Seronegative Myasthenia Gravis

Reviewed by: HU Medical Review Board | Last reviewed: August 2022

Myasthenia gravis (MG) is an autoimmune disease that affects your muscles. Those living with MG have antibodies in their blood that attack the areas where nerves communicate with the muscles they control. This area where muscles and nerves communicate is called the neuromuscular junction. There are many receptors in this area for molecules that tell the muscle to move. These antibodies bind to different receptors and disrupt their signaling.1

Because the muscles do not receive signals correctly, those living with MG experience muscle weakness. This weakness often worsens throughout the day the more those muscles are used.1

MG comes in 2 main types, generalized and ocular. There are also subtypes of MG, including seronegative MG.1

What is seronegative MG?

In people with MG, the body creates proteins called antibodies. These antibodies bind to and attack healthy parts of the muscle that communicate with nerves. This keeps the muscles from working correctly and leads to weakness.2,3

The first antibodies identified in MG were to the acetylcholine receptor (AChR) on muscle cells. Historically, people with MG who did not have AChR antibodies detected were said to have seronegative MG. Over time, researchers identified new antibodies to other parts of the neuromuscular junction in this previously defined seronegative group.2,3

Currently, MG antibody targets that have been identified and well-defined include:2,3

  • Acetylcholine receptor (AChR)
  • Muscle-specific tyrosine kinase (MuSK)
  • Low-density lipoprotein receptor-related protein 4 (LRP4)

Blood tests can show whether the body is making these antibodies. About 80 percent of people with MG have antibodies to AChR in their blood. About 10 percent have MuSK antibodies, and ever fewer have LRP4 antibodies.4

However, between 6 and 12 percent of people with MG have none of these antibodies detected in their blood. This is the currently defined seronegative MG group, which includes people with:4,9

  • Antibody levels that are undetectable by standard tests
  • Other antibodies that have an unclear role in MG
  • Non-antibody mediated MG

Several studies suggest that other rarer antibodies to other parts of the neuromuscular junction or muscle may be present in some people with "seronegative" MG. Since seronegative MG does not represent a single entity, there are major differences in the underlying cause, symptoms, and response to treatment in people currently classified with seronegative MG.4,9

What are the symptoms?

The symptoms of seronegative MG are similar to seropositive forms of MG where known antibodies are present. The defining symptom is muscle weakness that worsens with activity and improves with rest. The weakness typically affects specific muscles or muscle groups including the eyes, throat, arms, and legs.5,6

The muscle weakness may:5,6

  • Make it hard to keep your eyes open
  • Cause double vision
  • Impact swallowing
  • Make it hard to perform continued activity

Similar to seropositive MG, the muscles affected and the severity of weakness can greatly differ from person to person.5,6

How is it diagnosed?

If your doctor thinks you have MG, they will use a combination of a health history, physical exam, and a variety of tests to make a diagnosis. Tests to check breathing and lung function, blood work, and muscle strength tests are commonly used.4

Blood work is often used to make a definitive diagnosis of MG. However, since people with seronegative MG do not have detectable antibodies in their blood, this makes their diagnosis more difficult. As a result, many people with seronegative MG are initially misdiagnosed or have a long delay to a correct diagnosis, which can be frustrating.7

Your doctor may also try the ice pack test. With this test, your eye will be covered with an ice pack for 2 minutes to see if your eyelid strength improves. Improvement means your symptoms may be related to MG.4

Nerve conduction studies and electromyography (EMG) are useful tests to help diagnose seronegative MG. These tests measure the speed and strength of the electrical activity in the nerves, neuromuscular junction, and muscles. A specific technique called repetitive nerve stimulation (RNS) is a common test used to help diagnose MG.4

Another test called single-fiber electromyography (SFEMG) is the most sensitive test for detecting neuromuscular transmission impairment, such as in MG. SFEMG may be needed in some cases, especially in cases of seronegative MG. SFEMG is more technically demanding than RNS and is not available at all centers.4

How is it treated?

Those living with seronegative MG have similar symptoms to those living with seropositive MG. Also similar to seropositive MG, the distribution and severity of symptoms and response to treatments can greatly vary from person to person.4

Some treatments focus on the symptoms of MG by improving nerve signals to the muscles. These drugs are known as acetylcholinesterase inhibitors. They are effective for some people but may not help everyone with MG. These drugs are effective for some people with seronegative MG.8

Another type of treatment is to suppress the immune system. If the immune system is less active, it will reduce the amount of damage to the neuromuscular junction where nerves communicate with certain muscles. These drugs include steroids and other immunosuppressants. Unlike seropositive MG, many of these immunosuppressive therapies have not been well studied in seronegative MG.5

About 80 percent of people with MG have antibodies to AChR in their blood. About 10 percent have MuSK antibodies, and ever fewer have LRP4 antibodies.4

Some people with MG, including more rarely seronegative MG, have a tumor on the thymus gland. The gland is located in the middle of the chest and is an important part of the body’s immune system. Surgery to remove the thymus gland (thymectomy) may improve symptoms in some people with MG.8

Both seronegative and seropositive MG are chronic disorders that can be difficult to diagnose and treat. However, they can be successfully treated in some people, and some people even go into remission. If you have questions about treatment options or believe you are experiencing symptoms, talk to your doctor.8

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