EXECUTIVE SUMMARY

If previous patterns hold true, there could be an outbreak this year of acute flaccid myelitis (AFM), the frightening polio-like condition the CDC has been studying since 2014. Public health experts advise frontline providers to be particularly attuned to patients presenting with the hallmark limb weakness, and to report such cases promptly to their state health department.

  • Outbreaks of AFM have been occurring in the United States every other year since 2014, with the largest number of confirmed cases occurring in 2018.
  • Based on the cases seen in 2018, the illness primarily affects young children (average age = 5 years).
  • In most cases, the onset of limb weakness occurs about a week following a non-distinct illness associated with respiratory symptoms and fever.
  • Management of AFM primarily consists of vigilant supportive care, with about one-third of patients requiring respiratory support.

As if frontline providers do not have enough to worry about with COVID-19, the CDC warns 2020 could be another peak year for cases of acute flaccid myelitis (AFM), the frightening polio-like condition that primarily affects children.

Since an outbreak of the neurologic condition in 2014, the illness has tended to reappear in higher numbers in an every-other-year pattern, making 2020 an “on” year for another outbreak.

This prediction is consistent with what epidemiologists believe is the primary cause of the illness: enterovirus D68 (EV-D68), an illness that has been making a more pronounced appearance in the United States in recent years, following the same every-other-year pattern of AFM. The vast majority of children who contract EV-D68, or one of the other viruses that have been linked with AFM, will not go on to develop the serious neurologic symptoms associated with AFM. However, those who do develop AFM may require ventilator assistance. Many face permanent disabilities.

By the end of July, the CDC reported it had confirmed more than a dozen cases of AFM in 2020, and dozens more were under investigation.1 But the peak season for enteroviruses, and likewise for cases of AFM, is August through November, noted Robert Redfield, director of the CDC, during a Vital Signs news conference on Aug. 4 during which he cautioned clinicians to be on the lookout for potential cases.2

“Clinicians need to remain vigilant for AFM and promptly evaluate patients even as frontline healthcare workers, family physicians, and other medical professionals continue to work under the constraints of the ongoing COVID-19 pandemic,” he said. “While phone and telemedicine can be used for initial evaluations, AFM is a medical emergency that requires immediate medical care and monitoring as this condition can progress rapidly to respiratory failure.”

Redfield added that clinicians should not delay in hospitalizing patients with suspected AFM. “We don’t know how the COVID-19 pandemic and the social distancing measures may affect the circulation of enteroviruses or if COVID-19 will impact the healthcare system’s ability to promptly respond to AFM,” he said. “[Cases of] AFM may be fewer this year or the outbreak delayed ... but AFM is a public health priority.”

There has been a national increase in AFM cases every two years since the CDC began surveilling the illness in 2014. The third and largest outbreak occurred in 2018, Thomas Clark, MD, a pediatrician and deputy director of CDC’s Division of Viral Diseases, noted during the Aug. 4 press briefing.2 In that year, the CDC confirmed 238 cases from 42 states, with most cases occurring in young children.

“Most patients with AFM had a fever or respiratory illness about six days before limb weakness onset,” Clark shared. “Once they developed limb weakness, it was common for them also to have difficulty walking, neck or back pain, limb pain, and fever.”

Clark noted many of these patients sought care within one day of developing limb weakness, with most presenting to the ED. “Overall, 98% of these patients were hospitalized, 54% were admitted to intensive care units, and 23% required ventilation,” Clark reported.

While most patients were hospitalized quickly, Clark observed 10% of these patients were not hospitalized until four or more days after they developed limb weakness. “This could indicate delays in recognition of AFM and present an opportunity for improvement in patient outcomes,” he explained.

Although some cases of AFM were associated with other enteroviruses, EV-D68 was the most common one detected in patients with AFM. These cases tended to be more severe, with patients more likely to require treatment in the ICU and ventilation.

“[The] CDC urges clinicians to consider and promptly recognize AFM symptoms, to hospitalize patients immediately, to collect specimens early, and to report all suspected cases to their state or local health department,” Clark said. “The CDC is prepared to respond if an outbreak develops this year, and we will continue to learn about AFM, its risk factors, treatment, and patient outcomes.”

Janell Routh, MD, MHS, medical officer and AFM team lead at the National Center for Immunization and Respiratory Diseases at the CDC, shared more information about the illness with clinicians during a presentation on July 21.3 She noted there have been more than 600 cases of AFM confirmed in the United States since 2014.

Routh noted that during the 2018 outbreak, there was no apparent geographic clustering. “The median age was 5.3 years, and 94% of the cases were pediatric,” she explained. “Of those cases with complete data, 53% identified as white, 20% as white or Black Hispanic, 9% as Black, and 3% as Asian.”

