Overview of MG

1. What is myasthenia gravis?
2. Who does myasthenia gravis affect?
3. What are the symptoms of myasthenia gravis?
4. What is the cause of myasthenia gravis?
5. What is the role of the thymus in myasthenia gravis?
6. How is myasthenia gravis diagnosed?
7. Blood tests (serologic tests)
8. Nerve tests
9. Other tests
10. Arriving at a diagnosis of myasthenia gravis
11. How is myasthenia gravis treated?
12. Thymectomy
13. Acetylcholinesterase inhibitors
14. Corticosteroids and other immunosuppressants
15. Targeted treatments
16. Intravenous immunoglobulin
17. Therapeutic plasma exchange
18. What does the future look like for myasthenia gravis?
19. References

 

 

What is myasthenia gravis?

Myasthenia gravis (pronounced `my˖ĕs˖`thēēn˖ē˖ă `grăv˖ĭs), is a rare, chronic, autoimmune disorder affecting the signals between the nerves and the muscles which causes the muscles to feel weak and easily tired. It is the most common condition that affects these signals at the neuromuscular junction. People with the condition may experience flare-ups (exacerbations) followed by periods of remission, during which their symptoms improve.^1,2 There is no known cure for myasthenia gravis, but treatment options are improving^1-3 and there are several treatments that can help to keep the symptoms of the condition under control.^1,2,4 While symptom improvement and even remission can occur without treatment, most people with myasthenia gravis do require treatment. Every case of myasthenia gravis and therefore treatment strategy is unique.¹

 

Who does myasthenia gravis affect?

Globally, approximately 150 to 200 out of every million people have myasthenia gravis.¹ In the US, it is estimated that 37 out of every 100,000 people have myasthenia gravis. This estimation from 2021 shows that a growing number of people are affected by the condition, which could be due to people living for longer or because we now have better tools for diagnosis.⁵ While myasthenia gravis can affect people of any age, more women under 50 years old are likely to have MG compared to men. Conversely, men aged 65 and older tend to have more cases of MG than women in the same age group. In general, it is most common in people over the age of 50.⁵

 

Myasthenia gravis can affect people of all races and ethnic backgrounds; however, it is slightly more common in people of African descent.¹ Certain characteristics of myasthenia gravis can also vary depending on ethnic background. For example, research has shown that if you are of African American descent, you may be more likely to develop myasthenia gravis at a younger age and may be more likely to have a specific type of antibody called muscle-specific tyrosine kinase (MuSK) antibodies than people who are Caucasian.¹

 

What are the symptoms of myasthenia gravis?

When people develop myasthenia gravis, one of the main symptoms is muscle weakness and tiredness that is worsened by activity and improved by rest. This weakness can affect many areas of the body.^1,6 Approximately half of those who develop myasthenia gravis experience weakness in the eye (ocular) muscles first, which can include double vision, blurred vision and drooping eyelids.^1,6 Some people with myasthenia gravis will only experience eye muscle weakness, and this is called ocular myasthenia gravis.^1,6

 

However, approximately 8 out of 10 people who develop ocular symptoms will go on to develop more widespread (generalized) weakness within 2 years.¹ This can include facial weakness and weakness of the neck, arms or legs. These people may report difficulty when talking, swallowing or chewing tough food, climbing the stairs, getting up from a chair or raising their arms above their head.^1,6 When people develop weakness in muscles other than the eye muscles, this is called generalized myasthenia gravis (gMG).⁶

 

Sometimes people with myasthenia gravis may develop severe weakness in their breathing muscles, which is called a myasthenic crisis. This is a medical emergency and requires urgent  evaluation in a hospital setting.^1,6 If you have worsening severe breathing or swallowing difficulties and are from the US, you must call 911 (for other countries please call the relevant emergency services number) for assistance immediately, as you may need emergency treatment in the hospital.

 

What is the cause of myasthenia gravis?

For a muscle to function normally, a neurotransmitter called acetylcholine attaches to acetylcholine receptors at the neuromuscular junction (where the nerve and muscle connect), producing a signal between the nerve and the muscle which causes the muscle to contract. In myasthenia gravis, abnormal autoantibodies are produced which block the attachment of acetylcholine to its receptors and the follow-on effects that affect the signals between the muscle and the nerve at the neuromuscular junction.^1,2

 

Autoantibodies are produced by the immune system to help fight infection and disease. While the immune system is usually helpful in this manner, for people with myasthenia gravis there is a disruption to the balance of how the immune system works.¹ This disruption causes the production of abnormal antibodies, for example, acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4) antibodies.^1,2 These abnormal antibodies then affect the signals between the muscle and the nerves at the neuromuscular junction, causing the symptoms of myasthenia gravis, including muscle weakness.^1,2

 

Another important part of our immune system is a pathway called the complement pathway.⁷ While the complement pathway is usually helpful, in people with myasthenia gravis this pathway can be overactive, causing changes to the neuromuscular junction.⁷ These changes reduce the number of acetylcholine receptors, meaning that there are fewer receptors for acetylcholine to bind which also affects the signals between the nerves and the muscles which results in muscle weakness.¹

 

What is the role of the thymus in myasthenia gravis?

