Accepted Manuscript

Recognition and Management of Acute Flaccid Myelitis in Children

Gary R. Nelson, MD, Joshua. L. Bonkowsky, MD, PhD, Elizabeth Doll, MD, Michael
Green, DO, Gary L. Hedlund, DO, Kevin R. Moore, MD, James F. Bale, Jr., MD

PII: S0887-8994(15)00479-8
DOI: 10.1016/j.pediatrneurol.2015.10.007
Reference: PNU 8766

To appear in: Pediatric Neurology

Received Date: 18 May 2015

Revised Date: 4 October 2015
Accepted Date: 11 October 2015

Please cite this article as: Nelson GR, Bonkowsky JL, Doll E, Green M, Hedlund GL, Moore KR, Bale Jr.
JF, Recognition and Management of Acute Flaccid Myelitis in Children, Pediatric Neurology (2015), doi:
10.1016/j.pediatrneurol.2015.10.007.

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Recognition and Management of Acute Flaccid Myelitis in Children

Gary R. Nelson, MD1, Joshua. L. Bonkowsky, MD, PhD1, Elizabeth Doll, MD1, Michael Green,

DO2, Gary L. Hedlund, DO3, Kevin R. Moore, MD3, James F. Bale, Jr., MD1

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Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of

Medicine, Salt Lake City, Utah; 2Physical Medicine and Rehabilitation, University of Utah

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School of Medicine, Salt Lake City, Utah; 3Department of Medical Imaging, Primary Children’s

Hospital, Department of Radiology, University of Utah School of Medicine, Salt Lake City, Utah

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Keywords: Myelitis, flaccid paralysis, enterovirus, poliomyelitis, Guillain-Barré syndrome

Financial Disclosure: No author has any financial relationships relevant to this article.
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Funding Source: None. Dr. Bonkowsky is supported by NIH DP2 MH100008.

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Conflicts of Interest: The authors have no conflicts of interest to disclose.

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Address correspondence to: Gary R. Nelson, Division of Pediatric Neurology, Department of

Pediatrics, University of Utah School of Medicine, 81 N. Mario Capecchi Drive, 4th Floor. Salt

Lake City, Utah 84113, [gary.nelson@hsc.utah.edu]; phone: 801-213-3599; fax: 801-213-7739.

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ABSTRACT

Background: In 2014-2015 several regions of the United States experienced an outbreak of

acute flaccid myelitis in pediatric patients. A common, unique feature was disease localization
to the gray matter of the spinal cord. Methods: We report 11 children, ages 13 months to 14

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years (median 9 years), in the Intermountain West who presented with extremity weakness (n =
10) or cranial neuropathy (n = 1) of varying severity without an apparent etiology. Results: All
had acute paralysis, and ten had symptoms or signs that localized to the spinal cord. Maximum

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paralysis occurred within four days of onset in all cases. All had spinal gray matter lesions
consistent with acute myelitis detected by magnetic resonance imaging; no single infectious
cause was identified. Despite therapy with intravenous immunoglobulin, corticosteroids or

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plasma exchange, nine of 10 (90%) children had motor deficits at follow-up. Conclusions:
Recognition of this disorder enables clinicians to obtain appropriate imaging and laboratory
testing, initiate treatment and provide families with accurate prognostic information. In contrast
to other causes of acute flaccid paralysis in childhood, most children with acute flaccid myelitis

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have residual neurological deficits.
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INTRODUCTION

In the spring and summer of 2014 the U.S. experienced an outbreak of acute flaccid paralysis

that was noted by clinicians and reported to the health departments of several states and to the

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Centers for Disease Control and Prevention (CDC).1, 2 As more cases appeared, clinicians

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recognized that the disorder represented a unique acute flaccid myelitis (AFM) with prominent

motor deficits and limited sensory involvement. Although the outbreak coincided with a spike in

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respiratory infections with enterovirus (EV) D68, a nonpolio enterovirus, the CDC and other

laboratories have not established a definite causal link between EV D68 and the U.S. myelitis

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outbreak.3, 4 In the Intermountain region (Utah, Nevada, western Wyoming, southern Idaho,
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western Colorado, and Montana) 11 pediatric patients presented with AFM over a one year

period. These cases illustrate the neurological features associated with AFM and emphasize the
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importance of recognition in directing appropriate work-up, testing and treatment. In contrast to

