Enterovirus 71 Infection May Delay Childhood Neurodevelopment

TAIPEI, Taiwan, March 22 -- Enterovirus 71 infection in children, associated with central nervous system involvement and especially cardiopulmonary failure, may stall neurodevelopment and cognitive function, researchers here reported.

In a study of 142 children with enterovirus 71 (EV71) infection with CNS involvement, 21 of 28 patients (75%) who also had cardiopulmonary failure had delayed neurodevelopment, Luan-Yin Chang, M.D., Ph.D., of the National Taiwan University here, and colleagues, reported in the March 22 issue of New England Journal of Medicine.

By contrast, only one patient (5%) with severe CNS involvement but without cardiopulmonary failure had a delay in the gross motor and personal-social categories, the researchers said.

EV71 is a common cause of hand, foot, and mouth disease and encephalitis in Asia and elsewhere, although the long-term effects of this viral infection are not well understood, the researchers wrote.

Neurodevelopment and cognitive function may be affected by viral encephalitis or by bacterial meningitis leading to effects that may go unnoticed until school age, they added.

From 2003 to 2005, the investigators enrolled the 142 children (85 boys, 57 girls) after EV71 infection with CNS involvement. Among them, 61 had aseptic meningitis, 53 had severe CNS involvement, and 28 had cardiopulmonary failure after CNS involvement.

The children (ages six or younger) had laboratory confirmed EV71 infection with hand, foot, and mouth disease, herpangina, or febrile illness. The median age of disease onset was 1.8 years and five years at assessment.

At the 2.9-year follow-up, the children received physical and neurologic examinations. The Denver Developmental Screening Test (DDST II) was given to children ages six or younger and the Wechsler intelligence test to children age four or older.

All 43 children with mild CNS involvement (aseptic meningitis) recovered completely and neurodevelopment was normal, the researchers reported.

Nine of the 16 patients with a poliomyelitis-like syndrome (56%) and one of the five patients with encephalomyelitis (20%) had unilateral limb weakness and atrophy.

Eighteen (64%) of the 28 patients with cardiopulmonary failure after CNS involvement had limb weakness and atrophy, 17 (61%) required tube feeding, and 16 (57%) required ventilator support.

Among patients who underwent DDST II assessment, delayed neurodevelopment was found in only one of 20 patients (5%) with severe CNS involvement but without cardiopulmonary failure and in 21 of 28 patients (75%) with cardiopulmonary failure (P<0.001 for the overall comparison).

Children with cardiopulmonary failure after CNS involvement scored lower on intelligence tests than did children with CNS involvement alone (P=0.003).

In addition, clinical severity of the disease and age of onset were significantly associated with IQ. Children who were younger than two years at disease onset were more likely to have a full-scale IQ of less than 85 than were children two or older at the infection's onset, the researchers reported.

The cause of the long-term neurologic damage might be related to neuron damage, either by direct virus invasion or by hypoxia, the researchers wrote.

These findings raise important questions about the biology of the virus and its mode of spread so that further investigation is mandatory to help control the infection, the researchers said.

Because psychiatric problems after EV71 infection may be noticed only when children start school, there may be higher rates of learning and behavioral disorders -- attention-deficit-hyperactivity disorder (ADHD), for example -- resulting in behavioral problems and the need for medication or special educational services, the researchers wrote.

"Early evaluation and intervention for psychiatric and cognitive problems may prove beneficial for children after EV71 infection with CNS involvement and cardiopulmonary failure and for children who are infected at a very young age," Dr. Chang's team concluded.