And thank you so much for joining us so early this morning to talk on Navigating the Rehabilitation and Orthopedic Complications of Spinal Muscular Atrophy. This talk has been sponsored by Novartis Gene Therapy's educational talk. Now, why is this happening? Okay, my name is Claudia Chiruboga. I'm a child neurologist at Columbia University Medical Center. And I'm delighted to be joined today by Dr. Tina Duong, who's the Director of the Clinical Outcomes Research and Development in the Neurological Sciences at Stanford University. These are our disclosures. So what do we hope to accomplish today? Those are our learning objectives. And one will be to summarize the disease pathophysiology, review the broad range of the phenotypic expression of pediatric and adult SMA patients, identify signs and symptoms associated with SMA progression, including the orthopedic manifestations that Dr. Duong will cover. We'll discuss the variable biomechanical complications seen in the different forms of SMA and options for management. And choose and organize suitable rehabilitation programs based on available standards of care. And we'll also review the influence of therapies. On the interest of time, I'm only going to cover approved therapies and not those in development. But there are a lot that are in development, mostly affecting muscle. Don't know why this is not working. Okay. So, let's begin. What I'm going to talk about is SMA, which is the 5Q-SMA. There are different types of SMA, but this is the classic SMA, the old wording Hoffman, also known as 5Q-SMA. And that's where all the therapies are directed. So, as many of you know, SMA is a progressive neurodegenerative disorder that affects many cells, but preferentially motor neurons. And it's one of the most common autosomal recessive neuromuscular disorders with a carrier rate of about one in 50, but it varies across populations. There's a wide spectrum of disease severity. And it starts at zero when it's the connatal form. That's rare, but we recently had a baby born with type zero, which is very severe. They have contractures and they're born unable to breathe or move and unable to swallow. That's the rarity. The most common one will be one through three, and we'll talk about those pediatric phenotypes. Type four is an ambulatory form of adult presentation, which has a milder progression. The disease is caused by a mutation in the SMN1 gene. And what that gene does is produce SMN protein, and there's less of that, and that's what causes the disease. And it's modified by the SMN2 copy number, and I'll go over all of this in more detail as we go along. I wanna use this, but I can't. Okay. So just to introduce you a little bit to the molecular biology, we have two SMN genes. One is the SMN1, which as you can see, it produces, this pre-mRNA has eight exons and introns. When it's spliced, the mRNA has all of those exons, including exon seven, and that produces a full-length SMN protein. And that's when you're normal and you have no mutation. The SMN2, which is a paralogous, that differs from a few oligonucleotides, but the main one is that T4C substitution, which what it does is that the product of the SMN2 protein is missing exon seven, and hence is non-functional. But it does make a difference, and we'll talk a little bit more about that, because in SMA, you don't have SMN1, so all of your SMN protein will derive from the SMN2 gene, and I'll explain that a little later as well. But 90% of it is non-functional, that delta seven SMN protein, but the 10% that is produced does have a functional SMN protein that's made. So let's talk about phenotypes, and how is it that a single, a monogenic mutation causes such a widespread phenotype, from severe connatal to late adult onset? And that has to do with the number of SMN2 copy numbers that humans have. Not only humans have the SMN2, and so if you don't have the SMN1, and you have very few copies, well, let's see if this works. This doesn't work either. Yes, okay. This worked when we were practicing, but not here. The fewer SMN2 copy numbers in the presence of SMA, the more severe the phenotype, and if you have more SMN2 copy numbers, the milder the phenotype, and we'll see how that plays out. So to understand the phenotypes, and this is before treatment. Hopefully we won't be seeing babies, and this is a live feed. This is a baby who's very hypotonic. Is it a live feed? Yes, it is a live feed. That is moving, but very minimally, just distally and no anti-gravity. You see the frog legs position. The hands moving, the parasol deformity, the paradoxical breathing, and look at the face, very expressive. Always ocular motor function is preserved, and this is the most common of the forms of SMA. They typically have two SMN2 copy numbers, though there is overlap, and it starts with hypotonia in the limbs, and they all have a reflexia, and then it advances, and the classification in SMA is based on ultimate level of function, and that was prior to treatment. So by definition, SMA type one babies are those who never sit, and the main issue with them is dysphagia, respiratory insufficiency, which causes death early. Most of them succumb before age two, and what we look for when we're talking about treatment is event-free survival, and that would be either death or needing permanent ventilation, which is described as 16 hours. By the time symptoms develop in SMA type one, you've lost about half your motor neurons, and that makes a difference, and we'll see a little bit how that difference is displayed with pre-symptomatic treatment, and if you're going to wait for lingual fasciculations to make your diagnosis, you have waited too long. This is the natural history. You can see that there's a rapid decline in event-free survival. It's 10 1⁄2 months, 50% survival, or eight months with the Neuronex, the CHOP-N10, which is a measure of function in very weak children with SMA, and it was developed by CHOP that they decline, and they never reach 40 points without treatment, obviously. Okay. This is SMA type two. This turns off, so that's no good. SMA is the intermediate type. It's about 1⁄3 of 27%. By definition, these babies sit. This is a very weak type two, because you can see that she's barely sitting and very hypotonic and having breathing problems and has dysphagia because she has her G-tube, not all type twos have that, and they typically have three SMN2 copy numbers. The presentation is between six and 18 months. Under six months is the type ones, and they will present oftentimes just with a hypotonia, develop motor delay, or they can start losing function. Lower extremities especially is what you will see. Oftentimes, they don't bear weight, or they lose function, the ability to crawl, or the ability to stand, and by definition, they never walk, and they do sit, though they can lose that ability over time. They have a shortened life expectancy, and it's mostly the skeletal deformities