the time of this writing (Olivier 2012; Rup 2013).

Eculizumab

The complement cascade is a network of approximately 25 proteins in the immune system that helps to amplify an immune response to destroy bacteria. Under normal circumstances, complement proteins circulate in the blood and search for activated antibodies attached to bacteria. The first protein in the complement system recognizes the activated antibody and binds to it causing the activation of the complement cascade. Binding of the remaining complement proteins results in the insertion of a cylindrical complex – the membrane attack complex (MAC) – into the cell wall of a bacterium, causing its eventual destruction (NIAID 2008). Scientists have shown that the complement cascade also plays an important role in the development of myasthenia gravis. Self-antibodies against the acetylcholine receptor cause complement proteins to bind to sites at the nerve-muscle junction (Jayam Trouth 2012). Complement activation might be an important pathogenic mechanism in myasthenia gravis, even in patients without acetylcholine receptor antibodies (Vincent 2008). This leads to the destruction of the cell membrane of muscle cells. Components of the complement system and the MAC are often observed in the serum and at the nerve-muscle junction in patients with myasthenia gravis. Many experimental studies have shown that inhibition of the complement cascade improves symptoms of myasthenia gravis (Kusner 2012), and researchers are examining the effect of targeting the complement system in clinical trials. A small phase II study showed that a drug called eculizumab (Soliris®), which inhibits the complement system, reduced symptoms of myasthenia gravis more than a placebo after 16 weeks of treatment, and it was well tolerated (Howard 2013). Additional results are expected from a larger phase III study involving myasthenia gravis patients (ALXN 2014).

Granulocyte Macrophage Colony-Stimulating Factor

Granulocyte macrophage colony-stimulating factor (GM-CSF) is a protein that helps stimulate the immune system to fight infection. It is primarily used in patients following chemotherapy to prevent the decrease of certain immune cells called neutrophils. GM-CSF also plays an important role in enhancing the suppressive activity of regulatory T cells (T_reg). Given that defects in regulatory T cells are known to mediate the development of myasthenia gravis (Thiruppathi, Rowin, Li Jiang 2012), agents that stimulate their activity may be effective treatment options. A case study reported on a 77 year old patient who had prolonged myasthenia crisis and was resistant to standard immunomodulating agents. The patient was treated with 750 mcg of GM-CSF daily for 2 days, followed by 250 mcg daily for an additional 3 days. GM-CSF treatment significantly improved the patient’s symptoms and the activity of regulatory T cells (Rowin 2012). A pilot study assessing the effect of GM-CSF in myasthenia gravis is pending enrollment as of the time of this writing (Meriggioli 2012b).

Belimumab

Many patients with myasthenia gravis have high serum levels of a protein called B cell activating factor (BAFF) (Thangarajh 2006). BAFF is a protein that helps B cells survive, and high levels of BAFF in patients with myasthenia gravis may allow B cells to produce self-antibodies. Belimumab (Benlysta®), a drug that inhibits BAFF, is FDA-approved for the treatment of systemic lupus erythematosus (Ragheb 2011). A phase II study is recruiting patients as of the time of this writing to determine if belimumab is effective in treating myasthenia gravis (GSK 2014).

Etanercept

Etanercept (Enbrel®) is a drug that inhibits a protein called tumor necrosis factor-alpha (TNF-α) (Shi 2013). TNF-α is involved in inflammation and contributes to the development of several autoimmune diseases, including rheumatoid arthritis (Kodama 2005; Feldmann 2001). Etanercept is FDA-approved for the treatment of rheumatoid arthritis and plaque psoriasis (Haraoui 2007; Nguyen 2009). TNF-α is believed to play a role in the development of myasthenia gravis through its pro-inflammatory effects. Furthermore, a certain variant of the TNF-α gene is associated with early onset myasthenia gravis in some women. This version also leads to increased production of TNF-α (Huang 1999). A small pilot trial of etanercept in myasthenia gravis patients found that six out of eight patients who completed the trial had significant improvements in symptoms, while two patients had worsening of symptoms (Rowin 2004). However, a recent case study reported that a patient developed myasthenia gravis while taking etanercept and the symptoms resolved after the patient stopped taking the drug (Fee 2009). Additional studies are needed to determine if etanercept is an effective treatment option for myasthenia gravis and which patients could benefit from it.

Diet

Patients with myasthenia gravis have a unique set of obstacles to overcome in regard to diet and nutrition. The muscle fatigue associated with myasthenia gravis can make eating a difficult task, and patients may not obtain adequate nutrition. It is important for myasthenia gravis patients to eat a balanced diet. Doctors recommend eating during periods when patients have more strength and eating 5–6 smaller meals throughout the day instead of 3 larger meals (MGFA 2009).

If chewing and swallowing become difficult and patients begin losing too much weight, doctors recommended that patients mash or puree their food to make it easier to swallow. It is particularly important to have family and friends become familiar with the Heimlich maneuver to deal with potential choking hazards (MGFA 2009).

Some medications prescribed to myasthenia gravis patients may have unwanted side effects that further complicate attaining proper nutrition. Acetylcholinesterase inhibitors can cause diarrhea. Patients in these circumstances should avoid spicy, greasy, and high fat foods; caffeine; tea; and chocolate. Steroid medications can cause bone thinning and fluid retention. Physicians may recommend supplements (eg, calcium and vitamin D) to support bone health, and a low-sodium, high-potassium diet to avoid fluid retention (MGFA 2009).

