Episode 37 - Myoclonus

(upbeat music) So welcome back to the Neurology Exam Prep Podcast. My name's Aaron Bauer. I'm one of the PGY3 Neurology residents here at Yale. And today we're going to be talking about myoclonus with both Dr. Shaker and Dr. Muller. - Thanks for having me on, I'm excited. - Thanks Aaron, I think that'll be a lot of fun. Our listeners may know that Dr. Shaker is a movement disorder specialist, and I'm an epilepsy specialist, and myoclonus exists in the borderland between those two specialties. So I think this will be really fun to team up and tackle this very complicated process. - Agreed, this is definitely one of the weaker points in my education. So going through this a little bit systemically and systematically was helpful. And definitely learned a lot from this. I'm so very happy to share what I've kind of gone through with everyone. The general setup moving forward for today, we're going to talk a little bit about the phenomenology of myoclonus, you know, what is it? What do we see on exam? What other things are associated with it or can look like it? And then we'll focus more on the localization. And through the localization, a little bit about etiologic considerations and ultimately a brief discussion of just the basic treatments that one can consider for myoclonus. And if it's okay, then we can kind of start with what exactly is myoclonus? In general, myoclonus is going to be one of your hyperkinetic movement disorders. Generally it's characterized by very brief, involuntary muscular jerks is kind of how it's described when seen. This can be both in the positive direction and negative direction. So positive and negative myoclonus. Positive myoclonus is going to be more of a jerky contraction of the muscle and negative myoclonus will be a jerky kind of relaxation of the muscle that then comes back. - Can I jump in here? I just wanna say, you know, the other word for negative myoclonus would be asterixis. And the reason that we test asterixis classically with the stop position, stopping traffic position is because it requires consistent activation of the wrist extensors. And so you're able to see that involuntary relaxation of the muscle and then a recovery to back to the position. - Definitely very much so. And then in terms of the additional movement disorders or at least hyperkinetic movement disorders that may be confused with myoclonus or one should think of one approaching a patient, we can generally think of a few. So one could be just a tick. So very simple motor ticks may be confused with myoclonus. Generally they're going to be more repetitive. They'll be stereotyped. And in terms of ticks, there's usually an associated urge and they'll be briefly suppressible. In terms of something like a startle, sometimes we may see patients with pathologically exaggerated startle and that's called hyperplexia. However, generally speaking, this is gonna be involving more proximal distal muscles that will be bilateral, it'll be synchronous, but it will be very stereotyped, moving with like arm abduction and then flexion of the neck, trunk, and extremities. There's very stereotyped movement for a startle as well. For Korea, this is gonna be non-stereotypes. And instead of this jerky kind of muscular jerking that we see with myoclonus, for Korea one would think of more flowing hyperkinetic movement disorders. Korea is just a little slower than myoclonus. The actual contraction of the muscle is slower in Korea. They can be difficult to distinguish. - And the only last one that sometimes we see, particularly in children and very young children, an infant is a shivering can be a little bit different and difficult to really distinguish between the myoclonal jerking. And that's usually the big difference is it's a much more custard appearance in terms of shivering and a little bit more generalized. - Sarah, can you talk us through, I think of all of us have seen multi-focal myoclonus and toxicencephalopathy or epileptic myoclonus and somebody with juvenile myoclonal epilepsy common sorts of versions of this. But there's broad phenomenology as Aaron is alluding to. And that's part actually I have trouble with too. So what are the focal, segmental, generalized and then where it occurs or in what context it occurs with rest or with activation or in between. Can you talk through your evaluation of somebody with myoclonus and some tricks that our listeners might have to distinguish the different types? - Sure, well, just to talk a little bit about the language. So focal myoclonus is in one, for example, in one nerve distribution such as hemophacial spasm is just in the distribution of the facial nerve. Segmental when we refer to movement disorders means in segments that are adjacent to each other in the body. So segmental dystonia could be in the neck and arm, for example, 'cause those are segmentally related to each other. Generalized in when we talk about myoclonus means the whole body all at once. It can kind of look like a startle and it's one myoclonic jerk in the body, whereas multifocal is all over the body but lots of little myoclonic jerks. - That's very clear. And what about what provokes them, whether they occur with rest or action or with certain tasks? - Sure, so there are certain myoclonic syndromes that may be more specific to one thing or another. For example, post-inoxic myoclonic syndrome called Lance Adam syndrome is