Acute Flaccid Myelitis: Answering Questions Through National Collaboration

>> Hello, and welcome to CDC’s Public Health Grand Rounds Thanks for joining us As you know, we have transitioned from live, in-person sessions to virtual ones To minimize any technical issues, we have recorded our speakers in advance, but they are all here with us today and will be participating in our question and answer session at the end of the presentations Be sure to email your questions to grandrounds@cdc.gov Dr. John Iskander is our host for today’s session Dr. Iskander? >> Welcome to our July 2020 Virtual Public Health Grand Rounds on acute flaccid myelitis I’m Dr. John Iskander with CDC’s Office of Science Thank you for joining us Public Health Grand Rounds has free continuing education available for physicians, nurses, pharmacists, veterinarians, health educators, and others The course code if PHGR10 That’s Papa Hotel Golf Romeo followed by the number ten Please see our website for the CDC continuing education website for more details Here’s our continuing education disclosure statement for this session Grand rounds is available on the web and all your favorite social media sites Please send questions to grandrounds@cdc.gov, and we’ll try to include your question during our Q and A part of today’s session Want to know more? We have a featured podcast on our website called Beyond the Data which is posted after the session This month, I’m speaking with Dr. Janell Routh from CDC We’ve also partnered with the CDC Public Health Library to feature scientific articles about this session The full listing is available at cdc.gov/scienceclips We thank our speakers and all those acknowledged here for their work on this important session Here’s a preview of next month’s grand rounds topic Please join us on the web at your convenience For more information about acute flaccid myelitis, please look for next month’s CDC Vital Signs, and yes, we did plan it that way It’s now my pleasure to introduce CDC’s Principal Deputy Director, Dr. Anne Schuchat >> Hello and thank you for tuning in today Acute flaccid myelitis is a very important topic For parents everywhere, for families already affected by this devastating condition, for clinicians, for CDC, and for me Every parent worries about this kind of thing, and today’s session offers some insight into what to do In November 2018, I first met with Rachel Scott along with other parents whose children were struck by AFM I had learned about AFM in the scientific literature and knew the CDC statistics, but I could not have understood its awful impact until I heard firsthand from the terrible challenges AFM families have faced and the courage they have shown moving forward Meeting Rachel and the other parents reaffirmed for me the priorities CDC puts on finding answers and working toward prevention and care The hallmark sign of AFM is sudden limb weakness in a child who is perfectly healthy This can signal a medical emergency as the child may quickly progress to respiratory distress Timing is critical for AFM Delays in AFM recognition and care can put patients at risk As you will hear today, AFM is a CDC priority We want to do everything possible to learn more about recognizing, treating, and preventing AFM and helping families to heal There is a great deal we don’t yet know We don’t know yet if the months ahead will continue the every two years pattern of AFM epidemics We don’t know if the COVID-19 epidemic will complicate detection and management, nor do we know whether social distancing efforts will reduce the risk of occurrence But, we do know we need to be ready, and today’s meeting will prepare us for action Today’s grand rounds targets both parents and clinicians at the front lines of pediatric care We want to be sure that no AFM warning sign goes unheeded and to make sure that every child with AFM has the best possible chance to survive and thrive >> Our first speaker is Dr. Janell Routh >> Good afternoon

This presentation is designed to give providers an understanding of AFM epidemiology, a parent’s perspective of AFM, the clinical presentation and management, and what is being done to better understand this illness in the United States Acute flaccid myelitis or AFM started making national headlines in 2014 following reports of healthy children presenting with acute onset of limb weakness CDC has conducted national surveillance for this serious neurological condition since its emergence AFM presents with sudden onset of weakness in one or more limbs with progression of weakness in hours to a few days Cases continue to occur mostly in children Cranial nerve involvement is seen in about 25% of cases with difficulty speaking or swallowing and facial droop or ptosis Lesions are primarily located in the gray matter of the spinal cord shown here by the blue box Notably in an anterior horn cell distribution and manifests most commonly in the cervical or upper spine My colleague Dr. Messacar will describe the clinical presentation in more detail The source of CDC surveillance data for AFM is via health departments from the reporting clinician Once a clinician recognizes that a patient may have AFM, they alert the health department who assists in the collection of pertinent medical information, magnetic resonance images, and specimens such as cerebrospinal fluid and a nasopharyngeal swab These are sent to CDC who works with an expert panel of neurologists to review the information and images and provide a case classification The surveillance case classification is communicated back to the health department and then to the clinician and family Completion of this process may take time, and it’s not meant to contribute to a patient’s diagnosis or treatment plan It’s primarily used as a standardized method to measure AFM trends from one year to the next Here are the current AFM surveillance case definitions for 2020 A confirmed case is the acute onset of flaccid limb weakness and a spinal cord lesion that is predominantly gray matter over one or more spinal segments A probable case is the acute onset of flaccid weakness and a spinal cord lesion where gray matter involvement is present, but predominance cannot be determined A large national outbreak of severe respiratory disease in children associated with enterovirus D68 or EVD68 also occurred in 2014 In this slide, EVD68 positive respiratory cases are represented by the yellow line and the right axis Cases of AFM are shown by the blue bars on the left axis AFM cases peaked in September, just slightly after the peak in EVD68, giving us the first piece of evidence of a temporal association There has been a national increase in AFM cases every two years since CDC began conducting surveillance in 2014 with over 600 cases classified as confirmed You can see there’s a clear periodicity of every two years