Update on Pediatric NMJ Disorders-Session recording

Session recording

Video Transcription

Good morning. Thank you for rising up with the sunshine. We're going to be talking about updates in pediatric neuromuscular junction disorders. My beginning of the talk would  be on the genetics and the title is Pediatric Neuromuscular Junction Disorders and Evaluation Genetically Diverse and Missed Diagnoses. I hope this will help you to understand how  to better inform your patients as well and how to better diagnose these disorders. So I do not have anything relevant to the topic of this to disclose. We'll be going over  some cases and their key clinical findings to help you recognize these syndromes and some basic diagnostic testing, although my colleague, Dr. Sumit Verma, will be more direct  in that. And one of the things I wanted to focus on is genetic testing interpretation, some of the pitfalls that we face and how to get through those. So case number one is  a five day old little boy who was born full term and everything was normal during the pregnancy, came out okay, but then started having respiratory failure. And as all babies  do they have an elevated CK. He had also some other features that were unusual. He had some absent cranial nerve reflexes. You can see a photo of him here up in the upper corner.  You'll notice his eyelids are on the droopy side. And he had some multiple joint contractures.  We call those arthrogryposis. Otherwise brain MRI and MRS were normal. And at this time this was in the pre-SMA screening days, but we got a cytogenetic microarray as well as  the spinal musculatrophy gene testing. Both of those were negative. So the next step, this was at an age where we were testing out at our institution rapid exome testing.  And this was very crucial to the diagnosis of this little boy. We saw him at day of life five and by day of life 11 it resulted in two vooses. We call them variants of uncertain  significance. These are the bane of the genetic counselor's existence. But we as neurologists  should be able to help figure these out. And he had one in the choline O acetyl transferase gene. I'm going to call that the CHAT gene from here on. And that's a crucial gene for  making acetylcholine, which we'll go into a little bit more. This is what the report said. The C.406G to A changes the position of valine to a methionine and the cytogene  at 1,663 position changing a guanine to an adenine. And then you have that changing a glutamate to a lysine. So you might think back on your biochemistry days, wow, valine,  methionine, they're both hydrophobic. This is what they look like, an upside down V changing  to methionine, more like a zigzag with a sulfur. And you're thinking, hmm, the second mutation is a glutamate, positive charge to a lysine. How many of you do this? Well, I actually  like to go back and look at the biochemistry because I want to understand the mutation. And that's actually a little bit nerdy, but very crucial in understanding. So I also look  up where is this gene? It's on the 10th chromosome. Sometimes this actually helps you because  contiguous mutations can happen. But I do look these things up. And some of it's a little bit nerdy. But this is very important. It's a presynaptic gene. And you can check it to  see if this is causing a problem in the child by doing repetitive nerve stimulation. And  you might do what we call a neostigmine trial. So here is the mutation, this area right here.  And if this is your neuron at the end in the presynaptic area, choline acetyltransferase helps your acyl-CoA change into acetylcholine. So your main neuromuscular transmitter for  muscle movement. Here we are with our little boy. And we're doing repetitive nerve stimulation  at the ADM. And these are the doses I use for premedicating the child because, as you  know, neostigmine can cause drooling and bradycardia. And he's already having a trach here in place  because he's already respiratory dependent, ventilator dependent. So those are the doses.  And with neostigmine, you can see pre-neostigmine, the ptosis, droopy eyes. And after, he's like,  whoa, what happened to me? I'm wide awake. The eyes are open. They stay that way. Neostigmine,  the nice thing about it, we used to use the tensilon test in clinic. But you can actually go into respiratory arrest and have bradycardia. So it's actually easier to use neostigmine  because all of us know mestinon lasts four to six hours. But neostigmine just lasts a perfect one hour. So if you're doing a child and you want to see if their ptosis resolves,  you can check that and you premedicate with the atropine. So in summary, we used RapidExome. This child was one of a series that tried to show that RapidExome was actually very  helpful and ended up getting published. But one thing I want to caution you with, all these children or babies that have ventilator dependency also may need to have myelotonic  dystrophy gene testing separately because whole exome sequencing does not pick up these two things, repeat expansions like Friedrich ataxia, and it does not pick up, depending  on the gene level of depth, less than three exons duplication or deletions. So if you  have an autosomal recessive disorder and a point mutation on one and a duplication that's just two exons duplicated, you may miss your diagnosis. So a panel might be able to pick  that up, and some gene panels include duplications and deletions and some do not. Prevention  Genetics is one commercial lab that used to have separate ones for duplication and deletion gene panel and one for sequencing because they're differently done. So you might also  need to confirm with nerve conduction and EMG testing for all of your voices. You're going to get a whole bunch of variance events or significance in this age because not all  of these cases are reported. So you'll need to do your nerve conductions and EMG, and then you can consider a neostigmine trial. I would do this in the ICU setting for confirmation  in many of the congenital myasthenic syndromes. This rapid diagnosis allowed for more specific medication which helped this little boy, and we used liquid albuterol. Now going on to  the next case, we have a six-year-old boy who presented to Child Neurology for a very common thing we see, which is delayed motor milestones. He walked by 18 months of age,  and he was not able to alternate steps. That's when you take alternating step on a stair until about four years of age. Most kids do that by two. He had some difficulty running.  There was no speech delay, and after a block of walking, he would have some groin pain. His poor grandmother would have to pick him up. He would fall and trip frequently, never  complain of dizziness or loss of consciousness. He rides a trainer bike, likes swimming. He's a normal kid, in other words. His right eye has kind of been droopy since four to five  months old, and it's just always been that way. Otherwise, normal birth, just a little cesarean, normal pregnancy, and CKs were normal. There were other family members who had a  droopy eye, so they didn't make a big, I mean a lazy eye, they didn't make a big deal of the eye. The problem is he's a first grade in regular classes. So, okay, so my first  thing was I recommended, actually we checked him out, and he had the right ptosis. He has a little bit of shoulder weakness, and we had him do 20 squats. I usually do a special  test, and we'll go over this a little bit more, of fatigable, checking them for fatigue and weakness, and one of those is I had them do squats with me. It's a fun game, and I'm  trying to race them. It keeps me fit, and we checked to see if he can jump, and he had poor leg lift when running. So, my initial recommendations, let's get a nerve conduction  with EMG in the right lower extremity, in the arm, and maybe the face, and I'm explaining that we might have to put little stickers on his face, give him a little gentle shock  to see if it has, you know, a normal mountain peak, and we'll hold off on the MRI because he can't hold still for a half hour. He would require general anesthesia. We don't need  to do that, or we would get a limited MRI, but I think that's lower on the list, dot, dot, dot. Well, they did not follow up after those recommendations. I was very kind and  gentle and wise, I thought, but no, no, they didn't follow up until he was 10 years old. So, at that point, he cannot run, but he's not really fine. He just stumbles when he  runs, and he struggles to pick things up, and this has been noted since three to four years old. He's still got the right droopy eyelid. Physical exam hasn't really changed.  He still has a four out of five deltoid strength, biceps, iliopsoas strength, so mostly in the  proximal muscles, normal reflexes, and the right droopy eyelid. So, this time, I decided,  okay, we're going to check your blood. Just get a poke and get a CK again, check the neuromuscular  gene panel, and at that time, it was a free sponsored gene panel, and it was very helpful, and it was potentially positive. However, there were six vooses. So, this is not my  record breaker. I've had more than 10 before, so you may have to wade through this. This is very, very common for us in child neurology, and I'm sure you're starting to find it  in the adult world as you're trying to do genetic testing. So, how do you wade through this? This is what I'm going to kind of go through. I don't want you to look at all  the details in the test report, but as an example, all the disorders listed are autosomal  recessive, so that's really crucial to understand, because that means you need two hits, and the only gene here that had two hits here is our DOC7 mutation. Okay, so we have two  hits there. So, that's one thing. Are they damaging? That's the next question you want to ask. So, DOC7, this one is actually pathogenic, so that means it's a hit. It's a positive,  and it causes a premature translational stop codon. That means you don't get the whole protein, okay, made, and that means you're, that's not going to get a good DOC7 protein.  The second one disrupts the splice site, so that hints at the fact that it's going to not make a full protein product. So, you have to read the fine line and understand  the biochemical sort of makeup, and some of these companies have good prediction models,  and some of them don't. They all use individual, there are public gene pools that you can look  at normative data, and then there are private ones within each institution, so you have to be very careful with using these. But the next question is, the rest of the ruses,  are they damaging or not? Because you might have an intronic problem, and so you have to be careful. You can't throw out everything, but are the rest of the ruses normal or not?  The rest of them were non-damaging, or they had insufficient data, so we can throw them out. So, what are the next steps? If it's an autosomal recessive disorder, that means  you have to have two mutations, and they have to come from opposite alleles. So, then you have to ask, are they in cis or trans? And you're like, what the heck is cis or  trans? Well, the way you can test this is to check and see who's affected in the family, and usually it's important to also test the family, the parents. So, if you have both  biological parents, that's really key. I often ask if both parents are available for testing  before I start genetic testing, because sometimes you have foster children, and you're going to have these ruses you're going to have to figure out, and you can't. You don't have  access to the parents. So, test both the parents to see if each parent carries one of the variants.  This can be tricky, so I often have a genetic counselor help, because you can't order parental  testing unless it's somewhat covered through the testing company, for instance. So, that  can be very tricky. So, you need your geneticists on board with you to help figure out. We call this variant resolution testing, okay? So, you're doing now variant segregation, and  you're testing to see if it's coming from mom or dad or both sides, and so if both copies are seen in one parent, then they are carried in cis, and that means the mutation is a one  hit. It really counts as one hit. So, we went and tested the parent, both of them, and testing for the Doc7 variants was performed  in the submitted family samples, and based on these results, these variants are likely on opposite chromosomes. So that's a hit in my book. That means it's potentially positive.  