James F. Howard Jr., MD

: As you see a patient, De novo, brand new, new diagnosis, how do you start with treatment? What considerations do you have?

 Yeah. There are a couple of considerations at least. First and foremost, how severe is the disease? How old is the patient? Do they, or do they not have a thymoma? And we'll talk, I think about thymectomy a little bit more as we continue our discussion. What other medical problems do they have? Are there medical problems that would lead me towards, or against maybe prescribing a certain therapy early on? What other medications are they on? It's cool because, it's not really a cookbook. Every patient's a little bit different. Sure, there's an algorithm. Sure, there are guidelines that we follow. But I think that we have to be facile in terms of what therapies we choose based on some of these factors that I had mentioned. Also, antibody status is important as well. As some of the subtypes might respond better to some treatments rather than others. And some treatments may not be available based on antibody status as well.

: Yeah. It's not called a snowflake disease without reason. And while there are common themes, the individual nuances of color, how we approach them. Cholinesterase inhibitors, pyridostigmine, Mestinon, neostigmine, in some instances have been a mainstay of therapy, symptomatic therapy clearly. And interestingly, it improves certain muscle groups, makes no difference with others, and actually makes some muscle groups worse. And it's a very difficult drug to use. It's simply not pop them on a pill three times a day and be done with it as you try and titrate to the effect that you want. And you're quite right. Certain subtypes MuSK myasthenia, for instance, some 70%-plus do not tolerate that drug and may actually be made worse by it. But very common in use. But very problematic from the adverse event perspective. And particularly, with the GI side effects. What do you find most helpful in treating the GI side effects of cholinesterase inhibitors?

: Well, I think first and foremost, it is all about communication. Letting people know that that's a common side effect. And generally speaking, the common side effects of most of these medications. But to answer your question, I usually will prescribe hyoscyamine as an antidote, so to speak for the GI side effects, or glycopyrrolate at times if that's not available. And most, but not all patients, I think find benefit with that.

: Yeah. The one drug we would not use would be atropine that some use because it's a cardio accelerator and sometimes that's worse than what you're trying to accomplish. Because it's symptomatic improvement, are there populations of your patients where that's all you do?

: I would say for ocular patients, yes. It's the rare generalized patient where I've been able to get away with, as I say, using only cholinesterase inhibitors. I can think honestly, of one patient right now that I'm following with generalized MG where I've got him managed on a cholinesterase inhibitor alone. And that's not that it hasn't led to improvement in other patients, but I've often not been able to get them maximized on their therapy without using something else. It's rare, but it happens. And it always makes me a little nervous to think that I'm managing people with the cholinesterase inhibitors alone that have generalized disease. But maybe I'm being too cautious in my approach.

: Yeah. It's the rare patient who has cosmetic ptosis that I will use only cholinesterase inhibitors. It's an immunological disorder. With time, it's a progressive disorder and my belief is it should be treated as such. Do you have a preference for an immune suppressant that you like?

 Yeah. I have generally had good results with mycophenolate. And it's not to say that's a one-size-fits-all therapy as we've already hinted to or hinted at. Generally speaking, in my experience, people tolerate it fairly well. There are some patients that do develop GI side effects on it, where you have to move on from it. But I've been able to put many people into remission using mycophenolate trying to overtime, lower the dose so that we mitigate potential long-term hazards with it. There's a risk of infection; risk of malignancy. That's true for a lot of the immunosuppressants that we use. But generally speaking, what I'll do is I'll put people on steroid prednisone and I'll bridge them with prednisone until about nine months to a year when that mycophenolate - if it's going to have an effect, which I think for many people it does, will take that effect that I'm able to successfully wean most people off of prednisone or put them on a pretty low dose. How about yourself?

: Yeah. I gravitate to mycophenolate in decades past. It was azathioprine. But we abandoned it because it takes nearly 10, 12 months to start working, in three years for full effect. Mycophenolate has been a nice addition to the program. We have found that with our GI distress and it's commonly diarrhea that switching to myfortic acid sometimes will alleviate that. That's what our GI folks have recommended. And then in this recent conference, some of the Europeans are going to, rather than every 12-hour dosing, three to four times a day dosing, and they found that was beneficial. I've not tried that, but that's something I would keep in the back of my mind to see if that would help alleviate it. The other nice thing about it is it requires very little monitoring, unlike many of our drugs. Azathioprine monitoring liver and bone marrow, and the cyclophilin monitoring renal function, et cetera. This one has been relatively benign in that regard. And so, that's been beneficial. We can often get drugs paid for. It's the ancillary monitoring therapy that patients have difficulty with their insurance companies. And if you're looking at something every month and getting $40, $50, $100 bills, that gets pretty tiring quickly. For sure.

