Myasthenia Gravis: Practice & Research Updates

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast, exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab and psychiatry.

Glen Stevens, DO, PhD: The onset of myasthenia gravis can be sudden, with severe and generalized muscle weakness, but more commonly, symptoms in the early stage of disease are subtle and variable, making it difficult to achieve a diagnosis correctly and quickly.

In today's episode of Neuro Pathways, we're discussing the current diagnostic and therapeutic guidelines for managing myasthenia gravis.

I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Yuebing Li join me for today's conversation. Dr. Li is the Head of the Myasthenia Gravis Program in Cleveland Clinic's Neuromuscular Center and Neurological Institute.

Yuebing, welcome to Neuro Pathways.

Yuebing Li, MD, PhD: Glen, thank you very much.

Glen Stevens, DO, PhD: I've heard myasthenia gravis called the snowflake disease, as there can be variability in patients, in terms of course, muscles affected, the degree that they are affected.

Could you briefly tell us a little bit about myasthenia gravis, common symptoms, presentation, underlying mechanism of action.

Yuebing Li, MD, PhD: Myasthenia gravis. Myasthenia, the terminology means muscle weakness. Gravis means severe, so that's an old term. It has been recognized for about more than 200 years. In the beginning, we could only recognize those people who had severe symptoms.

Now, we can recognize people who have relatively mild symptoms, sometimes subclinical symptoms, so it's no longer a grave disease. Typically, this is recognized as an antibody-mediated disease. We are able to find antibody in about 90 to 95 percent of patients with myasthenia gravis.

The antibody typically affects a component at the junction between the nerve and the muscle, so this is a sort of autoimmune disease that can occur almost at any agehood, from neonates up to patients who are 95, 100 years old.

Glen Stevens, DO, PhD: Has the incidents changed over time, or just our ability to diagnose it changing?

Yuebing Li, MD, PhD: It's both, both are true. Our ability to diagnose this disease have improved dramatically. There are many more neurologists, available people, not only doctors, but also patients have much more information to look. You can go to Google, internet. Sometimes, you can self-diagnose yourself. There are improved tests, more antibody testing. The techniques for diagnosing this disease have improved. We have better ways, a better awareness of this disease.

On the other hand, there have been substantial evidence to suggest that the incidence of myasthenia gravis have been increasing over the last 30 years, at least. We used to think this is a disease of the young female and older females. It's no longer true. We still see patient, predominantly young females, but we see equally high incidence in older female and older males.

This is becoming a disease of elderly, and in the elderly group, I would see defined as more than 65 years of age. The incidence here probably has been increased by at least the threefold over the last 30 to 40 years.

Glen Stevens, DO, PhD: Patients that end up having myasthenia, what would be the common symptoms that you would see in those patients?

Yuebing Li, MD, PhD: The myasthenia gravis, most of the patients start with eye symptoms. Typically, it's a droopy eyelid or double vision. About 70 percent of patients of myasthenia gravis will present this way.

Then the remaining 20 percent will present with what we call the bulbar symptoms, and people have speech problem, people have swallowing difficulties, and then, there is about 10 percent of people will present with arm weakness, leg weakness, neck weakness. Very rarely we see people start with breathing difficulty, but most people have eye symptom to start with.

A key feature of myasthenia gravis is it's usually not painful, and it tends to fluctuate. What I mean by that, you are maybe good in the morning, and then you have more symptoms in the evening. Or, today and tomorrow, they might be different.

Glen Stevens, DO, PhD: Let's talk about the typical diagnostic workup. I come see you. I've had a little bit of droopy eyes, maybe a little double vision. What's the diagnostic workup?

Yuebing Li, MD, PhD: Typically, you will need a pretty good neurological examination, or examination by an eye doctor to make sure that, indeed, it is an eye muscle problem. There is also a need to figure out whether you have weakness in other body parts, shoulders, legs, hand, neck.

A neurologic examination is necessary, and if the doctor agrees that diagnosis of myasthenia gravis need to be ruled out, the doctor, nowadays, typically, starts with other blood test, basically looking for antibodies. That's usually a first step.

