During this live webinar, Dr. Mackay will discuss the pathophysiology, diagnosis, and treatment of ocular myasthenia gravis. We will review common examination findings in patients with myasthenia with patient videos and review medical literature relevant to the disease. Participants will also learn about the utility of diagnostic, pharmacologic, and electrophysiologic testing in the evaluation of patients with possible myasthenia.
Lecturer: Devin D. Mackay, Director of Neuro-Ophthalmology, Indiana University School of Medicine, Indiana, USA
Devin Mackay: Hello everyone, my name is Dr. Devin Mackay and I’m the director of Neuro-Ophthalmology at Indiana University in the United States. I understand we have quite a large gathering here of people from around the world, and I welcome all of you and hope you’ll be able to learn something today about Ocular Myasthenia Gravis which I think is a topic that is, that is not discussed often enough in ophthalmology circles. And there’s something, I think that each of us can, can learn from this topic and how to manage our patients who have it.
Okay, so let’s go over some objectives for today’s Webinar. Today, I’d like us all to become familiar with a typical history and examination and also testing findings in patients who have Ocular Myasthenia Gravis. Also, we’re going to be able to describe antibodies that are associated with Ocular Myasthenia Gravis, there have been some relatively new antibodies discovered in recent years that role in the pathogenesis of the disease and can be tested for clinically. Also, we’re going to be familiar with some special examination techniques to elicit evidence of Ocular Myasthenia Gravis.
It is a clinical diagnosis, and so having tools in your examination tool bag, to be able to examine someone properly who may have Myasthenia Gravis could be really, really important in affecting your clinical suspicion condition. And then finally, we’ll want to apply some basic principles to the management of patients with ocular Myasthenia Gravis and discussing how do we care for someone with this condition and what are some principles to keep in mind.
Let’s start with an introduction to Myasthenia Gravis. It is an autoimmune disorder and it is caused by antibody mediated blockade of neuromuscular transmission and that causes specifically skeletal muscle fatigue ability and weakness. And this autoimmune attack, it impairs the function of specifically nicotinic post synaptic acetylcholine receptors on the muscle cell, and that’s also known as the motor end plate.
So, to understand Myasthenia Gravis, we also need to understand a little bit about normal neuromuscular transmission. And so, let’s look at that on the left side of the slide. We see a neuron that is innovating a muscle fiber and the small square at the top part goes into the middle portion of the figure and shows us a zoomed in portion that shows acetylcholine being, being released from the pre-synaptic terminal. And the acetylcholine goes into the synaptic cleft and then it activates receptors on the motor in-plate which is also the post-synaptic membrane. And the binding of acetylcholine to its receptor causes an opening of the channel and that causes an influx of sodium ions. The sodium ions cause a deep polarization of the muscle cell and that leads to contraction of the muscle.
Now what is the difference between that and normal neuromuscular transmission, at near muscular junction and Myasthenia Gravis. Well, as we see in this figure on the right side, acetylcholine being released into the synapse has fewer nicotine receptors available to it to cause muscle contraction. Because those antibodies are attacking the receptor that causes a decrease in the number of functionally available receptors and that results in decrease muscle power because there’s decreased muscle contractility in that state.
Here’s a figure that I really like from the New England Journal of Medicine from a nice review article published in 2016 and it looks at some of the important targets to understand the path of physiology of Myasthenia Gravis. So, a few things to focus on from this figure, one is of course the antibody target itself which is the acetylcholine receptor. Another is acetylcholine and these are going to be therapeutic targets when we’re talking about treatment of Myasthenia Gravis.
So, some of the treatments will be geared toward decreasing the antibody response to the receptor and other forms of treatment are geared toward increasing the activity of acetylcholine within the synaptic cleft. And another avenue of treatment is to modify the activity of the acetyl and acetate enzyme that is found in the synaptic cleft. Its job is to break down, it’s colin and so, inhibiting the activity of this enzyme causes an increase in the activity of acetylcholine in the synaptic cleft. And it’s also its activity in activating the acetylcholine receptor and that is of course very important because that’s how muscle contractility will be determined.
And then finally this underlined portion here the musk antibody receptor. So, this is a portion of the post synaptic membrane that is important for aggregating acetylcholine receptors and so that’s important for the development of the neuromuscular junction and also important in its function. So antibodies against that particular portion can cause Myasthenia Gravis, and then finally one more is the LRP4 receptor which is relatively recently described and the antibodies can develop through that receptor. It’s a receptor for Agrin which is a molecule that’s important again for the clustering of acetylcholine receptor, receptors at the post synaptic function here in the neuromuscular junction.
Now I’m going over these antibody types. Clearly the most important for Myasthenia Gravis is the acetylcholine receptor antibodies and there are three different flavors that can be tested. So, one is the binding antibody and that is the most sensitive. It’s rare to have false positive errors but they can happen with the binding antibody. And so, if you’re just going to test one antibody for Myasthenia Gravis, this should be the one, that should be the binding antibody.
Some places offer a panel for Myasthenia Gravis antibody testing that includes all three of these and that’s great if you have that. But if not, again the binding is the most important. The blocking antibody adds a little bit of specificity, it is helpful when you feel that there may be a false positive binding result. There’s almost no false positive with blocking antibodies, and so that can, that can be a helpful out on test in those cases.
And then the modulating antibody adds maybe about 5% of sensitivity to the binding and blocking antibodies. And so, it can help provide a more complete picture but again binding anybody’s are the most important. Other antibody types that can be tested for include the anti LRP4 antibodies and those occurring about one to 3% of Myasthenia Gravis cases. If we consider just zero negative cases, so in other words, cases where the acetylcholine receptor antibody testing is negative and MuSK antibody testing is negative and it could be about 10% of those cases that are still negative. They tend to have milder disease, so with only mild to moderate symptoms, and also it tends to be present in younger patients, the LRP4 antibody. It is quite rare in patients who have just isolated Ocular Myasthenia Gravis. There are a handful of case reports in the literature but it’s, it’s quite rare to see just isolated anti LRP4 antibody positivity with isolated Ocular Myasthenia Gravis.
Anti MuSK antibodies are a bit more common than LRP4 and it constitute about 8% of Myasthenia Gravis. It’s rare to find a case of isolated Ocular Myasthenia that is MuSK positive, but I have had patients who have ocular symptoms, it’s just that they’re not isolated Ocular symptoms. So, most patients will also have some bulbar weakness or facial weakness, those are typical findings in MuSK, however some patients can also have limb weakness or ocular findings. And then Seronegative patients about 6% of generalized Myasthenia patients end up being Seronegative, however the number is much higher for ocular Myasthenia Gravis. So maybe around 50% I see numbers anywhere from about 40 to 65% of patients who have Ocular Myasthenia Gravis who are negative, meaning all their antibody testing is negative. And those could be kind of a diagnostic challenge. And that’s why we’ll go over some techniques for how to diagnose those patients later on during this webinar.
Another pearl is that serological testing should typically be repeated after about six to 12 months if there’s been a previous negative result. That adds probably about 15% of patients will later on developed antibody positivity, whereas they don’t have it early on in their disease course. And so for that reason, if you have a negative test it’s often worth serological testing being repeated at some point in the next six to 12 months. All right so this brings up our first question or first webinar question. And that is which of the following muscles or muscle groups is most likely to show weakness related to Myasthenia Gravis? And the options are, the urinary bladder, the Frontalis, the Iris or the superior tarsal muscle. So this is a, this is a difficult one, don’t feel bad if you, if you don’t get this, but it does illustrate, I think the answer illustrates an important point about what muscles are affected by Myasthenia Gravis.
Okay so the, most people said the superior tarsal muscle. And that’s a great thought, you think well. Superior tarsal muscle, it causes elevation of the eyelid, and so if that’s not working that’s going to cause tarsals, right? And yes, it will. The thing that’s really tricky about this question though is that the superior tarsal muscle is actually not striated muscle. And so, it is, remember it is part of, it is a muscle that’s affected when someone has hoarder syndrome. So, it’s under control of the autonomic nervous system, the sympathetic nervous system.
And so, for that reason it’s involuntary muscle, and so it actually is not affected by Myasthenia Gravis. So, the only skeletal muscle on that list is the Frontalis muscle. So the Frontalis muscle would show weakness from Myasthenia, whereas the others are involuntary or non striated muscle. And so, they will not be affected by Myasthenia Gravis, so. So that’s important principle that only voluntary striated muscle is affected by Myasthenia Gravis.
