No definitive etiologic agent has been identified, though EV-D68 remains the prime suspect.

As this issue went to press, the most recent update of the investigation was that from Aug. 2, 2014 to Feb. 11, 2015 the CDC had verified reports of 112 children who have developed acute flaccid myelitis (AFM). The median age of the children is about 7 years. About two thirds of the children who have been observed (median 19 days) after their illness reported some improvement in symptoms, while about one third showed no improvement. Only one of the children has fully recovered.

Almost all of them were hospitalized and some were put on breathing machines. Most patients had fever and/or respiratory illness before onset of neurologic symptoms.

A temporal connection

Given their simultaneous occurrence, it is tempting to conclude that EV-D68 caused the paralytic syndrome.

However, there are problems with that conclusion and the CDC investigation continues and will be expanded to include a case control study.

While the cases of limb weakness coincided with the EV-D68 outbreak, not all of the AFM patients had fevers or tested positive for the enterovirus, says Jim Sejvar, MD, neuroepidemiologist in the CDC’s National Center for Emerging and Zoonotic Infectious Diseases.

“CDC and states continue to investigate whether the 2014 AFM cases may be linked to EV-D68,” he says. “However, enteroviruses rarely cause encephalitis and myelitis.”

Enteroviruses most often cause mild illness and sometimes aseptic meningitis, he says, adding that there are only two published reports in the medical literature linking children with neurologic illnesses to EV-D68 infection based on cerebrospinal fluid testing.

As EV cases fell, so did paralytic syndrome

The first cluster of AFM cases occurred in Denver, CO, in August 2014.1 Earlier in 2014, California clinicians had noted an excessive number of acute flaccid paralysis cases in children.2

Some infectious disease clinicians suspect that EV-D68 is the cause of the syndrome because when respiratory illness from EV-D68 dropped off, so did AFM.

In a report on the Colorado cases in Lancet the authors state: “Although our findings do not prove that enterovirus D68 is the cause of the neurological presentations described, several epidemiological, virological, and clinical factors suggest an association between the D68 virus and neurological disease.”3

Lead author Samuel Dominguez, MD, a pediatric infectious disease physician at Children’s Hospital Colorado, told a news service that “if enterovirus D68 potentially has a role, we would’ve expected the neurologic cases to go away when the respiratory cases went away, and that’s what happened.”4

The CDC issued a health advisory and began active surveillance for AFM cases on Sept. 21, 2014.

“Such an association could be entirely coincidental, and there still is substantial work to be done to demonstrate an association between EV-D68 and AFM,” Sejvar says.

It’s further complicated by inconsistency in enterovirus testing, including how and when nasopharyngeal swabs are taken. It’s possible for people who previously were infected with EV-D68 in 2014 to test negative for the virus, Sejvar says.

“The most important reason for this is timing,” he explains. “EV-D68 lives in the nose of an infected person for a limited amount of time. If a nasopharyngeal swab is taken too late in the course of illness, it could test negative for EV-D68 because the virus could no longer be detected.”

Another reason why a person exposed to the virus may test negative is because people exposed to most viruses, including the enterovirus, develop antibodies that protect them from re-infection, he adds.

“Among the children with AFM, it is more likely they were never infected with EV-D68, or that the specimens were taken at a time when the virus was unable to be detected,” Sejvar says.

The 2014 AFM cases are similar to illnesses caused by viruses, including poliovirus, adenoviruses, West Nile virus, herpesviruses, and other enteroviruses. Also sudden onset of weakness in arms or legs can result from non-viral causes, such as genetic disorders, environmental toxins, and syndromes like Guillain-Barré Syndrome, Sejvar says.

The similarity between enteroviruses and polio viruses is what first raised suspicion of a connection between EV-D68 and AFM, says Aaron Milstone, MD, MHS, associate professor of pediatrics and epidemiology at The Johns Hopkins Children’s Center in Baltimore, MD.

Enteroviruses are common, and there have been clusters like EV-D68 before. Few labs will type the virus to identify the enterovirus number. “That’s very specialized testing that even our lab at Johns Hopkins doesn’t do,” Milstone says.

Sudden onset of arm, leg weakness

The children with AFM presented with a sudden onset of weakness in their arms or legs, and MRI scans showed inflammation of the spinal cord’s gray matter, Sejvar says.

Although Johns Hopkins had no AFM cases, the health system has treated a number of children with symptoms of enterovirus illness, which can include mild fever, runny nose, sneezing, coughing, body aches, wheezing, and difficulty breathing, Milstone says.

“The enterovirus season is summer and fall, but kids have respiratory illness all year round,” he says. “We saw respiratory illnesses with fever as a common presentation; they seemed to cluster in quite a few areas.”

The Johns Hopkins Children’s Center screens patients for respiratory illness and follows standard transmission precautions, including hand washing and advising patients to stay home if they have a fever, cover their mouths when they cough, and stay away from people with respiratory infections, Milstone says.

“We follow good core principles and did not do anything special because we felt this outbreak was the same thing we do with a bad flu season,” he adds.

Few treatment options


Unfortunately, there are no effective treatments or medications for EV-D68 or AFM. The enterovirus-caused respiratory illness mainly impacts children who have not been exposed to it previously and whose immune systems are less protected from infection.

“We’re interested in doing some genetic studies to look at genetic predispositions to severe viral infections,” Milstone says. “Why do some people just get a cold, and why do others develop acute flaccid myelitis? We’re collecting cases to answer this question.”

The CDC also is researching EV-D68 and AFM. “CDC is pursuing a multi-pronged approach to further explore the potential association of AFM with EV-D68 and other etiologies, as well as risk factors for AFM,” Sejvar says. “We are planning a case control study, and we’re also continuing to test specimens from AFM cases for a wide range of viruses that may be associated with this clinical presentation, as well as testing to possibly detect previously unrecognized pathogens.”

The protocols are under development, he adds.

“Right now, there are a lot of unanswered questions,” Milstone says.

One question the CDC will pursue is whether the syndrome is a virus-specific phenomenon or a host phenomenon, Sejvar says.

“We continue to investigate these cases,” he says. “There are numerous possible causes for AFM, and CDC is carefully exploring multiple hypotheses.”


  1. Pastula DM, Aliabadi N, Haynes AK, et al. Acute Neurologic Illness of Unknown Etiology in Children — Colorado, August–September 2014. MMWR 2014;63(40);901-902
  2. Ayscue P, Haren KV, Sheriff H, et al. Acute flaccid paralysis with anterior myelitis – California, June 2012 – June 2014. MMWR 2014.63:903-906.
  3. Messacar K, Schreiner TL, Maloney JA, et al. A cluster of acute flaccid paralysis and cranial verve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA. Lancet 2015 (Early online publication Jan 29)
  4. Roos R. Report on polio-like illness in kids supports link to EV-D68. CIDRAP News. Jan. 29, 2015: