Myasthenia gravis translates, roughly, to “grave muscle weakness.” The name is no exaggeration, but the disease doesn’t always announce itself that way. It can start with signs that are easy to wave off: a drooping eyelid, double vision that blinking won’t clear, an arm that gives out halfway through holding your kid. Underneath them, the immune system has turned on the tiny junction where nerves tell muscles what to do, and that same process can build until it affects swallowing, speech, even breathing. For the next entry in our autoimmune series, our collaborator Nicole, an epidemiologist living with MG, starts us off in her own words.

Personal Experience with MG

I (Nicole) was going about my life in late 2021, with no indication that I was sick, when I woke up one morning with blurry vision. Blinking wouldn’t make it go away. By the next day, I was also seeing double. As an epidemiologist, I immediately went into research mode trying to figure out what was wrong while I waited for an appointment. I had heard of myasthenia gravis because I assist with investigations of botulism, which can present with similar symptoms. I shared my suspicions with my doctor (among a list of other differentials), and after a blood test, it was confirmed–I had ocular myasthenia gravis.

After several months of standard treatments and a thymectomy, we wanted to expand our family while I was stable. I was able to get pregnant quickly but unfortunately, while I was pregnant with my second child, my ocular MG progressed to generalized MG, causing a lot of very difficult symptoms. Ocular MG involves muscle weakness of the eyes. It can progress to generalized MG, with muscle weakness in the eyes, bulbar region, arms, hands, legs, and chest. You can struggle to breathe because your diaphragm muscle isn’t working. Overall, generalized MG is more serious and can be more dangerous. People can end up in crisis, in ICU, intubated. My neurologist took a conservative approach, and I couldn’t take any of the newer treatments because I was pregnant. The focus was to just make it through the pregnancy with a healthy baby.

Looking back, I wish I had put more of a plan in place for what happens after her arrival. After my daughter was born I really went downhill, both in terms of physical and mental health. I did not have the arm strength to hold my newborn and spiraled into post-partum depression. I wish I had changed neurologists sooner. Finding the right doctor, who really listens and supports your decisions as a patient, is a critical piece of treating any chronic disease. Figuring out when to push back and stand up for yourself is extremely important.

I started one of the new complement inhibitors about 18 months ago, and it has been a game-changer. Many new targeted therapies have come on the market in the last five years or so, and while they don’t work for everyone, I was able to find one that has brought me back to “normal.” I do daily injections and have to manage my energy levels, but it’s such a difference.

A few weeks ago, I was on a Disney cruise with my family. One day as we were coming back from an excursion, I realized it was exactly three years since my worst MG exacerbation. I had just been swimming in the ocean, fighting the waves, snorkeling, and carrying my children around. The fact that I could do those things…what a difference three years had made. I found myself feeling so emotional and grateful for my life.

One thing I have taken away from my experience has been to appreciate the little things I used to not be able to do or never thought I would do again. I don’t take that for granted. You have to look for those silver linings in life. I am using my voice now that I am in a better place to share my story and encourage others in a way I wish I had seen when I was first diagnosed.

What is Myasthenia Gravis (MG)?

Myasthenia gravis is a chronic neuromuscular disease that causes muscle weakness in specific muscle groups. It is caused by errors in how nerve signals are sent to muscles, specifically when communication between nerves and muscles is interrupted. The degree of muscle weakness can vary considerably between individuals. This condition can affect men and women across all racial and ethnic groups. It is most common in women under 40 and men over 60 but can occur at any age, including during childhood. The prevalence is estimated at 150-200 cases per million people.

When the immune system mistakenly targets the neuromuscular junction

Myasthenia gravis is an autoimmune disease in which the immune system mistakenly targets the communication point between nerves and muscles, called the neuromuscular junction. Normally, nerves release the chemical acetylcholine, which binds to receptors on muscle cells, to trigger contraction. In myasthenia gravis, B cells (guided by helper T cells) produce autoantibodies that bind to key proteins at this junction, most commonly the acetylcholine receptor (AChR), but also proteins such as MuSK (muscle-specific tyrosine kinase) or LRP4 (low-density lipoprotein receptor-related protein 4) that play an important role in nerve signals reaching the muscles.

These antibodies interfere with signaling in several ways: they can physically block acetylcholine from binding, trigger internalization and loss of receptors, and (especially in AChR-positive disease) activate the complement system, a cascade of immune proteins that damages the muscle-side membrane. The result is a reduced number and function of acetylcholine receptors, so the nerve’s signal becomes weaker with repeated use, producing the hallmark fluctuating muscle weakness and fatigue.

