Hi everyone, welcome to this month's AAPMNR lecture. So today we are joined by Dr. Brea. Dr. Brea is a current pediatric rehabilitation fellow at the Gillette Children's Hospital. She obtained her medical degree at the Rutgers New Jersey Medical School and then did her training in physical medicine rehabilitation at the University of Miami Jackson Memorial Hospital. She is going to be talking today about AFM and transverse myelitis in pediatric rehab. So I'll let her take over. All right, good afternoon, everybody. Like they said, I'm gonna be presenting on acute flaccid myelitis, AFM versus transverse myelitis or TM in pediatric rehab. Please feel free to type into the chat or ask questions as we go along. I'm okay with this being kind of interactive. Overall, no disclosures. And then our objectives for today are gonna be to characterize acute flaccid myelitis and AFM and transverse myelitis TM as two distinct entities. We'll talk about kind of the evaluation, diagnosis and treatment of these two diagnoses. Talk a little bit about rehabilitation in the pediatric population. And then we'll also go into a particular study that I think is pretty helpful regarding some measures or diagnostic tools to help identify and distinguish the two. So getting started, acute flaccid myelitis is characterized by a flaccid paralysis that's secondary to inflammation of the spinal cord gray matter, namely the anterior horn cells. And it spans over one or more spinal segments. Most AFM cases, more than 80 to 90% in various studies have been seen in young children. The condition is often preceded by a viral prodrome which can be anywhere from one to four weeks before developing the development of symptoms, the neurologic symptoms. The strongest kind of association or correlation is with enterovirus D68 or EVD68 and enterovirus A71. So there's other reported potential sporadic causes of AFM and these have implicated Flaviviruses such as West Nile and Japanese encephalitis viruses, as well as herpes viruses or adenoviruses. Although it's not entirely sure if these are true manifestations of AFM. The mechanism by which infection with enterovirus leads to AFM is not totally clear. Typically you see kind of a respiratory disease. However, there's other enteroviruses such as polio that implicate the nervous system and spread to the gray matter of the spinal cord. So it's felt that kind of there's a similar mechanism between these enteroviruses and other known ones. So incidence and prevalence. The CDC very closely tracks AFM starting since 2014 when there was a significant spike in cases. That year there was about 120 cases that were documented. So since then two more major increases were noted in 2016 with 153 cases and 2018 with 238 cases. This year, the CDC reported 11 confirmed cases out of 33 which are represented kind of on this map. The darker light blue states are the locations in which these confirmed cases have presented. 33 potential patients were reported under investigation and only 11 were confirmed. If we wanna compare to kind of the other years beyond 2018, 2020 had 33 cases, 2021 had 28 cases and 2022 had 47. There was a concern with the COVID pandemic whether or not there would be kind of an uptick in cases since it seems that AFM has a somewhat cyclical pattern based on the method of infection with enterovirus. It doesn't seem to be the case just yet when you compare it to kind of previous years that the pandemic has had any effect but it's still something that's being tracked pretty closely to make sure that we don't miss that uptick. In total, there've been 737 cases since the CDC started tracking. So the clinical presentation, typically there's a prodromal illness that precedes the neurologic presentation with that enterovirus D68, it's usually a fever and kind of respiratory symptoms. A study by Helfrich et al demonstrated that AFM, it was a comparison between AFM and transverse myelitis patients. 100% of the AFM patients demonstrated a prodromal illness while only 39% of the transverse myelitis patients had a prodromal illness. So it's very clear that there is an infectious cause preceding the neurologic findings. The onset of neurologic symptoms typically occurs one to 10 days after that infectious prodrome, though, as I mentioned before, you can see the neurologic findings develop even up to four weeks after that infection. Typically what you see is a flaccid asymmetric paralysis with predilection to the upper extremities. And when we start to go over transverse myelitis, this will be kind of a point of comparison or contrast, I would say in the two diagnoses. This can often be associated with pain, but it's not necessarily like a heralding feature. And that same study by Helfrich et al did demonstrate that the weakness in the arms was noted in 90% of those AFM patients while only being noted in 33% of transverse myelitis patients. So kind of confirming what's typically understood as the clinical presentation. The weakness can also include vulvar, facial, trunk, and respiratory