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Acute Flaccid Myelitis: Drawing Attention Amid the Peak Months

SAP Partner | <b>Siegel Rare Neuroimmune Association</b>

Olwen C. Murphy, MBBCh, and Matthew R. Vogt, MD, PhD, discussed the current clinical understanding of AFM and the need to recognize this condition amid the “peak” months of infection: August, September, and October.

With Acute Flaccid Myelitis (AFM) Awareness Month taking place in July, the need for the clinical community to be aware of this infection becomes critical as the peak months—August, September, and October—for cases come and go.

AFM is a disabling illness that mainly affects children and somewhat resembles polio. Outbreaks of AFM have occurred across multiple global regions since 2012, and without a sensitive and specific test available, the diagnosis leans heavily on the identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics.

In a recent conversation about the features of this disease, NeurologyLive® spoke with a pair of experts: Olwen C. Murphy, MBBCh, assistant professor of neurology, Johns Hopkins University; and Matthew R. Vogt, MD, PhD, assistant professor of pediatric infectious diseases, University of North Carolina at Chapel Hill. They discussed the current clinical understanding of AFM and the existing treatment approaches to it, as well as the need to improve awareness ahead of the peak infection months.

NeurologyLive®: What is the clinical community's understanding of AFM as it stands today?

Olwen C. Murphy, MBBCh: From the neurology perspective, AFM—or acute flaccid myelitis—sort of emerged as a newly recognized illness over the last 12 to 15 years or so. It tends to affect children primarily. What was recognized was outbreaks, initially in areas like Colorado and California, of children with a paralytic illness which looked very similar to polio. So, children would report a viral illness, maybe respiratory symptoms like coughing and wheezing, and then a few days later experience acute severe weakness, typically affecting one or more limbs, and then, in severe cases, affecting the muscles of breathing, speaking, and swallowing. Severely affected children were ending up in intensive care units with this paralytic illness.

It was only over time, when this pattern of cases of acute flaccid myelitis was emerging every 2 years or so, since 2010 or 2012, that the link with an infectious etiology was made, and the sort of words worlds of neurology and infectious diseases kind of come together. There's been accruing evidence over the years on the specific types of viruses that can trigger AFM, in particular Enterovirus D68, which is thought to be the main trigger for the vast majority of cases of AFM. Now, we've moved into the phase more of recognizing that is the primary cause of AFM and what can we do about it.

Matthew R. Vogt, MD, PhD: As Dr. Murphy said, we progressed from what we would initially call an association of 2 things—we have lots of kids getting respiratory illnesses, oftentimes those respiratory illnesses can be attributed to this virus, Enterovirus D68, sort of in the same timeframe, or within a couple of days typically, of their weakness setting in. Now, that's an association, that's not causation. Over the past many years, we've done a lot of work—and I say we as the global scientific community—to really link these 2 and show that this is definitely a virus that causes the vast majority of cases of AFM. Certainly, where we have a lot of good epidemiologic data around AFM is in the United States and in Europe. The initial way these were linked was, again, sort of a timing thing. Lots of respiratory illness and lots of this paralytic illness in close proximity to each other. There's now been a lot of work in mice, that when we infect mice with Enterovirus D68, they develop an illness that sort of resembles AFM and they also get disease in the anterior horn motor neurons, in their spinal cord—the same place where we see a lot of the pathology when we do imaging of patients with AFM.

But then, back in the summer of 2018, there were 2 groups that did really nice complementary studies that use slightly different methods but came to almost the exact same conclusion—which was really nice and made it a very, very believable conclusion—where they saw a lot of patients with AFM. When they looked at the spinal fluid from those patients, they had antibodies to Enterovirus or in some cases, specifically Enterovirus D68. In something on the order of 70% to 80% of those patients, they could find those antibodies. Then, when they looked at spinal fluid from people with everything else under the sun, where they could get their hands on spinal fluid, it was more like maybe 7% or 8%. There was a very dramatic increase in the presence of Enterovirus antibodies in the spinal fluid of patients with AFM. That was another really big moment, where we kind of had the association more tightly linked to say a causation.

Then we—meaning a group of people that I'm working with—recently, were able to reexamine an autopsy from a patient who was a 5-year-old boy, and he had died of what we would now call AFM back in 2008. We really didn't actually use the term AFM until 2014, when sort of was developed as a case definition for by the CDC. But that patient is 1 of the few patients who has died during the acute phase of their illness of acute flaccid myelitis—and in this case, about 3 days into the onset of weakness—but also one of the few patients who had an autopsy in that same setting. So, we were able to really take advantage of this sort of unique set of samples that really searched far and wide. I called everybody I knew and everyone I could try to get to know to find other samples to do the same studies on, and what we saw was that the virus, Enterovirus D68, we found both RNA and protein of the virus capsid shell that surrounds that RNA genome present in the neurons, and those same spots that we suspected—the anterior horns of the spinal cord, where the motor neurons live. It really showed that, at least at that time point of infection, this is definitely a neurotropic virus, it definitely infects the neurons, and there's a lot of inflammatory cells around, too. The question would be, are the inflammatory cells helpful or in fact, potentially harmful, in this case and killing the neurons that are infected?

