Acute flaccid myelitis

Acute flaccid myelitis (AFM) is a rare but serious^[1] neurologic illness of sudden onset, usually in children. It presents with localised limb weakness of unknown cause. A leading candidate for the cause of the condition is enterovirus 68, a member of the enterovirus genus and thus related to poliovirus. Although the illness is not new,^[1] its increased incidence since 2014 is new;^[1] the existing literature about it is tentative and should not be taken as established medical opinion. There is no established treatment for the condition or the virus that may cause it.

Signs and symptoms

Symptoms of AFM include:

• Difficulty moving the eyes or drooping eyelids
• Facial droop or weakness
• Difficulty with swallowing or slurred speech
• Sudden arm or leg weakness^[2]

A summary of the condition was issued by the United States Centers for Disease Control as part of a September 26, 2014, health advisory:^[3]

The CDPHE, Children's Hospital Colorado, and CDC are investigating nine cases of acute neurologic illness among pediatric patients. The cases were identified during August 9–September 17, 2014 among children aged 1–18 years (median age 10 years). Most of the children were from the Denver metropolitan area. All were hospitalized. Common features included acute focal limb weakness and specific findings on magnetic resonance imaging (MRI) of the spinal cord consisting of non-enhancing lesions largely restricted to the grey matter. In most cases, these lesions spanned more than one level of the spinal cord. Some also had acute cranial nerve dysfunction with correlating non-enhancing brainstem lesions on MRI. None of the children experienced altered mental status or seizures. None had any cortical, subcortical, basal ganglia, or thalamic lesions on MRI. Most children reported a febrile respiratory illness in the two weeks preceding development of neurologic symptoms In most cases, cerebrospinal fluid (CSF) analyses demonstrated mild-moderate pleocytosis (increased cell count in the CSF) consistent with an inflammatory or infectious process

The CDC requested that physicians provide information about cases meeting four criteria: patients diagnosed after August 1, 2014, who are no older than 21 years of age, showing acute onset of focal limb weakness, with a spinal cord lesion largely restricted to grey matter visualized by MRI.^[3][4]

A group in Texas reported having observed a pattern in 2013 of one to four cases per year with similar polio-like characteristics.^[5]

The CDC Morbidity and Mortality Weekly Report^[6] and a CDC Clinician Outreach and Communication Activity (COCA) conference call,^[7] noted that many cases had neck, back, or extremity pain, but otherwise those affected generally had normal sensation in their limbs.^[8] A few participants in the conference call discussed whether pain, later abating, might precede the onset of paralysis.^[7][9]

An October 21 report in Neurology News described outbreaks in California and Colorado, suggesting that the number of cases might be 100 or more nationwide. Diagnosis included a good medical history, MRI imaging, and the elimination of transverse myelitis or Guillain–Barré syndrome as potential causes. Physicians were using a listserv online mailing list to communicate about similar cases in Alabama and Kansas. The largest known cluster of cases was in Colorado, with 29 total, 12 of which were reported since August.^[4]

Three out of four cases treated in Alabama involved a complete inability to move one arm, reminiscent of peripheral nerve injury:

The three cases since August really look like each other. They have severe arm flaccidity and no mental status changes. All of them have similar spine MRIs showing gray matter involvement. You could lay all three MRIs on top of each other and they look almost the same. It's pretty striking. ... It you lift the arm up, it literally drops. Sensation is usually intact. There might be slightly decreased sensation in the other arm, but these are younger kids, so they’re not always so cooperative in giving you a good sensory exam.^[4]

Children’s Mercy Hospital, where three or possibly four cases had occurred since August, reports:

The sudden onset of flaccid paralysis in single or multiple limbs with absolutely no sensory findings, the MRIs all showing uniformly a signal increase in the ventral horns of the spinal cord — this is exactly the same region of the spinal cord affected in polio ... Almost all of the patients have an increase in their white blood cells in the cerebrospinal fluid. Some of the patients have brainstem findings and cranial-nerve findings. This is all the same as what polio does. None of us has ever seen anything like this before, with few exceptions.^[4]