And we then go to nerve conductions. Always check the motor and the sensory nerves first before I do RepStim. And you can see when we did the owner nerve here at the ADM,  that was normal looking, and then we went to the accessory spinal where he's truly weak, and you can see there's a true decrement. He had, in fact, a 41% maximal decrement  at the three-minute mark after repetitive nerve stimulation. So right after EMG, on that day, I started him on a medication because I knew he had a Doc7 mutation.  So I hope this helps you to know what to do. So I started him on that medication, and now he can play basketball, and he can lift the ball  over his head and throw it, which he could not do before. And the right ptosis is still stable. He's had that since four months old.  And then I moved up the dose to TID, and now he plays sports. He doesn't have to hold on the railing on climbing stairs. He doesn't waddle with running.  And the exam showed some modest improvement. He's still a little bit weak, but this kid had been at a four out of five all his life, and now he's got some really good resistance.  And he can do the 20 squats without buckling. So Doc7, just a quick brief run-by on that one. It binds to muscle-specific kinase, which is a tyrosine kinase receptor.  And that releases phosphorylates rapsin. So I think of it as like you want all your acetylcholone receptors to come together as a bouquet of flowers.  So it makes it so you have neuromuscular transmission that's much more efficient, because you have an acetylcholone receptor, and it's got a group of receptors it can bind  to very fast instead of having to find it along the, the postsynaptic junction. Usually, children present, start having symptoms at one and a half to four years old.  Sometimes, they can have respiratory problems at birth. And it's usually a limb girdle muscular weakness pattern. They do not respond as well to mestinon, but they do respond  to a beta-2 adrenergic agonist like oral albuterol. I don't know if you know that albuterol, this is a medication that we use as an inhaler mostly, but this is liquid.  And you give it BID to TID. So there are models that showed transfected cDNA with Doc7 mutations looking for acetylcholone receptor clustering on mild tube surfaces.  And when you see you have a Doc7 knockout, it affects the structure of that synaptic surface. So patients, you have to remember, they gradually respond to albuterol.  And the time to raise arms and legs improves. The early treatment, the better off they are. And you can see improvement, but it usually takes on the order of months.  Okay. So it's not something you're going to see in clinic that they're going to improve right away like your neostigmine trial. So most genetic test results will be variants  of uncertain significance. And I want you to be aware of using pyridostigmine. Some congenital myasthenic syndromes are worse with pyridostigmine.  For instance, COL-Q, you can get respiratory arrest. So I usually get the genetic testing before I try. Some people might want to try, but be very cautious.  And it's less effective for slow channel congenital myasthenic syndrome and Doc7 congenital myasthenic syndrome. So this is just a reminder.  Check for cis or trans in parental testing. Check your EMG rep stim. Do a medication trial. And think about liquid albuterol. The FDA prohibited use of ephedrine in the U.S.  So we use liquid albuterol here. And it stabilizes neuromuscular junction, reduces acetylcholine receptor dispersion, which is kind of like the bouquet flower result.  And then you see the effect in months. So watch out. You can get a little hypokalemia at high doses. So an EKG and that may be needed.  So now we're going to go on to a little bit of the epidemiology and pathophysiology, a summary of some of the things we see in children.  But also in adults, you'll see ptosis, muscle weakness, hypotonia, neonatal death of a sibling, such as sudden infant death syndrome,  bulbar weakness, ophthalmoplegia, arthrogryposis. And one thing that sometimes gets confused with epilepsy is episodic apnea. So testing fatigable weakness.  This is one of the things I do is a one-minute sustained upward gaze, followed by a one-minute sustained eye closure that's very tight. And I make it a game with the kids.  So I have my arms out, I have a little toy I'm holding up with them, and I'm testing them for fatigable weakness with shoulder abduction at 90 degrees, or might be  like chicken wings here. And I'm pushing on their shoulders while I have them look at my toy, they're allowed to blink. We do the operations for a minute while I hold the arms.  I have them hold their arms for three minutes. And they eventually kind of feel, you know, lower them down. You're looking for the time to lowering.  And you can follow that over time to see if they improve on medication. The last thing I do for lower extremity is I do squats. Depending on the age of the child,  some of them cannot do 10 squats. And you're trying to see at subsequent clinical appointments whether they improve in their proximal muscle weakness.  So you're doing squats with them. This is where I say you're going all the way down and back up and just make sure your pants are loose. You don't tear any.  I've had that happen before.  So some of the families were described as early as the 1930s. This disease was described before acquired myasthenia and gravis in 1970s and labyrinth myasthenia by 1980.  So the congenital myasthenic syndrome presentations are varied. And even within the same family, you can have some starting off  with ventilator dependence, stridor intermittent apnea with stress, a sibling with sudden infant death syndrome and arthrocryposis like our first child case.  And then developmental delay may be the only presenting symptom. Think about these following mutations with HIE or SIDS due to repeat apneic attacks, so CHAT, COL-Q and STN4A.  So this is somewhat debatable. I was looking for what's the prevalence in the United States? We really don't know. The incidence may be 1 in 100,000 per angle in the UK.  They have a rough estimate of 3 to 15 per million or average of 9 patients per million. So their congenital myasthenic syndrome population  outnumbers their autoimmune juvenile myasthenia gravis. And Brazil may be 1 and a half patients per million. So this is likely underestimated due to undiagnosed CMS patients now.  I am not going to go into the in-depth of all the pathophysiology because now there are more than 35 genes described as causing congenital myasthenia syndrome.  So this paper in 2023 divided into 14 subcategories. It's an excellent paper. You might read it in sections because you might fall asleep. It's really hard to keep this in head.  But I try to learn a little bit every time when I see a new patient with these mutations. And I draw a picture of a nose. So here's the nose. I draw a little acetylcholine vesicle.  And then I draw lips or mouth here. And I explain to the families when I have this mutation what their disease is. And in our first child, I did a more simplistic one  for the DOCK7, how it holds all the receptors together like a bouquet, okay? And we have our CHAT mutation up ahead here. So these are simple things you can actually illustrate  for family. You don't want to memorize all the different genes involved. But I try to categorize them into presynaptic, synaptic, and postsynaptic.  I think this helps us to understand how to treat and how to explain these to families. The other things are just understanding the, what are the most common mutations?  And the most common is the acetylcholine receptor. That makes it easy. The acetylcholine receptor is made up of a pentamer, five subunits, two of which are alpha, beta, delta.  And then there's a gamma epsilon subunit, which in your fetal form, you depend on your gamma. And then as you get a little older as a child, it switches over to the epsilon subunit.  And so that's why you might see an epsilon receptor, I mean, acetylcholine receptor epsilon defect at childhood onset because they have fetal form that's being used early on.  The next most common mutations are the ones that I've shown you wraps in here. DOC7, the child that didn't want to do the nerve conduction at first, and then slow channel.  Those are the next most common. And then fast channel, CoQ, CHAT, presynaptic are less common. So these worsen with periodostigmine,  slow channel syndrome, because you have excess prolonged bursts of the acetylcholine receptor. These are all acetylcholine receptor mutations.  And so if you have more acetylcholine around, it's just going to make them worse. So you use fluoxetine. CoQ is like the anchor for uptake of acetylcholine esterase.  OK, so it leads to reduced acetylcholine breakdown. So you have more acetylcholine around. So why make it more available? That's going to worsen your symptoms.  So here you're going to use albuterol. And then DOC7, there's no effect or worsens weakness. Just use albuterol. OK, so why learn about congenital myasthenia gravis?  I think this is a wonderful topic to understand. But they're rare. And they're treatable disorders. And they're often misdiagnosed. This paper came out in 2018 from the Mayo Clinic.  And they looked back at the patients that were misdiagnosed with myasthenia gravis and found 34 of them misdiagnosed over a period of 16 years. And of those, here are the mutations  that they found associated with them. One thing that really caught me was that 13 of them just had mild ophthalmoparesis. So they're floating in your clinics.  And 19 with predominantly limb girdle weakness. So the median time to diagnosis for many of them was 26 years. That's sad when you think about a treatable disorder.  That's three decades. In children, I mean, they also, the other thing is the CK can be elevated up to four times the upper limit of normal.  And abnormal REP stim can be seen in the majority of them. But 32 were misdiagnosed. So that's a great paper to understand and read about. 94% were misdiagnoses.  And of those, who were they? 16 of them were seronegative myasthenics. 15 were diagnosed with myopathy. 8, weakness of undetermined cause. Some others.  And of those that were diagnosed with myasthenia gravis, you wouldn't believe, they had a thymectomy and immunotherapy. Of course, it didn't work.  And then 14 of the 25 receiving peritostigmine did not improve or worsen. So the two leading misdiagnoses were seronegative myasthenia  and myopathy, leading to unnecessary immunotherapy, thymectomy, even muscle biopsy. So it's not that much better than pediatric population.  We have about 80% misdiagnosis with a delay of about four years. So key findings, again, to wrap up on this is the symptom onset early in childhood  might key you off on a congenital myasthenic syndrome. You might want to consider gene testing, all those seronegative myasthenics. Doesn't mean you have to do it, just consider it.  And then if they have more than one family member similarly affected, think about genetic screening. And fatigable weakness, limb girdle weakness with normal extracular movements.  Don't have to have ptosis. And one key feature that my colleagues will tell you about is a little extra C-MAP bump after the initial one. That keys you on.  It's a signature feature for end plate cholinesterase deficiency or slow channel congenital myasthenic syndrome. But you don't see it in myasthenia gravis.  And a medication trial can be cautiously done when you have a seronegative myasthenic. You might see some improvement with fluoxetine,  which is the geriatric of Prozac, OK, and Dox7. Think about that. Slow channel, Col-Q, when they fail or worsen with cholinergic meds.  And then you have to think about acetylcholine receptor serology positive myasthenia do improve with cholinergic meds, but not muscle-specific kinase positive.  