EXECUTIVE SUMMARY

Confirmed cases of acute flaccid myelitis (AFM) in 2018 reached 90 by the end of October, according to the CDC. This is the third such spike since 2014 as outbreaks of the baffling disease have occurred in the United States every other year. While the CDC has yet to confirm what is causing AFM, experts strongly suspect that the disease stems from common viral infections. Still, it is not yet clear why just a small number of patients go on to experience paralysis in one or more limbs, a characteristic disease feature.

  • AFM, which mostly affects children, typically follows a preceding respiratory or gastrointestinal illness. It is characterized by the rapid onset of weakness in one or more limbs and the emergence of spinal cord gray matter lesions.
  • The CDC is depending on frontline providers to ensure that appropriate specimens are collected from suspected AFM patients and to route specimens quickly through their health departments to the CDC.
  • While there are no consensus guidelines, the CDC has published interim considerations for the clinical treatment of AFM. Drafted in 2014, the considerations have been updated recently following a peer review of the latest literature and consultation with national experts.
  • Currently, the three main treatments used for AFM are IV immunoglobulin, corticosteroids, and plasmapheresis.

The number of confirmed cases continues rising. Still, public health authorities are not ready to state definitively what causes acute flaccid myelitis (AFM), a rare but frightening condition that is characterized by the rapid onset of weakness in one or more limbs and spinal cord gray matter lesions.

While the existence of AFM has been recognized for years, cases surged during the autumn months, the third such spike in the past six years. From January through October 2018, the CDC reported there were 90 confirmed cases of AFM, with the vast majority occurring in children younger than 18 years of age.

“In 2016, there were about 150 confirmed cases. In 2014, there were about 120 confirmed cases. That is the pattern we have seen so far,” observes Olwen Murphy, MB, BCH, MRCP, a neurologist and fellow at the Johns Hopkins Transverse Myelitis Center. “Every couple of years, this has been occurring between August and November.”

Most patients present to EDs or urgent care centers. Providers in these settings need to be particularly attuned to the signs and symptoms that differentiate AFM from other ailments. However, frontline clinicians have been frustrated at the dearth of guidance on what is causing the disease and how to manage such patients.

“It is just unusual that [several] years into a novel illness in the United States that we have no cause,” notes Ali Khan, MD, MPH, former director of the CDC’s Office of Public Health Preparedness and Response. “It is disturbing and very tragic for any child to find themselves paralyzed, especially since I have seen case reports of very significantly affected children ... but until you can identify what it is, you can’t drive a prevention strategy, nor can you drive a treatment strategy.”

The CDC has not collected all the evidence it needs to make definitive statements about what is behind the recent AFM outbreaks. However, experts say the fact that most identified cases are preceded by a respiratory or gastrointestinal illness is strongly suggestive of an association with circulating viruses.

“[AFM] is probably a very rare complication of common infections. We suspect that these viruses, in particular enterovirus D68, infect a lot of people,” Murphy notes. “For example, in 2014, the first outbreak of D68 occurred. There were over 1,300 cases notified to the CDC; yet, there were probably tens of thousands more that went unnoticed in the community. Still, less than 120 children actually developed AFM.”

The timing of the AFM outbreaks also is suggestive of an association with specific enteroviruses. “[AFM outbreaks] seem to come before a lot of other viruses,” says Murphy, noting that there is evidence that these outbreaks depend on climate factors such as humidity and temperature for their circulation in the population. “The typical pattern that we have seen over the last three outbreaks has been [a surge in cases] from August to October or November. Then, as the weather starts getting cooler, the cases seem to drop off quite quickly.”

Murphy adds that it is likely that less than 1% of people who experience these kinds of viral infections go on to show neurological manifestations. Consequently, while the viruses themselves are transmitted from one person to another, the neurological manifestations are not, she says.