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many other forms of acute flaccid paralysis, children with AFM have prominent motor
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involvement, limited sensory symptoms, and a high probability of residual motor deficits.
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METHODS

Patient Population: This report describes a retrospective cohort study of pediatric patients with

acute flaccid myelitis admitted to Primary Children’s Hospital (PCH) from February 2014-

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January 2015. PCH, a 289-bed children’s hospital, is the tertiary pediatric referral center for a

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population of approximately 2 million children from 0 to 18 years of age residing in the

Intermountain West, a region encompassing Utah, Nevada and parts of Idaho, Montana,

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Wyoming and Colorado.

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Children were considered for inclusion if they met the August 2014 CDC diagnostic criteria for
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AFM, which consisted of: age 21 years or younger, one or more limbs with weakness or

paralysis, and MRI findings demonstrating gray matter T2 signal hyperintensity. This condition
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has been designated AFM, to distinguish it from other known causes of acute flaccid paralysis.
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Children were excluded if they had alternate explanations for their symptoms, such as GBS or
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transverse myelitis.
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Neurodiagnostic studies: As part of the evaluation of their weakness, all children underwent

focused magnetic resonance imaging (MRI) examination of the neuroaxis based on their
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neurological history and examination findings. Magnetic resonance imaging (MRI) of the spine
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and brain was acquired on either a 1.5 or 3.0 Tesla HDX MRI system (General Electric

Healthcare). The protocol included: sagittal and axial T2 weighted imaging (WI), sagittal short

T1 inversion recovery (STIR), sagittal T1 weighted fluid attenuation inversion recovery

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(FLAIR), post-intravenous contrast sagittal and axial T1WI. Two children also underwent

diffusion weighted imaging (DWI) of the spine.

Laboratory Studies: Laboratory evaluation included cerebrospinal fluid (CSF) analysis with

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routine studies (cell count, protein, glucose), gram stain, bacterial cultures and viral assays. The

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latter included conventional polymerase chain reaction (PCR) studies for enteroviruses and the

herpesviruses. Respiratory Film Array, a PCR-based detection system that simultaneously

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assays clinical samples for several viral pathogens6, was used to assess children for intercurrent

viral infections of the upper respiratory tract. Several children also underwent conventional cell

culture assays for enteroviruses.

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RESULTS

Patient Population and Clinical Features: Eleven children were identified; selected

demographic and clinical characteristics are summarized in Table 1. The children ranged in age

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from 13 months to 14 years (median of 9 years). Ten of the eleven (91%) were male. All

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children had been born term without complications, and none had developmental delays or other

major health issues prior to the onset of their neurological abnormalities. No patient had travelled

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outside the US, and all patients were fully immunized per parental reports. Seven children had a

prodrome consisting of headache, nausea, vomiting or cough 1 to 7 days prior to onset of

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weakness; five had intermittent, low-grade fever. None described paresthesias or sensory loss.
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Eight children had abrupt onset of focal flaccid paralysis that worsened over 48-72 hours and
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then stabilized. Two had paralysis that rapidly progressed over 96 hours to quadriparesis, and
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one had cranial nerve involvement only. Although the latter child did not meet the CDC
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criterion of having focal extremity weakness, the child was included because of the motor cranial

nerve abnormality, a common feature in several AFM cases, and the MRI findings in the cervical
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spine consistent with AFM. Seven children had a proximal pattern of weakness. Only one child

required intubation for respiratory failure.

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Neurodiagnostic Studies: All children underwent MRIs of all or part of the spinal cord, and

eight children also had MRIs of the brain. The entire neuroaxis was imaged in two children. All

children had similar T2 hyperintensities involving the anterior horn gray matter of the spinal cord

(Figures 1-3). Four children also had T2 hyperintense lesions involving brainstem (Figure 2)
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and/or cerebellar nuclei. No supratentorial abnormalities were identified in the eight children

with brain MRIs.

