Within days, the boy went from having cold symptoms to being unable to walk. To Peter Wright, a pediatric infectious diseases physician at Dartmouth Hitchcock Medical Center, it looked similar to polio — a condition not seen in the United States anymore. It had to be something else.
The case occurred back in 2008, and tragically, the 5-year-old New Hampshire boy died. But his family permitted the scientific team to conduct an autopsy, to help solve “the mystery around the child’s death and illness,” Wright recalled. The researchers found something unusual: evidence of a common pathogen called an enterovirus, but in the fluid that bathes the spinal cord.
“Enterovirus 68 has not been previously reported as a cause of neurologic disease,” the team wrote in a case report, citing the specific enterovirus — D68 — they encountered.
A decade later, and another researcher named Matthew Vogt was studying a syndrome that had only been classified in the subsequent years, picking up the name acute flaccid myelitis. By that time, researchers suspected that AFM, a puzzling condition that caused muscle weakness and left some children paralyzed, was a rare consequence of an infection from enterovirus D68, known as EV-D68, which typically causes respiratory symptoms. Vogt, then a fellow at Vanderbilt University, was wondering if there might be any autopsy records out there that could help explain what was going on in these children’s central nervous systems.
Vogt reached out to Wright: Were there still samples from that autopsy he had once written about?
It turned out there were. And in a paper published Wednesday in the New England Journal of Medicine, Vogt, Wright, and colleagues described how a new analysis of those samples — with techniques that weren’t in use at the time of the original autopsy — revealed direct infection by the virus in the motor neurons in the spinal cord. They also found evidence of an inflammatory immune response that, instead of being protective, might damage the neurons.
The paper further corroborates that EV-D68 is driving cases of AFM, and provides a snapshot of what that infection looks like. It also highlights the value of autopsies when people die of mysterious causes — a value that can continue to accrue years later.
Until now, “we’ve never had direct evidence of what the virus was doing in the spinal cord during AFM,” said Kevin Messacar, a pediatric infectious disease physician at Children’s Hospital Colorado, who was not involved with the new research. He called the endeavor “an incredible piece of medical detective work.”
Reading the original report today, it’s clear it’s describing an AFM case before the term existed. A number of the boy’s classmates had had cold-like symptoms, and he first had a low fever, sore throat, and neck tenderness. Within a few day, his arms grew weak, and eventually, he couldn’t walk. He died soon after.
It was only in 2014 that health authorities started tracking cases of AFM nationally. There seemed to be bursts of cases starting roughly in August every two years, following patterns of EV-D68, with the highest number of cases — 238 — identified in 2018. (The pattern was thrown off by the coronavirus pandemic, which greatly dampened the transmission of other respiratory pathogens.)
Since AFM started being documented, scientists have been building the evidence that EV-D68 was a cause, from correlating the timing of AFM spikes to transmission of the virus, to showing the virus could cause paralysis in mice, to finding antibodies to enteroviruses in the cerebrospinal fluid of kids with AFM. (Another enterovirus, A71, is suspected of causing some AFM cases as well.)
With supportive care, most children who develop AFM survive, and the deaths that do occur typically happen later on as a result of complications, after the infection has cleared.
All that made the samples from the 2008 case even more valuable: the boy died early on in his infection. And in the new study, the researchers reported they found both proteins and RNA from the virus in motor neurons in a region of the spinal cord called the anterior horn, which helps control movement in the limbs.
The updated autopsy findings don’t answer many of the questions researchers still have about AFM, including what causes the paralysis. Is it the infection that’s damaging the neurons, the subsequent inflammatory response, or some combination of the two? That could dictate how clinicians should treat the condition — with medicines that target the virus, or those that can quiet the immune response.
Researchers also still aren’t sure why a relatively common virus triggers such a devastating response in a handful of children. It’s a similar question to the one that scientists globally are grappling with as they try to unravel the mystery of what’s causing a spate of unexplained hepatitis cases in children, and what role a common pathogen — in that case, adenovirus 41 — may play.
Vogt, now a pediatric infectious diseases physician at the University of North Carolina, cautioned that the scientific team was just describing one autopsy, from one point in the illness, so “you can only draw so many conclusions.”
But more broadly, Vogt stressed the value of autopsies for people who die under confusing circumstances. It can be a delicate decision, particularly when it concerns a child. But the hope is that studying these deaths can inform scientists’ efforts to identify what may start as riddles but that research can turn into something treatable.
“The hope would be that no other specimens like this ever exist,” Vogt said.