Okay, we'll get started. Thank you very much for coming. Thanks for the AAM to invite us. We're going to talk about the selected topics on my senior graduates. There's only a few selected topics. I'm Yueping Li from Cleveland Clinic. I have Dr. Marko here from University of Vermont and my colleague, Dr. Ben Carter from Cleveland Clinic. We selected three topics, and the first one I'm going to cover some of the general aspect of my senior graduate career. I have an email list here. If you need a copy of this presentation, just show me an email, I'll be happy to send it to you. These are my disclosures. So we're going to touch a few topics. One is we can talk about trends in the epidemiology of my senior graduates very briefly. We'll talk about MG specific symptom science and using the ADL because that's the most popular tool. We'll touch based on a few general topics, sleep, depression, exercise, nutrition. We'll spend some time talking about vaccination and infection risk. And finally, we'll cover, if I have time, we'll cover some of the infrequent topics. So this slide shows four diagrams, and I think everybody's very familiar with the first one. It's from Dr. Jeff Guptill from Duke looking at the incidence of MG. It's predominantly a disease of young females and older male. That was 20, 30 years ago. And similar data coming from the same group, Duke University, if you look at it, it actually become predominantly a disease of elderly male and females. The incidence in the younger patient group become much less. If you look at the data from Canada, look at the change in the incidence prevalence over the years, you can clearly see there is a significant increase in the older patient who are older than 65 years old. A easy number to remember now in United States is actually people who are 65 years or older represent about a 65% of MG patient. In the elderly, we begin to see more patients with ocular subtype. It's no longer the 15% to 85% division. It's actually become a 40% to 60% division. Finally, the frequency of thymoma become less. We used to use a number of 10% to 15%. Right now, it's actually less than 9% to 10%. Everybody's familiar with ADL. I'm not going to talk about it. It's basically 8 IMs, each with a maximum score of 3, total of 24. Looking at ocular symptoms, the ocular symptoms are mainly caused by weakness of three groups. One is the levator muscle, the levator muscle, and the muller muscle, which is actually a smooth muscle. It has a conjoined tendon, and it causes ptosis. The diplopia is due to the various rectus and the oblique muscles. And then the eye closure weakness, and it's due to the orbicularis orifice. The droopy eyelids, it's typically fatigable, and usually the definition is has to touch the upper lid of the iris. And usually asymmetrical, and with time, usually become bilateral or alternating. If you have a patient with alternative droopy eyelids separated by days or weeks, it's almost quite a diagnostic of myasthenia gravis. On the other hand, if you have a patient with droopy eyelids, a lot of frequent eyelid blinking, it's sort of suggestive of mostly a functional neurological disorder. Eye closure weakness, patients are often unaware of this, and it's often missed during the exam as well. It's less influenced by subjectivity because patients generally don't know about this. Therefore, it's actually a fairly good indicator of MG as well as MG severity. If you have a patient with fluctuating weakness and eye closure weakness, it's almost diagnostic of MG as well. You can ask the patient to close their eyes, they open, you can see the improvement in the ptosis, which is a very easy bedside test to do to suggestive of diagnosis of myasthenia gravis. Depalopia, it's usually asymmetrical and variable. It can be different manifestations, horizontal, oblique, vertical. Usually in an MG patient, it's usually multiple, but the medial rectus is the one that is most frequently involved. Typically, the patient comes in open, and the pupil is usually not involved. Rarely, you can have pseudo INO, and you have involvement of only one muscle. And very rarely, you have seen a patient report manifesting under one and a half syndrome. Other ophthalmology colleagues often divide eye ocular deviations into two types. One is called a commutant, the other is called an incommutant. The picture on the left shows a commutant deviation. Basically, this patient has a right hypertropia of 8 diopter. No matter whether he look at left, right, middle, up, or below, the degree of deviation does not change. We typically see this in senior health disorders. The other is incommutant strabismus or ocular deviation. It's basically this person has a right hypertropia. It's most significant when you look up, right, upwards. When you look at left, downwards, you don't see it. And typically, we are very familiar with this. Typically, we think of this as peripheral nervous system disorder. Actually, we see both in my senior graduates. One is suggested by one of our neuropharmacology doctors, Kostmatsky. He had this very meticulous and inseminal observations. He said many of his patients with MNG has actually commutant ocular myasthenia deviation. When we look at it, it's actually seen in about 20% of patients. And often, in follow-ups, they often change from commutant to incommutant. So when you see incommutant deviation, it does not mean the patient does not have myasthenia gravidis. This occurs partly due to the central adaption process to peripheral muscle weakness. And also, we have to bear in mind that the patient's ocular complaints may not coincide with what you object to with a physical exam of the ocular findings. Orbital symptoms, mainly dysarthria, chewing difficulties, and swallow difficulties. Dysarthria, you reflex it. Very rarely, they have a torsus. Very rarely, they have a striator. Chewing difficulties, many times, it's confused with TMJ. Dysphagia in MNG ADL, there's only one item that is choking. But when we evaluate a patient, it should not be just choking, lack of choking, or difficulty with eating. They may have already restricted their food choice. They may have a need for regurgitation, especially with liquid intake. They may have difficulty handling secretions, of course, lose weight, and side operation leads to frequent pneumonia. Respiratory failure, likely, mostly, typically, occurs with a trigger. And often, typically, an evolving process. Typically, MNG patients don't have a respiratory failure in the morning and getting intubated in two hours. And you can do, very rarely, this is an isolated symptom without other findings. You can do bedside counting, and our colleagues in Ohio State have done a good study looking at the correspondence between counting and the two FVC. I just want to remind there are two exceptional scenarios. One is in the general population, especially in this country, we see high frequency of exertion dyspnea. We see that in about one third to half of the patients, we are relatively healthy. So exertion dyspnea can be a misleading symptom in the evaluation of MNG. The other is a group of patients on chronic steroids. They often have this perception of dyspnea, and this is commonly described in patients with asthma, and we see that in some of the MNG patients as well. Arm and leg weakness, and if you look at MNG-ADL, it's proximal arm and proximal leg weakness. It's pretty clear, you can look at leg weakness, the hip flexor weakness is very frequent. But I want to remind people that actually, the distal hand weakness is because the finger extensor and finger abductors actually, it's fairly common in patients with myasthenia gravis. Actually, we see people with ultra-myasthenia gravis, they have no other symptoms. You look at their hand, actually, their hand can be weak, and they are unaware of it. And the repetitive nerve stimulation study has been done and shown that actually, the meeting and renal nerve are more sensitive than the owner. All right, so how do you score MNG-ADL? Well, nowadays in research, and FDA-required patient reported outcome, so we often rely on the patient to do this MNG-ADL scoring. There has been study looking at MNG-ADL scoring scored by a patient and physicians, they're not much different, and often quoted studies, Korean study, the problem with the study is the mean ADL score was three, two or three. So when the mean score is so low, there's not much difference between what a patient score and what a doctor score. When the score is high, there might be a difference. When you look at the MNG patient, and everybody can agree easily, some symptoms are clearly due to MNG. Some of them may not. When there are difficulties, become equivocal, and as physicians, we should try to help the patient try to pick up the right score. You have to also try to learn your patient as well. I think everybody's familiar, there are patients who think everything in symptoms is caused by MNG, and there are patients who think none of the symptoms is caused by MNG. I think the scoring in those patients' problem can be dramatically