with peaks in 2014, ’16, and ’18 with the largest number of cases having onset of limb weakness in September during those peak years The largest outbreak so far was in 2018 with 238 confirmed cases AFM has multiple causes, including infections like enteroviruses and flaviviruses and other conditions such as neuroinflammatory conditions or spinal vascular disease that share similar clinical and radiographic findings Almost six complete years of national AFM surveillance suggests a low level baseline rate of AFM highlighted here in the red box which is consistent from year to year and likely caused by a mixture of infections and the other conditions I just mentioned The question remains as to what is causing these new every other year peaks in AFM Although national case reporting for AFM did not begin until 2014, retrospective searches for AFM cases have documented low numbers including one at five pediatric academic centers that conducted retrospective MRI reviews from 2005 through 2014 Results showed that the number of AFM cases in 2014 was about three to fivefold higher compared to each of the other years These data suggest that the epidemiology of AFM shifted during or slightly before 2014, likely reflecting a changing or emerging etiology Because 2018 was the most recent peak for AFM, these data presented are taken from an analysis of the 238 cases that CDC confirmed Cases come from 42 states and jurisdictions without any apparent geographic clustering The median age is 5.3 years, and 94% of cases are pediatric

Fifty-eight percent are male, and of those with complete data, 53% identify as white, 20% as white or black Hispanic, 9% as black, and 3% as Asian Ninety-eight percent of cases are hospitalized, and 54% are placed into the ICU either for monitoring or for respiratory support as paralysis can progress rapidly Eighty-seven percent of cases have an increased number of cells in their cerebrospinal fluid or CSF with a median white blood cell count of 94 and a lymphocyte predominance Number of limbs affected is variable with over 1/3 presenting with one affected limb, and about 1/4 presenting with all four limbs affected There is a predilection for the upper extremities Forty percent of cases have only upper extremity involvement, and 16% have only the lower limbs affected Most children present with symptoms consistent with a viral illness about one week before limb weakness onset The proportion of cases with each symptom is shown by the blue horizontal bars on the left Ninety-seven percent of AFM cases have some combination of symptoms that are consistent with a viral illness What’s interesting to note is the timing of these symptoms The number of days from the start of each symptom to limb weakness onset is shown by the light blue bars on the right of the slide with the median number of days in the dark blue circles AFM patients generally start with an upper respiratory illness and then develop fever just shortly before weakness onset One of the working hypotheses about pathogenesis is that viral replication occurs in the upper respiratory tract, causing these initial symptoms, and then the virus gets transported to the spine where it directly invades the cervical cord, causing fever in that typical neck or back pain that we see in many patients Weakness develops shortly afterwards Diagnostic testing for cause of AFM has remained low yield, especially in sterile site specimens This slide illustrates the CDC testing results for 2018 Each horizontal bar highlights a different specimen type, and the colors indicate the types of enteroviruses detected, EVD68 in yellow, EVA71 in blue, and other entero or rhinoviruses are shown in purple Negative specimens are indicated in grey For 2018, only two CSF specimens sent to CDC were positive, one for EVD68 and the other for EVA71 Stool pathogens were the usual mix of enteroviruses and parechoviruses Respiratory specimens gave the highest yield, and EVD68 was the most common virus isolated with 30% of specimens testing positive But, overall, you can see that less than half of the specimens we received returned a positive result Because so few specimens are positive, it’s hard to be conclusive about what is causing AFM in these peak years If there is one major cause for AFM in these peak year, however, we thought that cases in peak years should look different than cases in nonpeak years where we think there are multiple causes So, we compare cases in 2016 and 2018, the two peak years we have complete data for, with 2015 and 2017, our nonpeak years And, peak year cases do appear different They’re significantly more likely to have pleocytosis, a greater proportion of upper limbs only affected, preceding respiratory symptoms prior to weakness onset, and entero or rhinovirus isolated from any specimen Of note, only cases in peak years tested positive for EVD68 In contrast, cases in nonpeak years were significantly more likely to be older, to have lower limb weakness, and to be more severe than cases in peak years We define the case as severe if they had weakness in all four extremities, required mechanical ventilation, and had symptomatic cranial nerve involvement These data suggest that something different is occurring in peak years that may be driving these clinical distinctions The higher proportion of EVD68 detection in peak years is striking, and it does add evidence for the association with AFM in those years However, when comparing the two peak years, 2016 versus 2018, there are still significant differences Cases in 2016 were more severe, had more cranial nerve involvement, and had a higher proportion of specimens testing positive for EVD68 Cases in 2018 were more likely to report fever and respiratory or gastrointestinal symptoms before weakness onset There were more cases with specimens positive for EVA71 in 2018 due to an isolated outbreak in Colorado This variable did not reach significance, but I included it here to highlight differences between enterovirus types from year to year So, in summary, the epidemiology and laboratory data presented here suggests