The thymus gland is in the middle of your upper chest, behind your breastbone.⁸ This gland is associated with our immune system and the production of antibodies. The thymus helps with the development of T cells (a type of white blood cell that is associated with our immune response). T cells are involved in the production of antibodies and can produce abnormal antibodies that cause autoimmune conditions such as myasthenia gravis. The thymus is most active in early childhood up until puberty, after which it gradually shrinks and does not play an important role.^1,8

 

The thymus gland is known to play a role in myasthenia gravis. Many people with the condition may experience:¹

• Enlarged size of the thymus gland (hyperplasia)
• A tumor of the thymus gland (thymoma)

 

Around 1–2 out of every 10 people with myasthenia gravis have a thymoma and roughly 7 in 10 people with myasthenia gravis have hyperplasia of the thymus.^6,9 If there is a dysfunction in the thymus, it could lead to a change in T-cell development and therefore the production of antibodies including abnormal antibodies that are responsible for the symptoms of myasthenia gravis.¹

 

It is not fully understood how changes to the thymus gland are associated with myasthenia gravis; however, for someone with thymoma-associated myasthenia gravis, it is likely that their symptoms are moderate-to-severe and generalized, and that they may have AChR antibodies.⁶

 

How is myasthenia gravis diagnosed?

The symptoms of myasthenia gravis can often be very similar to the symptoms of other conditions, particularly other neurological conditions. This means that myasthenia gravis can be difficult to diagnose, and your doctor needs to rule out other conditions that may be causing your symptoms.^6,10

 

Initially, your doctor will ask questions to fully understand your symptoms, which may include double vision, eye drooping and muscle weakness. This may be accompanied by a physical examination.³ There are a range of tests that your doctor may suggest to confirm whether you have myasthenia gravis. As myasthenia gravis is different for each person, this may include a variety of tests to help diagnose your symptoms.³

 

Blood tests (serologic tests)

Most people with myasthenia gravis have a type of abnormal antibody that is responsible for the symptoms of the condition, for example, AChR, MuSK or LRP4 antibodies. These abnormal antibodies attach to or block the acetylcholine receptors and cause changes to the neuromuscular junction. This leads to problems with the communication between the nerves and muscles and in turn, muscle weakness.^1,3

 

One of the most used tests is a blood test to look for abnormal antibodies. If your blood test shows that you have higher than normal levels of abnormal antibodies, it would indicate that you might have myasthenia gravis.^6,11 Abnormal antibodies can be detected in most but not all people with myasthenia gravis. If blood tests do not detect abnormal antibodies in your blood, you may have seronegative myasthenia gravis, and other tests may be required to confirm your diagnosis. Alternatively, a lack of abnormal antibodies in your blood may mean that you do not have myasthenia gravis.¹²

 

Nerve tests

When you have myasthenia gravis, the signals between your muscles and nerves are affected. To assess these signals, your doctor may suggest electrical tests called nerve conduction studies (NCS) or single fiber electromyography (EMG) tests.⁶

 

If you are being investigated for myasthenia gravis, your doctor will usually suggest a certain type of NCS called repeated nerve stimulation (RNS). During RNS small electrodes (metal disc plates or bars) will be placed over a nerve. Small, repeated electrical impulses will be passed through the nerve and the test will measure how much of the signal is passed to the muscle.13 This test helps to see whether the nerve signals are working normally, slowly, or not at all. If the nerve signals lessen during the test, it is a sign of myasthenia gravis.³

 

A specific type of EMG test called a single-fiber EMG test (SFEMG) may also be suggested to diagnose myasthenia gravis. During an SFEMG test one small needle will be inserted into the muscle to measure the electrical activity in the muscle and how the neuromuscular junction is functioning.¹³ This test can help to assess whether there is a disruption to the signals between the nerves and the muscles, which is the hallmark electrical sign of myasthenia gravis.^3,6

 

Other tests

Scans
As people with myasthenia gravis can have changes to their thymus gland, if you receive a diagnosis your doctor will suggest a CT or MRI scan of the chest to look for thymus abnormalities (thymoma or an enlarged thymus).^6,12

 

Acetylcholinesterase inhibitors
Myasthenia gravis affects the ability of acetylcholine to attach to acetylcholine receptors, which disrupts the signals between the nerve and the muscles.^1,2 Acetylcholinesterase is an enzyme that breaks down acetylcholine.¹

 

