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Nicholas J. Silvestri, MD: Welcome to Medscape InDiscussion: Myasthenia Gravis. I'm your host, Dr Nick Silvestri. This is our first episode of season 1. Throughout the season, I'll ask neurology colleagues how they think about and manage common situations when caring for individuals with myasthenia gravis (MG) — a relatively rare condition. Today, we'll start with circumstances typically encountered during diagnosis. What are the critical signs, symptoms, and diagnostic tests? What do we need to know about the immunopathogenesis of MG? How does our understanding of the immunopathogenesis inform how we treat patients with MG? For expert guidance, we've invited Dr Carolina Barnett-Tapia, staff neurologist and clinician scientist at the Prosserman Family Neuromuscular Clinic in Toronto, Ontario, Canada. Welcome, Carolina.
Carolina Barnett-Tapia, MD, PhD: Thanks for welcoming me today.
Silvestri: An absolute pleasure, as always. Carolina, you're known for your expertise in clinical epidemiology, health system research, and patient outcome-focused research. What led you to focus on this unique combination of clinical and epidemiologic expertise and skill in populations with MG — essentially prioritizing the patient perspective and their perceived symptom burden?
Barnett-Tapia: It's one of those situations in which I was in the right place at the right time. I had the unusual combination of doing my fellowship and my PhD training at the same time. As I was doing clinic with patients with MG, I noticed that when I examined certain patients, their clinical exam didn't always fit what the patients were telling me. Since I was doing the training for clinical epidemiology, I realized that it was a good opportunity to better understand how the disease was impacting patients, so we could have a better explanation on how to improve their care.
Silvestri: That's interesting and something that I see in clinic frequently, where we're taking a history and it doesn't always gel with what we're really seeing with patients either on exam or with some of the measures that we evaluate. So, it does sound like you were in the right place at the right time.
Let's start with some discussion points. How about the perspectives that may not exist in textbooks? Since MG is a relatively rare autoimmune condition, what does the diagnosis look like from your perspective? What should we know about the patient perspectives?
Barnett-Tapia: One of the things that comes to mind is how heterogeneous and variable MG can be between patients. Symptoms can change so much for patients, even within the same day. So, for instance, patients will tell you — and you've probably seen this in your practice — that they may start the day feeling well and having no symptoms. But perhaps by 5 PM, they're experiencing double vision and ptosis. It's important to understand how those fluctuations can make diagnosis harder, because sometimes it's easy when you see it, but when you don't see it, it becomes hard. So, remember to think about that and how these fluctuations really reflect the underlying disruption to the neuromuscular junction that these patients have.
Silvestri: Absolutely. To speak to your point, not only is what you say true, but it's also important to talk about all of their symptoms to make sure we're making the right diagnosis and to understand how those symptoms are impacting patients on a day-to-day basis.
Let's move on. Tell me a bit about what mechanisms underpin the development of MG in terms of the involvement of different components of the immune system and how they contribute to the immunopathogenesis, as well as any environmental factors you've noticed that may contribute to the disease.
Barnett-Tapia: The most common type of acquired autoimmune MG is seen in those patients with antibodies against the acetylcholine receptor. It's really 80%-90% of people with MG, and I feel like we've learned so much more about how these antibodies disrupt that neuromuscular junction, because they do block the receptor, which is the obvious mechanism. But we have learned that it's not just that, right? These antibodies induce the receptors to be degraded, so you end up with fewer receptors. And they use complement deposit and secondary damage to the muscle membrane. So, there are multiple mechanisms by which these antibodies are causing damage. What's interesting is that some of the new treatments are targeting some of these specific mechanisms, such as complement inhibitors.
Silvestri: Absolutely. It's important for our listeners to remember what we talk about today, because in a subsequent episode with another one of our colleagues, I'll talk about different therapies. In fact, I'll talk with Chip Howard about emerging therapies targeting some of these portions of the immune system.
Please talk to us a little more broadly. Tell us more about muscle-specific kinase (MuSK) MG, for example, and how the immunopathogenesis there might differ from acetylcholine receptor disease and how that might inform treatment a bit differently.