An October 23 special session at an annual meeting of the Child Neurology Society, where a show of hands suggested that the 250 participants had collectively treated more than 100 cases. Though a third of the participants raised their hands when asked if they had seen a recent case, only two hands were raised when they were asked if they had seen a complete recovery. A hospital in Philadelphia had seen at least 10 cases. At that time the nationwide CDC count was given as 51. The Stanford University School of Medicine suggested an even higher number: "I was on a conference call a few weeks ago with about 50 doctors from medical centers across North America. Every center had seen cases. That puts the numbers real high, real fast." The number affected was still far less than the tens of thousands affected in polio seasons. Fortunately, as with polio, the number of cases appeared to be decreasing with the onset of cold weather.^[10]

Of 64 patients meeting the CDC criteria before October 29, 80% had had a preceding respiratory illness and 75% reported fever in the days leading up to limb weakness, the onset of which was generally abrupt.^[11] By November 20 the number of confirmed cases stood at 88 from 29 states.^[12]

Causes

Maximum likelihood phylogenetic trees of enterovirus species A, B, C, D and rhinovirus A, B, C isolates from Latin America. The 5'UTR region is much more affected by recombination events than the VP4/VP2 coding sequence.^[13] Polio is in the enterovirus C species; enterovirus 71, a strain of enterovirus A, has been reported to cause rare neurological complications; the suspected cause of the 2014 cases is a strain of enterovirus D. Most enteroviruses and rhinoviruses cause only common cold symptoms.

The September 26, 2014 CDC health advisory that described the cases continued with the identification of enterovirus 68, a member of the enterovirus D species, as a suspected cause:^[3]

CSF testing to date has been negative for West Nile virus and enteroviruses, including poliovirus. Nasopharyngeal specimens were positive for rhinovirus/enterovirus in six out of eight patients that were tested. Of the six positive specimens, four were typed as EV-D68, and the other two are pending typing results. Testing of other specimens is still in process. Eight out of nine children have been confirmed to be up to date on polio vaccinations. Epidemiologic and laboratory investigations of these cases are ongoing.

The United States is currently experiencing a nationwide outbreak of EV-D68 associated with severe respiratory disease. The possible linkage of this cluster of neurologic disease to this large EV-D68 outbreak is part of the current investigation. CDC is seeking information about other similar neurologic illnesses in all states, especially cases clustered in time and place. CDC has particular interest in characterizing the epidemiology and etiology of such cases.

One moderator of the October 3, 2014 CDC COCA conference call (Steve Oberste) described the then-current test for enterovirus D-68 as a generic polymerase chain reaction amplification of enterovirus sequence, followed by sequencing to determine the serotype, but said that a faster and less labor-intensive real-time PCR assay was in the process of validation.^[7] On October 14, 2014 the CDC began using the new test.^[14]

The MMWR report noted the difficulty of establishing causation by the virus:^[6]

This cluster of acute neurologic illnesses occurred against a backdrop of detection of EV-D68 causing severe respiratory disease in many parts of the United States, including Colorado (1,2). There are two case reports in the literature of EV-D68 causing neurologic illness (acute flaccid paralysis and encephalomyelitis) as evidenced by detection of EV-D68 in the CSF (3,4). However, given the current suspected widespread circulation of EV-D68 respiratory infections in Colorado, and the antecedent respiratory illness in most of these children, the detection of EV-D68 in nonsterile upper respiratory tract specimens in those with neurologic illness might be coincidental. Epidemiologic and laboratory investigations of these cases are ongoing.

Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke and president of the International Society for NeuroVirology, compared the situation to the prolonged investigations that led to confirmation of HIV as the cause of AIDS. In response to the suggestion that the enterovirus might be taking over the role of polio, Nath said that enterovirus 68 was far less virulent and spread much more slowly than polio, and that, unlike in polio, only a few cases of paralysis were seen per thousand children infected. He also suggested that adults with respiratory diseases should also be evaluated for neurologic deficits, and that infectious disease should be considered as a cause when patients presented with neurologic symptoms.^[15]

A subsequent report described 29 cases of enterovirus D68-associated acute flaccid myelitis in Europe in 2016, noting that "these probably represent only the tip of the iceberg."^[16]

As of October 2018, the CDC regarded the cause of AFM as having "a variety of possible causes such as viruses, environmental toxins, and genetic disorders", listing poliovirus, non-polio enteroviruses, West Nile Virus, and adenoviruses among the potential causes.^[17]

Diagnosis

AFM is diagnosed by examining a patient’s nervous system in combination with reviewing images of the spinal cord. A doctor can examine a patient’s nervous system and the places on the body where he or she has weakness, poor muscle tone, and decreased reflexes. In addition, a doctor can do an MRI (magnetic resonance imaging) to look at a patient’s brain and spinal cord, do lab tests on the cerebrospinal fluid (the fluid around the brain and spinal cord), and may check nerve conduction (impulse sent along a nerve fiber) and response.^[18]

Prevention

The CDC MMWR report advised, "To prevent infections in general, persons should stay home if they are ill, wash their hands often with soap and water, avoid close contact (such as touching and shaking hands) with those who are ill, and clean and disinfect frequently touched surfaces."^[6]

Unlike polio, acute flaccid myelitis cannot currently be prevented with a vaccine.

Treatment

At the time of the report there was no known treatment for the disease; specifically, it was not established whether steroids were helpful or harmful.^[4] Other techniques such as plasmaphoresis, intravenous immunoglobulin, and experimental antiviral drugs have been attempted on a trial basis, but have not been reported to be effective.^[5] On November 7, 2014 the CDC issued "Interim Considerations for Clinical Management of Patients with Acute Flaccid Myelitis", based on "consensus guidance drawn from experts in infectious diseases, neurology, pediatrics, critical care medicine, public health epidemiology and virology." Mark Sawyer of the American Academy of Pediatrics, who contributed to the guidance, was quoted by the organization's newsletter:

The most important issue summarized in the document is that there is no clear evidence that therapies intended to modify the immune system (e.g., corticosteroids, immune globulin, plasmapheresis) have a beneficial effect in this condition. Plasmapheresis is specifically not recommended because the potential for harm is significant in the absence of any evidence of benefit.^[11]

Transplantation of nerves from the ribs and diaphragm, done within 8-12 months after onset of paralysis, has been reported.^[19]

Outcomes

Six of ten children in Denver were sent home for outpatient treatment; some with mild symptoms have recovered from temporary limb weakness, while the fate of those more severely affected remains unclear. Intensive physical therapy and occupational therapy may be beneficial for recovery.^[5][20][21]

Epidemiology

At the October 23, 2014, meeting of the Child Neurology Society, it was a matter of debate whether acute flaccid myelitis would be likely to return the next year.^[10] Enteroviruses D68 and A71 tend to cause neurological symptoms more often than other enteroviruses, but have been infrequent causes of colds.^[5][22] It is possible that enteroviruses have been causing acute flaccid myelitis at a very low rate for many years, misdiagnosed as transverse myelitis, and enterovirus 68 simply happened to become more prevalent in the 2014 season.^[5]

The CDC had confirmed 538 cases of enterovirus 68 infection in 43 states. The CDC has determined and submitted to GenBank complete or nearly-complete genomic sequences for three known strains of the virus, which are "genetically related to strains of EV-D68 that were detected in previous years in the United States, Europe, and Asia."^[14][23]

While rates of paralytic symptoms appear to be correlated with the number of respiratory infections, in initial anecdotal reports the cases are not clustered within a family or school, suggesting that the paralysis per se is not directly contagious, but arises as a very rare complication of the common respiratory infection.^[5]

Community response

The case of Kinley Galbreath at Children's of Alabama prompted the local FOX affiliate to call for donations after the girl, 5, was affected so severely that she could only move her feet. As described by the station, "Kinley is taking strong steroids, has undergone a blood filtering process and is in lots of pain."^[24]

Research directions

Efforts to develop a vaccine for the virus will depend on whether multiple strains of enteroviruses actually cause acute flaccid myelitis and, if so, whether a vaccine can be designed to protect against them all.^[5]

References