that develop over time, and then the contractures of the hips and the knees invariably happens, and Tina will talk a little bit more about that. I just want to make one point. You're used to using Botox for contractures. This is one place where it is contraindicated because the contractures here is because the muscle is immobile. It's not moving, and it's shortened because of that, because it's very, very weak. You don't want to paralyze an already weak muscles, and it doesn't really work, but Tina will go into more details what kind of therapies do are helpful. The natural history, it is a bit more gradual. This is from the PNCR network, of which Columbia was a part. These are prevalent cases, not incident cases. Usually at an incident, there's a little more decline shortly after diagnosis, and then it stabilizes, so over a year, type two and type three don't decline very much on the Hammersmith, which is one of the measures of function that Tina will talk about in a bit, but there is progression over time, so over two, three years, you will see change, so even though patients don't think that they are progressing, especially the adult patients, they are losing function. It just is at a much slower pace because they're on that plateau, so scoliosis is very common. Even with treatment, we continue to see it, and these are all children who have been treated with nusinersen, and you can see the progression over time from three to five years. One difference that has happened as a result of early treatment is that babies with type one that never sat at all and never developed scoliosis, now are starting to sit, but they're weak, and they will develop scoliosis very early, often in the first one or two years of life, and that's something that we need to be mindful for, and you can see the severity of it, and the middle child is a child who's so skinny that he can't get his hardware in, and we're trying to fatten him up, and that's proven a struggle, so here is the pre-rods, and then when you have the rods, it straightens up, and this is typically what we do in pediatrics with these growing rods. These are the magic rods, which with a magnet, you can extend so that it takes them a while to outgrow their hardware. One other thing that we've seen, since nusinersen more so, is the onset of kyphosis, and it's a high cervical kyphosis, and so now the orthopedic surgeons are starting to do the traction in that middle one, and this, I think it's dying. Now it died completely. What happened to my? Ah, there we go. So the traction, what's being done, and it's about six weeks of traction followed by the surgery, and oftentimes there's not so much scoliosis because they're a little stronger, and it might have to do with the distribution of the antisense oligonucleotide nusinersen that we'll talk about in a bit. And the least common of the pediatric SMA forms is the type three. SMA type three are ambulatory patients, at least at some point in time, and oftentimes there's a delay, and the delay is because they're oftentimes sent to the orthopedic surgeon because their legs are turning in. It's not until they start falling and they notice that the child is very weak that they are sent to neurology, and oftentimes you lose vital time. Another thing that's quite common is to see more of the Trendelenburg gait with the hips falling. That's very common, not so much the waddling gait, though you can see that as well, but less common. And then the interning of the leg, and sometimes even scissoring because they lose strength in the psoas, in the gluteus, but the adductors are quite strong, and usually that's relatively preserved. It's oftentimes confused because of its pelvic girdle distribution with a limb girdle muscular dystrophy, but of course the CK is not terribly abnormal, though it can be elevated, and the more active they are, the higher I've seen it, up to 1,000 or so, but usually not that high, certainly not in the level of a muscular dystrophy. So fatigue is a very important aspect of SMA, and you see it more in the type three patients because they are so much more active. So these are children that before treatment, they couldn't do anything after five o'clock because they were wiped out, but that is not something that, fortunately that's something that has improved with therapy as well. The SMA type three is classified into type 3A and type 3B, and you've noticed that the earlier the presentation of symptoms, the worse the prognosis. Children who develop after 18 months, which is when it can start, after age three do much better than those who present under age three in that hazard, you can see there that 20 years into your diagnosis, if you present after three years of age, you're likely to be walking 90%, whereas only 44% of the children who present early, this is before treatment, are walking 20 years into their diagnosis. Electrophysiology, we use it rarely in pediatrics just because it's complicated and it's not terribly helpful. When you have an infant with SMA type one and type two, it's more easily identifiable, and genetic testing is so much easier to do, but it's used in adults especially where it's not so clear cut, and they're not so prominent, and the delays in diagnosis are much more prevalent in the type threes, especially in older onset. I've treated adults where the mother thought the child was an adolescent who was lazy until she was in college and couldn't climb a hill and they noticed that she was very weak, or another patient who now is in one of my studies who's in his 60s, who he was 18 trying to lift weights and he couldn't make any progress, and the trainer told him, you should go get yourself checked because I think there's something wrong, and nobody had identified that there was a problem. So if you think that it can be a problem, you should do the EMG if you can't localize it, but unfortunately in the type threes, the EMG isn't terribly helpful, but it can distinguish neuropathic from myopathic much more easily. In infants, the C-MAP is very helpful, and it's a biomarker, and it can tell you if there's rapid progression or recovery. And on the bottom, you'll see there there's, and that's I think from Kathy Sobota, just showing that the C-MAP is so much lower in the type ones, and I am not going to use this, I'm afraid of this, okay. That, and then, but in between the twos and the threes, there's some overlap, so it's not always helpful in determining that. And you'll see the munis, which is a motor unit estimation that reflects motor neurons, that they're lowest, showing that you've lost quite a few with the type ones, then next is a type two, and then the type three, because it's so variable and milder that you have quite a wide range there. So, what does it mean when you lose your motor neurons? Well, it reflects your motor function, and Tina will talk a little bit more about that. And you can consider it, at least this is my thoughts, of