different. There are symptoms signs that are not coded or included in the MNG ADL. Neck flexor extensors, facial weakness, patient with myasthenia grafts often have this vertical smile. When they smile, their mouth does not open wide, and their eyes don't close as much, so give you a snare expression. There are patients with ovarian myositis, hyperexcitability disorder, cardiac symptoms, gastrointestinal symptoms, urinary symptoms, and many other very rare symptoms. These can also all be related to MNG. What about nutrition in MNG? I don't have much to tell you, really not much data to support this. We should check on patients with MNG. There are some suggestions that low vitamin D is increased risk for autoimmune disorders, and there are suggestions of probiotics, gluten-free diet, Mediterranean diet, or autoimmune diet. These are all less stimulant diet you can ask your patient to try. Some patients may benefit. I don't think we have very good data to suggest one or the other. This is a handout tip I summarized. I have printed out to give to patients in terms of what to do when you're facing dysphagia or treating difficulties. What about fatigue in MNG? There are two types of fatigue. One is called physical or peripheral fatigue. In patients with this kind of fatigue, you can observe there is a correlation between strength and a perception of fatigue. There is a perception of fatigue, which is a central fatigue. This kind of fatigue is a central processing problem. Typically patients, when you exam them, they don't have weakness in manual strength exam. This is not a sign of chronic impairment, and this is also worsening with repeated thinking and repeated physical activity. Some people feel that this is kind of a protecting mechanism to rest for the MNG patient to take a rest. Fatigue in MNG is very common. Forty percent is probably an underestimate. Eighty percent might be a little bit of overestimate. It's probably somewhere in between. We typically see inpatients with more fatigue in female patients, patients with depression, and patients with poor sleep. And when the disease is more severe, you tend to see more fatigue. However, the pure MNG or repetitive stimulation generally don't tell us much about this fatigue. And also patients who are completely stable remission, or even patients with pure ocular MNG, they are also completely fatigued. There are a variety of factors that contribute to fatigue. I have this diagram. You can see the muscle wasting, how severe the disease is, the present depression, comorbidity, and even medications all can contribute to fatigue. There are a lot of scores you can use, many, many skills. You don't have to do every one of them, and you can probably pick up one. They are probably good enough. And how do you manage the fatigue? And of course, we give immunosuppressant therapies to improve strength. However, we actually don't have evidence that immunotherapy will improve fatigue independent of their improvement in the muscle strength. We ask people to do exercise, especially aerobic exercises, and this has been shown to alleviate fatigue in a number of neuromuscular disorders. Of course, we screen for depression, sleep-related disorders. There are a variety of sleep-related disorders. Sleep disorder, breathing, obstructive sleep, restless leg syndrome, insomnia, some of them due to the MNG, some of them due to MNG medications, such as prednisone. So many patients with MNG may need a sleep study. Depression with MNG, the depression with MNG has nothing to do with acetylcholine receptor antibody. We actually can detect acetylcholine receptor antibody in the spinal fluid of MNG patient, but they don't bind to the nicotinic acetylcholine receptors. The MNG mobility, of course, is a fluctuating process. Patient family and coworkers may not understand this patient, and so this may put a lot of stress on the patient, and they feel frustrated, depressed. Loss of factors, the duration of MNG illness, how severe the MNG is, whether there is significant improvement, whether patient is often hospitalized, female patient, the dosage of steroids, and whether depression with pregnancy exists or not. All these could contribute to the presence of depression. How do we manage it? We actually have a psychotherapist in our clinic who is very, very helpful. And there are mostly SSRIs you can use, and some of them have been shown it does not cause MNG exacerbation. Typically, we avoid HALDO or these stronger medications. Typically, we recommend lithium should not be used in patient myasthenia gravis unless it's absolutely necessary, and ECT in general is safe. A lot of MNG patients can actually complain pain. It's mostly associated muscle and skeletal pain, and the pain can also be actually often drawn into two scenarios. One is we give patient steroids, they got it better. When we give them steroids, patient said, my MNG is better, my pain is back. The others, several of the newer generation therapies actually cause myalgia, diffused myalgia as a side effect. I don't need to explain that benefits of exercise for MNG patient, it should be significant. It's specifically, in terms of MNG, it can reduce the frequency of osteoporosis. It can also modify your autoimmune process. The problem is MNG patient, often the benefit has to be a long-lasting exercise, and some MNG patient may not be able to do it. There is a long list of exercise studies in MNG patient, most of them show some benefit. The most important one we had is a random study looking at the exercise. The take-home message of this study is that it only provide transient benefit, but most patient, they are well-tolerated, the exercise is well-tolerated, and the exercise does not cause MNG exacerbation. What is the take-home message? Patient with MNG should take regular exercises, they should avoid prolonged endurance type exercise, they should rest before exercise, and they should do it when it's cool or cold rather than in hot temperature, and there is a minimal recommended exercise intensity protocol. Infection with MNG, infections, there are a few virus or bacteria infections have been speculated to cause MNG, but it's never proven, but the infection as a trigger occurs even one-third of the cases, so it's a common trigger of MNG exacerbation. The immunotherapy, the traditional immunotherapy clearly increases risk of infection in MNG. For the newer therapies, we all know the newer therapy are fairly specific. One of the, you know, advantage, putative advantage, it may not cause infections at the older generation. The problem is all these medications are actually very strong. If you look at rituximab, it actually depletes your B cells within a very short period of time. If you look at some of the complement inhibitors, it inhibits your complement very rapidly, more than 95 inhibitions in a few days. Some of the FCRN inhibitors, we do cycles, shorter cycles, reduce your IgG by 60%, but frequent cycles will lead to a much more significant reduction of IgG level. The risk of infections in most patients is dosage-dependent, so on stable MNG patients, we should try to minimize the dosage as much as we can. Rituximab, when we use it, we need to screen for hepatitis B. The PMIR risk in MG is virtually nonexistent. We only had one case of PMIR reported so far in MG literature. However, the rituximab does cause persistent low IgG immunoglobulin level. And in some patients, especially in the patient who had coexisting lymphocytes and lymphopenia, who has undergone an increased risk of infections, some of them we need maintenance IV IgG treatment. Commonly inhibitors, they will increase risk of some special type of bacteria. But it will also cause sepsis, endocarditis, and fungal infections. The incidence of this seems to be occurred more in the HUS and the PAH population than in the MG patient. In the MG community, ecolizumab, there have been reports of some bacterial infection, as well as endocarditis. Rituximab, there was a patient with meningitis, but the organ is not proven. And we have no data on Zilocopram because it's just proved. This keeps on changing, and I hope you can consult your pharmacist before giving vaccinations for the patient who are accompanying the inhibitor. I just want to remind people, this is not a scenario that you tell the patient, go to Walgreens, get a meningococcal infection, a vaccine. That's not going to work. There are two types of vaccines. One is quadrivalent. One is monovalent. Both need multiple doses in the beginning, and both need a booster doses in a few years. So this protocol may change, but each patient will need five, six doses of vaccines. If the patient cannot have vaccines, they need antibiotics. It's not only just for the meningococcal vaccines. There are also other vaccinations, especially elderly patients, should be considered. What about other vaccines? Other vaccination, M&G patients are mostly safe. The immunotherapy, however, it do decrease the efficacy immunization. The flu vaccine is generally safe, and people generally don't think about it. They do not cause