Okay. Well, welcome, everyone, to our live session of Next Level Neuropathies. I'm Shawn Jordanson. I'm the moderator. And I am privileged to be joined by an all-star faculty, Dr. Nassim Raad, Dr. Sandra Hearn, and Dr. Dave Arnold. Our goal here is that you will hopefully leave this session being able to handle all the neuropathies that you get at the next level. Okay. Before we get rolling, a couple housekeeping items. We're hoping to have a very active chat, so the people who aren't speaking may answer questions for you live. So you can type them up as we're talking. The other thing is on CME. As a reminder, you can earn CME for attendance in this session, and your participation has been recorded. Due to high volume, it may take up to 48 hours for all data to be transferred to your Academy online account. For those attending the AA in real time, the Academy recommends claiming your CME beginning Wednesday morning to ensure all of your participation has been accurately transferred. Okay. And with that, I'm going to get started. Okay. So we're going to try to help you get to the next level on handling neuropathies in four different areas. I left the complicated things to the smart people, so we're going to work on the kind of basic distal symmetric polyneuropathy of unknown source that you may run into. So I'm Shawn Jordanson. I'm a partner at Adirondack Rehabilitation Medicine in upstate New York. I'm a clinical professor at Albany Medical College, adjunct professor at Robert Larney Medical College at University of Vermont. I have no disclosures. And please email me. I covered a lot more than time would allow, so I'm glad to answer any questions. Okay. So basically, where we're starting here is that you have a patient in your lab or your office and you have established that they have a length dependent neuropathy by history, by physical, and by electrodiagnostic studies, but there is no obvious answer for why they have it. They're not a known diabetic. They don't drink very heavily. They don't have chemotherapy exposure. So how do we handle that situation? You know the basics. How do we take that to the next level? And the goal to trying to figure out what the cause is, is twofold. One is obviously to try to discover some reversible or at least treatable cause, but also patients want to know what's going on with them, and there's value just in that by itself. So that's our goal. How do we achieve that? Well, as we know, the differential for neuropathies is very broad, and if you want to try to capture all those, you end up getting a workup that looks something like this. The problem is this workup probably costs upwards of $10,000, and it's going to generate tons of homework for you, headaches for the patient, running back and forth to the lab, anxiety. This is the equivalent of swinging a sledgehammer in your EDX lab. This is not next level, but what I'm hoping for myself and yourself after looking at this, is we can do this a little better in a way that's not an assault on the healthcare system, and that is just more rational. I'm hoping we can do this with a scalpel, so let's see. Now when considering which of those tests are really worth doing, one of the big considerations is yield. Are we going to get a decent hit rate, because if not, why bother? But that's not the only thing. If we're going to get something valuable, it has to have some association with the neuropathy. Possibly causal, although not always, and then of course in a perfect world, we want to catch everything that's treatable. So this talk would take a minimum of an hour if, in 2012, the AANEM hadn't already done this work to some degree. They came out with this practice parameter, which was endorsed by the American Academy of Neurology and our own American Academy of PM&R. In fact, some of our neuromuscular medicine and EDX member community members were actually helped author this, and they did almost all the work. But as I treat patients in the lab, I find that there's some questions that I still have, and you may have too. So in deciding which test to really recommend, they kind of started in a similar place to us. But what they focused on was the yield. Which ones of these are high yield and worth doing? And I kind of put it in my next slide here. What they came up with is looking for vitamin B12 deficiency, diabetes and prediabetes, and monoclonal demopathies were the things that were really high yield. So we're going to dive into those. So let's talk first about vitamin B12 deficiency. We don't know the exact mechanism. We know that vitamin B12 is an enzyme that converts many reactions, and probably at some level this involves myelin, but that's kind of the extent of it. Now clinical presentation is not our focus, but it is worth noting that vitamin B12 deficient neuropathy often has some very striking characteristics that you almost never see in other causes of distal symmetrical polyneuropathy. And those are a simultaneous upper and lower limb onset, and often a sudden onset as well. So if you see those, be thinking of vitamin B12 deficiency. The main focus here is how do we diagnose this well? And it's well known in the medical world that patients who have kind of an established vitamin B12 deficiency, hematologically, clinically, on all their lab tests, often their vitamin B12 level itself is not abnormally low. And so just getting the vitamin B12 level is not enough. And so as they get into in this practice parameter, what you can do is you can get a homocysteine and methylmalonic acid level. These are precursors to the reactions that the vitamin B12 catalyzes. And so when the vitamin B12 isn't there in enough levels, these start to build up, and you can detect that in the blood. But why do we care about those? As it turns out, those are much, much more sensitive for functional vitamin B12 deficiency. Now one of the questions I came to is, well, why don't I just order those? If they're much more sensitive, what's the utility of the vitamin B12 level? Well, as it turns out, and I literally had a patient this week where this happened, where the homocysteine and methylmalonic acid levels were normal, but the vitamin B12 level was actually low. So the bottom line is you need all three. The question is whether you need to get all three at the same time. Personally, I found that the vitamin B12 level was almost never low. And so I don't get that first and then get the homocysteine and methylmalonic acid. I get them all at the same time. All right. And in terms of treatment, vitamin B12 deficiency is one that we hold out to patients as one of the possibly treatable and reversible causes of neuropathy. However, it's not always reversible, and we should note that just staying