I am Colin Franz. I'm going to introduce our second part here to advances in neuromuscular medicine. I'll be presenting along with Dr. Chung from Johns Hopkins and Dr. Boone from Mayo Clinic. The topics we'll be covering include motor neurodegeneration after spinal cord injury. Dr. Chung will be talking about POTS and our neuromuscular medicine approach to POTS. Diagnosis and management and Dr. Boone well known to many of you as a trailblazer neuromuscular ultrasound. We'll be talking about her some of her latest work. And we're really happy to be following our first session with presentations by Dr. Lieber, Dr. Rad and Dr. Arnold. So my talk is entitled Practical Implications of Motor Neuron Degeneration After Spinal Cord Injury. I'll give you a quick introduction to myself and my approach to this topic. And then we'll go on through the anatomy and some physiology of this issue as well as a more practical approach for and with clinical correlations of why it matters. No disclosures, I will point out that I'm coming at this not from a spinal cord injury medicine perspective, not as a surgeon and peripheral nerves or thoracic surgery what-have-you, but I'm a neurophysiologist and neuromuscular medicine fellowship trained physiatrist as well as a scientist interested in motor neurons. I'll introduce myself in saying that I'm a kind of a nerd when it comes to motor neuron diseases and peripheral nerve injury. In addition to seeing patients with these problems, we have some active research project we're lucky to have some external funding for including looking at the relationship between forms of neurotrauma and neurodegenerative diseases like ALS. And for example, looking at the relationship between hit injury and lower motor neuron degeneration and how individual patient factors could influence whether or not someone might develop a disease like ALS. We take an unusual approach for a PM&R based research program and that we'd like to get tissue and do things to it like reprogram cells into IPS cells which are a form of stem cell that's similar to an embryonic stem cell but can be derived from a patient and make neurons from them. This is an example with the collaboration of Dr. Fine and at the University of Illinois in Chicago where we built a robot that can actually punch cell cultures with patient derived neurons growing in a dish and look at their trauma response that we've had funding through the NIH to work on together. Other projects include nerve regeneration models using drugs or electrical stimulation to promote axonal regrowth with people Northwestern, Dr. Rogers and Jordan who've been on me with projects through NIH funding as well as Dr. Jordan and I have an NSF sub award. So I'm really interested in this topic and and as I've seen a lot of patients with spinal cord injury in my diagnostic practice this issue is really crystallized for me and I'm going to share some thoughts with you about it. So there's both white and gray matter damage when the spinal cord is injured dramatically as you can see in this cartoon here with the descending cortical spinal tract or the upper motor neuron axons degenerating here where they're injured and I think we all recognize that as given our based clinicians and scientists. But on many levels in addition to having the upper motor neuron and the injury with the cortical spinal tract, I think one thing that's underappreciated is the injury to the lower motor neuron in this disease. For example seen here I've depicted two lower motor neurons here in this particular scenario that are at the site of the injury that ordinarily would connect to say a muscle in the limb or in the upper extremity for example. But often after injury you don't just lose the upper motor neurons the cortical spinal tract you'll lose lower motor neurons and this isn't a big secret, but we sometimes don't focus on this issue a lot because it seems to be of lesser importance than to the upper motor neuron injury. Plus the motor neurons that are left behind often sprout and reconnect to the muscle, so you don't really notice severe atrophy in many patients, at least not early on. But in some patients more of the motor neurons are lost and you can have really severe atrophy with denervation just like after peripheral nerve injury, but in these patients and that can have some serious ramifications. So I'll get to those in a moment. I wanted to show you some data from Dr. Christine Thomas who's passed away, but she was doing great work at the Miami project and she had actually looked directly at this issue by quantifying motor neuron loss in patient tissues post-mortem. And this is a healthy spinal cord here. We're looking at the ventral horn and these are some examples of patients who had traumatic spinal cord injuries and the alterations you see on a macroscopic level to the spinal cord tissue. You can see that in addition to seeing a reduce of size overall that the gray matter itself is greatly disrupted. Which isn't surprising. She did some elegant work where she quantified the number of motor neurons that are lost after spinal cord injury and I think she has one of the better studies looking at this because she looks at it so directly. And you can see that when you average across a series of patients here, you can see that there's at the epicenter of the injury, which is labeled E versus levels above and below, you can see that there's a number of levels where there's pretty significant motor neuron loss when you normalize it at an injured spinal cord. Where you have fewer than half the motor neurons on average surviving the spinal cord injury and that can extend two to three levels above and below the injury site. But it varies a lot from patient to patient and when you look at the individual patient data, you can see some patients are extremely devastated with very few motor neurons remaining at those levels. And if you put it at this injury at the wrong site, you can lose very critical functions both the upper motor and the lower motor neuron supply. Which has implications on prognosis and what we can do to treat these patients afterwards as I'll get to in a second. So if we want to look at this clinically, what's the the first reaction is okay, let's order an EMG and I would see time-to-time