“There is a slightly different perspective from the CDC compared to neurologists and infectious disease specialists dealing with [AFM] on the ground,” Murphy explains. “The CDC would really like to have some definitive lab evidence [so they can] understand the biological processes of how enterovirus D68 [or other pathogens] could cause this before they say it is definitely linked. But from a more basic epidemiologic perspective, we have quite strong — but not 100% — evidence that the two things are linked.”

What is not so clear is why AFM occurs most often in children. There are a couple of dominant theories. “There is reasonable evidence that enteroviruses, and in particular the enteroviruses D68 and A71, may be causing these outbreaks of AFM. It is possible that adults have encountered various enteroviruses over their lifetimes and have some immunity,” Murphy offers. “The other possibility is that in children, there is a marked immune response and more secondary inflammation — that is what is causing the problem in the spinal cord ... compared to an adult’s immune response.”

It has been well reported that there is an informal, multidisciplinary group of experts that is ahead of the curve in determining what is causing AFM and how to diagnose and manage patients with the condition most effectively. That is not unusual, according to Khan, who today serves as the dean of the University of Nebraska’s College of Public Health.

“It is not unusual at all for excellent clinical groups across the U.S. who are seeing most of these cases to be actively involved in trying to identify what is going on and to be collaborating with others across the U.S.,” he says. “It is something we encourage that is good. We want clinicians to be actively engaged in thinking about what this could be due to, identifying potential cases, and making sure that samples get to the right place.”

Khan’s advice to clinical and administrative leaders in the ED is to make sure everyone working in the department is aware of this illness. “Not just physicians, but the people who do the check-ins and triage as well,” he stresses. “There may be a child that we need to make sure that we pay extra attention to and report to the state and local health departments.”

While it continues to investigate the etiology of AFM, the CDC is taking steps to equip clinicians with all the evidence it has collected to date. In a call with practitioners conducted on Nov. 13, a panel of experts updated practitioners on what is known about the clinical presentation of AFM.

Sarah Hopkins, MD, MSPH, section head of multiple sclerosis and neuroinflammatory disorders in the division of neurology at Children’s Hospital of Philadelphia, explained that in patients with AFM, the onset of weakness in the limbs can be rapid. In some cases, onset may progress over four or five days. “The weakness occurs in one or more extremities and may be accompanied by a stiff neck, headache, or pain in the affected extremity,” she noted.

Typically, patients complain of neck, shoulder, or back pain before the onset of limb weakness. The pain in an affected limb may be severe, leading to an initial diagnosis of an injury.

“Cranial nerve abnormalities can be present. These can include a facial or eyelid droop, difficulty swallowing or speaking, and a hoarse or weak cry,” Hopkins explained.

Although such symptoms can be indicative of other illnesses, a diagnosis of AFM should be considered, particularly when there have been preceding viral symptoms and the timing is in the late summer and fall, Hopkins offered. To narrow potential diagnoses, she recommended that clinicians conduct a thorough medical history, including collecting details about any illness in the previous four weeks as well as respiratory or gastrointestinal symptoms and fever.

“We suggest asking about hand-foot-and-mouth disease, as we know that viruses associated with [this ailment] are also associated with AFM, such as enterovirus A71, which was noted in the outbreak [of AFM] this year in Colorado,” Hopkins said. Other symptoms to ask about include decreased appetite; difficulty swallowing; increased sleepiness or inactivity; pain in the head, shoulder, back, or extremities; difficulty holding the head up; and bowel or bladder changes.

The CDC is depending on frontline providers to ensure that appropriate specimens are collected from potential AFM patients, and that these are routed quickly through their health departments to the CDC. Hopkins noted that investigators have found that rapid collection is essential to increasing the opportunity to identify pathogens. (Editor’s Note: Specific instructions on what specimens to collect and what procedures to follow are available at: https://bit.ly/2Q86E9y.)