If the antibody coming back negative, and doctors may do a test called EMG as a workup, specifically for myasthenia gravis. If the diagnosis of myasthenia gravis is confirmed, everybody will need a chest CT at least one time. There is a less than 10% of people, means one in 10 people with myasthenia gravis, will have a tumor in the thymus gland called thymoma. Everybody with myasthenia gravis will need a chest CT scan.

Well, some people, like you said, Glen, some people present gradually. We do have time to take this test as a stepwise approach. Some people progress pretty fast. In those situations, you might want the EMG first, while you draw blood for the antibody, because antibody testing may take sometimes seven to 10 days. The EMG test can give you a diagnosis, sometimes right away, so you can start treatment as soon as possible.

Glen Stevens, DO, PhD: For the EMG test, can I get that around the corner? Or, does it need to be specialized? Do patients need a single fiber EMG, or can you do a routine EMG?

Yuebing Li, MD, PhD: You really cannot do a routine EMG. These are, generally, there are two kind of EMGs, specifically for myasthenia gravis.

One is called a repetitive nerve stimulation. Basically, the technician will give you a series of electric shocks to see how your muscle respond. Typically, people with myasthenia gravis, their muscle will fatigue quickly on the electro diagnostic testing, so that's basically the basis to make a diagnosis of myasthenia gravis.

The other special test is called a single-fiber EMG. It's a very specialized EMG technique. There are less than a handful of doctors doing this. In Cleveland Clinic, we only have three physicians doing this right

now. It require some skills, even the repetitive stimulation. I would say it require good technical skills. You want it to get done in a lab, who are familiar with this test. It's not a lab who just do routine EMG.

Glen Stevens, DO, PhD: Let's just go back for a second to the antibodies. As mentioned, you can check acetylcholine receptor antibodies. How helpful are the blood tests?

Yuebing Li, MD, PhD: The blood tests are very helpful. Basically, when we looking at a test to help diagnose a disease, we typically pay attention to two numbers, two terms. One is called sensitivity. The other is called specificity.

The antibody test both have fairly high sensitivity and specificity. It's not 100 percent, but, in general, 85 to 90 percent of the MG patient will have positive antibodies to acetylcholine receptor.

There is additional 5 percent will be positive to another antibody called musk, M-U-S-K. Sometimes, we see false positive. It means that you have the antibody, but you do not have myasthenia gravis, but these are relatively rare.

Glen Stevens, DO, PhD: I know when I'm on hospital service, the residents are always excited to give somebody an ice pack test on the eyes if they're a little bit droopy. Have you found that to be very helpful, or is that more just clinical interest?

Yuebing Li, MD, PhD: I would say it's clinical interest. Some other doctors might disagree with me. It sort of suggests myasthenia gravis, but its sensitivity and specificity are not as quite high as the other tests we have talked about. I tend now to do this with MG patient. I think it can be misleading at times.

Glen Stevens, DO, PhD: What about current guidelines for therapy? Now, we believe they've had the EMG, they've had the antibody test, you've done the good neurologic examination. You feel they have myasthenia gravis. What about treatment?

Yuebing Li, MD, PhD: The treatment, in my personal opinion, and it really depend on the severity of the disease. I mean, we help people who have myasthenia gravis, who are intubated because they cannot breathe. I mean, those becoming less and less, and right now, I would say less than about 20 percent of the patient with myasthenia gravis, or less than one in five.

Then, there are people who have very minor symptoms, and they get used to it. The treatment guideline for a patient with different degree of severity would vary. For a person with mild symptoms, and sometimes if they are not disabling, or not bothersome, you can just watch them without much treatment.

If they do bother them, you could consider starting with very benign medications, such as pyridostigmine or mestinon. If this does not help, you start with relatively low dose prednisone. For a patient with relatively severe or significant symptoms, even if the patient is not on the ventilator, you begin to consider very aggressive treatment, that typically include in a relatively high dose prednisone, and other treatment such as intravenous immunoglobulin, or IVIG, or sometime plasmapheresis.

For a patient who have intermediate symptoms, you probably can start with middle-dose prednisone and middle-dose arrange such as 30 or 40 milligram a day, and usually, such a treatment will lead to improvement in three, four, five weeks. Then, you can gradually taper and see whether the patient's symptom will come back or not.

Some people can be kept at a very low-dose prednisone without need for other treatment. Some people will need additional immunotherapy, because they cannot come off prednisone, or they cannot be started on prednisone, and those are what we call immunosuppressive treatment.