Let’s say a few words here about the epidemiology of this condition. So, it’s worth knowing that there is a bi-model age distribution in Myasthenia patients with acetylcholine receptor antibodies. So we see that here in this chart, which shows that men and women have different incidences of Myasthenia Gravis at different stages of their life. So, the white bars show men who are positive for acetylcholine receptor antibodies. You notice a peak in the seventh and eighth decades there where patients who are at that age are more likely to be men. Whereas, if you go to younger ages, on the fourth and fifth decades for example and even the third decade most of the patients who have acetylcholine receptor antibody positivity are women.
And so, so again women higher prevalence in the ages, 20 to 40 and men have the higher prevalence in ages over 60. Now let’s talk a little bit about the history that you’ll hear from a patient who may have Myasthenia Gravis. So what are some of the things you want to watch out for, and maybe even specifically asked for if you suspect Myasthenia Gravis? One of the things to know is that fluctuating ptosis and diplopia are really the cardinal features of Ocular Myasthenia Gravis especially, especially the variability.
And more than 50% of all Myasthenia patients first present with ptosis and/or diplopia. So that includes even generalized Myasthenia patients. There are some other common symptoms to screen for and to ask about if the patient doesn’t volunteer them. One is weakness of bulbar muscles. And so those are muscles that control the lower part of the face and control our ability to smile and to chew and to swallow. And so, it can cause fatigue ability of those muscles.
And speech, so speech may sound mazel also with palatal muscle weakness or their voice maybe kind of hypo phonic, so they may have difficulty projecting volume. And the nasal quality of the speeches, again due to the MuSK, palatal muscle not being able to elevate appropriately when it’s weak, and then patients can also have facial muscle weakness and that can include difficulty smiling or what’s been referred to as the myasthenic sneer. And that’s what this young woman has in the top right hand part of the slide. You noticed the woman that kind of has a sneer on her face and she’s trying, she’s trying really hard to smile but she’s not able to smile normally because of her myasthenia. She was at a graduation party and you can see everyone else having a great time, and she is too, she’s just not able to express it as well.
And with the myasthenic sneer, the middle part of the lip will come up but the corners of the mouth don’t come up as well, and also the lip position will often be down as well and that leads to this sneer like quality to the facial expression. And patients have orbicular weakness as well that makes it difficult for them to fully close their eyes in some cases. And then also neck muscles can be effective. I will often ask my myasthenia patients; do you ever have difficulty holding your head up? And then patients with real severe cases, they sometimes even need to wear a neck brace to help keep their neck up because the neck is so week. Here’s some statistics that could be useful in helping us know what to expect with some of our possible myasthenia patients. And about 15 to 25% of patients with myasthenia, the patients only have symptoms of their extractor muscles.
So in other words they’ll get double vision and limitation of ages that will be from myasthenia and have no other symptoms at all. About 90% of patients who have purely ocular myasthenia, if they have, and it’s still purely ocular myasthenia at two years from the time they’re symptoms started then they probably won’t ever develop generalize myasthenia, so it will probably stay ocular, so most patients who do have a conversion to general Myasthenia Gravis do so within the first two years. And then about 50 to 60% of patients who have initially isolated ocular involvement going to generalize weakness. So more than half, and that’s typically within the first three years after symptom onset. Majority of patients have ocular symptoms at onset, so that’s most patients of course and even if they already have, even if they also have generalized weakness.
Now let’s look at some measurements of lid position. When we’re examining a patient for possible myasthenia, we need to have some of the fundamentals really mastered and one of those I think would be to be able to reliably measure the lid position. Let’s go over some terms that you may be familiar with. One is the MRD1 distance and that is the distance between the corneal light reflects and the upper lead margin. And MRD2 is the distance between the corneal light reflects and the lower lid margin. And then the Palpebral Fissure height is the distance between the lower and the upper lid margin. One thing that is very important in the physical examination of someone who has ptosis, especially in someone who has suspected myasthenia causing ptosis is to be able to properly measure the levator function. And that is measured us followed, as follows.
You can place a ruler at the upper lid margin of the patient while they’re looking down. So, this patient is looking down as far as they can, and you place the zero on the ruler right at that upper lid margin. And then you have the patient look up completely, look up as far as they can, and you do that without changing the position of the rulers, keep the ruler in the same position and make sure their head stays still. And you measure the distance that that upper lid traveled between the down position and the up position. In this case it would be about 16 millimeters which would be normal and this is a very useful measure of levator muscle strength. And it’s very helpful I think in distinguishing ptosis that’s related to muscle weakness from mechanical ptosis.
It’s important to note that measuring the elevator function and if it’s abnormally low that does not confirm that it’s myasthenia. But it does confirm that the muscle is the problem and that could be really helpful if you’re trying to distinguish a mechanical cause of ptosis with normal muscle function from one that has abnormal muscle function or abnormal neuromuscular junction function as in Myasthenia Gravis. Let’s look at some signs that we can see on the physical examination that can suggest Ocular Myasthenia Gravis. One is fatigable ptosis with sustained upgazed.
For this, what you do is have the patient look up for two minutes, two minutes is a very long time and often we don’t have the patience to wait exactly that long. If a patient develops ptosis that is worsening during those two minutes, you don’t necessarily need to finish with the entire two minutes but if you don’t see it to really say there’s no fatigable ptosis, you really need to continue it for the two minutes to know that for sure.
And you can compare the MRD1 distance or the palpebral fissure height before and after the sustained upgaze. And in this figure, we see the patients face on the left is before doing sustained upgaze, and then afterwards you see the lead position in both eyes is lower than it was before. This is helpful and can support a diagnosis of Myasthenia Gravis. However, it does not exclude non myasthenic causes of ptosis. There are other causes of ptosis that can also show some fatigability. So that doesn’t mean this test is useless, but it does mean that it really shouldn’t be the only feature that would support myasthenia there should be other features as well.
Now let’s look at a phenomenon called enhancement of ptosis. And this is a patient I saw that will play a video for in just a moment. What I will do is I will raise the patient’s left upper lid with my finger, and as I do that, I want you to pay attention to the right upper lid and see what happens when I flip the left lid. Noticed that right lid, what happened to it? And now on the other side, the left lid it came down as I pulled up the right lid, so as I pulled up one lid, the other lid had more ptosis. And so, we can describe that as an enhancement of ptosis. And that is explained by the Hering law of equal innervation.
So if you raise the eyelid on one side, you’re effectively decreasing the innervation that’s being provided to both upper lids and that will cause a increased ptosis in both eyes. We don’t see it on the side that we’re pulling the eyelid up on because we’re pulling the eyelid up. And so that relaxation of the contralateral levator can be a sign of myasthenia, it’s not perfectly specific for it but it is one feature that can help support the diagnosis. As a warning, it can also be seen in other causes of ptosis such as congenital ptosis and sometimes some non myasthenic causes of ptosis as well.
Cogan’s lid Twitch is another well described abnormality, and as we look at this video, we’re having the patient look down and as the patient is looking down, the patient is resting their lid, their upper lids. As they arrested, we know in patients with myasthenia the lid is going to work better. And so when the patient is asked to then look straight ahead, the lid will come up quickly and it will come up so quickly that they will often be a twitch near the top of the movement, and then the lid will settle down again as fatigability quickly sets in again. So, let’s see that in this patient, notice especially her left upper lid as I play the video.
So, there was a twitch as she raised the eye lid up. And that was only after a period of resting the lid. What I typically do is have the patient looked down for about 10 to 15 seconds and as they do that, that’s resting the lid, and then I have them look at my nose or some other target that is straight ahead and that’s a saccade produced illicit twitch of the lid.
The principle is that the ptotic lid overshoots and then the fatigability of the lid sets in and that lets the lid settle down in a lower position. So that’s called Cogan’s lid Twitch. In the same patient, we’ll also look at an example of a Pseudo INO or Pseudo Internuclear Opthalmoplegia. This patient right now is looking to the left as we’re starting the video and once the video starts, I want you to pay attention to the left eye and what it does is it’s doing an abduction movement toward the nose. Never look left and do it right one more time, look at that left eye.
So notice that not only was the abduction incomplete, but we also noticed that the saccade was slowed toward the end of the saccade more than at the beginning of the saccade. So in other words, the movement started quickly but then slowed down toward the end. And that’s a common feature with Myasthenia Gravis that at the end of the saccade there will be a market slowing.