where you are in terms of motor neuron loss and disease severity, because it is very heterogeneous, and there's a wide spectrum. So, there's a pre-symptomatic stage, which I'll talk a little bit when we talk about newborn screening, but then early stage is when first presents and starts to lose function. And that is an important time for intervention from a therapeutic perspective. And then there's a chronic stage, where there's been quite a bit of loss of function, but also there have been neuromuscular changes, musculoskeletal changes, but there is that progression that we talked about, but it's very slow. And this is especially important with adults who might not notice that they're losing that little bit of hand function that is helping them use their joystick. So, there is reason to intervene, even if you feel that they're relatively stable. They're not as stable as one might think. Okay, and the longer the disease duration, the complications are higher, and in type two, you can see the onset of dysphagia and respiratory issues, and that is without treatment. And we'll talk about treatment after Dr. Duong talks. Tina. Thank you so much, Claudia. So, in the next few minutes, I'll discuss some of the rehab aspects of managing patients with SMA. But before we move from a more pediatric-related talk, I always want to emphasize that this is not only a pediatric disease. As you can see here, adults are impacted as well, and so you can see at the top row, that's ambulatory. You're a physiatrist, I'm a physical therapist, we know what that means, there's a broad spectrum of how one would describe ambulatory. You can see the strong ambulatory group over there. Sit-to-stand's not so hard, they're walking pretty well. You may not even notice if they're walking down the hall, compared to the young man on the right, where this is how he gets up from sit-to-stand. Incredibly difficult to get up from a chair, right? So this is the broad spectrum. We usually divide function into ambulatory, sitter, and non-sitter. In the bottom half of the screen, you'll notice a young lady who's sitting. She's able to move her hands really well, and get her hands to her mouth, do her activities of daily living, while the young lady on the, I get my rights and lefts confused, but the non-sitter side, you can see that they have a hard time getting their hands to their mouth, even small minor finger movements. All that being said, as Claudia talks about treatment, keep in mind that in the U.S., adults are able to get treated with disease-modifying treatment. So that changes the game for us as therapists in the rehab profession and U.S. physiatrists, meaning that there would be more, you'll see more of these patients that you may not have seen before because there wasn't treatment for them. And you'll notice a lot of these adults are very productive individuals. Before treatment, they were too busy to come see physical therapists or physiatrists whenever there's not a treatment available. That being said, I'll focus on a little bit about the historical perspectives on the standards of care. In 2007, there's a consensus statement on standards of care, and the big approach there was focused on pediatrics, where there was a proactive approach focusing on respiratory and non-invasive ventilation. Then there was approval in 2016 for nusonursin, and I won't speak about that more because Claudia will mention that at the end of our talk, but then in 2018, there's a standards of care that was put out, and this, again, also I really want to emphasize, even though it was published after the treatment, first a treatment approval in December 2016, it still is based on a natural history cohort that is not treated. As many of you know who have been part of Standards of Care, it takes years to get consensus, and then just as long to publish. So keep that in mind, that now, the Standards of Care that you see out there is not necessarily associated with treated patients, okay? But the nice thing is, it has more of an anticipatory care model, meaning you as clinicians need to have a better understanding of the disease progression so that you can make clinical decisions that we're all kind of learning as we go as these patients are getting treated. In the Standards of Care, for pediatrics and adults, we do promote a multidisciplinary care approach. In the adult world, this is really hard because the patients have to act as their own care coordinator. In the pediatric realm, there's multidisciplinary care models that are more integrated within the neuromuscular clinic. Keep in mind that because this is a multi-organ disease, you have to address neuromuscular aspects, pulmonary, orthopedic, nutrition, all of that together. And so when you're the treating physician, you just wanna make sure that all those pieces are also recommended for your patients, okay? Next, I'll enter a little bit about measurements because when you read about SMA, you'll notice there's a lot of talk about different types of outcomes that are used to assess function. And this is because many of these outcomes stem from our understanding of the natural history and its use in clinical trials. I won't talk about biomarkers, but what I'll talk about is clinical outcomes. And these are assessments that are used primarily in clinician-rated outcomes, and that is the Hammersmith, the CHOP and TEN, the ROAM that you see in many of the published studies. And these are functional motor composite scales to assess the ability to use your muscles. And then there's performance-based measures, and these are time tests. And the difference between the two is the clinician-rated one is based on the clinician looking and assessing how a patient does over time. So you would imagine that consistency in who's doing the evaluation's gonna be highly important because if you have a therapist doing your evaluations in clinic who's never done this before and you have many different therapists doing it, your results may look different than what's published that you've read from some of the clinical trials. In the performance-based ones, there's less subjectivity being that usually it's timed. However, we're limited because as you heard from Claudia that this is gonna be limited to the ambulatory type three population because they're time measures. A lot of the outcomes are based on what you're very familiar with, which is the ICF model. When you're doing the evaluation, the typical body structures, strength, range of motion, fatigue may be assessed there. And then a lot of what you're seeing for the functional composite scales fall under the activities. So you see CHOP in 10, WHO motor milestones, and then some of the more adult-based measures or pediatric and adult measures are Hammersmith, Rome, and the time function test in the middle category. But also keep in mind that there are things that we cannot measure physically. So patient-reported outcomes are really, really