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Original Investigation |

Clinical Characteristics and Functional Motor Outcomes of Enterovirus 71 Neurological Disease in Children

Hooi-Ling Teoh, MBBS1,2; Shekeeb S. Mohammad, FRACP3,4; Philip N. Britton, FRACP4,5,6; Tejaswi Kandula, FRACP1; Michelle S. Lorentzos, MBBS3; Robert Booy, PhD4,5,7; Cheryl A. Jones, PhD4,5,6; William Rawlinson, PhD8; Vidiya Ramachandran, MBBS8; Michael L. Rodriguez, FRCPA9; P. Ian Andrews, FRACP1; Russell C. Dale, PhD3,4; Michelle A. Farrar, PhD1,2; Hugo Sampaio, FRACP1,2
[+] Author Affiliations
1Department of Neurology, Sydney Children’s Hospital, Sydney, Australia
2Discipline of Pediatrics, School of Women’s and Children’s Health, UNSW Medicine, The University of New South Wales, Sydney, Australia
3T. Y. Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, Australia
4Discipline of Pediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, Australia
5Marie Bashir Institute, Sydney Medical School, University of Sydney, Sydney, Australia
6Department of Infectious Diseases and Microbiology, The Children’s Hospital at Westmead, Sydney, Australia
7National Centre for Immunization Research and Surveillance, Kid’s Research Institute, Sydney, Australia
8Serology and Virology Division, Prince of Wales Hospital, Sydney, Australia
9Department of Forensic Medicine, NSW Health Pathology, Sydney, Australia
JAMA Neurol. 2016;73(3):300-307. doi:10.1001/jamaneurol.2015.4388.
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Importance  Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines.

Objective  To further characterize EV71-related neurological disease and neurological outcome in children.

Design, Setting, and Participants  Prospective 2-hospital (The Sydney Children’s Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013.

Main Outcomes and Measures  Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed.

Results  Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P < .001).

Conclusions and Relevance  Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.

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Figure 1.
Magnetic Resonance Imaging Findings in Patients With Enterovirus 71

The arrowheads point to the findings in A through F. A, T2-weighted signal hyperintensity and expansion. B, Gadolinium enhancement. C, Gadolinium enhancement. The arrowhead is sitting over the L2/L3 intervertebral space. D, Restricted diffusion. E, Apparent diffusion coefficient map. F, T2-weighted signal hyperintensity.

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Figure 2.
Pathological Findings Within the Brainstem in Enterovirus 71 Disease

An 18-month-old patient was seen at the hospital with a 2-day history of fever, anorexia, and vomiting. On examination, she was in shock, with supraventricular tachycardia (225 beats/min). There was ptosis and rightward deviation of the left eye, as well as right eye nystagmus. She had cardiac arrest in the emergency department and was unable to be resuscitated. A, Shown are marked and widespread microglial activation and microglial nodules (immunostained for major histocompatibility complex class II antigens [CR3/43]). B, Foci of necrosis (asterisk) with perivascular lymphocytes (hematoxylin-eosin) are shown. C, Shown are microglial nodules (arrowheads) (hematoxylin-eosin).

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Figure 3.
Clinical Characteristics and Outcome of Enterovirus 71 With Neurological Disease

DWI indicates diffusion-weighted imaging; IVIG, intravenous immunoglobulin; MRS, modified Rankin Scale score; WHO, World Health Organization.

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