So take-home messages, think about gene screening on seronegative myasthenics, especially with childhood symptom onset, a positive family history,  repetitive C-MAP, or worsening lack of benefit with periodostigmine. Genetic testing interpretation is like solving puzzles. Autosomal dominant versus autosomal recessive.  Think about cis or trans, heterozygosity. And then variant resolution testing may be needed in family members. Verify with repetitive nerve stimulation,  and do a cautious medication trial that might take months. So I hope you understand. Do you have any questions? Well, maybe we'll do questions at the end. Thank you.  We'll hold questions for the end.  Good morning, everyone. I'd like to thank the A&EM and my colleagues for inviting us to the presentation. I'm going to present on the neurophysiological testing  of children with neuromuscular junction disorders.  I have no financial disclosures. The learning objective of my talk would be to talk about stimulated jitter analysis using a concentric needle electrode.  We've seen a few examples of repetitive nerve stimulation, how to clinically apply these techniques to your patients, what are the available normative data and specificity  and sensitivity of these tests when you perform them, and I think more importantly, how to be a successful pediatric electromyographer in the lab  because many of these cases are very challenging. Let's talk about this technique called stimulated jitter analysis. We have been using single fiber EMGs in the past,  but with the advent of concentric needle electrodes which are disposable, the technique using concentric needle electrode is a little different, and that's  what I'm going to highlight on. So the action potentials you generate when you use the concentric needle electrode in a small territory which you're trying to examine  is called apparent single fiber action potentials. The variation in time between the pairs, which we will be noticing in the next coming slides, between these action potentials  is defined as jitter or mean consecutive difference. A lot of this work comes from Dr. Sanders at Duke and his colleagues at Stahlberg, and quite a bit  has been started to be adapted in pediatric age group, and some of the labs in the country are doing this. So this is a cartoon showing how the nerve impulse comes  to the muscle, and then we, as electromyographers, record those single action potentials, and we look for whether there is a variation in time,  or there is an absence of that response called blocking. This particular technique which we use is stimulated jitter analysis, is we use a monoportal needle to stimulate  the branch of a facial nerve. In this particular case, if you're doing the orbicularis oculi muscle, or you're doing the frontalis, so in the first, there is a stimulation  which is going through the stimulating electrode to the nerve and going into the muscle, and then you're using another electrode, which is your concentric needle, into that muscle,  and that's where you record potentials. As you notice that in this particular slide, when you do the stimulation, you record multiple potentials  in one go, versus in the voluntary single fiber EMG, where you have to use a trigger to record from the two potentials, and then you look for the variation or jitter.  So this technique has the advantage that you can record, in one setting, multiple potentials. So the time to do this particular study is much shorter.  So in like our lab, we will use about 10 to 15 minutes to finish up, versus if you've observed or you've done yourself voluntary single fiber EMGs,  you will notice that patients would take at least up to 30 to 40 minutes, sometimes even longer, depending on how they can cooperate raising their eyebrow and forehead.  So it's much shorter, and as you can imagine in children, this is very useful because they don't have much patience, and they will start, and a lot of the work we do  is without sedation, so we end up having a shorter time window to our advantage.  This technique is usually popularized by Dr. Matthew Pitt at Great Ormond Street in London, and since through the, several workshops over the year  has now been used by many pediatric labs, and I was one of the fortunate ones to learn from him and adapted it in our lab, and have been using it for last 10 years.  So what are the prerequisites? What do you need to successfully do this? Obviously, you need the simple disposable 25 millimeter concentric needle electrode,  which is the red needle, which we all know, or the facial needle. You use a monopolar needle, which is a small little, like a 10 inch kind of electrode length,  and the small little tip, which is about 1 1⁄2 inches. These are commonly used in your IOM monitoring lab, so if you ask your EMG tech, or EEG tech,  or even IOM tech, they'll give you the monopolar needle. Obviously, simple disc electrodes, which are disposable, like surface electrodes, ground electrodes,  and then in your setting, depending on what machine you use, if you use the Natus, Cadwell, or you use a different Nihon Kodan, you may wanna have them put in a software  called the stimulated jitter analysis software, or a stimulated single fiber. Most of these machines come with single fiber EMG software,  but the stimulated single fiber can be added at a very minimal cost to you or your institution. These settings can be pretty similar.  You're trying to record from a very limited area, so your high pass filter, or the low frequency filter, has to be jacked up a little bit, up to one kilohertz,  so that you can record from a smaller area, instead of a large area. The current settings, which we use, is two to three milliamperes,  and then the pulse duration is .2 milliseconds, and the frequency is 10 hertz.  This is a picture of one of our patients. She's a myasthenic, who's not sedated. She's lying comfortably. When they come into the lab, I try to explain to them what we're gonna do.  For first five to six years, I used to use a lot of amyla cream, but now, more recently, we're using a cold spray. We cover the eye, we use a little cold spray,  and we tell them we're gonna put a little pressure above their zygomatic bone. We use a little fingertip and give a little pressure,  and then just gently slide in the monopolar electrode.  If I'm gonna go to the pointer, and you see this black electrode right there, that's where the monopolar goes. That's the zygomatic, just above the zygomatic arch. It's easy to do.  One may think it might be very painful, but that area really is very easy to access, also.  Most kids, even if they're very chunky or if they're very thin, you can easily feel the zygomatic bone, so you have a good milestone, or you have a good spot to go in.  Once you're in, you want to turn the frequency to about three hertz and start the stimulation, because you wanna see if the eyelid is really twitching.  If your eyelid starts to twitch, or the orbicularis oculi, you're in the right spot. Otherwise, you'll have to move the electrode a little bit, and that could be a little painful,  so you have to be careful in the first point that you're in the right spot. Once you're in the right spot, then you use the second electrode,  which is the concentric needle electrode, which is the facial needle, and you go gently above the edge of the eye. What I do is usually keep my finger  at the outer canthus of the eye, and then go above from the top, so that way I have a little, so to speak, a protection that I'm not going into the eyeball or so forth.  If you're not comfortable doing the orbicularis oculi, you can even slide it slightly up on the frontalis muscle. By doing this, you would be able to complete the montage,  and then you can change the frequency to 10 hertz and start the process. Once you start the stimulation, you would notice on the right hand of your,  there is a stem artifact, which is marked by T, and then on the subsequent, there are lots of multiple potentials which are firing,  which are called apparent single fiber action potentials. This particular one is a raster mode. You can, most of the machines will give you a combined,  so you will see all of them lining up on top of each other, but it's good to do the raster mode, so then you can look carefully that each one is lining up properly or not,  or there is a jitter or a jiggle going on, or in some cases, there may not follow through, then that's called blocking. So this technique also engages the patient to,  in this particular case, the patient doesn't have to do any activation. You are doing the stimulation for them, and you're recording the thing. Once you're done with the first one,  then you do have to move the concentric electrode slightly into a different corridor, so you're recording from a different area, so that way, you're not recording  the same kind of potentials at every apparent single fiber potential. You wanna be in different parts of the process, and interestingly, if you notice,  several potentials are being recorded in this, and you can utilize all of them throughout if they have a nice rise time, which seems to be in the case here,  so in one particular thing, you can record in this like seven or eight, and most of us who do this quite often  would tell you that 20 to 30 potential, apparent single fiber action potentials is more than enough to give you an idea if this is going to be an abnormal or a normal study,  so really a wonderful way to screen patients with neuromuscular disorders. This is a child with normal-looking traces, so if you see, the cursors placed on the top  of the potentials are all lined up very normally, and none of them are missing, so you know that this particular patient is going to be having a normal neuromuscular junction,  so not always have to rely on the machine giving you the data. You can also look visually, and which is very, very powerful, I would say, when compared to just at the end,  looking at the machine giving you the results.  This is a child who has abnormal jitter, and if you look at the potentials which are being recorded at the far end are pretty variable, or they're not lining up as nicely  as I showed you in the previous slide, and in some of the, if you look downstream, they're almost missing a few potentials, so this is a case where there is markedly abnormal jitter  associated with blocking.  So one of the pearls for good recording when you're doing this kind of work is to make sure your baseline is flat, so whenever you walk in the room, EMG labs,  and nowadays EMG labs are used for many other things, like, for example, in the night, they'll do EEG sleep studies there, or your EEG tech might be using,  and several machines are plugged into your lab, so be cognizant of that fact. Try to remove all the additional technology which is not needed. Unplug these electronic beds nowadays,  so make sure your baseline is flat, because if your baseline isn't flat, you're not gonna get a good recording. Do not ignore any potentials irrespective of amplitude and latency.  One may say, oh, I'm gonna take only these, so try to be more comprehensive when you're recording. You would notice that there will be a lot of challenges  when you're doing this in young kids, and especially a lot of business comes from these congenital myasthenia in kids with negative antibodies, but still with a lot of fatigue,  and this test is very helpful with the sensitivity as up as 85%, especially in seronegative and questionable CMS, so be tolerant and work with these children  and expect that you will get some challenges in young kids, but when it comes to older kids like the girl I showed you with juvenile myasthenia, you also have to be perfect there  because you don't want to over or underestimate those kids as well. Sometimes potential seems to fade away, always be due to some subtle movements,  and I'll show you one or two recordings, so there also give it a little time, and you can, it sounds very difficult that you have all these electrodes and can you give them a break,  but sometimes we've seen giving them a pacifier or feeding them or holding them, or even moms being there or sometimes watching a nice thing on their iPad  with a child life specialist can make life very easy and you can proceed on with the study.  