Researchers seeking the cause of mysterious cases of childhood paralysis seem to be closing in on a culprit. Since 2014, more than 500 children in the United States have suddenly lost muscle control in their arms and legs, a condition called acute flaccid myelitis (AFM), which can cause permanent disability. But the leading explanation—that a normally mild viral infection occasionally results in AFM—has been hard to prove. A new analysis of young patients’ spinal fluid now offers evidence linking a group of common viruses known as enteroviruses to AFM. But questions remain about how such viruses damage nerves and why they seem to do so only rarely.
“I think it’s time to stop debating” whether enteroviruses cause AFM, says Raina MacIntyre, an epidemiologist at the University of New South Wales in Sydney, Australia. “This is very strong evidence.”
Epidemiologists tracking recent U.S. cases of AFM already had reasons to suspect a relatively common enterovirus called EV-D68 known to cause generally mild respiratory illness. The timing and location of AFM cases seemed to coincide with EV-D68 outbreaks in 2014, 2016, and 2018. AFM patients, most of them young, commonly had other symptoms consistent with EV-D68 infection, such as cough and muscle aches, days before the condition struck. And a strain of EV-D68 can trigger AFM-like symptoms in mice.
Researchers previously detected enteroviruses in phlegm and stool from children with AFM, but when they’ve looked for enterovirus RNA in spinal fluid—an indication that the virus had invaded the nervous system—most samples came up negative. “Just like other folks, we’ve tried over and over again,” says Michael Wilson, a neurologist at the University of California, San Francisco, and an author on the new study. There were multiple possible explanations for the absent viruses, Wilson says, including that they had come and gone by the time doctors sampled spinal fluid. But the missing evidence bred a “lingering concern,” he says. “The question has come up: Is there some other infection we’re missing?”
In the new study, Wilson and his collaborators searched for indirect evidence of a viral invasion: antibodies in spinal fluid that would suggest the viruses had provoked an immune response. They analyzed fluid from 42 children with AFM and 58 children with other neurological diseases, who acted as controls. The researchers exposed each sample to viruses displaying peptides from thousands of different viruses on their surface. Only levels of antibodies to enterovirus peptides were significantly higher in the AFM patients, the researchers report today in Nature Medicine. Even though just one of the AFM patients had detectable enterovirus RNA in spinal fluid, 69% of them had elevated antibodies against enteroviruses versus 7% of controls. “[Enterovirus] infection probably underlies most AFM cases tested in the present study,” the authors conclude.
That finding reinforces the results of another recent study using fewer samples and a different technique to search for antibodies. “These are really complementary papers,” says virologist Ian Lipkin of Columbia University, an author on the earlier study. Published in mBio in August, it reported that 11 of 14 AFM patients had antibodies to some enterovirus peptide in their spinal fluid, versus three of 26 people in control groups, which included adults with diseases of the central nervous system and children with a rare inflammatory illness called Kawasaki disease. It also showed that six of the patients had antibodies to a protein fragment specific to EV-D68, which co-author Nischay Mishra, a virologist at Columbia, describes as “the most surprising and interesting result.”
Both studies acknowledge a limitation in design. Ideally, each sample from a child with AFM would be matched with a control child’s sample, taken in the same place and during the same season. “I think that’s what everyone’s hoping for,” says Priya Duggal, a genetic epidemiologist at the Johns Hopkins University Bloomberg School of Public Health in Baltimore, Maryland. Otherwise, it remains possible that samples from areas where AFM spiked also show signs of enteroviruses just because an enterovirus happened to be circulating in that location, and not in the locations where control samples were taken, she explains. A study funded by the National Institute of Allergy and Infectious Diseases will compare samples from AFM patients and matched controls.
The new research doesn’t explain what makes certain children susceptible to AFM after contracting a relatively common infection. These children could have a genetic predisposition to viral invasion of the nervous system, contract a particularly harmful strain of the virus, or get exposed to the virus at especially high levels, he says.
Until those questions are answered, the new finding at least gives clinicians hints about how to help young patients, Wilson says. Giving children intravenous immunoglobulin—an infusion containing a mixture of antibodies pooled from hundreds or thousands of donors—is worth investigating, he says. The new evidence could also help researchers agree on a diagnostic test and a strategy for developing a drug or vaccine, he says, “if this continues to be an increasing problem over the coming years. Hopefully it won’t be.”