Neurovirologists Confer Over Mysterious Neurologic Disease

Pauline Anderson

October 17, 2014

Although the neurovirology community in the United States is relatively small — probably at most a few hundred specialists — these doctors are abuzz with shop talk.

The topic of conversation? The recent spate of neurologic disease suspected to be related to a human enterovirus called D68 (EV-D68).

They're conferring and comparing notes on the clusters of this disease popping up across the country, according to Avindra Nath MD, chief, Section of Infections of the Nervous System, Clinical Director, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, and president, International Society of Neurovirology, Bethesda, Maryland.

"I spent all day Sunday talking about this to multiple neurologists around the country," Dr Nath told Medscape Medical News. "Everyone wants to know what's happening."

His colleagues, he said, are discussing how to diagnose this mysterious disease, and how to treat, investigate and monitor it.

"People are putting their heads together, trying to figure out how we can team up to answer these questions," said Dr Nath. "We don't have all the answers, but we're asking the right questions."

Neurologists and others have been alerted to a cluster of acute neurologic illness of unknown cause, characterized by focal limb weakness and abnormalities of the spinal cord gray matter, occurring in children in Colorado, and to cases of acute flaccid paralysis with anterior myelitis that have occurred in California over a 2-year period.

The Centers for Disease Control and Prevention (CDC) described these clusters in separate issues of Morbidity and Mortality Weekly Report earlier this month, reported by Medscape Medical News at that time.

Prevailing Wisdom

But there are other similar clusters across the country, according to Dr Nath. For example, cases have been reported at Children's Hospital in Philadelphia, Pennsylvania, and "sporadic cases" emerging elsewhere across the country.

The "prevailing wisdom," he said, is that these cases are all connected. Many of the children have presented with similar extremity weakness, nerve dysfunction, and brain stem involvement, he said.

These clusters represent a unique, "not a garden variety," syndrome that has been seen previously only in the context of polio, said Dr Nath. "So you have this polio-like illness that is occurring in kids that we haven't really noticed before."

Since almost all the children — in both the Colorado and California cases — are presenting with fever, "you start to wonder that maybe it's some viral pathogen that's causing it."

But although experts believe EV-D68 is the culprit, they haven't confirmed a connection between the neurologic disease and any infectious agent, said Dr Nath.

However, he noted that although finding EV-D68 in the cerebrospinal fluid of the children is proving difficult, investigators have found the virus in the nasal mucosa.

"It's very hard to prove causation; the best you have is epidemiological evidence to show that there may be an infection associated with a neurologic disease, but trying to prove that it's actually this same pathogen that's causing it requires another level of interrogation."

In any such circumstance, it takes time to cement the cause and effect.

Dr Nath pointed out that it took years to convince people that AIDS was the result of HIV.

"Even though huge public health measures were in place to convince everybody that HIV actually caused AIDS, it took many, many years."

Not Just Kids

Enteroviruses are among the most common human pathogens. They can cause a wide range of clinical symptoms, from mild febrile illness to fatal meningitis and encephalitis.

EV-D68 was first isolated from samples obtained in California in 1962 from four children with pneumonia and bronchitis, according to a paper published by Tokarz et al in the Journal of General Virology (2012;93:1952-1958). Compared with other enteroviruses, EV-D68 is biologically more similar to human rhinoviruses in that it's mainly associated with respiratory disease.

Although there now appears to be a global upsurge of EV-D68–associated respiratory illness, it's possible that the increase merely reflects improved case ascertainment, according to some experts.

"In previous studies of respiratory disease, EV-D68 may have been misidentified as a rhinovirus which would lead to underestimation of its prevalence and importance," Tokarz and colleagues write.

"Continued efforts toward the improvement of diagnostic techniques and surveillance are necessary to further assess the epidemiology of EV-D68 and to assess its role in respiratory disease," they add.

As with these newer clusters, most (about 80%) of the previously reported EV-D68 cases were in children. However, this might be because these reports highlighted only pediatric cases.

According to Tokarz et al, one report from the Netherlands, which focused on screening for the virus in archived respiratory samples without age bias, noted a preponderance of adult cases. A relatively large EV-D68 cluster in patients aged 14 years and older was also reported in New York City.

"We anticipate that, with increased screening, EV-D68 may ultimately be recognized as a respiratory pathogen in all age groups," they write.

Polio-like Syndrome

Why is this polio-like syndrome emerging now? Although it's only speculation, some experts believe that as some enteroviruses are eliminated — for example, the poliovirus — it leaves a vacuum for others to emerge in its place.

Dr Nath stressed, though, that this doesn't mean EV-D68 will cause the same devastation that polio did in the 1940s and 1950s. Polio was a much more virulent infection and spread more rapidly than what we're seeing now, he said.

As well, he added, "with polio, you didn't have a lot of asymptomatic infection; you got the infection, you got the disease, but here, thousands of people get the infection, but very few actually develop the disease."

To develop a vaccine against this particular pathogen might become an important endeavour, depending on such factors as how rare and how variable the virus turns out to be, said Dr Nath.

Dr Nath stressed that EV-D68 doesn't always result in neurologic symptoms; in fact, such symptoms are occurring in "only a handful of people," he said.

But even though few affected patients have neurologic involvement, "this needs to be monitored more carefully," he said.

He stressed that other conditions can sometimes mimic these neurologic syndromes. "All these patients need to be investigated appropriately and part of the investigation should include looking for this virus."

Getting the Word Out

Meanwhile, experts are putting their heads together to discuss possible treatment approaches that include existing drugs.

"The neuro infectious community is small and we all know one another fairly well, so when something like this happens, we talk to one another," said Dr Nath. "Lots of ideas are being thrown around and are gradually being crystalized."

He praised the CDC for doing "a great job getting the word out" and said that the public health system is "very effective in managing" these kinds of outbreaks.

"The message is getting out there."

Part of that message, he added, is that doctors should evaluate adults as well as children who present with a respiratory illnesses, to make sure they don't have any neurologic deficits.

"And for patients coming in with acute neurological deficits, they should ensure that there isn't an infectious etiology there. If they find something, they should report it to the public health service and, as with other neurological patients, provide supportive treatment until they get better."

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