So this is a common pattern of eye movement abnormality in patients with myasthenia and I’ve had quite a number of patients referred to me for what someone thought was Internuclear Opthalmoplegia and instead they ended up having Myasthenia Gravis. So that brings up an important point. How would I distinguish those in my clinical practice? How would I distinguish Pseudo INO from myasthenia versus a true Internuclear Opthalmoplegia? There are some principles that could be helpful. One is that abduction typically improves with convergence in true Internuclear Opthalmoplegia and that’s because with Internuclear Opthalmoplegia, the convergence centers in the midbrain are not involved. And therefore, abduction can still continue normally. However, with Pseudo INO from Myasthenia Gravis, abduction should not improve with convergence because the effect is on the final common output of that convergence movement which is at the neuromuscular junctions. There’s not a way to get around that as there is with, with a true Internuclear Opthalmoplegia.
And again the slowing at the end of the abducting saccade, you really have to look for that but once it’s pointed out it is something that’s fairly obvious in some cases. Again, in some cases it could be more subtle, that’s helpful when you do find it. Other causes like a cranial nerve palsy that can cause a slowing of, of saccade. They do so fairly uniformly throughout the movement and it wouldn’t just be at the end of the movement as in the case with myasthenia. And here we’re going to discuss a signing called, the Peak sign. You’ll notice that there’s a code in the top right corner of this slide and that will allow you with your smartphone to get out your camera and you can focus on that QR code and you can actually pull up the journal article for this Peek sign. There will be several other articles that are referenced in this way throughout the talking and feel free to access each of those with a QR code if you’d like.
The Peek sign is caused by Orbicularis weakness which causes eye closure weakness. And so, we see in panel A, the patient has her eyes open and looks normal with a fairly normal lid position. And in panel B, the patient is being asked to gently close their eyes and you’ll notice that the eyes are fully closed, there’s not any show of the sclera there, no sclera is visible. However, within two seconds of the patient keeping her eyes closed, the palpebral fissure widens and that exposes this sclera. So that’s called the Peek sign. It’s not a very sensitive test for Myasthenia Gravis, it’s only seen in three out of 25 patients in this particular study, but it is more specific.
It was only seen in one out of 50 patients who had facial weakness from other neuromuscular disorders. So in other words if you see the Peek sign, it’s fairly helpful in saying that yes this could be from Myasthenia Gravis. If you don’t see it, it’s not as helpful in saying whether someone does or does not have myasthenia, so the Peek sign can be useful. It can also be the only sign of myasthenia in some patients.
The Ice Pack Test has been a very popular test and has generated a lot of questions from people about how best to use and how to interpret the test. This is from a picture in, from a journal article in the New England Journal of Medicine showing a patient in panel A, before the application of a nice pack and then the ice pack being applied and then B, and then afterwards and C, showing some market improvement in the left upper lid ptosis. The reason the Ice Pack Test seems to work is it reduced muscle temperature is thought to inhibit ascetical and asteria activity.
So, in other words, you’re increasing the concentration of acetylcholine within the synaptic cleft and that’s going to improve transitly neuromuscular transmission. It’s also worth noting that the patient is also keeping their eye closed during the duration of the test, and so that rest may also contribute to the positivity of the Ice Pack Test. But primarily it’s thought to be an issue with reducing the muscle temperature that increases the abundance of acetylcholine within the synaptic cleft.
Now, the way you do it is, you place an ice pack on the patient’s eyelid for about two minutes. If the patient has bilateral ptosis, you could spread out that ice packing over both eyes and over the bridge of the nose or if it’s just one eye, you could have them placed the ice pack just over one eye. And so that two minutes is important, we really need those two minutes. Sometimes longer test could also be done, however it’s, it could be quite uncomfortable for the patient. If any of you have tried to put an ice pack right on your eye for two minutes, it’s very uncomfortable. So, two minutes is usually sufficient for our purposes.
It’s important to note what we’re looking for when you take the ice packed away. What you’re looking for is a change in the lid position not necessarily a change in the ocular alignment and that’s a common misconception. So, patients eye alignment often won’t change and that’s probably because the ice pack effect is not getting deep enough into the orbit to really affect the extra ocular muscles in a meaningful way. But it is right there on the elevator muscle and so that can affect that much more easily.
With longer ice duration you might be able to affect the function of the extra ocular muscles, but again, that’s quite uncomfortable for the patient and also is less well studied. For myasthenia related to assist the sensitivity of this test is fairly high, 92%. What it’s not as good at is being specific for myasthenia which is about 79%. So that combination gives it a fairly high negative predictive value which makes it helpful in ruling out myasthenia related ptosis. So where I think the Ice Pack Test is most useful is if you’re not quite sure if someone has myasthenia and you’re really trying to rule it out and especially in patients who have ptosis.
So if you put the ice back on and it does not change the ptosis then it’s likely that they don’t have Myasthenia Gravis. However, if it’s, if you’re not sure if someone has Myasthenia Gravis or some other cause of muscular weakness causing ptosis, it may not be as helpful in distinguishing those. But if you’re looking for is mechanical ptosis versus myasthenia or something like that it could be very useful. So I do tend to use it in my clinic.
All right we’re ready for another question here, and so the question here is do you have access to edrophonium or neostigmine? These are medications that are sometimes used to pharmacologically give a diagnosis of Myasthenia Gravis. Personally, I don’t have access to either of them and I know in the United States it’s difficult to get either one. But I would appreciate any feedback from anyone about if you do have it or if you have one of the other or neither. And some of the slides later on in this webinar we’ll deal with how to how to use edrophonium or neostigmine and testing, but we may go through those quickly if no one seems to have access to it.
Okay, so looks like 71% have no access to either, about 6% have both, some have just edrophonium and then some more have the neostigmine. So I’ll go through this part of the webinar fairly quickly since most people don’t have access to either. But also this webinar can serve as a reference in the future and you could go back to these slides to help understand how you would use both of these.
So just briefly the edrophonium test is a reversible acetylcholine, excuse me, acetylcholinesterase inhibitor and it’s injected intravenously. The benefits to it or it’s very rapid onset, less than 30 seconds and also a short duration last about five minutes and then the effect is on. So the way you would test the patient is you had measure their lead position and eye alignment and then you would put 10mg of edrophonium in a syringe, you give a test dose ivy of 2mg and you look for improvement in the ptosis or the eye alignment or the range of the eye movements. If you notice an improvement in those things then the test is positive and you don’t need to continue. If there’s no improvement after about 30 seconds then you keep giving 2mg about every minute or so until you notice a response or until you’ve reached the maximum of 10mg.
There are some major side effects that can happen in a minority of patients including bradycardia, even asystole, a syncope or seizures, so it’s important to have atropine in available at bedside at the time of the test. The sensitivity is somewhere between 60 and 95% in Ocular Myasthenia Gravis, so it’s not perfect and therefore a negative test does not definitively rule out myasthenia. Also, you can get some false positive tests and certain other conditions like Guillain-Barre or ALS or botulism, and so not a perfect test but can be very helpful if you have access to it.
And now we’ll spend a minute talking about Neostigmine, so the neostigmine test is a little bit different. It has a longer duration of action than edrophonium, and so for that reason it’s especially helpful in patients who have diplopia without ptosis and also for children where it’s a little harder to measure them or to capture their examination findings in the time you need to do other tests. So, the procedure for administration here is to mix some atropines 0.6 mg with 1.5 mg of neostigmine and you put that into a 3-cc syringe and you can inject it into deltoid or gluteus muscle. And the effect is not as not as quick as euphonium but it, you look for in effect within about 30 to 45 minutes. You need to monitor the patient with pulse oximetry and cardiac monitoring for about two hours afterwards, so it is kind of a intensive test in that way.
The sensitivity is pretty good, so 70 to 94% that you’ll see some change after administering the medication. All right now let’s talk about some other tests here that are part of the physical examination. One is the Rest Test, and so what was done in this particular study is that there was a measurement of the baseline lead position and the ocular deviations or ocular misalignment and it was also photographed.
So then, the patient was told to rest with their eyes closed for 30 minutes and then the lead position and ocular deviations were again looked at and photographed, and that was done repeatedly over the next five to 10 minutes. And what they found was that 42 out of 42 patients who had already been proven to have myasthenia with a tensilon test had a positive rest test, so all of them had the positive rest test.