patients who've had an EMG ordered after a spinal cord injury and one of the things that we usually rely on to make statements about innervation or denervation of muscle would be the initial spontaneous activity and insertional activity when we place a needle in a muscle. These are some examples of positive sharp waves and fibrillation potentials that you might get with innervation. Except when you look at spinal cord injury patients, and this is some example of some data that was on a series of patients who had injuries and then had EMGs done at in the lower extremity remote from where the injury site was in the thoracic or spinal or cervical level. And the thing that I wanted to point out here is if you look at spontaneous activity levels in the vastus medialis and gastroc and the tibialis anterior muscles. So muscles that are really far removed from where the injury was. You actually can see increased spontaneous activity that mimics some of the changes we associate with innervation. Making an important point that you have to be very careful how you interpret standard electrical physiology tests in these patients. Because these two changes don't always represent denervation at least a peripheral nerve injury or from motor neuron loss per se. And this is problematic because when you look at most textbooks and materials about how to interpret what a you know what a fibrillation potential might represent you have a long list of disorders that can produce them. Absent from that is typically the mention of spinal cord injury. So this is something to be aware of if you're ever in the situation where you're doing a study and trying to make sense of what these results could mean. You have to be very careful. And part of the reason just getting into the basic physiology here and looking from animal studies where you isolate the neuromuscular junction and do electrophysiological recordings. You can actually estimate the size or the or change in size of the end plate area through electrophysiological methods using sharp electrode recordings, for example. And you can see that they actually over time after the injury the neuromuscular end plate actually can get increase in area and become more diffuse. And on top of that you can see that it doesn't change in every scenario. So this is a TA muscle in a rat that had a spinal cord injury at a thoracic level and so it should be unaffected. And you can see perfectly healthy looking neuromuscular junctions in some situations with the axon here and the acetylcholine receptors is visualized here in red. And then in this other end plate beside it here, you can see the axon on the left with a much more branched and diffused pattern. And then below it you don't not see a corresponding cluster of acetylcholine receptors indicating that the the synapse is broken down. Which may be why we see these changes, for example, of fibrillation and positive sharp legs after spinal cord injury, even if we have to be very careful with our standards. We go about assessing motor neuron health understanding that these changes can take place. Well, there are some things to think about. So first of all, why are we even ordering these tests? And one of the things that we focus a lot, and I highlight some of Dr. Lieber's work that he talked about in an earlier session related to tendon transfers, is we often are considering these patients with cervical injuries for nerve versus tendon transfers to reconstruct upper limb function. And there's some, the point of this talk isn't to get into the details of which is better, although there's some pros and cons to either approach. But we know that with nerve transfers, the status of innervation of the nerve that's being injured, the blue line approaching represents a spinal nerve above the injury level, and then the red line represents one below. And then if you look to the right, you'll notice that there's a nerve that's neurologically intact and connected to the brain above the neurological level of the spinal cord injury. And you can actually borrow axons and transfer them over to the red nerve to power a muscle that had been disconnected there from the brain and you had lost volitional control over. So now you can borrow axons to power functions that have been lost after the injury. For example, restore elbow extension or a key grip pinch. And to see how this can make a big impact, we take a patient here who had a brachialis to AIN transfer to restore a key grip and better grasp and doing a PEG test here. And this is working with the WashU neurosurgery program and plastic surgery program where they do these transfers. And they were kind enough to share. You can see that that grabbing one of those pins is very difficult for this patient before the injury, before the transfer. And then after the, ten months after the nerve transfer, this hand function is greatly improved. However, you know, we have all seen a person who've had a spinal cord injury and their hands kind of look like this. And I'm putting the red arrows there highlighting the areas where there's clear muscle atrophy of the intrinsic hand muscles. Which implies to me that there may be motor neuron degeneration and you have to be careful about moving a nerve to restore function in this situation. To sometimes avoid nerve transfers or nerve repair surgeries for any reason, including brachial plexus injury and so forth. And it's underappreciated that this can impair people's candidacy for these procedures after spinal cord injury. And so to have a more rational approach for screening patients for these potentially important procedures to restore function in chronic injury, there's a number of electrophysiological approaches to consider. The Wash U group has proposed eliciting compound muscle action potentials from both donor and recipient sites. And if they're present early on after the injury, you'd be reassured that there hasn't been a lot of lower motor neuron degeneration and a nerve transfer following it to the left would be an option at any time because there's no chronic muscle denervation or fibrosis. However, if these responses are absent, you need to either proceed very early with a procedure like this or after a year, according to the current recommendation, is that you