that etiologic drivers in peak years appear different from those in nonpeak years But that even during peak years, significant differences may suggest multiple causes These data point to enteroviruses and EVD68 in particular as the primary cause of AFM in the United States since 2014 and the drivers of these seasonal biannual peaks But, the outbreak of EVA71 in 2018 reminds us that many enteroviruses do have the capability to cause AFM, and it’s important to continue to conduct broad clinical and enterovirus surveillance to understand this full spectrum Whether it be a single or multiple etiologies causing these AFM peaks, the underlying mechanism of disease remains the critical unknown If EVD68 is the primary cause is peak years, why does this ubiquitous virus cause paralysis only in a few cases, and do these differences in clinical characteristics in peak years give us a clue about that disease mechanism? Understanding the pathogenesis for AFM will be vital to the development of treatment and prevention strategies moving forward The question remains as to what we should expect for AFM this year given the social distancing and improved hand hygiene practices as a result of the COVID-19 pandemic These practices may result in decreased circulation of other viruses including enteroviruses and therefore either decrease or delay AFM this year We continue to track AFM activity each day, and so far we’re not seeing an increase in any cases However, we do remain vigilant for an increase, and we are prepared to respond Our summer has been busy with activities to increase awareness across the spectrum of providers who may come into contact with AFM patients, from front line clinicians and emergency departments and urgent cares to subspecialists like neurology and infectious disease doctors Together, we continue to learn about this devastating illness and are working to provide answers to patients and their families And, speaking of families, I will now turn this over to an incredible mother, colleague, and AFM advocate to provide a personal perspective about AFM and to highlight her work with other parents to raise awareness about this condition Thank you >> Hello. I’m so honored to have the opportunity to speak today, and I’m extremely grateful to CDC and the clinicians that are prioritizing acute flaccid myelitis right now I’m here to share a parent’s perspective of acute flaccid myelitis My name is Rachel Scott I’m the mom of five kids I live outside Houston, Texas, and I am a parent of a child with AFM My son was diagnosed with AFM four years ago in July of 2016 Like so many parents who are suddenly faced with a rare, life changing diagnosis, we learned a lot very quickly, and I’m here to share a bit of that with you today Braden was five in July of 2016 He had just finished preschool and was learning to read before kindergarten He never stopped moving He was always bouncing around and moving a million miles an hour and proudly showing us how he could hop on one foot His story is very similar to the stories of hundreds of other kids with AFM He got a summer cold, just like all my kids, and Braden didn’t recover On the fourth of July, Braden didn’t want to swim when we went to a friend’s house, so we let him stay home and rest Later that evening at a barbecue, he threw up when he tried to eat a chip I put him in our friend’s guest room and let him sleep while we celebrated We had to carry him to see the fireworks, and he laid on our chest in the grass Over the next few days, he still couldn’t swallow anything and kept getting weaker On the sixth of July, I finally carried him into the emergency room They told me he had strep and mono which seemed like a horrible diagnosis at the time I remember thinking about how the recovery from mono would take months So, they pumped him full of fluids and steroids and antibiotics and told me he’d be better that evening But, he wasn’t He continued to decline, so we took him back in Then, we were admitted All this time, I attributed everything to what I believed was a sore throat In my mind, he was weak because he wasn’t eating, and he wasn’t eating because his throat hurt We never once entertained the possibility that perhaps his swallowing muscles were paralyzed, and that paralysis was slowly spreading through his body On July 9th, the paralysis reached his diaphragm, and we were so fortunate that a nurse was already in his room and was able to quickly take care of him when he stopped breathing What if it had been the middle of the night? What if the paralysis had spread faster and we were still at home when he stopped breathing? He was intubated and flown to a major hospital in Houston Two days after we arrived in Houston, Braden finally got an MRI

It was only after a failed extubation attempt that they realized that something neurologic was happening Guillain-Barré and anterior horn cell disease were both diagnoses I remember being floated, but eventually, they pulled us into the little room and told us about acute flaccid myelitis We had never heard of AFM The doctors had never treated anyone with AFM We had a million questions and no answers Eight days after his first symptoms, we finally had that diagnosis and they started treatment, but what if we’d acted faster? What if our doctors were familiar with AFM and had it as part of their differential and got him treatment quicker? What if his legs were paralyzed first instead of his swallow? Would we have gotten a diagnosis quicker? Braden’s paralysis spread everywhere except his left hand He was left with the ability to do a few hand signs to communicate with us while he was intubated Braden got IVIg, and we held out hope that maybe they would give us back enough that he could be extubated They attempted extubation again and failed Twenty-five days in they took him away for a tracheostomy and a permanent feeding tube All our hope was crushed that he would bounce back and come home soon, but we were so grateful to be able to see his face again and hear little bits of his voice He spent two months in the hospital before he was able to transfer to a rehab facility The closest inpatient rehab facility that took kids on vents was in Dallas, five hours from home, so we shuttled our kids back and forth to Dallas, and we took turns being there with Braden He had daily physical therapy, occupational therapy, and speech therapy We learned how to suction a trach, how to change a trach, how to disassemble and reassemble his vent, run his tube feeds, administer his medications We left rehab as amateur pulmonologists and therapists We were experts at reading his x-rays and listening to his lung sounds We learned so much Braden spent five and a half months there working as hard as a five year old can to recover, motivated primarily by playing his iPad At discharge, he could take a few little steps with maximum assistance He still had no ability to swallow and has to have the saliva suctioned from his mouth every few minutes He was dependent on help for every aspect of his life He was able to spend a few hours off the vent at a time and was beginning to tolerate a speaking valve His left arm was recovering, and his right arm was still totally paralyzed Braden had been gone for over seven months when he came home I carried him out to the car in July and in February, he came home in an ambulance It still seems unfathomable to me We converted our downstairs office into a mini ICU for him and learned how to reincorporate him into our lives We had home nurses in our house 24/7 and nothing was the same We carried on and did as much