muscles, which can then have significant sequelae when it comes to respiratory function, swallow, and nutrition. About one third of patients require intubation and ventilation. And you kind of tend to see this presentation in more proximal muscles than distal muscles. On exam, you'll find hyporeflexia. And typically you have no association with sensory deficits or altered mental status from the condition itself. Some of the secondary sequelae can lead to altered mental status, but AFM as a diagnosis is not necessarily associated with that finding. So your differential diagnosis can be very broad. This is by no means a comprehensive list, but some of the diagnoses that we see regularly that would need to be considered would be transverse myelitis, hence why we're kind of comparing the two in this presentation. Guillain-Barre or other demyelinating myelitises, NMO, multiple sclerosis. You can have MOG, antibody-associated myelitis that presents similarly, poliomyelitis, affecting those anterior horn cells, flexitis, botulism, spinal cord strokes, or other kind of spinal cord conditions, compressive masses or abscesses, nutritional deficiencies, and several autoimmune conditions can kind of have similar presentations. So when it comes to diagnosis, it typically has to kind of be a broad diagnostic workup to make sure that we're ruling out kind of other conditions as well. So MRI of the spinal cord is one of the most useful diagnostic tests in AFM because you will see this T2 hyperintensity of the spinal cord gray matter that spans several spinal segments. On lumbar puncture, you can see CSF pleocytosis, so it's pretty nonspecific. You can have a mild to moderate elevation in white blood cells, a mild to moderate elevation in protein, and these findings are typically noted in that acute phase of infection. So, you know, may not be as useful later on in the disease course, but it can sometimes differentiate from other causes of facet paralysis or less likely to demonstrate this pleocytosis. One of the best diagnostic correlations would be direct isolation of the enterovirus, either D68 or A71. So nasopharyngeal or respiratory swabs showing the presence of EVD68 or rectal and stool samples showing EVA71 can really help kind of confirm the diagnosis. Other lab tests that can be helpful in ruling out AFM or kind of parsing through a differential diagnosis can include AQP4 IgG running positive in the serum. This can rule out, this is associated with neuromyelitis optica spectrum disorder, so can kind of push your diagnosis away from AFM. Same as MOG IgG in the serum can rule in MOG antibody-associated myelitis. Antiganglioside antibodies in the serum can support diagnosis of GBS. So several findings in the serum that can kind of help work through your differential diagnosis. EMG and nerve conduction study is not necessarily required for diagnosis, especially in those early phases of infection. You're not gonna see many findings on your nerve conduction study or your EMG. Typically anywhere from like a week to two weeks after that initial presentation is when you might start to see some findings. The most characteristic findings present start to kind of develop around that one week to 10-day mark. You can have diminished or absent CMAFs. And a key point is that you should have normal sensory studies. AFM is mostly purely motor condition. So abnormal sensory studies may push you away from AFM as a diagnosis. On EMG, you can have reduced or absent recruitment of motor potentials. And later on in the course, you can start to see fibrillations or positive sharp waves, especially as you start to see kind of a reiteration patterns. These findings can be very similar to GBS. However, some of the key things that you can use to differentiate between the two would be in GBS, you'd see a more symmetrical finding and these findings would also be length dependent in comparison to your AFM findings where you would typically see a very asymmetrical pattern of involvement as well as a more proximal to distal presentation when it comes to the findings on EMG. EMG nerve conduction study findings overall are just representing an axonal motor neuropathy. So here is a representative image of kind of what an MRI would look like when identifying AFM. I have a pointer, but looking at the image A right in the middle of the spinal cord, you see this ill-defined kind of T2 hyperintensity in the central cord that's involving the gray matter. And if you look at image B, there's kind of the axial representation of the same thing. Image D and E show just a smaller area of hyperintensity that's only localized to that anterior horn cells, which you can see on the axial image as well. So even more specific kind of involvement of the gray matter. So in terms of acute treatment, studies indicate that about 96% of identified AFM patients require hospitalization. So pretty devastating diagnosis and 58% require ICU level of care mostly for cardiorespiratory support. Treatment overall is mainly supportive, specifically that