Hello, welcome to our session on COVID and neuromuscular medicine challenges and opportunities. I'd like to welcome everyone in the neuromuscular medicine and electrodiagnostic community to the session. And anyone else who's been compelled or interested in joining us. We're going to have some quick housekeeping questions and answers we're going to actually have a panel discussion at the end of the session but you can put questions in at any time to the chat. We may get to them in real time after the presentations but there will be no time in between the presentations until the end for the presenters to answer the questions on the broadcast. Currently, our group has done some sessions on advances in neuromuscular medicine this year we felt compelled to do a session on covert 19 I think for obvious reasons. I think you'll find that the session today is some original thinking, and will be insightful. For those of you who joined in. We've done our best to make it so. And I'll give a quick introduction to coven and introduce the faculty. Quick review for for most of us now, but the SARS Kobe to can enter cells to the ACE two receptor and begin replicating itself inside of the cells which causes infection and is often, you know, one of the key aspects of this infection is how the immune system responds to it, and as this pertains to neuromuscular complications I just thought I'd mentioned that one of the secrets to the coronavirus is in general is that they can evade the interferon response in the body, often leading to as you can see here on the right, a delayed immune response in which by the time it kicks in, leads to really amplification and a massive inflammatory state. And we think that that in, you know, I will say in our own work that my lab has done and other groups has been one of the key elements to why we see so many muscle conditions like myopathy or polyneuropathy of critical illness less often. And of course, some work that we presented even last year the session on modern neuritis multiplex, and may come up again in the session today. I think that some really insightful work just came out of the group from Brigham and Harvard, showing some actual biopsies and implement inflammatory infiltrates. So, for example, here to the psoas muscle, where you can see an example of hypercellularity, that's perivascular, perimensial cells here that light up with many of the different immune cell markers from T cells, B cells, macrophages, and then necrotic muscle fibers. And you can see the same hypercellularity inflammatory signature in nerve biopsies. These are all from autopsied patients who died from COVID-19. Interestingly, not a lot of demyelination has been observed, but there's a paucity of evidence for direct neural invasion and muscle invasion of the virus, but more so just overwhelming inflammatory response. With that said, I think this sort of sets up this complication that we've seen in the neuromuscular setting on an inpatient rehab service that Dr. Ryberg, my colleague here at Shirley Ryan Ability Lab, has some insights to share. Dr. Ryberg has been running our COVID rehab program for inpatients since the pandemic began. She has seen probably as many post-COVID patients as anyone I know in the world, and will give us case-based examples of neuromuscular complications from the motor nerve, the sensory nerves, to the muscle, in terms of what can happen and what is seen in that setting. This is going to be followed up by Dr. Arnold. Dr. Arnold is a leader in both physical medicine and rehabilitation subspecialty in neuromuscular medicine, but also as a clinician scientist in PM&R as well. He's from the powerhouse neuromuscular group at The Ohio State University. Sorry, I almost got the miss there, but I think he'll give us, as he can almost uniquely do, give us some unique insights into the defects here happening at the single motor unit level and in the muscle level in a way that I think isn't usually talked about or taught in the classroom. Of course, we have Dr. Paganoni here with us. She's someone I think has been described as kind of a godparent of neuromuscular medicine and physiatry to many of us coming up behind her. I think her accolades speak for themselves. The year of 2020, we think of COVID coming in and dominating our scene, but let's not overlook the fact that it was a big year in ALS research, and she is one of the most prominent ALS researchers in the country and in the world. The Centaur trial, which here you can see published in the New England Journal, was a positive trial for a new therapeutic agent for ALS. I think 2020 also represented the launch of the Healy platform trial for ALS. I think Dr. Paganoni is uniquely qualified to tell us about how we kept going and how we can keep going with clinical trials and innovation in the era of COVID because diseases like ALS don't stop progressing despite the pandemic. I will not try to take up any more time, but I want to introduce Dr. Ryberg to begin her presentation, and we'll keep rolling from there. Thank you. Hi, everyone. I'm Leslie Rydberg. Thanks for the great introduction, Dr. Franz. I'd like to point out that I really am truly a clinician and not a researcher. Here is a picture of me in our COVID rehabilitation unit at the Shirley Ryan Ability Lab. So I have cared for patients recovering from complex medical conditions for years. In fact, I'm a general physiatrist really with an interest in neuromuscular, some neuromuscular disorders, a lot of medically complex conditions, heart failure, LVADs, transplants, and prolonged ICU stays. And so when my hospital was talking about how we were going to care for patients in the pandemic, I volunteered to immediately be a part of this. And so on April 14th, 2020, we opened up our COVID rehabilitation unit and had our first three patients who came through. And this is actually a picture of Gordon Quinn, one of our patients who came in on day one who was featured in the Chicago Tribune. And he was one of our first graduates and he did very well. But we've learned a lot since the first days of the pandemic. So our hospital has served probably 300 patients so far with COVID infections from relatively mild to more severe, depending on the clinical picture. We've also partnered with a couple of our rehab partners in the Chicagoland area. So Mary and Joy Rehab Hospital and Alexian Brothers Rehab Hospital. And we've started looking at what are the demographics and functional outcomes that we've seen across the spectrum of these admissions. So looking at kind of our first couple of hundred patients, we saw that our average patient age was 64.4 with a range of 23 to 92 for the age range. And I have to tell you that patient who was 92 actually did very well. I discharged him home. We have seen more women than men that have been admitted post COVID hospitalization