They also examined 26 other patients who had ptosis or Opthalmoparesis from other causes unrelated to myasthenia and all of them showed no improvement after that 30 minutes of rest. So, this looks to be a very promising test and I’ve used it a few times myself and it’s, it’s been useful where you can, the main difficulty with using it is that it requires the eyes to be closed for about 30 minutes. If you see a market improvement in someone’s ptosis or eye alignment after less rest in that, that’s okay and that can still support myasthenia. But to really rule that out it would need to be 30 minutes or maybe, or maybe even longer in some patients. But it’s a very useful test and of course there’s no side effects, if someone happens to need to be in the waiting room for another reason, anyway you can instruct them to do this and it’s a very good use of that time in the waiting room, and so it could be very useful to support a diagnosis of myasthenia.
Now how about diplopia? How would we approach diplopia in patients with myasthenia? Well, the first is to obviously verify that diplopia is binocular. If it’s monocular it’s not going to be myasthenia related. It’s also useful to measure the misalignment if you can, if you have prisons available to you that could be really useful in documenting the variability. It’s also worth noting that any pattern of misalignment is possible, so myasthenia could do just about anything with regard to ocular alignment patterns. Common pattern is Pseudo Internuclear Opthalmoplegia as we discussed earlier but really again any pattern alignment is possible.
A myasthenia related diplopia is really not well treated with prisms or strabismus surgery in most cases unless there’s an exceptionally stable ocular misalignment or exceptionally stable ptosis which is very rare. Now how do we get the diagnosis? Well, it’s made clinically, typically with the history and examination. Positive antibody testing does confirm the diagnosis, but many cases are Seronegative, especially ocular myasthenia cases. So pharmacologic testing is no longer use as commonly in the past, so most of us don’t have that available to us to confirm the diagnosis but it’s great to use still if you do have it. And so, confirmatory testing with electrophysiology is helpful in Seronegative cases and this is really what I try to use if someone comes to me and I think they have Myasthenia Gravis but I’m not entirely sure and their antibody testing is negative, what I usually do is proceed with electrophysiology testing.
So one way to diagnosis those cases that are Seronegative is to combine the clinical characteristics, the EMG findings and then also the expected response to therapy if you do choose to known therapy. I usually think it’s a good idea to seek EMG confirmation of Myasthenia Gravis if possible, in seronegative cases before using any immunosuppressant medications. And that’s really because of the side effects of them and really needing to make sure that we have an accurate diagnosis before we put someone through that. And again, consider repeating anybody testing later on down the line if you have a seronegative case.
As far as the expected response to therapy, medications like pyridostigmine that inhibit the acetylcholinesterase enzyme. Those often work in about 30 minutes, and so if patients have a reliable improvement in their symptoms, 30 minutes after taking that medication, that also supports the diagnosis of myasthenia, I have also seen what I think is a placebo effect in some people who don’t have myasthenia who have tried it as well, so you do have to be careful with that.
Now, electromyography, there are different parts of electromyography that are useful in the diagnosis of myasthenia, so we’ll go over two of them right now. One is a technique called repetitive nerve stimulation, and what it involves is stimulating a motor nerve at a frequency of about two to three hertz and then recording the compound muscle action potential that’s on the CMAP. And the CMAP, if you do that repetitive stimulation and someone who’s normal will look like the upper tracing in this figure which is that the amplitude stays constant.
However, in someone with myasthenia, they expected effect is that there will be a detriment in the amplitude of the CMAP with that repetitive testing, and you’ll notice after about four to five stimuli that are applied, you get this kind of maximal decrease in the amplitude of the CMAP and then that fear that that kind of stabilizes. So if that document is more than 10%, that’s something that would support a diagnosis of myasthenia.
This is really useful especially in generalized myasthenia, it’s not a sensitive and ocular myasthenia but when you do find it it’s pretty specifics. So about 90% specific for myasthenia if you do find it, so the absence of it doesn’t mean that someone doesn’t have myasthenia but if you do find the document that really strongly supports the diagnosis of myasthenia, so that’s one technique repetitive nerve stimulation. Now before I talk about the second technique, I want to see how many of you have access to it. So it’s called single fiber electromyography. And so, so let us know if you have that available either at your practice location or nearby, you could easily refer to someone who has it to get that testing on so it’s useful for you.
Okay so the majority was no, about 68% no, however a good number, yes about 32% said yes that they do have it. So I’ll go over this briefly for those who do have it. And this explains what it is. So single fiber electromyography is a, is an EMG technique that is more technically difficult than standard EMG, and so for that reason it tends to not be available everywhere where people do EMGs and it’s more specialized centers in lot of cases. It’s often performed in screening for Ocular Myasthenia Gravis in patients who are Seronegative. And so, and those patients that can be done in the Frontalis muscle, some patients have it done in the Orbicularis muscle instead. And so, either one of those could be done. And what happens is an electrode is positioned to record action potentials from to muscle fibers that are innovated by the same motor neuron. And so, we see a graphic of that on the left side here, we have an electrode and it’s recording from two muscle fibers and they’re both innovated by the same motor neuron.
You may also use the, see the term used motor unit which is defined as the muscle fibers that are innovated by one motor neuron. And the difference in latency between the stimulus to the nerve and the muscle action potential between those two fibers is called the jitter. So if there’s more variability and how long it takes that impulse to get from the nerve down to actually causing a muscle contraction, the more variability there is, the more jitter there is, and the more that would support an abnormality of the neuromuscular junction. And in many cases that would be Myasthenia Gravis. So that’s how single fiber electromyography works. And again, that’s kind of my go to test if possible, in patients with suspected Ocular Myasthenia Gravis who are zero negative and I’m still needing more confirmation of diagnosis.
Also an important part of myasthenia management is to get media spinal imaging done. And that’s because about 10% of patients with myasthenia have a thymoma that prevalence increases with advancing age. However even patients with thymic hyperplasia may also benefit from thymectomy. And so, CT imaging can also be useful in that regard as well. And it really should be done in all patients with myasthenia and the primary purpose is to screen for a thymoma. So the thymus plays a key role in inducing acetylcholine receptor antibody production in myasthenia patients. And all patients who have a thymoma should undergo thymectomy, like it’s a recommendation. Now patients who are younger who developed myasthenia. So age less than 50 or 60 kind of depending on what, what literature you’re looking at, those patients who have generalized Myasthenia Gravis are almost all antibody positive.
And those patients almost all have thymic hyperplasia, and so those patients usually do benefit from what we call early thymectomy. So there is some debate over what that exactly means, early thymectomy, but in most cases it’s recommended within three years of the onset of symptoms, and so again, these are for younger patients with generalized myasthenia who typically have antibody positivity and also they will, yeah. They are in positivity. The other thing to know is that if there is no thymoma, a thymectomy is not recommended, if they have anti MuSK antibodies or anti LRP4 antibodies or if they have Ocular Myasthenia Gravis alone. So those patients tend to have a milder course of illness and, and the benefit is not as clear from thymectomy.
The one exception in ocular cases maybe if they have truly disabling Ocular Myasthenia Gravis than it could be considered. All right, so let’s have a question here to understand the, the utility of thymectomy and the management of myasthenia. So in which of the following patients with myasthenia with thymectomy be most strongly recommended? A, a 60 year old man with purely ocular myasthenia, B, a 45 year old woman with generalized myasthenia and positive anti MuSK antibodies, C a 30 year old woman with generalized Myasthenia Gravis or D a 70 year old man with a generalized myasthenia and no thymoma. So, in which of these would thymectomy be most strongly recommended?
Okay most said that 30 year old woman with generalized Myasthenia Gravis, and that is the correct answer, good job. The reason some of these others are not correct. So the 60 year old man with purely ocular myasthenia, again purely ocular usually not thymectomy is usually not recommended unless they have a thymoma. And then the 45 year old woman, she had positive anti MuSK antibodies and that is usually not an indication for thymectomy and then a 70 year old man with generalized myasthenia just being in the older age range on those patients may not benefit as much from thymectomy unless there’s thymoma and this patient had no thymoma.
Now let’s go over symptomatic therapy. Pyridostigmine is the preferred drug of treatment for symptoms, so it does not modify the disease but it does treat the symptoms by inhibiting the function of the acetylcholinesterase enzyme which increases the availability of acetylcholine within the synapse. The doses decided based upon the effects on the symptoms and also those dependent side effects that will often limit how you can go on the dose and those side effects can include things like diarrhea, abdominal cramps, increased flatus, nausea, urinary urgencies, sweating, salivation increases.
And remember these are all effects that happen because you’re increasing the availability of acetylcholine. However, that’s going to have effects on non nicotine receptors as well, so it’ll have effects on muscular equine receptors on the autonomic nervous system, and so that’s where the side effects come from. If the symptoms are mild and they’re near-remission, you really don’t need to have any other drug therapy, Pyridostigmine alone is fine.