Barnett-Tapia: That's such a great question, because recently I heard someone giving a talk about how they're probably different diseases. They both are autoimmune diseases of the neuromuscular junction, but MuSK MG is seen in a smaller proportion of patients — perhaps no more than 10% of patients with MG were the target of the MuSK protein. Yes, it has to do with the clustering of antibodies, but the thymus is not involved, as opposed to MG. The antibodies in MuSK MG are IgG4, compared with acetylcholine receptor MG, in which the antibodies are IgG1 and IgG3. So, these antibodies do not trigger complements, for instance. Right away, you have some important therapeutic considerations. In general, IgG4 diseases respond very well to B-cell depletion therapy, such as rituximab, which is a good option for people with MuSK MG. So, it's interesting to see how learning about these two types of MG would pull them together, because although clinically they may present in similar ways, the underlying mechanisms are quite different.
Silvestri: So, let's take a step back. Let's say you have a patient in your clinic, and based on the history and the examination, you strongly suspect that the patient has MG. Would you mind taking us through your diagnostic paradigm?
Barnett-Tapia: Sure. Clinical history for me is one of the most important tools we can all do at the bedside, regardless of where you are. So, we want to look for those symptoms that are very typical in MG. Double vision, droopy eyelids, and ptosis are very common, but patients often have other symptoms. Sometimes patients have a hard time explaining that they can have slurred speech and can lose their voice. Patients don't always tell you. They just say that people do not understand them. I used to have a teacher whose voice became soft, and she used to have to wear a megaphone to her class so her students could hear her. A reduced voice can be a symptom. Young women are always very concerned about the loss of facial expression because of the bifacial weakness. Patients don't tell you their face is weak. They tell you they've lost facial expression; they always look angry. Or sometimes, there is slurring and a little bit of dribbling. Those are subtle cues, especially if their symptoms fluctuate. In terms of diagnosis, today with antibodies, we can diagnose a vast majority of people, because about 90% of the patients will have detectable antibodies. That's key for a diagnosis. We still do electrophysiology single-fiber electromyography (EMG) or repetitive nerve stimulation. We are a neuromuscular lab, so it's very easy for us to do it right away. I lecture my people that we live in North America, and we have lots of options for testing, but in some places in the world, antibody testing is a luxury. So, people must rely on older techniques, such as electrophysiology and clinical history.
Silvestri: That brings up a good question. In every single patient that you see in whom you suspect MG, even in the presence of positive antibodies, you'll still do electrophysiology. Is that right?
Barnett-Tapia: In my practice, if they're clearly diagnosed, have positive antibodies, and they're fit, we probably won't do it. If we don't have the antibody results yet, we will order them, but we will do the electrophysiology. We are biased because we're a training center. We have fellows who are learning how to do a single-fiber EMG, so we want them to be exposed and be proficient. We may do more than the other centers, but for sure, if you don't have antibodies available for any reason or if someone is seronegative, you need to confirm with electrophysiology that you see an underlying dysfunction of the neuromuscular junction.
Silvestri: I agree. My own practice is to request acetylcholine receptor antibodies. If those are negative, I'll move on to MuSK antibodies. And if those are negative, and I have a seronegative patient, then I will move on to electrophysiology. I've had a few situations, though, where I've had patients who were initially seronegative, and you test them again a couple of months later and they become positive. Have you had that situation as well?
Barnett-Tapia: Yes, we've had that. You mentioned Chip Howard and his experience. For most people, it's about 6 months; it's great to see that over 6 months. The other point is for people doing the acetylcholine receptor antibodies to know that the majority of the labs do the standard assay, which is the radioimmunoassay. Although this assay is very good, it will not detect the number of people who are truly acetylcholine receptor-seropositive and have antibodies that need to be tested differently, which is done using a cell-based assay. It is a very specific and time-consuming task, so it's not always available. So, some negatives are truly acetylcholine receptor-positive in disguise.