and a relatively diverse spectrum of backgrounds in terms of race and ethnicity that is relatively similar to the Chicago breakdown of different backgrounds. And looking at the past medical history for the patients that we've seen in patient rehab, a lot of high blood pressure, cholesterol issues, and diabetes, which is consistent with the data that we've seen around the country in terms of who's likely to have more severe COVID infections. I would like to point out that about 8% of this cohort did have an underlying neurologic disorder. And I think that speaks to people who have an underlying neurologic disorder who get COVID pneumonia are probably more likely to require inpatient rehab, just because of their baseline functional status and probably not a lot of functional reserve. And then about 5% of our patients had immunosuppression conditions and about 5% had an active cancer diagnosis where we're undergoing treatment for cancer at the time of diagnosis. Thinking about a couple of patients when Dr. Franz asked for kind of some case examples of patients with neuromuscular conditions, I really thought back to who are the patients who've really stood out in my mind. And of the 250 to 300 patients that we've seen, many of them stick out in my mind. It's been a really interesting year and a half heading towards two years. But this is a great example of kind of rehab and the role that we can play. So this was a 72-year-old man with a couple of premorbid conditions. And he was basically hospitalized for three months before he made it to inpatient rehab. So he had severe COVID-19 with mechanical ventilation, hypoxic respiratory failure, tracheostomy, G-tube placement, and had a huge stage four sacral pressure ulcer. And when he made it to us, he had significant weakness in all four limbs. So his weakness was proximal greater than distal. And because of his severe weakness, you know, about one out of five in hip flexion, he really came in requiring max to total assistance with all mobility, with all ADLs and functional mobility. And so what we've seen is that we're seeing a lot of patients with severe COVID who had striking proximal or generalized weakness up to the point of quadriplegia or tetraplegia. And so he came over with a clinical diagnosis of critical illness myopathy. And we've seen this for years in inpatient rehab with patients with respiratory failure, SERS, liver and lung transplants, any kind of critical illness. And so we're used to working with this patient population. We're used to making this diagnosis. But we're really seeing it in much larger numbers in the post-COVID patient population. So it's a topic that I like to walk through with my residents because when you think about your medical rehabilitation population, sometimes it's hard to think about why these patients need rehabilitation. But when someone has this severe weakness, it's really, you have to think about the neurologic condition that's also affecting someone who's really undergoing rehab for medical conditions. And so it's been interesting just seeing how common this is. And so, you know, looking at the incident, so a lot of, there's been a lot of different case reports looking at this diagnosis. And so it's starting to be a lot more common. And thinking about what the underlying cause of the myopathy that we're seeing, you know, is it really related to critical illness? Is it more related to the immune myositis, the inflammatory infiltrates that Dr. Franz is talking about? I leave it to our great researchers and possibly Dr. Arnold to elucidate this a little bit more clearly for us in terms of what the underlying mechanism is. But from a clinical standpoint, what I've been seeing really is that our patients with kind of this critical illness myopathy picture, generalized weakness, more proximal weakness with preserved sensation and the relatively preserved reflexes, they're actually doing very well in inpatient rehab. So I'm seeing really good functional outcomes. So this gentleman who did give us permission to be shared, this is actually a picture of him, had significant strength improvement during his inpatient rehab stay. We were able to remove his tracheostomy. We were able to remove his feeding tube, his sacral pressure ulcer. We did end up doing MRI imaging and a bone biopsy and we treated them for osteomyelitis. And his wound did improve once we were able to do that. And at the time of discharge from inpatient rehab, he went from kind of the max to total assistance level to ambulating over 600 feet with a rolling walker with supervision. And he was able to do tub transfers, toilet transfers, bathing, dressing with contact guard assist. And so it was really just remarkable to see the degree of weakness that he had and really the significant improvement that he had during inpatient rehabilitation. So a second example, so this is a 57-year-old man with a history of gout and some lumbar spinal stenosis. He was hospitalized in August and had a complicated course with his severe COVID infection. So he had a GI bleed, coronary artery spasms. And he's actually currently in my inpatient rehabilitation unit. And he came in with quadriparesis, tetraparesis. So he had significant weakness in all four limbs. Again, one out of five strength in the hips and shoulders, four out of five strength in the wrists and hands. But what was striking was that he also had distal lower extremity weakness with the classic stocking distribution sensory loss. And he's requiring total assistance for all mobility maybe else. So lift transfer, assistance for feeding, you know, very, very impaired from his neuromuscular condition. And so with that sensory loss, that makes me think that this is not just a myopathy picture. So we've actually looked at nine patients who have undergone inpatient rehabilitation with us and looked for myopathic potentials to confirm the diagnosis of myopathy. And so of our nine subjects that we went through, all of them did see evidence of motor unit changes consistent with the myopathic picture. Of our nine patients, 100% were male, 78% required tracheostomy, 57% had spent time at a long-term acute care hospital. And what was really striking was that by the time they were in inpatient rehabilitation and getting electrodiagnostic testing, they had been hospitalized. The duration of time from COVID diagnosis was over 100 days. So it was 118 days by the time they were getting electrodiagnostic testing, looking at the cause of their weakness. So our electrodiagnostic testing did confirm a diagnosis of myopathy, but what was really interesting was that a lot of these patients, in fact, all of these nine patients did have a second or even third neuromuscular diagnosis that was found on electrodiagnostic testing. So my patients that I was talking about with this case actually had a myopathy on