where you are and not progressing is still a win. All right? So that covers that. Now let's talk about diabetes and pre-diabetic neuropathy. The pathophysiology of this is also not straightforward. Probably involves toxic metabolites of glucose, but it's probably more complicated than that. So why do we care about pre-diabetes? Patients ask me this all the time. Oh, they say I'm almost not diabetic or barely diabetic. Why does this matter? Two things. Number one, your risk of becoming an actual diabetic is much higher if you're pre-diabetic. And number two, being pre-diabetic itself is a risk factor for microvascular disease. Both the conversion to diabetes and the microvascular complications, or at least some of them, are preventable by lifestyle changes and medications. So this is actually really important information. The patients have the ability to change their destiny to some degree. Is the being pre-diabetic associated with the neuropathy? It does seem so, at least according to most studies. OK. But again, our focus is on the diagnosis. So how do we diagnose this? Well, there's three tests that we can use. And unfortunately, the A1C wasn't really discussed in the practice parameters. But you can have an elevated fasting glucose. You can have an elevated two-hour glucose tolerance test or an elevated A1C. Any one of these makes you pre-diabetic. And unfortunately, not every patient will have all three of these or even two of these abnormal. Really the big question to me is, can I skip the two-hour GTT? And I've gone back and forth on this in my practice. And after doing a deep dive, I think the answer is unfortunately no. Why is that? Well, like I said, many patients will not have all three of these be abnormal or even two. They might only have one. And in fact, this happens most often with the impaired glucose tolerance group. Anywhere from a quarter to a third of these patients will have a normal fasting glucose in A1C, but their GTT will be abnormal. So if you never do it, you're going to miss a big portion of pre-diabetics. It also interestingly seems to be the case that this group that only has impaired glucose tolerance is actually the ones that benefit from the lifestyle modifications and medications that we were just talking about. So they're the ones you really want to catch. So the bottom line is, I don't think you can skip it. And this is bad news because first of all, it's pretty expensive. Second of all, your patient has to wait in the lab for two hours. And third of all, it's pretty gross. And just another interesting note, the best evidence we have is that tight glucose control will neither reverse nor even really stabilize the neuropathy that's associated with pre-diabetes or type 2 diabetes. Lastly, we're going to talk about monoclonal demopathies. Why are they associated with neuropathies? We don't know. But again, probably has something to do with myelin. Is it associated with neuropathy? Yes, it does seem to be. About 10% of patients with a polyneuropathy have a monoclonal demopathy. That's much higher than the general population. But is there a causal relationship? Doesn't seem to be, except for those that are IgM. One big thing to take home from this is that you should not diagnose this with an SPEP, but rather get a serum immunofixation. It's much more sensitive. Now what can this represent? And when I'm getting these blood tests, patients are always asking me, well, what are you looking for? What are you going to find? I don't say cancer, because number one, I've almost never caught it. And it's just kind of not something they want to hear. The vast majority of the patients that you find a monoclonal demopathy on are going to have a monoclonal demopathy of uncertain significance, or MUDIS. Well, why is MUDIS important? Well, it does do some end organ damage itself. But the bigger thing is that these will transform to a hematologic malignancy at a rate of about 1% a year. Now figuring out who is going to just stay MUDIS versus who is going to develop myeloma or something else is very complicated. It's changed since I came out of training. I recommend you just have a hematologist help you out with this. So in conclusions, if you want to take handling distal symmetric neuropathies in your lab to the next level, here's some things to take home with you. They can be caused by a lot of different diseases, but most of those are not discoverable or treatable. And looking for them is considered a waste. You have to consider the yield on what tests you're going to order. And as it turns out, the highest yield investigations are vitamin B12 level with methylmalonic acid and homocysteine, fasting glucose and glucose tolerance test, an A1C wasn't mentioned in the practice parameter, but does make sense, and a serum immunofixation. That's all I got. Here are my sources. Please email me or chat me if you have any questions. With that, I'm going to hand it over to Dr. Nassim Raad. She is an assistant professor at the University of Washington. She is a co-director of the ALS and Muscular Dystrophy Clinic and the residency or the rehabilitation director of the EMG Lab. And we're going to let her go now. Thank you. Thank you. So today, I'm going to have the pleasure of talking about practical genetic testing in a patient with suspected inherited neuropathy. I have no relevant financial disclosures. I'm hoping that today we'll be able to review the diagnosis of inherited neuropathies and more specifically talk about what is the need for genetic testing. I'm also hoping to spend a little bit of time discussing the current standards for genetic testing and the implications this has for clinical management. So to begin with, inherited neuropathies have a prevalence of 10 to 40 per 100,000. And of that, CMT is the most common form, also known as hereditary motor and sensory neuropathy, which has a population prevalence of 1 in 2,500. Now in this particular lecture, when I refer to inherited neuropathies, I'm going to be talking about CMT. But just as a reminder, inherited neuropathies also include hereditary motor neuropathies and hereditary sensory neuropathies. Inherited neuropathies clinically present with distal weakness, sensory loss, and muscle atrophy. Prior to genetic testing, CMT was defined as either demyelinating versus axonal. And this was based on conduction velocities in the upper extremity. So conduction velocities below 38 meters per second were defined as demyelinating and classified as CMT type 1. Conduction velocities above 38 meters per second were defined as axonal and classified as CMT type 2. And conduction velocities between 25 and 45 meters per second were defined as intermediate CMT. Then along came advances in genetics. And