important. And for the adults, I usually use, for non-ambulatory, I usually use EK-2. And fatigue is not something that we've talked about frequently, but it's a huge problem in SMA. And I suggest that you use some kind of patient-reported outcome to assess fatigue, such as the fatigue severity scale. Clinical outcomes in SMA is really based on function. As you can see on the left, it goes from non-sitter to sitter. And this is just a nice schematic showing you all the tools that are available based on function. And I suggest that you use, when you're assessing the patients, see where your patients fit functionally, whether they're pediatric or adult, and use one of these tools that have been validated within those functional groups. On the far right, what you'll see is we also added pre-symptomatic because now that there is a disease-modifying treatment, kids are being treated pre-symptomatically. And as Claudia said, treated younger is better. And so now we use more normative scale versus SMA clinically-derived scales to assess those patients. Whoops. Okay. Now I'll talk about some of the orthopedic manifestations. First, we talk about contractures. So Wang, in 2004, long time ago, published some of the manifestations that's seen in contractures. And as you can imagine, in type two who are non-sitters, this goes from highest contracture to lowest contracture, knee extension is the most prevalent, followed by ankle dorsiflexion and then the pelvic girdle muscles, including the hips and the shoulders. In the upper extremities, you're looking at limitations in elbow extension, particularly forearm supination, that's gonna be a factor. In type three, because they're walking, they have less contractures associated with decreased movement. And most of that's gonna be in the ankle dorsiflexors, where you're gonna maybe first see some of the contractures due to tightness, where they may not even get above zero or 90 degrees, followed by some knee extension, hip extension, contractures, and again, focusing on more of the distal contractures that's associated with type three and muscle weaknesses or imbalances, as you can imagine. One thing I wanna highlight, there was a natural history study published by Salazar looking at a network of mainly pediatric patients, but what they found was even minimal hip and knee contractures were associated with changes in the Hammersmith motor function scale. You can see here in type two that over 90% of them have hip and knee contractures, while even just as high as a percentage in type threes also have hip and knee contractures. And so this is gonna change a bit with treatment, and contractures is defined as a hard infield versus tightness. And our patients talk about that all the time, where they say, oh, I'm on treatment, my contractures got better. And as we know, if it was a true hard infield contracture, that probably didn't get better, but we do see that tightness is improving because of the improvements in strength. And so that again promotes the referrals to physical medicine, physical therapy as a concomitant treatment alongside disease-modifying treatments. Some of the conservative approaches I'll go through quickly. It's very similar to your treatment methodology now, including passive and active stretching, bracing, serial casting, and the use of standards. Stretching programs really should be first initiated and supervised by a PT or OT, and then we'll also talk a little bit about the surgical tendon lengthenings and scoliosis, et cetera. This is a dynamic, moving field because as patients are getting treated, we're all learning as we go in this process. So communication is gonna be key in this new era of disease-modifying treatments for patients with SMA. Some of the examples of stretching and positioning devices that are out there are what you already know. Serial casting is done. You have spica splints, knee extension braces, dynamic and static bracing in the lower extremities. And in the standards of care, what are the suggestions are in 2018 for non-sitters? The primary focus is really the respiratory system and good nutritional care, okay? And so this is really the infants that Claudia talked about before. Rigid bracing can be used as long as it doesn't interfere with their breathing. Okay, a lot of times if you have maybe an abdominal cutout for those kiddos, that helps a little bit. And this is, again, changing because of the disease-modifying treatment. In sitters, you're looking at trying to manage the scoliosis. Again, as Claudia said, there's increased kyphosis that we're seeing with kids who are being treated. The standards of care based on natural history is that if there is greater than 20 degrees of scoliosis, they should be monitored every six months until skeletal maturity. Some of the treatments that are based on consensus out there are spinal orthoses due to the hypotonic trunk. There's really no consensus whether it should be rigid or solid. I say work really closely with the physical therapist who's working with your child, as well as the family and the orthotics person to really fine-tune this because the most important thing is to have the patient wear it longer. So it has to be comfortable. So it may be a combination aspect of both soft and rigid, depending on their scoliosis. I know that research does not show that it actually halts progression, but it's more of a palliative aspects of it. But if you think about biomechanics of movement and tightness, I'll show you an X-ray that would promote its use for patients wearing it. In standards of care, they have this nice breakdown. If you have scoliosis based on an X-ray, what you should do. If it is less than 20 degrees, you monitor it. If it's greater than 50 degrees, then you should really start discussing surgery. And if they are skeletally immature, you may consider growing rods, while those who are in the area of skeletal maturity, the older range, you may consider spinal fusion. The question about surgery, there's one abstract that was presented on the CHERISH and SHINE study, and these are treated pediatric patients. Basically what they found is the greatest improvements were seen in patients who had a Cobb angle of less than 20, as you can see on the green bars on the right side. And these are treated patients. So similar to what we've been saying, treated earlier, less scoliosis results in improved motor function. And then based on what we've seen, and the standards of care, the one thing I want you to take from this slide is that at Boston Children's, they've looked at 87 patients who have SMA, and treated and untreated. Keep in mind, this is not a randomized control trial. This is a natural history they're reporting. They found that people with a Cobb angle of less than 50 degrees, their pulmonary function had the capacity to change after spinal surgery. However, if it's greater than 50 degrees, what they found was there was