When examining a patient, Hopkins noted that it is important to pay close attention to muscle tone and the reflexes in each extremity. “Look for asymmetry in muscle strength and gait,” Hopkins said. “Parents often report that their child appears clumsy when trying to pick up objects, or they notice that a foot is dragging, the child is limping, or refusing to walk entirely,” she advised.

Clinicians should be attuned to the fact that the weakness associated with AFM tends to be proximal or more centralized. “A child may have normal finger movements, but be unable to lift an arm above his head,” Hopkins said. “Having the child sit on the floor and stand, or squat and recover, are easy ways to assess proximal lower extremity strength.”

Generally, in patients with AFM, a sensory exam is normal. Nonetheless, this is an important exam to conduct and document because it contributes to the differential diagnosis. Hopkins further recommended that clinicians conduct a thorough cranial nerve assessment to detect any facial or shoulder strength asymmetry, and to assess for hoarseness or a softening in speech volume.

If an emergency clinician suspects a diagnosis of AFM, hospitalization is recommended, in part, because of the potential for rapid deterioration in limb weakness and respiratory distress. “We have had several patients who presented who were doing quite fine and seemed to just have upper extremity weakness. Then, they very rapidly progressed to respiratory difficulty,” Hopkins noted.

Hopkins added that hospitalization may provide an opportunity for earlier specimen collection and possible pathogen detection. Also, it is easier to conduct an MRI that might confirm AFM. Working with staff neurologists and infectious disease experts could facilitate faster, better consultation to guide the case management process.

When it comes to treatment, there is little published evidence to rely on other than case reports or patient case series, noted Janell Routh, MD, MHS, medical officer for the AFM team at the CDC, during the Nov. 13 call. Further, she noted that treatments usually are administered in combination or sequentially, making it difficult to identify the effect of a single agent.

Consequently, to establish some guidance for clinicians, the CDC has been consulting with subject matter experts from a range of disciplines, including infectious disease, neurology, pediatrics, critical care medicine, virology, and public health epidemiology.

Routh noted that opinions from these individuals formed the basis for interim considerations for the clinical treatment of AFM. Drafted in 2014, these considerations have been updated recently following a peer review of the latest literature and further consultation with national experts. (Editor’s Note: Learn much more information about the considerations at: https://bit.ly/2S4Zu34.)

Routh stressed that the interim considerations are not consensus recommendations or official guidelines, but rather a summary of approaches experts used to treat AFM. Currently, the three main treatments used for AFM are IV immunoglobulin, corticosteroids, and plasmapheresis.

“There is not enough human evidence to indicate a preference or an avoidance of their use at this time,” Routh noted. “The possible benefits of using corticosteroids for spinal cord edema or white matter involvement must be balanced by the possible harm due to immune suppression in the setting of a viral infection.”

Although fluoxetine has demonstrated activity against enteroviruses, there is no indication for its use in AFM patients as it has not demonstrated improvement in neurologic outcomes, Routh said. She added that there are no data to indicate the use of any other antiviral medications or for the use of interferon in AFM patients. Routh reiterated that clinicians should make treatment decisions in conjunction with neurologists and infectious disease experts when managing the care of a patient with AFM.

(Editor’s Note: For more information about treatment considerations and CDC’s activities in conducting surveillance and establishing the cause of AFM, visit: https://bit.ly/2C7CL1S. Also, clinicians who are unable to access specialized input on a diagnosis can contact the Transverse Myelitis Association, which then can connect clinicians with AFM expertise in their region: https://bit.ly/2s1VYut.)

SOURCES

  • Ali Khan, MD, MPH, Dean, College of Public Health, University of Nebraska; Former Director, Office of Public Health Preparedness and Response, Centers for Disease Control and Prevention, Atlanta. Email: ali.khan@unmc.edu.
  • Olwen Murphy, MB, BCH, MRCP, Neurologist and Fellow, Johns Hopkins Transverse Myelitis Center, Baltimore. Email: omurphy2@jhmi.edu.