in 1991, a duplication in the short arm of chromosome 17, which contained the PMP22 gene, was identified. And this was classified as CMT type 1A. By 1993, mutations in GJB1, PMP22 deletion, and MPZ were also discovered. These genes, so the duplication and deletion of PMP22 mutations in GJB1 and MPZ, account for 76% of all cases of CMT type 1. Now if we include the MFN2 gene mutation that was discovered as a cause of CMT type 2A, we have now identified 90% of all inherited CMT. In 2003, the Human Genome Project was completed, and that identified 22 genes known to cause CMT. Currently, we have about 70 identified genes for CMT. So this schematic here is just an important reminder that even though genes have been identified and linked or are more common to certain conditions, there is significant overlap. So genes can cause CMT type 1, type 2, hereditary motor neuropathy, and hereditary sensory neuropathy. So clinical exam and history and additional testing is still important. So the diagnosis of a suspected inherited neuropathy is still largely driven by history and clinical examination. And due to time restraints with this talk, we're going to be focusing on the genetics and not necessarily the presentation. But still do remember that history and clinical exam is leading the suspicion of inherited neuropathies. This can be challenging, though, because we now know that there are many more sporadic cases, and these sporadic cases are going to lack family history. Electrodiagnostic testing is still very important in distinguishing sensory motor or sensory motor involvement and defining demyelinating or axonal forms of CMT. So why is genetic testing even needed if you have a strong suspicion, a strong family history, and you have electrodiagnostic evidence? Well, we now know that CMT presents with a broader clinical scenario. So for example, in GJB1 and SH3TC2 and a few other gene mutations, patient history and EMG findings have thought to be more consistent with CIDP, although did not respond to treatment and ultimately were diagnosed and defined as CMT. We also now know that there is phenotypic overlap between axonal forms of CMTs and ataxias, distal myopathies, and even hereditary spastic paraplegias. So there are some genetic mutations for other diagnoses that start a presentation with a pure peripheral neuropathy, and so they're initially diagnosed as CMT or distal HMN and then later progress in their clinical presentation and are ultimately redefined. In 40% of patients with CMT, we still do not have a genetic diagnosis, and this is even with identifying over 70 genes for CMT. So there have been recent advances that make genetic testing more applicable to our patient population. So next-gen sequencing now allows us to sequence the entire genome or exome in a matter of a few days. So you can either perform whole-exome sequencing or whole-genome sequencing. The difference being is that the exome is the protein coding sequence, but we now know that introns play an important role in disease and that with whole-exome sequencing, we may miss introns. Whole-exome sequencing is not currently commercially available. So you can use disease-specific multi-gene or testing panels to regions of exomes that contain known CMT genes. You can also use just smaller panels that cover a particular phenotype. Using genetic testing has allowed us to identify novel genes and increase our knowledge base of other genes that are causing CMT. Now, a word of caution, genetic testing is complicated by interpretations of variants of unknown significance. What these are, are genes that are not identified in population databases, but they're also not identified as variants that have been known to cause disease. Over time, these variants may change classification into pathological variants or may be determined to be seen in the normal population and therefore benign. But it's important to counsel patients on this because it can be stressful for them to get this result and not understand the implications. Prior to next-gen sequencing, and it's still available, is targeted Sanger sequencing. This involves individual gene sequencing. It can be time-consuming, costly, and given the last slides that we showed where there is much genotypic overlap, it can be really unrevealing if you don't pick the right gene to test. So, the goals of genetic testing are to get a definitive diagnosis and to provide prognostic information for individuals. Unfortunately, much of the management will likely not change, and it's important for patients to understand that because we still don't have a cure for CMT. It is important for patients who are considering antenatal or preimplantation genetic testing, going in line with diagnosis, it's important to rule out MIMIC. So, for example, those CID patients who aren't responding to treatment. And certainly, with advances in clinical trials, being able to have genetic confirmation may allow patients to participate in gene therapy specifically for their gene mutation. So, I hope from this you've taken away that inherited neuropathies are phenotypically and genetically heterogeneous, which makes diagnosis challenging. That when you have patients that don't have the classic CMT1 phenotype, you should consider next-gen sequencing for either specific panels, whole exome sequencing, or whole genome sequencing when it becomes commercially available. And remember that interpreting variants is a challenging process and one that you may need to refer out to genetic counselors for. So, with that, I conclude, and I have the honor of introducing the next presenter, Dr. Dave Arnold, who's an Associate Professor at The Ohio State University in the Departments of Neurology, PMNR, Neuroscience, and Physiology, and Cell Biology. Thank you. So, first, I'll start off with my disclosures. These are mostly not directly relevant to the talk today. So, for the next few minutes, what I hope to do is give you a maybe a little bit oversimplified approach to understanding how the evaluation can be initiated when you are considering the possibility of immune-mediated neuropathies. And so, what I'm going to do is primarily focus on clinical patterns that raise the possibility of an autoimmune pathogenesis and talk a little bit about the differential and other things to consider. We're not going to do a very deep dive into electrodiagnostic findings or other workup that is helpful, but mainly help you understand the patterns that really may signal an underlying autoimmune pathogenesis. So, really, this starts with all evaluations of any kind of neuropathy. It starts with six main questions. And so, this talk is largely based off a very nice article from Neurologic Clinics from 2013 that was