Laboratory Studies: After MRIs were completed, lumbar puncture was performed, and the

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CSF assayed for potential infectious cases. Seven children had CSF pleocytosis, ranging from 7

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to 170 WBC/uL with a median of 36 WBCs/uL in those with pleocytosis. No infectious

pathogen was detected in the CSF of any patient. Because of the association of acute flaccid

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paralysis with enterovirus infections, extensive enteroviral testing was performed, consisting of

PCR of CSF (n = 8) or serum (n=1) and cell culture assays of nasopharyngeal swabs (n = 6) or

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stool (n = 6). In addition, several samples, including CSF (n = 5) and serum (n = 3), were sent to
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the CDC for enterovirus detection. All children had at least one virologic study for

enteroviruses, and all enteroviral studies were negative. Respiratory film array, performed in
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eight children, was positive for influenza A H3 in one child and parainfluenza 2 in another. An
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additional child had rhinovirus detected in a nasopharyngeal swab by a conventional viral assay.
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Treatment and Outcome: Six children were treated with intravenous (IV) methylprednisolone
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(15-30 mg/kg/day for 5 days with a brief taper), and four of these children also received IV

immunoglobulin (IVIG) (2 g/kg given over 3-5 days). Five children received IVIG only, and
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one child received IV methylprednisolone, followed by plasma exchange and later, IVIG. One
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child had a mild allergic reaction with the first dose of IVIG and required IgA-depleted IVIG

subsequently. Otherwise, all therapies were tolerated without complications. One child received

a second dose of IVIG 4 weeks after presentation without benefit, after a plateau in improvement
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led to spinal imaging which showed lumbar anterior nerve root enhancement. Nerve root

enhancement has been seen previously in children with AFM.

The follow-up intervals ranged from 1 to 19 months (median 6 months); one child lacked follow-

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up at the time of this report. Although the neurological abnormalities improved in all children,

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regardless of the treatment, all but one child had residual motor deficits. The deficits consisted of

persistent ventilator and gastrostomy dependence despite the ability to ambulate (n = 1),

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weakness with impairment of daily function (n = 4), and mild to moderate focal weakness

without functional impairment (n = 3). The child with cranial nerve deficits only has recovered

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completely, and one child who presented with bilateral arm weakness has mild residual weakness
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of one hand only. Two children, both requiring walkers for extended distances, have persisting

neurogenic bladders. No sensory deficits were identified during follow up.

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DISCUSSION

Flaccid paralysis, a constellation of signs or symptoms in children or adults, results from several

neurological disorders, including Guillain-Barré syndrome (GBS), acute transverse myelitis,

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paralytic poliomyelitis, and poliomyelitis-like conditions. Classically associated with

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polioviruses, acute flaccid paralysis has persisted in many regions despite coverage with the

polio vaccine. The World Health Organization (WHO) has used this condition as a marker for

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poliomyelitis outbreaks.7 However, acute flaccid paralysis can result from infection with any of

several pathogens, including West Nile virus8 and the non-polio enteroviruses.9-11 Until the

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recent outbreak of AFM, acute flaccid paralysis not due to GBS was rare in the US, and its
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clinical symptoms and management were unfamiliar to many practitioners.
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This report and others indicate that AFM represents a unique subset of acute flaccid paralysis
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distinct from GBS and transverse myelitis.7,12,13 GBS typically presents with an ascending
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paralysis and can be associated with facial paralysis and sensory symptoms.14 Children with

transverse myelitis have weakness and prominent sensory loss, often manifest as a spinal sensory
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level. By contrast, the majority of children with AFM have focal, poliomyelitis-like spinal cord

paralysis with minimal or no sensory symptoms. Approximately one-third of children with AFM
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also have deficits of motor cranial nerves.3 One child in this series had spinal MRI features
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consistent with AFM but motor cranial neuropathy only, suggesting that there may be forme

frustes of the disorder.

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Children with AFM show T2 hyperintensities in the gray matter of the spinal cord or brainstem,

shown well in Figures 2 and 3, whereas MRI demonstrates enhancement of the dorsal nerve

rootlets in GBS15 and involvement of both grey and white matter in transverse myelitis.16

Children with AFM can have spinal nerve root enhancement17 in the subacute phase of the

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illness.17 CSF findings can differentiate GBS and spinal cord disease, with cytoalbuminologic

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dissociation in GBS14 and lymphocytic or mixed pleocytosis in both transverse myelitis and

AFM. Approximately 70% of children with AFM have moderate CSF pleocytosis.18

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The etiology of AFM remains enigmatic. As of July 2015, 120 cases of AFM have been

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reported to the CDC, and no pathogen has been consistently identified.18 Although cases of
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AFM appeared during the US outbreak of EV-D68, a cause of severe respiratory disease in

children, EV-D68 and other respiratory pathogens have not been identified conclusively as the
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cause of AFM. Three children in this series had viruses (influenza A virus, parainfluenza and
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rhinovirus) identified in the respiratory tract, but none had viruses detected in the CSF. We
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suspect that the presence of these three viruses was incidental to the children’s AFM. Extensive

investigation for enteroviruses, using both PCR and virus culture methods, was negative in all of
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the children described in this report.