classically an action-induced myoclonus. So when the patient is at rest, they don't have much by way of myoclonus. And as soon as they lift up their arm to do something, the myoclonus comes out in full force. There are also stimulus-induced myoclonus that we see and we do test for this on examination. And this can be a little bit difficult to distinguish from a startle. And when we're trying to evaluate a startle, we might clap very loudly, unexpectedly in the exam room and see if they have a hyper-ecplactic response. But with stimulus-induced myoclonus, we may take a pin or the reflex hammer and tap on their arm and then they may have a local myoclonic response to the tap. And that is often seen in patients with neurodegenerative cortical diseases such as cortical basal syndrome or crates filled yachup disease. - Well, that's a $60 word if I've ever heard it, which is hyper-ecplaxia, which is this exaggerated startle. - Yeah, you heard me say that very slowly because it's difficult to say. - You stuck the landing on it. That was very good, but a good one for our listeners to know about. - Very good. So I think we definitely touched on a lot of the key things for the phenomenology of myoclonus there. The basic definition of it being a very jerky and voluntary hyper-connected movement disorder, the differences between positive and negative myoclonus, the other features that we really want to try and note on the exam, including, you know, it's being focal, segmental or generalized and what kind of specific activities or at rest these movements will occur. And then some of the additional movement disorders are at least to think about, including like startle, ticks, career, shivering. So I think that's a really good start to kind of lay the found work for this talk. So I think at this point, we can talk a little bit more about localization, which Dr. Schaefer has alluded to a little bit. So we can think about this, like most of the problems in their access. We can kind of go through each one step by step. In terms of, you know, the highest level that we can get to, in terms of cortical, we can think of, essentially, this will generally be multifocal or a generalized process. Typically, classically, at least affecting the face, and distal limbs, it will be both spontaneous, action-induced, or stimulus-sensitive, as we talked about a little bit here in terms of, like, touch or visual stimuli. This can be both negative and positive when we see on exam in terms of the myoclonal activity. In terms of some broad things to think about in terms of looking at myoclonus with some additional information in order to figure out exactly the localization, some people can utilize polymyography to help narrow down where exactly the myoclonal activity is originating from. And we can talk about this through each one. So for example, with cortical myoclonal activity on the polymyography. So when we're just recording over the affected muscles, the activity generally will be less than 100 milliseconds. And this will be correlated with EEG activity as well. - Yeah, just a comment here. This is the type of myoclonus, with which I have the most experiences in epileptologists because a very common type of cortical myoclonus would be epileptic myoclonus. Most commonly with disorders like juvenile myoclonic epilepsy, also with the progressive myoclonus epilepsy disorders. And then of course, in children with a number of epileptic myoclonic disorders. And in all cases, there's brief synchronous bursts, which can be seen as spikes or poly spikes on EEG, on plane EEG. And as you said, Aaron, the actual myoclonic movements are extremely brief and extremely quick. You know, you're saying less than 100 milliseconds. And my rule of thumb with epileptic myoclonus, with a subtype of cortical myoclonus, is that the movement is so quick that it really cannot be voluntarily simulated. So that if I wanted to simulate or show what a jerking looked like, it would be slower than the movement that you would see with epileptic myoclonus in general. That may not always be the case, but is often the case. And 100 milliseconds, you know, that's a tenth of a second. So these are very quick brief jerky movements. So the things to remember are brief jerky movements, very quick, harder to simulate, and associated with spikes or poly spikes on scalp EEG in most cases. - No, thank you for that extra information. That's definitely something once we get to etiology that I'm looking forward to hearing a lot more detail from you as well. For moving down the nerve access a little bit, we can start thinking about sub cortical etiologies, I'm a sub cortical localization for myoclonus. So once we kind of get into the brainstem, this is similarly to cortical will be more generalized or synchronous activity. Usually a little bit more axial and proximal involvement, and similarly can be their spontaneous or stimulus sensitive. And then once we get below the cortical level, this is really where the polymyography is going to be longer duration. So less short generally greater than 100 milliseconds. Dr. Schaefer, would you want to talk about the myoclonus dystonia? That was a new topic for me. - Oh, sure, myoclonus dystonia. That gets more into etiology. That's a genetic syndrome. That is also called dyt11, and it's seen in children. And it's called myoclonus dystonia clinically because some people may have more myoclonus, some