Myasthenia Gravis

Nicholas J. Silvestri, MD: Hi there. My name is Dr Nick Silvestri, and I'm at the University of Buffalo. Today, I'd like to answer a few questions that I commonly receive from colleagues about the treatment of myasthenia gravis. As you know, over the past several years, we've had many new treatments approved to treat myasthenia gravis. One of the common questions that I get is, how do these new treatments fit into my treatment paradigm? 

First and foremost, I'd like to say that we've been very successful at treating myasthenia gravis for many years. The mainstay of therapy has typically been acetylcholinesterase inhibitors, corticosteroids, and nonsteroidal immunosuppressants. These medicines by and large have helped control the disease in many, but maybe not all, patients. 

The good news about these treatments is they're very efficacious, and as I said, they are able to treat most patients with myasthenia gravis. But the bad news on these medications is that they can have some serious short- and long-term consequences. So as I think about the treatment paradigm right now in 2024 and treating patients with myasthenia gravis, I typically start with prednisone or corticosteroids and transition patients onto an oral immunosuppressant. 

But because it takes about a year for those oral immunosuppressants to become effective, I'm typically using steroids as a bridge. The goal, really, is to have patients on an oral immunosuppressant alone at the 1-year mark or thereabouts so that we don't have patients on steroids. 

When it comes to the new therapies, one of the things that I'm doing is I'm using them, if a patient does not respond to an oral immunosuppressant or in situations where patients have medical comorbidities that make me not want to use steroids or use steroids at high doses. 

Specifically, FcRn antagonists are often used as next-line therapy after an oral immunosuppressant fails or if I don't feel comfortable using prednisone at the outset and possibly bringing the patient to the oral immunosuppressant. The rationale behind this is that these medications are effective. They've been shown to be effective in clinical trials. They work fairly quickly, usually within 2-4 weeks. They're convenient for patients. And they have a pretty good safety profile. 

The major side effects with the FcRn antagonists tend to be an increased risk for infection, which is true for most medications used to treat myasthenia gravis. One is associated with headache. And they can be associated with joint pains and infusion issues as well. But by and large, they are well tolerated. So again, if a patient is not responding to an oral immunosuppressant or it has toxicity or side effects, or I'm leery of using prednisone, I'll typically use an FcRn antagonist. 

The other main class of medications is complement inhibitors. There are three complement inhibitors approved to use in the United States. Complement inhibitors are also very effective medications. I've used them with success in a number of patients, and I think that the paradigm is shifting. 

I've used complement inhibitors, as with the FcRn antagonists, in patients who aren't responding to the first line of therapy or if they have toxicity. I've also used complement inhibitors in instances where patients have not responded very robustly to FcRn antagonists, which thankfully is the minority of patients, but it's worth noting. 

I view the treatment paradigm for 2024 as oral immunosuppressant first, then FcRn antagonist next, and then complement inhibitor next. But to be truthful, we don't have head-to-head comparisons right now. What works for one patient may not work for another. In myasthenia gravis, it would be great to have biomarkers that allow us to predict who would respond to what form of therapy better. 

In other words, it would be great to be able to send off a test to know whether a patient would respond to an oral immunosuppressant better than perhaps to one of the newer therapies, or whether a patient would respond to an FcRn antagonist better than a complement inhibitor or vice versa. That's really one of the gold standards or holy grails in the treatment of myasthenia gravis. 

Another thing that comes up in relation to the first question has to do with, what patient characteristics do I keep in mind when selecting therapies? There's a couple of things. I think that first and foremost, many of our patients with myasthenia gravis are women of childbearing age. So we want to be mindful that many pregnancies are not planned, and be careful when we're choosing therapies that might have a role or might be deleterious to fetuses. 

This is particularly true with oral immunosuppressants, many of which are contraindicated in pregnancy. But medical comorbidities in general are helpful to understand. Again, using the corticosteroid example, in patients with high blood pressure, diabetes, or osteoporosis, I'm very leery about corticosteroids and may use one of the newer therapies earlier on. 

Another aspect is patient preference. We have oral therapies, we have intravenous therapies, we now have subcutaneous therapies. Route of administration is very important to consider as well, not only for patient comfort — some patients may prefer intravenous routes of administration vs subcutaneous — but also for patient convenience. 