M&G exacerbating either. The older patient should have the shingles vaccine. The live attenuated vaccines should be avoided. And the patient on rituximab, you should give the vaccines before the rituximab or a few months after the last dosage. What about the Africa trichromat? And Dr. Gabatier has done study on looking at either a trial patient. The take-home message is the vaccine-generated antibodies is also reduced corresponding to the IgG reduction, but the protection is still above threshold for most patients, and there are proposed guidelines. What about the COVID vaccine and COVID? And this is a large Canadian study looking at a few thousand 4,400 patients with M&G. The take-home message is the COVID infection does increase risk of, does increase M&G comorbidity. However, most M&G patients will receive COVID vaccine. The risk of M&G exacerbation due to vaccine is minimal. It can be neglected, and finding the vaccine remain protective against COVID for most M&G patients. What about the PGP prophylaxis? And this is, I'm pretty sure everybody, most of people here have argument with your pulmonary medicine specialist or rheumatology colleagues. I can tell you that occurrence of PGP in neuromuscular disease is exceedingly rare. How rare is it? This is a Canadian study. They look at 4,000 M&G patients over a period of 13 years, and I think they only had only a few patients, it's five or six patients with PGP. We look at our data, our 10-year data, we only said two M&G patients that had PGP, both had active cancer. And this is not because we use the vaccine a lot. We only, the PGP prophylaxis in our institution has been given to less than 10% of M&G patients. So in general, we do not feel the PGP prophylaxis is indicated for most M&G patients. While Dr. Kleder sitting here and I, we actually had an opinion article, this is just opinions, we feel a small portion of the M&G patient could still be given Bactrim, you know, PGP prophylaxis. And those are the patient who has baseline residual pulmonary disease, those are the patient that has low lymphocyte count, those are the patient with organ failure. Okay, finally, what about, we often get consult from our, you know, surgery colleagues, we have M&G patient, I'm going to do surgery, and what should I buy? Should I give the patient IVIG or plasmophoresis? We actually had a good study, a small study, 47 patients, looking at a mostly thymectomy, but also other surgery. The take-home message is, in patients who are stably controlled M&G, you don't need to give IVIG or plasmophoresis. And actually, they made some concrete recommendations that were very useful. The QMG score less than eight, roughly equal to ADL score for less than four, or actually more than two liters, or more than 70%. I'm going to stop here. I'm going to introduce Dr. Markov here. I'm going to answer questions at the end of the talk. I'm going to introduce Dr. Heer from University of Vermont, and to talk about medication-induced myasthenia gravidis excision. Thank you. Thank you to the AANEM for supporting this session today. So I'm going to talk about something that we often sort of talk about a little bit, and we talk about lists of medications, but we're going to do a bit of a deeper dive into the medications of caution for myasthenia. I do some consulting for companies that make medications for myasthenia. So we're going to talk about medication-induced exacerbations in myasthenia, and then I wanted to go through sort of more common groups of medications that we use in myasthenia, rather than doing a more exhaustive dive. I thought this would be more useful. So there's this nice paper that was published a couple of years ago at the University of Missouri that was talking about factors associated with exacerbations of myasthenia, and they examined a cohort of patients who did and did not experience exacerbation. They looked at what things they were being treated with. And what they found was is that about 20% of the people that had exacerbations in their cohort were exposed to a medication of caution. But also I wanted to highlight that almost 20% had a vaccine-preventable illness because they were not vaccinated, which I think is also quite striking. And we're going to talk a little bit more about vaccines as well. And these are some of the medicines and the odds of having an exacerbation. And we worry a lot about cardiac drugs. We worry about antibiotics. And you can see here in this particular cohort, the only medication class that was associated with developing exacerbation that was statistically significant were beta blockers. And actually gentamicin had a negative correlation with developing exacerbation, which I thought was interesting. Which might relate to these guys. So like non-vaccine preventable illnesses. And then if people are going to have an exacerbation of their illness with exposure to these medicines, it's often within days. They had a few people that they reported that were out up to a month out from the period of exposure. But for the most part, it was people within days of being exposed. I think it's really important that we empower our patients. And the Myasthenia Gravis Foundation has an app that all of our patients can download onto their smartphone that has this nice list of medications available separated out by class. So there's antibiotics, cardiac medications, rheumatologic conditions, and then immune checkpoint inhibitors as well. So brief word about corticosteroids. So I think many of us in our clinical practice have all experienced where patients will have a transient worsening of myasthenia for a few days after either starting steroids or after an adjustment in a patient's steroid dose. In this study, they did a look back at 27 studies, 15 of which in which patients had received prednisone. And they looked at how many patients had exacerbation in relation to prednisone. And I think one thing to highlight is that there's often this argument, and I think we talk too much about prednisone anyway, but there's definitely schools of thought. So there's the start high and go low group and the start low and go high group. And everybody argues that their way is better and has some comment about the exacerbation. But if you look at this cohort of studies, it's somewhere between 20 and 30% of patients will have an exacerbation regardless of which way you start the steroids. So I'll leave that there. Cardiac medications. So these are often prescribed. Beta blockers are the ones that showed statistical significance in this particular cohort. And I think it's also important to remember as we're discussing these classes of medicines is that these medicines are all treating important medical conditions for our patients. So in theory, we need to be trying to keep our patients on these medications rather than taking them off because they need them for some reason. And beta blockers are very important medicines for our patients with cardiac disease. However, we gotta be careful because in this study, they increased the aggravation of MG by 2.7 fold. And again, it can occur within days more likely than weeks to months. But there's some studies in the 90s that were really cool where they looked at patients who had moderate MG and they exposed them to either a beta blocker or a calcium channel blocker. And they looked at decrement on repetitive nerve stimulation in the deltoid. And in this part where it was being looked at over minutes after exposure, you can show that with IV administration of these medicines that there was no change in jitter with either propranolol or verapamil. Looking at oral medications, a similar study was done in the 90s that also looked at this. And then over weeks, there also didn't seem to be a big change in mean decrement with exposure to calcium channel blocker or beta blocker. The other class of medications that we often talk about when we're thinking about cardiac medications are statins. This is a big data using this database here, the WHO's database. And they looked at patients who either received statin or didn't receive statin and how many patients had myasthenia. You can see that in patients who didn't get statins, there were many patients that developed myasthenia. In patients who did develop statins, there were a number of patients that developed myasthenia with multiple of the different statin medications that we use. When these patients were either removed from their medication or they were treated, like 70 to 80% of them had a good outcome. Very few, 20% didn't have a recovery. So there's some other papers that were published, case series, case reports, looking at statins and exacerbation of MG. I'm gonna show one here in the interest of time. And just to highlight a couple of things. So in this case series, people again seem to develop the dysfunction within weeks to up to a month or two after instituting therapy. And then with removal of the drug or addition of treatment, most patients seem to recover over time. So I think in summary for cardiac meds, I think these medications are likely safe. I think there's