just really no change in thoracic insufficiency. Some of the explanations to that would be maybe there's irreversible thorax or lumbar parenchyma changes, as well as increased stiffness in the thorax, scar tissue buildup and rigidity that results in no change in pulmonary function. So keep that in mind. Those numbers kind of help guide you on how closely you should monitor a patient based on their spine x-rays. And some of the conservative treatments here are just pictures and examples of, you may see dynamic DMO suits that are more flexible versus TLSO and soft orthoses. And the other thing is muscle activation. Keep in mind with treatment, there's potential for strengthening and improved thoracic pressure. So that means the abdominals and the extensors have to work together to help support the spine. So we do recommend kids using bracing alongside exercise to keep the upright posture. So these are just some examples. And then I'll further emphasize that with a quick case study on this. This young lady, she was diagnosed with SMA type two. She was treated with Neuson-Nursen and also on a trial, Scholarock trial for anti-myostatin. She was symptomatic at one year with three copies of SMN2 and has been treated with Spenraza for four years. Her scoliosis is what I wanna show you here because she's in this funky place now that should we do surgery, should we not do surgery? This is the question you're gonna get a lot. And we don't know. So we're monitoring her really closely and I just wanna show you, in 2020, she had x-rays done with braces and without braces. You'll notice without braces, there's a 42 degree curve and then with a brace is 35. And so that's nearly a 20 degree difference. If you can just imagine, she's sitting all day without a brace, the tightness that would be associated at the accessory muscles, the lateral trunk, and if she doesn't have a brace, that's just gonna get tight and become permanent, right? And so we really look at bracing as a way to, not necessarily prevent, but advocate for better functional movement because of decreased tissue tightness, okay? She's had about a greater than five degree decline of her scoliosis over the past year or so. So what are we doing? Aggressive rehab. So this is very unusual. She is elite in regards to the amount of exercise she does, but she gets physical therapy through the state two times a month for OT and PT. She goes to the gym two times a week for an hour and does exercises, which I'll show you, horseback riding once a week. And her goal is primarily is to be more independent with her transfers, walk without her walker. And she's seven years old. And so she just basically wants to do all this by herself, including getting in and out of the car by herself, transferring from the toilet all independently. These are just videos of examples of the RYSE gym that she goes to. She gets a lot of one-on-one, making sure that it's the quality of movement and not the quantity. They use a Pilates reformer to get her to work on trunk stabilization alongside some of the other strengthening exercises. You can see here how much time they actually spend on more neuromuscular education so that she activates her muscle appropriately and in a timely manner with the function that she's doing. And she's absolutely fantastic. And this is the same girl that the x-rays show a 52 degree curve, okay? And here are some of the other exercises she's doing. When you ask her, what do you want to do for fun? She wants to practice doing the stairs. And I really think it's because she wants to be more independent at it and feel safer, okay? So then with this young lady, she's treated with nusinersen and on the anti-myostatin trial. What would we do anything different? I just wanted you to just take a look at what she looks like. And based on the standards of care, what would you do? In 2021, she had a 60 degree curve with greater than five degrees of change. She's wearing her rigid TLSO for nine to 10 hours and going to the gym, as you saw very frequently. This is the best case scenario when it comes to a patient being incredibly adherent to the standards of care and on treatment. So she's not presenting the same as we typically expect kids without treatment to present. So what should we do with this young lady? We know that we're on the cusp of, should we recommend surgery or not? Working very closely with the orthopedic surgeon. We know that in the standards of care, they suggest that if there's progression of greater than 10 degrees every year, that maybe with a greater than 50 degree curve, we really should look at surgery. However, we know that with fusion or rods, that there will be a decrease in function because of the decreased flexibility in her spine. So the parents are really trying to avoid that. So for the last two years, we've increased her rehab and she's stabilizing a little bit. And we're on this cusp of maybe not delaying surgery for that reason, okay? And her spine is still a little bit more flexible than it typically was, I think, if she wasn't doing all the therapy and treatments. Lastly, I'll just quickly go over hip dysfunction because this is also prevalent in patients with SMA, as you can see here, more so in the type twos than the type threes for reasons being ambulatory versus not. I wanna just talk about some of the operative care associated with the hips. There's increased documentation of hip pain that's emerging. Some of the indications for post hoc management or indications for operative hip management would be maintenance of pelvic alignment, treatment for the pain associated with arthritis, the pelvic obliquity associated with it because of the scoliosis, and to help improve balance, okay? Conservatively, the way that we manage that, we'd use sometimes hip abduction orthoses to preserve the muscle length and the joint itself, positioning in more of a straddled position, using a stander, but the stander should be in a slightly abducted position, and assisted ambulation. For a lot of these patients, we also suggest to avoid high kneeling for the weaker patients with really, really weak pelvic girdles. Post-operatively, the suggestion is to have them in a wedge for about three weeks, and this is really from Boston Children's recommendations from Snyder's group. A lot of active assisted range of motion and gradual weight bearing, starting maybe with decreased weight through the pool. And I think mainly the summary for rehab management of these patients, this is changing. I suggest really talk to the neurologist managing the patient care, and the therapist, that's who's also doing the rehab. One of the things that we should think about as a rehab community is with disease-modifying treatment, should there be intensive rehab, maybe even possibly inpatient, or some modified type of rehabilitation, and not just outpatient, because we do know with an opportunity to increase muscle strength, muscle does not