would no longer be a candidate for a nerve transfer. In addition to doing C-MAPs, which the one group advocated as the most trustworthy approach interoperatively when you validated the physiology compared to a needle exam, our standard approach to a needle exam, which is more qualitative, could be replaced with a more quantitative techniques being used to characterize particularly the dopaminergic donor sites above the neurological level, where you can see and quantify the recruitment changes, which might imply that there's been motor unit dropout if you have reduced firing rates, or sorry, a reduced recruitment. I also advocate, as this is sort of an emerging issue as we do more of these reconstructive surgeries, to use every possible test available to characterize these patients. One of the options as well is neuromuscular ultrasound, where you can get an example here of a tibialis anterior muscle seen here on the left, a healthy one, where you get the classic starry night appearance of a healthy, large, cross-sectional area muscle seen on an ultrasound, and then to the right, you can appreciate a chronically denervated TA, which has a much smaller muscle. There's arrows pointing to some hyper-echogenic changes that are likely result of chronic denervation and fibrosis, and in that situation, you need to be aware of the potential for substantial motor unit loss. Not to mention that ultrasound could be, in a paralyzed patient, could be a key way to identify the muscle targets that we're trying to evaluate by needle electromyography, since they can't with consistency activate the muscle or activate it at all. Some other red flags that can be picked up by advanced imaging, when someone has a spinal cord injury, with a high-velocity or high-energy mechanism, might be common at nerve injuries to the peripheral nerves, like the brachial plexus injury seen here in this patient, with the arrows sort of pointing out the hyper-intensity on an MRI, and that will be a red flag, since we would expect that there could be severe denervation as a result of this, and therefore a compromise of either recipient or donor to a nerve transfer. MSK ultrasound can be used to also evaluate other muscle health for things that are harder to study electrophysiologically, and I won't belabor the point, since Dr. Boone is here and is about to talk a bit about diaphragm ultrasound, but I'd like to point out just how you could get information about the health of the peripheral nerve based on looking at things like muscle thickness, or in the case of a diaphragm muscle here, which is hard to assess, although again, we'll hear more from Dr. Boone about this, but the lack of atrophy in some scenarios, or the severe atrophy, can be very informative, and I think the take-home point here is that lower motor neuron degeneration after spinal cord injury is an important problem. It's often an overlooked problem, and it has implications, number one, for the prognosis of the patient and the potential to recover function. It has implications for how we manage these patients in terms of restorative surgery and rehabilitation, not to mention things like breakthroughs in neuromodulation, which we didn't have time to include the presentation today because of time restrictions, which is really changing the way we view about someone being neurologically complete or incomplete. As well, a emphasis that physiatrists, as we have more tools available to assess the innervation status of muscle, EMG and beyond, should be employing all the tools to precisely define the nature of the injury, to best dictate and coordinate care options for the patients. For example, someone may not be a candidate for a nerve transfer because of denervation, but could be an appropriate candidate for tendon transfer. Thank you for your attention, and we'll move on to Dr. Chung's presentation. Hi, my name is Tae Chung. I'm from Johns Hopkins. I'm also a physiatrist, but fellowship trained in neuromuscular medicine. So I'm going to be talking about POTS. I think some of you may have heard about POTS here. Probably most of you guys haven't heard about it. Then what is POTS, and why do you want to know about it as a physiatrist? I'm going to talk a little bit about it. This is a little more clinical talk. Okay, so what is POTS? It stands for postural orthostatic tachycardia syndrome, but it sounds like some kind of cardiac condition, but it's not a cardiac condition. You actually have to rule out any heart conditions to diagnose POTS, and why do you have to know about it as a physiatrist? First of all, it's very common. Some actually estimate up to 1% of entire population may have this POTS, and more importantly, there's a good chance that you may be already seeing this patient in your clinic. So why am I saying that? Now, imagine a patient comes to your clinic, an anxious female, mostly a young female, who's complaining of chronic headache, chronic myofascial pain everywhere in their body. You name it, they have their pain in the neck, shoulder, and back, or anywhere. You name it, and they have some probably some GI symptoms as well, and more characteristically, they have severe chronic fatigue and some depression and anxiety as well. And their fatigue and headache are just completely disabling out of proportion. At the same time, they've gotten so many different labs and a lot of different imaging studies. Everything's normal. So first of all, have you ever seen these patients before? I'm pretty sure. I've actually done this talk to a lot of different places, and most people probably raise their hands. Of course, you've probably seen these patients. You can probably imagine some of your patients last week. A young female patient with chronic fatigue having this chronic pain as well. So what's your diagnosis? What do you think is happening on these patients? I guess a lot of people here may give diagnosis of fibromyalgia by default. Not sure if the fibromyalgia is a real diagnosis or not, but this is kind of out of scope of this talk. Maybe some may think this is all psychological, maybe conversion disorder. However, conversion disorder, classic conversion disorder, has a little different phenotype. I have a lot of psychiatry friends who see my past patients as well. They feel