electrodiagnostics, but also had evidence of a peripheral polyneuropathy. And so you can see we saw polyneuropathy, median neuropathy, femoral and obturator neuropathies, ulnar neuropathies, radial neuropathies. So everything that we saw was really a myopathy plus something else, which I thought was just really fascinating that even in the small cohort of patients were seeing all of these dual diagnoses. All right, looking at another patient, so this is a 45-year-old man with a history of diabetes and severe COVID pneumonia, and he did require intubation and prone positioning. So he had severe bilateral digit 4 to 5 numbness and hand weakness on top of his generalized weakness. And so he required moderate assistance on admission. And this was consistent with what we're seeing in the literature that a good number of patients with severe COVID infections are coming in with focal weakness on top of their kind of generalized weakness. And so Dr. Franz and the faculty at Shirley Vine Ability Lab and at Northwestern were able to kind of get some advanced imaging and really think about what the underlying localization was for some of these neurologic injuries. And so you can see here this patient had bilateral severe ulnar neuropathies on EMG that we were unable to localize. But on MR neurography of the right elbow, we can see that the images show hyperintensity of the ulnar nerve consistent with axonal injury at the level of the right elbow. And so looking at kind of the review of some of our patients that we saw in inpatient rehab, 12 of our first 83 patients, so 14%, were diagnosed with a focal peripheral nerve injury. And so looking at this patient population, the mean average age was about 60 and 33 days on mechanical ventilation. And the majority of those patients had been prone at some point in the acute care hospital. So in terms of what the underlying cause of the focal neuropathies are, one hypothesis obviously is the prone positioning. And so there's some researchers at our institution actively looking at ways to prevent prone related injuries. So how can we reduce pressure over certain pressure points? There's some other theories looking at mononeuritis multiplex as the etiology, because with these axonal injuries in multifocal places within the same patient, it's interesting to theorize that they would all be from positioning. So I think there's still some work to be done there to really understand, you know, what the cause of the neuropathies really is. All right, and case number four. So this is a 49-year-old man with no past medical history with acute hypoxic respiratory failure secondary to COVID. He did require tracheostomy, prolonged mechanical ventilation, and stay at the LTAC. So by the time he made it to inpatient rehab, he did have significant weakness, did require maximum assistance for mobility and ADL. But it was really interesting that when he made it to inpatient rehab, his tracheostomy was out, he was completely off of oxygen, his oxygen saturations were 95% and above. But he was found to have significant impairments in endurance and stamina despite being on room air during inpatient rehabilitation. So he was seen by our cardiopulmonary therapist. They worked on diaphragmatic breathing, pursed lip breathing, expiratory muscle strength training, incentive spirometer use, and they were working on building up his endurance. So he was referred for electrodiagnostic ultrasound of the, excuse me, ultrasound of the diaphragm. And what we've seen is that about 76% of patients with severe COVID require mechanical ventilation and inpatient rehab. So this is our patient population, did see abnormalities of the diaphragm muscle on testing. So this, you can see here, this is Dr. Franz's research. So looking at the diaphragm here on expiration, that's looking at the diaphragm thickness at max expiration and looking at the diaphragm thickness on max inspiration, we can calculate the thickening ratio, which corresponds to the diaphragm muscle contractility. And so that's why we care, is if we're seeing these changes in the diaphragm, then the diaphragm muscle is not contracting as well, which is affecting their neuromuscular respiratory function. And so in our patient, he did have a couple of changes that were seen. So he had low diaphragm thickness on max expiration and low thickening ratio, which again correlates with the low diaphragm muscle contractility. So you can see here his thickening ratio was 0.86 with normal being 1.2. So he had a low thickening ratio. So this patient continued to undergo inpatient rehabilitation. He made it to outpatient rehabilitation and on followup, his diaphragm was scanned again. And on repeat ultrasound of the diaphragm, his thickening ratio had actually improved to 1.21. So this is something that can improve over time. And in this case, why did his diaphragm improve? Was it related to obviously our great doctoring? Was it related to his therapies? Was it related to natural recovery? I don't think we know that yet. But this is an important thing to think about, the diaphragm muscle function and how that affects our patient's respiratory status. And then the last case I wanted to go over, a 64-year-old woman with a history of breast cancer who developed COVID-19 infection in January of 2021. She had a relatively mild course, did not require hospitalization. But three weeks later, she did develop AIDP-Ganbray syndrome with the classic tetraplegia, respiratory failure, tracheostomy, dysphagia, G2 placement. So she was hospitalized for five months after her initial diagnosis due to her severity of her respiratory failure. And when she came to inpatient rehab, she required total assistance with mobilities and ADLs, trach with a trach collar, and significant weakness in all four limbs. And there really has been many case reports of the association between AIDP and COVID, which makes sense because it was a viral illness which could theoretically serve as a trigger. However, looking in the most up-to-date literature, several different organizations, including the International GBS Outcome Study, have compared the number of cases of Guillain-Barre syndrome or AIDP that we've seen in the last few years. And there has not been a significant increase in the number of cases that have been seen, which we would expect if we're really seeing Guillain-Barre syndrome related to COVID infections. You can see here on the left, this is the study in England. So in 2016, 2017, 2018, and 2018. So you can see here in 2020, we're actually seeing that's the red value. We're actually seeing fewer cases than expected per month. And this here, the red line, is really when we've seen the highest increase in the number of COVID-19 cases. So we're not seeing more cases in a population of Guillain-Barre. And then on the right, you can see this picture looking at