get stronger by you sitting and just taking medication. The medication allows our patients the opportunity to get stronger, and so really consider that whenever you know a patient's being treated on your recommendations now compared to what it was before treatments were available. Speaking of, we'll have Claudia finish up with some of the treatments. Thank you, Tina. Let's go quickly through the SMA-approved therapies. The goals of treatment is to restore the SMN protein, and that helps prevent damage and progression of disease. The treatments that are available are all SMN-modifying treatments, meaning they're geared towards increasing SMN protein. How do we do that? Well, on the right, you can see the mRNA-based therapies. That's your friendly SMN2 gene, and as you can see, there's a very thin little line over here that's that 10% of alternative splicing, which means that instead of skipping that exon, there's an exon skipping that exon. Say that four times. The two therapies that do increase this pathway, that green arrow, are, and there's a blowout of exon 7 and intron 7, is nusinersen, which acts on intron 7, and rizdoplam, an oral medication that acts on the interface of both. Another way of restoring or recovering some degree of SMN protein is through gene transfer therapy, and that's with the AAV9, which introduces its cargo, which is the human SMN gene that is fully functional, and we'll talk a little bit about those treatments momentarily. So these are the FDA-approved SMA treatments. Nusinersen, also known as Spinraza, and you can see antisense oligonucleotides do not go through the blood-brain barrier, so they have to be introduced intrathecally, and it's indicated for SMA patients of all types, and there's a loading dose, and then you need to administer every four months for the rest of their lives. Most of the side effects are LP-related. It's relatively inert. The second one that was approved is onosemnogene apoparvovic XIOI, also known as Solgensma. I'll refer to it as gene transfer therapy, and that's only for infants, for children under two years of age. It's given intravenously one time, and it has greater side effects because of the viral load that's administered. They have to be immune-suppressed, and they can have transaminitis, troponin elevation, because the liver sees the lion's share of that, and the transfection of the heart is quite prominent. And some children have had a very immune process, thrombotic microangiopathy, kind of like a hemolytic uremic syndrome. And the newest one is Ribs de Plem, known as a RISD, which is an oral once a day liquid. And as a systemic medication, it has interactions with mate substrates, and it can affect male fertility while the medicine is on board. And it's supposed to be transient, but there's no data on that, so there's a warning in that regard. And it's contraindicated during pregnancy, obviously. That is indicated for children and adults above two months of age, but there are studies on neonates that are being done. So what does the clinical trial show? And I want to focus your attention to the bottom lines. The red one is an open-label infant study, and below that is the placebo control arm, the treatment arm of the placebo control. And you can see, and on the y, this is the HYNI, which is a motor milestone that goes up to 26. It's when they're walking. And you can see that they improve over time. And that was the ENDEAR study. The top blue one is the NURTURE study, which is a pre-symptomatic. And I'll show you a little bit more about that later. So there is progression. There is advancement of motor milestones with treatment. So what do these children look like? And these children, which were all in the various studies, now there are maybe seven or so, or eight. You can see that they're sitting. They look very different from that first child that I showed you. They should not be sitting. They have good arm use. None of them have permanent ventilation. The biggest problem is they all have dysphagia and dysarthria, but they're doing better overall. And some children even stand and walk. But for the most part, this is as best as they advance. You'll see also that there's quite a degree of kyphosis in the first and the fourth one. The third one, unfortunately, was in the placebo arm. So he still is trying to catch up. And there's a window of therapeutic benefit that he missed, unfortunately. But they're doing better. Obviously, a departure of the natural history, because none of them should have survived by this age. The CHERISH is the late-onset study that Tina was talking about that included the scoliosis issue. These children were milder. They couldn't have more than 30 degrees at entry, and they were younger than nine years of age. This is the Hammersmith, which is what is used commonly in the US, gross motor function. And they improved about four points. You know the scale. Two points is a full item that's improved, and three is thought to be clinically meaningful. And there was a decline over 15 months of one point, which is not unexpected. And over time, you can see that there continues to be improvement, not as profound as early on, but they maintain it, and they gain a bit more. You can see that the upper limb module, that continues to improve. And a lot of this is, as Tina was referring to, that the Hammersmith can't reflect strength that happens in the arms. And there's only so much that you can advance with the lower extremities as they develop the contractures, because they are sitting most of the day. So what does it look like with treatment? This was one of my youngest patients. Now she's maybe 11. She was treated back in 2012. This was the dose finding study. She was on nine milligrams. She presented at 20 months, she had lost the ability to crawl on all fours. And here she is two months into her treatment with nine milligrams of intrathecal nusinersen. And you can see she's still commando crawling. But by three months, we see her crawling on all fours. And by four months, she's walking with some support. So seeing this, you'd say, well, she must be running by now. And unfortunately, no. They do very well with the loading dose. Over time, it's the same dose for babies as it is for adults. And I think they're looking into higher dose of treatment, because clearly, when they did the study, it was looking at CSF. And that volume doesn't change, but the volume of the spinal cord does. So she is walking with a walker. But she's had hip issues and has needed surgery. But she has not needed scoliosis surgery, which most of my patients have needed. What about ambulatory patients? And there weren't very many patients. This was the open label study that we dosed the first patient in 2011. There were only about a handful, maybe 10. In this dark blue, I think, you can see that on the left panel, the Hammersmith doesn't change very much with treatment. And that's because it's the ceiling