A ten-year retrospective evaluation of acute flaccid myelitis at 5 pediatric centers in the United States, 2005–2014

Background Acute flaccid myelitis (AFM) is a severe illness similar to paralytic poliomyelitis. It is unclear how frequently AFM occurred in U.S. children after poliovirus elimination. In 2014, an AFM cluster was identified in Colorado, prompting passive US surveillance that yielded 120 AFM cases of unconfirmed etiology. Subsequently, increased reports were received in 2016 and 2018. To help inform investigations on causality of the recent AFM outbreaks, our objective was to determine how frequently AFM had occurred before 2014, and if 2014 cases had different characteristics. Methods We conducted a retrospective study covering 2005–2014 at 5 pediatric centers in 3 U.S. regions. Possible AFM cases aged ≤18 years were identified by searching discharge ICD-9 codes and spinal cord MRI reports (>37,000). Neuroradiologists assessed MR images, and medical charts were reviewed; possible cases were classified as AFM, not AFM, or indeterminate. Results At 5 sites combined, 26 AFM cases were identified from 2005–2013 (average annual number, 3 [2.4 cases/100,000 pediatric hospitalizations]) and 18 from 2014 (12.6 cases/100,000 hospitalizations; Poisson exact p<0.0001). A cluster of 13 cases was identified in September–October 2014 (temporal scan p = 0.0001). No other temporal or seasonal trend was observed. Compared with cases from January 2005–July 2014 (n = 29), cases from August–December 2014 (n = 15) were younger (p = 0.002), more frequently had a preceding respiratory/febrile illness (p = 0.03), had only upper extremities involved (p = 0.008), and had upper extremity monoplegia (p = 0.03). The cases had higher WBC counts in cerebrospinal fluid (p = 0.013). Conclusion Our data support emergence of AFM in 2014 in the United States, and those cases demonstrated distinctive features compared with preceding sporadic cases.

Introduction Acute flaccid myelitis (AFM) is a term developed in 2014 to describe a severe illness similar to paralytic poliomyelitis in clinical, electrodiagnostic, and radiological features, occurring primarily among children [1][2][3][4]. Clinical presentation includes acute flaccid limb weakness, sometimes with cranial nerve involvement or respiratory compromise. Passive AFM surveillance was established in the United States after a cluster of AFM was investigated in Colorado beginning August 2014 that occurred amidst an outbreak of severe respiratory disease caused by enterovirus-D68 (EV-D68) [2]. In 2014, an AFM case was defined as a person �21 years, with acute onset of limb weakness and with spinal cord magnetic resonance imaging (MRI) revealing lesions predominantly of the gray matter, and excluded those with spinal cord trauma or an otherwise known etiology of limb weakness [4]. Ultimately, 120 AFM cases were reported with onset during August-December 2014; direct laboratory evidence linking AFM with EV-D68 infection was inconclusive [4]. With the elimination of poliovirus in the United States (last outbreak in 1979) [5,6] and the discontinuation of the live-attenuated oral polio vaccine (OPV) [6], notifications of poliomyelitis are rare. However, because there was no formal surveillance system in place to capture AFM cases prior to 2014, the extent to which 2014 was truly different from other years in the recent past was unknown and therefore formal retrospective evaluations were needed.
During the 2014 investigation it was noted that, in addition to the clinical similarities among the cases, the spinal cord MR imaging had consistent features, including longitudinal signal hyperintensities in the anterior spinal cord gray matter on T2-weighted images [7,8].
Also, longitudinally extensive lesions that primarily involve the gray matter but may not be confined to the anterior horn cells, may be seen early in the course of AFM [7,8]. These features were also critical in distinguishing AFM from other causes of acute flaccid paralysis. Hence, features of spinal MRIs could have high specificity for AFM and potentially be used as a surveillance tool for AFM to be followed by medical record review for clinical confirmation.
Continued U.S. surveillance under a standardized AFM case definition demonstrated much lower case numbers reported in 2015 and 2017, and increases in 2016 and 2018 with a seasonal peak of cases remarkably similar to 2014 [9][10][11]. To understand the occurrence and features of AFM in the recent past, which would inform investigations on causes of this potentially emerging condition, we performed a retrospective evaluation of AFM cases in different U.S. regions over a 10-year period.

