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Updates in the Management of Myasthenia Gravis Peers and Perspectives - Episode 1

Understanding and Diagnosing Myasthenia Gravis

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James F. Howard Jr., MD and Nicholas J. Silvestri MD, FAAN discuss an overview of myasthenia gravis and important tools for diagnosis of myasthenia gravis.

Dr. James F. Howard: Hello and thank you for joining this NeurologyLive Peers & Perspectives presentation titled, “Updates in the management of Myasthenia Gravis.” I'm Dr. James Howard, Chip Howard, to many of you. I'm a professor of neurology medicine and allied health at the University of North Carolina School of Medicine in Chapel Hill. I'm joined today by Dr. Nicholas Silvestri clinical associate professor of neurology at the University of Buffalo Jacob's School of Medicine and Biomedical Sciences. Today, we're going to discuss an overview of the management of myasthenia gravis and the recently approved FDA agents to treat this disorder. Thank you so much for joining us. Let's begin. Hello, Nick, and welcome. And I'm so happy you could participate. I think let's start by giving folks an understanding of MG and what it is and its incidents and prevalence, et cetera. I'll just kick it over to you and we'll start.

Dr. Nicholas J. Silvestri: Sounds good. And thanks so much for having me, Dr. Howard. It's always a pleasure to collaborate and thanks for everyone tuning in. Myasthenia gravis is the prototypical autoimmune disorder of the neuromuscular junction. Most cases are caused by antibodies to acetylcholine receptors. About 85% of cases of generalized myasthenia with a smaller percent being due to antibodies against the MuSK protein or the LRP4 protein. We think the incidence of the disease or the prevalence rather is about 60,000 to 80,000 in the US. And so, it qualifies as a rare disease, but it's not so rare that most neurologists take care of patients with MG and many of us spend our careers taking care of patients with MG. Thankfully, for us, it's a treatable disorder and I look forward to talking about a lot of the treatment options we have for our patients with MG as the talk progresses.

Dr. James F. Howard: Yeah. I think it's one of the most best-understood autoimmune disorders out there. And I think it's a prototype for many of other autoimmune disorders, particularly with the advent of our newer targeted therapies that are in production or coming down the pike. The signs and symptoms of MG, the cine qua non that goes way back in the mid-1600s, sir, Thomas Willis British anatomist had this one patient that he described in his very famous tone and said, there's this woman with very spurious and obnoxious palsy who could speak readily and freely enough. And then under about an hour, became muted as a fish. And demonstrating the fatigable component of the disorder. And then the astute observation that she could recover her voice over time. And I think that's the cine qua non, the demonstration of fatigable weakness made worse by activity and improved with rest. In your practice, what common tools, how do you make the diagnosis?

Dr. Nicholas J. Silvestri: I think first and foremost, Dr. Howard, as you mentioned, it's really history and exam, right? Really listening to the patient, understanding what symptoms they're having, and really trying to probe for that fatigability. And then obviously, trying to reproduce that on exam. Common symptoms and signs that I hear early on are droopy eyelids of ptosis, double vision, and then bulbar symptoms as well, problems with speaking, chewing, swallowing, breathlessness and exertion, weakness of any - pretty much any muscle of the body as you well know. In terms of diagnosis after the history and the exam, there are some neat little tricks we can do at the bedside that I think the medical students and residents find very intriguing as well. Things like the ice pack tests. Using an ice-packed and putting it on a tonic lid and seeing if we can get the lid to raise temporarily. But for a more firm diagnosis, I rely on serological testing. As I mentioned before, the majority of patients with generalized myasthenia have antibodies, and we'll send those out for acetylcholine receptor and MuSK antibodies if those are negative. And then in those patients where we strongly suspect myasthenia based on the history and exam, and they have negative antibodies that's when we're moving on to more sophisticated electrodiagnostic testing. Repetitive nerve stimulation, single fiber electromyography.