people may have more dystonia, some may have a lot of both. But it's a generally not extraordinarily progressive issue that is familial and is, as I said, characterized by both myoclonus and dystonia. - So heading out of the sub cortical regions, then we can start thinking about spinal. So once we get into the spine, this can be broken down generally into two different kind of subcategories as well. So we have segmental and proprio spinal. So with the segmental spinal myoclonus, this is generally gonna just involve a single segment. So as Dr. Schaefer alluded to before, kind of just like single proximal limb or maybe up into the face, more segments of the spine itself. These are generally gonna be spontaneous, less likely action induced, and similarly to the sub cortical myoclonus, this will be longer duration of polymyography activity. So greater than 100 milliseconds. In terms of proprio spinal, this is generally gonna be a very fixed pattern and it is all about the axial muscles of the trunk and the abdomen as kind of an up and down pattern for what you see with the myoclonic activity. And this one will be more both spontaneous and stimulus sensitive. And similarly on polymyography, we'll have that longer duration of greater than 100 milliseconds. - I should say that one way that we do examine these patients who come in with history is consistent with proprio spinal. Myoclonus is that we lie them down and we tap on their stomachs and try to induce the myoclonic jerk, which as you said spreads from the area of injury, proximally and distally affecting basically the whole body more or less simultaneously. - Thank you for that additional info. In terms of the next kind of segments moving down the nerve access. So after the spinal cord, we can start thinking about the peripheral nervous system and peripheral myoclonus is generally gonna be much more focal, generally just affecting maybe a part of the distal limb. It will be spontaneous, it'll be action induced and generally it's going to be accompanied by a degree of weakness and/or atrophy just as we're affecting the peripheral nerves at that time. In terms of electrophysiology, this one would be slightly different than either the cortical, sub cortical, or spinal. Generally, there will be relatively short bursts of activity as well and usually less than even 50 milliseconds and is associated with other signs of lower motor neuron damage via fisculations or underlying myocymia. I think peripheral myoclonus is really interesting because, and this may be an oversimplification, but I kind of think of it almost like an epilepsy of the peripheral nerves, right? Then the pathophysiology of peripheral myoclonus, the most common of those disorders being hemifacial spasm, for example, is if faptic transmission between axons because of focal demyelination. So the most common cause of hemispatial spasm or one of the most common causes would be neurovascular compression, right? So compression of an aberrant blood vessel adjacent to the brainstem near the CPA angle causing focal demyelination of an irritation of the facial nerve, the proximal facial nerve. And so that when one nerve fiber fires, the adjacent nerve fibers fires simultaneously and synchronously so that you rather than having sort of more nuanced motor control of the face, you have this sudden activation of a large population of axons going to multiple different regions of the face, and you get simultaneous synchronous contraction of the facial muscles. And this can be further worsened by activation of those muscles, right? If you ask the patient to close their eyes for a prolonged period of time, really squint and activate the facial nerve, you'll often see a burst of these facial jerking that's happening afterward. And it really has all about cross-talk and synchronous discharges within the axons, which sort of feels to me like an epileptic paradigm, but of course, this is the way I see the world. And interestingly enough to carry it forward, right? Before botulinum toxin therapy, the treatment for these disorders tended to be anti-susur medications, a carbamazepine or something like that. Now, where my argument falls down is that they don't work all that well, and that in the most cases, treatment is going to be more effective with decompression or botulinum toxin, a neurovascular decompression of botulinum toxin. But kind of think of it as an epilepsy of the peripheral nerve. I'm digressing a little bit, but I kind of think of trigeminal neuralgia as being the same thing. Spontaneous-affaptic transmission through the trigeminal nerve, causing spontaneous synchronous activation of a large number of axons leading to excruciating pain, because it's a sensory phenomenon. So there's your little pathophysiology corner, and another $60 word, ephaptic, which is about axonal crosstalk. - Well, thank you, Dr. Muller. It's definitely good to go back to the most fundamentals that we can, especially during these talks, so I definitely appreciate that. Kind of to summarize. So now we've gone through at least the general localization that we can think through, so be a cortical, subcortical spinal and moving out into the periphery. And we've discussed some of the basic overview of what they kind of look at, and some of the key electrophysiologic findings on polymyography that we will see. So I think at this point, it would be a good time to start discussing