therapy as we could at home We bought expensive equipment that was denied by insurance and kept him moving and going forward as much as we could About 15 months post onset, we did a nerve transfer in L.A. The transfer performed was moving the nerve for the right wrist extensor to give Braden the ability to do a pincher grasp We’ve seen a little return there and hope that it will continue to improve as he grows Since our initial discharge from rehab, we’ve traveled to Kennedy Krieger in Baltimore for six intense weeks of rehab and returned to Dallas for another month of rehab We traveled to Saint Louis for a nerve decompression to his femoral nerves to help increase the signals to his leg muscles He had his trach removed in September, a little over three years into his recovery, and one of the silver linings of everything being canceled right now means that we’re doubling down on his therapy at home Our amazing home nurses get him on the treadmill and move him through exercises using electrical stimulation every single day They have contributed immensely to his recovery and are invaluable to our family Today, Braden can walk short distances independently Some days, he even walks home from school He’s been trach free for ten months After years of no progress with his swallow, it’s finally returned a bit He manages all his oral secretions, he drinks sips of water, and is somehow able to eat all the Chex Mix and Chick-fil-A nuggets we can get into his little hands Four years out, he keeps making progress and has shown no sign of plateauing We’re so proud of how willingly and how hard he works to be healthy, and sometimes, I cannot believe that we’ve been fighting this disease for four years Next year, he’ll have lived half his life as a quadriplegic People like to tell me that it’s a marathon and not a sprint, but I know that they are wrong This isn’t a marathon because eventually marathons end,

and there’s no end in sight for us We’re always looking for a new, innovative therapy or new equipment for Braden to try We’ve flown him coast to coast getting him the help that he needs Our battle is unending We are so desperate for more awareness and more research that kids can be quickly and effectively treated, and I’m so grateful for you tuning in today to learn more about AFM I want to switch gears and tell you a little bit about the incredible community that we’ve become a part of Back in 2016, AFM was still far from being a household name Googling didn’t tell you much I can still remember the exact feeling I had when I finally understood what AFM was My sister is a surgeon, and she had gotten in contact with a neurologist who had treated a significant number of AFM kids, and she tried to learn more I was sitting in the window of Braden’s ICU room when she told me that many kids go home in wheelchairs and need long-term ventilation I couldn’t imagine those things How is it possible that my now healthy child wouldn’t be able to walk or breathe on his own anymore? What would we do? [sigh] In 2014, a few of those mothers with children with AFM found each other through the media Those mothers formed a Facebook group to provide support to one another and to fight this rare diagnosis together Over the past six years, the group has grown to over 800 members It’s a source of comfort to parents, a place they can vent and share their battles and their victories, and it’s become a source of information Cases of AFM are so incredibly diverse The level to which kids are affected and their recovery varies wildly No two cases are the same Some kids are fully paralyzed and make little recovery Some are impacted in just one limb and have no noticeable deficits Some kids have their breathing impacted and require a ventilator, and some don’t Even if a specialist or a neurologist has treated kids with AFM, it’s still very unlikely they will have seen a child with the same set of paralysis and recovery Many families have learned about nerve transfers from each other Many doctors weren’t aware of these procedures four years ago, and we were pressing each other to investigate them and seek out the most skilled surgeons and get the nerve transfers before the window closed on recovery Beyond providing support to one another, our parents work so hard to raise awareness They contact the media They share posts on Facebook, participate in fundraisers I’m amazed at how far our grassroots efforts have taken us In 2018, we traveled to D.C. together to meet with legislators and members of the CDC We traveled to Atlanta to share our perspective on CDC’s AFM taskforce in early 2019 We formed a nonprofit, the Acute Flaccid Myelitis Association, to help provide further support to families and raise more awareness The AFMA provides grants to help support families affected by AFM, and we’re currently working to put together a children’s book that will be available for families and providers to help explain AFM to kids in a language they’ll understand The value of awareness is so evident in the story of our buddy Corbin A friend shared Braden’s story early on, and a girl named Elizabeth started following all the way back in 2016 Fast forward to 2019 One day, Elizabeth sent me a message Her son was getting weaker and was in the hospital Could it be AFM? And, we walked through those next days and weeks together, and sure enough, it was AFM Fortunately, we took everything I had learned to help her advocate for Corbin He was quickly diagnosed and got the treatment that allowed him to walk out of the hospital, and Braden reminds me often that we saved Corbin and insists that I can’t stop telling people about AFM And, I truly believe that awareness about AFM will save children in the coming months Even in our current pandemic, parents must know that any sign of limb weakness following a cold must be taken seriously And, clinicians need to know how to properly diagnose, treat, and report cases of AFM so we can learn more about this disease and how to save future children from its heartbreaking effects >> I’m Kevin Messacar, a Pediatric Hospitalist and Infectious Disease Consultant at Children’s Hospital Colorado as well as a clinical researcher and Associate Professor of Pediatrics at the University of Colorado in Aurora, Colorado Today, I’ll discuss the clinical presentation and diagnosis of acute flaccid myelitis The primary objectives of this talk are to be able to recognize the presenting signs and symptoms of AFM,