It’s also worth mentioning that there are some medications to avoid in Myasthenia Gravis and these are drugs that interfere with neuromuscular transmission and that for that reason can exacerbate myasthenia. And so, here’s a list, there’s a long list and there are more that are not on this list, but these are some common ones to be aware of that can interfere with neuromuscular transmission and really be a bad idea in patients with myasthenia. There are even some ophthalmic drops that do have some systemic absorption and they are also capable of exacerbating myasthenia. So those are, some of those air listed here. And these effects are not enough to cause symptoms in most normal patients, but if you have someone, especially someone with brutal myasthenia, a medication like this can interfere with this small amount of remaining normal neuromuscular transmission that they have.
Now what about immunosuppressive therapies? So most patients do need to meet a suppressive therapy, and the first line treatment usually involves prednisone or prednisolone and also often a combination of that and azathioprine. And there is some weak evidence that alternating day dozing can reduce side effects, but that’s not definitive. And that alternating, the course of medication also usually doesn’t cause any disease fluctuation, so it’s safe, but again it’s not, not definitive evidence that that helps but I see some people doing that. Prednisone, when it started, it usually started at a lower dose of maybe like 20 mg a day and then it’s increased up to somewhere between 60 and 80 mg. It could be an alternating day or on a daily basis. And the increase is usually done about every three to five days.
You start out with 20 mg, you might increase by five mg every three to five days until you get up to the max and then you taper more slowly maybe five to 10 mg per month or so, and then once you get down to lower doses of below 30 mg and you slow down the tape for a little bit more and maybe about five mg a month at that point. So, after the stable control of symptoms, you can start tapering. So if you get the relief of symptoms before you get to 60 or 80 mg you could just stop where you are hold for maybe a month and then start to slowly wean off the medication prednisone. There is some evidence that prednisolone monotherapy reduces the risk of generalization of ocular Myasthenia Gravis, but all of the data there is retrospective. There has not been a prospective study looking at that, so we really don’t know. So, it might reduce the risk of generalization but that again that’s not definitive.
Mycophenolate mofetil can also be considered as a first line medication instead of as a thigh print. However, both of those medications probably take somewhere between six months and a year to really become fully effective and to allow you to effectively decrease the dose of prednisone, so don’t expect those medications to work quickly. Some alternatives, if needed include methotrexate, cyclosporin and even tacrolimus. Rituximab has been used in cases with severe symptoms and can be effective. And also IVIG and plasma exchange which we can talk about here with severe exacerbations.
Most patients with a severe exacerbation need to be hospitalized and that’s because of the risk on respiratory muscles and the effect that it causes there and often the need for intubation and a lot of these patients. If for that reason may require intensive care, IVIG or plasma exchange are often useful there, those could take a little bit of time to take effect but they’re helpful in those acute severe exacerbations.
Supportive care with treatment of the precipitating event if there’s an infection or something like that, that should obviously be treated. And then, long term immunosuppression should be intensified after the patient improves, or if they’ve never been treated with immunosuppression that should be started. But again, the patient really should be stable first. So, make sure that their symptoms are under control first. And then I mean, a suppression can be dealt with afterwards to help maintain the new state of close to remission.
And here are some references that are available if anyone’s interested. All right. So, that concludes the lecture portion of the webinar. And now, we’ll go ahead and answer some questions that came up in the chat. So, does Ocular Myasthenia gravis cause fatigue? Well, it can cause a sensation of fatigue. So, some patients may interpret their muscle weakness as being fatigue. But I guess it depends on how we’re defining that term. I would say that, I would say that it really doesn’t cause fatigue itself, but it can cause a sensation like fatigue, because of the muscle weakness. But it shouldn’t cause other features of fatigue like, sometimes sleepiness or other things can be part of fatigue, and it doesn’t do those things.
Okay. And then Vivek Anandan asked a question about the relation between Myasthenia Gravis and a facial palsy. And so, Myasthenia Gravis can cause a facial palsy. It would be unusual to have a profound facial weakness from myasthenia with no other signs or symptoms of myasthenia. So, that would be a red flag for me if I see pretty profound facial weakness on one side, and no other signs of myasthenia.
And again, you also want to make sure that you look at the fatigue ability and see if that’s an issue. So, try to make the patient smile and maybe hold a smile or you can try other things to increase the muscle activation. And again, the principle with myasthenia is the more you activate entire out that muscle it just, it tires out abnormally quickly. So if that happens, then that’s going to support your diagnosis of myasthenia well. So, that can be useful.
Samia Ar [Phonetics] asked the question, is the convergence, presence or absence a sign of interior versus posterior? I don’t know. So, yes, in a way, I guess it depends on how you’re using the terms interior and posterior. So, there is a version of internuclear ophthalmoplegia, that involves the very top portion of the medial longitudinal fasciculus. And if it’s up there, it can actually involve part of the third nerve complex as well. So, the ocular motor nerve nucleus, and if it does that, then you also, even with convergence, you won’t get proper convergence in that eye because the third nerve is involved. And so, you can get INO plus a third nerve there that will cause that so. So, in those INO, yes, but most INO’s don’t involve the third nerve nucleus. And so, most of them will have preservation of convergence for that reason.
It’s especially helpful I think, in patients who have a really profound adduction weakness in INO patients who have one that’s only mild or there’s just slowing of the adducting suckered. Those can still look like they have full convergence, and it can be just really, really hard to tell the difference. But if they have a really profound INO then that’s really useful to see that the convergence is present.
Okay, and then we have a neurologist from Ukraine, who asked a very good question about how should we manage a pregnant patient with Ocular Myasthenia? So, a lot of the same principles apply to a patient who is pregnant who has Ocular Myasthenia gravis, really pyridostigmine can still be used, and that’s appropriate if it’s helpful. And also, prednisone is probably the medication of choice in patients who are pregnant with myasthenia.
If patients who are pregnant with myasthenia and have a pretty active disease before their pregnancy will continue to have active disease usually. And it seems to be worse probably in the first trimester and also in the postpartum period. Those times seem to be most active. Patients who didn’t have much in the way of myasthenia symptoms before their pregnancy might not expect much of a change during pregnancy either.
But again, during that first trimester and in the postpartum period are the times to really be aware of kind of heightened risk for exacerbation during that time, but otherwise, a lot of it applies and is the same. Of course, any use of immunosuppressive medications other than prednisone really should be cleared with the patient’s obstetrician. And it really should be a renewed discussion of the risk and benefit ratio for any of those medications to be used and also the potential for harm to the fetus from the medication.
What is electrophysiology change in Ocular Myasthenia Gravis? So, there are two different things that can happen with Ocular Myasthenia gravis and really with Myasthenia Gravis in general with regard to the EMG, one is the presence of an abnormal decrement with repetitive nerve stimulation. And for that a patient is given a stimulus at a rate of about two to three per second, so two to three hertz. And so, that stimulus is given to the motor nerve, and then the compound muscle action potential is recorded. And if the amplitude of that decreases, you know, it’s usually within four or five stimuli that you see that decrease. If it decreases by more than 10%, then that’s about 90% specific excuse me, for Myasthenia Gravis.
So, it’s really helpful test and that applies also to Ocular Myasthenia. They just need to be done in a muscle around the eye, of course. Now, the other option is to do single fiber EMG. And that’s usually helpful. Patients who haven’t done in myasthenia here at Indiana University usually have it done in the front talus muscle, which has been very useful when we’ve had it done. Another option is to do it in the orbicularis oculi. And that can also be very helpful.
And with that, what you see is increased jitter. And remember, jitter is the term used to describe the difference in latency between one muscle fiber being activated and another being activated when both of those fibers are innervated by the same nerve. And so, that’s a function of how variable that neural transmission is at the neuromuscular junction, which again is a sign of Myasthenia Gravis.
And then Damien Hacienda [Phonetics] asked, is there any link with fever? I’m not aware of any link I think with fever with myasthenia. However, it’s worth noting that a lot of generalized systemic illnesses that cause fever will also cause an increase in weakness or sometimes even precipitate an exacerbation and some of them with myasthenia. So, for example, infection can do that. And obviously, infection can cause fever at times. So, yes, in that sense, and fever can also make someone feel more fatigued and run down and weak even when they don’t have myasthenia. So, of course, if someone has myasthenia, those factors will be compounded and the patient will feel even more weak.
Do you have any experience with Eb Prostigmine? Maybe you mean, intravenous Prostigmine, I do not, I just know about the intramuscular version. I don’t have any experience with that. I’m so sorry about that.