at least some of the etiologic considerations. So once you have clinically seen myoclinus, have at least an idea of where it's localizing to, then you can kind of start thinking about how you want to approach it diagnostically speaking. So cortical and subcortical myoclinus generally have a much larger differential, and we'll be one that we'll talk about second to start. I think we can do a little bit of a warmup with at least peripheral or spinal etiologies to start. So in terms of spinal etiologies, generally speaking, myoclinic activity and spinal myoclinus is usually seen after pretty bad traumatic or compressive injuries, is generally gonna be where people will see it most clinically, just given the relative occurrence of these injuries in the population. Outside of that, especially if somebody's coming in with an infectious pro-drome, fever's chill systemic signs, you can also start thinking about infectious etiologies, so infectious myolytic processes, and in somebody maybe with a autoimmune history concerned for MS, NMO, more the autoimmune pathway, then you can start thinking about more systemic rheumatologic processes as well. Sarah, I would love to hear you talk about this. This is again an area I have huge challenges with, so you talked about spinal segmental myoclinus and proprio-spinomaoclinus is being sort of too distinct entity, so what do these patients look like? And how do we work them up? - Well, it's really more focal or segmental than you know where to image in that person's spine, right? To try to figure out if there is, as Aaron said, any kind of inflammation or compressive lesion and cord signal that might show you a focus for the myoclinus. People with proprio-spinomaoclinus, we will image their spine and hope that we see something that explains what's going on with them, but I have to say that often the spinal imaging is not remarkable, and so there's a debate in the field actually as to whether the proprio-spinomaoclinus syndrome is related to some kind of spinal injury or hyper-excitability that is at a level that is just unable to be seen on MRI or if this is actually a lot of times functional in patients. And so there are whole groups of people who think that proprio-spinomaoclinus only exists as a functional disorder, so this is a debate within movement disorders, and it's tough even electrophysiologically to tell because as Aaron mentioned, if you're looking at cortical myoclinus, the bursts are less than 100 milliseconds, which is shorter, as Dr. Mueller said, then people are able to mimic in a functional disorder, but in proprio-spinomaoclinus, the bursts are much longer than that, and so it's difficult to distinguish electrophysiologically between a functional and organic ideology. - I'm feeling better about being confused about this disorder, especially proprio-spinomaoclinus. It's somehow reassuring to hear that experts like you are somewhat challenged and be well-dored by this in many cases as well. - Absolutely, experts are always challenged and be well-dored. - That's how you become experts. - The more expert you get, the more challenged and be well-dored you become. - I should get that on a t-shirt. - Okay, so outside of the spinal ideologies, looking at the periphery, I think we've kind of discussed a decent amount of ideology as well, thinking about like, underlying causes for a plexopathy, is ridiculous off of these, and I know Dr. Mueller's talked a little bit more in the case of facial spasm and focal irritability that can really lead to this hyper-excitability of the peripheral nerve. So any of those ideologies be it infectious, rheumatologic, traumatic, can all lead to some of these peripheral myoclonic processes. Particularly, once we're getting into more peripheral nerves, then add something that may be beneficial diagnostically. One good thing about is an EMG nerve conduction study to really isolate down to the nerves, or nerve roots, or plexus that is involved. So moving forward, we can really start talking about kind of the meat of a lot of myoclonus and cortical myoclonus, which does have a pretty broad differential to say the least, and we'll have Dr. Mueller comment a little bit specifically on myoclonic epilepsy and progressive myoclonic epilepsy. Generally speaking, coming and assessing somebody with myoclonus and you're kind of localizing them to a cortical or sub-cortical region. One of the first thing that's really good to think about first are some kind of toxic metabolic considerations. One thing that we say a lot of, at least in the hospital when we get consulted on this is drug-induced or overall systemic illness that is really contributing to the cortical hyper-excited ability and consequent, more generalized myoclonic activity that we can see on our patients. Some of these toxic metabolic considerations. One of the first things that we can do when going through a patient, particularly a good medication, a reconciliation to see if there are any contributory medications at this time. Some of the ones that are at least neuropsych related that we generally prescribe frequently as neurologists and should be aware of would be some anti-seasure medications like fennatone, gabapetin, fragabalin, lymotrogene. Some anti-parkincinsteroids can also contribute to myoclonus, cinemetbromocryptine, amantidine, anticapone can all contribute. Some anti-psychotics, more of the older generations like