Acetylcholinesterase inhibitors are a group of medications that prevent this breakdown, meaning that there is more acetylcholine available to bind to the receptors. If there is more acetylcholine available to bind to receptors, the signals between the muscle and nerves will be improved, resulting in better muscle activation.^{14, 15}

 

This test is not frequently used; however, your doctor may suggest a trial of an acetylcholinesterase inhibitor medication to help diagnose myasthenia gravis. If this medication improves your symptoms, it suggests that you may have myasthenia gravis.⁶

 

Arriving at a diagnosis of myasthenia gravis

As myasthenia gravis is different for everyone, some or a combination of blood and nerve tests may be used to assess whether you have the condition. Generally, once the doctor has a full understanding of your symptoms and has completed a physical examination, blood tests for AChR and MuSK antibodies will be carried out. If they detect these abnormal antibodies, the doctor may be able to diagnose myasthenia gravis without further tests.³

 

If abnormal antibodies are not detected in your blood or further investigation is needed, your doctor may suggest a nerve conduction study or single-fiber EMG test to confirm your diagnosis of myasthenia gravis. Other tests such as the use of acetylcholinesterase inhibitors and/or scans may be suggested to aid in arriving at a diagnosis.³

 

How is myasthenia gravis treated?

As myasthenia gravis is individual for every person, you and your doctor will decide on a treatment plan for your specific needs. Your treatment and treatment goals may depend on your age and gender, how severe your myasthenia is and how much it affects your day-to-day life.¹⁵ There are several treatment options available that can improve your strength, help to keep the symptoms of myasthenia gravis under control and assist you to lead a full life. This may include a variety of treatments and sometimes emergency treatment if your symptoms get worse.^1,4,14

 

You may find it helpful to read the myasthenia gravis treatment guidelines, which are a set of recommendations about the various treatment options available for the condition and were developed by myasthenia gravis experts over several years. As new treatments are developed and as our knowledge of the condition improves, the guidelines are updated with leadership from the MGFA’s Medical Advisory Committee members and international disease experts. You can view the guidelines that were published in 2016, titled ‘International Consensus Guidance for Management of Myasthenia Gravis’ and the latest update of the guidelines that were re-published in 2020, titled ‘International Consensus Guidance for Management of Myasthenia Gravis Update 2020’ here:^16,17

 

• Guidelines (2016): https://www.neurology.org/ doi/10.1212/WNL.0000000000002790
• Update (2020): https://www.neurology.org/ doi/10.1212/WNL.0000000000011124? url_ver=Z39.88-2003& rfr_id=ori:rid:crossref.org& rfr_dat=cr_pub%20%200pubmed

 

An outline of the various treatments for myasthenia gravis is included below; however, for more detail on the specific treatments, please click here.

 

Thymectomy

Thymectomy is the surgical removal of the thymus gland.¹⁴ Thymectomy can be carried out if you have myasthenia gravis with or without thymus abnormalities. If you do not have a thymoma, the surgery may be recommended early on in your treatment pathway to improve your symptoms in the long term and is strongly recommended if you have a thymoma.^16,17 The surgery can help to improve your muscle weakness and reduce the number of medications needed or may even provide remission of your symptoms.¹⁵ Following thymectomy, you may not experience improvements immediately, and the amount of improvement that you experience may differ compared to other people treated with thymectomy.^14,16

 

Acetylcholinesterase inhibitors

For a muscle to function normally, acetylcholine attaches to acetylcholine receptors, producing a signal between the nerve and the muscle which causes the muscle to contract. In myasthenia gravis, abnormal autoantibodies block the attachment of acetylcholine to its receptors which affects the signals between the nerves and muscles, causing muscle weakness.^1,2

 

Acetylcholinesterase is an enzyme that is responsible for breaking down acetylcholine.¹ Acetylcholinesterase inhibitors prevent this breakdown, meaning that there is more acetylcholine available to bind to the receptors. This in turn increases the signals between the muscle and nerves and improves muscle activation.^14,15 Acetylcholinesterase inhibitors are often part of the initial treatment for myasthenia gravis, and one of the most used drugs is pyridostigmine bromide.¹⁶

 

Corticosteroids and other immunosuppressants

A corticosteroid is a medicine that acts as an immunosuppressant, which means that it reduces the action of our immune system.¹⁸ While the immune system is usually helpful in fighting infection and disease, in myasthenia gravis there is a disruption to the balance of how the immune system works.¹ This disruption causes the production of abnormal antibodies, for example, acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) antibodies.^1,2

 

Immunosuppressants reduce the action of the immune system by reducing the creation of certain white blood cells called T cells and B cells that are involved in your body’s immune response and produce antibodies.^17,18 By reducing the action of the immune system, these medicines reduce the number of abnormal antibodies that are produced. Therefore, there are fewer abnormal antibodies to attach to and block your body's acetylcholine receptors and less change to the neuromuscular junction. This helps the communication between the muscles and the nerves and increases muscle activation.¹⁸