Exercise

Several studies suggest that exercise may improve muscle fatigue and weakness in patients with different types of neuromuscular diseases, including myasthenia gravis (Lucia 2007; Stout 2001; Wong 2014). However, it is critical that those with myasthenia gravis do not over exercise, as this could exacerbate symptoms (Berrih-Aknin 2013). There is some controversy within the medical and scientific communities as to whether myasthenia gravis patients should engage in structured exercise programs (Grohar-Murray 1998). Generally, it is suggested that myasthenia gravis patients should participate in mild to moderate exercise activities, but should not over-exert themselves and should stop exercising at the first signs of muscle weakness. It may also be advisable to avoid exercise on days when patients feel especially weak (MGFI 2014).

A case study of one subject with both myasthenia gravis and McArdle’s disease (a rare condition characterized by exercise intolerance, fatigue, and muscle pain) reported improvements in well-being and the ability to perform daily tasks following low- to moderate-intensity exercise 5 times a week. The subject improved her exercise time by 44% and her peak oxygen uptake increased by 50% over a 3-week period (Lucia 2007). A second study reported that balance strategy training (BST) exercise in 7 patients with myasthenia gravis over a 16-session period resulted in significant improvements in symptoms, balance, and mobility (Wong 2013). A phase I clinical trial assessing the impact of exercise in patients with stable myasthenia gravis is underway as of the time of this writing (Hafer-Macko 2013). It appears that breathing exercises, such as pursed-lip breathing and diaphragmatic breathing, may also benefit myasthenia gravis patients, especially with regard to respiratory endurance (Fregonezi 2005; Rassler 2007; Weiner 1998).

Hormone Fluctuations during Menstruation

It has been well documented that sex hormones affect both pro-inflammatory and anti-inflammatory immune responses. Experimental studies have shown that estrogens play an important role in antibody production and may allow the generation of self-reactive antibodies. Estrogens are important for the generation of T helper and regulatory T cells. The effects of estrogens on immune cells, in the context of timing and environmental conditions, may influence inflammatory responses and shape the development of autoimmune diseases (Berrih-Aknin 2014; Qi 2011).

Symptoms of myasthenia gravis in some women may worsen 2–3 days before menstruation and may last up to 3 days into their cycle. Occasionally, it may be necessary to alter medication doses to deal with increased symptoms (Leker 1998). Pregnancy may also aggravate the symptoms of myasthenia gravis, more likely in the first trimester and postpartum. It is important to consider treatment effects on the fetus. Typically, pregnant women are mainly treated with acetylcholinesterase inhibitors or corticosteroids. Plasma exchange and immunoglobulin therapy have also been safely used (Ferrero 2005). There have been no clinical studies assessing the impact of hormone replacement therapy on the presence of myasthenia gravis symptoms as of the time of this writing. However, one case study reported that a 20-year old woman with myasthenia gravis and premature ovarian failure developed worsening symptoms one week following estrogen therapy. She immediately stopped taking the estrogen supplements and her symptoms improved after acetylcholinesterase inhibitor and steroid treatment and plasma exchange (Li 2010).

Vitamin D

Vitamin D plays an important regulatory role in the immune system. Our bodies produce vitamin D in the skin through exposure to sunlight, and some foods are fortified with vitamin D (MedlinePlus 2014; Hewison 2012; O'Donnell 2008). However, it is difficult to obtain optimal blood vitamin D levels through these sources alone because people tend to spend less time outdoors than in the past (MedlinePlus 2014). A pilot study in 2012 showed that supplementation with vitamin D has beneficial effects on autoimmune response and may alleviate fatigue associated with myasthenia gravis. The researchers demonstrated that 16 patients with myasthenia gravis had 26% lower baseline serum levels of vitamin D than 50 healthy patients (20 ng/mL vs. 27 ng/mL). Thirteen myasthenia gravis patients treated with vitamin D (800 IU/day) had 22% higher serum vitamin D levels and a 38% improvement in muscle fatigue. Researchers suggest that serum vitamin D levels should be monitored in patients with myasthenia gravis and supplementation should be considered if levels are found to be inadequate (Askmark 2012).

Astragalus

Extracts of astragalus have been used for centuries as an herbal remedy for cardiovascular disorders, hepatitis, kidney disease, and skin problems. Astragalus is composed of saponins, polysaccharides, and flavonoids. The most prevalent saponin with medicinal activity identified in astragalus is astragaloside IV. Numerous experimental studies have demonstrated that astragaloside IV improves cardiac function, promotes blood vessel growth, inhibits fibrosis in different organs, and regulates immune function (Ren 2013). In a 2009 study comparing the effects of astragalus and the steroid prednisone on immune response in 60 myasthenia gravis patients, astragalus was as effective as prednisone for reducing symptoms of myasthenia gravis. Also, astragalus was more effective than prednisone for reducing ratios of CD4+/CD8+ T cells (Niu 2009).

Creatine

Creatine is an organic acid produced by the body that is also present in food — primarily meat. Creatine supplementation helps increase lean body mass, muscle strength, and energy; it also improves active performance in healthy individuals and patients with neuromuscular diseases such as muscular dystrophy (Kley 2013; Stout 2001). An analysis of 6 randomized, controlled trials in muscle diseases reported that patients who supplemented with creatine had a significant improvement in muscle strength versus placebo-treated patients, with a mean difference of 8.5%. Patients from 4 trials receiving creatine also reported an overall improvement in well-being (Kley 2013). Creatine supplementation has also been reported to help patients with myasthenia gravis. A 26-year old man with myasthenia gravis who self-administered 5 g of creatine daily for 15 weeks combined with resistance exercise training, along with prednisone and azathioprine, had significant improvements in muscle strength, body weight, and fat free mass (Stout 2001).