written by Rick Baron, who was recently at Kansas University and has now moved to Missouri University. And I encourage you to check it out because, really, this is the basis of a lot of the concepts that I'm going to talk about today. But these are the six questions that I think really can give you a good head start on trying to figure out what's the underlying pathogenesis of the neuropathy. So, first, what systems are involved? Is it sensory and motor? And what submodalities may be involved within each of those systems? Then, once you determine if there is weakness, motor involvement, then try to determine what's the overall distribution of the weakness. If there is sensory involvement, what is the nature of the sensory involvement? Is it primarily small fiber modalities, so pain and temperature or autonomic? Or is it primarily large fiber, so loss of reflexes, loss of proprioception, vibration, and so on? It's also very important. You can have mixed combinations of neuropathy with peripheral involvement as well as central involvement. And Sean mentioned B12 deficiency. And in my experience, most B12 deficiency is actually associated with more prominent myelopathic changes. So, very prominent, you know, increased reflexes and so on. So, that's always a key piece of the history in physical. And then, thinking about hereditary versus acquired causes of neuropathy and specifically autoimmune, thinking about how the symptoms started. Was this a subacute or acute onset? And sometimes people can't tell you when it exactly started. And that gives you some insight into the chronicity. It may suggest that it's been there longer than the patient even realizes. And sometimes, whether or not the symptoms align with the history can also give you insight as well. And so, one common scenario is people come in and say, oh, this started about a year ago, but then you see very, very prominent sensory loss and weakness. And sometimes, in my experience, that highly suggests a hereditary form of neuropathy because people kind of get used to symptoms before they really notice the weakness and the sensory loss. And so, sometimes their clinical symptoms are more overt than their complaints. When the opposite is true, so more complaints and less clinical involvement, that normally suggests less chronicity in my experience generally. So, this is a chart that lists 10 basically clinical patterns. And seven of these can sometimes raise the possibility of an acquired autoimmune neuropathy. And so, we're going to go through the main patterns here and touch upon some underlying disorders that fall within these clinical presentations. So, the first one that we're going to talk about is the kind of what most people think about when they think about autoimmune peripheral neuropathy. So, this is the pattern that would fit with Guillain-Barre syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. So, Guillain-Barre syndrome is actually a very large mixed group of disorders. But when most people think about that, they think about the AIDP form of it or the demyelinating form of GBS that presents as a polyradiculoneuropathy. So, the big distinguishing factor or features between GBS and CIDP is really timing. So, by definition, CIDP has to have a chronicity of at least eight weeks. And GBS is generally a monophasic process that only progresses up to four weeks by definition. Occasionally, people describe this SIDP or the subacute version that kind of falls between these two. One thing to keep in mind is CIDP is a chronic condition with relapsing, remitting kind of or progressive kind of natural history without treatment. But it can sometimes present acutely. And so, it can mimic GBS. And so, that's something to keep in mind within the treatment. So, generally, these patients present with mixed motor and sensory deficits. It is normally most prominent in the most distal segments of the upper and lower limbs, but cranial nerves are commonly affected in GBS, less so in CIDP. But it is a polyradiculoneuropathy. So, oftentimes, the presentation is non-linked dependent. And so, the main mimics that should be considered are other acute forms of neuropathy. And so, like, for instance, thiamin deficiency can sometimes very closely mimic GBS and CIDP and other things like that. So, the workup would include exam history, electrodiagnostic testing, and CSF analysis. But we won't go through all those details today. The next presentation is a demyelinating, oftentimes demyelinating form of autoimmune neuropathy, which we call anti-MAG or distal acquired demyelinating sensory and motor neuropathy. Sometimes people call it DAD. So, it presents with features of prominent demyelination on electrodiagnostic testing, but it really mostly affects the distal nerves. And the symptoms are usually sensory more than weakness. And so, this is associated with IgM monoclonal gammopathy. You can order anti-MAG antibodies. This will sometimes look like hereditary neuropathy, but the history will suggest a less chronic presentation or onset. This is a relatively rare disorder, but something you don't want to miss because it can be associated with underlying monoclonal gammopathy. The next presentation is asymmetric distal weakness and sensory loss. So, this actually can have the most common presentation that will present like this will be a generalized neuropathy, link-dependent neuropathy with superimposed mononeuropathies at compression sites. So, the common one may be diabetes with superimposed carpal tunnel or ulnar. But there is a specific, somewhat rare form of immune-mediated neuropathy that is demyelinating called, sometimes people call it Lewis-Sumner syndrome. Some people call it MAD-SAM or multifocal acquired demyelinating sensory motor neuropathy. And so, it is in a lot of ways like CIDP in that there is demyelination and there's signs of multifocal conduction block and temporal dispersion and CSF protein can be elevated. But it typically is asymmetric where CIDP is very symmetric. It is most commonly in the more distal parts of the limb or where CIDP is more proximal and distal generally. If there is very prominent features of pain and you may have a more abrupt onset or stepwise kind of progression, you can also see this presentation with vasculitic neuropathy. So, vasculitic neuropathy is basically loss of blood flow to individual nerves because of autoimmune inflammation of the blood vessels that supply the nerves. And so, you get these stepwise basically strokes of the nerve that cause very prominent pain. So, if you have somebody with an asymmetric neuropathy and particularly with pain, then you really need to think about vasculitic neuropathy. That's one of the few indications for potentially considering