to order and interpret appropriate tests to diagnose AFM I’ll help to identify resources to help manage AFM cases and provide recommendations for reporting and specimen submission I’ll start with an overview of the clinical presentation of acute flaccid myelitis summarized by the following figure demonstrating a timeline of four stages of the illness Then, we’ll drill down into the detailed characteristics within each phase First comes the prodromal, often febrile illness which proceeds neurologic onset by around a week This is followed by the abrupt onset of neurologic symptoms in those who progress to have CNS disease From this point, rapid, progressive neurologic injury leads to flaccid limb weakness over hours to days Ultimately, there is a prolonged phase of rehabilitation over months to years with improvements in function but persistent motor deficits in most First, focusing on the prodromal illness Most cases of AFM begin with a preceding acute illness This is typically a nondistinct illness that in over 90% of cases is associated with fever and respiratory symptoms such as cough, congestion, sore throat, and sometimes asthma-like symptoms such as wheezing and shortness of breath Gastrointestinal symptoms such as vomiting, and diarrhea are seen less commonly in around 1/3 of patients In cases associated with particular enteroviruses such as enterovirus 71, distinctive lesions on the palms, the soles, and the back of the throat characteristic of herpangina or hand, foot, mouth disease can be seen The onset of the prodromal illness precedes the onset of neurologic symptoms by around five to seven days on average Many patients report that their prodromal symptoms were improving or resolved by the time their neurologic symptoms started At the time of neurologic onset, fevers which may have gone away may come back or increase Meningeal signs such as headaches leading to vomiting, stiffness in the neck, and back pain are common In older patients, many complain of pain in the limb that ultimately goes on to become paralyzed Shortly following onset of these neurologic symptoms, the phase of rapid, progressive neurologic injury begins with a hallmark of AFM, the acute onset of flaccid limb weakness This is a lower motor neuron pattern of hypotonic or floppy and hyporeflexic or areflexic weakness This weakness tends to be asymmetric, affecting one side of the body more than the other, and unlike polio and Guillain-Barré syndrome, tends to affect the arms more commonly than the legs The proximal or more central muscle groups such as the shoulder girdle are more affected than the distal muscle groups in the forearm and the hand Underrecognized is a wide spectrum of severity of this illness While some children are profoundly affected with complete quadriparesis, others may have very mild four out of five strength in a single limb Cranial nerve dysfunction is seen in addition to limb weakness in around 1/3 of cases which can present as abnormal eye movements or double vision, asymmetric facial droop, or most important to recognize, bulbar weakness Difficulty swallowing, a soft voice or loss of the gag reflex can be signs of bulbar involvement that may require rapid intervention to secure the airway As AFM is a predominantly motor neuron disease, it’s less common to see sensory changes Findings characteristic of encephalitis due to brain parenchymal involvement such as seizures or altered mental status are also less likely as AFM predominately affects the spinal cord and brain stem AFM should be considered in the differential diagnosis in any case presenting with acute limb weakness AFM has most commonly been mistaken for musculoskeletal injury, attributing weakness to an unrelated trauma, brachial plexus injury, or as many of these children are toddlers with limp arm weakness, a nursemaid elbow dislocation When the asymmetry and focality of findings is not appreciated, AFM has been attributed to generalized fatigue, malaise, and weakness associated with viral illnesses And, unfortunately, some patients on the milder end of the AFM spectrum have been sent home with psychiatric diagnoses such as conversion disorder or malingering A careful history that this weakness occurred following a preceding illness and in association with fever as well as a complete neurologic exam to characterize strength, tone, and reflexes will help differentiate these mimickers on the differential Other neurologic conditions that may require different treatments have also been described in cases misdiagnosed as AFM These include auto antibody conditions that cause myelitis such as myelin oligodendrocyte glycoprotein disorder or MOG, and neuromyelitis optica or NMO, transverse myelitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis

or ADEM, or even anterior spinal strokes In the following slide, we’ll go through some of the clinical laboratory and neuro imaging workup that can help to differentiate AFM The diagnostic evaluation of AFM can be split into two categories First, how to confirm a diagnosis of AFM and second how to look for a cause In addition to the careful neurologic exam to detect flaccid limb weakness, a brain and spinal cord MRI and lumbar puncture is recommended to help diagnose AFM On MRI, most AFM patients will have distinctive longitudinal lesion in the spinal cord, the long, white stripe in the middle image Initially present throughout the grey matter, and then over days to weeks, more focal to the anterior horn region, the owl’s eyes in the cross section below Particularly in those with cranial nerve deficits, focal nonenhancing lesions in the brain stem and cerebellum may be present as highlighted by the arrows in the cross sectional image above Cerebrospinal fluid indices are lumbar puncture supportive of a diagnosis of AFM include a lymphocytic CSF pleocytosis with normal glucose and normal to mildly elevated protein In order to search for an etiology or cause of the patient’s AFM, collection of biologic specimens as early in the course of disease as possible is recommended This includes both sterile site specimens, CSF from the lumbar puncture and serum, as well as nonsterile site specimens from stool and respiratory sampling of the nasopharynx and oropharynx May sound counterintuitive to look in the respiratory tract or GI tract of a patient presenting with neurologic symptoms, but many of the viruses associated with AFM are not found in CSF or blood at the time of presentation So, sampling these sites is necessary to detect where the virus may still be shedding When you think AFM, you should be reporting any suspected case to your state health department On the CDC website is a job aid for clinicians that will walk you through the steps of reporting and collecting and submitting biological specimens for testing Making sure that every suspected AFM case gets reported is essential to surveillance to understand the burden of disease and biologic specimens are necessary to further our understanding of how to better diagnose, treat, and prevent this disease The mainstay of management of AFM is vigilant, supportive care Due to the risk of respiratory decompensation, it’s recommended that all patients be hospitalized during the stage of progressive