It’s an epidemiological mystery with no clear culprit just yet.

This Tuesday, a group of researchers in JAMA reported their findings on a polio-like illness that has afflicted 59 people in the California area since 2012, and killed two. These cases of acute flaccid myelitis, as it’s more formally known, leave the sufferer with varying but rapidly worsening degrees of muscle weakness and paralysis, primarily affecting the limbs. Though they found some encouraging evidence for a possible origin — a bug that normally causes respiratory illness called enterovirus D68 — the researchers cautioned that we’re still largely in the dark when it comes to understanding the condition.

“The etiology (cause) of acute flaccid myelitis cases in our series remains undetermined,” they wrote. “Although the syndrome described is largely indistinguishable from poliomyelitis on clinical grounds, epidemiological and laboratory studies have effectively excluded poliovirus as an etiology.”

An Old Enemy With A New Face

With the defeat of polio a half-century ago, cases of paralysis brought on by infection have either been virtually non-existent or gone unnoticed within the U.S. ever since, barring the occasional West Nile infection or a rare complication known as Guillain-Barré syndrome. In the past year, however, a string of these cases have occurred among children in various states. According to the Centers for Disease Control and Prevention, there have been 120 verified cases of acute flaccid myelitis in 34 states from August 2014 to June 2015, with sporadic reports continuing to trickle in.

The California Department of Public Health (CDPH), perhaps slightly ahead of the curve, opted to expand its surveillance of neurological conditions possibly tied to infection in 2012. Using the CDPH data, the current JAMA authors were able to track down 59 cases of acute flaccid myelitis left unexplained by other known causes within the state from June 1 2012 to July 31 2015. Aside from the prerequisite limb weakness, which can progress to respiratory failure and require a ventilator, the researchers also looked for people whose MRIs showed signs of inflammation in their spinal cords, or myelitis (only 3 didn’t have conclusive MRIs, though there was evidence of it elsewhere).

In these 59 cases, nearly all experienced signs of a respiratory or gastrointestinal illness (54) immediately before their muscle weakness. Thirty would go on to have bowel problems caused by their neurological damage, 21 had strange physical sensations like prickly skin, and 20 would need a ventilator. Of the 2 deaths, both occurred in older adults who were already severely immunocompromised (one had HIV/AIDS). Despite that, the median age of patients was 9 years.

The use of steroids to treat patients’ muscle weakness appeared to do nothing, and of the 45 patients with available clinical data at 9 months follow-up, only 6 achieved full motor recovery (a 7th occurred at the >12 month mark). Coupled with the circumstances behind the deaths, these findings suggest “that immunosuppressive treatment regimens for patients with acute flaccid myelitis should be considered cautiously,” the researchers wrote.

A 'Novel Clade'

Though all the patients had submitted biological samples, delays in reporting only allowed 45 of these to be tested in the lab. Of those, 20 carried signs of a possible infectious agent, with 9 showing consistent evidence for enterovirus D68, though an additional 6 had evidence of another member of the enterovirus species. These findings support earlier research that found D68 in some patients. As added support for the D68 hypothesis, they also noticed an uptick in cases of acute flaccid myelitis at the same time that an outbreak of the virus swept the country from August 2014 to January 2015.

Enteroviruses are a diverse group, with upwards of 60 species known to cause human disease. These include the titular poliovirus, as well as the rhinoviruses, the main source of the common cold. Up until now, D68 was only thought to resemble the common cold if and when it did sicken a person. As the researchers note, however, there’s emerging evidence elsewhere that the strain cultured from these patients has become more genetically similar to the poliovirus. This “novel clade” is thought to have sprouted up at least 4-and-a-half years ago.

Though the circumstantial proof for D68’s new villainous turn is sturdy enough, there still isn’t a smoking gun. The researchers weren’t able to find it nor any other virus in the patients’ spinal fluid (other studies have found D68 in spinal fluid, but not to a large extent). Without further verification, it’s entirely possible that D68 might be a red herring, coincidentally infecting people at around the same time as the true cause of the illness.

Disheartening as that might be, if nothing else, this latest study does at least provide future researchers with a more cohesive strategy to better fight back against this enigmatic illness.

“To our knowledge, the California surveillance program for acute flaccid paralysis is the first to use specific case criteria and report subsequent incidence data for the subset of paralysis cases attributable solely to acute flaccid myelitis and may serve as a guide for similar surveillance efforts in the future,” the authors concluded.

Source: Van Haren K, Ayscue P, Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015. JAMA. 2015.