a nerve biopsy is if you have asymmetric neuropathy with pain because that vasculitic involvement can spread to other systems and can be associated with high risk mortality. So, it's really critical to have initiation of immunomodulatory treatment at an appropriate timeline. And so, that is a potentially very serious form of asymmetric distal sensory motor loss. Now, people always talk about mononeuropathy multiplex. Vascular neuropathy can present like that. A lot of times, it's just slightly asymmetric. So, sometimes you really have to tease apart with the history. You know, how did the neuropathy start? Most neuropathies, this distal link-dependent neuropathies are symmetric. But if you have asymmetry, think about superimposed processes or things such as vascular neuropathy, particularly with pain. If you have asymmetric distal weakness without sensory loss, the first thing that people think about with that is, of course, motor neuron disease or ALS. But there is multifocal motor neuropathy that can sometimes have conduction block or not. When it has conduction block, it makes it a lot easier to diagnose. There's also anti-IgM antibodies that are present in about half of patients. And so, this is a immune-mediated neuropathy that does respond very well to IVIG. And so, the big mimicker or the two overlapping presentations are motor neuron disease. If it's just lower motor neuron, it makes it even more difficult. If there's upper and lower increased reflexes, that can be more helpful to tease that apart. But when it's purely lower motor neuron involvement, it can be difficult. The big distinguishing features are, is multifocal motor neuropathy follows peripheral nerves, where motor neuron disease falls myotomal. So, it's more like root level because of the motor neuron loss versus the involvement of peripheral nerve. Fasciculations actually can happen in both disorders. And so, multifocal motor neuropathy actually is associated with conduction block. It's probably related to sodium channelopathies at the nodes of rhombiae. But distal to the block, you can actually get hyperexcitability of the nerve. And so, you can have fasciculations. And in fact, I've had patients that had fasciculations and cramps, and the cramps were some of their biggest symptoms. But that's somewhat unusual. Asymmetric non-linked dependent sensory loss. This is a very unusual clinical pattern, one that we would typically say non-linked dependent sensory loss. So, when we see that, we are concerned about potentially sensory ganglia loss. And that raises the possibilities of a toxic process. Perineoplastic anti-hue antibodies can cause this problem. So, if you are doing an evaluation for neuropathy, it's always good, as I tell my residents and fellows, is to surround the abnormal with normal. So, don't just do a leg. Make sure you go up to the arm and make sure it is truly linked dependent. It's also good to see that it's symmetric. So, if your serral's gone or say your serral's reduced and your radial is reduced and they're kind of similarly reduced, one thing you have to worry about is this a non-linked dependent process. And so, perineoplastic processes are things to really think about in that situation. So, a perineoplastic panel might be helpful or maybe even important. Last one that I'm going to talk about is even more rare than the other ones that I've presented. So, acute onset of autonomic dysfunction can sometimes be an autoimmune neuropathy of the autonomic nervous system. And so, these can be very prominent where people present with very prominent symptoms of autonomic failure and can be modulated with various treatments. Sometimes the outcomes aren't great, but the earlier this is recognized, the better. And sometimes there are forms of autonomic neuropathy that sometimes people link into kind of a phenotypic variant of Guillain-Barré syndrome. So, sometimes it can present very acutely like that. Sometimes it's more chronic and progressive. So, really the take-home lessons that I was hoping to convey in just a few short minutes is really think about the clinical patterns. Ask these questions. Check out this article by Rick Barron. I highly suggest it's a nice resource. And really kind of this is a kind of a lumping strategy, but think about these variants and these patterns, and they can kind of help you think about maybe what's the next step? What are the other possibilities? What is the worst thing I can miss? Or what is a treatable condition that I don't want to miss? And then each of these have different treatment implications potentially, which we don't have time to talk about today. But if you have specific clinical questions, you're welcome to throw those in the chat or send me an email. I'm happy to answer anything I can. And so, with that, I'm going to hand things off. So, our next speaker is Dr. Hearn. She is an assistant professor and the director of the residency program at the University of Michigan, and super excited to hear her talk. Good afternoon, everyone. I'm Sandra Hearn. It's great to be here. I have no relevant financial disclosures. What we're going to speak about today is thinking about the mild peripheral polyneuropathies. I'm going to open with a case and then show you where we're going with this. Meet Mrs. Smith. She presents to the electrodiagnostic lab, saying, since around last summer, my feet feel numb. It's like a feeling of cardboard on the bottoms of my feet. I find I'm tripping more when I'm hiking downhill and when I'm trying to walk in snow. My feet cramp up, and I have to really concentrate to keep my balance. Take a pause point here. Think about her story and think about your differential diagnosis, how you might plan her study. I'm thinking she might have an early neuropathy, and this is something we can look for in the lab. Let's go. So, many of us look to the sural sensory study to define early neuropathy. You can see a quote from the consensus paper in 2004, suggesting that for run-of-the-mill axonal peripheral polyneuropathy, we want to see abnormalities in at least two peripheral nerves, of which one must be the sural nerve. So, we go for it, and she's got a right sural sensory study with an amplitude of 6.5 microvolts, a little above our lab's lower limit of normal at 5. We got the contralateral side. Left sural sensory is 7.3 microvolts. What are we thinking now? Go ahead and get the motors. We do tibial and deep fibular motor nerve conduction studies, and those come out in the 2 to 3.5 millivolt range. No distal slowing, normal F-wave minimum latencies. So, is this looking like neuropathy to us? We could do a needle EMG, but we have a fair bit of data here already. I don't know what you're thinking. I'm thinking this could be borderline, but the question is, for us as physiatrists, where do we go from here? Well, we could say this is a normal study. There is no electrodiagnostic evidence of peripheral polyneuropathy, but you know what we're going to hear back, right? Mrs. Smith is going to say, but why? Why are my feet numb? And why do I have more trouble keeping my balance when hiking? And so this is what I'd like to think with you all today on. What can we as physiatrists offer to help Mrs. Smith? Is there more we can do to understand her set of symptoms in conjunction with the electrodiagnostic data that we have? And does it matter if she has a mild neuropathy or not? That's what I'd like to explore with you today. The punchline here really is this. Distal neuromuscular function is not black and white, and that gray zone spectrum, that impacts function. How do we know this? How do we know that there even is a gray zone for neuromuscular function? How do we know that distal neuromuscular decline probably matters and it probably comes about earlier than frank neuropathy findings do? And how do we know that they matter, that they influence things like falls risk? Well, Dr. Callahan et al. did a large study published in 2015. This was a case control study using a cohort from the health and retirement study that used a Medicare claims database. And what they were able to do is identify 953 cases of incident neuropathy. Okay, so that's new diagnoses of neuropathy. And then they were able to look back in the years prior as well as ahead in subsequent years to see how patients answered the question of whether or not they're falling. Specifically, have you fallen in the last two years? They matched their cohort with 953 controls matched for age and other risk factors. And what they found here is not terribly surprising. Firstly, people who have a new or incident neuropathy diagnosis as you see there in the orange line, these people are more likely to have a false history. And that increased false risk carries forward over time. And as you can see, the separation between cases and controls. But where things get interesting is if you look back instead of forward. And if you look back at how those patients answered the question about falls in the years prior to their neuropathy diagnosis, what we find is that the difference in falls is detectable as early as three years prior to their neuropathy diagnosis. That right there between those lines, that's the gray zone. And it matters. It impacts function. The cases are different from the controls. Does it make sense? Probably many of you were thinking intuitively it makes sense to us, right? That the distal sensory and motor functions that we can measure in electrodiagnostics, that they would impact patient's mobility and falls risk. Here's one mechanism. Dr. Kelly et al in 2012, they looked at 10 healthy male subjects to see whether foot intrinsics matter for balance. They put EMG needles inside the foot intrinsic muscles and measured activity at rest. So you can see the subject seated with EMG needles and three muscles, quadratus plantae, flexor digitorum brevis, and abductor hallucis. And there's not too much activity there. How about double leg stance? There's some low level of activity in the foot intrinsic muscles. But where we really see them act in is on single leg stance. And there we see the foot intrinsic muscles activity goes up markedly. And that activity level actually correlates with the center of pressure speed of the patient's foot over the force plate. In other words, foot intrinsic muscle activity correlates with postural demand. They are active when we need them to be active to maintain balance. These results indicate that the plantar intrinsic foot muscles are active during quiet stance and that they increase in activation with postural demand. And so in addition to impacting patient's falls risk now, does it predict the future? Distal neuromuscular function can actually predict to some degree mobility disability. This is a study by Ward et al in 2014, looking at patients from two centers. They looked at over 1600 older adults without mobility disability and followed them over time. First, they measured their sensory signs, sensory symptoms of neuropathy. And then also they did electrodiagnostics insofar as a deep perineal compound muscle action potential. And what they found following these patients over a mean of 8.5 years was that about 30% ended up developing mobility disability as defined by difficulty walking a mile or 10 steps. And interestingly, the deep fibular motor amplitude, something that we can measure in the electrodiagnostic lab, was one of the major predictors of development of disability. This is the first report that poor peripheral nerve function predicts incident mobility disability in late life. And in their study, it was largely independent of diabetes mellitus. So what I hope I've been able to show is that that gray zone of low, but perhaps slightly above what we've thought of as normal distal neuromuscular function exists and that it's relevant to our patients now and our patients in the future when we think about function. In this next part, let's talk about what tools you and I have in the electrodiagnostic laboratory to use this background and inform our patients' care. I'd like to put forth three things. Firstly, we can interpret that fibular motor amplitude functionally, meaning thinking about it in terms of how it informs our patients' function, not just whether it gets them into a neuropathy diagnostic category or not. Number two, we can look more distally than the Searle sensory study takes us. We can do that through a distal sensory or mixed nerve study. And number three, I'd encourage us to think about EMG of a distal dorsal foot muscle, really bringing us distally and looking at a part of our electrodiagnostic test that can see small amounts of axon loss and that isn't dependent on population norms. Let's take a little look here. I'd like to take this moment here to thank my personal and professional mentor. That's Dr. Jim Richardson at University of Michigan. He is a researcher and an expert in gait, balance, falls, and neuropathy. It's been my pleasure and privilege to get to work closely with him. This is his work, what I'm showing here. What he did here was measure ankle proprioceptive function, which is a measure of sensation. And what you see in the apparatus is a specially designed cradle for the foot in his lab, such that the cradle can deliver small amounts of rotation to that ankle. And the patient can express that he or she can detect it by moving the joystick. In other words, his lab apparatus enables us to detect a sensory proprioceptive threshold, a number of