We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
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.
Text Size: A A A
Published online

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.

Figures in this Article


Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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).

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location




Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.


Some tools below are only available to our subscribers or users with an online account.

0 Citations

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles

The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Original Article: Does This Patient Have a Torn Meniscus or Ligament of the Knee?

The Rational Clinical Examination: Evidence-Based Clinical Diagnosis