probably a slightly higher risk of developing exacerbation with a beta blocker. And it's just important for us to monitor patients because they're gonna be treated with these medications for other reasons. Antibiotics and MG, this is another really important class to think about. So back to that same paper. So they had a number of patients that were treated with different antibiotic classes. So you can see Zithromax here, fluoroquinolones, gentamicin. And there wasn't a statistically significant signal in this group seeing exacerbation in patients who were exposed to antibiotics. I thought this was an interesting signal, the gentamicin, because one of the other big groups in this study were people who had vaccine preventable illnesses. And we know that illness can exacerbate myasthenia. And so it would make sense that if you treat illness, the patients may do better. In this study where they were looking at fluoroquinolones and beta-lactams and macrolides and having exposure of our MG patients to these medications. And they did sort of three time looks at the difference in occurrence of exacerbation in these patients. And at 15 days, there was a trend in fluoroquinolones towards a possible exacerbation, but it was not statistically significant with wide confidence intervals. Macrolides did not seem to be an issue and in fact had a negative correlation with exacerbation. Again, my theory is that we're treating infection. And it was similar at 30 days. So slight signal for fluoroquinolones, macrolides seemed to be relatively safe. Just a deeper dive. So there are some other studies that have looked at fluoroquinolones. We usually treat either respiratory infections or urinary tract infections with these medications. The average exacerbation started within a day of starting these drugs. And you can see that there were a smattering of different fluoroquinolones used in this study. And when the patients had exacerbation, they had sort of the range of myasthenia symptoms. And when the medication was removed and then re-challenged, about 20% of patients experienced a recurrence of myasthenia again. So I think in summary for antibiotics, I think that there are possible exacerbating agents if you can avoid the antibiotics on the list and find a different choice, that's great. But if our patients are in trouble from the standpoint of infection, we need to treat their infections and monitor them closely. And I think the data suggests that when we're treating infections, we're likely helping our patients avoid exacerbation. Another big category to talk about is anesthesia. We all get lots of questions about what we should do with our patients when they're having surgery for various conditions. And what we're really talking about when we're thinking about MG exacerbation in the setting of myasthenia are neuromuscular blockers. And there's sort of two classes of neuromuscular blockers. So you have the depolarizing neuromuscular blockers, which need to bind to the acetylcholine receptor to be effective and they cause the junction to become insensitive to acetylcholine. And this is a problem to use these in patients with myasthenia because their neuromuscular junction is already not normal. And these medications may be of less benefit or have less of an effect in the patient. So often anesthesiologists will go with the non-depolarizing neuromuscular blockers. And those medications, what they do is they competitively inhibit the binding of acetylcholine at the acetylcholine receptor and prevent it from being able to be activated. And in general, it's probably okay to try these medications. The longer acting ones should be avoided if possible. But the good thing is that nowadays we have a way to reverse the non-depolarizing neuromuscular blockers. So there's this medication, which I don't know how to pronounce, that has rapid onset. And basically what the medication does, depicted here in the cartoon, the red is the neuromuscular blocker and it sort of binds to and removes it from circulation. And when it does this, it restores neuromuscular junction function very rapidly. So this is a study that was looking at what happened when patients were getting thymectomy and they were given the non-depolarizing neuromuscular blockers. And you can see that it was a combination of people who got open and videoscopic thymectomies. And the patients did well. And so you can see, so these are people that had post-operative myasthenic crisis and there was half the rate of it in patients who had their neuromuscular blocker reversed with medication. Another way to look at this, so when patients are in the operating room, if you remember back to sitting in surgeries in medical school, that anesthesiologists have that train of four device that I think they usually put on the ulnar nerve that looks at motor stimulation. And it's a way to see if the neuromuscular junction is functioning. And what they did is they gave people rocuronium, which is a non-depolarizing neuromuscular blocker, and then they reversed them. And the mean time to recover, it's called a train of four, so they give four stimulations. The mean time until there were four stimulations recorded was 111 seconds after administration of the reversal agent. And 100% of the patients in this study were extubated in the PACU and there were zero crises. So I think it's safe to use these drugs in our patients as long as we're reversing the neuromuscular blockers. So a little bit about vaccines. Vaccines are so important for our patients, and I think it's just important to recognize that our patients are immunosuppressed when we treat them, and vaccinations can be lifesaving for our patients. The concern of many of our patients and many people in the community who are vaccine hesitant is that vaccine will exacerbate disease. So this is a study looking at influenza vaccine, and patients received either flu shot or placebo and had all of their MG metrics measured at four weeks. And then the group that got placebo, because it wouldn't be ethical to not give them a flu vaccine, got a vaccination here in between the four and eight week points, and then there were eight and 12 weeks assessments. And at the four week assessment between the placebo and the influenza arm, there was absolutely no difference in this cohort in the metrics of monitoring patients with myasthenia. So the QMG, the MG composite, MG ADL was flat between the two groups. So the flu vaccine seems to be quite safe. Similarly, in 2023, we're worried about COVID vaccines. As just as Dr. Lee was just showing, the COVID vaccine can be quite effective for our patients with myasthenia. So they did a similar study with the original series of COVID vaccines. You can see here there was the first dose and the second dose and they were measuring ADL both after the first vaccination series after the second dose in the vaccination series. And you can see that the mean ADL score stayed pretty similar between seven days after post-dose one and after post-dose two. That's a typo. In a rare subset of patients, about 10%, there was a slight worsening in myasthenia and the symptoms tended to improve with treatment. The other thing that was noted in this cohort was that the majority of the patients had an antibody rise. So they were mounting a response to the vaccine, which is exactly what we wanted. So in summary, our patients are immunocompromised. Flu vaccine seems safe. COVID vaccine seems safe. All the patients in that one study recovered who had an exacerbation. So I'll talk very briefly about immune checkpoint inhibitors and I will couch this in saying that there was just a wonderful talk on immune checkpoint inhibitor complications. And if you weren't at that talk at 1.15 or 1.30, whenever it was, listen to Amanda Guidon's talk on the topic. So I'll just talk very briefly and I'm going to talk about these drugs in relation to patients who have existing MG rather than de novo development of MG. So immune checkpoint inhibitors are medications that activate our immune system, activate T cell function, and release the immune system to fight off very refractory cancers. They are of two types. So there are PD-1 and PD-L1 inhibitors. This is pembrolizumab, nivolumab, and ipilimumab. I can't say any of these words. And then there are CTLA-4 inhibitors, two different pathways. And it's important to know which of these medications the patients are on because it's going to matter which neurological complications the patients may develop. So I just wanted to highlight the types of cancer that these medications are treating because in these types of meetings, we're always talking about the complications of the drugs. But these drugs are so very effective for treating really refractory cancers. And you can see there's just a number of cancers that are treated, melanoma, lung cancers, breast cancers, gynecological cancers, glioblastoma, the hardest to treat malignancies. So it's really important that we try and keep our patients on therapy if we can. So the ones that we're most interested in in the neuromuscular community