$1 million awarded for VCU research on rare pediatric neurologic disorder

By Joe Kuttenkuler

RICHMOND, Va. – A Virginia Commonwealth University researcher, who has focused his career on deciphering the mysteries of a rare form of brain damage in children, recently received his sixth National Institutes of Health grant, bringing his total research funding to more than $6 million. 

For the past 20 years, Steven Shapiro, M.D., professor in VCU School of Medicine's Department of Neurology, has received almost continuous federal funding for his study of a disabling syndrome called kernicterus – a type of brain damage caused by excessive jaundice that can develop in newborns. The three-year, $1 million grant awarded earlier this year, will enable him to continue studying the disease that virtually disappeared for two decades in the U.S., but has been newly diagnosed in about 200 infants each year for the past 10 to 15 years.

Jaundice results from a build up of bilirubin – a toxin created during the normal process of red blood cells breaking down and dying. Babies with jaundice have a yellow hue to their skin and sclera – the "whites" of the eyes. Because newborns have higher levels of oxygen-carrying hemoglobin, about 60 percent of infants and 80 percent of premature babies develop jaundice. Patients with blood incompatibility disorders like Rh disease also are more likely to develop jaundice.

Under normal circumstances, bilirubin is processed by the liver and eliminated. Because a newborn's liver is still immature, the enzyme that converts bilirubin to a non-toxic substance sometimes does not begin functioning immediately, which can cause bilirubin levels to rise in the body. Left untreated, high levels of bilirubin – called hyperbilirubinemia – can damage parts of the brain.    

"Damage can occur quickly – almost immediately if the bilirubin gets very high. A few hours of sustained high bilirubin levels can result in a lifetime of damage," said Shapiro.

Babies with hyperbilirubinemia become increasingly sleepy and lethargic. They develop weak, limp arms and legs, a high-pitched cry and do not nurse well. As the condition progresses into kernicterus, areas of the brain develop lesions that can lead to permanent problems with hearing and auditory processing, muscle tone, eye movements, balance and coordination.

High bilirubin levels can be treated effectively. The gold standard for treating infants with jaundice is phototherapy, which uses special blue florescent lights to chemically change the structure of bilirubin from toxic to water soluble – enabling it to be eliminated through the kidneys. In more serious cases, exchange transfusions are performed that replace the baby's entire blood volume to rid the body of excess bilirubin. 

According to Shapiro, one of the challenges for doctors is recognizing at what point levels of bilirubin become too high. "What might be a dangerously high level in one baby, might be totally fine for another. We need to determine how much bilirubin is actually free to move out of the tissues to the brain," Shapiro said. "Right now, we are only measuring the amount of bilirubin that is in the blood, which is different than the amount actually reaching the brain."

The bulk of Shapiro's work focuses on the auditory nervous system. Using a technique called evoked potentials – a non-invasive way of measuring and tracking nerve impulses as they move through the brain – Shapiro can determine early on whether certain areas of the brain are becoming damaged. "We can stimulate with a click in the ear and track the signals as the impulse moves through the nerves, past different points to the bottom of the brainstem. In a child with kernicterus, the duration between these points is longer – like a train slowing down from station to station." 

Being able to recognize abnormal signals and treat for them early can normalize a baby in the early stages of the syndrome.

Shapiro's new grant will fund research to examine where the brain damage tends to localize, how and why the brain is susceptible to damage from bilirubin toxicity, how long the nerves can be adversely affected and still recover, and how the bilirubin actually attacks and kills cells. Shapiro also is interested in patients who appear to have some, but not all the classic symptoms of the syndrome. He believes some cases of learning disorders and motor disabilities may be linked to hyperbilirubinemia.

Part of Shapiro's work also involves educating other physicians and parents about the syndrome. He regularly attends national kernicterus symposia and has watched the awareness of the disease rise along with the number of cases. "Years ago, the moderator at these meetings would ask the 50 physicians in the room how many cases of kernicterus they had seen, and no one would raise their hand. At the most recent conference, half of the 1,000 doctors in attendance raised their hand.

Each week, Shapiro receives one or two calls from parents or physicians somewhere in the country inquiring about kernicterus. He is discouraged by the number of newly diagnosed cases each year and is pushing for better system-wide bilirubin screening. "Any newborn can develop hyperbilirubinemia, so every infant should be screened."