Many of our patients with myasthenia gravis have very busy lives, with full-time jobs and other responsibilities, such as parenting or taking care of parents that are maybe older in age. So I think that tolerability and convenience are very important to getting patients the therapies they need and allowing patients the flexibility and convenience to be able to live their lives as well. 

I hope this was helpful to you. I look forward to speaking with you again at some point in the very near future. Stay well. 

Nicholas J. Silvestri, MD: Hi there. My name is Dr Nick Silvestri, and I'm at the University of Buffalo. Today, I'd like to answer a few questions that I commonly receive from colleagues about the treatment of myasthenia gravis. As you know, over the past several years, we've had many new treatments approved to treat myasthenia gravis. One of the common questions that I get is, how do these new treatments fit into my treatment paradigm? 

First and foremost, I'd like to say that we've been very successful at treating myasthenia gravis for many years. The mainstay of therapy has typically been acetylcholinesterase inhibitors, corticosteroids, and nonsteroidal immunosuppressants. These medicines by and large have helped control the disease in many, but maybe not all, patients. 

The good news about these treatments is they're very efficacious, and as I said, they are able to treat most patients with myasthenia gravis. But the bad news on these medications is that they can have some serious short- and long-term consequences. So as I think about the treatment paradigm right now in 2024 and treating patients with myasthenia gravis, I typically start with prednisone or corticosteroids and transition patients onto an oral immunosuppressant. 

But because it takes about a year for those oral immunosuppressants to become effective, I'm typically using steroids as a bridge. The goal, really, is to have patients on an oral immunosuppressant alone at the 1-year mark or thereabouts so that we don't have patients on steroids. 

When it comes to the new therapies, one of the things that I'm doing is I'm using them, if a patient does not respond to an oral immunosuppressant or in situations where patients have medical comorbidities that make me not want to use steroids or use steroids at high doses. 

Specifically, FcRn antagonists are often used as next-line therapy after an oral immunosuppressant fails or if I don't feel comfortable using prednisone at the outset and possibly bringing the patient to the oral immunosuppressant. The rationale behind this is that these medications are effective. They've been shown to be effective in clinical trials. They work fairly quickly, usually within 2-4 weeks. They're convenient for patients. And they have a pretty good safety profile. 

The major side effects with the FcRn antagonists tend to be an increased risk for infection, which is true for most medications used to treat myasthenia gravis. One is associated with headache. And they can be associated with joint pains and infusion issues as well. But by and large, they are well tolerated. So again, if a patient is not responding to an oral immunosuppressant or it has toxicity or side effects, or I'm leery of using prednisone, I'll typically use an FcRn antagonist. 

The other main class of medications is complement inhibitors. There are three complement inhibitors approved to use in the United States. Complement inhibitors are also very effective medications. I've used them with success in a number of patients, and I think that the paradigm is shifting. 

I've used complement inhibitors, as with the FcRn antagonists, in patients who aren't responding to the first line of therapy or if they have toxicity. I've also used complement inhibitors in instances where patients have not responded very robustly to FcRn antagonists, which thankfully is the minority of patients, but it's worth noting. 

I view the treatment paradigm for 2024 as oral immunosuppressant first, then FcRn antagonist next, and then complement inhibitor next. But to be truthful, we don't have head-to-head comparisons right now. What works for one patient may not work for another. In myasthenia gravis, it would be great to have biomarkers that allow us to predict who would respond to what form of therapy better. 

In other words, it would be great to be able to send off a test to know whether a patient would respond to an oral immunosuppressant better than perhaps to one of the newer therapies, or whether a patient would respond to an FcRn antagonist better than a complement inhibitor or vice versa. That's really one of the gold standards or holy grails in the treatment of myasthenia gravis. 

Another thing that comes up in relation to the first question has to do with, what patient characteristics do I keep in mind when selecting therapies? There's a couple of things. I think that first and foremost, many of our patients with myasthenia gravis are women of childbearing age. So we want to be mindful that many pregnancies are not planned, and be careful when we're choosing therapies that might have a role or might be deleterious to fetuses. 

This is particularly true with oral immunosuppressants, many of which are contraindicated in pregnancy. But medical comorbidities in general are helpful to understand. Again, using the corticosteroid example, in patients with high blood pressure, diabetes, or osteoporosis, I'm very leery about corticosteroids and may use one of the newer therapies earlier on. 

Another aspect is patient preference. We have oral therapies, we have intravenous therapies, we now have subcutaneous therapies. Route of administration is very important to consider as well, not only for patient comfort — some patients may prefer intravenous routes of administration vs subcutaneous — but also for patient convenience. 

