Clinical Features of Acute Flaccid Myelitis Temporally Associated With an Enterovirus D68 Outbreak: Results of a Nationwide Survey of Acute Flaccid Paralysis in Japan, August-December 2015

Abstract

Background: Acute flaccid myelitis (AFM) is an acute flaccid paralysis syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015.

Methods: An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens.

Results: Fifty-nine AFM cases (58 definite, 1 probable) were identified, including 55 children and 4 adults (median age, 4.4 years). The AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in 9 patients: 5 in nasopharyngeal, 2 in stool, 1 in cerebrospinal fluid (adult case), and 1 in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from 1- to 4-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on magnetic resonance imaging (median, 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50 of 59 cases (85%), and 8 of 29 (28%) were positive for antiganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score >3, normal F-wave persistence, and EV-D68-negative status.

Conclusions: EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development.

Figure 1.

Overview of the study design. The first phase consisted of a national acute flaccid paralysis (AFP) survey, an event-based surveillance program initiated under special provision of the Infectious Diseases Prevention Law for the period August–December 2015. A second collaborative phase of the study aimed to clarify clinical characteristics of acute flaccid myelitis (AFM). Fifty-nine cases of AFM were identified after reviewing available clinical data. Sixteen other infectious or inflammation-related neurological diseases that did not satisfy the case definition of AFM were assigned as non-AFM AFP. Abbreviations: AFM, acute flaccid myelitis; AFP, acute flaccid paralysis.

Figure 2.

Cases of enterovirus D68 (EV-D68) infection and acute flaccid myelitis (AFM) in Japan during August–December 2015. The national acute flaccid paralysis (AFP) survey was commenced on 21 October 2015, for the surveillance period of August–December 2015. Epidemic curves of AFM cases positive for EV-D68, AFM cases negative for EV-D68, and AFP cases not meeting the definition of AFM (non-AFM AFP) are shown in parallel with EV-D68 infection cases reported to Japan’s National Institute of Infectious Diseases through surveillance data of the Infectious Agents Surveillance Report. Although data for all of 2015 are shown, correlation analysis was conducted for the surveillance period only. Abbreviations: AFM, acute flaccid myelitis; AFP, acute flaccid paralysis; EV-D68, enterovirus D68; IASR, Infectious Agents Surveillance Report.

Figure 3.

Age distribution and distribution of spinal T2 lesions of patients with acute flaccid myelitis (AFM). A, Median age at onset of patients with AFM was 4.4 y (arrow) with an interquartile range of 2.6–7.7 y. A total of 35 male and 24 female patients, including 4 adult patients, was reported in this period. B, Extensive longitudinal lesions were observed in most of the cases. *Unknown due to incomplete data (total spinal magnetic resonance imaging not done) or poor radiographic images.

Figure 4.

Representative magnetic resonance imaging findings. A–E, T2-weighted images of a 5-y-old child 2 d after the onset of acute flaccid myelitis (AFM). A, Longitudinally extensive hyperintense lesion involving the entire spinal cord was observed. B, This patient also had brainstem lesions ranging from midbrain to medulla oblongata. C, Axial images of medulla showed hyperintensities mainly in pyramids and around the obex. D and E, Axial images of spinal cord demonstrated hyperintensities in gray matter and surrounding white matter (at C5 level in D, and at the Th11/12 level in E). F, Panel shows gadolinium-enhanced T1-weighted images of a 4-y-old child 20 d after the onset of AFM. Enhancement was observed in anterior roots of cauda equina.

Figure 5.

Cerebrospinal fluid (CSF) white blood cell (WBC) count during clinical course of acute flaccid myelitis (AFM). Boxplot of CSF WBC count taken during 0–5 d, 6–10 d, 11–15 d, and ≥16 d after neurological onset from patients with AFM. The Kruskal-Wallis rank-sum test with significant values adjusted by the Bonferroni correction for multiple tests was used. The median WBC count with interquartile range indicated in bracket of each group was shown. *P < .05. Abbreviation: CSF, cerebrospinal fluid.