This is a child who's crying and has very unstable baseline, and then the mom starts singing to the child and then it becomes very easy for us to move forward,  so having the family or the patient's mother or father being there is very useful and we'll talk about that and the tips of being a good electromyographer.  So here are some recordings where there are different size and latency of potential and you can still kind of work with them. You can record this  and you can utilize it to your advantage.  We're gonna switch gears and talk about RepStim a little bit, and that's probably one of the most common studies we do in our lab and easily available.  You definitely would like to do a routine motor nerve stimulation, and even when you're doing stimulated jitter analysis, I will talk at the end of my presentation  that it's important to do routine EMG and the RepStim and even the nerve conductions because everything comes together at the end and it's important not to do just piecemeal study  because you're not gonna get too many times for this patient to come back to the lab. We as pediatric electromyographers will only get one opportunity probably  to see the child in the lab because unlike EEGs and maybe other tests like MRI which can be repeated several times, EMGs are not that easy to repeat  except if you have a very strong indication and we'll talk about that in a minute. So the reason why motor nerve stimulation is important is like Dr. Sakanju showed you earlier,  double CMAP response, which can be a clue to a slow channel myasthenia  or a estalcolin esterase deficiency.  You can also see that when you're doing these CMAP studies, sometimes in conditions like botulinum, for example, when you're evaluating a baby, you may not get a very nice CMAP  and that could be another important clue that there could be a problem with the neuromuscular transmission. It can happen with myopathy as well,  but make sure that you look for your RepStim and needle exam.  It's not the best example, but we had a kid and I wanted to show you a 10 month old musk gene positive baby with a slow channel myasthenia  and I was doing the RepStim and this is from our lab and the baby had this after going potential. Like I said, it's not the most robust, but it gave me enough clue in the lab  that this kid has got something with a slow channel. So as soon as I saw this, I decided not to do mestinon but only do albuterol and the kid responded to albuterol nicely  so there are ways as an electromyographer you can help the families in the lab because you're also their treating physician in most of the cases.  Slow RepStim is performed in a similar manner as adults so it's pretty similar. Make sure you have a nice positioning of the...  A lot of kids would move and so doing a RepStim in pediatrics is very tricky and often the abnormalities is not because the patient has a problem,  it's because more technical problem. If you've done either not a proper stimulation or you moved quite often and so those are challenges you want to be aware of.  We would use a bar electrode on many occasions because with that you can have the stability of doing the RepStim in the median and ulnar and very important to a proximal RepStim.  I'll show another example where ulnar ADM was normal but when we went up to the trapezius, there was a quite a bit of decrement in a young lady who came to us with myasthenia.  So always try to do two pairs, both distal and proximal and just not rely on distal only which is often what most people end up doing.  There is a lot of literature coming out on CMAP decrement, what is the ideal number? A lot of labs are now looking into whether you really need a 10% decrement  or even as low as 7% is enough to call someone as abnormal. Especially if you're planning to do a RepStim of the face like the nasalis and the muscle,  even up to 6% to 7% decrement would be considered positive and there's no pediatric literature on that yet but I think it's more and more labs are starting to recognize.  Although for your right exam, all the residents in the room and for your ANEM, it's 10%.  This is a ulnar ADM which is pretty normal and then the same young lady back in 2012 when we did this study with the trapezius,  you see a big drop and when you do the facilitation, you would see an increment and the exercise test and that would be helpful for you to make a diagnosis of myasthenia gravis.  Fast RepStim is a little bit challenging I must say although there are several labs which try to attempt it. I think there's a combination of problem. A, it's very painful.  B, the technology of recording RepStim which is fast 50 hertz is very limited because the paper speed or the speed has to be changed  and you have to make a lot of modifications to your lab. So it's not easy to do that fast RepStim but in cases like infant botulism or in presynaptic CMS or cases like Lambert-Eaton  which are quite rare, these would be very useful and there are reports of infants with congenital myasthenia  who have subsequently found abnormalities on fast or prolonged RepStim because they were missed earlier on the regular RNS.  This is a fast RepStim. I got it from Dr. Sakenju's lab. So this is how the study was performed and you see an increment which happens in these cases.  So at the 50 hertz at the bottom on the right table, you see a 22% or 201% increment with a nice CMAP up.  So why do we talk about all these neurophysiological tests? What is the application of this? How can we make this more intuitive and more helpful to our families?  So I'm gonna show you a couple of examples and then we'll talk about some of the things. So a case one, a four-month-old who's a boy who's healthy  suddenly develops poor suck and weak cry and drooling and constipation.  So gets into the ICU and I think that all of us are thinking of right away, is this a botulism case? Patient is lethargic, has got ptosis, facial weakness,  has got a weak gag, head lag, generalized weakness but preserved reflexes. So often the residents would come up or the fellows would say,  is this Guillain-Barre or is this something else? Is this, but in a young kid, less than six months, this kind of presentation botulism should be on your mind.  So this kid had admission to the PICU, was ventilator, need to be ventilated and recovered with baby big and I'll show you why EMG was useful.  So the study which was performed in the lab, in the ICU, had normal sensory and motor nerve conductions. There was no significant decrement or facilitation  in the compound muscle action potential, but I must say this was usually done at the slow rep stim. And then when we did the stimulated jitter analysis,  which I showed you that in my first few slides, there was quite a bit of increased MCD values with almost 93% of the potential showing increased jitter and about 7% were blocked.  Another case like this, a three-month-old female with just nothing acute, nothing at birth, but suddenly a weak cry, drooling, constipation, again, lethargic, had doses on exam,  similar exam like a previous kid, and had a similar study which was performed and had increased jitter and blocking at this time led to the diagnosis of botulism.  In both these cases, what I want to highlight was that being available in the lab and in the hospital with this technique, we were able to make the diagnosis  of botulism within 72 hours. The stool toxin in our lab, and I'm from Atlanta and we have CDC next door, but still the botulinum toxin, botulinum stool took us seven business days.  So it really takes a long time for those things to come.  So being clinically and electrophysiologically strong, you can really rapidly get these kids diagnosed and get them treatment, and as you know,  the early treatment saves them quite a bit of time because it improves their outcome and less time to be in the ICU and recovery is better. So most of these are one of the ways  to look at how the application is very helpful. As this data is coming along, several labs, including Dr. Jabre and Matthew Pitt, and some of the data coming from our lab  has shown that there is some normative values to jitter. Jitter values in infants is a little bit higher than normal. I think part of the reason is they're also not myelinated,  so it takes time for the impulse to move from one end to the other. So having some normative values on this has been useful to us. We have used jitter in correlation  with myasthenia severity, and in a work done in our lab a few years ago, we looked at the severity of myasthenia by the MGFA scale and the jitter values,  and it was a quite nice correlation, and we were able to help these families and patients who would come for serial studies to kind of tweak their medication,  especially if they're going through a relapse or their IVIG frequency is differing, and I think this is going to be very helpful as we move into clinical trials  with these novel drugs, which we heard in the Myasthenia Gravis Foundation symposium yesterday, that you can utilize jitter values  to kind of help them understand if they're improving, especially young kids. You would like to also include the MGFA scores along with the QMG,  which is the PEDS equivalent of the myasthenia scales, but this could be a nice addition which can be put into these clinical studies.  This was one such example of a young lady who I took care of many years ago with congenital myasthenia, who we had tried a drug called 3-4-DAP or MFAPiridine, and she was very weak.  She has the CHRNE defect, which is the most common postsynaptic defect in myasthenia, and she would be very droopy, would have feeding difficulty, and we tried this medication.  So pre- and post-treatment, if you notice, there was quite a bit of drop in the jitter values, almost 20%, and the blocking almost went away.  So another good example of using jitter as a biomarker in many of these studies could be considered in the future.  We're right now working on creating a little bit of a revised version because we were noticing that when we're using the jitter values of individual as 36 and the mean of 24,  we were sometimes over-calling these patients as abnormal. So one of the presentations this evening in the Pediatric Network Dinner, which I am putting a shameless plug there,  but you would like to join us there because one of our students from Georgia Tech who just became a medical student at Dartmouth, Vishwa is presenting,  he got the Best Pediatric Research Award. He will be presenting on that work and how we have found the data once we revise the individual jitter  that our sensitivity and specificity in particular has gone up and we're able to make that diagnosis or say it with more confidence  that this is a neuromuscular junction transmission defect. So moving from just being a screening to becoming more of a,  so this is, I'm gonna leave it to Vishwa for him to explain a little bit more on the individual jitters. I wanna conclude with a few things which are important to all of us  as a pediatric electromyographer because having a relationship in the lab with the parent and family is very important. You're setting a rapport at the onset,  whatever you're doing, whether you're nerve conductions, EMG or advanced studies like RepStim or single fiber, you want the parent should be there. You want the parents to expect  what they want will be coming out.  It's good to examine children in comfort of their parents so that if they would like to be with them or they have a pet they have or their brothers and sisters were coming in  or just having a more soft, cuddly and a more quiet environment really creates a lot of ease in doing these studies. I think many of us who are fortunate  to work at children's hospitals have started to recognize the value of child life specialists. I'm sure many of you have seen child life specialists  who walk with these iPads, a lot of toys and some of these service dogs which are available in many children's hospitals. They create a lot of ease environment  which is very helpful in making this study much more palatable. I must say that all of us should be honest in what when we describe to families what is the discomfort of this test  because it's not good to sugar coat and say oh, it's gonna be all okay or we're doing this very easy test. I think letting them know that this is a painful test  or at least discomfort if not painful. Although I must say that several studies have shown already that putting a pain of doing the EMG is equivalent to doing a blood draw.  