Now, we're very confident that this virus that is Enterovirus D68, that really is, for all intents purposes, a respiratory pathogen that behaves just like the common cold except in the small number of cases where it does invade the central nervous system, where it then infects those motor neurons in the spinal cord, and it causes this this acute flaccid myelitis. The causation link is no longer really a question. It's just a matter of now continuing to push our understanding of the steps that lead from what is typically a very harmless respiratory tract infection, but in the unlucky few is far worse. Why are those people the unlucky few? And how is the virus doing it? How is the virus causing the paralysis? Those are definitely studies that are ongoing in multiple groups, not just ours.

July was AFM Awareness Month, so in light of that, is there any messaging you'd like to get to the clinical community to help them better identify these cases when they do occur?

Matthew R. Vogt, MD, PhD: I do think that at least with pediatricians as a whole, which is sort of another community that I'm a part of, the American Academy of Pediatrics has participated a lot with groups like the CDC, or the Siegel Rare Neuroimmune Association, and partnered together to produce a lot of educational material. There are, for example, free courses available through the American Academy of Pediatrics PediaLink website around acute flaccid myelitis. Those are actually a little hard to find on their own, but if you just go to the CDC’s Acute Flaccid Myelitis webpage, amongst all the many, many resources on that webpage, is a link to that.

I think nowadays pediatricians are more and more aware. I wouldn't consider myself a part of the community of emergency room or urgent care providers necessarily, but I think also another group that we've tried really hard to make outreach to, to make sure that they're aware that this is something that presents. I think the reason, or at least one reason, that July is a really good month to be Acute Flaccid Myelitis Awareness Month is because we have seen, in the past, these peaks of AFM illness during years where we do have big spikes in August, September, and October as the main peak months. To be aware heading into those months is a really good thing, so definitely for the next few months, if you see a child that has especially an antecedent just febrile illness, especially with respiratory components, but could also be sort of a febrile GI type illness, and then within a few days, or even as that illness is starting to subside, they have this acute onset of weakness or cranial nerve changes—sometimes it can be painful in these in these affected limbs, but oftentimes not, and sometimes they can have sort of that meninges that comes with having a bit of a meningitis component as well—any of those things should really make you at least think about AFM.

Maybe you find an alternative diagnosis quickly, and that's fine. But if AFM remains on your differential, reach out. I would really, really stress, even as someone who studies AFM, if I'm worried about this clinically in a patient of mine, I'm reaching out to my neurology colleagues, hands down. I'm also pulling out Dr. Murphy's Lancet article. It's a really comprehensive article.1

It's also one of these things I tell everybody: if it's on your differential and you want some resources, I just Google, “CDC AFM” and loads and loads of resources on the CDC AFM webpage show up. Actually, one of the main resources that they highlight is that Lancet article, which is just a really well written article that goes through the different differential that you may want to consider aspects of all disease.

Olwen C. Murphy, MBBCh: I think that that was a great summary. I think there's resources out there that are available for when AFM is a suspect diagnosis because we recognize that this is a rare illness. Most physicians who are going to encounter this, this might be the only case they ever encounter in their life. Reach out to your colleagues. That's what we're here, for these people specializing in research of this rare disorder. Through the Siegel Rare Neuroimmune Association, through the CDC, there's help available in the larger academic centers to help diagnose these cases, and sometimes, transfer affected patients.

From the first meeting perspective, what frustrates many of our parents of AFM children—I've had the privilege to work with many families affected by AFM—and what's very traumatic for parents sometimes, is that their child has been discharged from an urgent care department or an emergency department with AFM because it wasn't recognized. It may have been at an early stage. The manifestations can be quite mild initially and one of the unusual things about AFM is it can affect the arms first in some cases. Often, we have a child that presents a few days into a viral illness with focal weakness in one arm, and you know the diagnosis entertained is something like a compressive neuropathy or something like that, and the patient's discharged home and deteriorates rapidly. I would just flag for any physicians in those sort of acute care environment stuff and a child with a viral illness and focal weakness, you need to be thinking about AFM and the potential for deterioration.

Transcript edited for clarity.

Click here for additional AFM resources can be found here: CDC – Acute Flaccid Myelitis and here: SRNA – Acute Flaccid Myelitis.

REFERENCE
1. Murphy OC. Messacar K, Benson L, et al. Acute flaccid myelitis: cause, diagnosis, and management. Lancet. 2021;397(10271):334-346. doi:10.1016/S0140-6736(20)32723-9