neurologic injury Respiratory status should be assessed through examination of the gag reflex, ability to protect the airway, and measurement of negative inspiratory flow to assess respiratory muscle function Around 1/3 of patients will require respiratory support with some requiring intubation and ventilation for respiratory failure Autonomic dysfunction including constipation and urinary retention are common and may require a preventative bowel regimen and catheterization Those with bulbar dysfunction may need enteral feeding tubes to provide hydration and nutrition support Given that AFM is a relatively new and uncommon condition, seeking advice from neurology and infectious disease experts with experience in managing cases may be helpful At this time, little is known about which therapies, if any, are most effective in treating AFM, as there have been no controlled prospective studies in humans Most cases are treated with immunomodulatory therapies used for other neuroinflammatory conditions such as intravenous immunoglobulin or IVIG which may contain neutralizing antibodies against potential infectious agents as well as provide immunomodulatory effects High dose intravenous steroids which are recommended if there’s spinal edema leading to upper motor neuron signs due to cord compression and therapeutic plasma exchange or PLEX Currently, there are no FDA approved antiviral therapies against the enteroviruses associated with AFM, and analysis of fluoxetine, and antidepressant that had invitro in the lab activity against circulating strains of enterovirus D68 showed no signal of efficacy when comparing treated children to untreated children with AFM in 2016 The CDC has a detailed expert review of the literature of what is known about these therapies and others in the interim considerations for clinical management link listed below In addition, the Siegel Rare Neuroimmune Association now has an AFM physician consult and support portal which providers can access through the CDC AFM website to request peer to peer consultation with neurologists specializing in AFM on a case to case basis As far as prevention, it’s important to remember that polio myelitis due to polio virus is historically the most important cause of acute flaccid paralysis

and in preventable by vaccination Currently, there are no vaccines available in the U.S against enterovirus A71 or D68, though research is ongoing to identify vaccine candidates Early, aggressive, and continued rehabilitation therapy which may include physical, occupational, speech, respiratory, and psychological therapy is key to maximizing recovery More recently, nerve transfers, splitting and moving functioning nerves to muscles paralyzed by AFM without functioning nerves, and tendon transfers have led to functional improvements and may be an option in selected cases While long-term outcomes are still unknown, we know that cohorts followed since 2014 show that most patients with AFM show some functional improvements The distal, less affected muscle groups show the best recovery with proximal, more affected muscle groups showing less recovery, and the muscle groups showing complete denervation with no functioning nerves were seeing little to no recovery and a polio-like muscle atrophy or muscle wasting pictured here Most of the recovery occurs early, in the first few months However, continued rehabilitation is important because patients will show slow but steady improvements even a year after onset In total, around 75% of patients will have persistent motor deficits one to two years from onset In summary, as healthcare providers, we all need to recognize acute flaccid myelitis when it presents to our clinic, ER, or hospital We should think AFM in any patient with new onset weakness, particularly in children with asymmetric flaccid weakness when following a febrile illness They have a high index of suspicion in the summer to fall season during enterovirus outbreaks We can diagnose AFM by a careful neurologic exam, MRI images of the brain and spinal cord, and lumbar puncture while looking for a cause by collecting biological specimens, CSF, blood, stool, and respiratory specimens, early in the course of disease We need to know the basics of how to manage AFM through vigilant supportive care and rehabilitation therapies and know the resources that we can use to reach out for help, such as the physician support portal to have a one on one consultation about the particular patient in front of us Lastly, we need to report all suspected AFM cases to our state health department The CDC job aid is a great reference to help us with reporting and submitting biological specimens Thank you >> My colleagues have summarized what we have learned about AFM over the past few years Though nonpolio enteroviruses were always suspected to be the culprit, they were rarely isolated from cases, and it is clear that other viruses can cause ASM as well Identifying the specific cause is important for targeting therapeutics and other preventative strategies such as a vaccine We now have evidence to suggest that many cases and perhaps most over past few years in the United States, were caused by enterovirus D68 We don’t understand whether the virus damages motoneurons directly or whether the host immune response causes this damage There are, these are key questions for research We also don’t understand why some children are uniquely vulnerable to this condition if they become infected with EVD68 and whether there is some genetic susceptibility By using sophisticated tools on panels of cerebrospinal fluid samples from patients with AFM, scientists from two different groups were able to independently identify antibodies that indicate a specific immune reactions to enteroviruses These were not present in samples from negative controls They published these reports earlier in 2020 At NIH, we recognize that more systematic collection of wider panels of cerebrospinal fluid samples and of blood samples would be necessary to further develop diagnostic tests for AFM and also to conduct other types of studies to characterize AFM more completely To support research that could address some of these questions, we are funding a natural history study The coordinating center is at University of Alabama Birmingham, and the principal investigators are David Kimberlin of UAB and Carlos Pardo-Villamizar at Hopkins The study will collect a large number, will allow a large number of sites to collect a standard set of specimens and clinical data according to a common protocol It will also support specimen collection in household contexts This will allow for researchers to define why some children are vulnerable to AFM when their siblings who might also be infected with the same virus do not suffer the same consequences