And then Sabina Clemente asks, do you still do eyes test and a positive in the absence of accessibility to other tests? Would you rely on this to diagnose Ocular Myasthenia gravis? So, yes, I do still do the eyes test. Again, the test is more sensitive than it is specific. So, it’s really helpful to rule out myasthenia. I probably would not rely on it if it’s just being used to really diagnose myasthenia. So, if you just have someone with ptosis, and nothing else to suggest myasthenia, they’ll be hesitant about assuming someone has myasthenia just based on that test.
I was referred a patient a number of years ago by a prominent physician who found that someone had ptosis and they did an ice pack test and was positive and so, so they thought, well, they have to have myasthenia. And so, they sent him to me and I did every test, I could and put the patient on some presumptive treatment. And they never improved. And I really don’t think they had Myasthenia Gravis, after all, we ended up finding another cause for their ptosis. So, again, you can be misled by the test of time. So, it’s helpful really in ruling out myasthenia as a cause of ptosis. But it’s not as useful in definitively confirming myasthenia or things like that. That’s how I’d use that.
Okay, and then for Tekna Huong [Phonetics], can you tell the dosage using pyridostigmine for adults and children? So, the dosage, so I often start out at either 30 or 60 milligrams three times a day is usually a good starting dose. And then you can always adjust that if the medication is not lasting long enough, but it’s effective that I read up on to increase the frequency of the dosing. If the medication is insufficiently effective, but it’s lasting long enough, then I would try to increase the dose rather than the frequency. And so, that’s how I would use that to help.
And if the patient doesn’t approve pyridostigmine and had intolerant to the steroid what kind of immunosuppressive would we prefer? [indiscernible] [00:59:38] would be a first line medication or Microphylla itself those would be the first line immunosuppressive medications and then others could be considered if those are ineffective. You have to remember though, that those immunosuppressants take probably six to 12 months to really become effective.
Okay. And then Helen Martindale asked about monocular versus binocular ptosis. So, so, yes, patients can have either monocular or binocular ptosis. So, it’s more common I would say for it to be bilateral or at least a symmetric bilateral. For it to be purely unilateral always raises a red flag in my mind that was, is this really myasthenia? It’s makes me question it a little more. But I’ve definitely seen cases where it’s just in one eye, so, that can happen.
Youngest patient I’ve seen well, I don’t know, I actually don’t see children. So, in my practice, so, I would have to defer that to someone else. But I do know it happens in children as well. And they’re managed with a lot of the same principles. One key difference in children is that a lot of immunosuppressive medications can be harmful to their growth. And so, you want to stay away from those and you would use pyridostigmine. You want to stay away from prednisone as much as you can just because the chronic side effects of steroids and it can even reduce bone growth in patients and kids. And so, IV IG and plasma exchange might be more readily used in a pediatric patient than it would be in an adult for that reason.
Okay. And then the MRD3 measurement have any role to play in Ocular Myasthenia gravis? I’m not familiar with the MRD3 measurement. So, I’ll have to have someone informed me about what that is. But the MRD1 and the palpebral fissure height, I think are the ones that I use most often. And again, levator functions probably the most helpful out of all those I’d say.
And is the presence of acetylcholine receptor antibodies required for deciding thymectomy? No, it’s not. So, patients who have, who don’t have positivity, so, they’re so negative, they can’t be considered. You have to weigh that really carefully. You have to be really confident in the diagnosis, I think in cases where there’s not a thymoma. But yes, that can still be considered.
All right. And then how often is Myasthenia Gravis symmetrical versus asymmetrical? I actually don’t know the numbers on that. I would say in most patients, I see there is some degree of asymmetry. I think it’s also fairly rare for it to be purely unilateral in a patient, especially the more prominent the symptoms are and the more unilateral it is, the more I really think maybe this isn’t myasthenia, after all. So, that’s a little vague, but I think that’s about the best I can answer that.
How frequent is the occurrence of thyroid disease with myasthenia? So, I don’t know about the incidence of thyroid disease in general. I do know, however, that thyroid eye disease has a higher incidence in patients with myasthenia than on average. And I’ve had a patient who had both of them together. And so, so that certainly does happen. So, just a word to the wise too, just because someone has features of one of those conditions doesn’t mean they can’t have the other as well. So, be aware that thyroid eye disease and myasthenia can occur in the same patient at the same time.
And then Imuran Khaled asks, can you elaborate use of spirometry in Myasthenia Gravis? So, I use that in patients who are in the hospital. And so, things like vital capacity and the negative inspiratory force and things like that can be really helpful, especially the negative inspiratory force if the patient is giving a good effort can really be a marker of someone’s respiratory function and how quickly it may be declining. And that can help inform the decision about whether to intubate a patient. And so, that’s the main usefulness of that. And it can often be checked depending on the severity of the patient’s illness, it can be every four hours or two hours or maybe even more frequent, if necessary, or not as frequent if someone’s at lower risk.
Congratulations from Jose Mercado. Thank you. And then what do you know about [indiscernible] [01:03:51]. So, I have not heard of that medication. So, maybe someone else can inform us about what that is and what its usefulness would be in myasthenia. One thing I forgot to mention also was eculizumabis a relatively newly available medication that can be useful in refractory cases of Myasthenia Gravis as well.
So, is there a specific indication when we should give immunosuppression therapy or just give pyridostigmine? Yeah, so, pyridostigmine is useful if you’re just looking for symptomatic control. So, the patient is having mild symptoms and you really don’t need to modify the disease that much and you just need to cover up the symptoms a bit and let them get through it, then just pyridostigmine is fine. Where you need immunosuppression is really when that’s not getting the job done, and someone’s having symptoms that aren’t controlled sufficiently by pyridostigmine.
All right. And Leah Oriente asks, when is the right time to start immunosuppressive agent after initially giving steroid, and do you also give steroid in patients with ptosis as the only Ocular Myasthenia symptoms. So, as far as the right time to start an immune suppressive agent, I would say if they’re in the middle of a flare, like, especially if it’s severe, you might want to hold off on that until they’re more stable. But steroids can be started, essentially right away, if you know that, that this is their significant symptoms that are not going to be adequately controlled by pyridostigmine.
And do it give steroids when patients only have ptosis? I’d say it really depends on how debilitating that ptosis is, if it’s really debilitating, and pyridostigmine not enough, then yes. If it’s not that debilitating or the patient has high risk for side effects from prednisone, then maybe no.
And then, Wale Hulude asks, could you exclude Myasthenia Gravis if the eye test is positive? So, if the eye test is positive, some patients still may or may not have Myasthenia Gravis. So, again, it’s not a not a super specific test. I mean, it’s fairly specific. It’s not exceptionally specific. It’s more sensitive than specific so, it’s better for ruling out myasthenia than it is for ruling it in.
Okay. Then, Pagna Hyoung [Phonetics] asked about timolol eyedrops, so, should that be avoided too? Yes, timolol eyedrops can exaggerate myasthenia so, avoid them if you can, if you really need the medication, then you just weighed out against the potential risks in this patient if they are well controlled myasthenia, probably not a big deal. If they have really brutal or exceptionally sensitive myasthenia than I’d probably stay away from that.
And Martinez, thymectomy without [indiscernible] [01:06:40]. I’m not quite sure what that means. And then another question about [indiscernible] [01:06:46], which I’m not able to answer. And then the question about how exactly can we distinguish the peak test from the rest test for Myasthenia Gravis? So, you know, those are going to be similar. So, you really don’t need to distinguish them, I’d say either one of those is going to really help you.
You know, one thing to know is the rest test really should be done for a longer period of time. So, rest tests can be done, you know, so 30 minutes was the way it was done in the study by Jeff Odell and colleagues. And then the peak test. So, that can be done as a matter of minutes and just have them close their eyes all the way and it doesn’t necessarily have to be tightly just closing kind of gently and then to see if those, if the eyelids peak open after a little bit. So, that’s how you do that.
And then a question about apart from the peaks and is there any way to confirm the orbicularis involvement? One thing that you can do also is to have someone really close their eyes tightly and try to pry their eyes open and you can usually get a sense for their orbicular strength doing that. It’s useful to have a baseline by doing it. Having done it on a number of normal patients, you know what normal feels like and then when someone has abnormal orbicularis strength, you get to know it that way.