Silvestri: Right. I think in most cases, it's straightforward when you have traditional antibody testing that's positive — especially positive at a high-level titer in the context of that clinical history and examination. It's interesting that just this past week, I had a patient who was referred to me with a very low-level titer of acetylcholine receptor antibodies and a story that didn't quite make a lot of sense to begin with. So, I repeated the antibodies, and they were negative. I brought the patient back and did a single fiber, and the single fiber was floridly abnormal. I think that taught me a few things, but one of the important things was that I went back and really drilled down into the history about some of the more specifics on the symptoms. Obviously, the retrospective scope, as I call it, was always 20/20. But the history really did make the diagnosis — just in a bit of a reverse order.
Barnett-Tapia: Yes. And remember that just as you can have false negatives, you also can have false positives. We've had cases referred to us with a positive antibody, but it was a different case in which the story was not very convincing. After doing electrophysiology, the patients had an alternate diagnosis that said myopathy or something else. So, therefore, you must put everything together.
Silvestri: How often do you do the ice pack test in clinic with your fellows?
Barnett-Tapia: In clinic? Very rarely. We do it more on rounds when we're seeing the rare case in the ward that's a new diagnosis, because it's very easy but very good. So, for people who are listening, especially for ptosis, if you put an ice pack on for about a minute, the ptosis will resolve. It's almost magic. It's like doing an edrophonium test, which no one has available anymore. It's a high-sensitivity test for neuromuscular junction disorder.
Silvestri: I know it's fun and you're right, it's interesting on the wards. You have that patient, and the students and the trainees think it's great using such low-level technology to make a diagnosis. You mentioned the lack of availability of edrophonium, or Tensilon. Do you ever do what I would call a pyridostigmine test?
Barnett-Tapia: Yes, I do. It's hard to see because it takes a little bit longer. But sometimes, especially in people with pure ocular MG, those are tricky to diagnose because they have antibodies only half the time. They're also less likely to be abnormally repeated in their nerve simulation, which is the most widely available electrophysiology. So, if you do single-fiber testing, you're more likely to pick them up. But it's a very technically demanding test. Sometimes we give someone pyridostigmine, and they get better. That's very suggestive that they indeed have pure ocular MG.
Silvestri: Yes. Speaking of being on the wards, I was on service not that long ago. We had a patient with just dysarthria, and there wasn't really a clear history of fluctuation. It had been a couple of weeks of maybe a little fluctuation, but something just told me to try pyridostigmine. We gave the patient pyridostigmine and came back on rounds 60 minutes later, and the patient was speaking totally normally. Subsequently, she had positive acetylcholine receptor antibodies. But again, I thought that was a cool little trick we have in our bag.
Barnett-Tapia: That's a very good story, and it's not something you can just see. I remember once I used to work in a place where we had edrophonium testing, and we had a patient with pure respiratory failure with no cause. So, we did forced vital capacity (FVC) respiratory measures before infused edrophonium, and they dramatically improved. It's nice to see what you can apply for some symptoms that are hard to diagnose.
Silvestri: Yes, that's a great case. Let's say in the case of a patient who has the right clinical history — has acetylcholine receptor antibody positivity — I imagine you're then, as a part of your diagnostic pathway, doing imaging of the chest, correct?
Barnett-Tapia: Absolutely. Anyone with newly diagnosed myasthenia gravis — especially if they are acetylcholine receptor-positive — needs a CT scan of the chest, because about 15% to 20% of patients will have a thymoma, which really changes the course of management. They need surgery, and it must be open, extended. So, you need to diagnose a thymoma. Young people with acetylcholine receptor-positive MG will benefit from having a thymectomy, even in the absence of a thymoma. You still need that imaging to help in making those decisions.
Silvestri: Absolutely. And for our listeners, we'll discuss the thymus and thymectomy with my colleague Dr Gil Wolfe in a subsequent episode. Carolina, you touched on this a bit earlier, but looking forward, tell us about any insights you have into the future of diagnostic testing with MG.
Barnett-Tapia: I think one of our big gaps is people with pure ocular disease. Many patients start with only eye symptoms — double vision, droopy eyelids. Even if they're going to generalize later, it's a very common presentation of MG. But when patients have pure ocular disease and only half of their antibodies are positive, those patients are difficult to diagnose, because it's 50/50 doing the antibodies, and it's hard to get the electrophysiology.