are the PD-1 and PD-L1 inhibitors. And that is because those are the ones that are most associated with dysfunction in the peripheral nervous system. So either myositis, myasthenia gravis, or neuropathies, radiculoneuropathies. So it can either occur with those medications in isolation or increasingly oncologists are using combination therapy of PD-1 and the CTLA-1 together. Our central nervous system colleagues are more worried about this class of medicines because those are the ones associated with autoimmune encephalitis. In general, when patients are exposed to one of these checkpoint inhibitors, the median time to developing MG symptoms is somewhere around 30 days. This can occur within days to weeks or can occur out as far as three, four months. And this study was looking specifically at patients with myasthenia gravis. And you can see that at about 30 days was sort of the mean in that study. This study was looking at all complications of immune checkpoint inhibitors. And if you just lump all neurological complications together, it was at a similar time frame. So we need to think about these. And we need to think about them for a long period of time after patients start on the checkpoint inhibitor therapies. Amanda's talk is great. There are algorithms and guidelines. But I'm just going to point out that in patients that are having a very severe exacerbation of myasthenia or a checkpoint inhibitor-induced exacerbation of myositis or myasthenia gravis, often if they're going to be hospitalized with things like respiratory failure or other severe complications, if patients are treated with steroids and IVIG or PLEX at first line, they're more likely to have a good outcome when their complications are severe. If they're having a more mild exacerbation of myasthenia or myositis or some other illness, you may be able to treat patients with low doses of steroids. And the patients will do very well. So I think it's important to understand. So what I'm going to talk about a little bit in the next couple of slides. So I'll also couch this by saying that when patients develop checkpoint-associated symptoms that look like myositis, as we're learning as a community, these patients may have involvement of other parts of the nervous system, particularly muscle. So we worry a lot about patients who develop concurrent myositis and symptoms that look like myasthenia gravis together. And the patients who develop myositis or develop cardiomyopathies can be very severely affected. And those are the ones that we really want to think about treating more aggressively. The other thing that I'll say is that in patients who are presenting with checkpoint-induced myasthenia, often they might be antibody negative. In some patients, we may be uncovering an antibody-positive patient. And this is just uncovering their illness. So what I want to think about, though, because we're talking about medications of caution. So I want to think in terms of patients who already have myasthenia, just for a couple of minutes. So in this series out of MGH with Amanda's group, these are patients that developed a checkpoint disorder and then were re-challenged. And you can see here that these are patients who did not get re-challenged with their checkpoint drug, and these are patients who did. And up to 80 percent, 40 percent can develop, 60 to 40 percent can develop recurrence of their autoimmune complication with re-challenge. It's much more common if patients get combination therapy. So a double hit, a double activation of the immune system is more likely to induce things to come back. An interesting group of patients are our patients who have myasthenia, who then develop a bad cancer and require one of these medications. So there's limited data right now. I know there's a lot of data being collected. So this is data out of MD Anderson. So these were 13 patients who had known antibody positive generalized MG and had had it for a mean of five years before developing the cancer. 70 percent of them were on immune system therapies, and when exposed to checkpoint inhibitor therapy, 85 percent had a disease flare. And you can see that very few of them were ocular only, and many were class 3, 4, and 5. I will couch this by saying that this is a report of 13 patients and that we need to learn a lot more, but I think it's really important to take home from this data that when we're activating the immune system in a patient with a known autoimmune disease, they may have an exacerbation. And I have an anecdotal patient, as I'm sure many of you do, who developed a melanoma in the last couple of years, and she had very well controlled generalized acetylcholine receptor positive MG and was on, I think, two and a half milligrams of prednisone every day and had no symptoms, no side effects. And she developed melanoma, got put on a PD-L1 inhibitor, and I saw her every month by telemedicine for two years through her checkpoint inhibitor therapy. And she did develop a mild exacerbation of her myasthenia with some return of ocular and bulbar symptoms, and it required us to increase her prednisone to 10 milligrams a day with resolution of her symptoms. So I think there are patients who have mild exacerbations as well. So I don't think everybody who has an exacerbation on a checkpoint drug is going to land in the hospital, but we have to learn a lot more about this cohort. So I think it's important to recognize that MG and myositis can occur together. It's the myositis that's often driving the more severe presentation in these patients. These can occur out to 16 weeks after exposure, and worsening of MG can happen often if our patients are re-challenged, so we should be thinking about closely monitoring them. So I think, just sort of in conclusion, it's important to empower our patients. Get that MyMG app for your patients so that they can show their doctors in the emergency room or their primary care doctors these lists of medications. But I think, in general, my thesis, thinking through this on a deeper dive in preparation for today's talk, is that, for the most part, if your patients need these medications, if you monitor them closely, we can treat them if absolutely needed. So I thank you for your attention. I'll turn it over to Dr. Kleder. I have to stay here. I don't want to answer his question for him later. Yeah, I apologize. I have to leave early. I think Dr. Lee is more than capable of answering questions on my behalf. Thank you for listening. Thank you. So for my portion of the talk, I'm going to be going through my stint in crisis diagnosis and management. I'd like to thank you, Bing Lee, for inviting me to be here. It's really an honor to share the stage with him and Mike Heyer, so it's really a privilege to be up here. I have no financial disclosures. Based on the number of pharmaceutical companies here, I think this is a good place to acquire some, so I might work on it. Here's kind of the general outline of what we're going to talk about. So in the first portion of the talk, I'll go through just kind of an introduction to the topic, the epidemiology of myasthenic crisis, what are some common triggers, and what patients tend to get myasthenic crises. I think kind of the heart of the talk, though, will be some important management decisions surrounding patients who have myasthenic crisis, so when to intubate, how to treat, extubation. And then towards the end, we'll be talking a little bit about things like outcomes and mortality. So first, I just want to define myasthenic crisis, so we're all really talking about the same patients. This is respiratory insufficiency caused by weakness due to MG. And really, the second piece of this is the need for either non-invasive ventilation, so like BiPAP, or mechanical ventilatory support. The other population that we define as crisis are patients who are undergoing a surgery and have a delay in their extubation beyond the expected time point by more than 24 hours. That would be considered a post-operative myasthenic crisis. So kind of very broad brushstrokes of the management of patients in crisis. So obviously, the most important points initially are surrounding respiratory and circulatory support. You want to be confirming a diagnosis of myasthenic crisis, be evaluating for other causes of respiratory insufficiency to make sure the patient truly has crisis and not some other reason to have respiratory failure. Kind of concurrently, you're going to be looking for different triggers for the crisis, trying to eliminate those triggers or treat them where you can. You're going to be deciding on immune modulatory therapy, and then while the patients are in the ICU and the hospital, you really want to be surveilling for and trying to prevent complications of this disease. So about 15 to 20 percent of patients with generalized MG will develop myasthenic crisis somewhere in the course of their disease. Usually that's within the first year or so. Now certainly we can see patients who develop crisis outside that time frame, but usually it's within the first year of their diagnosis. I think a