This immune misfiring is often linked to abnormalities of the thymus, an immune organ involved in T cell development, highlighting how breakdowns in immune tolerance can directly disrupt basic physiological processes like muscle contraction. The thymus normally grows with a person until puberty, begins to shrink from puberty onward and is eventually replaced by fat in adulthood. In individuals with myasthenia gravis,  the thymus often fails to shrink in size.

Clusters of immune cells may also be found in the thymus and in a small percentage of people, small tumors called thymomas (usually harmless but can become cancerous) may develop. About 5-10% of people with MG have another autoimmune disease including thyroid disease, rheumatoid arthritis, and systemic lupus erythematosus.

What causes Myasthenia Gravis?

The exact causes of MG are not well understood but there are several factors that have been shown to play a potential role in the development of disease. Disease most likely arises from a combination of genetic susceptibility and environmental triggers.

Genetics

MG is rarely an inherited condition with only 3.8-7.1% of patients reporting a family history of disease. While some autoimmune conditions have specific genes associated with diagnosis of that disease, MG does not seem to be highly inherited from what has been discovered in scientific and clinical studies thus far. In the context of all autoimmune diseases, there is a predisposition to autoimmunity itself and not necessarily a specific autoimmune disease that is commonly passed down from generation to generation. Those with the predisposition to autoimmunity ‘inherit’ immune systems that are prone to go rogue and attack the body. In some people, the target is the insulin-producing beta cells in the pancreas (i.e. T1D), in others it is the myelin surrounding the nerves in the brain (i.e. MS), while in others the target is the cells within the small intestines (i.e. Celiac). It’s the ability of the immune system, specifically T cells and B cells, to mistakenly attack self that is inherited itself and not the target.

In the context of MG, some specific genetic susceptibility markers have been identified. Examples include some forms of human leukocyte antigen (HLA) genes, the methylation status of cytotoxic T lymphocyte associated protein 4 (CTLA4) gene, tumor necrosis factor receptor 4 family member 11a (TNFRSF11A), and NFkB activator genes, that varied with early and/or late onset disease. All of the identified genes play a role in the immune response, including the display of antigen to T cells (HLA), cell-to-cell signaling (CTLA4, TNFR) or the activation of immune-specific genes (NFkB).

Environment

Several environmental factors have been associated with the development and flares of MG including:

• Relapse in disease has been shown to be associated with both stress and depression
• Viral infection, including hepatitis C, herpes simplex virus, Epstein-Barr virus, Cytomegalovirus, Human T-lymphotropic virus, West Nile Virus, and more recently SARS-CoV-2, have been associated with MG but results are mixed and no clear causal relationship has been established.
• Several studies have shown a potential association of pesticide exposure to MG but no causal relationship has been established

What Does Myasthenia Gravis look and feel like?

The most common presenting symptoms for MG are ocular (eyes) and muscle weakness, which improves with rest. The prevalence of disease differs across geographical areas and ethnicities.

Common symptoms of Myasthenia gravis:

• Weakness of the eye muscles, including drooping eyelids, blurred or double vision, facial expression changes
• Difficulty swallowing
• Shortness of breath
• Impaired speech
• Weakness in the arms, hands, fingers, legs and neck

Muscles required for breathing can weaken to the point that a ventilator is required. This is called a ‘myasthenic crisis’ and requires emergency medical attention. Around 15-20% of those with MG experience at least one myasthenic crisis in their lifetime after diagnosis.

Piecing together a diagnosis

Medical teams

• A diagnosis for MG is usually made by a neurologist upon referral by a general practitioner or an eye doctor.

Diagnostic tests

• Physical and neurological exam including muscles strength and tone, coordination, sense of touch and eye movements
• Electrodiagnostics including nerve stimulation tests, single fiber electromyography (EMG) is considered the most sensitive test for myasthenia gravis and can detect impaired nerve to muscle transmission.
• Blood tests for autoantibodies for patients suspected of MG that look for elevated antibodies directed against specific proteins, including acetylcholine receptors (AChR), muscle specific kinase (MuSK), or low density lipoprotein receptor related protein 4 (LRP4)- although seronegative subtypes of MG also exist.

There are several types and subtypes of MG characterized by different clusters of symptoms or different antibodies identified in blood tests. The subtype of disease may influence the kinds of symptoms experienced and also help tailor a treatment plan for effective support.