Many of our patients with myasthenia gravis have very busy lives, with full-time jobs and other responsibilities, such as parenting or taking care of parents that are maybe older in age. So I think that tolerability and convenience are very important to getting patients the therapies they need and allowing patients the flexibility and convenience to be able to live their lives as well. 

I hope this was helpful to you. I look forward to speaking with you again at some point in the very near future. Stay well. 

Nicholas J. Silvestri, MD: Hi there. My name is Dr Nick Silvestri, and I'm at the University of Buffalo. Today, I'd like to answer a few questions that I commonly receive from colleagues about the treatment of myasthenia gravis. As you know, over the past several years, we've had many new treatments approved to treat myasthenia gravis. One of the common questions that I get is, how do these new treatments fit into my treatment paradigm? 

First and foremost, I'd like to say that we've been very successful at treating myasthenia gravis for many years. The mainstay of therapy has typically been acetylcholinesterase inhibitors, corticosteroids, and nonsteroidal immunosuppressants. These medicines by and large have helped control the disease in many, but maybe not all, patients. 

The good news about these treatments is they're very efficacious, and as I said, they are able to treat most patients with myasthenia gravis. But the bad news on these medications is that they can have some serious short- and long-term consequences. So as I think about the treatment paradigm right now in 2024 and treating patients with myasthenia gravis, I typically start with prednisone or corticosteroids and transition patients onto an oral immunosuppressant. 

But because it takes about a year for those oral immunosuppressants to become effective, I'm typically using steroids as a bridge. The goal, really, is to have patients on an oral immunosuppressant alone at the 1-year mark or thereabouts so that we don't have patients on steroids. 

When it comes to the new therapies, one of the things that I'm doing is I'm using them, if a patient does not respond to an oral immunosuppressant or in situations where patients have medical comorbidities that make me not want to use steroids or use steroids at high doses. 

Specifically, FcRn antagonists are often used as next-line therapy after an oral immunosuppressant fails or if I don't feel comfortable using prednisone at the outset and possibly bringing the patient to the oral immunosuppressant. The rationale behind this is that these medications are effective. They've been shown to be effective in clinical trials. They work fairly quickly, usually within 2-4 weeks. They're convenient for patients. And they have a pretty good safety profile. 

The major side effects with the FcRn antagonists tend to be an increased risk for infection, which is true for most medications used to treat myasthenia gravis. One is associated with headache. And they can be associated with joint pains and infusion issues as well. But by and large, they are well tolerated. So again, if a patient is not responding to an oral immunosuppressant or it has toxicity or side effects, or I'm leery of using prednisone, I'll typically use an FcRn antagonist. 

The other main class of medications is complement inhibitors. There are three complement inhibitors approved to use in the United States. Complement inhibitors are also very effective medications. I've used them with success in a number of patients, and I think that the paradigm is shifting. 

I've used complement inhibitors, as with the FcRn antagonists, in patients who aren't responding to the first line of therapy or if they have toxicity. I've also used complement inhibitors in instances where patients have not responded very robustly to FcRn antagonists, which thankfully is the minority of patients, but it's worth noting. 

I view the treatment paradigm for 2024 as oral immunosuppressant first, then FcRn antagonist next, and then complement inhibitor next. But to be truthful, we don't have head-to-head comparisons right now. What works for one patient may not work for another. In myasthenia gravis, it would be great to have biomarkers that allow us to predict who would respond to what form of therapy better. 

In other words, it would be great to be able to send off a test to know whether a patient would respond to an oral immunosuppressant better than perhaps to one of the newer therapies, or whether a patient would respond to an FcRn antagonist better than a complement inhibitor or vice versa. That's really one of the gold standards or holy grails in the treatment of myasthenia gravis. 

Another thing that comes up in relation to the first question has to do with, what patient characteristics do I keep in mind when selecting therapies? There's a couple of things. I think that first and foremost, many of our patients with myasthenia gravis are women of childbearing age. So we want to be mindful that many pregnancies are not planned, and be careful when we're choosing therapies that might have a role or might be deleterious to fetuses. 

This is particularly true with oral immunosuppressants, many of which are contraindicated in pregnancy. But medical comorbidities in general are helpful to understand. Again, using the corticosteroid example, in patients with high blood pressure, diabetes, or osteoporosis, I'm very leery about corticosteroids and may use one of the newer therapies earlier on. 