really important point here is that 20 to 30 percent of patients in a lot of these different cohorts who presented with myasthenic crisis had no pre-existing MG diagnosis. So this is something that you absolutely have to have on your differential if you're called to evaluate a patient with unidentified respiratory failure in the neuro ICU or in the medical ICU, because you will sometimes pick up a new diagnosis of MG who's presenting with crisis. In terms of who gets crisis, it tends to affect middle-aged to older individuals. So the average age of patients with myasthenic crisis in a large U.S. claims-based study was just north of 56 years. And I think really when you think about crisis, it tends to affect patients with more severe disease. So in patients who had pre-existing MG, you can see MGFA classes in those who developed crisis kind of skewed more towards twos, threes, and fours, which is not terribly surprising. Patients who have musc MG are more likely to develop crisis. And patients with crisis really commonly harbor thymoma. So that's actually probably another really important risk factor. In terms of triggers for myasthenic crisis, they are varied. The most common and I think important one is infection. So infection probably causes a myasthenic crisis in anywhere from a third to half of patients. So it's really our job when we're initially evaluating these patients to do a good thorough look for infection, particularly pulmonary infections. Those tend to be the most common. But in a significant minority of patients, anywhere from 20 to 40 percent, we don't identify a specific precipitating trigger. And then I've listed some other categories up here, and probably the percentages in each of these categories is, you know, a few percent each. So we know that surgery is a common time where we can see a crisis. So here are some factors that are associated with the development of crisis after surgery. Now, keep in mind that a lot of this data is derived from patients who are undergoing thymectomy. So, you know, how much you could apply it to other surgical scenarios like cardiac surgery isn't clear. But I think there are some general, you know, broad brushstrokes to be gleaned from this data. So I kind of break these risk factors down into preoperative risk factors, intraoperative risk factors, and postoperative risk factors. You know, the big one preoperatively is just how severe is the MG. Patients who have low vital capacity, bulbar symptoms, abnormal rep stim. So more severe MG disease before the surgery, more likely to develop crisis after the surgery. In terms of intraoperative risk factors, it's really the extent of the surgery. So more invasive, more extensive surgeries, more likely to develop crisis afterwards. And then postoperative pneumonia is a really important predictor of development of crisis. Now, Dr. Lee kind of touched on this a little bit, so I'll go quickly through this. But, you know, because we know that crisis is more likely to happen after surgery, we can use either IVIG or plasma exchange to prevent it. Again, in patients with mild or well-controlled MG, you probably don't need to treat them. My preferred regimen is three rounds of plasma exchange and about a week or two prior to surgery. One important point here on timing, though, is you want to make sure that your last session of plasma exchange was at least 48 hours before the surgery to allow reaccumulation of coagulation factors. In terms of the pathophysiology, a lot of the basic science mechanisms of crisis really aren't that well studied or well understood. We know there are changes in antibody titers, there's shift in cytokines to more inflammatory milieus, there's complement activation. So probably all of these play a role. Again, I think Dr. Lee and Dr. Heyer were kind of mentioning this, but when patients experience exacerbations of their myasthenia gravis, they usually don't develop crisis immediately. This is something that evolves over days and sometimes even weeks, and this is important to remember because this really gives us a window to intervene and hopefully try to prevent patients from progressing to crisis. Really, the two cardinal features of crisis are oropharyngeal weakness and respiratory muscle weakness. Sometimes you can see respiratory muscle weakness without oropharyngeal weakness or vice versa. Typically, though, you see these both together. Initially, in the kind of course of respiratory failure, there's microatelectasis, and patients are able to compensate by increasing their respiratory rate. Paradoxically, early on in the course of respiratory failure, you may see a normal or slightly low CO2 level. As their respiratory muscles get weaker, though, their CO2 level will normalize. Again, I think an important point here is that an ABG with a normal CO2 in a patient who you think is progressing to crisis might not actually be a reassuring finding. It might be a sign that their respiratory failure is progressing. Then, as things get worse, CO2 starts to accumulate, you get hypercapnia, and then a very late finding is hypoxemia. So, in terms of some of the initial steps, when a patient presents to the hospital, the emergency department, you want to confirm the diagnosis of myasthenia crisis. You want to think about other potential causes of respiratory failure in these patients to make sure you're treating the right thing. You're going to be searching for an underlying infection. I think doing a good medication reconciliation, have they been exposed to any medications that could worsen their MG? Has there been a reduction in their immunotherapy recently as a potential trigger? I think doing some basic labs is a good idea, looking for electrolyte derangements, anemia, thyroid dysfunction, all of those could potentially worsen weakness. And then you're going to be admitting these patients, ideally to an ICU setting, and monitoring them closely for respiratory failure and intervening early, which we'll talk more about. So, again, I think some basic workup, chest x-ray, ABG, really needed to make sure that the respiratory failure is, in fact, due to MG and not some other cause. And those, though, who have a pre-existing MG diagnosis, this is pretty clear. There's often not too much diagnostic ambiguity. In the 20 to 30 percent of patients who don't have a known history of MG, though, I've listed some of the other differentials that you may want to consider. So in those who don't have a known MG history, in order to obtain a diagnosis, you may be thinking about sending serology, although those results are going to take days. You could think about doing electrodiagnostic studies. You know, slow rep stim has a reasonable sensitivity in the setting of crisis. But doing electrodiagnostic testing is challenging to get really high quality studies in admitted patients in an ICU who are intubated. So, really, if you have a high clinical suspicion, you really shouldn't be waiting for these tests to come back before you're initiating treatment. So, again, if there's no pre-existing MG diagnosis, oftentimes we're kind of making diagnoses clinically and starting treatment early. So just a couple of important signs that you really want to be looking for when you're evaluating patients who you think are progressing towards a myasthenic crisis. So neck flexion weakness can serve as a proxy for diaphragmatic weakness. If you're seeing patients who are demonstrating a paradoxical breathing pattern, those are patients who are almost always going to go on to need intubation. You want to be paying attention to their respiratory rate and heart rate. I think these are sometimes things as neurologists that we don't always keep an eye on. Again, if you're seeing tachycardia and tachypnea, that's probably a sign that the patient is trying to compensate for micro-atelectasis. And so that's a patient you're going to be more worried about. and then like Dr. Early talked about, the breath test is a really useful, I kind of think of it as a poor man's vital capacity. When to intubate should really be a clinical decision. I think serial assessments in this scenario are really important, right, because myasthenic patients are going to fluctuate, but if you're seeing a general trend towards worsening of their respiratory exam, worsening of their myasthenic weakness, you're obviously going to be really concerned. Pulmonary function tests, chest x-rays, ABGs all have a role here, but right, I don't think you can depend on any one of these specific assessment tools to decide when a patient needs to be intubated. I put up a couple helpful numbers in terms of pulmonary function test findings that should really trigger a strong consideration for intubation. Again the caveat here is a lot of patients who are experiencing crisis have a lot of facial weakness, so getting reliable numbers can sometimes be difficult. Again we talked about how a lot of changes on ABG are very late, and so if you're waiting for hypercapnia or hypoxia to develop on an ABG before you're intubating patients, you're probably waiting too