Preferred antiglaucoma drugs in Myasthenia Gravis, well of course that just depends on the glaucoma and what they’ve responded to and there’s a lot of factors that go into that. Obviously try to avoid the ones that cause an exacerbation in myasthenia. So, timolol and some of those can be ones that can cause exacerbations. And again, if the patient is really well controlled myasthenia, not a big deal, if someone has really brittle or more severe myasthenia you probably want to select an alternative agent if you can.
And then how about myasthenia with anti-MuSK antibody? When should we start immunosuppression and what medications should be chosen? So, you know, that’s a lot of that’s the same as other forms of Myasthenia Gravis. However, patients with anti-MuSK antibodies might not respond as well to pyridostigmine so, it’s just worth keeping that in mind but some of the same immunosuppression rules would apply as with acetylcholine receptor antibody positivity.
Can Ocular Myasthenia happen suddenly without any risk factors? Sure, absolutely can. Here’s a question Ocular Myasthenia patient is under control with medicine on 60 milligrams three times daily and 30 milligrams of steroids. How long should I wait to start tapering and how fast? So, once you get up to the dose that controls their symptoms, then you probably want to stay there for maybe a month and then you can start tapering the medication. You may want to taper if you’re above 30 milligrams taper by maybe five to 10 milligrams a month until you get down to about 30.
And once you’re about 30, then go a little bit more slowly may want to do five milligrams every month or so, something like that. If you go too fast, you’ll know it because the patient will have exacerbations and if that happens and you go up a bit on the steroids and kind of taper again. And so, that’s kind of how you would go with that.
Will patients with myasthenia benefit from ptosis surgery? That depends. So, some patients might, I wouldn’t rule it out in all patients. Of course, the better, if the better option if someone’s ptosis purely due to myasthenia obviously to control myasthenia as best as possible. But in patients who have other causes for ptosis as well, or if they have an exceptional lack of variability of their ptosis, then some of those might benefit from or maybe a candidate for ptosis surgery. So, just have to be careful about who you’d recommend for that.
How would you differentiate myasthenia diplopia from thyroid disease diplopia? So, a couple of ways, one is that if you have access to the ability to do force deductions, that can be one that would be helpful. Because thyroid eye disease is a restrictive process causing diplopia, then you should have an abnormal force reduction test where you can’t physically move the eyes in the directions they need to because they’re restricted, that would not happen in myasthenia where the problem is a weakness without restriction. Otherwise, both thyroid eye disease and Ocular Myasthenia tend to affect the medial rectus muscle more severely than other extra ocular muscles in general.
And so that can be useful because if you have weakness of the medial rectus, what you get is an EXO deviation. And so, that can be a little bit more common in myasthenia. Whereas, if you have medial rectus involvement from thyroid eye disease, you get restriction. And that can actually lead to an esodeviation or esotropia. And so, so, that can sometimes help but again, those are not in all patients. And so, we have to be careful about using that as a definitive rule.
Okay. Another question here how to treat our patient who has suspected Ocular Myasthenia with only a simple tests like the ice pack test? Do we have to refer to another center before we start to treat? Good question. I think it really depends on how confident you are in that diagnosis. So, the ice pack test can support a diagnosis of myasthenia and if they have other features of myasthenia then great, you can probably start to treat. If you have a serious doubt about the or you feel uncomfortable about how certain you are about the diagnosis, then it would be preferable to refer to another center, or to do other testing if you can. So, again, single fiber EMG, or repetitive nerve stimulation can be really useful. And testing for some of the less common antibodies can be useful in some cases. And those can really help you get the EPA diagnosis.
Okay. And then two questions. One is why two minutes of updated are used for the fatigue test, why not one minute or three minutes? Well, just because that’s, that’s what someone made up. Not a good reason for there just be two minutes, it’s just that if you do less than that, you may miss the ptosis developing and it takes a few minutes. Three minutes, it’s just a lot of us don’t want to wait and sit there for three minutes and wait for ptosis.
And then the other question is any psychological changes can be seen in a patient with myasthenia either ocular generalized? Yes, you can and obviously it with any chronic illness that a patient has, you can have psychological difficulties that accompany it. It’s not part of the actual pathogenesis or of the disease itself, but it’s really just having a chronic illness and that it’s hard to have a chronic illness and so, psychological changes happen from that, but that can be with any chronic illness, not just myasthenia.
All right. And then, is the pupillary reflex affected in myasthenia? No. That shouldn’t be affected in typical myesthenia. And do we need to take a CT of the chest for all Ocular Myasthenia patients? Yes, that would often be that that is helpful. Really, the reason for that is you need to screen for thymoma. So, any patient with a thymoma no matter how old they are, they need to have that taken out. If you don’t see if a thymoma then then there’s some, you know, differences obviously, age plays a role which antibodies they have positive if they’re periocular or not, those are all factors that go into whether to get a thymoma or subarea thymectomy if you don’t have a thymoma. But yes, go ahead and get mediastinal imaging, doesn’t have to be a CT of the chest. It could be an MRI or some other imaging modality but yes, that’s helpful.
Also, it’s worth noting that even a CT of the chest isn’t 100% sensitive for thymoma or for thymic hyperplasia. So, sometimes there are actually additional antibodies that can be helpful that someone could send. So, for example, anti-striated muscle antibodies and anti-tighten and there’s some other antibodies available that are more commonly positive and someone who has who has either a thymoma or thymus dysfunction. So, those can also be considered if you’re still really suspecting thymus pathology, but the mediastinal imaging was negative.
When to treat ptosis in Ocular Myasthenia gravis with surgery? Really, that would be again, if there’s really a striking lack of variability. And if there’s exceptionally severe ptosis, that is refractory to all other treatments, and it’s really debilitating, then you could consider that in select cases. But it’s again, it’s going to be rare that you’d want to consider that in select cases, but it’s going to be rare that you want to consider that. Which nervous stimulate around the eye and I am not sure what that’s asking exactly.
You know, I guess if you’re asking in regard to, like, for single fiber EMG, if you’re stimulating the, you know, the frontalis muscle, so, there will be, you know, branch of the facial nerve would be the one that makes the makes those muscles contract. So, so that would be the one you’d want to stimulate if you’re if you’re looking at single fiber EMG, for example.
Okay. And someone asked me for a repeat explanation on the eyes test. Sure, I’ll do that. So, the ice pack test is done by taking an ice pack and placing it over either one eye or both eyes of the patient, if they have ptosis. And you would keep it on the eye for two minutes actually pull out a timer and measure it exactly two minutes. And I measured the amount of ptosis before the ice pack test and after immediately after the ice pack test. And if there’s a significant difference, then I would interpret that as a positive test. And if there’s not a significant difference, it would be a negative test.
And then a question about, do you know the register of vestibular ocular reflex from Switzerland? What if they can be useful instead of jitter? Okay, yeah, there, so, there may be other ways to kind of get some additional information. I’m not familiar with that specific test in Switzerland, but yeah, there may be others. I don’t have that test available to me here. So, I’m not as familiar with that.
And then question, who will treat Myasthenia Gravis the neurologist or the ophthalmologist? If there’s a neurologist available, usually it would be the neurologist. However, you may be in a location where a neurologist is not readily available, we’re not able to manage these patients for whatever reason, in which case, an ophthalmologist may manage them. But it really either specialty could do it. In Myasthenia Gravis, could I give pyridostigmine alone or in combination with steroids? Yes, you can give pyridostigmine alone or you can give it in combination with steroids either is fine.
And then question about I would like to ask about a pyridostigmine trial dose and sensitivity? Yeah, pyridostigmine can be useful even just on a trial basis is an empiric test to see does this make this patient’s symptoms better? And to see how reliable it is about 30 minutes after the dose is given orally. And if it really reliably makes the symptoms better, that’s a very strong vote in favor of myasthenia however, as I mentioned earlier, I have had patients who I think have a placebo effect, who clearly didn’t have myasthenia but were given it by someone else and they felt like it improved things. So, you do have to be careful with that. But it can be an option to provide additional evidence for someone having myasthenia.
Is a fourth nerve palsy a normal finding for Myasthenia Gravis? So, it wouldn’t be a fourth nerve palsy per se, but superior oblique weakness can happen from myasthenia. And yes, I’ve seen cases of that where it’ll look and measure exactly like a fourth nerve palsy and it turns out to be myasthenia. And so, that’s why I warned that Ocular Myasthenia gravis can cause any kind of ocular alignment problem.
Well, the symptoms of Ocular Myasthenia gravis disappear completely after thymectomy when it is indicated. It’s often not that it disappears completely, but it often just it helps in the management allows patients to be less affected and also to have lower doses of immunosuppressant therapy and also lower doses of prednisone to manage their condition.