Another aspect is patient preference. We have oral therapies, we have intravenous therapies, we now have subcutaneous therapies. Route of administration is very important to consider as well, not only for patient comfort — some patients may prefer intravenous routes of administration vs subcutaneous — but also for patient convenience. 

Many of our patients with myasthenia gravis have very busy lives, with full-time jobs and other responsibilities, such as parenting or taking care of parents that are maybe older in age. So I think that tolerability and convenience are very important to getting patients the therapies they need and allowing patients the flexibility and convenience to be able to live their lives as well. 

I hope this was helpful to you. I look forward to speaking with you again at some point in the very near future. Stay well. 

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.

1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.

MG has an annual incidence of approximately  four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.

MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.

2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.

gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.

Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.

Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.

3. Emotional stress can trigger an MC.

MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.

MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.

MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.

4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.

All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).

The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.

For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.

5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.

More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.

Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.

Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.

1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.

MG has an annual incidence of approximately  four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.

MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.

2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.

gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.

Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.

Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.

3. Emotional stress can trigger an MC.

MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.

MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.

MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.

4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.

All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).

The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.

For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.

5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.

More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.

Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.

Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.

1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.

MG has an annual incidence of approximately  four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.

MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.

2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.

gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.

Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.

Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.

3. Emotional stress can trigger an MC.

MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.

MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.

MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.

4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.

All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).

The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.

For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.

5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.

More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.

Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.

In the dynamic field of myasthenia gravis (MG) treatment, characterized by recent therapeutic advancements and a promising pipeline, Nicholas J. Silvestri, MD, advises early-career professionals to approach the whole patient, considering not only the disease manifestations but also its broader impact on their lives, including work and family.

Emphasizing the importance of tailoring therapies based on individual needs, Dr Silvestri encourages early and aggressive intervention, citing evidence supporting better long-term outcomes, and underscores the significance of treating the whole patient rather than just the disease.

In the dynamic field of myasthenia gravis (MG) treatment, characterized by recent therapeutic advancements and a promising pipeline, Nicholas J. Silvestri, MD, advises early-career professionals to approach the whole patient, considering not only the disease manifestations but also its broader impact on their lives, including work and family.

Emphasizing the importance of tailoring therapies based on individual needs, Dr Silvestri encourages early and aggressive intervention, citing evidence supporting better long-term outcomes, and underscores the significance of treating the whole patient rather than just the disease.

In the dynamic field of myasthenia gravis (MG) treatment, characterized by recent therapeutic advancements and a promising pipeline, Nicholas J. Silvestri, MD, advises early-career professionals to approach the whole patient, considering not only the disease manifestations but also its broader impact on their lives, including work and family.

Emphasizing the importance of tailoring therapies based on individual needs, Dr Silvestri encourages early and aggressive intervention, citing evidence supporting better long-term outcomes, and underscores the significance of treating the whole patient rather than just the disease.

Kelly G. Gwathmey, MD, offers three key tips for clinicians early in their careers regarding myasthenia gravis (MG): First, prioritize listening to patients, as their experiences may not always align with clinical observations. Second, advocate for shared decision-making when starting or changing treatments, considering individual patient preferences and medical conditions. Third, understand the significance of ongoing monitoring using patient-reported outcome measures and MG scales to assess treatment response and optimize care for patients with MG.

Kelly G. Gwathmey, MD, offers three key tips for clinicians early in their careers regarding myasthenia gravis (MG): First, prioritize listening to patients, as their experiences may not always align with clinical observations. Second, advocate for shared decision-making when starting or changing treatments, considering individual patient preferences and medical conditions. Third, understand the significance of ongoing monitoring using patient-reported outcome measures and MG scales to assess treatment response and optimize care for patients with MG.

Kelly G. Gwathmey, MD, offers three key tips for clinicians early in their careers regarding myasthenia gravis (MG): First, prioritize listening to patients, as their experiences may not always align with clinical observations. Second, advocate for shared decision-making when starting or changing treatments, considering individual patient preferences and medical conditions. Third, understand the significance of ongoing monitoring using patient-reported outcome measures and MG scales to assess treatment response and optimize care for patients with MG.

Nicholas J. Silvestri, MD, recounts a memorable experience with a patient with myasthenia gravis (MG) during early neurology residency, detailing the diagnostic process and initial treatment with standard therapies. Despite the patient's positive response in terms of efficacy, tolerability issues and side effects posed challenges.