Disease subtypes:

• Generalized MG: can start with ocular symptoms but will progress to more systemic effects- tends to be more severe
• Ocular MG: generally confined to symptoms related to the eyes
• Pediatric MG
  • Transient neonatal MG: occurs in infants born to mothers with MG, tends to be transient as mother’s antibodies disappear from the infant’s bloodstream
  • Juvenile MG: rare form that develops before the age of 18, systemic effects that can affect everyday activities

Antibody-based subtypes:

• Acetylcholine receptor antibody-positive MG (AChR)- most common
• Muscle-specific kinase antibody positive MG (MuSK)- more common in women, generally impacts face and head more than body
• Low density lipoprotein receptor related protein 4 antibody positive MG (LRP4)- antibodies against a different receptor
• Triple seronegative MG- similar symptoms but no autoantibodies present.

How is Myasthenia Gravis treated?

Current treatments

Treatments for MG focus on blocking each step of the pathologic process that causes disease. There are treatments focused on promoting the activity of acetylcholine to enhance signaling and transmission at the neuromuscular junctions. Surgical approaches can “reset” the immune system. Other treatments focus on inhibition of pathways that contribute to pathology, block production of autoantibodies or directly degrade or remove autoantibodies from circulation.

• Anti-cholinesterase medications: pyridostigmine (brand name Mestinon) can slow the breakdown of acetylcholine at the neuromuscular junction improving transmission and increasing muscle strength
• Thymectomy: operation to remove the thymus- can rebalance the immune system and decrease symptoms. This approach can provide complete remission in about 50 percent of the individuals who undergo the treatment.
• Complement inhibition: complement is a collection of proteins that are part of the immune system and can contribute to the pathology of MG. There are FDA-approved medications like eculizumab which can inhibit key complement proteins known to contribute to neuromuscular junction damage in MG.
• Immunosuppressants: some immunosuppressants can also improve muscle strength by suppressing abnormal antibodies. These medications may include prednisone, azathioprine, mycophenolate mofetil and tacrolimus but these all come with side effects that require careful monitoring by a physician.
• Plasmapheresis and IVIG:  these therapies are used in severe cases to remove destructive antibodies that attack the neuromuscular junctions- they usually help for a few weeks to months.
• Neonatal Fc Receptor Blockers (FcRn): these medications are targeted biologic therapies given by injection that intercept and degrade the specific autoantibodies that destroy neuromuscular junctions- examples include Imaavy, Vyvgart and Rystiggo.

Innovative treatments

In recent years there has been an increase in approved targeted therapies for MG. In addition to the treatments above there are many areas where additional progress in diagnosis and treatment of MG are occurring.

• CAR T-cell therapy: several approaches using CAR T-cell therapy are in development to help reprogram the immune system to destroy the B cells that produce the damaging autoantibodies driving disease
• B-cell depleting antibodies: in phase III trials and focus on selectively eliminating B cells responsible for producing the MG autoantibodies
• Oral targeted therapies: oral inhibitors would allow patients to take a pill rather than needing IV infusions or injections. Currently the targets of oral therapies inhibit complement proteins (innate immune defense mechanism) and BTK (an intracellular signaling molecule within B cells, the cells of the immune system that produce antibody).

Final Thoughts

Three years before that Disney cruise, Nicole was at her lowest. Swimming in the ocean and carrying her kids around would have been unthinkable. That kind of turnaround is more possible with MG than it used to be. It’s one of the more treatable autoimmune diseases, and the last few years have brought a wave of targeted therapies that didn’t exist before. They don’t work for everyone, but for a lot of people they’ve been the difference between getting by and getting their life back.

If you’re at the start of this, the things that helped Nicole are worth stealing: push for answers when something feels off, find a doctor who treats you like a partner and not a chart, and hold onto the fact that you’re not doing this alone.

Where to Find Resources and Support

If you or someone you care about has been diagnosed with MG—or you suspect MG might be a concern—we’ve gathered a list of trusted resources to help you learn more and find support.

Support resources:

• https://www.mg-united.com/
• https://myasthenia.org/understanding-mg/overview-mg/
• https://www.mgteam.com/

General MG resources:

• https://www.hopkinsmedicine.org/health/conditions-and-diseases/myasthenia-gravis
• https://www.mda.org/disease/myasthenia-gravis#causes

This article is a collaboration with Unbiased Science, an organization of multidisciplinary scientists dedicated to making health and science information accessible to the public and meeting people where they are.