like their conversion disorder, their phenotype, is very different from those of these POTS or these patients that I just presented. At the same time, you've already seen this patient. They're very characteristic in terms of their population and clinical phenotype. So can we say this has some kind of clinical syndrome? And the answer is probably yes. In fact, it's not just you. Back in 19th century, there's this thing called neurasthenia, and the literal translation is nerve exhaustion. And Dr. Baird, a neurologist back in New York City back in 19th century, he described neurasthenia as tenderness of scalp, sweating hands, dry mucous membranes, insomnia, inappropriate phobia, and fatigue. In fact, the neurasthenia, this term, this diagnosis is still in ICD-10 code, and a lot of people who went to med school back in those days actually recently talked to a primary physician who just retired last year in his mid-70s, and he remembers learning about this neurasthenia. You know, Dr. Baird called this disease of Fifth Avenue because at the time, a lot of these patients are young, rich, young female daughters of very rich family coming from Fifth Avenue. And he also said it's Americanitis because you see this condition in industrialized rich countries like America. Moving on to late 19th century or early 20th century, there's a thing called DaCosta syndrome. Another name for this is soldier's heart. After the American Civil War, some soldiers develop anxiety, palpitation, with a steady intolerance, and chronic severe fatigue. And it's named after a physician, Dr. DaCosta, so-called Dr. DaCosta syndrome. And you also observe that a lot of these people develop this chronic disabling fatigue and with a steady intolerance after a bout of fever or diarrhea. It kind of sounds like Guillain-Barre syndrome. As you know, Guillain-Barre syndrome is a nerve inflammation that happens after some kind of GI infection, or it can be any viral infection as well. But most well-known after campylobacter infection. DaCosta syndrome, he described more in men than women, which is slightly different from what we know for POTS population, because POTS is more predominantly women. So I guess at the time, again, just imagine this back in 19th century, we didn't have MRIs or CAT scans or other fancy diagnostic tools. So I guess when they labeled DaCosta syndrome in New Estonia, they had probably a bunch of other conditions as well. So I kind of wonder, there are some PTSD patients when he labeled DaCosta syndrome. Now, more modern term for this condition, I think it's probably POTS, Postural Respiratory Tachycardia Syndrome. It's coined by Dr. Philip Lowe at Mayo in 1993. So if you think about it, it's not that old terminology, just pretty recent. Actually, Dr. Philip Lowe, he's still, I heard he's actually semi-retired, but he still sees patients. Dr. Boone is at Mayo, she may know better about it. So he found that a lot of these patients, mostly young female anxious patients with chronic fatigue, he put them on the tilt table test. As you can see, the table tilts up to 70 degree. When the table went up to 70 degree, these patients have pretty characteristic hemodynamic changes. Their heart rate goes up dramatically, usually at least more than, way more than 30 BPM increase within 10 minutes, typically more than 120 BPM within 10 minutes. And often, typically accompanied by reproduction of their symptoms, and when I say symptoms, that means chronic fatigue, brain fog, severe tachycardia, palpitation, and anxiety. Now at the same time, it's not a cardiac condition. Actually, you have to rule out any heart condition, because if you have a heart failure or any type of arrhythmia, you may have dissimilar hemodynamic changes. So you have to rule that out, or echocardiogram or whole-term monitoring if the patient hasn't gotten it before. So basically, you get these characteristic hemodynamic changes on the tilt table without any, with their heart being normal, suggesting that there's some kind of failure in neural control of their blood circulation. So let's go back to a little more detailed clinical features of POTS. Typically start with some kind of infection in mononucleosis in late teens or early 20s, or it can be any infections. It can be some viral or bacterial infection. In fact, you probably heard about COVID-19, post-COVID-19 chronic fatigue. There's actually literature coming out, more increasing case reports coming out, showing that, suggesting that this chronic fatigue from COVID-19 is likely POTS. You probably hear that, so ME-CFS, which is a little different discussion. But anyways, it can be any type of viral infection, up to 40 to 50% of patients can tell they have some kind of infection, and just about a month later, they develop severe profound fatigue. Now this profound fatigue is actually nothing you can even imagine. We're all doctors here, we know what fatigue means, we work hard, but this is not this type of fatigue. A lot of my patients can even tell me when this chronic fatigue started, like 10 years ago, July 17th, and that's exactly when their fatigue started, so profoundly disabling that they can remember that. And not only do they have a chronic fatigue, they have orthostatic intolerance, like palpitation. However, there's a little caution for that. Orthostatic intolerance, meaning a disease of lightheadedness and standing, is a classical symptoms of POTS. But a lot of patients may or may not perceive that as a positional changes. I have a lot of patients whose heart rate goes up to 180, but she says it's not palpitation, she says it's kind of some weird headache or discomfort. So even if they don't have it, especially for those who are chronically ill, they may not perceive that as actual orthostatic intolerance. Now on top of that, they have a chronic muscle pain, kind of looks like very much like myofascial pain, headache. Also they have a lot of GI symptoms, like nausea, vomiting, or alternating constipation and diarrhea. They also have shaky, jerky movements, usually it's not an epileptic seizure. They have a temperature dysregulation. And also another thing that's characteristic of POTS is that most of the times, the onset is very acute, and over time, it fluctuates quite a bit. So sometimes even without