haloparital can definitely contribute to a degree of myoclonus cause a pin or lands a pin as well. And then in terms of more antidepressants, definitely lithium, the SSRIs, MAOIs, and TCA's can all lead to myoclonic activity, especially in super therapeutic ranges. - I think what you're telling us, Aaron, is that if you see transient myoclonus, it's a good bet that it could be drug-related very much so. - So the things that, just to narrow this down a little bit, the things that I look at first and foremost would be the sodium channel blockers like fennatone and carbamazepine, and as we said, carbamazepine can actually treat peripheral myoclonus but can worsen cortical myoclonus. Those are less likely to be on a med list than gabapentin and pre-gabbalin or lyrica. Those are biggies, especially in hospitalized patients who may come in with a little AKI. They've got a little bit of a worse creatine clearance than they did at home. And all of a sudden, those medications that are renaly cleared like gabapentin and pre-gabbalin end up at toxic levels in those patients and start to cause multifocal myoclonus. Those are, I think, 40% of inpatient consults on multifocal myoclonus is going to be one of those medications. Opiates is another big one. And then you mentioned a lot of psychiatric medications and mostly, you know, narrowing in on the medications that can cause serotonergic overload and serotonin syndrome as myoclonus is one of the things that helps us to differentiate without a med history, which, of course, is the most helpful. Helps us to differentiate serotonin syndrome versus neuroptic malignant syndrome versus Parkinsonian hyperpirexia syndrome, all of which have fever and rigidity and potentially some C.K. elevations. But myoclonus is quite common with serotonergic overloads as well as hyperreflexia. And every neurology resident, every neurologist needs to know that sodium channel blocking agents can worsen myoclonic epilepsy syndromes, can worsen epileptic myoclonus in many cases and should specifically be avoided in one of the myoclonus syndromes that we're going to talk about. Progressive myoclonic epilepsy in infancy, also known as Dravet syndrome, which is related to amutation in the sodium channel gene. And sodium channel blocking agents can make that much worse. So sodium channels in myoclonus is something that should be well known. Similarly, when you're seeing your postcardiac arrest patients who are in myoclonic status epilepticis or later with Landsatum syndrome with cortical myoclonic spikes, you're going to be avoiding those medications and those patients and throwing all of the other medications at them that aren't going to worsen the situation. So outside of the medications, more generally speaking, we can also just think about just common metabolic durations, hepatic failure, renal failure, the sodium, calcium, magnesium, all are just a very brief good look through the chart just to make sure none of those durations are there because they can also similarly worsen and contribute to a more generalized multifocal myoclonus. And now to be a little bit more focused, we can start talking about some of the critically-based myoclonic syndromes and the differential that's more related to central neurologic processes. So I think we can start focal nervous system lesions, be it post-tumors, trauma, all of those ultimately can lead to a cortical myoclonic process. Can I just add something about toxic metabolic before we move on? So you mentioned renal and hepatic failure, so uremia, hyperemonemia, electrolyte disturbances. But the other thing to look at is chronic hypoxia and chronic hypercarbia, especially the hypercarbia can go unnoticed. People, for example, with COPD or with undiagnosed or untreated obstructive sleep apnea can develop multifocal myoclonus and treating the underlying issue can help with that. - Thank you for that. Definitely one thing we see a lot of in the hospital as well, a lot of undiagnosed sleep apnea. - So at this point, Dr. Moller, would you want to kind of go into the considerations for epileptic myoclonus? - Yeah, I think this is worth a subtle little diversion because I think it's one of the most common types of cortical myoclonus besides that related to toxic and metabolic disorders as we've discussed. A framing about how to think of syndromes that can produce epileptic myoclonus. I think a useful framing would be to consider two main factors, the first being the age of onset and the second being severity. So the general ages of onset of disorders would be those that occur in early infancy right after birth within the first weeks to months. Those that occur in infancy, but maybe a little later, those that start in childhood and those that may start later on in life. And I think if you divide it into those categories, you can generate a more concise list of disorders and it will allow you to hone your illness scripts as you're preparing for examinations and as you're caring for patients. I'll start with the area which I am least comfortable with which would be early infancy. I am an adult epileptologist, but in early infancy you can have benign neonatal seizures which can sometimes have chronic or myoclonic components and then you're more severe myoclonic seizures that occur in early infancy are gonna be those related to disorders like early infantile epileptic and cephalopathy, odoharis syndrome which