the same thing. So here in 2020, with this little green box is where we're seeing the SARS-CoV-2 infections. And there's not a significant increase in the number of people that have had Guillain-Barre in 2020. So I think that thinking about what we can do from a societal and patient rehab setting is that we're really seeing a lot of patients with neuromuscular disorders that need our help, that really need inpatient rehabilitation, have major functional changes. And so we've looked at the outcomes of our first cohort of graduates from the inpatient rehabilitation program. And so looking at the quality indicator, which is our functional domain that we're currently using, so the patients have come in on average needing partial assistance or moderate assistance for showering, transfers, walking 10 feet, and substantial assist for lower body dressing and toileting. On average at discharge, they're requiring set up to independent level. So they've really had great functional outcomes in inpatient rehab, looking at all comers of people undergoing inpatient rehabilitation after COVID infection. And so you can see there's really a large increase in the overall quality indicator score on inpatient rehabilitation. So as physiatrists, we really have a very important role in the functional recovery of people with all different impairments after COVID infections. And there's a lot of research that needs to be done in the neuromuscular patient population. Hi, David Arnold. I'm going to next talk about some mechanisms, at least our understanding of the mechanisms of weakness associated with ICU-related stay. And it's clearly this is an important topic in the context of COVID-19 and the severity of disease. So my main objectives today are to just give a really high-level overview of what ICU-related weakness or acquired weakness is or what we think it is. And then I'm going to dive into some of the potential mechanisms that are associated with ICU-related weakness. And then just a little bit of data about differences between COVID-19 and non-COVID-19-related weakness, which has already been alluded to somewhat in the prior talk. So what is ICU-acquired weakness? It's basically just a very generic diagnosis of weakness, and this can be related to a series of different mechanisms, particularly at the muscle, the peripheral nervous system. And then also I'm going to show some more recent data suggesting that actually the central nervous system may be a driver of ICU-acquired weakness as well. It's important to keep in mind there are different risk factors that can predispose individuals to more severe weakness following ICU stay, and COVID-19 appears to be one of those major factors. Other factors that are really important are comorbid medical conditions. Older age is also a highly significant risk factor. Also things that we do to the patient. So corticosteroids can increase the risk of critical illness-related myopathy, and neuromuscular blockade can also do those. So those things are factors that we want to try to minimize so we can lessen the risk or the impact of the ICU stay on the neuromuscular system. So I'm going to kind of go through these three main potential mechanisms very briefly because of limitations of time, but the first one that I'm going to start with, and it's really like the first mechanism that was highlighted now over two decades ago, is critical illness myopathy, and this has been called by several different names, but we're going to focus mostly on the muscular system for this first part of the talk. So what are some definitive characteristics of the critical illness myopathy? Well, first of all, it's muscle wasting or atrophy, and the amount of wasting that you get is out of proportion to what you see with just disuse atrophy. So there's clearly a negative synergistic effect on critical illness as well as immobilization. There also is, when you do like a muscle biopsy analysis of patients with critical illness myopathy, there is this prominent and significant loss of thick filament myosin loss. So it's a myosin loss presentation, and that's one way historically people have tried to propose as a diagnostic strategy, but that's a very invasive thing. So critical illness myopathy, one of the biggest gaps is how do we consistently diagnose this, and it's a major, major gap. There's also features of changes in muscle excitation or excitability of the muscle, and that's actually where I want to spend a little bit of time today to talk about how have we historically diagnosed or identified that, and what are some potential new ways to look at this phenomenon. So that excitability dysfunction is something that has been associated with critical illness myopathy very consistently. So this is a, so one of the things, so I'm a nerve and muscle disease specialist at OSU, so the main focus of my clinical work is really taking care of patients with nerve and muscle disorders, and as part of that, I do actually see a lot of patients in the acute hospital on the front end during the ICU stay, and so patients with inability to wean from the ventilator or diffuse weakness is a common referral in my practice, and so this is just a simple, on the left side of the screen, this is a simple screenshot of a compound muscle action potential response in a patient with a clinical diagnosis of critical illness myopathy, and a couple things that I'll draw your attention to is looking at the sweep of the screen and also the sensitivity of the screen. So you can see that these CMAPs, this is just from the adductor digiti minimi, are very, very low, are moderately low, but one thing that's really striking is the duration of the CMAP is quite long, and you can see it almost spreads across the whole screen. So what that suggests is this altered sodium channel function in the muscle leading to excitability dysfunction as well as likely propagation of action potentials are being altered as they go through the muscle. So if EMG and nerve conduction studies are a common diagnostic approach to kind of look for neuropathy or myopathy and ultrasound is now, you know, contributing to our kind of tool set, but if you have a patient that has absent compound muscle action potentials, one thing to keep in mind is that could both be related to complete nerve loss or complete muscle dysfunction, and one approach that people have used historically is this direct muscle stimulation, and so comparing when you stimulate directly the muscle or stimulate the nerve, what kind of pattern do you see? And if you see that when you stimulate the muscle, you still get a response, but you don't get a response when you stimulate the nerve, then that suggests critical illness neuropathy or critical illness polyneuropathy, but if you can not get a response all the way through, then that argues more for critical illness myopathy. So