any treatment, it gets better and it flares up. Now how do you explain the phenomenon? Like I suggested in the beginning, there's some indirect evidence that this is kind of failure to regulate the blood flow. So for example, our autonomic nervous system, in particular sympathetic nervous system, one of their main job is to regulate their blood flow to the different organ. So for example, if you're exercising or if you're using your muscle, our autonomic nervous system should be able to detect the metabolic needs from the muscle. For example, if you're moving your muscle, muscle needs more fuel, which comes from the blood. So as we respond to increased metabolic needs, our sympathetic nervous system should be able to increase blood flow to the muscle. And basically, there's some evidence that POTS comes from this basal motor denervation, so sympathetic nerve system not being able to regulate the blood flow. So imagine if you cannot increase blood flow as a response to muscle activity, you're going to have a lot of cramps and pain after some kind of muscle activity or exercise, kind of like dormant-like pain. And also, they have a pretty severe characteristic exercise intolerance. And also, when they stand up, especially from lower to higher position, our sympathetic nervous system has to pump the blood against gravity. And if that doesn't happen, they're going to have a lot of orthostatic intolerance. And also, our brain consumes a lot of energy normally. And if you're concentrating, trying to read a book, and if blood flow doesn't increase as we respond to the metabolic needs, you're going to have a lot of brain fog or reduced concentration. So basically, I say this, I call this a pump failure. And as a reminder, this is a basal motor innervation from sympathetic nervous system to the arterioles. And if there's any increased need for blood flow, basically, the sympathetic nerve kind of pumps blood to the muscle or brain or GI system or against the gravity to increase the blood flow. And there's some suspicion that in parts, the sympathetic nerve is denervated from the blood vessels. So in a fancy term, it's a basal motor innervation. And this is actually one of the nice evidence for that. So this is actually a study from Dr. Stewart, Julian Stewart. And basically, the blood volume changes on different positions. So basically, it's a tilt table. They check the blood volume changes in different parts of the body, starting from the thorax all the way to the pelvis and legs. And this black bar is a normal person, as you can see. Obviously, on standing, all the blood in the thorax, which is higher up, goes down. And all the blood volume in the lower part of the body will increase towards the gravity, which is a pretty normal phenomenon. However, in POTS patients, which is green bar, you have this exaggerated hypovolemia in the thorax. And there's more blood pooling towards the lower part of the body, which is presumably from this basal motor innervation or dysregulation of blood volume. And because of the exaggerated hypovolemia in the thorax here, there's a reduced cardiac preload, which causes basically chronic fatigue, because these patients are circulating reduced volume of blood due to this basal motor innervation. Now, at the same time, that's not the only thing that's happening in POTS patients. They have intact baroreflex function in the central nervous system. So probably this is more peripheral basal motor innervation, but in the central area, there's an intact baroreflex function. And as you all remember, it detects reduction in the blood volume in the aorta, and it triggers strong sympathetic response, basically increases adrenaline, epinephrine, norepinephrine, so it can cause tachycardia. So basically, it's a reduced blood volume to compensate for that. It causes tachycardia to compensate for the less volume. But the problem is, when they increase adrenaline, epinephrine, norepinephrine, they cause all this very uncomfortable fight or flight reaction, and as a result, they have a lot of what I call sympathetic symptoms, which causes anxiety, palpitation, orthostatic tachycardia, nausea, vomiting, and hyperajorsis. So I basically classify all the different symptoms into two different categories. One is pump failure symptoms that comes from sympathetic hypofunction, which explains chronic fatigue, muscle pain, orthostatic intolerance, migraines, and so on. There's a set of symptoms I call the sympathetic overcompensation, which causes anxiety and nausea, vomiting because of GI dysmotility, palpitation, sleep problems, and other things as well. And as you can see this, and both symptoms can be equally disabling for these patients and very uncomfortable. And at the same time, you know, these parts is simply paradoxical sympathetic dysfunction in the sense that you have hypofunctional sympathetic system and hyperfunctional sympathetic nervous system. So now, how do you treat these parts then? So like I said, the treatment strategies for hypofunction, pump failure, and sympathetic compensation should be different because it's completely different, opposite end of the same sympathetic function. For pump failure symptoms, I do aggressive volume expansion, which is usually very important main strategy for the treatment for parts. For volume expansion, there are different strategies for volume expansion. We start with oral hydration, they have to drink four liters or one gallon water, five grams of sodium, it's a lot of water and salt. And also oftentimes I do IV saline infusion three times a week and use various medication like midazolam fluid to retain the fluid in the body. Also physical exercise is actually really important. Basically you're using skeletal muscle pump, and this pump is actually very powerful. During active cardiovascular exercise, normal cardio output from one to two gallon per minute increases to 46 gallons, so increase in pretty significant volume to the patient, which is why a lot of POTS patients, when they exercise, they get actually more energy. But at the same time, they have exercise intolerance as part of their symptoms. I never tell patients to go to gym and do their exercise. I have to be very careful because if they do exercise right away, unprepared, it can trigger more