 Do you ever use double immune therapy, a combination of ISTs?

 I do not. I can't remember the last time that I did it if ever. Certainly, there are times where I have to change a person from one to another because of lack of efficacy or side effects, but generally, I try to taper one off before I put another one on. Because I also find that if I feel like I'm at the point where I might need dual therapy, that I might need to move on to a little bit more down the pipeline in terms of “more aggressive agent” to control the disease.

Videos

James F. Howard Jr., MD and Nicholas J. Silvestri MD, FAAN, share insights regarding acetylcholinesterase inhibitors and immunosuppressive therapy as first-line treatments for patients with myasthenia gravis.

Use of AChEI and Immunosuppressives in Managing Symptoms

: As you treat patients, what's the ultimate goal?

: Really for me, I push the envelope. I've been aggressive about this for a long time, and I really want to get patients symptom-free or as close as symptom-free as I can safely get them. And then the flip side of that is I want them to tolerate their therapies. I want them to have few or even ideally no side effects on their therapy. Basically, I want to make their disease go away and let them know they have the disease by either the symptoms or side effects of therapy.

 And I would agree with 100%. There's some controversy in the recent international myasthenia conference, was held and there was discussion about this topic. And there was a segment who said, as long as they feel OK, regardless of how weak they are, that's their endpoint. And my concern is that as patients have a chronic disease, particularly one that is insidiously evolved, they reset what normal is, and they don't know what normal is until they're better. And then they look back and say, oh my goodness, I didn't know this. Or I gave up golf because I thought I was getting old and now I can swing a club just as well. And so, that's a concern I have is that we give up. We, the community sometimes give up too quickly in part, because the patient is accepting of what they have, their limitations. Not realizing that there may be - and it's not for everybody, but there may be a better life if we are more aggressive.

 Yeah, I couldn't agree with you more. As you know, there was a paper co-authored by the late Nancy Law and some of other patients and advocacy groups that really talked about the patient's perspective of treatment for myasthenia. And one of the topics that the authors brought up was this idea of what you're talking about, which is treatment inertia either on the part of the clinicians not really wanting to push a little bit more aggressively, and sometimes there may be good reasons for that. Other times, not. And sometimes on the part of the patient; to speak to your point that patients don't know that there might be a way to get even better. I think that approach certainly has to be individualized. Maybe I'm not as aggressive with more frail or otherwise medically ill patient, because I'm worried about potential side effects or tolerability issues, or quality of life with therapies. But I think that really is the exception rather than the rule. I think we need to be aggressive in treating our patients. And I think that one of the joys of treating people with myasthenia as contrasted with a lot of the other neuromuscular disorders that we treat is that we can actually make a meaningful impact. And so, improvement is great, but minimal manifestation status or minimal symptom expression, I think really should be the aspiration.

 And just to elaborate that for those who may not know, there are several outcome measures that we routinely use in following our patients with myasthenia gravis. One is an activity of daily living score composed of eight items that we query the patient in a very structured fashion and minimal symptom expression, or those individuals who have a score of zero or one, which essentially means no disease. And minimal manifestation is a state in which the treating physician believes there's no functional weakness and there's no symptoms. And these are our targets that we now shoot for particularly with our newer therapies that are coming online, where we can more easily achieve this. What role does the patient have in determining their therapy?

 I would say in my practice, they have a pretty prominent role. But again, I think it varies by patient by patient, right? I have some patients who they want to be the directors of their therapy. And sometimes I think that their recommendations or their requests are very reasonable. And I'm fine with that. There are times where it's, I don't think reasonable and we have to talk through why that's the case and what other therapies might be a better option. And there are some patients and not to be ages, but just as a general observation, tend to be older, who tell me, you're the doc, just tell me what you want me to do, and I'm going to do it. And so, I try to really gauge each patient; see how involved or how uninvolved they want to be with these decisions. But certainly, I view it as a team effort between the patients and oftentimes their families and I, in terms of what we do going forward in their therapy.

: Yeah. And I can't agree more. The patient needs to be their advocate, particularly in healthcare situations where their treating neurologist is not available or they're traveling, whatever. And so, they need to know their disease and we spend a lot of time educating them on their disease and on their medications and why we've done what we've done. And then they in turn can be their advocate in those situations where we're not readily available, so to speak.

Thought leaders offer practical advice on setting therapy goals for patients with myasthenia gravis, with an emphasis on patient inclusion.

Goals of Therapy and Patient Communication

: In your experience, what leads to misdiagnosis?