 

Corticosteroids or other immunosuppressants are usually the next lines of treatment if acetylcholinesterase inhibitors are not effective.^15,16 Corticosteroids can be very effective for many people, with 7–8 out of every 10 people on steroids seeing marked improvement in their symptoms.¹⁵ However, some people may experience a temporary worsening of their symptoms when they start to take steroids and like all medicines, they have several side effects.¹⁵ Other types of immunosuppressants that are not classified as steroids are currently used in treating myasthenia gravis and can also produce marked improvements in symptoms.^15,18

 

Targeted treatments

Over recent years several new medications have been approved to treat myasthenia gravis that target specific antibodies and proteins in the body to improve the symptoms of the condition. Therefore, these treatments are only available for people with myasthenia gravis who have specific antibodies that can be targeted by the medication.2

 

B cell-directed treatments are one type of targeted treatment. B cells are a type of white blood cell that has an important role in making antibodies and the immune response thought to cause the symptoms of myasthenia gravis. Treatments that target B cells are thought to reduce this immune response and the levels of abnormal antibodies that can cause myasthenia gravis symptoms.^2,7,14

 

Neonatal Fc receptor blockers are also an example of a targeted treatment. They attach to and block the neonatal Fc receptor. This receptor helps to extend the life of immunoglobulin G antibodies. In myasthenia gravis, the abnormal antibodies are primarily immunoglobulin G antibodies. Therefore, by reducing the levels of these antibodies, including the abnormal ones, neonatal Fc receptor blockers can improve the symptoms of myasthenia gravis.²

 

Complement inhibitors are another type of targeted treatment. These medications reduce the activity of a part of our immune system called the complement pathway.⁷ The complement pathway is usually helpful but is thought to be overactive in people with myasthenia gravis who have abnormal AChR antibodies. This overactivity can cause changes to the neuromuscular junction and the acetylcholine receptors, which can affect the signals between the muscles and nerves.¹ Complement inhibitors are thought to help myasthenia gravis symptoms by reducing the activation of the complement pathway.⁷

 

Intravenous immunoglobulin

Your body's immune system naturally produces antibodies called immunoglobulins to help fight infection and disease. Intravenous immunoglobulin is a treatment that uses these antibodies from donations of plasma (a part of our blood). This treatment increases the levels of immunoglobulins in your blood and results in multiple effects on different aspects of the immune system, including reducing the levels of abnormal antibodies responsible for the symptoms of myasthenia gravis.¹⁹

 

Intravenous immunoglobulin is used as a short-term treatment in an emergency, if other treatments are not working or when a quick improvement in strength is needed, for example before surgery.¹⁶ If you need intravenous immunoglobulin, it will be given to you via an intravenous infusion (a drip containing the immunoglobulins). The intravenous infusion can be given over a period of 2–5 days for emergency treatment or every 3–6 weeks as a maintenance treatment and is typically given in a hospital setting. After treatment with intravenous immunoglobulins, improvement in your symptoms can be temporary and you may therefore need repeated treatments.^14-15

 

Therapeutic plasma exchange

Therapeutic plasma exchange, also known as plasmapheresis, is a treatment that takes your blood and separates the different components to remove the blood plasma that contains the abnormal antibodies responsible for myasthenia gravis symptoms. The blood is then returned with a replacement plasma that does not contain the abnormal antibodies. The procedure is carried out using needles that are inserted into your veins.^15,20,21 With fewer abnormal antibodies, the signals between the nerves and muscles are improved resulting in greater muscle activation.1
Plasma exchange is used as a short-term treatment in an emergency, if other treatments are not working or when a quick improvement in strength is needed, for example before surgery. As your body will continue to produce abnormal antibodies, repeated plasma exchange treatments may be needed.¹⁶

 

What does the future look like for myasthenia gravis?

In recent years there have been significant advances in what we understand about the immune system and its role in myasthenia gravis. This has helped to develop how we diagnose and treat myasthenia gravis to maximize quality of life for people with the condition.^2,7,22
Many people with myasthenia gravis still experience physical, mental and social difficulties even with the treatment options that are available. Myasthenia gravis experts are continuing to carry out research and clinical trials to help understand these difficulties more and to explore new treatment options.²² These significant and continued advancements represent a hopeful and exciting time for myasthenia gravis awareness and management.

 

 

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References

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17. Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 Update. Neurology 2021; 96: 114–122.
18. Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity 2010; 43: 428–435.
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20. Ipe TS, Davis AR, Raval JS. Therapeutic plasma exchange in myasthenia gravis: A systematic literature review and meta-analysis of comparative evidence. Front Neurol 2021; 12: 662856.
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