Acute Flaccid Myelitis: A New Epidemic?
Alison Christy, M.D., Ph.D., Pediatric Neurologist
In the summer of 2014, respiratory symptoms associated with Enterovirus D68 (EV-D68) brought over one thousand children nationwide to the hospital. That same summer, eleven children came to Children’s Hospital Colorado with new, unusual symptoms: asymmetric weakness of the arms or legs, sometimes accompanied by double vision, problems swallowing, or neck weakness, with decreased reflexes in the affected limbs, and long lesions on spinal cord imaging. Four of these children tested positive for EV-D68 in respiratory secretions.
Since then, surges in EV-D68 infections in 2016 and 2018 have been associated with increasing numbers of cases of acute flaccid myelitis (AFM). The Centers for Disease Control (CDC) have confirmed over 500 cases of acute flaccid myelitis in the United States between 2014 and 2018, and additional cases have been reported worldwide. What do we know about this disease, and what are we doing about it?
Presentation of Acute Flaccid Myelitis
AFM occurs almost exclusively in the pediatric population, with a median age of four years, although adult cases have been reported. There is no association with particular racial or ethnic groups, or with vaccination status.
Usually, infections with EV-D68 and other enteroviruses cause no symptoms at all, or only mild to severe respiratory symptoms. Rarely, following a respiratory illness (or less frequently gastrointestinal symptoms), affected children develop asymmetric weakness over hours to days. The paralysis usually affects the upper extremities more than the legs, with proximal muscles more affected than distal muscles. Reflexes are decreased or absent in the weakened limbs. Cranial nerve abnormalities can include facial droop, double vision and difficulty swallowing. Usually sensation is intact, and seizures or encephalopathy are rare.
Magnetic resonance imaging reveals T2-hyperintensity of the central gray matter of the spinal cord. White blood cells are usually elevated in the cerebrospinal fluid, and protein may be elevated as well. The combination of hyporeflexia, gray-matter predominant spinal cord lesions on imaging, and cerebrospinal fluid findings can confirm AFM.
All patients diagnosed with AFM have tested negative for poliovirus, another enterovirus that can cause similar symptoms, usually with greater paralysis in the lower extremities. It can be challenging to detect an associated EV-D68 infection, due to delays in diagnosis and shedding of virus at different sites. As soon as acute flaccid myelitis is suspected, nasopharyngeal, oropharyngeal, rectal, blood, and cerebrospinal fluid specimens for microbiologic testing should be collected.
Treatment and prognosis
The destruction of the anterior horn cells of the spinal cord may be caused by an active infection, or by abnormal inflammation, provoked by infection. Treatment has focused on either modifying inflammation or inhibiting replication of the virus.
Steroids, commonly used to suppress inflammation, have not been found to be helpful, and could potentially worsen an infection. Most patients with AFM have received intravenous immunoglobulin (IVIG), but without controlled human trials, we do not know whether this treatment improves outcomes. Fluoxetine (Prozac) prevents Enterovirus D68 replication in vitro, but in initial studies shows no clear benefit in AFM.
Most patients improve regardless of choice of treatment, but many have persistent weakness when they leave the hospital. With intense rehabilitation, some patients continue their recovery for over a year from disease onset.
What comes next?
Physicians specializing in neurology and infectious disease, along with epidemiologists, biologists, virologists and geneticists at institutions around the country, including the Centers for Disease Control (CDC), the Virus Pathogen Resource, Children’s Hospital Colorado, Johns Hopkins University, Stanford University, Mayo Clinic, University of California at San Francisco, Columbia, Vanderbilt, University of Maryland, Boston Children’s Hospital, Children’s National Hospital and Children’s Hospital of Philadelphia, are working together to predict, prevent, and treat acute flaccid myelitis.
Two animal models have been developed to allow further testing of treatments and outcomes. A mouse model developed at Children’s Hospital Colorado uses neonatal mice infected intracranially, intraperitoneally, intramuscularly, or intranasally with contemporary strains of EV-D68. These mice then develop flaccid limb weakness (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322875). Another model developed at Utah State University’s Institute for Antiviral Research involves 10-day-old mice who are deficient in a receptor for the cytokine interferon αβ/γ. Intraperitoneal infection of these animals leads to flaccid limb weakness as well (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795446).
The Centers for Disease Control are collecting information and specimens on all patients with acute flaccid limb weakness, regardless of imaging or laboratory results. Clinicians should contact their state health department or the CDC directly to report all suspected cases and submit specimens for testing (https://www.cdc.gov/acute-flaccid-myelitis/afm-surveillance).