POTS symptoms. So I usually start with an aggressive volume expansion and then slowly increase their cardiovascular capacity over a few to several months, and that's how it works. To summarize, as you can see now, I think POTS is very ideal for physiatry clinic because first of all, a lot of these POTS patients are completely debilitated, a lot of these people quit their work, stop going to schools, it's very debilitating. And also the treatment approach requires multidisciplinary approach with the physical therapy, nutritionist, psychologist, and various other specialists, and lifestyle modification is the core of the treatment. So as an example, in our clinic at Hopkins, I started three years ago just a single provider, and now over three years, actually last year we saw more than 2,500 patients, and it's been growing very quickly and successfully. So I think it's probably very good model new disease condition for physiatry, and I hope a lot more physiatrists become more interested in these POTS. So this is my end of the talk. Good afternoon. I'm going to talk to everybody today about the role of ultrasound in the workup of respiratory failure. I don't have any disclosures. I'm a professor in the departments of PM&R and also neurology at the Mayo Clinic in Rochester. As part of that, I spend half of my clinical time in the EMG lab, and that's where I've developed this interest in ultrasound of the diaphragm. So I thought today I would use a case history to kind of highlight some of the ways ultrasound can really be quite helpful. This is actually the case that started us using ultrasound in our practice. So we had a 68-year-old man who had had cervical stenosis and had undergone a decompression at an outside facility because of quite significant myelopathy that was progressing. He had severe neck pain with any movement, but he was able to ambulate the first two or three days after surgery, and then very suddenly he developed this ascending numbness followed by quadriplegia, progressing over a few, 30 minutes basically. And a week later he had to be intubated because he had complete respiratory failure. They did an MRI, which showed cord edema that was very suspicious for infarction of the spinal cord. He had a past medical history that was significant for a prosthetic valve, which he had to stay on CUDAN for with an INR of at least 4.0. And he also had a history of prostate cancer and high blood pressure. So this is just an MRI of a spinal cord showing the infarction. Sorry, I don't have a, I can't use a laser pointer to point out the area, but it's fairly obvious the signal change in the cord. So we, our lab was asked to do a workup to help localize the weakness. He was quadriplegic. They, the consultant who saw him from our EMG practice did Phrenic Compound Muscle Action Potentials and on the right side they got a small response of 0.1 millivolts, and on the left side they got a response of 0.3 millivolts, which is at the lower limit of normal for our lab. The remaining CMAPs that were done in the limbs were low amplitude and did have quite prolonged durations, which is something we see in critical illness myopathy a lot. Needle EMG in the right upper limb showed dense fibrillation potentials and no motor unit activation. The diaphragm was not needled because he did have an INR of 4.0. So the clinical interpretation at that time was that this was probably critical illness myopathy. And these are the CMAPs. So you can see they look reasonable. They look like there's probably something there, although they're technically not great. So then a month later the neurosurgeons requested another EMG to try to help with prognosis and at that time the person doing the study got CMAPs that had increased significantly. So 0.6 millivolts on the one side and 0.4 millivolts on the other. So they reported this as showing significant improvement in the phrenic responses bilaterally. And these CMAPs look a little better. I might believe that those are phrenic CMAPs, although they're still not super typical of what we see. So about another month later they requested a third study and the reason for this is because the patient was quadriplegic, completely ventilator dependent. He was in his late 60s and he had decided that if he was not a candidate for a phrenic pacemaker, he didn't want to continue to live dependent on a ventilator and quadriplegic for the rest of his life. He was a very active guy. He hiked a lot prior to the surgery. It was kind of an elective surgery, although he did have myopathy. So it was needed. So this time we decided to use ultrasound when we went to see the patient and we actually watched the diaphragm with ultrasound while we were doing the phrenic nerve conduction studies and this is what we got this time. No responses. We use two different techniques when we do phrenic CMAPs in our lab and we just see which one picks up a better response, but none of them picked up. So they were actually not present and probably weren't on any of the other studies and we were able to look at the diaphragm while we were stimulating the nerve at the superclavicular area and there was no contraction evident. And so then after discussion with him regarding the risks of needle EMG given that his INR was four, he wanted us to proceed. And so with ultrasound assistance, we were able to put a needle in the diaphragm on both sides and he had fibrillation potentials and on one side he had no motor unit activation. On the other side, he did have some motor units, but it was markedly reduced recruitment and the motor units were abnormal. This is just to review how we do our needle exam. Prior to using ultrasound, we would just look for the intercostal space as far down as we could get where you could still get a needle in between the ribs. You know, when you get to the costal margin inferiorly, they often get very close together. And so I just kind of feel for where I can get my finger in between the ribs and I go down as caudally as possible to stay away from the lung. And on the left, you can see these are the structures you go through. You put the needle in perpendicular to the chest wall and you're going to initially pass through, you sometimes pass through some abdominal wall muscle, then you're going to get