degrees of motion below which the patient can no longer detect the position change. So that's a sensory measure of distal function. He also has a motor measure, which is ankle rate of torque development. That is not shown on the diagram, but you can imagine a force plate that can detect ankle force and torque. Now, these are both measures that you and I don't have, right, in the clinic or the lab. We need to go to his research lab for that. But what we do have is electrodiagnostics. So what he did then was look at how those measures correlate with fibular motor amplitudes, something easily accessible to us for each patient that we see in the lab. I'll mention here that both sensory and motor measures that he looked at have been shown to correlate with fall risk. What he found was that the fibular motor amplitude predicted almost 60 percent of ankle proprioceptive threshold, the ability to detect one's ankle position, in a sample of older subjects with a spectrum of peripheral neurologic function. And most interestingly to me is that even looking at those without neuropathy, the relationship persisted. So what you see here on the plot is the subjects are dots, x-axis is the mean fibular motor amplitude, okay, so the higher the better. And on the y-axis is the ankle proprioceptive threshold, so their sensory function. Now, lower is better for the threshold. Lower threshold means that you can detect smaller degrees of change in position. And so what you see here, if you read the graph really from right to left, you can see that once you get below a fibular motor amplitude of about five millivolts, that's when things start to get more variable, right, in terms of sensory function. You see that sensory function dropping off, as in that line is going up as you move left. So what these data suggest is that even people without meeting a frank diagnosis of neuropathy, in other words, even people with the fibular motor amplitude falling in the two to five millivolt range, they're already different from people with higher amplitudes. There's something functionally relevant there. Let's move on to tool number two. Tool number two is the mixed medial plantar study, which allows for assessment of distal sensory function. The setup for the study is as shown in the diagram here, which is taken from Preston and Shapiro's textbook, so I won't walk through that technique in detail. But that is something that can look more distally. Various studies have shown it has fairly good reproducibility. It can be reliably obtained in subjects up to about 70 years of age, and it significantly improves sensitivity for detecting neuropathy in the right patient populations and people who have a clinical phenotype that fits for distal symmetric polyneuropathy. And you can see here how the sensitivity of the medial plantar study is quite a bit higher than the Searle in three separate studies looking at this question. So something to think about. Personally, I tend to do this study in the younger patients, people under the age of 60, to see if I can get a response or not. And if I can't get a response at all and the person has borderline Searles and a good history for neuropathy, I do think that correlates with some distal neuromuscular decline that's relevant. Lastly, we can consider EMG of a distal dorsal foot muscle that can reveal distal axonal loss. Doesn't depend on population norms. We know here that if someone's actively losing axons, there'll be multiple muscle fibers at any one time that are denervated and fibrillating. Why this muscle? Well, a dorsal location may make it a little more protected from stepping hard on our feet when we're running and jumping. And it's also not against a bony prominence. Siddiqui et al in 2007 showed the fourth dorsal interosseous as a potential muscle for study. And this group showed that it's frequently abnormal in neuropathy and in, not surprisingly, S1 radiculopathy. But it's rarely abnormal in controls. So this is a reasonable thing to check. I do study this muscle and I look for prominent positive sharp waves and fibrillations, two plus positive sharp waves and fibrillations to feel that this is decidedly abnormal. Or extensive atrophy and decreased insertional activity. So let's go back to Mrs. Smith. You recall the data that I showed you before. But now with our understanding of distal function and our tools, we can add to this. We can add a right medial plantar mixed nerve study. We get no response. We can then study bilateral first dorsal interosseous or fourth dorsal interosseous muscles of the feet. And we see two plus positive sharp waves and fibrillations, decreased recruitment of units with large amplitudes. And so now we can start to form an impression using a smattering of mild abnormalities, but abnormalities that correlate with one another and with Mrs. Smith's presentation. And we can now say there are electrodiagnostic findings that support early sensory and motor distal neuromuscular decline. This could be early neuropathy, Mrs. Smith. And it could well explain the changes you described and how your feet feel and your changes in balance. So why do all this? I think it gives us clarity. It allows us to correlate our findings, our objective findings with the patient's experience. It enables us to start talking about early interventions and suggestions. And it gives the patient a realistic and relevant outlook on prognosis. Mrs. Smith and her doctor no longer have to worry that she might have some weird manifestation of a rare disease or that she's a medical mystery where her symptoms don't make sense. We can offer that as her physiatrist. And so in summary, I encourage us to think about distal neuromuscular function along a spectrum, not a black and white classification of disease. Not all that lies above thresholds for norms are functionally optimal. So we can think about our data in terms of function and still use that to guide our patients. Tools we hit today, thinking about the fibular motor amplitude functionally, recognizing that less than five millivolts could reflect suboptimal function, looking at a distal sensory or mixed nerve study, and considering EMG of a distal dorsal foot muscle. With that, I'm going to close up this section of the presentation and we will open it up to Q&A. Thank you. Okay. Thank you, Dr. Hearn. And now we're going to open it up to any questions you have. Why don't you type them into the chat while we're talking? We actually have two for Dr. Hearn, if you want to answer those. And then if you guys have other questions, you can put them in the chat and we'll look at them while she's answering those. All right. So one question for me is, this is fibular motor amplitude to the EDB only you're