So not that blood draw is easy but still it could be similar. So just to give you a perspective, it's not, nobody's chopping off your arm or leg here.  Explain that you will recognize the difference between irritation and discomfort. A lot of times you will notice when you're doing nerve conduction that in EMG kids are very scared  and they are really anticipating a problem. So recognizing that little difference and when you're doing the EMG, it's very tricky. You also have to watch the parents,  the room, the temperature of the room. If the parents are getting off and you're getting very upset, you should know when to stop. It is okay to stop because it's not,  you don't have to pull through it or go through it or bulldoze through it. No, nothing like that. You just be kind and you will get through it.  And do you need to discuss the results?  I have left it to several physicians differently because many times if you are just the EMG-er for that patient, you may not want to discuss, you may just want to send the report  to the primary who sent you there because sometimes people feel offended if you discuss themselves. But if you are their primary neurologist,  you may want to discuss or if it was referred by a pediatrician or a primary care doctor or a nurse practitioner who you understand may not be able to understand those results,  then it's good to discuss. But keep in mind when you're discussing, you're gonna also end up having to see that kid in the clinic and will have to discuss more.  So that's very important, brings me back to how do you select EMG patients? Not many of us will have that ability to select doing EMGs because anything  which is ordered, you'll have to do. But if you can select patients properly, you can sometimes avoid EMGs. Like on several locations, I will discontinue the order  or will say that this is not needed. So having some access to the scheduling system would also help you in these cases.  So this is what I follow and many of us who do single fiber and EMGs would follow is that if there is a concern for neuromuscular junction, you perform the single fiber.  But don't leave the needle out. You can look at the muscle for other things like is there a myopathy, is there a neurogenic? When I trained with Paul Barkhouse many years ago,  he would do a single fiber EMG and he would never leave the needle out unless he'd also very comfortably tell what the potentials look like. And he would make a special addendum  in the single fiber report about the EMG finding of the orbicularis oculi. And I still follow that rule because sometimes you will notice that there is an underlying  neurogenic lesion or a myopathic lesion. In those cases, the potential, the stimuli would be always abnormal. You would like to confirm with the RepStim if possible  because sometimes it can help you pre versus post-synaptic  because single fiber does not help that much with that. And finally, examine the muscle and the nerve studies just in one limb, making sure you're not missing  a diffused myopathy or a diffused neurogenic lesion.  This I pulled from Dr. Matthew Pitt again, who I feel is a mentor to many of us who do this kind of work and how he would do a single fiber  and then would eventually look for other study abnormalities like bulbar weakness, especially of the genioglossus. Then would RepStim and then myopathic.  And you can really build your own little bit of protocol in your lab so that you don't miss some of the common problems like bulbar palsy and motor neuron disease,  big one, and then obviously if it's a diffused myopathy. I think with advent of genetic testing, it's becoming much more easier. But when you don't have results of genetic testing  available in the EMG lab, we have to look for all the other possibilities which is causing the problems such as hypotonia, low mass fatigue, or weakness.  So with that, I'd like to end my slide. I think I'm a little over time. Sorry, Matt.  Thank you.  You're good. You gave me plenty of time. Let me just get right here.  Hi, I'm Matt Ginsberg, a pediatric neurologist from Akron and it's my pleasure to talk to you today about some of the management of pediatric neuromuscular junction disorders.  These are my disclosures. And today I'm gonna talk first about treating juvenile myasthenia gravis. There are a lot of really good talks at the AANEM about myasthenia.  So today I'm really gonna focus on what are the aspects of juvenile myasthenia gravis that are specific to the pediatric population and not try to cover everything  because we have a fairly limited time. We'll talk about some of the data and limitations in the data for this population and then review the general treatment approach  for congenital myasthenic syndromes. I do want to put a caveat right up front that if you're the kind of person who likes like a flow chart or an algorithm,  at the very end of the presentation I have a QR code linking to some of the resources and some like an annotated list of some of the references  that actually does have some of that information is kind of more like something you could look up later. So let's just start with the case.  So this is a 13 year old previously healthy female. She came in with some ptosis and double vision. She was totally healthy before all of this  and on exam she had some fatigable ptosis, some mild restriction of her extraocular movements and her acetylcholine receptor antibodies were very elevated.  She did not have musk antibodies. So this isn't like a diagnostic conundrum. She has autoimmune myasthenia gravis at this point with ocular manifestations.  And the question is so now what are we going to do to manage those symptoms? So before we talk specifically about the case, in general I think most people believe  that the pathophysiology of autoimmune myasthenia gravis is pretty similar between adults and children. It's the same underlying disease process.  But in children we have to think a little bit differently about the side effect profiles of the medications and the toxicity because they may react to medications differently.  We also have adherence issues. It's hard to get adults to take medication but a teenager is sometimes an exceptional challenge. And then we have a lack of trial data  in a lot of these populations. And that can sometimes be a problem maybe for individual people's comfort but also for obtaining insurance approval or access  particularly if you're thinking about one of the newer medications that's expensive.  And then there's been historical concern about the physiologic role of the thymus when considering the amectomy for some of these patients. So for someone like this oftentimes  whether it's an adult or a child, many people would start with symptomatic treatment with an acetylcholinesterase inhibitor like pyridostigmine. And as you already heard,  most of you know how pyridostigmine works by inhibiting acetylcholinesterase and improving cholinergic transmission in the neuromuscular junction.  It's used kind of similarly to adults with the exception that we do use a weight-based dosing in children. Usually it's around three to seven milligrams per kilogram per day.  But it's still very individualized based on patient response and when they're having symptoms in terms of how many times you're gonna give it a day  and how to maybe distribute the doses. There are extended release formulations of the medication. I think some people use them more than I do. I mostly use it just if it's somebody  who has early morning or nocturnal symptoms. And the dose could be a little bit high overall if you have a very young child.  And the side effects are basically similar to adults. I would say most of the patients I have on it tolerate it really well. They don't have a lot of the muscarinic side effects  that you would expect.  The other medications I wanted to just mention briefly are alpha-1 agonists, oxymetazoline and apriclonidine. There have been some case reports, actually really more in adults,  of using these as topical eye drops to help with ptosis and myasthenia gravis. And these act on Mueller's muscle, which is the sympathetically innervated muscle  that assists in lifting the lid. And so they may be helpful for ptosis, not for any other myasthenia symptoms, but it does potentially avoid some of the systemic toxicity  of the other medications we'll talk about. So it might be an option if you're really just trying to target ptosis as a symptom. It just might be a little challenging  to get through insurance.  Okay, so this patient was started on peridostigmine. It was up titrated. She initially had some improvement, but then she developed difficulty walking.  Her hands began to feel heavy, difficulty chewing, nasal regurgitation. And on her exam, she still had particular ptosis, but she had hyponasal speech,  generalized weakness that was MRC grade three. And at this point, we're starting to see that she has generalized myasthenia gravis, maybe an impending crisis.  She was admitted, given IVIG, two grams per kilogram over a couple days, and started on prednisone 20 milligrams daily. And just like in adults,  IVIG or plasma exchange are often used for crisis or exacerbations, but most people will start patients at this point  on some kind of maintenance immunotherapy. She had some initial improvement with IVIG, but didn't return to full strength, and then had some worsening.  Her prednisone was increased to 40 milligrams a day, but then the weakness got worse and she backed down. So then the question is, what options do we really have  for juvenile myasthenia gravis patients in terms of immunotherapy? Because at this point, that's what we need to think about. So there's a really large menu of options  for immunotherapy in myasthenia gravis right now. And that, I think, adds, it's great that we have all these options, but it adds to the complexity.  And I don't even really have time to talk about all of them. This is kind of a pathophysiologic map of some of the interventions, and again, this resource is at the end.  But we can think about them more proximally targeting the autoreactive B and T cells of the disease, as including interventions like thymectomy, which we'll touch on,  and corticosteroids, which are often one of the first immunotherapies used, but also azathioprine and mycophenolate mofetil. I am actually gonna kind of skip over  or breeze past those last two, azathioprine and mycophenolate, not because they're not used. They are used in pediatric or juvenile myasthenia gravis,  but because there's not actually that much data on their use in the population. And they come with a lot of baggage, I personally feel like. So they're given orally,  meaning that adherence is a potential concern. They require a lot of laboratory monitoring. They take months to potentially kick in. And azathioprine does have a potential risk  for skin cancer with chronic use, and we're talking about very young patients. So I know a lot of people do use them, but I'm gonna breeze through that.  