Is migraine associated with myasthenia? No, not particularly, at least that I’m aware of. And were their lifestyle could help improve the health? Yeah, really, that’s going to depend on if there are any, is there anything that’s provoking exacerbations in that patient you want to obviously avoid those things if you can. How specific is the rest test and diagnosed in myasthenia if the ice test is negative? I’m not sure we have data looking at the comparison of those and especially looking at it when one is positive and the other is negative.
So, I’m not sure we have that. The ice test it’s worth knowing is, again, it’s pretty sensitive for myasthenia but not at specific. And then the rest test and the trial in which it was done, it was really 100% sensitive and 100% specific. But of course, those numbers were small. So, we really don’t know what the numbers would be like with a larger cohort.
When the patient with myasthenia stabilized with the medication strabismus surgery could be a successful result? Yeah, that could be if they have non variable diplopia, if it’s very stable diplopia, then yes, they could have helped with that.
Comments on patients with extra ocular muscle involvement treated with pyridostigmine, alone versus pyridostigmine with steroids. So, again, pyridostigmine is just to treat the symptom, so, it won’t modify the disease so much. Whereas, steroids do modify the disease and are often more effective than pyridostigmine alone in patients who need it. So, again, the question is do they really need the steroids and how significant other symptoms and how well controlled are they in pyridostigmine? And also, what are the side effects like on pyridostigmine?
And one question, how reliable are leaves peas for the diagnosis of Myasthenia Gravis? So, I don’t know what leaves peas are and maybe that’s what’s explained here in the next part, that Ocular Myasthenia gravis has no proptosis, no pain, no pyridostigmine, no perception deficits and no pupil involvement. So, yes, that is all true. Very, very good.
About myasthenia prognosis in children. So, I don’t know how long myasthenia can continue in those patients. So, again, so, I don’t know the answer to that. Do you biopsy from Myasthenia Gravis? No, biopsy is not helpful unless you’re trying to rule out an alternative diagnosis that could be demonstrated on biopsy. Okay. The question about managing a diabetic with Myasthenia Gravis? Well, so that, so, diabetes, or blood sugar control can change while someone is on a medication like prednisone or a steroid. And so obviously their blood sugar’s need to be checked more frequently. And they need to, usually I would enlist the help of a primary care doctor or someone who knows more about diabetes management then I do offer help with that.
Question about why does vertical diplopia occur in myasthenia? And that’s because the vertical acting muscles can be involved. And remember, there are four vertically acting muscles in the eyes. So, there’s the superior rectus, the superior oblique, the inferior rectus and the inferior oblique, those are the primary ones that are the vertical movers of the eyes. And so, any of those can be involved in myasthenia that would give vertical level vision.
Is it necessary to add a neuro protector to the treatment for myasthenia? I’m not aware of any neuro protectors that are helpful. Okay. Another question about the common duration of steroid treatment. And so, steroid treatment can be a long time, it can be years. So, everyone’s going to be a little different, depending on disease severity, how to respond to the side effects, whether an immunosuppressant medication is used or not. So, lots of variables go into that, but it can be years.
How about if a patient has glaucoma then we have myasthenia, what are we going to do with the patient? Well, that really depends on how severe the myasthenia is, if it’s really severe, you want to avoid some of the medications, like timolol, and others that can help exacerbate myasthenia. But if their myasthenia pretty well controlled, it’s probably still okay to use it. One thing you can do is just try it out and see, you know, you could even try it in the office and see if you have some timolol or one of the similar medications, try it once with the patient there and see what it does if it causes severe symptoms and obviously, you want to stop it.
Question. Why does myasthenia cause double vision? It’s because of a misalignment that happens from my muscle weakness. Another question about the moment when they decided operate ptosis in myasthenia patient, which clinic parameter can we use for that? It’s really going to be the, I’d say the variability of it. So, if the ptosis is really variable, might not be a good idea. Also, if the ptosis resolves completely at times, also not a great idea. However, if there’s always, always, always at least some baseline of ptosis that the patient has, then that that might be a patient that would benefit from ptosis repair.
What can you advise employees and employers with Ocular Myasthenia during this pandemic? So, as far as employees and employers, you want to take normal precautions with your myasthenia, I think the things that would be important during the pandemic are really patients who are on immunosuppressive medications want to be especially careful. But otherwise, it’s business as usual and taking the standard precautions that all the rest of us have to take as well.
Okay. And then HIV AIDS, what is the recommended therapy? I’m not sure about any change in HIV AIDS for therapy. I don’t think I’ve ever had a patient with myasthenia, and AIDS, you’d want to be careful about the immunosuppression part obviously. And if someone else is managing the AIDS or the HIV are probably be worth a discussion with them and see if any of the medications that you’re planning on using could interact with the medications they’re on for HIV, or if it could interact with the HIV itself, or the or cause further harm to the patient’s already compromised immune system.
Okay. And then, when you did review of postop in patients with myasthenia with surgery, surgery technique do you see is better. So, I don’t do surgery. So, I wouldn’t be able to answer that question. That would be a good question for an ocular plastic surgeon. Instance of uveitis with myasthenia? So, I’m not aware of a link between those two, other than the myasthenia patients do have a higher incidence of autoimmune disease. So, there may be an increased incidence for that. For that reason, as far as exactly how common that is, I don’t know.
Can you have myasthenia without ptosis? Absolutely, yes. Some patients just have double vision without the ptosis. And do you use tacrolimus drug and treatment regimen. So, you would use the oral form of the medication for tacrolimus. As far as the specifics of dosing and those things, that’s something I would have to look up, I don’t have that off the top of my head.
How much time of treatment do you wait to include strabismus surgery? You really, again want to look at the fatigue ability and the variability of their double vision. And also, you want to see that they’re myasthenia is very well controlled or is well controlled as it can be and that it’s stable and if and that’s and then you can maybe think about strabismus surgery. In that case, I’ve had maybe one or two patients where I’ve referred for strabismus surgery, and they’ve had a really stable misalignment and probably Myasthenia Gravis was not the main cause of their strabismus at that point.
How frequently do you need to use rituximab and pure Ocular Myasthenia gravis? Not very commonly really depends on how refractory the treatment it is and how debilitating the patient’s symptoms are. But yeah, it’s rare that we need to get to that in purely ocular Myasthenia. Okay. And then very discreet unilateral ptosis with impaired abduction, and diplopia compatible with the diagnosis of myasthenia. So, you know what ptosis with impaired abduction. So, that still could be from a third nerve palsy where the third nerve palsy is there along with internuclear ophthalmoplegia, because the adjacent MLF is involved. So, that could be what’s going on instead of myasthenia. But myasthenia can also do that. So, you’d have to look more carefully and try to do some of the other maneuvers that we discussed in this webinar today.
Do you give oral atrophying to counteract core logic side effects of pyridostigmine? I typically haven’t given oral atrophying but other anti-anticholinergic agents can be used to treat some of the side effects of pyridostigmine, yes, that can be done.
Is treatment of Myasthenia Gravis lifelong? Typically, not as in a lot of autoimmune conditions, it can burn out at some point and just kind of become irrelevant or just in remission, and it just doesn’t ever come out of remission. So, that’s often the case, but it’s variable about how long it takes for that to happen in given individuals. Yes, you can have shortness of breath with myasthenia.
Have I encountered any patients with Ocular Myasthenia and total ophthalmoplegia? Yes, I have never seen that before. So, that’s on the differential for that. Surgical technique other than frontalis sling? So, I’m not a surgeon, so, I won’t be able to answer that. And how do you treat along with thyroid disease? You would still treat myasthenia the way we talked about in this talk, and there wouldn’t be anything really different about it because thyroid eye diseases is there as well, unless there’s an interaction between medications or other things like that. Supplements useful for the prevention or treatment of Myasthenia Gravis? I’m not aware of any.
And then, how often have I encountered Lambert-Eaton Myasthenic Syndrome myasthenic syndrome? So, I don’t encounter that very often. And part of that is because I practice with a group of very well renowned neuromuscular specialists and they usually get most of those cases. So, I haven’t treated much of that. Diagnostic test to confirm Myasthenia Gravis. So, acetylcholine receptor antibodies are probably the best. And then anti-musc antibodies or anti LRP for antibodies can also be helpful in terms of serologic testing. Other diagnostic tests include electro monography, so, EMG and especially the repetitive nerve stimulation and single fiber EMG. Those are very helpful. And then of course, there’s your clinical examination, which is probably the most important of all. All right. Thank you everyone. That’s all the questions.