Materials and methods
We sought to identify 5 centers (number based on the funding available) that reported �1 AFM case during 2014, were from �3 different geographic regions, and were interested in and capable of performing a retrospective review.  [4], not an AFM case, or indeterminate. Search strategies were piloted and optimized at CHOP, involving review of 2,723 spinal MRI reports covering two years (S1 Appendix). Each hospital's IRB (CMKC: Children's Mercy IRB; STL: Washington University IRB; CHOP: Children's Hospital of Philadelphia IRB; Hasbro: Lifespan IRB; PCH: University of Utah IRB and Intermountain Primary Children's Hospital IRB) approved the protocol and waived the requirement for informed consent, including for data abstraction from medical charts. The medical charts were not anonymized at the sites before review by site investigators. The CDC Human Subjects Committee approved the protocol. Only anonymized data were provided to CDC from the sites.
Beginning in 2015, site investigators searched ICD-9 codes of electronic medical or billing records for January  Fig). Additionally, a text search of all spinal MRI reports issued for persons �18 years during the 10-year period was conducted to identify scans ordered for any of 36 conditions included in the acute flaccid paralysis evaluation by Zangwill et al [12], or that contained those terms in the report (Table B in S1 Appendix). These subsets of MRI reports were read individually to identify those that documented any of four findings: myelitis, increased T2 signal in the spinal cord, cord edema, or cord infarction, without a known explanatory condition (e.g., tumor). If these criteria were met, corresponding MR images were reviewed by study neuroradiologists (at 1 site, experienced pediatric neurologist for some images) to determine if the spinal cord had area(s) of signal abnormality, and if yes, to identify those with largely grey matter involvement. They classified images as overall not consistent with AFM, consistent with AFM, or in the indeterminate category. For patients with images in the last two categories, brain MR images (if imaging performed), and medical charts were reviewed to establish if the clinical presentation was consistent with AFM (acute and flaccid paralysis, absence of upper motor neuron signs) without a clear alternate diagnosis (for instance, documented spinal cord trauma; brain MRI with white matter lesions and encephalopathy consistent with acute disseminated encephalomyelitis; neuromyelitis optica antibody positivity). Site investigators made a final case classification as AFM, not AFM, or indeterminate case, based on the imaging and clinical information.
Two procedural modifications occurred. At PCH, MRI reports from 2005-2008 could not be searched for the 36 terms, so possible cases for those years were detected by discharge ICD-9 codes as the first step. At STL, neuroradiologists were more inclusive and reviewed images from all patients identified by the search strategies.
We used annual hospitalizations in persons �18 years to reflect the catchment population size, and as denominators for describing AFM incidence rates (S1 Table). Temporal clustering was assessed using multivariate temporal scan statistic: 1-month windows, Monte Carlo replications to total 10,000 (SaTScan, version 9.4.4) [13]. Other analyses were performed using Stata 13 (StataCorp, College Station, TX).

Results
At all sites combined, 48 patients had spinal MR images assessed as consistent with AFM and 43 had images in the indeterminate category (S1 Appendix). All had clinical records reviewed. Among the 48 patients with spinal MR images assessed as consistent with AFM, the final classification following clinical review was AFM in 38 (79%), indeterminate in 4 (8%), and not AFM in 6 (12%). Among the 43 patients with spinal MR images in the indeterminate category, the final classification was AFM in 8 (19%), indeterminate AFM in 9 (21%) and not AFM in 26 (60%). Of the resultant 46 with final classification of AFM, two were excluded from further analysis: one because weakness onset was in 2004, one because the patient did not receive neurological care at the site but had only a later MRI in 2007 and year of limb weakness onset was unknown. All cases met the CDC 2014 case definition [4].
Hence  Table). At each site, the 2014 rate of 'AFM cases plus indeterminate cases combined' was higher than the site's mean during 2005-2013 (Figs 1 and 2). Each site also had �2 years without an AFM or indeterminate case. The number of possible AFM cases with images reviewed and assessed as not AFM in 2014 was similar to mean annual number for 2005-2013 (S1 Appendix).

Case characteristics
Because late 2014 appeared different and passive surveillance began with August 2014 cases, we distinguished two onset periods for analysis: January 2005-July 2014 ("period 1", n = 29), and August-December 2014 ("period 2", n = 15). Compared with period 1, period 2 cases were significantly younger (median 7.1 years vs 11.7 years, p = 0.002;  found in 61% (8/13) of cases from period 2 and 58% (14/24) of those from period 1. Among those with abnormal brain imaging, findings were similar for cases in periods 2 and 1, and infratentorial lesions were most common (S3 Table).
Cases in period 1 had lower CSF WBC counts (median, 4 cells/uL) than cases in period 2 (median, 33 cells; p-value 0.013; CSF was collected a median number of 2 days after weakness onset for each period (Table 1,