Dr Silvestri highlights the evolution in MG treatment, emphasizing the availability of newer, well-tolerated options with proven efficacy, suggesting a more balanced approach between effectiveness and patient safety in contemporary MG management.

Nicholas J. Silvestri, MD, recounts a memorable experience with a patient with myasthenia gravis (MG) during early neurology residency, detailing the diagnostic process and initial treatment with standard therapies. Despite the patient's positive response in terms of efficacy, tolerability issues and side effects posed challenges.

Dr Silvestri highlights the evolution in MG treatment, emphasizing the availability of newer, well-tolerated options with proven efficacy, suggesting a more balanced approach between effectiveness and patient safety in contemporary MG management.

Nicholas J. Silvestri, MD, recounts a memorable experience with a patient with myasthenia gravis (MG) during early neurology residency, detailing the diagnostic process and initial treatment with standard therapies. Despite the patient's positive response in terms of efficacy, tolerability issues and side effects posed challenges.

Dr Silvestri highlights the evolution in MG treatment, emphasizing the availability of newer, well-tolerated options with proven efficacy, suggesting a more balanced approach between effectiveness and patient safety in contemporary MG management.

Kelly G. Gwathmey, MD, recounts shadowing a neurologist during an early phase of academic training and how witnessing examinations of patients with conditions like myasthenia gravis and amyotrophic lateral sclerosis inspired a career path in neuromuscular medicine.

Dr Gwathmey also reflects on the evolution of myasthenia gravis treatment over the past two decades, noting the introduction of new medications like eculizumab, complement inhibitors, and FcRn inhibitors — offering more targeted options and hope for patients with fewer side effects — and anticipates further advancements in treatment leading to improved disease control.

Kelly G. Gwathmey, MD, recounts shadowing a neurologist during an early phase of academic training and how witnessing examinations of patients with conditions like myasthenia gravis and amyotrophic lateral sclerosis inspired a career path in neuromuscular medicine.

Dr Gwathmey also reflects on the evolution of myasthenia gravis treatment over the past two decades, noting the introduction of new medications like eculizumab, complement inhibitors, and FcRn inhibitors — offering more targeted options and hope for patients with fewer side effects — and anticipates further advancements in treatment leading to improved disease control.

Kelly G. Gwathmey, MD, recounts shadowing a neurologist during an early phase of academic training and how witnessing examinations of patients with conditions like myasthenia gravis and amyotrophic lateral sclerosis inspired a career path in neuromuscular medicine.

Dr Gwathmey also reflects on the evolution of myasthenia gravis treatment over the past two decades, noting the introduction of new medications like eculizumab, complement inhibitors, and FcRn inhibitors — offering more targeted options and hope for patients with fewer side effects — and anticipates further advancements in treatment leading to improved disease control.

Nicholas J. Silvestri, MD, expresses gratitude for the impactful relationships and mentorship in the field of myasthenia gravis. Dr Chip Howard at the University of North Carolina is distinguished as a humble and inclusive mentor, considered influential in the field.

Dr Howard's influence goes beyond the efficacy of medications, emphasizing the importance of considering patient care comprehensively, including side effects and overall safety. This perspective has significantly shaped Dr Silvestri’s treatment approach, leading to a more holistic and patient-centered care paradigm for individuals with myasthenia gravis.

Nicholas J. Silvestri, MD, expresses gratitude for the impactful relationships and mentorship in the field of myasthenia gravis. Dr Chip Howard at the University of North Carolina is distinguished as a humble and inclusive mentor, considered influential in the field.

Dr Howard's influence goes beyond the efficacy of medications, emphasizing the importance of considering patient care comprehensively, including side effects and overall safety. This perspective has significantly shaped Dr Silvestri’s treatment approach, leading to a more holistic and patient-centered care paradigm for individuals with myasthenia gravis.

Nicholas J. Silvestri, MD, expresses gratitude for the impactful relationships and mentorship in the field of myasthenia gravis. Dr Chip Howard at the University of North Carolina is distinguished as a humble and inclusive mentor, considered influential in the field.

Dr Howard's influence goes beyond the efficacy of medications, emphasizing the importance of considering patient care comprehensively, including side effects and overall safety. This perspective has significantly shaped Dr Silvestri’s treatment approach, leading to a more holistic and patient-centered care paradigm for individuals with myasthenia gravis.