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Although the children in this series have shown clinical improvement, most have residual
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weakness, consistent with the cases reported to the CDC.18 IVIG was the primary therapy in

this series, based on reports of clinical deterioration in some cases of EV-71 treated with

corticosteroids.19 Because of the risk of respiratory failure in patients with AFM and cervical

spine lesions, respiratory status was carefully monitored; approximately 20% of the cases
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reported to the CDC have required ventilator support.3 The oldest child in this series continues

to be ventilator dependent 19 months after the onset of AFM. Children affected by AFM also

require monitoring of urinary function; two children in the current series have neurogenic

bladders. Because AFM does not appear to be a demyelinating disease, the risk of developing

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chronic demyelinating conditions seems low. However, longer periods of observation are

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necessary to establish the nature of any late complications.

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Because sporadic cases of AFM continue to be identified, practitioners must consider this

disorder in children who present with presumed GBS or transverse myelitis. Recognizing AFM

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facilitates the ongoing search for its cause and enables practitioners to provide accurate
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prognostic information to families. In contrast to the relatively favorable prognoses for children

with GBS or transverse myelitis, children with AFM are less likely to recover fully.
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Recognizing AFM can prepare families and children for the likely possibility of permanent
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neurological deficits. Unlike transverse myelitis20, however, AFM appears to be a monophasic

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event with a low risk of recurrent neurological disease. Because of uncertainty regarding the

cause and eventual outcome of the disorder, cases should continue to be reported to the CDC.21
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ACKNOWLEDGEMENTS

The authors thank the following providers who cared for and assisted in diagnosis of these

patients: Susan Benedict MD, Russell Butterfield MD PhD, Meghan Candee MD, Ai Sakonju,

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MD and Clint Nelson MD. We also thank the residents, nurses and therapists who contributed to

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their care.

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REFERENCES

1. http://www.cdc.gov/ncird/downloads/acute-flaccid-myelitis.pdf

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(accessed 1/27/2015).

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2. Messacar K, Schreiner TL, Maloney JA, Wallace A, Ludke J, Oberste MS, Nix WA,

Robinson CC, Glode MP, Abzug MJ, Dominguez SR. A cluster of acute flaccid paralysis

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and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68

in children in Colorado, USA. Lancet 2015;Pii:S0140-6736(14)62457-0.

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3. Notes from the field: Acute flaccid myelitis among persons Aged </=21 years-United
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States Aug 1-November 13, 2014. Morbity and Mortality Weekly Report Jan 9,

2015/63(53);1243-1244
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4. http://www.cdc.gov/ncird/investigation/viral/sep2014/investigation.html
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accessed 2/14/15.
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5. http://www.cdc.gov/ncird/investigation/viral/sep2014/hcp.html#case

accessed 2/14/15.
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6. This assay is performed using the FDA cleared FilmArray Respiratory Panel from Idaho

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acid purification, reverse transcription, and nest multiplex real-time PCR with high-
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resolution melt analysis. This test was evaluated and its performance characteristics

validated by Intermountain Healthcare Laboratories.

7. Acute Onset Flaccid Paralysis WHO, Geneva, WHO-AIREN Meeting on The

Differential Diagnosis of Acute Onset Flaccid Paralysis. 29 September-1 October 1992.

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8. Hainline ML, Kincaid JC, Carpenter DL, Golomb MR. West Nile poliomyelitis in a 7-

year-old child. Pediatric Neurology 2008;39(5):350-4.