Routh noted the AFM hallmark, limb weakness or paralysis, can progress rapidly in patients with AFM. In the cases confirmed during the 2018 outbreak, 87% showed an increase in the number of cells in their cerebrospinal fluid (CSF), a median white blood cell count of 94, and a lymphocyte predominance, she explained. “The number of limbs affected was variable, with over a third [of patients] presenting with one affected limb, and about a quarter presenting with all four limbs affected.”

Routh added that in the 2018 cohort of cases, there was a predilection for limb weakness in the upper extremities, with 47% of cases exhibiting only upper extremity involvement and 16% showing only lower limb involvement. Ninety-seven percent of cases featured some combination of symptoms that were consistent with a viral illness. “Acute flaccid myelitis patients generally start with a respiratory illness and then develop fever just shortly before weakness onset,” Routh explained.

However, she noted that a relatively small number of specimens return a positive result for a viral illness, making it difficult to conclusively determine a cause for the illness. For example, in the cases identified during the 2018 outbreak, only two CSF samples sent to the CDC returned a positive result: one for EV-D68 and the other for EV-A71. Stool samples revealed a viral illness in 13 samples, and respiratory specimens delivered the highest yield, with 71 delivering a positive result for a viral illness, the most common of which was EV-D68. Overall, less than half of the specimens returned a positive result, Routh reported.

Interestingly, investigators found intriguing information when they examined cases of AFM in peak years in comparison to non-peak years.

“We compared cases in 2016 and 2018, the two years we have complete data for, with [cases from] 2015 and 2017, our non-peak years,” Routh shared. “Peak year cases do appear different. These [patients] were significantly more likely to have [CSF] pleocytosis, a greater proportion with only upper limbs affected, preceding respiratory symptoms prior to weakness onset, and enterovirus or rhinovirus isolated from any specimen.” Routh added that only cases in peak years tested positive for EV-D68.

The cases of AFM identified in non-peak years were significantly more likely to be older, to feature lower limb weakness, and to be more severe than cases in peak years, according to Routh.

“We defined a case as severe if [the patient] had weakness in all four extremities, required mechanical ventilation, and had symptomatic cranial nerve involvement,” she explained. “These data suggest that something different is occurring in peak years that may be driving these clinical distinctions.”

Routh noted the higher detection of EV-D68 in peak years is striking, and adds evidence for an association with AFM during those years. She also said patients diagnosed with AFM in 2018 were more likely to report fever and respiratory or gastrointestinal symptoms before weakness onset. Further, Routh shared there were more cases testing positive for EV-A71 in 2018, which she attributed to an isolated outbreak of AFM in Colorado that year.

“[That] reminds us that many enteroviruses do have the capability to cause AFM. It is important to continue to conduct broad clinical and enterovirus surveillance to understand this full spectrum,” she stressed.

Still unclear is what clinicians can expect to see of AFM this year, considering the COVID-19-related push for physical distancing, masking, and improved hand hygiene practices. “These practices may result in decreased circulation of other viruses, including enteroviruses, and therefore either a decrease or delay in AFM this year,” Routh offered.

It is important for clinicians to understand and recognize the four stages of AFM, beginning with the prodromal illness that often precedes the neurologic symptoms by about a week, according to Kevin Messacar, MD, MPH, who also spoke during the July 21 presentation.3

“This is typically a non-distinct illness that, in over 90% of cases, is associated with fever and respiratory symptoms such as cough, congestion, sore throat, and sometimes asthma-like symptoms such as wheezing and shortness of breath,” said Messacar, a clinical researcher and associate professor of pediatrics at the University of Colorado. “Gastrointestinal symptoms such as vomiting and diarrhea are seen less commonly in around one-third of patients.”

Messacar added that in cases that are associated with particular enteroviruses (e.g., EV-A71), there also may be distinctive lesions on the palms, the soles of the feet, and the back of the throat that are characteristic of hand-foot-mouth disease.

After five to seven days, on average, the second stage of AFM, the onset of neurologic symptoms, generally begins, Messacar noted. At this point, many patients report their prodromal symptoms have resolved or are improving. But once the neurologic symptoms start, fever may return or rise, and there may be meningeal signs such as headaches, which lead to vomiting, neck stiffness, and back pain.

“In older patients, many complain of pain in the limb that ultimately goes on to become paralyzed,” Messacar shared.

Not long after the onset of neurologic symptoms, the third stage of AFM (rapid, progressive neurologic injury) begins with the acute onset of flaccid limb weakness, which is a hallmark of the illness.

“The weakness tends to be asymmetric, affecting one side of the body more than the other. Unlike polio and Guillain-Barré syndrome, it tends to affect the arms more than the legs,” Messacar explained. “The proximal or more central muscle groups, such as the shoulder girdle, are more affected than the distal muscle groups in the forearm and the hand.”

There is a wide spectrum of illness severity that can occur in patients with AFM. For instance, Messacar noted some children are profoundly affected with weakness in all four limbs, while others may experience only mild weakness in just one limb.