cardiorespiratory support, which can include ventilatory support is important. Preventing other complications of immobility are paramount in DVT or VTE in general and development of wounds. And early rehabilitation is a hallmark of management even in the acute phase to really maximize outcomes. IVIG and or plasmapheresis are often used in that acute management of the disease. There seems to be a potential immunomodulatory effect, hence why these treatments are tried. There are some mouse models that show that early IVIG reduced incidence of paralysis where steroid treatment alone resulted in an increased viral titer in the spinal cord. And another study demonstrated that there was no evidence that initial treatment with IVIG resulted in greater improvement as compared to initial treatment with steroids in actual human patients. So the question still remains whether or not IVIG and plasmapheresis are necessary or true treatment processes, but it's definitely kind of the first line that is used. And as kind of mentioned before, the use of high dose steroids remains kind of uncertain. They can be helpful in cases with significant spinal cord edema, but like I mentioned in that mouse model, having a steroid treatment in an acutely infectious process did result in increased viral titer in the spinal cord. And it's unclear whether that increased titer would correlate with worse outcomes, but definitely something to consider when treating with steroids. There is some information out there regarding antivirals or other medications in different classes that have an antienteroviral and neuroprotective effect, medications like fluoxetine, and these have shown mixed results. And recently there's been a lot of, or more research describing nerve transfers that can be considered in patients with poor recovery of a particular muscle group. Usually we consider this intervention in patients that have three months or more of kind of residual weakness. There was one recent study by Rivera et al that evaluated 23 nerve transfers on 19 upper and four lower in AFM patients. And it demonstrated that muscles receiving the nerve transfers did do significantly better than those that did not. But the best outcomes were noted in restoration of elbow function and in the upper extremity nerve transfers as compared to the lowers. So in terms of prognosis and outcome, which is why we think it's important to really differentiate these two diagnoses, MRI and EMGs and nerve conduction studies can provide helpful prognostic information. There are some quantitative measures of gray matter MRI involvement that can maybe predict some motor outcomes and the location of the lesion could correlate closely with that distribution of weakness, but because it's so patchy and asymmetric, it's hard to really parse out where those MRI findings are related to. Denervated muscles on EMG and nerve conduction study with severe neurogenic changes in the weeks to months after acute illness are often likely to experience residual weakness or have worse outcomes from a strength perspective. Recovery in these patients is highly variable, but less than 10% of patients recover completely. Most of the recovery happens in the first few months after onset and cranial nerve dysfunction is more likely to improve than the limb weakness. Limb weakness then kind of recovers in a distal to proximal pattern, which kind of makes sense as the proximal muscles seem to be more affected than distal muscles. So recovery kind of works back from least affected to most effective. Some studies do suggest that if the causative factor is EVA71, then you can have a milder presentation with less weakness and better recovery than those that are associated with EVD68. So moving on to transverse myelitis. Transverse myelitis is defined as an acute immune-mediated inflammation of gray and white matter in one or more adjacent spinal cord segments. Usually these are found to be at the thoracic level. They're just more common there. Symptoms typically include motor and sensory and autonomic deficits. So here we start to see kind of the differences between AFM and TM, where we're getting more sensory involvement and autonomic involvement in transverse myelitis. Lesions are typically demyelinating in nature. And again, the mechanism is kind of unknown. Some cases do follow viral infection or even vaccination, but there's really no slam dunk association with some sort of prodromal event. Very little is known about the actual pathogenesis of the condition as well. There are some theories that are based on the idea of molecular mimicry of other infectious conditions that then cause an immune response against self-tissue and some humoral-based dysregulation that can lead to an inflammatory sequelae. But there's really not a lot of information out there as to what the true pathogenesis is. There are some pathologic studies that show intraparenchymal and perivascular cellular infiltrates that are associated with this demyelination and neuronal injury. So some pathologic histologic