you can see that these responses on the right are kind of consistent no matter whether you stimulate the nerve or the muscle, where here when you stimulate the nerve, you don't get a response, and so that argues for a critical illness polyneuropathy. Previous studies have suggested that critical illness myopathy is more common, and we're going to talk about the prevalence of myopathy versus neuropathy and COVID later in this talk, but before I get there, this is a recent paper that came out with a more sophisticated way to assess muscle excitability, so this is not something that people use clinically at this point, but it's based off a simple compound muscle action potential measurement. You can also do this from the nerve as well, but I'm going to show you a recent paper that where they looked at muscle excitation in the tibios anterior in patients with critical illness-related weakness, and so basically this is a setup to where you stimulate the muscle distal to where the nerve connects with the muscle, so distal to the motor point, and then you record more proximal, so basically what you're trying to do is stimulate across the muscle without involving the nerve, and what they do is they stimulate at different frequencies, and look how quickly the action potentials travel to the muscle. It's a very simple approach to do, but the system that does it is more sophisticated than most EMG machines are currently, so what they did in this study is they looked at patients that were in the ICU with weakness, and they used standard approaches, and then they used this non-standard approach, and what they showed, so I had mentioned previously that this decreased CMAP amplitude and prolonged CMAP duration is like the classic critical illness myopic pattern, but in this series, the long duration CMAP was a very rare occasion, occurrence, and decreased CMAP amplitudes were less sensitive, where this approach actually approached 100% sensitivity and specificity, so this highlights that there are likely mechanisms at the muscle driving hypo excitability or excitability changes that our current approaches actually aren't very good at picking up, so there are changes that a typical CMAP response just can't identify, and so that is kind of a forward look of a measure, but it shows you kind of where the gaps are, so people are coming with weakness, but we can't really define physiologically what the mechanisms are, so next what I want to do is shift to talk about critical illness polyneuropathy, and so I alluded to earlier that neuropathy in the setting of an ICU stay is less common than myopathy. In the past, critical illness myopathy has often been falsely attributed to neuropathy when the CMAP amplitudes were absent, but the development of this direct muscle stimulation approach has really identified that, in fact, a lot of patients have myopathy when we think they have polyneuropathy, but polyneuropathy does happen. Historically, it generally has a more severe prognosis, less full recovery in patients that are affected with neuropathy as compared with myopathy, but what I was very interested in looking at, and this kind of relates to the last talk, is what do we know about the prevalence of critical illness polyneuropathy and myopathy in the setting of COVID and non-COVID, so keeping in mind the caveat, this is within the context of our current approaches to define these myopathies and neuropathies, but here they did a study where it was prospective in Sweden looking at patients with critical illness polyneuropathy and myopathy using a variety of biomarkers, clinical, electrophysiological, and plasma, and then they wanted to compare COVID versus non-COVID, so you can see the boxes there kind of highlighting small number of ICU-related weakness in non-COVID patients as the control, and then a larger group of COVID patients, and of these, a subset developed critical illness-related weakness, and when they compared patients with COVID that developed weakness, critical illness, myopathy, or neuropathy or not, a couple of differences popped out. One was gender, and then the other was body mass index, and patients that developed ICU-acquired weakness, either related to neuropathy or myopathy, were more likely to have higher body mass index, which perhaps is not surprising because that also pertains more prognosis to more severe disease, so of these 111 patients that had COVID-19, 11 developed this clinically defined critical illness, neuropathy, and myopathy. This was associated with more severe illness, longer ICU stay, and more thromboembolic diseases. ICU, critical illness, neuropathy was much more frequent in patients with COVID as compared with patients with non-COVID-related ICU-acquired weakness, which I think that really strongly supports the prior presentation and observations, and I think that's one of the areas where I think physical medicine is so exciting because it's dynamic and we can see these things in real time, we can combine our multiple skill sets to identify the problems related to COVID and then respond to it and provide powerful rehabilitation interventions, and so that's one of the things I'm most proud about our field is how dynamic we are. People have alluded to that, you know, post-COVID is like the next polio, and I really do think that's true, and I think like keeping our eyes open, paying attention, and then responding to that and meeting that challenge is really important. Another thing that they noticed is they looked at neurofilament light chains. This is basically a measure of axonal degeneration. It's been used in neurodegeneration, ALS, Alzheimer's. We recently published a paper in SMA, so it basically just shows breakdown of axons, whether it's a central or peripheral nervous system, and they showed a clear striking increase in neurofilament light chain in patients with COVID-related critical illness or ICU-acquired weakness, which further suggests that the nervous system is more affected in COVID. So the last little bit I want to talk about really aligns with some of the areas that I do really on the in my research area and some conceptual domains really looking at more upstream neurological mechanisms, and this connection is a little loose, but it comes from my observations and seeing these patients in the ICU. So when we do the nerve conduction studies and electromyography, you know, the multiple challenges when people are in ICU and ventilated and sometimes sedated, sometimes not, but having encephalopathy, the electromyography exam is very limited, and that could be because of cooperation, could be, you know, could be part of the pathogenesis, which is part of what I'm going to propose here, and so when we see the reduced motor unit activation, and I'm not talking about decreased recruitment, so this is slowly firing motor units and not bringing