: I think milder infrequent symptoms often that can be overlooked by the doc or sometimes even patients. I have got patients that have come back and said, oh, in retrospect, actually, I have been having these symptoms for a couple of years now, and I just thought it was maybe eye irritation or allergies or something along those lines. I think milder symptoms, I think, age of the patient, and healthcare literacy, I think sometimes can play a role. I think there are some patients who like you referred to are on social media and they're there three days later with their diagnosis. And there are other patients who I think either want to believe that nothing's wrong or really don't advocate for themselves maybe as strongly as they should. I'll tell you in the hospital when patients come in with symptoms of myasthenia, initially, they're always ruled out for stroke. I don't know why that is. It seems to be the number one diagnosis people get, and then they're told, oh, you don't have a stroke. You actually have myasthenia, which can be a little worrisome too, until that diagnosis is made. Those are just some of the things I've seen over the past couple of years.

: Yeah. In our practice is much the same. The other interesting ones are those who have ptosis only and get labeled as bell's palsy. And the patient with myotonic dystrophy with bilateral ptosis, our thoracic surgeons call us. We now see any patient being referred in for thymectomy because they've been burned in the past. And I think it boils down from a physician's perspective that they've not taken an accurate critical history searching for that fluctuating nature. And given the busy time of everyone's practice, that often gets overlooked. The details aren't obtained, hence the misdiagnosis. And there's a flip side that we see with the - because of social media, patients come to us insistent that they have myasthenia who clearly do not. And fatigue of some sort, fibromyalgia, if I can use that term. And there is much of a problem in trying to un-establish a diagnosis as we do have and trying to make a diagnosis in some folks. And I don't know if you see that as well.

: Absolutely. I see it on both ends of the spectrum. We have patients that have fatigue and really not much in the way of other symptomatology to go along with a diagnosis. And then it's trying to chase that to see where that might be. But one of the more recent cases that was referred to me for myasthenia was given the diagnosis of serial negative myasthenia; was actually a patient that had chronic progressive external ophthalmoplegia, CPEO, that we were able to confirm genetically. There are two ends of that spectrum, right? There's the patient with nondescript symptoms and maybe, maybe not a neurological diagnosis, but then the other flip side are patients like you mentioned with myotonic dystrophy or CPEO that can look like myasthenia or oculopharyngeal muscular dystrophy. Now, I haven't seen a case of that in a while, but that's another potential misdiagnosis. Or even I had a patient, one of my patients with Kennedy's disease was initially thought to have myasthenia. Different neurological disorders can be mistaken, but I think it's really that history, as you talked about fatigability of intermittent symptoms that I think distinguish myasthenia from pretty much all the other diseases that I mentioned.

: Right. And all that has neuromuscular jitter, say on single-fiber gene is not myasthenia. And CPOE is a prime example where they have increased jitter, but it's the history that differentiates it. Should community physicians be the sole provider of patients with myasthenia?

: Well, that's a very controversial question, Dr. Howard. I think it depends on the case, right? I think that in complicated patients, patients with severe disease, patients with frequent crises, probably not. On the other hand, I think patients with more mild or well-controlled disease, sure. I don't envy the job of community neurologists, general neurologists. They've got a lot of different types of patients to see. You got to keep up to date in a lot of different areas of neurology. And so, I think that's fantastic, but I do think that patients with a complicated case of myasthenia probably should be seen by specialists much as we would expect, let's say a patient with ALS to be seen by a specialist.

: What about internists, family practice docs, ophthalmologists out in the community?

: Well, I think that to speak to your point, I often treat those patients in conjunction with those providers. I'm certainly not going to be treating hypertension. I need rely on primary docs oftentimes to help me with side effects that I'm giving patients on some of the standard therapies. I'd say it's more of like a collaborative effort with those types of physicians than anything else.

: Yeah, I couldn't agree more. It's a joint venture in this day and age. And we value their input. And one can't be exclusionary. Let's change topics a little bit.

Expert panelists discuss misdiagnosis of myasthenia gravis and consider the question of whether this condition should be treated by community physicians.

Misdiagnosis Associated With Myasthenia Gravis and Importance of Multidisciplinary Teams

 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.

 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.

 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?

: 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.

: 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?

: 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.

: 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.

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

: 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?

 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.

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.

James F. Howard Jr., MD

Articles

Use of AChEI and Immunosuppressives in Managing Symptoms

Goals of Therapy and Patient Communication

Misdiagnosis Associated With Myasthenia Gravis and Importance of Multidisciplinary Teams

Understanding and Diagnosing Myasthenia Gravis

Latest News