long. So you really have to consider the clinical exam and use some of these ancillary tools and make a clinical decision. BiPAP has been studied in this setting as a tool to try to obviate the need for intubation, and I do think it has a role. The failure rate though is pretty sizable. So in small cohorts where this has been tried, up to almost 38% of patients fail BiPAP and eventually need to be intubated. In patients who have established hypercapnia or who have pneumonia or difficulty handling their secretions, BiPAP's not really going to alleviate hypercapnia. And if they're having secretions or they have pneumonia, that positive airway pressure is going to make handling those secretions even more difficult. So those may be some patients who might not be a great candidate for a BiPAP trial. But I think in select individuals, this is something that you could use potentially to stave off an intubation. Obviously if you're going to use BiPAP, it's still really important to monitor those patients closely. And if they seem to be getting worse despite BiPAP, you have to intubate. In terms of the next phases of care, let's say you've intubated these patients or you have them on BiPAP, they're in an ICU, you want to be monitoring them closely for complications. Cardiac complications are actually quite common in this population, so continuous cardiac monitoring is really important. Basically I think the next big decision that you have is on disease modifying therapy. And then as patients start to get better, we're going to have to decide when to extubate them. So we'll talk about these types of decisions next. So just a word on supportive care in the ICU. Our colleagues in the medical ICUs and neuroICUs do this day in and day out. So I won't really belabor the point. We kind of talked about why cardiac monitoring is so important. Patients with myasthenic crisis who are weak, who are in a bed all day long, are at high risk for developing DBTs, so it's important to have people on prophylaxis. Obviously treating infections and fevers very aggressively because those could worsen myasthenic weakness over time. And just a couple other points that I had listed up here. Lifeline disease modifying therapy typically is thought of as IVIG, 2 grams per kilogram, our standard dose over 2 to 5 days. Plasma exchange, anywhere from 3 to 5 sessions, depending on how the patient's doing clinically. And corticosteroids. In terms of plasma exchange, there was a small study that looked at doing lower doses of plasma exchange every day versus every other day and actually found that those two different regimens were equivalent, so something that you could consider. In terms of corticosteroids, many advocate for withholding steroids really early on until you either have some IVIG or one or two sessions of plasma exchange completed due to the potential risk of worsening weakness from those high-dose corticosteroids. But I think at some point it is reasonable to either initiate them, you know, anywhere from half to 1 milligram per kilogram, or if a patient's on steroids chronically for their MG, escalating that dose by, you know, 20% is reasonable. There have been a couple of studies that have looked specifically at the question of whether to use IVIG or plasma exchange for the treatment of myasthenic crisis. And I think that the general take-home points are that the use of plasma exchange seems to be associated with shorter ICU stays. There seems to be a more rapid improvement in myasthenia-specific metrics with plasma exchange compared to IVIG. And so for that reason, I really think that plasma exchange should be the preferred treatment over IVIG. It really leads to a fast and predictable recovery and might be associated with short ICU stays. Certainly in patients who have contraindications to plasma exchange or you don't have access to the people and ability to perform plasma exchange, IVIG is a very reasonable alternative. You can use these therapies sequentially, so IVIG after Plex or Plex after IVIG, not studied very extensively. And use of both therapies is not surprisingly associated with more prolonged hospital stays, probably because these patients are more sick and that are getting both of these sequentially. One I think lesser-known concept that I think is important is this idea of antibody rebound. So this has been described where patients, after finishing plasma exchange, have a rebound in their acetylcholine receptor antibody titers. So I think this really just demonstrates the need for ongoing immunosuppression, even after you've given patients IVIG or plasma exchange. So you want to make sure you're continuing to treat the disease. In patients who, say, don't respond to IVIG, plasma exchange, or both, there have been some cases that have described use of newer agents, including eculizumab and rituximab. I've not actually encountered any reports in the literature of people using FCRN antagonists in the setting of myasthenic crisis. Again, the data here is pretty slim, but they might be therapies that you would consider. At least in the cases that have been reported with eculizumab, it seems like there's an improvement in weakness seen within two weeks. And many patients are able to be extubated, or if they had a tracheostomy, they're able to be decannulated. Rituximab, I think, is an interesting one. If you're thinking about cost, it's obviously the clear winner on this page, and maybe has some longer-lasting effects than these other two agents, although its mechanism of action is slower. And there's really been kind of mixed results. There's been some positive case reports demonstrating that it's helpful. There have been other reports where there doesn't really seem to be as much of an effect. Just a word on acetylcholinesterase inhibitors. These historically had been used for the treatment of crisis, but I really strongly recommend against it because their use is associated with cardiac arrhythmias. And historically as well, it was advocated to initially stop patients' acetylcholinesterase inhibitors to try to differentiate cholinergic crisis from myasthenic crisis. In modern times, cholinergic crisis is exceptionally rare. Despite that, though, I think there is a rationale for stopping these medications early on in the course of myasthenic crisis. So the first thing is that a temporary discontinuation of the drug may actually augment response. So you may increase responsiveness to acetylcholinesterase inhibitors if you hold them for a period of time. I mean, I think the other important point here is that these drugs increase secretions. And in patients who are heading down the road to needing intubation or you have on BiPAP, that's really the last thing you want to do is increase secretions and really complicate the picture. So I think these should be held initially and could be restarted once a patient is preparing to be extubated. I think Mike did a great job of going through these. So I'll just list these here. There are some medications that you might want to use cautiously in the ICU. And again, I think this is a conversation that you have with the ICU provider. None of these are absolutely contraindicated. So if patients need them, they need them. But just some different classes of medication and some specific agents that you might encounter more commonly in an ICU setting that you might want to be cautious about using. So you've admitted patients. You've gotten them through the worst of their crisis. You've treated them with disease-modifying therapies. They're starting to get better. The next decision that you have to make is on extubation. So patients you want to think about extubating are those where if there's been a specific trigger, you've removed it. You've treated them successfully with some disease-modifying therapy. Their weakness and neurologic exam is improving. And the patients are awake and able to participate in a wean trial. Typically we do wean trials first thing in the morning. The amount of ventilatory support that a patient's getting is slowly weaned. And they're monitored for any evidence of respiratory failure. And that could be in the form of increased work of breathing, tachypnea. Sometimes all you see is agitation. And if the patient develops any of these, the weaning trial's over and you could potentially attempt another weaning trial in subsequent days. In patients, though, who pass wean trials, those are the ones who you're going to want to extubate. This kind of leads to my next point, extubation failure. Not uncommon in myasthenic crises. So again, in cohort studies, about 20% of patients with myasthenic crisis will be extubated and need to be re-intubated. And I don't necessarily think that this is a failure of our care. I think this really demonstrates that we're trying to be aggressive about liberating patients from mechanical ventilation. And we're going to have to fail some of the time. Otherwise, we're going to be keeping these patients intubated for too long. One important point I wanted to make is in some studies that looked at extubation failure