in enough motor units, that leads to insufficient activation of the muscle, and this raises the question is whether there is a central or upstream problem, and one of the main things I focus on in my research is motor neuronal function, and so to fully activate a muscle, the motor neuron has to fire and form titanic contractions of the muscle, and when you look at distribution of muscle function, proximal muscles require more of that fusion of tetanus contraction, so it wouldn't be surprising if a defect in motor neuronal activation or firing could cause a proximal predominant pattern of weakness as well as myopathy, so those two could mimic each other. So there was a very nice paper by actually a colleague of mine that's about an hour down the road at Wright State, Mark Rich in his lab, this is a pre-clinical model, so that with that caveat, but this is in a septic model in a rat where they do very detailed motor neuronal measurements while they're also measuring from the muscle, and you can see this is showing a pattern where a pattern where there is very little muscle force in a septic rat, you can see these dots on the top line are indicating a motor neuron discharge, so the motor neuron and all the muscle fibers it connects to, this is recording from the motor neuron itself showing these kind of sputtering action potentials, and this is just the current that they inject into the motor neuron to trigger the response, and so normally you should have sustained firing and consistent repetitive action potentials, and that's driven by the persistent inward current of the sodium channel, and so when they found this in this rat model, that strongly argues that in the context of sepsis that the central nervous system loses this ability to sustainly fire, and so is that perfectly equated to ICU-related weakness? Maybe not, so not everybody in the ICU has sepsis, but what they did here is they did this intervention with a small molecule compound, a drug, that would improve this current, and you can see in this kind of in vivo prep that they can dramatically increase the motor neuron firing instances, improve the muscle force, and then you can see the recordings from the motor neuron itself are very consistent, repetitively firing, so could critical illness also be related to motor neuronal excitability dysfunction is something that I'm interested in, because we have seen this in the context of aging, so we have other measures that we do in vivo where we stimulate the motor cortex or the spinal cord and record from the muscle, and we can see that there's excitability changes with age, and we have used this same compound in the context of aging and shown that we can improve muscle strength in vivo, and so it's very interesting to see, because age is a risk factor for ICU-acquired weakness, is this driven by excitability issues of the nervous system. So one last note I want to leave on is there are multiple reports of electrical excitability across different systems, and so there are reports of reversible nerve conduction study changes, so critical illness, polyneuropathy, neuropathy could also be loss of excitability of the nerve rather than axonal degeneration, so we don't normally see demyelination in the context of critical illness, but we do normally see axonal changes, but that doesn't mean the axon's gone. It could be that the axon is decreasing its excitability, excitation capacity, and so there are reports of rapidly improving nerve conduction study responses, sensory and motor amplitudes improving faster than you would expect repair of peripheral nerve, so that suggests maybe this reversible excitability dysfunction. This has also been associated in EKG recordings where you have reduction of the QRS complex, the voltage is reduced and you have this rapid change. And so one question that I think this raises, you know, looking at the critical illness myopathy excitability problem, looking at the peripheral nerve, looking at the motor neuronal findings in an animal model with that caveat, and also the conduction through the heart, could this be a multi-system excitability failure? And it could also support why we see encephalopathy in patients too, because that could be also an excitability change of the central nervous system as well. So that's just a parting thought that I think we need to improve our ability to determine what aspects of the nervous system are affected, and it may be different in different contexts of different critical illnesses. And then also that could inform our prognosis and our rehabilitation interventions on different phenotypes may need different kind of approaches to improve the deficits that are noted. So with that, I'm going to hand off the baton to Dr. Paganoni, really excited to hear her talk. Thank you. Thank you, Dave. Welcome everyone. In looking at the names of the participants, I see that there's many familiar faces. Great to connect with all of you virtually, and I see many new names as well, and it's wonderful to see how the number of physiatrists interested in neuromuscular medicine continues to grow, and that's fantastic. So now I'm going to switch gears and talk about something a little bit different. I'm going to talk about the impact of COVID-19 on clinical trials and clinical research, and I'm going to share the example of the Healy ALS platform trial. As Dr. Franz said at the beginning, my main occupation in terms of my research goals is to design and lead clinical trials for ALS or Lou Gehrig's disease in particular, and one unexpected learning from over the last couple of years is that we can make our trials even better thanks to COVID in a way, although that did present a few challenges. So I'm going to share this example to share how we can adapt our research in real time, the lessons learned, and hopefully how we can use these lessons to improve our research moving forward. These are my disclosures. Now let me start by sharing the problem. Many of you are familiar with ALS or Lou Gehrig's disease, and unfortunately the statistics are not very favorable. Every 90 minutes someone is diagnosed with ALS and someone dies from ALS. So even, you know, after we finish this program, we will have one more diagnosis, one more death on average in the U.S., and we know that ALS is 100% fatal, which really drives the urgency to find new treatments for ALS. Now there is one piece of good news. Over the last few years, there's been an explosion in drug development in ALS, and we know that there's now 200 companies working in the ALS space, and there's at least 40 investigational products that are awaiting testing. So we did all of this research and really established lots of collaborations with investigators and companies worldwide between 2018 and 2019, and we were thinking about changing the way we do trials so that we could make our