into the intercostal muscles between the ribs and then the next layer you should get into will be the diaphragm. And the diaphragm only fires with inspiration. So you can recognize that you're in the diaphragm based on the way you look at it. And this is the motor unit that we got in that patient. So on the one side, we had some, he had some maced motor units. Firing with reduced recruitment, there was a CRD at the end, or the beginning of a CRD as it sounded like. The recruitment was reduced, the units were really complex and there weren't many firing. So in this case, we were able to observe the diaphragm using ultrasound in real time. So we could see that it was moving, but it was just passively moving as the ventilator is lung, the diaphragm would move. So, this is how we put the transducer on the patient. I place it usually somewhere around the anterior axillary line, and I try to span two ribs so that the transducer, the long axis of the transducer is perpendicular to the long axis of the ribs. So, you will then get a fairly characteristic picture. On the left, this is the diaphragm at rest. The liver is at the bottom of the picture, there's a rib on either side, and then in between the ribs, the first layer is going to be intercostal muscle, and then the next layer is going to be the diaphragm. It has a D on it in this picture. And then to the right, that's the same diaphragm, but the patient is breathing in, and that bright white shadow is the lung and pleura coming into view, and displacing the diaphragm to the right. And you can see that it's a lot thicker, the diaphragm layer. As the patient breathes in, it doubles in size compared to the image on the left. And this is a video that hopefully, oh no, sorry, this is just showing how we measure it. So, after we kind of did the study, I started looking at the diaphragm a lot with ultrasound, and I was like, gosh, I think we could use this diagnostically, because I noticed that the really severely affected ones were very atrophied and very thin. So, we collected a bunch of data in 150 normals to see what was normal thickness, and basically anything thicker than about 0.14 centimeters or 1.4 millimeters is normal thickness. A lot of people have thicker diaphragms than that. And then it should thicken on the right again. It shows the lung on the left, and then the thickened diaphragm on the right that we're measuring. So, thickened by at least 20% is all it really needs to thicken by. A lot of people, it will double. This is thickening by 100%. But so long as it's thickening by at least 20%, then that's usually a normal diaphragm. This is a video showing the layer, okay, let's see, hopefully this is going to play. I think I have to do, okay. So, if you watch that middle layer, so there's the liver at the bottom of the screen and the layer right above the liver, you're going to see it thicken now, and then the lung comes in from the left. As opposed to this next image, which is an extremely atrophic diaphragm, it's a very thin little black line right above the liver. There's a rib on either side, and then there's, and we were actually stimulating the phrenic nerve there, trying to see if it contracted at all. But just by looking at that diaphragm, it was obviously abnormal, it was extremely thin and atrophic. Some people use M mode ultrasound as well. Everything I've shown you so far has been B mode, which is what I use all the time. M mode can be nice, but I just find it technically more difficult. You place the probe under the costal margin and you kind of push up underneath the ribs aiming towards the head, kind of posterior medially, and you're going to be watching the diaphragm moving up and down. So M mode is more like cardiac ultrasound and you see this line. So to the right of the transducer picture there is a normal diaphragm coming down towards the probe and then moving away from it as the patient breathes out. So when they breathe in, the diaphragm flattens and moves down towards the abdomen. And on the bottom two images to the right is a very abnormal one where there's actually paradoxical movement where the diaphragm moves away from the transducer when the patient breathes in because it's not contracting at all, it's being pushed up by the abdominal organs when they try to breathe in. So that was a case example of some of the things we're asked to work up in the EMG lab. You know, there's a number of different causes for respiratory failure and obviously cardiopulmonary are common reasons for it, but we get asked to rule out neuromuscular causes for respiratory failure. And that can be due to a central cause or you can get to the level of the spinal cord or you can get to the level of the spinal cord where you may get anterior horn cell involvement or nerve root at the C345 level. The diaphragm is primarily innervated by C4 in most people, but C3 and C5 contribute some. And then the phrenic nerve itself or polyradicular neuropathy that's involving the phrenic nerve. And then obviously you can get neuromuscular junction problems that will interfere with diaphragm function, you know, bad cases of myasthenia and exacerbation, and then the muscle itself, myopathy of the diaphragm. So there's a lot of things that we can look for in the EMG setting and help the referring physician with. So you know, we used to just do phrenic nerve conduction studies and needle EMG. And as I'll talk about in a minute, there are some limitations to those. First and foremost, probably that a lot of people who practice clinical neurophysiology are not comfortable doing these tests. And so it's not always available to the referring physician, but ultrasound can help when you're doing your phrenic nerve conduction studies, because you can use it to rule out false negatives like we had in that case. The first two cases, the first two times they did phrenics, they found responses, even though the patient didn't actually have a functioning diaphragm, because you can get a lot of volume conduction from other muscles, given how close you are to the brachial plexus when you're stimulating the phrenic nerve at the superclavicular level. One of the biggest help we've had from diaphragm in the lab is it helps us with knowing that we're putting the needle through the chest