ARTICLE IN BRIEF
Officials from the CDC and experts in neuroinfectious disease discuss the uptick in the number of cases of acute flaccid myelitis, a polio-like illness that has been linked to certain enteroviruses. They describe what clinicians should look for and how to treat it.
Amid a resurgence of acute flaccid myelitis (AFM) in children, medical experts are urging doctors to be alert for possible cases of the rare, debilitating polio-like illness.
At press time, the Centers for Disease Control and Prevention (CDC) confirmed 90 cases of AFM, with more cases still being investigated. The neurologic condition involving the spinal cord often is marked by a sudden onset of motor weakness and can result in paralysis that does not resolve.
The cause of AFM is not known, though researchers are focused on enteroviruses as a possible culprit, particularly the strains EV-D68 and EV-A71, common viruses that affect the digestive systems of children. Strains of rhinoviruses, which cause the common cold, have also been detected in some cases. There is also an immune-response component to AFM.
AFM cases, which have been reported in 27 states so far this year, are expected to decline as winter approaches, but experts say ongoing vigilance is needed because another cycle of illness is likely to occur over the next few years as common viruses continue to mutate into possibly troubling strains.
Since August 2014, the CDC has reported 396 confirmed AFM cases, mostly in children. A CDC graphic of cases shows spikes in late summer and fall 2014, during similar months in 2016, and now again in late summer and fall 2018.
“This is a horrible disease with long-term consequences. The outcomes are frequently difficult,” said Carlos A. Pardo, MD, associate professor of neurology at Johns Hopkins University and an AFM researcher and clinician at the Johns Hopkins Transverse Myelitis Center. He is helping to spearhead a multicenter working group of experts developing consensus guidelines for AFM diagnosis and treatment.
Kathleen Dooling, MD, MPH, a medical epidemiologist in the CDC's Division of Viral Diseases, said most patients experience sudden weakness and loss of muscle tone and reflexes in the arms and legs. Some patients have facial droop or weakness, difficulty moving their eyes, drooping eyelid, difficulty with swallowing, or slurred speech.
“The CDC has tested specimens to look for causes of AFM, but to date no pathogen has been consistently detected in the patients' spinal fluid,” Dr. Dooling said in an email to Neurology Today. “A pathogen detected in spinal fluid would be good evidence to indicate the cause of AFM since this condition affects the spinal cord.”
It is not known whether the damage to the motor neurons is a direct effect of a virus, a result of the body's immune response to the viral infection, or a combination of the two. EV-D68 has been detected in some children with AFM, but not all, as has EV-A71. Adenoviruses are thought to be another possible cause of some cases of AFM.
EV-D68 has been detected in some children with AFM, but not all, as has EV-A71. Strains of rhinovirus, which cause the common cold, have also been found in some AFM patients, Dr. Pardo said. It is possible an immune response to enteroviruses or rhinoviruses may be a mechanism of neuronal damage in AFM, but that needs more research, he said.
Also not understood is why most children get only mildly sick, or not at all, from infections with common circulating viruses, while a tiny fraction develop neurologic complications. Some children recover fairly quickly from AFM, while others have ongoing paralysis that requires longer-term care. In part because the disease is rare, there is no established protocol for diagnosing and treating patients.
MAKING A DIAGNOSIS
Diagnosis is typically made with a combination of a physical and neurologic exam, magnetic resonance imaging, and various testing (antibody studies, viral PCRs and RT-PCRs) of biologic specimens, including cerebrospinal fluid, blood serum, stool, and a nasopharyngeal swab.
Treatments that have been tried include intravenous glucocorticoids, IV immunoglobulin, or plasma exchange, but it is not known which, if any of these, are effective, experts told Neurology Today.
“The cases are rare and sporadic and spread across the country, so it is going to be hard to establish the gold standard,” said Kenneth L. Tyler, MD, FAAN, chairman of neurology and professor of medicine and immunology-microbiology at University of Colorado School of Medicine. He has been involved with AFM cases at Children's Hospital Colorado.
“The honest answer is we don't know what works in these cases and there is no therapy with truly proven benefit,” said Dr. Tyler. He said he is leery about using steroids for AFM because he thinks they may make things worse, and no-anti viral drug seems beneficial.