trials more efficient and test as many products as possible, as rapidly as possible, again because of the nature of the disease. So that work went on in 2018 and 2019, and so we were ready to launch something new at the beginning of 2020. We learned from colleagues in cancer that we could do something known as the platform trial that would allow us to test many of these products at the same time rather than testing them one at the time to gain a lot of efficiencies. So I'm going to share a very short video, part of a video that we produced last year to explain to patients what this was, and in early 2020 we launched this video again to share that we would soon launch the first platform trial for ALS, and hopefully you can hear. Oops. In the fight against ALS, the first ever ALS platform trial designed to accelerate the development of effective and breakthrough treatments for people with ALS. So what's different about the Healy ALS platform trial? Instead of testing just one drug, the Healy ALS platform trial evaluates multiple treatments at the same time. This means more opportunities to find groundbreaking therapies in a faster time frame. Imagine having to build a new dock every time a different ship came to port with new treatment cargo. This is how traditional trials work. In platform trials, there is one dock to receive all the cargo and connect the treatments to their final destinations. So that's how we were in March 2020. The first week of March, we were preparing to launch the trial at over 50 centers in the US. In order to launch the trial, we had organized an investigator meeting, meaning that there were over 250 people flying into Boston the second week of March. Then something happened. The week before, there was a super spreading event that basically started the COVID pandemic in the Boston area. This was related to a different conference from a pharmaceutical company. And there was this sort of event that really precipitated the situation in the city, so much so that our hospital decided to, for good reasons, to ban large events on our campus. So for this reason, in less than a week, four or five business days, we had to turn the investigator meeting virtual. Now, this seems like normal right now. But at the time, we had basically our working stations, like we have all sorts of cables, and learn how to use the Zoom technology, and learn how to do training in a virtual environment. So very quickly, literally in one week, we had to kind of completely change all plans. So we launched the trial. That's where the red arrow is, that's March 2020. We were about to start enrolling that week, right after the investigator training. But unfortunately, we did have to wait. There was a COVID delay. So we had to spend 2018 and 2019 to do all this prep work. And then when we were about to launch, we had to completely pivot and change plans. And then we ended up launching in July 2020. So I want to explain what happened between March and July that enabled the launch, and then what additional changes we had to make after launch. So between March and July 2020, obviously, all of you know that there's been clinical site closures, research restrictions at different institutions, lockdowns preventing participants from going to the clinical site. And of particular relevance to ALS, there were restrictions on pulmonary function tests, because of the concern that actually doing the maneuver would spread the virus. And actually, pulmonary function tests are incredibly important in ALS research, because we use them both for trial eligibility, as well as to monitor outcomes. So we just couldn't do the procedures that were supposed to happen as part of the trial. In addition, this is a large trial, hundreds of participants at over 50 sites, it's subject to FDA regulations, it's a pivotal trial. And so we had to adapt to the new regulations regarding data collection, which was really a big operational change, because the FDA then required to collect information on the impact of COVID on research data. So the complicated thing, obviously, this was a fluid situation, the regulations kept changing, as you may remember, we had sort of daily meetings at the hospital, to learn about the evolving regulations. And the same was true, not only on the clinical side, but also on the clinical research side. Again, with FDA and IRB, continuing to adapt, there was a lot of geographic variability, we were operating in 29 states at the time. And so the situation was very variable. And at the same time, from our specific patient population, we had a real push to, you know, patients really wanted to enroll, because ALS is, again, 100% fatal. And for them, you know, this trial was much awaited, and really, they wanted to enroll as soon as possible. So what we did was we created a COVID-19 task force. And I was part of that, we had investigators, clinical operations, colleagues, regulators, in close collaboration with several vendors, and we would meet every day between March and July to do, to really plan protocol amendments and operational changes to make the trial COVID-resistant, so resilient. So essentially, we wanted to launch the trial, first of all, but that was not the only goal. The goal was also to ensure robust enrollment, which was very uncertain at the time, and also ensure high data quality, because there is a huge impact when you change procedures in a trial that's so regimented like this, there's really concern about the scientific impact on data and outcomes. And so we met on a daily basis. And this, this is when we started basically being on Zoom all day long, with colleagues from around the world, to be able to adapt on a daily basis, almost using military operations in a way like really very, very structured operations to be able to pivot immediately. We used certain criteria to guide the amendment. Obviously, our first criterion was the safety of trial participants and site staff. We had to be very aware and mindful of the scientific impact of all the changes on the outcomes of the trial, because the trial is a scientific experiment. And if you change some of the variables, you can influence outcomes. We also had to really pay attention to operational feasibility. Now, one thing that we learned was that options such as virtual options like telemedicine, which, you know, can be deployed, you know, effectively, to in this context, can actually be expensive due to a series of operational changes that need to happen and regulations that you need to comply with. So we wanted to make sure that there was also attention to cost, participant and site burden, all the regulations, and obviously, with real attention to geographic distribution of COVID-related restrictions that, again, if you operate, you know, in many states, that does have a big impact. So what we did was to launch the first