referring to. That is correct. How do you interpret age extremes that have inherent EDB atrophy and have quite low EDB motor amplitude values? That's a really good question. And I think that that's where we're straddling that, what I'm calling the gray zone in that spectrum. In other words, for a long time, we thought that, well, having low peripheral nervous system function, whether it's sensory studies or motor studies in the distal extremities is normal for age. And it's what we expect to see based on population norms. But the question really we're asking ourselves is, do those population norms, do they reflect function, right? In other words, if someone has no sero response and has positive sharp waves and fibrillations in the foot intrinsics, are they functionally the same as someone who's got excellent sero responses? And I think the literature is pretty clear now that it is not the same. And so whether or not we want to call it, should our whole diagnostic threshold for calling neuropathy change versus whether we're saying, this is a type of decline that we often do see with age, but we're not going to call it neuropathy. That's kind of the gray zone for where the science and diagnostics are at right now. Other thoughts on that question are, if there's a very clear reason that we think their EDB amplitudes are low, then we've got to take that into account too. So if I know for a fact they've had an ankle crush injury and visibly the EDBs are atrophied, I'm going to take that into account and put less weight on that one abnormality. I think looking at the spectrum of abnormalities, so the clinical history, does it fit for mild neuropathy? Do the sensory parameters fit and do the motor parameters fit together as a whole? That would be telling. So for example, if they had rock star tibial motors and the deep perineal studies were low, I might be less inclined to call that neuropathy than if we're really seeing the spectrum of abnormalities together. Another question is at what age would you not be expected to find fibs in intrinsic foot muscles simply related to wear and tear? So the small to medium-sized studies I looked at suggested that most of the time, really frank positive sharp waves and fibrillations in the foot intrinsics, absent pathology is fairly rare. Do you want to keep going, Sarah? Help me out, Sean. If there are more for me, I'm just scrolling a little bit here. Yeah, go for it. The possible neuropathy of old age, I think that's the question that I also addressed in the prior. Will you look at fibular sensory, so superficial perineal or fibular sensory if you're expecting early? I agree. I think it can be useful. I wouldn't discourage people from doing it. My experience has been that the sorrel is a little easier to obtain and more robust in that population that is already borderline. So if I have a reason to think that their sorrels may be low for some reason other than neuropathy, I think that's a good time to get it. If the sorrels are overall a little higher than the superficial perineals and both are borderline, that's a common finding, I think, in this early neuropathy or distal neuromuscular decline population. Anyone want to take the question about HIV neuropathy? Yeah, I mean, I'm not real strong in that area, but one thing that we use a lot, so HIV-related neuropathy is oftentimes small fiber predominant and can involve the autonomic nervous system as well. So we do skin biopsies for diagnosing loss of intradermal nerve fiber density, and we also do quantitative pseudomotor axon reflex testing for assessing the small fiber functionality away. So for diagnosis, that can be very helpful. We always do the medial plantar to ensure there's no large fiber involvement, but sometimes even in patients where that's normal, you can have abnormalities on skin fiber density on skin biopsies, and so that's something that we use a lot. As far as interventions and pathogenesis and things like that, I don't know. I'm not necessarily expert in that space. I'll take the question on functional neuropathy. Is it fair to call a functional neuropathy a subacute neuropathy? I think by functional neuropathy, we're referring to these kinds of early ones where we might skirt normal values, but we think that there's some neuromuscular decline. I would not call them subacute neuropathy. To me, subacute neuropathy refers more to the time course. So if I hear subacute neuropathy, I would worry more about something like a CIDP that has progressed fairly rapidly over a few months. So I would probably say that the findings that could be consistent with early distal neuromuscular decline, I might say it could be age-related if I think that's the case, and that an early presentation of a mild neuropathy is possible. How about anyone have any thoughts on the seroradial amplitude ratio? We use that some. I've actually talked to one of the authors that published a paper on that, and he doesn't even use it. So I mean, I think it can be helpful in certain situations. So I didn't talk about this, but sometimes you have this instead of the serral being lower than the radial, the radial is lower than the serral. So you kind of have this serral sparing. So it can help for early detection as well as kind of non-linked dependent involvement. So looking at both of those nerves together is helpful. I don't think it increases the sensitivity of an EMG and nerve conduction study that much, but I think it's something to consider. If I remember correctly, there may have been an article that showed that that wasn't helpful after the original article came out. Does that sound familiar? I think so, yeah. I think so, yeah. The next question on the role of imaging, I think this is a really complicated and interesting question. Shear wave elastography is clearly on the cutting edge. So I don't think we know the answer on that yet. There are clearly some neuropathies like CIDP where people are using it before they even do spinal taps now, but I don't think it's really found its final place yet. Lumbar imaging when lower extremities CMAPs are diffusely low. I tend not to go there. I would want to see more in terms of the clinical presentation for something spinal than to do it purely based on CMAPs. Happy to hear from others too. The need for that more so than CMAPs. So we're out of time, but thank you everybody so much for attending and for all the great questions. I hope this brought you to the next level in handling the neuropathies that come to your lab and have a great rest of the assembly. Thanks, everyone.

neuropathies

evaluation

diagnosis

types

genetic testing

autoimmune neuropathies

distal neuromuscular function

functional impairment

fibular motor amplitude

falls risk