Dr. Rania Habib (Host): Myasthenia gravis is a rare autoimmune disease that is estimated to affect fewer than 200,000 patients in the US each year. Even though myasthenia gravis is a chronic condition, advances in treatment have helped patients lead relatively normal lives with normal life expectancy.

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Host: This is Expert Insights with the Carle Foundation Hospital. I'm your host, Dr. Rania Habib. Today's guest is Dr. Nabih Ramadan, a clinical professor of Neurology with the Carle Illinois College of Medicine and a neurohospitalist at the Carle Neuroscience Institute. Welcome, Dr. Ramadan. We are so excited for your expertise on this very interesting topic.

Dr. Nabih Ramadan: Thank you.

Host: To begin, what is myasthenia gravis?

Dr. Nabih Ramadan: So, myasthenia gravis is a condition of what's called the neuromuscular junction, which is essentially the connection between the nerve and the muscle. And as you mentioned, it is an autoimmune disease, which means that the person's generation of antibodies or those proteins that are related to immunity are attacking its own cells. And that is a condition similar to things like systemic lupus, rheumatoid arthritis and the whole host of autoimmune disorders again, where your body is generating proteins that are attacking its own cells.

Host: Being an autoimmune disease, what are some of the main causes of myasthenia gravis?

Dr. Nabih Ramadan: Actually, the main cause is the autoimmunity is in essence, whether it is something that is a precedent viral illness or it is a genetic predisposition, for some reason, there is an antigen or a protein that is foreign to the body that comes into the system. And as that foreign body comes into the system, our immunity is trying to attack it. And it's generating antibodies to attack that protein or that antigen. Now, there are similarities between those antigens and other proteins within the system. And essentially, that's what's referred to as cross-reactivity or superantigen response, and you end up with the generation of these antibodies against our own cells.

Host: How is myasthenia gravis actually classified?

Dr. Nabih Ramadan: There are several classifications of it. The most accepted term that's probably has been heard more often recently because of the interest in these orphan diseases and orphan therapies, the generalized myasthenia gravis is essentially the everyday myasthenia condition that we see in a neurology practice. But often in other practices would be something like ocular myasthenia, which it affects the movements of the eye with no involvement in other muscles of the body, Generalized myasthenia is when there is involvement in other parts of the body,

Host: What are some of the key identifying signs and symptoms with generalized myasthenia gravis or the ocular version?

Dr. Nabih Ramadan: Right. So as far as clinical manifestation, the hallmark of the clinical manifestations of myasthenia gravis is muscle weakness. So with respect to the eye symptoms, it is double vision, difficulty focusing at far. The manifestations that are more in the face would be difficulty swallowing, hoarseness. The manifestations that are in the body parts and the limbs would be things like weakness towards the end of the day, increasing fatiguability as the person is exercising more. And then if it gets to involvement of the respiratory tracts, then difficulty with breathing.

Host: Okay. Now, a lot of those signs and symptoms overlap with other neurological diseases or autoimmune diseases. So, how do you as the neurologist make the diagnosis of myasthenia gravis?

Dr. Nabih Ramadan: I mean, obviously, whether it is neurology or any other medical specialty, a clinical history becomes the most important component of arriving at a particular diagnosis. And so if the patient is presenting to us with eye symptoms such as double vision with face weakness, particularly on both sides of the face with complaints of fatigue that is increasing while the person is exercising or towards the end of the day, and if the weakness is involving more the proximal muscle like the shoulder girdle or the hip flexors, then we have this suspicion based on clinical history. And then on examination, we look for evidence of droopy eyelids or droopiness of the eyes when the person is looking upwards, double vision when looking to one side versus the other, the weakness of the face on both sides of the face, a change in the character of the voice. And then, we do a bedside examination where we test the muscles and a repeated muscle testing. So, we do it like four or five times. Grip, grip, grip, grip or keep your arms up in the air and then we push down a few times. If there is a progressive fatigue, along with the other symptoms that I mentioned, that would give us a suspicion that this is mythesthenia gravis and we go to the next steps of making the diagnosis.

Host: Okay. So, what tests or studies would you then order to confirm your working diagnosis of myasthenia gravis?

Dr. Nabih Ramadan: I mean, as long as we make sure that the patient does not have things like botulinum toxin, they've eaten raw meat or a canned meat and we are sure that it is more the symptoms are towards the end of the day as opposed to the beginning of the day, then we go about doing the basic screening tests, which are serum blood tests, for the various antibodies that are generated in patients with myasthenia gravis. And there is a whole host of them. And those are like the acetylcholine receptor binding antibodies, the modulating antibodies. And then, in terms of classification, there are patients who are acetylcholine receptor negative, and those are patients who have a different type of antibodies, and those are called the muscle-specific kinase enzymes. And there are other antibodies that we look for in general. So typically, what we do is we do a screening test with those serum in addition to our clinical examination and clinical history. And if the tests turn out to be negative and we have a strong suspicion, then we go to the next step of doing something called electromyography or EMG, which is looking at how the muscle activity performs at rest and with repeated stimulation.

Host: Okay. So once the patient is diagnosed formally with myasthenia gravis, what are some of the complications that they need to be aware of?

Dr. Nabih Ramadan: The most feared complication of myasthenia gravis is the respiratory. And because the muscles of respiration are not acting properly, the patient will have decreased airflow into the lungs and that can lead to all sorts of complications, whether it is heart failure, whether it is lack of oxygen to parts of the brain or to other parts of tissues. And then also, because the respiratory function or the swallowing and the ability to swallow properly is impaired in some of these patients, they can aspirate and these can lead to pneumonia. And also other complications, if the patient is not functioning properly or walking properly, they become more sedentary, then you can have blood clots in the legs, which can go all the way up to the brain as well or to the lungs.