He and colleagues published a report in Neurology last year of one-year outcomes for a group of Colorado children diagnosed with AFM. Six of eight children who were assessed periodically had persistent motor deficits, particularly with weakness in proximal muscles, and two demonstrated full recovery at one year. Dr. Tyler said his experience has shown that children with AFM who test positive for EV-D68 may fare worse than those with EV-A71.
Dr. Tyler has helped developed a mouse model for AFM, which is being used to test treatments and to figure out the pathogenesis of the condition. He has received funding from the National Institutes of Health for research related to EV-D68 and development of animal models.
“How does this virus get to, infect and kill neurons, especially spinal neurons?” Dr. Tyler asked. He and colleagues described in a recent paper how EV-D68 is able to enter and replicate in neuronal cells in mouse models and in cell cultures. Identifying genes that may increase susceptibility to severe complications from common viral infections is another priority.
“A viral illness that paralyzes hundreds of kids is not high in case count epidemiology, but it is very high on the emotional scale in our post-polio era,” Dr. Tyler said. “Most people now alive don't remember what it was like when polio was around.”
HOSPITALS ARE MONITORING
Sarah Hopkins, MD, a pediatric neurologist and section head for multiple sclerosis and neuroinflammatory disorders at Children's Hospital of Philadelphia, said although AFM is rare and there are peaks and valleys in the number of cases, it's important for hospitals to have a set system in place for dealing with possible cases. She began in 2014 to educate medical residents about AFM and has helped establish protocols for diagnosing and treatment. The emphasis is on “maximizing how quickly we get samples” and an MRI to look for telltale lesions in the gray matter in the spinal cord, Dr. Hopkins said.
“One of the problems we have is that some of our patients have already been in one or two hospitals and when they arrive at our center many of the biological samples may be deteriorated,” said Dr. Hopkins. Prior treatments may affect newly collected samples.
She strives to have frank discussions with parents early on about what's going on.
“I think it's important for them to know that this a very serious infection and that it's a long road to recovery, and we don't know at the moment what is the best thing to do with AFM,” she said.
Patients with upper body weakness need to be carefully watched for signs of breathing complications. Down the road, some patients with ongoing limb weakness on one side may benefit from nerve transfer surgery, though intensive physical and occupational therapy is most important, Dr. Hopkins noted.
Dr. Hopkins said Children's Hospital has established a neuroscience biorepository to store leftover biologic samples from AFM patients that can be used for research into viral and immune factors and “what it is about certain children and their immune system that predispose them to getting paralysis instead of just a common childhood illness.”
She is also a part of the AFM working group with Dr. Pardo at Johns Hopkins. Dr. Pardo said the group, which receives support from the Transverse Myelitis Association, is focused on a spectrum of issues, including clinical assessment and management, laboratory methods and diagnostics, intensive care unit management, neurophysiology, research opportunities, and rehabilitation.
“We need to focus on the causes and etiologies of acute flaccid myelitis. We need to clarify if this is the result of direct viral infection of the spinal cord (causing damage to motor neurons) or if it is the effect of an immunological response that has been triggered by a viral infection,” said Dr. Pardo, who serves on the scientific advisory board of the Transverse Myelitis Association and received research support from the NIH, Medimmune Oncology, and the Bart McLean Fund for Neuroimmunology.
“At the national level we need to establish better protocols for early diagnosis of the disease and raise awareness of the disease,” he said. Creating a national repository of AFM samples that can be used for research is also a goal of his group.
Dr. Pardo and colleagues recently published a paper in Developmental Medicine & Child Neurology showing that even as MRI images suggest improvement in a patient's condition, muscle weakness and disability often persist.
“These kids can be very disabled,” he said. “Many are left with atrophy of muscle groups and most of them are left with difficulties with gait and ambulation and a few with respiratory difficulties.”
Marc Patterson, MD, professor of neurology, pediatrics and medical genetics at Mayo Clinic in Rochester, MN, said his center has seen several cases of children with AFM. He said while there needs to be more awareness of the condition among medical practitioners and parents, it is also important to remember that most of the time when children get infected with common viruses such as enteroviruses the symptoms are mild or may not even be noticeable.
He said researchers need to figure out if “there are some genetic factors that make children susceptible” to developing AFM.
“The take-home message for parents is to prevent viral infections as best they can with hand washing and sanitizers,” Dr. Patterson said.