effect. These are all very high achievers, because they're walking. There's not much room. They're not going to start hopping and running upstairs. But their six-minute walk test doesn't prove. And you can see that over time, there's about 30 meters per year that they've improved as a group. And what does it look like? This was a little fellow who also showed the delay that we're talking about. Three years old, presenting at 14 months, and saw the orthopedist. And he's the one that, when he started to do this, started to fall, that they realized that he was weak. And he was referred to us. There wasn't treatment yet available, because it was just approved December 2016. And he lost, between then and when he started treatment, the ability to lift himself off the floor. So on the bottom, he's after a loading dose, four months. You can see that he is walking faster. His base is narrower. He's improved, what is it, three points on the hammersmith. And he's gained 30 meters on ambulation. So this is that early stage, where he's just starting to lose function. Prime time to intervene. And you see a very nice response. On a somnagen epipyruvic, how does it work? Well, it's AAV9, which is an adeno-associated virus, which is benign, non-pathogenic. It carries its human cargo. And it can do so because the SMN gene, as you saw, is not very big. And it is administered intravenously, and in young children, because it goes through the blood-brain barrier at that age. In older folk, they're doing research with intrathecal injections. And those studies are underway. Once it's administered, it introduces itself into the cells. It injects its DNA into the nucleus. But it does not integrate into the genome, so it's not oncogenic. And then it has a beta-trichinactin promoter that churns out a lot of SMN pre-mRNA, or mRNA, to make protein. And it transfects maybe 65% of motor neurons. And it goes everywhere, but it only stays in cells that do not replicate. Because rapidly, I think it stays in myoblast, because those, until they, but anything that replicates, they will be diluted, the effect of the SMN. So there are several studies. I'll just, in the interest of time, focus on the STRIVE-US, which is the US study that we published 2021 in Lancet Neurology. And this was the pivotal trial. And as you can see in the top green, their survival, and this is event-free, meaning alive and not needing permanent ventilation. And that was 91% at 14 and 1⁄2 months. And by 18 months, when the study ended, it was 88%. But importantly, 59% were sitting for 30 seconds. That's from the Bayley. 86-plus were fed only by mouth. And 82% were breathing without ventilatory support, though when they were younger, some of them needed that support. Now, this study treated babies very, very early. The mean age was 3 and 1⁄2 months. You couldn't have swallowing difficulties. You couldn't have breathing difficulties. So very early, before any of that developed, you can prevent it from occurring. Not sure it works very well when there's advanced disease. And this is a little girl who came to me from Poland. She has a brother who has SMA. And as you can see, he's trach-dependent, G-tube-dependent, and very, she was treated at four weeks. She's in STRIVE because she developed, she lost her reflexes and became a little hypotonic. But very early treatment. And so here she is at 18 months. And you can see, she's the loveliest little thing you can imagine. She's walking around, and she's still doing very well. I have other videos of her at the beach, and running around, squatting, getting up. And now, I think she's four or so. And she's starting to have more evidence of some issues with rapid mobility that the parents were thinking about adding Rizdiplam. But it can work very well for your early symptomatic, if you will. Now, Rizdiplam is the newest kid in the block. We already talked about. The thing it has is that it's oral, and that it distributes into the central nervous system more uniformly. Whereas with Nusinersen, you can have a gradient, more in the lumbar, about 30% reaching the bulbar region. And so oftentimes, patients on Nusinersen can develop swallowing issues or breathing issues that sometimes benefit from a switchover. And there are two studies. One is the infant study. And don't ask me why, but all of these are fish studies. So fire fish, and sunfish, and non-naive jewelfish. And this one was published in the New England Journal of Medicine, I think 21. And you can see that 12 months, 29% were sitting but five seconds, and they've continued to make progress. 93% survival, 85% event-free. 95% of those who survived were able to be maintained, maintain the ability to swallow. A note, these children were much older. I think the mean age was 6.4 months. And you could have swallowing difficulties. You could have other things. It wasn't as early asymptomatic as the STRIVE was. Now, and then the sunfish. And this is one of the newer studies to be, and it has been published. I'm sorry I don't have the reference here. It is for late-onset SMA, but it's more real-world, meaning that it's two to 25. It's the only controlled study that included adults. They were much weaker. They could have contractures. They could have scoliosis, and the majority of them did. And 28% had severe scoliosis greater than 40 degrees. This used the MFM, which is more prevalent in Europe, but it's a little more sensitive to changes in older patients. The natural history is 1.5 or 7 decline over one year, where we don't see that with the Hammersmith. And here, what you can see on the top graph is that there was a 1.55 difference in this cohort, statistically significant. And also on the revised upper limb module, there was a statistical significantly increase. Obviously more modest than what we saw in the children, but again, this is a more severe, more advanced, more chronic cohort. And I was surprised that there was any benefit at all. But that was found. Now, two words about natural history. Newborn screening, it's now in 95% are covered. And it's good for pre-symptomatic, and these are the pre-symptomatic. You can see with a Neuson-Nurson, and then this is the Heine, remember, 26 is the top, that there's a difference between two and three copies. In the green is the three copy, and they're normal, and the two copies lag. They continue to make progress, but they're not as advanced, and they're more delayed in their milestones. On the bottom is on a 7 gene, and in the gray is the Bailey gross motor, two standard deviations. And about half of the two copies are delayed, but continue to make progress, whereas those in the three copy are following a normal typic development. So the expected response differs if it's pre-symptomatic or whether it's early acute. And in the chronic stages, not having progression, having stability isn't itself a response. That's, I think we're running out of time. I just want to acknowledge all the folks on the