Discussion
At our 5 referral centers combined, we found AFM cases had occurred each year, with low and seemingly sporadic cases prior to 2014, and our data support a higher occurrence in 2014. Strengths of our study include representation from 3 U.S. areas, 10-year timeline, and comprehensive search strategies including >37,000 spinal MRIs. Given the rarity of cases, changes in case counts by even a few in a year can appear substantial. However, by ascertaining case timing during the 9.  [4])−the available data support that fall 2014 was unusual for AFM in the United States. Since the cluster first reported by Colorado, CDC has supported AFM surveillance through state health departments.
This timing suggests that the cases in the fall of 2014 resulted from an exposure that was geographically wide and occurred during a tight time-window. An infectious trigger is supported by the high frequency of preceding respiratory/febrile illness and the CSF pleocytosis, and the younger age suggests possible age cohorts without previous exposure. At the STL site, no case was identified from fall 2014. This may be a true finding and a consequence of expected variability in circulation of the causative pathogen(s) at the local level. It is possible, however, that there may have been an unidentified error in procedures. The overlap in timing of 2014 AFM cases with EV-D68 respiratory disease in the United States [4,[14][15][16], data from Colorado cases vs control groups [17], and similar epidemiological picture from Japan during fall 2015 [18], suggest that these AFM clusters were associated with EV-D68, but data were not conclusive. Subsequently, the highest number of cases reported to the US surveillance system occurred in late summer/fall 2018 [9] temporally associated with EV-D68 detection in respiratory specimens [19]. However, among the subset of 74 cases from 2018 with CSF specimens tested at CDC, a pathogen was identified in only 2 cases (EV-D68 and EV-A71 in one CSF specimen each) [20,21]. Non-poliovirus AFM cases have also been reported from several other countries in the recent past [22][23][24][25][26]. The clinical and radiological phenotype termed AFM can be caused by pathogens other than polioviruses, including other enteroviruses (EV-A71) and certain flaviviruses (West Nile virus) [27][28][29]. In our retrospective series, there was no obvious seasonality before 2014 that would suggest particular pathogens. However, our study identified 2 AFM cases at CHOP in September 2009. These cases coincided with the institution's increase in children with respiratory disease whose respiratory specimens yielded enterovirus; EV-D68 was detected in 42% of 66 specimens characterized at CDC [30]. Before 2014, September 2009 was the only month when CHOP had >1 AFM case.
Similarities and differences between our period 1 and period 2 cases may provide insights into the pathogen(s) and disease processes that result in AFM. In both periods, upper extremities   were most affected, different from paralytic poliovirus disease in which most patients have lower extremity involvement [31][32][33]. The occurrence of monoplegia/monoparesis (period 1: upper extremity in 2 patients, lower extremity in 1 patient; period 2: upper extremity in 5 patients) is more characteristic of focal CNS involvement, such as that seen with neurotropic infectious pathogens rather than a post-infectious immune-mediated process. Monoplegia has been reported in some AFM cases from most case series covering 2014 and later, most commonly an upper extremity, reflecting the common cervical cord involvement [17,18,[22][23][24][25][26]. The CSF WBC counts were low in many period 1 cases, which may suggest differences in pathogenesis between period 1 and period 2 cases. CSF pleocytosis is not common at onset in spinal infarct, which can appear identical to AFM on MRI, but is unlikely to have been a predominant cause of period 1 cases given the rarity of cord infarction in this age group [1,34,35]. Our study has limitations. First, site investigators could not be blinded to case time-period. Case classification involved judgement of radiological and clinical information and so it is plausible that possible 2014 cases were more likely to be designated cases rather than noncases or indeterminate. There were few indeterminate cases, however, and including these yields the same conclusions regarding 2014. Also reassuring is that the annual number of possible cases assessed as not AFM was similar in 2014 versus earlier years. Second, during recruitment, we only contacted hospitals familiar with AFM, demonstrated by their reporting of possible cases to CDC in 2014 and hence our sites may not be representative of all US children's centers. However, some other hospitals contacted that did not participate had reported greater case-numbers in 2014 than our sites, so it is unlikely that our 2014 findings were unique to our set of reporting hospitals. Third, At PCH, only ICD-9 code searches were performed for 2005-2008. Both search strategies were used for final 6 years, however, and conclusions are the same based on that period. Fourth, there may have been differences across sites particularly with the categorization of spinal MR images only (i.e., without any clinical information) to indeterminate category, and final classifications as indeterminate AFM cases.
Globally collaborative research and surveillance, with consensus inclusion and exclusion criteria for consistent reporting, will be important for investigating this emerging, severe illness.