B cell depleting therapies like rituximab are also used, and we'll talk a little bit more about that. And then in terms of targeting the circulating autoantibodies  in either acetylcholine or musk-positive patients, and we have the traditional therapies like IVIG and plasma exchange, there is actually some class three evidence  that they can be used for maintenance therapy for pediatric patients, even though in adults, they're more commonly used just for acute episodes. So that isn't uncommon, I would say,  in juvenile myasthenia gravis. Some of the newer medications that target the FCRN receptor and lead to increased degradation of circulating autoantibodies,  like efartigamide and rosanolixizumab, these are currently investigational. And then more distally, down at the end plate itself, there are a number of medications now  that target the terminal complement system and inhibit the development of the membrane attack complex and end plate damage. And those would include things like xylicoplan  and ecolizumab and ravelizumab. And there we have just a trickle of data coming in in the juvenile myasthenia gravis population. So of the few medications I'm gonna mention,  I'm gonna just briefly talk about glucocorticoids. There's actually not a ton of clinical trial data in juvenile myasthenia gravis, specifically assessing this in isolation,  but most people have extensive experience using it and still use it early in the course. So there are some data gaps in it. With glucocorticoids or other immunosuppressants,  in the pediatric population specifically, one of the issues that comes up is vaccines. So the first is that of vaccine safety. And I've seen patients with immunosuppression,  typically, we don't give live vaccines to. In this young age group, we're mostly thinking about the MMRV vaccine. And so most patients get that at age one and four.  But it's worth noting that you can give that second dose as early as three months after the initial one. So most patients really should be able to complete a course before they  start on immunosuppression. In terms of vaccine efficacy, there's also a question, are the vaccines effective, even the non-live vaccines, if they're on immunosuppression?  There's some data from the adult and pediatric rheumatology literature, actually, that the vaccines are effective in most cases.  Although with B cell depleting therapies like rituximab, there's going to be an attenuated response. If you are going to try to get vaccines in before, let's say,  B cell depleting therapy, many people recommend trying to do it two to four weeks beforehand. And then in terms of supplementary vaccines, do you need anything extra?  Well, besides the usual routine recommendations to get your influenza or COVID boosters, patients who are on a terminal complement inhibitor, like ecolizumab or revilizumab, you  are going to need to make sure that they're vaccinated against meningococcus, both with the quadrivalent and the serogroup B vaccine. That's part of the REMS program, which  is available for both of those medications. There's been some debate about whether everybody should also have the PPSV23, the 23-valent pneumococcal vaccine.  So I'll leave that to other people to think about. And so those are really, I think, the main vaccine questions. But steroids themselves also have another whole set of side effects  to consider in toxicity. So of specific concern to the pediatric population is linear growth, because it can affect your final height, and also your overall bone health  of putting on most of the bone marrow for your adult life during childhood and adolescence. And so that makes corticosteroids in the long-term less appealing, maybe to clinicians,  but also just weight gain, hair growth, rashes, all that could be very, very unappealing to most people, but especially to a teenager. I think some of the adult literature,  and this is just a helpful benchmark, so where doses below 7 and 1 half milligrams per day of prednisone tend to be more favorable in terms of risk-benefit profile.  And for children, we're often thinking about maybe starting doses of prednisone around a half mgs per kg per day, give or take. So most of these patients, you're  going to try to wean down to the lowest effective dose, or even off of steroids. Or if you can't get down into that safe range, maybe thinking about an alternative agent.  So this patient, because she had ongoing symptoms despite steroids, she actually started on Tuximab, and she was scheduled for a thymectomy.  Her symptoms remained stable, but unimproved. And then she actually had some worsening, prompting some IVIG re-administration. So what other options do we have after steroids,  and maybe even IVIG, if you wanted to go there? Well, we do have a little bit of data on rituximab, which has been used early in musk myasthenia patients,  but had sort of conflicting data in the adult world, thinking about the BEAT-MG and Renamax trials, with some people suggesting that maybe  early in the disease course, rituximab may be more effective, and maybe less effective late in the disease. In the juvenile population, rituximab has been studied  in more retrospective studies, and this is a study of 10 patients with myasthenia gravis, who mostly showed improvements in their MGFA scores  over a couple of years following a rituximab treatment, but obviously there's no comparison group here. And there was a larger French study,  which looked at sort of a large population-based sample, and they were able to compare 12 patients who received rituximab first line,  with another 12 who actually received it second line, so received it later on. And they found that there were some differences in the amount of patients who needed thymectomy,  the number of patients who were on corticosteroids, or were stable even without immunosuppression at all. So this, again, isn't like a placebo-controlled trial,  but it suggested that rituximab may have a significant role in juvenile myasthenia gravis. I think the other thing to keep in mind, in terms of advantages here,  is that it's dosed with a set of loading doses, either two or four loading doses, and then that's it for a while. You can redose at six months as B cells repopulate,  but some patients don't even need redosing, or they may just need it one time. So it's really good from an adherence standpoint. It's usually well-tolerated.  You can have infusion reactions or hypogamma glabulinemia, but it's very appealing for knowing that your patient's got the medication and having sort of a long-lasting benefit.  It's probably one of the longest-lasting of the medicines that we have. So the other medicine I wanna mention is ecolizumab. This is, again, a terminal complement inhibitor.  It's administered IV, and at maintenance, it's gonna be given every two weeks. And it was studied in the REGAIN trial in adults,  showing some relatively rapid reductions in symptom burden. And so it has been studied now in this phase three open-label multicenter study. This was in teenagers with refractory,  generalized myasthenia, and acetylcholine receptor antibodies. And it's important to keep in mind that this medication, these terminal complement inhibitors,  are really only for acetylcholine receptor-positive disease. 11 patients were ultimately included in the efficacy analysis. And basically, the patients were studied  for 26 weeks primarily, and then were enrolled in an open-label extension. So the toxicity of the side effect profile was pretty similar to adults.  There weren't a lot of significant adverse effects. And the pharmacokinetics, which were really kind of the primary outcomes,  were consistent with what was expected based on modeling. In terms of the primary outcomes on the QMG scale, which is the quantitative myasthenia gravis scale,  70% had a five-point reduction at least in that scale, and 50% a three-point reduction in the myasthenia gravis activities of daily living. And more significantly,  the time course for these changes was rapid, consistent with the adult data. So this is taking place over just one or two weeks before you start to see the effects  in most of the patients who respond to it. And so it suggested that this is probably gonna be a reasonable option for patients  in terms of efficacy. There was one patient who didn't really respond as well, and ultimately wasn't included in the primary efficacy analysis. So not everybody's gonna respond.  It's not a magic bullet.  But this medication's main limitation, I would say, besides cost and access, it's not currently approved, is it's given every two weeks. And so that could be a real challenge.  Many people might not wanna have an infusion every two weeks. There is a chemically modified version of this, Ravalizumab, which is very similar in terms of its mechanism of action.  And that's given every eight weeks and is currently in clinical trials right now. There are also currently enrolling clinical trials for zylucoplan and efartigamide  and maybe some others that I missed. But so this is an area where we're actually starting to see some clinical trials to address this population. So that's kind of exciting.  Okay, moving on to thymectomy. Thymectomy has obviously been around for a long time as treatment for myasthenia gravis. It was demonstrated to be effective  in acetylcholine receptor antibody positive adults in the MGTX trial. But it's also been used for many years in children as well. There was a theoretical concern about the thymus  being maybe more important in young patients, although infants who've had their thymus removed for cardiac surgery seem to do relatively okay. There's also a recent-ish adult study  suggesting that adult patients with thymectomy have had higher risks of mortality and cancer.  Other later commentary on that, I really suggest this probably doesn't apply to the myasthenia gravis community. So I don't consider it to be a significant issue for our population.  In terms of studies on it in children, they're mainly retrospective studies, but some of them are very large with hundreds of patients. In this particular one,  the patients who received thymectomy, they had a change in their overall steroid doses, IVIG, plasma exchanges, overall immunotherapy. They were even able to show a difference  in the cost to care for patients, or reduced care cost for them compared to non-thymectomy individuals. That's actually kind of significant given that a lot of the newer medications  that we're talking about are actually very expensive and probably increased cost of disease. Another study also suggested efficacy of this intervention  and suggested that some of the factors that influence the effectiveness of thymectomy included, obviously, the acetylcholine receptor antibody positivity,  and that's where it should mainly be thought about, hyperplastic thymic tissue, slightly later onset after puberty, severe disease, but also early intervention.  And so if somebody's not really looking like they're gonna go into remission and they have generalized disease, or particularly if they have severe disease,  I think it's often a good thing to think about.  So this patient, six months after thymectomy, her disease remained stable. Her rituximab was discontinued.  She considered participating in a clinical trial, but then started seeing improvements, and ultimately revealed that, about a year after thymectomy,  that she had just stopped her steroids on her own, and she was fine.  So she ultimately, she had some weakness, but she was improved from her baseline, and she started on IVIG maintenance therapy, because that's what she wanted to do every four weeks.  And she was in minimal manifestations of the disease about a year and a half after her thymectomy.  So with that, I'm gonna move, shift gears a little bit, and just talk about the congenital myasthenic syndromes briefly. We'll start with another case,  a three-year-old who had a long history of generalized weakness, born prematurely, had difficulty managing secretions, difficulty breathing from the ventilator,  similar to some of the cases that I presented. And she had a trial of protostimulant that had no effect on the NICU. MRI, genetic testings,  like microarray antibodies were all negative, but she did have a whole exome, which revealed a pathogenic variant in the CHRNB1 gene. And her RepStim is shown here.  She had a low baseline CMAP in the EDM with one of these after potentials, again, it's kind of subtle here, and an electrodecremental response on slow repetitive stimulation.  So her phenotype was consistent with slow-channel myasthenic syndrome. So when thinking about the approach to these patients, again, there's like tables and algorithms,  and I'm gonna link to that in a minute. But the overall strategy, there's really kind of like four main strategies to think about in my mind.  