Recognizing Congenital Zika Syndrome

VANCOUVER—Infants infected with Zika virus in utero may develop a syndrome characterized by brain volume loss, intracerebral calcifications, and spasticity. They may develop dyskinesia or seizures after several months, and a subset of children has severe arthrogryposis.

And although microcephaly at birth is common, infants may have a normal head size at birth, but develop postnatal microcephaly or other neurologic symptoms at six months, according to research described at the 45th Annual Meeting of the Child Neurology Society.

“The spectrum of congenital Zika syndrome is expanding as we come to understand it better,” said William B. Dobyns, MD, Professor of Pediatrics at the University of Washington in Seattle and a faculty member at the Center for Integrative Brain Research at Seattle Children’s Research Institute. “We all need to stop calling this microcephaly. This is much more than that. This is the congenital Zika syndrome.”

William B. Dobyns, MD

Zika virus is trophic for neural stem cells, and the first reports of microcephaly associated with prenatal Zika virus infection came from Brazil in January 2016. In the US, mosquitoes that transmit Zika virus, Aedes aegypti and albopictus, are present year round in Florida and seasonally in about a quarter of the states. “It is pretty clear that it will be coming.… We need to take precautions until treatments or preventives are available,” he said. In addition, child neurologists need to be able to recognize congenital Zika syndrome. “It is entirely possible for us to do so,” Dr. Dobyns said. “You do not even need viral titers in the more classically affected children.”

A Case Series of 57 Children

Dr. Dobyns worked with André Pessoa, MD, a child neurologist at Hospital Infantil Albert Sabin in Fortaleza, Brazil, and other neurologists in the region to compile data on a series of 57 children with congenital microcephaly and presumed or proven Zika exposure of the mothers during pregnancy. Microcephaly was defined as occipitofrontal head circumference of at least two standard deviations below the mean.

About half of the children had a bony protuberance of the occipital bone, known as an occipital shelf, Dr. Dobyns said. This feature occurs when the fetal brain, instead of growing and pushing out the skull plates, is severely injured and shrinks. The frontal and parietal bones, but not the occipital bone, collapse over the injured brain.

Almost all of the children had prominent calcifications in the brain. Unlike in children infected with cytomegalovirus, periventricular calcifications are the exception in children infected with Zika virus. Researchers observed subcortical or cortical calcifications on CT in 51 of the 57 children infected with Zika virus and basal ganglia calcifications in 33 of the 57 children.

Furthermore, calcifications with Zika virus infection tend to be diffuse and bilateral, whereas calcifications with cytomegalovirus infection tend to be patchy, Dr. Dobyns said.

All patients had the same general pattern of enlarged extra-axial space, ventriculomegaly, or both, indicating brain volume loss.

About 20% of patients had severe arthrogryposis multiplex congenita, and all of these children had abnormally positioned proximal joints.

Twenty of the children underwent brain MRI. MRI showed an abnormal cortex in all 20 children. The patients appear to have a diffuse cortical malformation that is most consistent with polymicrogyria, Dr. Dobyns said.

Nearly 20% of children in the series had microcephaly between two and three standard deviations below the mean. But 81% had microcephaly of three or more standard deviations below the mean. The mean occipitofrontal head circumference was four standard deviations below the mean.

Neurologic features included spasticity in 94% of the children and severe irritability or tremor in 64% of the children. About 20% had seizures after several months. Some patients had eye abnormalities, including optic nerve pallor, macular atrophy, and strabismus.

“The exam is characteristic,” Dr. Dobyns said. “They all develop a dyskinesia later in the first year of life. They have spastic quadriparesis. They frequently have tremors at birth. They feed poorly. They tend to be irritable and scream all the time. They are starting to have seizures as they get past six months of age.”

As in other studies, data from this series suggest that children whose mothers have a symptomatic illness or are infected earlier in pregnancy may be at higher risk of congenital Zika syndrome.

Infants Without Microcephaly at Birth

Dr. Dobyns presented preliminary data from children who were exposed to Zika virus but did not have microcephaly at birth. These children had most of the same features on exam as children with microcephaly, although the features tended to be less severe. The children started to have seizures after several months. When their head size was measured at six months or older, it fell below the second percentile, meaning that these children had postnatal microcephaly. The children did not have congenital contractures, Dr. Dobyns said.

Vanessa van der Linden, MD, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, Dr. Pessoa, Dr. Dobyns, and colleagues on November 22, 2016, published a description of 13 infants who had evidence of congenital Zika infection but did not have microcephaly at birth. Their report was published online in the CDC’s Morbidity and Mortality Weekly Report. The researchers found that head growth decelerated in all 13 of the infants by as early as age 5 months, and 11 of the infants had microcephaly. The findings suggest that infants exposed to Zika virus prenatally should receive comprehensive medical and developmental follow-up, even in the absence of microcephaly at birth, the investigators said.

That infants with prenatal Zika infection may develop postnatal microcephaly is not surprising, Dr. Dobyns said. Microcephaly, however, remains only one possible symptom of congenital Zika syndrome. “It is a pattern of features seen clinically, on CT scans, and behaviorally that will mark this syndrome,” he said.

—Jake Remaly

Suggested Reading

Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2016 Nov 3 [Epub ahead of print].

van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 22 Nov 2016 [Epub ahead of print].