Types of studies that examine this question might focus on genetics or on some other aspect of acquired immunity, for example We anticipate that there will be approximately 40 sites in four countries that will participate in this natural history study About half of these sites were activated in the 2019 2020 season which was not an outbreak season for AFM, and three participants have been enrolled to date The sites are diverse in geographic location, and that will allow for collection of specimens over time so that research can describe the evolution of the virus and also any genetic mutations that might evolve The NIH is also in the early stages of vaccine development that would target EVD 68 There are two approaches that we’re taking The first will involve supporting outside groups to develop a vaccine based upon whole inactivated virus This approach would be similar to the nonpolio enterovirus vaccines deployed in Asia for community outbreaks of hand, foot, mouth disease that was caused by enterovirus A71 A second approach of vaccine-like particles or BLPs is being undertaken by the NIAID Vaccine Research Center Virus-like particles are types of vaccine platforms that display antigens with a part of the virus that elicits an immune response that displays these antigens in an orderly structure as shown here in the cartoon on this slide These orderly structures are designed to be highly immunogenic The VLP approach shown here is the approach being used by the Vaccine Research Center An example of a virus-like particle vaccine design that has made it to the commercial market is the HPV vaccine which has been on the market for over a decade to prevent cervical cancer NIAID convened a workshop last February on AFM preparedness The objective of this workshop was to define a research agenda that would accelerate the development of counter measures for AFM On my next slides, I will summarize the key scientific questions that were generated by multidisciplinary scientists at this workshop that will be priority areas for research focus in upcoming years One thing we don’t understand about AFM is what changed in 2014 that would account for the rise in cases of AFM We don’t understand the every other year periodicity and whether this will continue It’s unknown what is different about a host, a child that gets AFM from their sibling that might get infection with enterovirus but not develop the complication of AFM We also don’t understand the b and t cell responses or epitopes in enterovirus mediated AFM We don’t have an understanding of the fundamental pathophysiology of nonpolio enterovirus mediated AFM We don’t understand the role of direct viral infection of cells versus what part of the damage might be caused by immune mediated responses We don’t understand the mechanisms of viral spread to the central nervous system or why the anterior horn cells are specifically targeted by EVD68 We also don’t know whether other types of cells such as interneurons or myocytes are also infected We don’t know whether the mutations are in EVD68 that occur over time are antigenically significant, and we don’t understand or know for certain how narrow the window of opportunity might be for therapeutic intervention if we are able to develop a strategy for treating AFM In summary, over the past few years, collaborations between the CDC, the NIH, academic investigators, and members of impacted families have strengthened our AFM research efforts, but there is much more to do in this area We have ongoing efforts to develop and improve animal models for AFM to improve our diagnostic tests, to develop possible therapeutics such as monoclonal antibodies and to continue with EVD68 vaccine development It will also be important to develop and test new approaches to rehabilitation Thank you >> So, thank you so much for joining us today As you can see, our speakers are with us live Emily, can I get to show your video, please? I see John, but I don’t see Emily Okay Let’s, I want to remind our audiences online

that we take questions, and I have a few to start with already, but you can send your questions to grandrounds@cdc.gov So, let’s start with one from Ann on Facebook Are the spikes happening at the same time that kids are returning to school? >> Susan, thank you I can take that question So, we do tend to see most cases of AFM occurring between the months of August and November Approximately 85% of cases do occur during that timeframe, and most, the majority of cases do have limb weakness onsets in the month of September So, it is, you know, depending on where you live in the country, it’s either during the time that children are returning to school or slightly after the time that children return to school >> And, another question from Jenn at Facebook She’s looking for a nonspecific cause So, what is common in the absence of a viral or bacterial indicator? >> So, that, yes, again, that’s a great question, and I think one question that we all really are trying to answer What do these children have in common I know that the parents group has been very active in looking across the children in the Facebook group to look for commonalities Here at CDC, we also did try to interview all of our confirmed AFM patients and families from 2018 to see if there may be commonalities other than viruses or bacterias as the questioner said So far, I think we haven’t turned over a smoking gun There doesn’t seem to be any risk factors that we’ve identified to date Mrs. Scott, Rachel, I wonder I don’t know if you would like to say a few words as well about the effort that the Facebook group undertook to look across children in that Facebook group >> Sure. Yeah I mean, as parents, we’re all desperately anxious to know why our kids Why did all of my kids have this cold, but only one of them were paralyzed, and why is this happening seemingly randomly across the country? So, we’re always asking each other questions and trying to find maybe links between our kids, and we really can’t I mean, one of the AFM parents, Dr. [inaudible] has done a, she’s a neurologist and has done a study kind of looking at our kids, and it’s really hard to find any link And, it’s scary to not have a reason that we know this is happening to certain kids >> I’ll just add that this has been a long challenge in the field of infectious diseases of very common exposures or infections leading to very rare complications And, even with polio virus, we knew that 200 to 500 people would be infected with that virus for every one that would get paralyzed The fortunate part is with new technology and new research advances We do have a way to look in ways that we’ve never been able to before at host genetics at environmental exposures, and a lot of those activities are going to be ongoing through the NIH natural history study, and our hope is with some of the new research technologies, we will be