9. Zexin Tao, et al. Non-Polio Enteroviruses from Acute Flaccid Paralysis Surveillance in

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10. Chen F, Liu R, Jianjun L, Xing Z, Huang S, Wen G. MRI characteristics and follow-up

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and mouth disease. International Journal of Clinical and Experimental Medicine

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11. Shaukat S, et al. Identification and characterization of unrecognized viruses in stool

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Journal 2014;11:146

12. Maloney JA, Mirsky DM, Messacar K, Dominguez SR, Schreiner T, Stence NV. MRI
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Padilla T, Pan C, Reichel J, Harriman K, Watt J, Sejvar J, Nix WA, Feikin D, Glaser C;

Acute flaccid paralysis with anterior myelitis – California June 2012-2014. Centers for
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Disease Control and Prevention (CDC). Morb Mortal Wkly Rep 2014 Oct 10;63(40):903-
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14. Hughes RA, Cornblath DR: Guillain-Barre Syndrome. Lancet 2005, 366(9497):1653-

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15. Mulkey SB, Glasier CM, El-Nabbout B, Walters WD, Ionita C, McCarthy MH, Sharp

GB, Shbarou RM. Nerve root enhancement on spinal MRI in pediatric Guillain-Barre

syndrome. Pediatr Neurol. 2010;43(4):263-9.

16. Wolfe VL, Lupo PJ, Lotze TE. Pediatric acute transverse myelitis overview and

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differential diagnosis. J Child Neurol 2012;27(11):1426-36.

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17. Maloney JA, Mirsky DM, Messacar K, et al. MRI findings in children with acute flaccid

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outbreak. AJNR. Amer J Neuroradiol 2015;36:245-50.

18. Centers for Disease Control and Prevention. Summary of findings: investigation of

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acute flaccid myelitis in the U.S. children.
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http://www.cdc.gov/ncird/investigation/viral/2014-2015/investigation.html.

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19. http://www.cdc.gov/ncird/downloads/acute-flaccid-myelitis.pdf. Accessed 04/01/2015.

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20. Deiva K, Absoud M, Hemingway C, et al. Acute idiopathic transverse myelitis in

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15/health-departments.html Accessed 09/8/2015.

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FIGURE LEGENDS

Figure 1: Sagittal, T2-weighted MRI (Case #8) shows extensive signal hyperintensity involving

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several levels of the central thoracic spinal cord (arrows).

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Figure 2: Sagittal T2-weighted MRI (Case #3) shows signal hyperintensities involving the

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dorsal pons and medulla (arrowhead). Also note T2 hyperintensity in several levels (C3 to C7) of

the cervical spinal cord (arrow). Case 3 presented with facial paresis only; MRI clearly

demonstrates spinal cord involvement, as well.

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Figure 3: Axial T2-weighted MRI (Case #3) demonstrates selective involvement of the gray
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matter of the spinal cord. Note the asymmetric involvement of the left anterior horn (arrow).
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Table 1. Selected Clinical Characteristics, Treatment and Outcome of Children with Acute

Flaccid Myelitis

Case Age Presenting Sign(s) MRI Abnormality* Treatment Outcome

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1 14 y R + L arm weakness C1-T10 MP, IVIG, Ambulatory; ventilator
PLEX dependent
2 7y R facial droop and R Brainstem; C1-T8 MP, IVIG Walks with AFO

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arm weakness
3 9y L arm weakness C2-C7; patchy T4-T7 MP L shoulder weakness
4 9y L arm weakness C1-C8 MP Proximal L arm

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weakness
5 7y R arm weakness Pons, medulla, C1- IVIG Proximal R arm
C8 weakness
6 11 y R facial droop Pons, medulla, C1- IVIG, MP Normal

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7 13 m R + L arm weakness C2-T5 MP, IVIG Minimal weakness L
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(severe) hand
8 7y R + L leg weakness T6-T9 IVIG R hip weakness;
neurogenic bladder
9 11 y R + L Leg weakness T2-T4 IVIG Walks with crutches
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10 12 y R + L leg weakness Patchy T1-T12 IVIG Requires walker for

long distances;
neurogenic bladder
11 21 m Diffuse weakness Subtle C1-C6 IVIG No data
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*All abnormalities consisted of T2 hyperintensities.

Y= years; M = months
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R = right; L = left
C = cervical; T = thoracic
MP = methylprednisolone
IVIG = intravenous immunoglobulin
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PLEX = plasma exchange

AFO = ankle-foot orthosis
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