I've seen lots of interesting research coming through about how to diagnose these patients. Some groups are doing vestibular evoked myogenic potentials, which is electrophysiology of the repetitive. They've shown that they can see this decrement in these potentials with repetitive stimulation. But it's a different technique, and it seems to be more sensitive. Some of our colleagues are doing work with oculography and capturing subtle movements and fatigability of the external eye movement. I think it would be very neat if we could diagnose those patients earlier and more accurately — to prevent misdiagnosis, to avoid immunosuppressing people who shouldn't be immunosuppressed because they have something else, or to treat someone earlier who needs it. For generalized MG, I think it's really the accessibility of good, reliable antibody testing. You're going to get most patients. Our number of seronegative patients is reducing based on the literature over the years. Now we're sitting at 5% if you do everything. And that's another thing that we will know. What are these patients? I suspect we will identify new antibodies in the future, and some of these patients may have something else, too, right? I suspect there's some congenital myasthenic syndrome patients mixed with the seronegative. We need to tease out this seronegative group a little bit better.
Silvestri: Yes, I agree. Absolutely. Carolina, what is the one thing you would want our listeners to do differently after hearing this podcast?
Barnett-Tapia: I would like to remind neurologists that MG is very heterogeneous, and symptoms fluctuate a lot. Sometimes, you'll see a patient with a normal neurologic exam, but they can still have MG. If the history is suggestive and they're having the symptoms that fluctuate or are worse with activity, it's worth ruling out MG. It might be something else, but if you don't think about it, you will not find it, and it will delay diagnosis.
Silvestri: I think that's a great take-home point. That nicely wraps up what we talked a lot about today, which is that history and physical examination are key, and the diagnostic tests are only as good as they are if we use them in the appropriate patients.
Thank you so much for taking us through the discussion of the immunopathogenesis of the disease and how that relates to the diagnostic odyssey. In subsequent episodes, we'll discuss treatment for our patients. Thank you again, Carolina, and thanks to all for joining our discussion with Dr Carolina Barnett-Tapia. There's much more ahead in the coming episodes, so be sure to check out the Medscape app, and share, save, and subscribe if you enjoyed this episode. I'm Dr Nick Silvestri for Medscape InDiscussion.
Resources
Pathogenesis of Myasthenia Gravis: Update on Disease Types, Models, and Mechanisms
Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations
Myasthenic Antibodies Cross-link Acetylcholine Receptors to Accelerate Degradation
Effect of Complement and Its Regulation on Myasthenia Gravis Pathogenesis
Complement Inhibitor Therapy for Myasthenia Gravis
Spotlight on MuSK Positive Myasthenia Gravis: Clinical Characteristics, Treatment and Outcomes
Role of Thymus on Prognosis of Myasthenia Gravis in Turkish Population
MuSK IgG4 Autoantibodies Cause Myasthenia Gravis by Inhibiting Binding Between MuSK and Lrp4
Acetylcholine Receptor Antibody in Myasthenia Gravis: Predominance of IgG Subclasses 1 and 3
Dysphonia as First Symptom of Late-onset Myasthenia Gravis
Bilateral Facial Palsy Without Ocular Muscle Involvement in Myasthenia Gravis: Case Report
Electrophysiological Study in Neuromuscular Junction Disorders
Seronegative Myasthenia Gravis
The Use of the Ice Pack Test in Myasthenia Gravis
Progress in the Treatment of Myasthenia Gravis
Ocular Myasthenia Gravis: A Review
Isolated Dysarthria as the Sole Manifestation of Myasthenia Gravis: A Case Report
Pulmonary Function Testing in Elderly Patients Treated for a Myasthenia Gravis Exacerbation
CT and Myasthenia Gravis: Correlation Between Mediastinal Imaging and Histopathological Findings
Incidence of Thymoma in Myasthenia Gravis: A Systematic Review
Thymectomy in Myasthenia Gravis
Repetitive Ocular Vestibular Evoked Myogenic Potentials in Myasthenia Gravis
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Cite this: Myasthenia Gravis: Which Test Is Best? When and Why? - Medscape - Jun 22, 2023.
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