So you can target the presynaptic terminal with a medication like 3,4-DAP or amifampridine to increase the release of acetylcholine-containing vesicles.  You can also boost cholinergic transmission by using an acetylcholinesterase inhibitor. You can improve that clustering that I talked about, like the bouquet,  with a beta-2-adrenergic agonist. Or you can take the complete opposite approach. If you have too much cholinergic transmission, like in slow-channel syndrome,  you can try to stabilize the closed channels or block some of the excess transmission through the channel. This is one of the original papers from Engel, I believe,  showing that the bursts through the wild-type acetylcholine receptor channel are shown above without and with the influence of fluoxetine,  which is often considered one of the first-line closed-channel stabilizers. There's not really a lot of difference. So it doesn't seem to block off healthy channels too much.  But in this known mutation that causes slow-channel, you can see that these bursts lengths are much more prolonged, but under the influence of 10-micromolar fluoxetine,  they're able to shorten down closer to the normal range. And this graph on the right just shows you that there's a dose-response curve. With increasing concentrations of fluoxetine,  you don't necessarily get all the way to normal, but you can actually get relatively close to the normal burst-length duration. And so fluoxetine is used first-line  for slow-channel syndrome. We wanna think about, again, those three main CMSs, Doc7, Col-Q, and slow-channel as being the ones where maybe you're a little more cautious  about pyridostigmine. Because if you don't have one of these, you can probably start with pyridostigmine with almost everything else. With the slow-channel syndromes,  the fluoxetine, there's kind of a long history of using it, and many people are more comfortable with it compared with quinidine,  but quinidine is also an option to treat these patients.  I would say that for Doc7 and Col-Q, though, obviously, albuterol is really gonna be the mainstay or ephedrine.  And then for everything else, if pyridostigmine's not effective, you might think about doing anion therapy. And again, there's a table that I'll link to later for these.  So this particular patient was started on fluoxetine at one mg per kick per day. She had some improvement, but didn't gain ambulation, and still had severe weakness.  Her trough level of fluoxetine was 500 nanograms per ml. Her dose was increased. And then she actually began walking with assistants, had a repeat trough around 1,000,  and no significant side effects. So patients can have, this is an SSRI and you could theoretically have serotonin syndrome or GI disturbances and other typical SSRI side effects.  But you may need to get the dose higher to achieve the therapeutic effect. And you can sometimes push it relatively high. It's higher than a lot of people would use for depressions  or anxiety symptoms. So it's just worth considering that when you're thinking about the dosing. Also, the half-life on this medication is very long. So you have to be patient  because it can take a month-ish to get to steady state.  Next case is a newborn who presented with persistent apnea cardiac arrest shortly after birth. He had hypotonia, ptosis, ophthalmoplegia. His periodostigmine challenge  resulted in significant improvement in tone and apnea. And his molecular testing showed a CHRN variant previously reported in acetylcholine receptor deficiency.  So he had a different CMS. And after a couple years, though, he seemed to plateau in his development. And so the question was, is there anything else we can add  besides just the acetylcholinesterase inhibitors? And so for patients who are amenable, again, to boosting cholinergic transmission, people have tried other medications,  including amifampradine and beta-adrenergic agonists. So for the albuterol, which is the main beta-2 agonist that I think most people use in the United States,  as I mentioned, this medication seems to improve the clustering of the acetylcholine receptor channels and improved axon pathfinding, which is, there's some in vitro data  on the right side demonstrating that. And again, this is given orally, right, two or three times a day. And these are some of the doses.  You can have some tachycardia or palpitation. Sometimes that's a dose-limiting effect, and you do need to give it weeks or months to see the result here in terms of the clustering  and the clinical effects.  Amifampradine, or 3,4-DAP, is a potassium channel blocker that increases calcium influx in the presynaptic terminal and improved quantal release of acetylcholine.  So this just shows you that you have this big boost in the amount of acetylcholine that you're releasing into the synapse. This medication does have a risk  of seizures associated with it, rarely. And in some of the clinical trials, there were elevated transaminases, so those might be considerations  if you're thinking about using it for a patient. There was a clinical trial of this that was completed with negative results, but it was a really small heterogeneous trial,  probably underpowered. I don't have additional major details about it, but I wouldn't say it excludes use.  All these patients have different mutations, and they may be responsive to different medications at the individual level.  Maybe one of the big challenges with this one is access.  Right now, I'd say most patients are accessing it via an expanded access program or an individual use IND, compassionate use program.  So it does add a layer of complexity to the treatment.  To kind of summarize some of that stuff, there are complementary mechanisms for some of these medications, so some patients may benefit from more than one of them,  like a beta agonist with an acetylcholinesterase inhibitor or potassium channel blocker.  The timescale is gonna vary for improvement, so while peritosteamine should act pretty rapidly, albuterol's gonna take months. You can have a plateau or a saturation effect  because some people's mutations are just not going to allow you to get past a certain point. And then in terms of pitfalls, there are side effects from the therapy,  some variable response from different mutations, adherence issues, again, and access issues, particularly in the case of emmifampridine.  I don't wanna wrap up without mentioning that there are some supportive care measures that we think about for kids for both juvenile myasthenia gravis  and for congenital myasthenic syndromes. There are medications to avoid that impaired neuromuscular junction transmission, which we mention to all families.  There are patient and family advocacy groups like the MGFA that can be really helpful.  Weight management and diet and exercise counseling, particularly for patients who might be on glucocorticoids.  And then school accommodations are really important in this age group because they might need a 504 plan, for example, to have a modified gym class  or an excuse not to carry a book bag between classes. And kind of this is the work for kids going to school and they really benefit from that.  And then finally, the burden of the disease plus the burden of the medications. This can be a lot for a young child or particularly for a teenager  who's just trying to live their best life. So it's just important to keep some of that in mind for patients when we're helping them. So quick summary for juvenile myasthenia gravis,  we use mesatinone and alpha-1 agonist for mild or ocular symptoms. IVHE, plasma exchange, and corticosteroids are often first-line immunomodulation,  but thymectomy should be considered early. Rituximab has some early data that you might want to consider it early on and has a great adherence benefit. And there are trials underway  for complement inhibitors and FCRN antagonists. And then for CMS, we're thinking about fluoxetine and quinidine for the slow channel syndromes. Albuterol as first line for DOC7,  Col-Q or second line and many others. Pyridostigmine for most other forms of CMS. And amifampidine as an adjunctive therapy to pyridostigmine in most of the conditions  where there's decreased cholinergic transmission. So that, well, thank you for your patience in sitting through all of this. And this is the code that just,  it's just a very simple website that has an annotated list of the references with PubMed IDs and a table just sort of comparing some of the medications  that you can use for reference later if you like that kind of thing. So thanks so much.  Thank you.  So there are two questions, one is the low dose for rituximab and the second question is about the timing of thymectomy, especially for young kids.  And maybe you'll have other opinions too. For the rituximab dosing, I'm aware of the data on it, I haven't personally used it in  the younger kids yet just because there hasn't been that experience, and I think the other  older papers were still on the more conventional dosing regimens, but I assume that's something that maybe there'll be more information to come in the JMG literature.  And then for thymectomy, I don't necessarily have a lower limit, I mean if you're absolutely positive that it's acetylcholine receptor positive antibody myasthenia gravis, I think  you know, given that there are some very young infants who have had their thymes taken out and been okay, I think it's a reasonable option.  Obviously, you know, there's also families may not want to have a surgery at that age or they may want to try other things first, so I think also, you know, it comes down to  family and parent preferences to a certain degree with some of these medication choices given the lack of definitive answers for a lot of them. I don't know if you guys had other...  I think the youngest acetylcholine receptor positive...  I wanted him to get through his vaccine, so I waited until 5, and he did.  I did wait until about five months. He had a little nodular.  Regarding your Rituximab question, what I have done, and again, these are anecdotals, and we don't have a whole lot of Rituximab patients, but we can do the frequency,  like three months or six months, and you can use 750 milligram per meter squared. Most kids, these are juvenile, so they will be maximum of a one gram dose.  And you can, we've done them over three months interval, and then the TBNK panel, and looked at the B cell count, and then really followed them along.  And if the B cell count is suppressed, the symptoms are better, then widen it out every six months. So I've not changed the dose, but the frequency is what I've worked on.  I'm sure there are other reports and other people who have experience with low dose, like 375 milligram per meter squared, and so forth. And with regards to a thymectomy, again,  majority of them are either peripubertal or around 5 to 10, but large number of cases from our group, which we do about two cases a year, so 15, 20 cases over the years.  If I put the median age would be close to around 12 to 15.  So I was talking to Dr. Maselli, the question is about the new drug for DOC-7, I think you're  referring to Arginix 119 or 117, the one which tries to cluster the acetylcholine receptor, is that correct? So I don't have personally, but I know Dr. Maselli had some answers.  So what I understand is not approved for London 18, right? Yeah  I think there is a clinical trial on, if I went up on the clinicaltrials.gov, but I wasn't, I'm not entirely sure on the inclusion criteria for that, yeah.  So you received a letter from CHOP inviting one of your patients to participate.  I have a similar patient like yours, a 14-year-old who's struggling and has got an outbreak. I've even heard there is an AV9 clinical trial which is being explored.  Just for the audience, there are two pipelines which we are thinking. One is the antibody-based monoclonal, which is trying to cluster the ester receptor antibody.  As you saw from the slide, the phosphorylation of rapsin is working.  Yeah, but either way, it's very exciting if something is on the docket, yeah.  Thank you so much for everyone for listening and coming to the talk.  Thank you.  Thanks.