can have tonic, myoclonic and other seizure types. This is a much more severe neurological disorder. It can be associated with severe neurological dysfunction and a burst suppression, discontinuous pattern on EEG and can be progressive and very difficult to treat. A little bit later you can have benign myoclonic epilepsy of infancy sort of later in infancy. This tends to occur in the first year of life. There are myoclonic seizures that are self-limited. These patients tend to have normal development. And then you can have much more severe and progressive worsening myoclonic epilepsy. And I mentioned this before, progressive myoclonic epilepsy of infancy also known as Draves syndrome related to a mutation of the SCN1A gene. Often the first seizures are febrile, febrile clonic seizures. Then there can be a mixture of multiple seizure types including myoclonic seizures and often a progressive neurological worsening. This is a disorder in which the sodium channel blocking agents should be avoided. If we move to sort of the next age which would be childhood, one of the more well-known disorders, although it's not that common, would be epilepsy with myoclonic atonic seizures. They used to be called myoclonic estatic seizures. And this is doses syndrome. Tens to occur in late infancy or early childhood and can be associated with seizures with both cortical myoclonus and often a drop, a sudden loss of tone. So this myoclonic atonic seizures and sometimes bilateral tonic clonic seizures as well. Sometimes it's treated with the ketogenic diet or antissusure medications. A little bit later, juvenile myoclonic epilepsy and I'm not going to get into much detail about that. Tens to start in teenage years or early 20s, rarely later than that. Generalized polyspec waves on EEG, photo myoclonic response in many patients, prominent response with sleep deprivation, alcohol, et cetera, generally responsive to antissusure medications and generally has a decent prognosis but patients often have to stay on medications lifelong. And then the last category, and this is your mixed bag of category is the progressive myoclonic epilepsy syndroms. And those are syndromes which are characterized by seizures including myoclonic seizures and progressive neurological disease of various types. And I'm just going to briefly mention a few things about each of these for the purposes of our listeners just making a mental checklist. You know, these have really interesting names in some cases. So one of the progressive myoclonic epilepsy syndroms is Unvericked Lundborg disease, also known as Baltic myoclonus, tends to have onset in school age or teenage years, prominently stimulus sensitive myoclonus. It's an autosomal recessive disorder and there is a specific gene, the CSTB also known as the EPM1 gene. I don't think it's as important to understand that but it is an autosomal recessive genetic disorder, variable severity but myoclonus along with other progressive neurological deficits which can include cerebellitis function, cognitive dysfunction, et cetera. Lafora disease, another with onset in teenage years, EPM2 gene, so these EPM genes that the labeling system has to do with them being progressive myoclonus epilepsy with progressive myoclonus EPM. And this one is EPM2A, it's a ribosomal encoding gene, also autosomal recessive. And the classic thing to know about Lafora disease is that there are Lafora bodies seen on skin biopsy. There is myoclonic epilepsy with ragged red fibers which is a mitochondrial disorder and the ragged red fibers should be the clue. You see ragged red fibers on muscle biopsy which is an indicator of a mitochondrial disorder. These patients often have a myopathy in addition to the myoclonus because of the mitochondrial disorder. Short stature, can have hearing loss or optic atrophy and again, all of those would be clues that this is a mitochondrial disease. And ragged red fibers, of course, are clumps of diseased mitochondria that tend to exist on the edges of the each muscle fiber and are seen best on a Gamori trichrome stain. So this used to be something that we had to be aware of when we prepared for exams. There's the neuronal steroid lipofusionosis. These tend to occur in childhood or early teenage years and there are multiple different types and they're usually autosomal recessive and they're sort of a classic type and then other types. The NCLs tend to be rapidly progressive and often there is a severe macular degeneration and one of the things that can be seen on EEG with the NCLs is an exaggerated photo-response with low frequency photo-extimulation possibly related to the macular issues. There's the psialidosis which are also autosomal recessive tend to occur in juvenile or cannecarine adulthood so this could be one of the ones that's later on set and you see the cherry red spot on the retina which is an important element of this disorder. The psialidosis tend to be a lysosomal disorder. There's dentato-rubral palidoluisian atrophy or Dirkla. I think I'm sticking the landing with each one of these. Very importantly, this is a trinucleotide repeat disorder. The repeat is C-A-G and the atrophin-1 gene. It's autosomal dominant and often you see midline atrophy on MRI structures along with white matter changes and this can have a later onset as well. So one to be known about that can occur in juvenile years or even in adulthood. So there's my list of