information there. Transverse myelitis can be associated with multiple sclerosis, different vasculitides, lupus, mycoplasmal infections, Lyme disease, syphilis, TB, COVID-19, and or viral meningeal encephalitis. So several associations that can lead to transverse myelitis. So the incidence and prevalence is a little bit different. There's approximately 1,400 new cases per year diagnosed in the United States, so several more than AFM. About 20% of these cases occur in children. And the pediatric cases are reported to occur in this bimodal distribution affecting infants from 0 to 2 or children from 5 to 17. Yeah, I don't know for sure if this bimodal distribution is totally accurate, because there's really not that much time between 2 to 5 years and the 5 to 17 range is pretty wide. But that's kind of how it's presented in terms of incidence. So your clinical presentation, it can also be preceded by a viral prodrome or typically preceded by something that kind of mimics a viral infection. Pain does seem to be a common initial symptom in children and can be kind of a heralding symptom before the other neurologic effects. This is then followed by motor and sensory deficits, atoxic gait, and bowel and bladder dysfunction. Now, in these patients, in comparison to AFM, lower extremity weakness is more common. So there's a predilection for lower extremity weakness as opposed to upper extremity weakness. And then the key differentiation factor is that sensory deficits are often present, and they can actually present kind of in a band-like distribution or almost as a sensory level and commonly at the thoracic level. In terms of some sequelae, weak muscles in this condition tend to develop spasticity in the long run, so something that definitely needs to be kept in mind when it comes to long-term follow-up and management. And then one of the other key findings is autonomic dysfunction that can be present in transverse myelitis. So lesions can occur at any spinal level, and then symptoms naturally correspond to kind of those affected levels. Cervical lesions account for about 20% of cases, and if they're high enough to involve the phrenic nerve, can lead to significant diaphragmatic dysfunction and respiratory failure. Thoracic lesions account for 70% of the cases. So as we've mentioned multiple times, the condition is more likely to occur at the thoracic level. Lumbosacral lesions account for about 10% of cases, and these can present then with kind of a combination of upper motor neuron and lower motor neuron findings, depending on the level of injury as you kind of approach the cauda equina and conus. And a sensory level, again, is very likely to be identified. So your differential diagnosis is very similar to that of AFM. In addition to kind of those that we mentioned previously, one should also consider compressive diagnoses, so compressive myelopathies, secondary to masses or abscesses or even compression fractures, and degenerative disc disease. And there is a high association with autoimmune conditions, so looking at infectious or autoimmune conditions during the diagnostic evaluation is highly recommended. So again, I won't belabor the point too much, but investigation is very similar to that of AFM. Here we have an image, again, of an MRI demonstrating that T2 hyperintensity. This is kind of more in the cervical extending to thoracic level. This involves the gray matter and the neighboring white matter, so you see a lot more involvement. And these are typically longitudinally extensive, so spanning more than three vertebral segments. CSF findings are very similar to that of AFM, mild to moderate white blood cell count, mild to moderate protein elevation. You can also analyze CSF for other things that may help rule out other conditions, such as oligoclonal bands. IgG and cytology can all be helpful in ruling out other diagnoses. Again, the serum studies, APQ for IgG antibodies, MOG antibodies, looking at vitamin deficiencies, specifically B12, and then also looking at ANA, RF for some of those autoimmune conditions, as well as your TSH. All of these things can be helpful in kind of parsing out what the differential diagnosis is. Some other evaluations that might be important would be neuro-ophthalmologic evaluation, perineoplastic evaluation, and even spinal angiograms in appropriate cases, as spinal cord stroke can present similarly. So treatment is directed at the cause or associated disorder, but is otherwise supportive. There's really no FDA-approved treatments. However, first-line therapy is high-dose steroids in this case. There was a benefit that was noted in a retrospective study that suggested better short-term and long-term outcomes in patients that were treated with steroids versus those that did not. So highly recommended kind of as a first-line treatment. Additionally, plasma exchange or IVIG may be useful, and it is recommended to trial empiric management because there is that potential benefit of treating something that may be more serious if it's hard to identify