Dr. James F. Howard: In our practice, we would agree with you. We typically don't reflex or order all the tests at once, but simply reflex. And when you start with AChR antibody, because it's the most prevalent one of the subgroups out there, and if negative, then go on, look for MuSK and LRP4. And in our hands, about 78%, 79% of these are positive. And I suspect there are many more that would be positive, but commercially we don't have some of the newer techniques cell-based assays readily available though there is a laboratory now in the US that will do it for us out in Washington State, previously in Oxford England with Angela Vincent. We do routine physiology on everybody primarily to exclude mimics and also to establish a baseline abnormality. And in our practice at Carolina, we don't rely on repetitive nerve stimulation. We use it as a teaching tool for our residents and all and rely very heavily on single-fiber EMG. It's the gold standard and the most sensitive in our hands. We're up in the high 90s in finding abnormalities there. And then I found it as an excellent tool to monitor disease. The patient who's complaining of lots of fatigue and seemingly weakness and whom we can't find much on exam. I rely on single-fiber very heavily. And previously it's been shown that if it doesn't change by more than 10%, there's no real clinical change. And I also find it to lead changes clinically. It'll start to improve before the patient improves and get worse as the patient begins to deteriorate. As I said, it's the most sensitive. The downfall or the problem is that it's not readily available throughout the country. It's very technically demanding. And clearly, in private practice, it's not feasible. One has to stay proficient with it. That's a problem. In terms of diagnostic delay, and I don't know what your experience is, one of my nurses did a study for her master's thesis, and we found that the average time for diagnosis, and this is late 80s, early 90s, it was a seven-year hiatus if you're a woman between the ages of 18 and 50 to make a diagnosis. Men and women sought attention very quickly within six months. Men usually were diagnosed within 18 months. But women had this very prolonged delay, which is tragic, unfortunate labeled as psychiatric depression whatever. And often, we're given medications for that. Modern-day, I think it's better. But what's your experience now in terms of delay?

Dr. Nicholas J. Silvestri: I think there's a range that I've seen in terms of people getting diagnosed with MG. I think on one end of the spectrum I can think of the patients that come in basically in myasthenia crisis and are diagnosed fairly quickly. But yeah, no, I do see people with - I'm going to use the term mild certainly not to trivialize the impact it has on their lives, but let's say a milder phenotype with let's say predominantly ocular symptoms, maybe some bulbar symptoms that are maybe not as frequent that it can be a couple of years where they have these symptoms before someone really listens and gets the fluctuating nature, the fatigability as you talked about before and really try to hammer that diagnosis down. I don't think that seven years is the average, at least in my patient cohort. And maybe it's not for yours either these days, but I would say anywhere from days to probably a couple of years are where that diagnosis is. But I would say that probably for the most part if I had to think about where that curve is, where that peak of that curve is, it's probably four to six months after the onset of symptoms.

Dr. James F. Howard: And I find that social media has been very helpful. Many times the patient comes in and says, read this. Here's my diagnosis. And so, that's one of the better aspects of social media.

Dr. Nicholas J. Silvestri: I agree.

Dr. James F. Howard: Who do you find is making the diagnosis? Are they coming out of ophthalmology? Are they coming out of family practice, internal medicine?

Dr. Nicholas J. Silvestri: Yeah. I think my referral base generally is either directly from ophthalmologists or from general neurologists who I think most often suspect the diagnosis, but don't necessarily want to make it because I think they want someone like myself, a neuromuscular doc to actually make the diagnosis and take care of patients, which I fully appreciate. I would say that the referrals direct from primary care doctors do happen, but I would say they're not as common as those that come from either ophthalmology or from general neurology practice. How about yourself?

Dr. James F. Howard: Yeah. We would see similar in that the internist or family practice is sending to a more local neurologist rather than to the university. And then they're being sent to us from the outside neurologist. And clearly, ophthalmology is a significant referral source there.

Transcript Edited for Clarity