Host: What percentage of patients would you estimate actually have more of the life-threatening complications?

Dr. Nabih Ramadan: The complications rate, as far as myasthenia crisis, is it's actually less than 10% of the patients. And most patients actually go through their conditions with very little, if any, having a myasthenia crisis. And the reason for this is because unless the patient has an intercurrent severe infection or severe condition, comorbidity illness, they are unlikely to go through a myasthenia gravis crisis, particularly if they are well medicated and well managed.

Host: That is great news for those patients. Could you actually describe the difference between crisis and impending crisis?

Dr. Nabih Ramadan: Sure. So when we think about an impending crisis, it's the patient, let's say, who's been stable with muscle weakness that is present, but it is not significant, they don't have respiratory issues, they have some swallowing difficulty, but it's not significant. And over the course of several days, they notice that they are getting significantly weaker, their voice is getting significantly weaker, they're getting more and more double vision, particularly earlier during the day. And so, those are suggestions that the patient is going to go into an impending crisis as opposed to the actual crisis, which is by definition a life-threatening condition with rapid worsening of the patient's myasthenia, particularly with airway disease with the potential for airway compromise, and those patients are going to need to be intubated or quickly evaluated in an intensive care unit or in an advanced care facility to make sure that they don't go into the crisis itself.

Host: Okay. It's very refreshing to hear that, with the advancement in treatments, you're really limiting those number of patients that are either exhibiting impending crisis or going into full crisis. Could you actually now discuss some of those current treatment options and any new advances that are being made?

Dr. Nabih Ramadan: Yeah. So, the treatment of myasthenia gravis traditionally has been divided into various categories. So, there is the maintenance therapy and the maintenance therapy involves what's called the acetylcholinesterase inhibitor, which is essentially the enzyme that breaks down the acetylcholine or that particular protein or neurotransmitter between the nerve and the muscle. And when you prevent its breakdown, then you allow more of this connection to be established or to remain between the nerve and the muscle. It's almost like a key and a lock. So if you think about the receptor as the lock and the acetylcholine as the key, if that lock has grease on it or has some stuff on it that prevents the key from opening it, what you need to do is you need to maneuver that particular key. And one way of maneuvering that key is making availability of the better greasing of the key itself and better greasing of the key itself is more acetylcholine. And that's generally in our system the way we clear the acetylcholine as we either take it back up into the nerve or degrade it by the inhibitor. And if you prevent that enzyme from degrading the acetylcholine, then they become more available at the neuromuscular junction of the muscle endplate and activating. So, this is the maintenance therapy.

Now, there are immune modulation therapies and those are divided into either steroids or steroid-sparing. So, corticosteroids would be the classic one. And the steroid-sparing would be things like azathioprine, cyclophosphamide, methotrexate. And then, you have the more recent introduction of the monoclonal antibodies in essence. So, those are the newer therapies that are available that do not use steroids, and that they are modulating our immune system to allow those immunoglobulins that are bad or those proteins that are bad from really being bad or staying bad and clearing that neuromuscular junction from these immunoglobulins.

And then, the last form of therapy is the therapy for the crisis itself or the impending crisis. And that, in essence, it's immunomodulation. It is either clearing the bad immunoglobulin through something called plasmapheresis or flooding the system with immunoglobulins that are not antigenic, that are not bad to our own systems. So, it's either IVIg or plasmapheresis. Those will be the two for the crisis that we typically use.

Host: Now with the advancements in these different technologies and different types of medications, does a patient tolerate one better than the other, like one class of drugs better than the other?

Dr. Nabih Ramadan: Certainly. Patients are going to tolerate the monoclonal antibodies more than the steroids or the immunosuppressive therapies such as the methotrexate, azathioprine. I mean, these are more cytotoxic than the currently used monoclonal antibodies. With respect to the difference between plasmapheresis and IVIg, it's really not that much difference. Both of these are given in the hospital setting. The biggest difference between these two is plasmapheresis has a tendency to give you a more rapid response early.

That being said, the apheresis or the procedure itself is much more engaged, much more laborious. The patient is hooked up to a machine like a dialysis machine, and they're taking blood out of their system and then putting their blood back into their system, so essentially filtering their system from the bad antibodies and replacing them by their own blood. But now, it is filtered to a normal blood. And typically, the plasmapheresis to avoid complications and to avoid clotting issues, we typically do the plasmapharesis every other day. So it is a five-course, so it takes about 10 days, as opposed to the IVIg, which is anywhere between two and five days total.

Host: Well, this has been such an enlightening session, Dr. Ramadan. Are there any key take-home points that you would like to leave for our listeners?

Dr. Nabih Ramadan: First for the patients who have myasthenia gravis, it's not like it's used to be thought, "Oh, this is going to be a debilitating illness and most patients are going to have issues over time. Many patients go into a remission after a year or two years. So, this is not something that the patient goes into despair because of the condition. The other thing is for patients who have issues or for people who have issues with double vision or progressive weakness, seek medical advice as soon as possible. Because if this is the diagnosis, it's very treatable and you do not want to get into situations where you have an intercurrent illness, you have undiagnosed myasthenia gravis, and you go into a crisis or an impending crisis as the initial presentation.

Host: Well, we are so proud of all your work. For more information and to get connected with one of our providers, please visit carle.org. Or for a listing of Carle providers and to view Carle-sponsored educational activities, head on over to our website at carleconnect.com. And that wraps up this episode of Expert Insights with Dr. Ramadan, with the Carle Foundation Hospital. I am Dr. Rania Habib, wishing you well.