As you mentioned, the myasthenia gravis is a snowflake disease. This term is also reflected in treatment. The treatment can be very different. Different neurologists may prefer different treatment, and it's better to be given a treatment a neurologist is very familiar with.

Finally, people who have tumor in the thymus gland, you really need surgery as a treatment, which usually helps to control the disease, as well. Younger patient will typically be people who are 60 years old or younger, may benefit from removal of the thymus gland, as well.

Glen Stevens, DO, PhD: Any specific medications that patients should avoid?

Yuebing Li, MD, PhD: Yes, there is a very exaggerated list of medications. There are a few antibiotics that could really exacerbate myasthenia gravis, but those antibiotics are rarely used nowadays. There are black box warnings on antibiotics, such as Cipro or Levaquin. I'm not so sure how often they truly make myasthenia gravis worse.

Nowadays, we see a lot of newly developed immunotherapy that treat cancer could lead to myasthenia gravis or make myasthenia gravis worse, but those are usually very, very specialized situation. There is old medication called the penicillin. We typically recommend people with myasthenia gravis not to use that.

From my point of view, Glen, if a person has unstable myasthenia gravis, then the doctor need to be cautious about many medications. If the myasthenia gravis is fairly controlled, I'm not so sure there are absolute contraindications, especially the commonly used medications.

Glen Stevens, DO, PhD: You make me excited when you start talking about oncologic drugs, and of course, you're talking about the immune modulating checkpoint inhibitors that can cause a degree of neuromuscular junction instability. In those cases, we usually just stop the medications, but as you say, with some of your previous treatment therapies, they may be required depending on the degree of the patient. What about new therapies? Anything exciting on the horizon?

Yuebing Li, MD, PhD: Oh, yeah, I would call this the good age for clinical research on myasthenia gravis. We have never experienced such a surge of new potential drugs, potential therapies for myasthenia gravis.

There are many, at least probably between five to seven, being studied right now as a treatment, mostly for generalized myasthenia gravis. There are a few kinds. One is complement inhibitor therapy. It's basically the complement activation has been proven to be an integral part of the myasthenia gravis.

One of the FDA approved product, eculizumab, is a complement inhibitor, so that has been available since 2017 for the treatment of myasthenia gravis. Due the associated cost, and also, not everybody respond to that, so they have been pretty much reserved for patient who have significant or refractory myasthenia gravis.

Another class that is quite active is the neonatal Fc receptor therapy, and this pathway basically tries to block the recycling of the immunoglobulin, including the antibodies for myasthenia gravis.

Preliminary data suggest this class is also fairly effective, but these have not been approved by FDA yet. There are other classes of immunotherapy being studied, so it's quite an exciting area for the research on myasthenia gravis.

Glen Stevens, DO, PhD: Anything else that you'd like to share with the audience that I haven't asked you about treating myasthenia gravis, or have we covered it?

Yuebing Li, MD, PhD: Well, for patient-wise, I can tell you is if you have a disease, you probably need to find a doctor who are more or less familiar with this disease, and get your disease stabilized, and then you can follow up with your family doctor, or other healthcare workers.

The treatment, again, of myasthenia gravis is very individualized. What I mean by that, a doctor may see two similar patient and may apply different treatment, just based on how good or how well the person look, the comorbidities, whether the patient have other medication or not.

One person go to see two neuro specialists, the treatment plan may be different. This is not a surprise, and in most cases, the immunotherapy for myasthenia gravis are effective. This disease, we do not think it really shorten a person's life span that much anymore. The mortality reach to our estimation is probably 1 percent or less, and there is a risk of crisis, but myasthenic crisis does not occur overnight. I mean, you would not wake up at night, and develop short breath, and get into crisis. There are a lot of promising and strong treatment that's going to be available. For doctor-wise, this is a very gratifying disease to treat, because the patient will almost always get better.

Glen Stevens, DO, PhD: Well, I appreciate. I think the one thing I've learned is that if I was looking after myasthenic patients, it would be well worth having them see a specialist in the area so that they can get regular updates for the management of their care. Yuebing, as always, it's been a pleasure talking with you. Thank you for joining me today.

Yuebing Li, MD, PhD: Thank you very much, Glen.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.