whether the condition you're treating is transverse myelitis. And these benefits outweigh kind of the cost and these benefits outweigh kind of the theoretical concerns or risks. There is some emerging consideration for immunomodulatory therapy as treatment. Cyclophosphamide, mycophenolate, or rituximab may be a benefit in kind of recurrent or resistant transverse myelitis, although there's really not a lot of information about that in the literature. And there is little but increasing evidence that a selected dorsal rhizotomy may be beneficial in the treatment of spasticity secondary to transverse myelitis in the longer-term course after the condition onset. So prognosis and outcomes. Generally, the prognosis of transverse myelitis is better than that of AFM, so it's important to have a confident diagnosis to be able to provide good prognostic information. Generally, the more rapid the progression of the condition, the worse your prognosis will be. And they typically talk about recovery in thirds. So about one third of patients pretty much fully recover. One third of patients retain some degree of weakness or urinary urgency or incontinence. And one third are significantly affected with significant weakness, persistent incontinence, and more requirements from a self-care assistance standpoint. The most common sequelae that remain are sensory disturbances and bladder dysfunction. About one fourth of patients end up being non-ambulatory or requiring some degree of walking aids. And in terms of predictors of disability, age younger than three, longer time from onset of the condition to treatment, higher spinal level, and longer segmental involvement on imaging are all predictors of longer-term disability. So in terms of rehabilitation and therapy, research regarding specific therapies in AFM and TM is pretty limited, but we can draw kind of from other methods used in other monophasic neurologic injuries, such as spinal cord injury or stroke and other neuropathies like polio and GBS to kind of guide therapeutic practices. The acute phase should focus kind of on activity-based therapy and mass movements, then moving on to kind of task-specific movements. There is some evidence that eSIM can be helpful in promoting muscle activation patterns in the plegic or paralyzed limbs. And over the medium to long-term course, it really is recommended that episodic therapy is pursued versus kind of continual nonstop participation to be able to focus on specific goals and developmentally appropriate milestones. So switching gears a little bit here, I wanted to talk about one particular study that was recently published that compares two diagnostic criteria for acute flaccid myelitis and transverse myelitis and tries to apply them to evaluate their effectiveness. So the name of the study is called Comparison of Acute Flaccid Myelitis and Transverse Myelitis in Children and Evaluation of Diagnostic Criteria. So we'll run through the study very quickly. I really just want to focus kind of on the criteria itself, but it was a retrospective cohort study with 21 pediatric AFM cases and 36 pediatric transverse myelitis cases. Inclusion criteria for both groups was patients less than 18 years old. In the AFM group, they had to have confirmed AFM associated with EVD68 between the years of 2015 and 2016. And the transverse myelitis group was selected from patients diagnosed with acquired demyelinating syndromes. So a diagnosis of AFM was based on the presence of acute onset limb weakness, MRI abnormalities, plus or minus CSF pleocytosis, and then that detection of EVD68 by PCR. Cases that were removed included any cases in the TM cases or any cases in which the diagnosis of AFM was even considered. So removed those from the list. And they also removed transverse myelitis that was associated with ADEM, optic neuritis, or multiple sclerosis to kind of really get a good representative type of case. So then there's two criteria that were applied. There's the TMCWG criteria, which is for transverse myelitis. And this criteria was then applied to both cohorts to see how effective it is in kind of parsing out the diagnoses. And we'll see in a chart a little bit better, but they applied the whole set of criteria to both cohorts. Then they applied the set of criteria with removing the sensory level criterion. Then they applied the set of criteria removing the proven inflammation criterion to see how removing any of those subcategories affected the criteria as a whole. Then they used the AFM criteria that's in the literature to both cohort and applied this to both cohorts. And then in this one, they did remove the criterion of decreased muscle tone in at least one of the weak limbs because it wasn't recorded in both cohorts. MRI images were reassessed, they were available, but they weren't necessarily part of the decision-making. So here are the two criteria that were evaluated, the criterion for idiopathic acute TM on the left side of the screen, and then the right side of the screen is that for AFM. So these were