protocol amendment right away that enabled us to use telemedicine. That was the big change. But even that is not actually simple, because you can only change certain specific visits for research or certain procedures to become telemedicine based, again, because of both the scientific impact and the operational impact, not to mention data privacy and other concerns. Then, a few weeks later, we launched the COVID-19 protocol amendment number two for our trial that enabled us to use different features. Now, telemedicine was easy to implement, because most hospital systems that we were working with had software that could be deployed for this reason. But then to go beyond that, we had, we wanted to basically offer a series of home services or collection of data in the home environment that took a little bit longer to organize. We set up home lab collection, home nursing for vitals. We use smartphone apps to collect certain outcomes, and we use the home spirometer that's pictured on the slide that basically helped us bypass that concern for pulmonary function testing in the hospital environment. People could then do the pulmonary function test at home rather than in the hospital, which was great, but took a lot of thought and consideration in terms of which specific device and how to set it up. We finally launched in July 2020. At the time, if you think about that time, there were still many uncertainties about the evolution of the pandemic. And then, well, we thought, well, at least we launched. But then, between July 2020 to present time, we've had to deal with a number of subsequent changes that, and challenges that continue to present themselves somewhat unexpectedly. So first of all, there's been significant challenges in terms of the supply chain. The first thing that happened was that our central vendor ran out of one specific tube for blood collection. The problem is that because all their lab kits are generated automatically, the fact that only one tube was missing basically blocked operations and kit availability. So this was a big challenge that required a lot of time and effort. Then we had to face staffing and home nursing shortages. Now we set up all the home blood draws and the home nursing services, only that when sites were asking for a visit to happen in their home environment, there was no local provider oftentimes because the agencies, which was sort of a top-notch agency, still couldn't find people to go into their home environment. And then there was obvious workflow challenges with essentially everyone working remotely, which really created a number of regulatory challenges in terms of supervision, oversight, and sign off on certain procedures. Again, we really had to adapt constantly and that continues to this day. So one thing that we learned was that communication and collaboration are really key. So essentially, I told you before that we had the daily meetings of the COVID-19 task force, and then we continue to this day to have daily central team meetings to maintain central control at the coordination center level. We also have weekly meetings with all the sites. We launched over 50 sites and now we added another 20. So now we are operating, I think, in 35 states. And so that means that we have to be in constant collaboration with all the PIs and the coordinators because new things come up. And then one thing that we learned from our patients is that in this new virtual environment, they wanted to connect with us and the sites essentially on a weekly basis. So before we were doing monthly webinars to keep, because the ALS patient community is very vocal and active, which is great. And for that reason, we were having monthly meetings with the patient community, public meetings, but they wanted us to do that on a weekly basis. And so we started being on the web on a weekly basis with patients. And that was really amazing because we really developed relationships from patients from all over the world and we got amazing suggestions and that really helped improve our processes. And actually in the first year that we've been doing these weekly patient webinars, we have connected with 15,000 patients from all over the world, over 40 countries. So this has been really a change, a learning experience for me to understand how to communicate broadly and really be open to feedback. We have been reflective with many colleagues in the last few years, we published papers, many more we are writing about the challenges as opportunities of COVID-19 in terms of its impact on care and research. So in addition to adapting to the changes, what can we learn? What are the positive aspects of this that we can leverage to improve care and research? And really we are continuing to work with many colleagues to optimize telemedicine, optimize smartphone data collection and develop new models that are good, not just because we have to do it in the context of COVID, but because they can improve the quality of our trials and especially improve access and inclusion in our trial. Taking some time, that's my last slide, to reflect on the positives. I wanted to share that these COVID adaptations really improved our trial and can be leveraged to improve access, operational feasibility and quality long-term. And throughout all of this, communication and collaboration with all stakeholders has been key and really being open to feedback. So just really to summarize this, I think that Charles Darwin was right, it's not the strongest of the species that survives, nor the most intelligent, it's the most adaptable to change. And that was the end of the presentation. Thank you. Great. Thanks, Dr. Paganotti. And thanks, Dr. Arnold and Ryberg. That was a great session. And I think we can stay on. Excuse me, I was going to say, Dr. Franz, my apologies. This is Sean, but I've been notified by my team that there is another session that is going to commence right now. And so my apologies, but we're going to need to wrap this up. Okay, we'll wrap it up. Thanks. We tried to answer some of the questions in the live chat. I know we're all willing to engage and answer questions due to time constraints we can't do right now. I would suggest put a plug in for the AAPM and our neuromuscular medicine and EDX community forum as a way of reaching out to all of us who we all follow along there and be happy to continue this discussion. Lots of good questions. Wish we could have talked about them. Yeah, I think we all have too much to say. Yeah. And of course, in person, we'd be excited to also meet people face to face and chat well after the session. So we're hoping maybe 2022 we can do that. Yeah. Thanks for joining. Thank you.

COVID-19

neuromuscular medicine

clinical trials

immune response

inflammatory processes

critical illness myopathy

polyneuropathy

Healy ALS platform trial

adaptation

collaboration