Columbia side and the folks on the Stanford side. And I do want to show this so that if you want to obtain CME credit, this is where you can go. And I'll open the floor for questions if you have questions for me or for Tina. Any autoimmunity? Any rejection of autoimmunity? Autoimmunity. Oh, autoimmunity, not with the oligosense antinucleotide. That's very non-immunogenic. They actually tweaked it so that it would not do anything there. Of course, with onosaminogene, it's a live virus. So there is, and it's thought to be an immune response. When they first studied, they didn't use the steroids, and there was a huge elevation of transaminitis. That was in the 10,000. Dr. Mendel, I think, almost had a conniption. But with steroid before and during, it's been much better. But still, it can occur and it can, there was one child who had some severe hepatic issues, which recovered, but with some fibrosis. And then the immune issue of the microcytic, the thrombotic microangiopathy. I think there may be six or seven worldwide, and one of them died in France. And that's all thought to be immune-mediated. Those children had intercurrent infections. Some of them had fever. So it's important that the child be healthy when they receive the onosaminogene, and that they be avoided, they avoid being exposed to other children for a period of time. I treat them as if they were a newborn, very susceptible to anything, and try to keep them guarded until they're off their steroids for a period of time. Other questions? Yes. Is there any evidence on combo therapies, that the combination might complement each other better? Well, the combination therapy is all the rage. So, combination therapy is the question. Yes, I'm supposed to do that, right? Combination therapy is what all the parents want. And what is now under investigation is using myostatin inhibitor. Now, myostatin regulates muscle growth. If you ever go online and look at Wendy the Whippet, she is like Mighty Mouse, or Mighty Whippet, hypertrophic because she has no myostatin. So it increases muscle growth if you inhibit it. And those studies are underway, and there's a whole slew of studies, not just the Scholar Rock, but Roche has a study, Biohaven has another. So that's the new combination therapy. Because of some quirks with the Shine study, which is the long-term nusinersen study that I showed you, the children, they allowed the addition of Rizdiplam. So I have children who have been on both, and have had no side effects. I think the main difference has been that there's a little more in the upper body, and I think that's more a distribution issue. And then some swallowing, and the articulation, and needing less. But it seems like the system is saturated, and you're just distributing. It's like you can't get more than what you already have. But at least the SMN, elevating the SMN in that way is not toxic, and they don't seem to interact with each other. But I don't think we're going to see that kind of combination therapy any time soon. There's really no incentive for that. Yeah, and the combination therapies are really focusing on downstream, increasing muscle force, fatigue, those type of treatments as combination versus increasing SMN type of treatments for combination. And in the real world, with insurance, and approvals, and things, we do not see that. So these are unique cases because they come from clinical trials. So as physiatrists who are writing these physical therapy prescriptions sometimes to PTs like you who know all about this, and sometimes the PTs who are less familiar with the neuromuscular patients, is there anything that you think that we should be making sure we're including in our prescriptions? Like I know you mentioned the neuromuscular retraining, or any high yield things that we should be requesting? Especially if you're in a neuromuscular specific clinic, I always recommend the physicians be more specific about their prescription than a strengthening program, or a rehab program, just because they may not know. And we promote a lot of collaboration between the specialty therapists and those who are not. There's a lot of training programs now to keep people aware, but really my primary thing is think of this as rehabilitation. Because neuromuscular education, those type of things, making sure that therapists who you're referring to understand we're not maintaining, we are actually trying to improve. So they can push the system a little bit more. I find the communities conservative because they're afraid of what may happen. So it's one of those things that if you can be a little bit more proactive and detailed in your prescription, I think that'll be a little bit more helpful. And giving resources for further education for both the evaluation piece of it, to evaluate over time how the treatment's doing, so you can get that feedback. And maybe even suggest it in your notes. Like, please use the Hammersmith, blah, blah, blah. Here are the links that are available if your therapists do not know how to perform these measures. Just a little more education. So another of my questions is, how intensely you guys can provide the therapy? Because you say intense therapy. Any guideline for the intensity of the therapy? So, unfortunately, there's no guideline. I mean, I advocate, honestly, I'm a little bit more aggressive, I think, in rehab. But in the standards of care, they say moderate intensity. What does that mean? You can exercise and talk and, you know. Yeah, and so that's the big thing. With fatigue, if they work out and they're not able to do their activities of daily living that day, that's just too much. Or they have increased muscle soreness, that doesn't go away. Keep in mind that with SMA, yeah, that's the unfortunate thing. There's not any real guidelines. And so I always recommend an exercise calendar so there are individualized guidelines looking at either rate of perceived exertion or heart rate and then monitor what kind of strengthening and what kind of cardio that they're doing so it's individualized. Because we don't have general guidelines, unfortunately. I really hope that with treatment that we, as rehab professionals, have more intensive therapies. I know that Sally, Dr. Sally Evans at Children's National, she actually, they recommended inpatient, right? For a little bit. And I really think that is something, a model that we should consider. Because, like I said, this is, you know, when you have surgery, surgery is not the end all, be all. It's the rehab after that may improve someone's function. And so that's something that we need to kind of change the mindset in how we're approaching some of these treatments. In the era of disease modifying, but combination treatment is not just medication, right?

Combination therapy

spinal muscular atrophy

SMA

Nusinersen

Onasemnogene Abeparvovec-xioi

Risdiplam

motor milestones

survival rates

SMN protein levels

myostatin inhibitors