applied to both groups. Just to get an idea of what the patients look like in terms of demographics, the median age of onset for AFM was about three years with an interquartile range of two to five. And the transverse myelitis group, a median age of onset was around 10 years with an interquartile range of five and a half to 15 and a half. In terms of presentation timing for the conditions, AFM presented between July and October in 16 out of 21 cases, about 76%. And transverse myelitis presented kind of in an evenly distributed manner. So it wasn't statistically significant. So then here are kind of the two charts with the evaluation of the criterion. So if you look at chart A, which is the TMCWG criteria, the transverse myelitis criteria, they applied these to both cohorts. And if you look for the blue bar, the AFM patients, none of the AFM patients fulfilled the complete set of criterion. Mainly because of that sensory level that was not present in the AFM patients. So it was pretty effective in separating out the AFM diagnosis. If you look at the orange column, that's when they remove that sensory level criterion from the whole set of diagnoses. And in that case, 73% of the AFM patients fulfilled the diagnostic criteria for transverse myelitis. So just that one criteria alone was enough to kind of change the effectiveness of that checklist. And then if they removed the inflammation of the spinal cord from an imaging perspective, if they removed that criteria, 83% of the AFM patients met the diagnosis for transverse myelitis. So then of the 30 children with transverse myelitis, sufficient input information, I should say, about seven fulfilled all the criteria. So this blue bar representing 23% fulfilled all the criteria demonstrated. If you omit the sensory level, then all the patients, or 61% of the patients meet the criteria. And without anything, all the patients meet the, without the sensory level or proven inflammation, all the patients meet the criteria. So at least to rule out AFM, this criterion is a pretty strong set of rules or things to evaluate. Now, looking at the AFM diagnostic tool, again, when it was applied to the full AFM cohort, about 58% of the patients fulfilled the criteria for definite AFM, and that represented seven of the patients. And 33% met the criteria for probable AFM, which represents about four out of the patients that were evaluated. When you look at the TM cohort and applying this AFM criteria to them, only one transverse myelitis patient fulfilled the criteria for definite, three of the patients for probable, and only nine, and up to nine for possible. So definitely favors the diagnosis of AFM if you're sure about all the criteria versus transverse myelitis, but still not a foolproof diagnostic tool. So then this is just one last kind of graphic I wanted to leave you all with from that same study. This Venn diagram demonstrates pretty succinctly the differing characteristics between AFM and transverse myelitis and the overlapping characteristics of the two. And so I feel like this is a good framework, one, when evaluating patients yourself, or just when trying to think of the two diagnoses in general, that I think is a pretty handy Venn diagram. So I think that'll be it for me. Any thoughts, questions? I think Julia has a question in the chat if the incidence is for kids and adults. Yeah, that means with acute flaccid myelitis. Yeah, so in acute flaccid myelitis. So I guess the number is not differentiating between the two. I'm trying to get to this map. Here we go. The total number is not differentiating between the two. This is just AFM tracking in general, but overall there's like an 80 to 90% predilection, or it presents in most of the cases, like 80 to 90% of the cases are pediatric cases and not adults. So I guess if we did the math, 737, 80 to 90% of that. Thank you. No problem. Great, I'm just looking for any other questions in the chat. Do you know if the CDC is expecting a bump next year for AFM again? That's a concern. I know that they're looking at the website. You know, they're on high alert, I guess, because there is this worry that after the pandemic and, you know, now with a period of masking and then not masking and the way that we've seen so many infections kind of running through the community, I think there is a big concern for it. But it seems like these first couple of years outside of the pandemic, we haven't. Seen, yeah, it's interesting. I thought 2022 would be a bad year for it, right? I don't know. Yeah. All right. Well, I don't see any other questions. Thank you so much. This was a great talk. And for everyone online, this will be available for CME once it's uploaded to the online education portal, you just have to fill out the survey and then you'll get your CME credits. So that'll probably be in a few days. All right. Thank you, everyone. Thank you, Dr. Brea. I thank you.

acute flaccid myelitis

transverse myelitis

pediatric rehabilitation

spinal cord inflammation

enteroviruses

diagnosis

treatment

prognosis