progressive myoclonus epilepsy syndromes and some of the buzzwords that you would need to know about these but just so you're aware of these. The takeaway, the most common ones you're going to see on an examination and in life. Jeremy, know that one inside and out? You should understand Drave syndrome. It's probably a good idea to understand something about dose syndrome and perhaps some of the benign disorders which can be clinically relevant. - I should say that I have diagnosed juvenile myoclonal epilepsy in my movement, clinic, a patient who was sent to me for myoclonus had never had a seizure to his knowledge and on history was having early morning myoclonus within the first hour of awakening which is classic. So you do see it even if you're not an epileptologist. - Well, that was fantastic. Thank you, Dr. Muller. I really appreciate you going through the epilepsy syndromes that we should be thinking about for myoclonus. I think the setting it up in terms of thinking about it through early infancy, infancy childhood and later on in those progressive epilepsy syndromes is exceptionally helpful. So thank you for that. - Yeah, this is a scary topic and I think dividing by age and then by severity can really help you break it down and there's only, well, I'm sure there are more but there's only a few in each of those boxes if you go progressively by age and severity that you really need to know about. And look, if you can narrow down and say I think this person has a progressive myoclonal epilepsy syndrome, then you can go back to the books and look up what you need to be looking for. - Very true. Definitely good to fall back to resources when needed. I won't even attempt to pronounce some of them that you went through. So in terms of other cortical syndromes that we can think about just a little bit more briefly, we can think about neurodegenerative conditions as well that are related to more generalize myoclonal activity. I think one of the classic ones that we may think about is gonna be pre-on diseases like CJD, specifically when looking for more of a startle myoclonal activity. And then we can think about most of the dementias. So CBD, so cortical base of degeneration, dementia with Louie body, Parkinson's disease, Alzheimer's disease, they can all be associated with a degree of myoclonal activity moving down the line with progression of their disease. Outside of neurodegenerative conditions, we can think a little bit more broadly about infectious, post-infectious conditions. A lot of viruses can definitely be associated with a myoclonal presentation. HSV, HIV can all be associated with some myoclonus outside of that bind disease, specifically syphilis or with those disease, which is associated with several hyperkinect movement disorders can also be associated with myoclonus as well. Those are gonna be a little less common, but obviously if somebody's coming in with a pro-drome of fevers, chills, infectious context, particularly if we're thinking about arboviruses or line disease, if there's any sort of environmental exposure that would really push us down an infectious etiology. Outside of infection, we can also think about some autoimmune conditions, specifically just perineoplastic disorders that are associated with myoclonus would be, you could think about obstaclonus myoclonus syndrome. So in children, we'd be thinking about children with neuroblastoma. Then in adults, it's more related to small cell lung cancer, breast cancer, and this would be a generalized myoclonus syndrome, but also predominant abnormalities in eye movements. So the obstaclonus part of these syndromes is something that's very interesting to see clinically. And in a setting of a backdrop of malignancy, your concern for malignancy is something we're thinking about. Some more incephalides, like NMDA incephalides can be associated with myoclonus. More movement related perineoplastic and autoimmune conditions, like stiff person syndrome or progressive encephalomyelitis with the rigidity of myoclonus or perine can similarly be associated with more diffuse myoclonic pictures. And obviously, in these patients, we're looking more, we're thinking more about malignancy history or risk for other autoimmune conditions. No, I mean, I would just say that there are a lot of autoimmune conditions that have been reported with myoclonus. And it helps that some of them say myoclonus in the name, obstacle in myoclonus and perm, but any really any cortical hyperexcitability, voltage gated potassium channel and cephalidities, all sorts of things can cause myoclonus. And then outside of that, I guess we have-- we've already kind of alluded to. Lance Adams a few times already at this point, but I think that one's OK. I think we've covered that one at this point. And I think you also alluded to the myoclonic dissonius as well before, so I think we've covered that one. In terms of evaluating the cortical or subcortical processes for myoclonus, a lot of it will be kind of generated by your clinical history and what you see on exam and the overall setting of the patient. Obviously, if we're leaning towards an autoimmune process or an infectious process, MRI, imaging, CSF studies, serum studies are all within the realm of things that you'd want to look into and would want to work up. If we're thinking more along the lines of progressive epilepsy syndrome or seizure, definitely EEG and maybe correlation