wall in a safe area. So we look first, and we can find an interspace where there's adequate room to get the needle in there, but the lung is not coming into the field of view when they breathe in deeply. And then we can see what depth the diaphragm's at. So now I just look, and most people, the diaphragm's somewhere between 1.5 and 2.5 centimeters. Once I know that on ultrasound, then I just put my needle straight into that depth, and I get into it very quickly, and that's a more comfortable exam for the patient. It's definitely helpful in situations where you otherwise probably wouldn't have done it. You know, very obese patients where you can't feel the ribs, you can see them with ultrasound. COPD patients were always a bit of a risk because you knew they had a hyperinflated lung, so you're worried that it might be down further than you'd expect typically. And then the biggest help for me has been the patients that have severe diaphragm atrophy. So when you, this muscle just wastes away more so than any other, like, skeletal muscle I see. So I did get patients, a lot of patients with severe brachial plexopathy, and they have three plus fibrillations and no motor units in their biceps, and even, you know, several years out, you'll still find the fibrillation potentials. But the diaphragm, we used to go in, and we'd go through the endocostals, and we'd be, where is it? You couldn't find it, and you'd be fishing around in there, and you're worrying about what you're in if you're not in the diaphragm. Well, what we've found with using ultrasound is if we put our needle tip in those very atrophic muscles, the very atrophic diaphragm muscles, they often have no electrical activity at all. There's no fibrillations, and there's no motor units firing. So those are usually the tools we use to get into a challenging muscle in EMG. So ultrasound's been a super big help from that standpoint for us. And then once we got our normal values, we were able to use it diagnostically. So we look at the thickness of the resting muscle after the patient has breathed out, and then we measure it as they take a deep breath in, and if we get completely normal values with that, often we don't even need to needle the diaphragm. So it's helped quite a bit from that point of view. So this is just our normal values. Like I said, greater than 0.14, that should say centimeters thick, sorry, or 1.4 millimeters is normal, and more than a 20% increase in thickness when they breathe in deeply. And there's a caveat there, if people aren't willing to take a deep breath in, not everybody uses their diaphragm for the initial part of the respiratory cycle. A third of patients we looked at didn't thicken at all with normal breathing. They had to take a deep breath in to see any thickening of that muscle. In phrenic neuropathy, we had excellent sensitivity and specificity for using ultrasound to diagnose that, and I'll give you some numbers in the next slide. We also looked at a small group of all the patients that we had with myopathy proven on EMG, myopathy of the diaphragm, and we found that the thickness was not super helpful. It was often normal in myopathy, as is the case with ultrasound and myopathy, but the thickening fraction was 70% of the time was abnormal, so they weren't able to thicken their diaphragm to a normal amount in the cases that had EMG proven myopathy. So this is a study we published in Neurology, where we just took all comers who were sent to our lab to rule out neuromuscular respiratory failure, and this is where we got very good sensitivity, 93% sensitivity for ultrasound. The only cases that we missed were a handful of cases that had a mild old phrenic neuropathy, and so they had some big motor units on the needle EMG, but their diaphragm was functioning well, so the thickness was normal and the thickening fraction on ultrasound was normal. We also had good sensitivity with phrenic nerve conduction studies, 91%, so they were abnormal, 91% of the time that the diaphragm was abnormal, but the converse of that was their specificity were not good. Phrenic nerve conduction studies only had 56% specificity, because it's so easy to get a false positive where you say that the diaphragm's abnormal and it's just technically you didn't stimulate the phrenic nerve, or the patient's obese and you weren't able to record over the diaphragm, you know, technical problems like that. Fluoroscopy and chest x-ray, which have kind of been the go-to prior to ultrasound, were not great. Sensitivity, 56% for fluoroscopy and 44% for chest x-ray. Their specificity was better, it was around 80%, but still not as good as ultrasound and EMG, which had 100% specificity. So I think that study highlights how useful ultrasound and the diaphragm can be, so long as you're trained and know how to do it, obviously. So in conclusion, I think the applications of diaphragm, ultrasound, and the EMG lab include situations where there is atrophy of the muscle. You can look at thickening, you know, normal thickening amounts. You can look at whether it's activating with the breathing. You can see if it's activating with phrenic nerve stimulation. And you can see fasciculations in it quite well, I've seen that in ALS patients. It's great because it is a sensitive test, but it's non-invasive, it's inexpensive, it's right there at the bedside. We have our current Cadwell EMG machines that we're using now have ultrasound incorporated, so it's right there on our EMG machine, which is really nice. You can just grab the probe and do simultaneous EMG and ultrasound, and I think we're going to get better and better machines for that, better technology, so that we can do high-level neuromuscular ultrasound in conjunction with our EMG studies. Obviously, it increases the safety and the accuracy of needle EMG and increases the sensitivity and specificity of phrenic nerve conduction studies. So I think there's quite a big role for ultrasound in this setting, and it's really been very helpful in our practice. And thank you very much for inviting me to speak, it's been a pleasure.

neuromuscular medicine

motor neurodegeneration

spinal cord injury

lower motor neuron

prognosis

restorative surgery

postural orthostatic tachycardia syndrome

POTS

ultrasound

diaphragm function