Video Summary

The presented content revolves around pediatric neuromuscular junction disorders, focusing on genetic evaluations, clinical cases, diagnostics, and treatment approaches. Initial discussions cover the genetics and common diagnostic challenges in pediatric cases, emphasizing the importance of genetic testing in early diagnostics, such as rapid exome sequencing and its role in identifying specific mutations like CHAT for acetylcholine production issues. The transcript explores a detailed case study of an infant and the steps taken towards diagnosis through mutations analysis and subsequent treatment strategies.<br /><br />Evaluative methods discussed include repetitive nerve stimulation and genetic testing fine-tuning, such as parental testing for cis or trans mutations. These methods help deduce the neuromuscular junction disorder type, leading to personalized medication plans, such as using neostigmine or liquid albuterol for treatment in congenital myasthenic syndromes like Doc7 mutation.<br /><br />Along with the diagnostic approaches, the transcript details various management strategies for treating juvenile myasthenia gravis and other congenital forms. It highlights the use of pyridostigmine for symptom management, corticosteroids, and more advanced medications like rituximab and ameliorative surgical interventions such as thymectomy. Moreover, the talk briefly mentions complementary drugs and therapeutic measures in specific genetic cases, cautioning against potential side effects and emphasizing personalized patient care based on clinical and genetic findings.<br /><br />Overall, the discussions underscore the complexity and nuances of managing pediatric neuromuscular disorders, emphasizing the critical role of genetic insights, tailored pharmacological interventions, and sometimes surgical measures to improve patient outcomes.

Keywords

pediatric

neuromuscular

genetic testing

diagnostics

treatment

exome sequencing

mutations

acetylcholine

myasthenic syndromes

pyridostigmine

thymectomy

personalized medicine

patient care