in myasthenic crisis, almost all of the patients who failed extubation had atelectasis. So this is, I think, I'm going to put in a plug for really good chest physiotherapy. And probably a good idea to do a chest X-ray in the day or two before you're trying to extubate patients to evaluate for atelectasis and treat it before you're going to extubate them. In patients who are needing intubation for more than two weeks, you're going to unfortunately have to think about a tracheostomy. In terms of complications that are associated with myasthenic crisis, so really if you look at patients with myasthenia admitted for crisis versus MG patients admitted for another diagnosis, those with crisis are more likely to develop DVTs. They're more likely to also have cardiac complications as well. And there are a few complications that are independently associated with prolonged hospital stays. So C. diff infection, heart failure, and anemia. One other potential complication that I want to point out is steroid myopathy. Many of these patients are being treated on high-dose steroids. And proximal weakness from a steroid myopathy is going to be really difficult to differentiate clinically from weakness from their MG. Prognosis is actually quite good. These patients do generally stay in the hospital for days to weeks, but we're able to extubate 75% of patients by one month. Importantly, the duration of intubation predicts their functional outcome. So in patients who need to be intubated for more than two weeks, 70% of them had some functional dependence at discharge. I think an important point that we need to be discussing with patients is that the presence of myasthenic crisis doesn't really seem to really determine long-term prognosis. So I think some patients have the perception that if they have a crisis, they are doomed to have severe and refractory MG for the rest of their life, but that's really not the case. 50% of patients who experience myasthenic crisis are able to go on to achieve minimal manifestation status. So even patients who have crisis, they still have very treatable disease. Mortality has improved significantly over the last century. This is a product of improvement in our immune modulatory treatments and ICU care. In a large U.S. claims-based study, the mortality was 4.5%, kind of variable in other parts of the world. And really the mortality is driven by two things. One of them is age. So in the same cohort study, there was not a single patient under the age of 40 who died from myasthenic crisis. So age is a really important predictor of mortality. And then really the other predictor is just the medical frailty of the patient. So the more medical complications or comorbidities that the patients have, the more likely they are to succumb to this condition. After a patient is discharged from the hospital, again, we kind of briefly touched on the importance of ongoing treatment with immune modulatory or immunosuppressive medications. So they're going to need timely neurology or neuromuscular follow-up to continue this treatment. In patients who needed a tracheostomy, they need continuing care and a decision needs to be made when it's time to decannulate them. Obviously employing the help of your rehabilitation colleagues for these patients are critical. Many of them are deconditioned. They have persistent weakness that can be rehabilitated. And then just one other thing that I'll briefly mention that I don't think really is recognized as much or certainly I think I need to do better about discussing with patients is psychological support after myasthenic crisis. So this was a study that looked at psychocognitive burdens in patients admitted to an ICU. And this was not MG patients specifically. This was across many different ICUs. And importantly in this study, the average length of stay was 4.2 days. The average length of intubation for myasthenic crisis is six days. So myasthenic crisis patients are much sicker than this cohort. But you can see the rates of cognitive impairment, anxiety, depression, PTSD, not only on discharge from the ICU, but also three months later. So I suspect if we were to study some of these metrics specifically in patients with myasthenic crisis, I think that we would see equivalent or potentially even higher numbers. So I think this is important to recognize. I think it's important to ask patients about, to talk to them about it, and to offer referrals and treatment when these issues arise. And the other thing is this is not a disease that just affects the patient. It affects the family members as well. There can often be loss of employment, financial hardships. And again, rates of depression, anxiety, and PTSD are also extremely high in family members of ICU survivors. So I think talking to patients and families about these issues really is an important quality of life issue. Okay. So I think that's all I have. And I know we'd be happy to take questions. Thanks. We do have time for a few questions, Dr. Bloomberg. You can yield. Loudly. This relates to myasthenon. So you didn't spend much time on the last slide, Dr. Lee, and something intrigued me. So when I read it very quickly, you said that late in the course of the disease, it may be less effective. And that's my impression. So one, is the mechanism because myasthenia gravis may be better controlled, so there's less neuromuscular junction function to improve, or is it less effective later on? And then Dr. Clayton talked about myasthenon or pritostigmine holiday. So if you could talk a little bit about the long-term use of the drug. Thanks. I ran out of time. I was watching time here. I did not have time for the last three slides. The myasthenon, the pritostigmine, it's a medicine that changes, modifies its target enzyme. It actually makes its target enzyme more efficient. The longer you use, the ACE becomes more efficient and will hydrolyze, so there will be less acetylcholine molecule available. So the longer you use, the less effective it is. Prantison does the same thing. So it's an alternative splicing form of ACE. One is more efficient and it hydrolyzes acetylcholine, the other is less. And they use myasthenon and limit its efficacy by itself. It's auto-induction, basically, and that's what happened. So you would argue that if you give a patient some drug holidays and then restart it, it might be more effective. I had a question for Dr. Lee, and that's something that I've wondered a lot about and don't know if there's really a right answer is the development of hypogammaglobulinemia after a tuximab treatment. I think this is really applicable to a lot of our musk patients who end up on CD20 depleting agents. Should we be looking for hypogammaglobulinemia and treating it? Should we really only be concerned about this in patients who seem to have recurrent infections? Do we really even know what the right thing to do is? Good question. Actually, it's just going into this case of my patient. The other immunologist basically showed me three things. Number one is all the patient's Ig level remain low and very low and don't change. Number two, the patient had coexisting lymphopenia. Number three, the patient had recurrent infections. So her argument is we should have given the patient mostly IVIG, but at a very small dose, like 0.4 gram per kilogram per day. If you look through the literature in the MS field and the other field, there are people talking about if the patient has recurrent infections in the setting of regular dosage of the tuximab, you should consider immunotherapy such as IVIG. I actually don't know if that same scenario will apply to the repeated usage of, or frequent usage of SCRN in the future. I think that's something we will have to watch. Hey, Gil. Just a simple, real practical question on extubation trials and so forth. Do you ever have hesitancy, maybe you have great staffing at Cleveland Clinic, but Fridays and Saturdays, do you ever have hesitancy in extubating patients on those two days? I think that's a good question, but I think that's why it's really important to do these first thing in the morning. So you want to be doing the trial first thing in the morning when there's lots of staff here. You don't want to try to extubate patients in the middle of the day or the end of the day, because when they get in trouble, no one's going to be there. So where we are, I don't typically worry about weekend extubations, but I do think it's important to prioritize and try to move extubation as early on in the day as possible so you can have as many eyes on the patient throughout the day, because that's really when they're going to worsen. I'm going to answer for Dr. Collator. I can tell you, when I see the patients, in the ICU, MG patient, before their extubation, I often examine the neck flexor strength. If the neck flexor is strong, I'll let the ICU doctor do whatever they want to do. Yeah. How strong? Do you want them at a five? I mean, they're usually not at a five at that point. Probably at least a four. Thank you very much.

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