with EMG would be very helpful in order to better classify and evaluate those. And obviously, if we're getting into more genetic ideologies where they're fitting into specific syndromes, considering mitochondrial study is considering specific, targeted genetic tests would all be exceptionally reasonable. Yeah, I mean, as we've talked about myoclonus can come from anywhere on the neuro axis and can come from almost anything that you can think of. And so your evaluation is going to be very patient specific. So at this point, I think we've done a good job covering overall ideologies. We've definitely covered a pretty wide array at this point that can really lead to myoclonus. So just to kind of end, I think we can talk briefly a little bit about treatment and treatment considerations. The first key step to myoclonus, especially in somebody who's generally ill admitted to the hospital with a multifocal myoclonus, first and foremost, is treat the underlying cause that you think is here. So if it's related to medications, peel those back and see if at least the improvement, if at all possible, if there's any underlying metabolic derangements definitely go and correct those. Initially, let's see if you get any improvement. But stepping back and thinking more towards where we've localized. So if we're thinking more of a cortical myoclonic process, some agents that have at least been helpful outside of, specifically epilepsy or specific syndromes, you can consider the use of bowel proe or leveterrest. And one that will be utilized pretty much throughout the neuro axis and will be helpful for myoclonus, it will be benzos like clenacepam. Particularly in subcortical myoclonus clenacepam, will be the most helpful agent. And that is similar when thinking about spinal myoclonic processes as well. So then once we're kind of out of the spine moving toward segmental and peripheral, one of the things that has seemed to be useful is been a bunch of line of toxin. So really focal injections in order to treat the underlying muscles that are most implicated in the myoclonic process. Yeah, if you have any movement disorder that's focal enough, then Botox is going to be a better option if possible because all of the medications we use for movement disorders are sedating. And when given systemically endoses high enough to actually impact the movement disorder, it can be, the side effects can be a big problem. So we do love Botox for our peripheral myoclonus or hemifacial spasm patients. Some of my patients do take carbamazepine and Botox or they take carbamazepine for the several weeks as the Botox is wearing off before they're due for their next dose, for example. But the vast majority of my patients exclusively use Botox for peripheral myoclonus. Some other things to consider, kind of similar to trigeminal neuralgia would be like muscle relaxants, like baclefin medications that we use for lots of different neurological conditions, like gabapentin and things like that, but really carbamazepines that has the best data in those peripheral patients. And then avoiding any medications that could worsen things. So if you're concerned about cortical myoclonus again, avoiding those sodium channel blockers, like Phenatone and carbamazepine. I agree, I definitely think the Botox is definitely super helpful for a lot of these patients in terms of avoidance, systemic side effects, and definitely go to consider the other medications that a patient is on and then make sure that we're not the ones exacerbating anything, especially when thinking about the sodium channel blockers. So I think those are all fantastic points. - I have to say the patients that come to my clinic for quote unquote tremor and end up with multifocal myoclonus due to toxic metabolic issues are my happiest of all patients because I take them off their gabapentin or treat their sleep apnea or whatever is going on and they're all better. They are the most grateful people. - Good to have satisfied customers. - Indeed. - And I don't know how many times we've said on this podcast in various different episodes, a medication reconciliation will help your patients. - Absolutely, critical. - Well, thank you all so much for the help of this talk. It's definitely a bit of a bear of a topic that go through just because of how the fuse and how many different things can really contribute to myoplonus, but I'm hopeful that this is helpful to a lot of people to go through some of the phenomenology, a general approach to localization. Some of the more common etiologies and particularly etiologies that we as residents will get tested on relatively frequently and then also some of the at least basic treatments and at least considerations for treatment based on that localization. So I really appreciate all the help with this one guys. - I think we tackled the bear. I'm not sure how to handle that metaphor, captured the bear, tamed the bear. Anyway, whatever we did with the bear, it was a positive thing. And Aaron, you deserve a lot of credit for narrowing this down, I think, into very bite-sized chunks for the bear to eat and I'll stop now. (laughing) This has just been so much fun and I learned a ton about this from both of you. - I learned a lot about pediatric epilepsy syndrome. - So. - There's a lot of those. - Lifelun learning, everybody. - All right, thanks, Aaron. - Thanks, Aaron. - Thanks for having us. - Thanks. (upbeat music)