More Than Microcephaly: Congenital Zika Syndrome

Laura A. Stokowski, RN, MS; William B. Dobyns, MD

Disclosures

September 21, 2016

In This Article

Fetal Brain Disruption Sequence

Medscape: What is happening in babies with so-called shrinking brains and collapsing skulls?

Dr Dobyns: About half of these babies have a condition called fetal brain disruption sequence. Their heads have a very striking appearance; the skull appears to have collapsed over the (shrinking) brain.

How does this happen? Consider how a baby's skull grows. The skull is normally pushed out by the growing brain. In a fetus with microcephaly linked to a genetic cause, the brain grows more slowly so the skull grows more slowly. Although the overall head is small, the brain fits the skull. In contrast, if there is normal brain growth pushing the skull out and then at some point the brain is severely damaged and shrinks, the skull doesn't shrink. Soft tissue can shrink, but bones do not. In such cases, there is nothing to support the skull bones and they collapse over each other. This is not rare. It occurs in half of all infants with congenital Zika syndrome.

The frontal and parietal bones collapse over each other, and the occipital bone (which doesn't have a suture line down the middle) no longer articulates with the other skull bones. We call this occipital bone, which is left sticking out, an occipital shelf.

Along with this is redundant and wrinkled skin over the scalp.. When the head is growing normally, the skin grows as well, so when the skull collapses, an excess of skin is left, similar to what happens on a person's abdomen after significant weight loss (Figure).

Figure. Characteristic phenotype of fetal brain disruption sequence in infant with congenital Zika virus syndrome.[5] (A) Craniofacial disproportion and biparietal depression. (B) Prominent occiput. Courtesy of CDC.

Medscape: What are the radiologic features of congenital Zika syndrome?

Dr Dobyns: On imaging, there is a significant loss of brain volume. No matter how small their heads are, their brains are usually even smaller. We typically see excess cerebrospinal fluid surrounding the brain and enlarged ventricles. This is what happens when there is not enough brain tissue during critical developmental periods.

All affected infants have cortical malformations, and these are not just the effect of disruption. For a cortical malformation to develop, there must be damage to certain types of critical developmental cells, called radial glial cells, in the late first or early second trimesters of pregnancy. A radial glial cell is an early cell type in the brain that sends a fiber from the ventricular zone (the base—the deepest layer of the brain) up to the surface. Developing nerve cells essentially climb up these radial glial cells to get to the cortex. Radial glial cells have two functions. They are the progenitor cells that give rise to the neurons and other proliferating brain cells and are the scaffolding of the developing embryonic brain, enabling the migration of neurons to other parts of the brain. If you infect and lose radial glial cells, not only is the number of neurons reduced, the ladder is also lost.

...calling the fetal effects of the Zika virus just microcephaly is so inadequate. These babies have so much more than microcephaly.

In summary, three things contribute to microcephaly and the other abnormal features of the brain. First, proliferating cells become infected and are lost, reducing proliferation. Second, there is cell death; even when cells are produced, they become infected and die. Third, the brain loses its scaffolding, so the nerve cells that are produced can't climb into their normal positions. The result is a combination of insufficient nerve cells, microcephaly, a congenital cortical malformation (owing to the scaffolding defect), and other evidence of injury. In addition to being small, these brains have scattered calcifications as a result of direct damage from the Zika virus.

This is why calling the fetal effects of the Zika virus just microcephaly is so inadequate. These babies have so much more than microcephaly. We can recognize congenital Zika syndrome from the clinical exam and the infant's brain scan. It has some similarities to intrauterine infection with cytomegalovirus (CMV), but it is more severe and there are different features.

Medscape: There have been recent reports of Zika-related arthrogryposis in infants born to mothers infected with the virus. Is this part of the congenital Zika syndrome?

Dr Dobyns: Twenty percent of the babies with congenital Zika syndrome have congenital joint contractures (arthrogryposis). These are not mild distal contractures of the hands or feet, they are severe, involving the big proximal joints. Among causes of severe contractures are some genetic diseases of connective tissue and ligaments, but in terms of injury to the brain as a cause, you need to look at the brain stem and spinal cord. This strongly suggests that these children have Zika involvement in the brain stem or spinal cord.

Children with congenital Zika syndrome are flagrantly abnormal in terms of neurologic development. They typically have severe microcephaly, half have collapsed skulls, and about one in five have congenital joint contractures. All have very abnormal neurologic exams. Congenital Zika syndrome is a very striking disorder that we can now recognize purely on clinical grounds, without even looking at the brain scans.

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