“Cranial nerve dysfunction is seen in addition to limb weakness in around one-third of cases. This can present as abnormal eye movements or double vision, asymmetric facial droop, or, most important to recognize, bulbar weakness,” Messacar said, adding that indications of bulbar weakness may require rapid interventions to secure the airway.

The fourth stage of AFM, which can last for weeks to years, is rehabilitation. For any case presenting with acute limb weakness, AFM should be considered in the differential diagnosis. Messacar noted AFM is commonly mistaken for a musculoskeletal injury, with the limb weakness attributed to a recent, unrelated trauma. He also said when the asymmetry and focality of the findings are not appreciated sufficiently, AFM symptoms may be incorrectly attributed to fatigue.

To accurately diagnosis AFM, Messacar said it is important to conduct a careful history, noting when limb weakness occurs following a preceding illness with fever, and to complete a neurologic exam to ascertain strength, tone, and reflexes.

Further, once limb weakness has been identified, MRI of the brain and spinal cord and lumbar puncture are recommended to assist in the diagnosis of AFM. “On MRI, most AFM patients will have a distinctive longitudinal lesion in the spinal cord,” Messacar observed. “Particularly in those with cranial nerve deficits, focal non-enhancing lesions in the brain stem and cerebellum may be present.”

When CSF from the lumbar puncture shows pleocytosis with a normal glucose level and normal or mildly elevated protein, that is supportive of an AFM diagnosis. Messacar recommended collecting biologic specimens as early as possible in the course of disease. These should include CSF, serum, stool, and respiratory sampling.

“It may sound counterintuitive to look in the respiratory tract or GI in a patient presenting with neurologic symptoms, but many of the viruses associated with AFM are not found in CSF or blood at the time of presentation,” Messacar stressed. “Sampling these sites is necessary to detect where the virus may still be shedding.”

Additionally, every suspected case of AFM needs to be reported to the state health department.4 “It is essential to surveillance to understand the burden of disease, and biologic specimens are necessary to further our understanding of how to better diagnose, treat and prevent this disease.”

Management of AFM largely consists of vigilant, supportive care. “Due to the risk of respiratory decompensation, it is recommended that all patients be hospitalized during the stage of progressive neurologic injury,” Messacar said. “Respiratory status should be assessed through examination of the gag reflex, ability to protect the airway, and measurement of negative inspiratory flow to assess respiratory muscle function.”

Messacar added that about one-third of patients with AFM will require respiratory support, with some needing intubation and ventilation for respiratory failure. More common complications in AFM patients include autonomic dysfunctions such as constipation and urinary retention. These may require preventive bowel regimens and catheterization.

“Those with bulbar dysfunction may need enteral feeding tubes to provide hydration and nutrition support,” Messacar added.

Unfortunately, it is unclear which therapies are most effective in treating AFM. Messacar noted most patients receive immunomodulatory therapies such as intravenous immune globulin, which may contain antibodies against potential infectious agents.

Further, high-dose IV steroids are recommended if there is spinal cord edema leading to upper motor neuron signs due to cord compression. Currently, there are no FDA-approved antiviral therapies against the enteroviruses associated with AFM, Messacar reported.

What has been shown to help AFM patients is early, aggressive, and continued rehabilitation. This may include physical, occupational, speech, respiratory, and psychological therapies.

“More recently, nerve transfer — splitting and moving functioning nerves to muscles paralyzed by AFM without functioning nerves — and tendon transfers have led to functional improvements, and may be an option in selected cases,” Messacar explained.

While long-term outcomes in patients with AFM remain unknown, the patients followed since 2014 have displayed some functional improvements with distal, less-affected muscle groups.

“Most of the recovery occurs early, in the first few months. However, continued rehab is important because patients will show slow but steady improvements even a year after onset,” Messacar said. “In total, around 75% of patients will have persistent motor deficits one to two years from onset.”

For clinicians newly confronted with a suspected case of AFM, it may be beneficial to seek added input from neurology and infectious disease experts with experience in managing the disease.

One option available is an AFM Physician Consult and Support Portal offered by the Siegel Rare Neuroimmune Association.5 Here, clinicians can request a peer-to-peer consultation with a neurologist that specializes in AFM.

REFERENCES

  1. Centers for Disease Control and Prevention. Acute flaccid myelitis. AFM cases and outbreaks. Page last reviewed July 31, 2020. 
  2. Centers for Disease Control and Prevention. CDC expects 2020 outbreak of life-threatening acute flaccid myelitis transcript. Press briefing transcript. Aug. 4, 2020.
  3. Centers for Disease Control and Prevention. Public health grand rounds. Acute flaccid myelitis: Answering questions through national collaboration. July 21, 2020.
  4. Centers for Disease Control and Prevention. Job aid for clinicians. How to send information to the health department about a patient under investigation (PUI) for AFM. Oct. 24, 2018. https://bit.ly/2QrPzGf
  5. Siegel Rare Neuroimmune Association. AFM physician consult and support portal.