Enterovirus Implicated in Acute Flaccid Myelitis

Nancy A. Melville

October 21, 2019

ST. LOUIS — Enterovirus is the likely cause of the rare but devastating pediatric disorder acute flaccid myelitis (AFM), new research suggests. AFM is a polio-like condition that can leave children with paralysis.

"We think that by showing that most, if not all, of pediatric AFM is caused by enteroviruses, the work could spur more interest in vaccine development for what appear to be the two biggest culprit enteroviruses: EV-D68 and EV-A71," lead author Ryan Schubert, MD, Weill Institute for Neurosciences, University of California, San Francisco (UCSF), told Medscape Medical News.

The findings were presented here at ANA 2019: 144th Annual Meeting of the American Neurological Association and were simultaneously published online today in Nature Medicine.

Subject Hits Close to Home

AFM, which began to appear only as recently as 2012, primarily affects young children. It starts as just a cold but within days has polio-like symptoms, potentially causing permanent or even fatal paralysis.

For coauthor Riley Bove, MD, also of UCSF Neurology, the research hits close to home. Bove's 4-year-old son developed AFM in 2014 after appearing to catch the cold that had been spreading in the family. However, within days, the boy was paralyzed from the face down.

After 6 weeks, Bove's son was able to walk again and has been recovering since then. However, she said the lesson from the experience is that clinicians need to be aware of the possibility of an AFM diagnosis.

"When parents complain of weakness, the doctor must perform a neurological exam so as not to miss the weakness as was done for most of the kids," she told Medscape Medical News.

The new study is important because "now we have more concrete evidence that the spike in incidence of AFM since 2012 is due to enterovirus," Bove said. "We had suspected this but knew it was hard to prove without advanced techniques."

Evidence had recently pointed to enteroviruses, specifically the D68 and A71 strains of the virus. However, with 98% of patients showing no evidence of enterovirus RNA in cerebrospinal fluid (CSF) samples using deep-sequencing technologies, that theory remained in question.

Causal Role?

To take a different approach, the researchers turned to VirScan, a customized version of the Nobel Prize-winning phage display technique, to search for antibodies to enterovirus — as well as thousands of other viruses.

They used the VirScan method to evaluate CSF from 42 children with AFM and 58 children with other neurologic diseases to act as the control group.

Antibodies against enterovirus were found in the CSF of nearly 70% of patients with AFM (29 of 42) vs fewer than 7% (4 of 58) of those without AFM. Use of the ELISA assay confirmed the finding, with enterovirus detected in 22 of 26 of the AFM group and 7 of 50 of the control group.

Patients with AFM also showed no positivity for other antibodies, therefore ruling out all other viruses in the test as possible culprits.

"The strength of this study is not just what was found, but also what was not found," coinvestigator Joe DeRisi, PhD, professor of biochemistry and biophysics at UCSF, said in a press statement.

"Despite rare detection of enterovirus RNA, pan-viral serology identified frequently high levels of CSF enterovirus-specific antibodies in AFM compared with controls, providing further evidence for causal role of non-polio enterovirus in AFM," the researchers write.

Vaccines in Development

If larger studies further validate that enterovirus is indeed the culprit, vaccines that are already in the works could be the next step in prevention, Schubert noted.

"Efforts to develop vaccines for these viruses are underway, and I would hope they could be ready for use within the next few years," he said. In the meantime, "there is intense research around developing therapies specifically aimed at repairing injured nerves. However, none currently exist."

Additional efforts are focused on developing treatments "aimed at neutralizing the virus in its tracks when children have AFM, so that the damage can hopefully be halted or reversed," Schubert said.

Reasons why the virus could cause AFM in children but not other groups, such as the elderly or immunocompromised, are not yet understood.

"It is possible that children have lower immunity than any other age group to these viruses, but we still have more to learn," Schubert said.

The advancements in serology that allowed detection of the virus in the study should help push the field closer to answering those and other pressing questions, he added.

"By zeroing in on antibody testing as the best method for detecting enterovirus infection in the spinal fluid of AFM patients, we think our work will aid the formal development of diagnostics for future surveillance efforts," he concluded. "This will allow us to see the true burden of CSF enterovirus infection, and to more accurately assess how many cases of AFM are enterovirus-related."

Important Piece of the Puzzle

Commenting on the findings for Medscape Medical News, Kenneth L. Tyler, MD, chair of neurology and professor of medicine and immunology-microbiology at the University of Colorado School of Medicine in Aurora, noted that a key study limitation was that intrathecal antibody synthesis, considered the highest-level evidence from previous CSF antibody studies linking a pathogen to a disease, was not shown.

Intrathecal antibody synthesis "means showing that the antibody detected was actually made inside the CNS," said Tyler, who was not involved with the research.  

"This is typically done by either demonstrating that an IgM antibody is present, as it is generally too large to cross the blood–brain barrier passively, or that the ratio of CSF/serum Ab levels is elevated compared to what would likely occur passively. Neither of these were possible in the current study," he added.

However, along with similar findings recently reported in mBio, the current research is valuable in providing an important piece of the AFM puzzle, Tyler noted.

Alongside the mBio study, the current study "is one of the strongest pieces of data from human AFM cases strongly supporting an association between enterovirus and AFM," he said.

The research "may lead the way to developing more widely available rapid assays that can lead to earlier identification of RV-associated AFM cases from other causes of AFM or other mimics," said Tyler.

The study authors have reported no relevant financial relationships. Tyler has received grant support related to research on EVD68 from the National Institute of Neurological Disorders and Stroke. He is also working with companies, including Mapp Biopharmaceuticals, to develop and test human monoclonal antibodies against enteroviruses. 

ANA 2019: 144th Annual Meeting of the American Neurological Association: Abstract M102. Presented October 14, 2019.

Nature Medicine. Published online October 21, 2019. Abstract

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