able to look into the cases with household comparisons to get a better idea of why certain children were affected and others not >> We have a question from Jim in our grand rounds email box He says what are the contributions or what might be the contributions of climate change or other changes in environment that make enteroviruses more prevalent in the environment, for example, water supply? >> Dr. Messacar, I know that you have done a lot of work thinking through climate, the effects of climate on enterovirus circulation So, maybe you can say a few words about that >> Yeah, so the enteroviruses are an interesting family of viruses in that they have been constantly changing throughout time Certain serotypes of enteroviruses will come and go away for long periods of time Others will come and stay in these repetitive patterns, and a good example of that is enterovirus 71 in the Asian Pacific area, although it’s shown up in the U.S. It really sporadically appears and hasn’t stuck around Whereas, in those countries, it comes every three to four years in repetitive patterns in large outbreaks There is some data as to what makes repetitive patterns of enteroviruses, suggesting that there needs to be enough susceptible people to make that virus circulate again So, if it has widespread circulation, you tend to not see it until you can build up enough susceptible hosts to circulate again And, there are some impacts to climate So, there’s some wonderful epidemiology that’s been done

out of data from Japan and some in the U.S. describing that dew point temperature, so the combination of temperature and humidity in the air actually helps us to predict why these viruses are showing up in the summer to fall in temperate areas So, as you get closer to the equator, you lose that pattern, but in areas like North America, that’s why we tend to see in mid and northern parts of the country these summer to fall outbreaks So, I think the field of epidemiology is giving us some insight into why we see circulation in these patterns We don’t know exactly the affects that climate change will have going forward, but it is something that our epidemiology colleagues are looking into >> From Ahmed Can you help us understand the difference between AFM and polio, the major differences? >> So, I can start and would welcome colleagues to jump in So, the two are clinically similar We do know that both polio myelitis caused by polio virus and the, again that grey, those grey cord abnormalities that we see with AFM present with limb weakness One key difference that we do note between polio myelitis caused by polio virus and AFM is that AFM tends to affect the upper extremities, as many of us have discussed, whereas polio virus tended to affect the lower extremities more predominantely You know, we at CDC request stool samples from every suspected case of AFM, and we do test those stool samples for polio virus So far, no stool sample has tested positive for polio virus, so I think we can say with certainty the AFM that we’re seeing right now is not due to polio virus >> And, just to reiterate that polio virus is in the family of enteroviruses which includes the nonpolio enteroviruses that were discussed in some of the talks, enterovirus 68 and enterovirus 71 So, just like Dr. Routh said, there is no evidence of polio virus in the more recent cases in North America and Europe However, these other nonpolio enteroviruses are some of the leading suspects for the increase in cases >> We have a lot of questions coming into our grand rounds email box, and also via Facebook Live From Sue, she wants to know why did the case classification of AFM change from 2018 to this year? >> So, every year after an outbreak, it seems like we learn more about the illness In, you know, recent years, we’ve been wanting to cast a wide net to help us understand this disease better Every, we learn more from every case that gets reported to CDC, whether it goes on to be a confirmed case of AFM of not This year, we realized that we had some more information about AFM to help increase the specificity of the case definitions So, rather than just casting a broad net for acute flaccid limb weakness which we know has many causes, we are now including the presence of grey matter lesions on an MRI because we know that that is one of the hallmarks of this illness To help us better define a confirmed case from probable or cases that we think might have another diagnosis associated with them, we have incorporated that, those MRI findings into the current case definition So, again, a confirmed case would be a case with predominately grey matter lesions, and a probable case would be MRI findings where we can’t distinguish the predominance of that grey matter in the lesion >> I would just add as a clinician that it’s really important that we recognize that the epidemiologic case definition, which is important for case ascertainment and epidemiologic purposes, is very different than a clinician making a clinical diagnosis We know in the real world setting, some children have delayed diagnoses where their MRI may not show changes anymore that meet the case definition There may be factors why in one way or another, they don’t check one of those boxes of the epidemiologic case definition, but it is completely reasonable to make a clinical diagnosis even if it does not fit with the epidemiologic case definition As Dr. Routh said, we’re learning more and more about this condition every year, revising those case definitions, and also working out clinical diagnostic criteria to help that doctors in the trenches who are seeing these cases that may have some caveats that really don’t fit the box of a predefined criteria for AFM

>> And, Dr. Messacar, I would just add to that, we do emphasize that the CDC case classification should not factor into a patient’s diagnosis It may come, you know, weeks after the patient has been in the hospital, and it’s not meant to supersede or overturn a diagnosis of AFM It’s purely used for surveillance purposes so that we can compare cases from year to year >> We’ve reached the end of our time available today, and before Dr. Iskander closes for us, I want to point out that our session in its entirety, including the slides and also references to some of our questions have asked for will be posted on our website Give us until the end of this week or the beginning of next week to make that happen John? >> Thanks very much Again, I’d like to thank all of our speakers for their expertise, for the time and work they’ve put not only into this session but into helping us all develop a better understanding of AFM so that we can have interventions going forward Please give them all a virtual round of applause, however you wish to, and please join us next month for the next episode of Public Health Grand Rounds Thank you