Groundbreaking new research provides strong evidence that inflammation and clotting abnormalities may be important causes of cerebral palsy (CP) in full-term babies, who account for about half of all children with this disorder. The study may lead to ways of identifying babies at risk for CP and ultimately to new therapies that might prevent brain damage in some children.
The new study examined levels of inflammation markers called cytokines, and of coagulation (blood-clotting) factors, in blood taken from infants shortly after birth. The results were dramatic. All of the babies who later developed CP had higher concentrations of five different cytokines in their blood than any babies who did not go on to develop the disorder. Many of these babies also had greater-than-normal concentrations of one or more coagulation factors.
"These factors appear to play a role in several different processes that can lead to CP," says Karin B. Nelson, M.D., a child neurologist at the National Institute of Neurological Disorders and Stroke (NINDS) and lead author of the new study.
The other authors include James M. Dambrosia, Ph.D., of the NINDS, Judith K. Grether, Ph.D., of the California Birth Defects Monitoring Program, and Terry M. Phillips, D.Sc., Ph.D., of George Washington University Medical Center in Washington, D.C. The results are published in the October 1998 issue of Annals of Neurology(1).
"We've applied state-of-the-art technology to the study of cerebral palsy," says Dr. Grether. "Our long-term goal is to provide answers that can lead to prevention of CP. This study may be a big step in that direction."
The findings may point to ways of preventing CP or lessening its severity. This disorder affects about 500,000 Americans and is caused by faulty development or damage to the motor areas of the brain. Despite improvements in obstetric and perinatal medicine in recent decades, there has been no decrease in the number of full-term babies who develop CP. For years, many cases of CP have been attributed to suffocation (asphyxia) during birth, but recent studies have indicated that this problem accounts for only a minority of cases.
The new findings support those of a study by Drs. Nelson and Grether last year (2) which showed that babies of normal birthweight who were exposed to infection in the womb had nine times the normal risk of developing CP. Other recent studies have linked prenatal infection to premature birth, which increases the risk of CP. However, the lengthy time needed to confirm a diagnosis of CP has made it very difficult to identify what causes the disorder.
"By the time the child is diagnosed, months or years after birth, the trail is already cold," says Dr. Nelson.
In the new study, the researchers measured concentrations of more than 50 substances in dried blood samples from 31 children who had developed CP and 65 who had not. Most of the children with CP whose blood samples were examined were born full-term and were selected from cases in which there was no clear explanation for the disorder. The blood samples were provided by the Newborn Screening Program of the California Genetic Disease Branch, which archives blood that is taken from all newborns in California shortly after birth to screen for metabolic disorders.
Using advanced immunochemistry techniques developed by Dr. Phillips, scientists measured the concentrations of many different substances in tiny amounts of archived blood. They found that every child later diagnosed with CP had higher concentrations of five cytokines, tumor necrosis factor alpha, RANTES, and interleukins 1, 8, and 9, than any of the children who did not develop CP. Most children who later developed CP also had substantial elevations of several other cytokines and of one or more coagulation factors.
The concentrations of these cytokines and coagulation factors were not related to the babies' gestational ages at birth, their birthweights, or the amount of time between their births and collection of the blood samples. This suggests that the findings associated with CP might be due to chronic or reactivated conditions, such as autoimmune disorders or chronic infections in the womb, rather than acute infections just before or after birth, which normally cause a rapid rise and fall of inflammatory cytokines, says Dr. Nelson.
It is not yet clear how elevated levels of cytokines might increase the risk of CP. "These cell signaling factors are usually found only in very small amounts in the blood. What they are doing in relatively large amounts in these children with CP is a mystery," says Dr. Nelson. Previous studies have shown that cytokine production can be influenced by many factors, including infection and autoimmune disorders, trauma, oxygen deprivation, and tumors. Any of these factors might prompt elevations in cytokines that then act as toxins, damaging neurons and their connections in the developing brain. Cytokine abnormalities might also reflect underlying genetic or environmental factors that affect the brain.
Because the levels of some cytokines were strongly related to development of CP, testing for abnormally high concentrations of these substances might one day allow doctors to identify babies at risk of developing the disorder. If so, they might be able to prevent some brain damage with medications such as antibiotics to counter infection-related inflammation or anticoagulants to combat clotting problems. However, much more research is needed before researchers can be sure whether such testing and treatment will work.
Despite the dramatic findings, the initial study measured samples from only a small number of patients, so the results must now be confirmed in a larger population. The researchers also plan to study levels of cytokines and coagulation factors in very low birthweight babies, who are at greatly increased risk of developing CP. Because combinations of cytokines and coagulation factors may act differently than single factors alone, future research should focus on an array of these substances in the blood, rather than on one substance at a time, they say. Researchers also need to clarify what concentrations of different substances are normal for infants of different ages and to examine how levels of these factors might become elevated and lead to brain damage.
The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain. The California Birth Defects Monitoring Program, a public health program devoted to finding causes of birth defects, is funded by the California Department of Health Services and jointly operated with the March of Dimes Birth Defects Foundation.
(1) Nelson, K.B.; Dambrosia, J.M.; Grether, J.K., and Phillips, T.M. "Neonatal Cytokines and Coagulation Factors in Children with Cerebral Palsy." Annals of Neurology, October 1998, Vol. 44., No. 4, pp. 665-667.
(2) Grether, J.K., and Nelson, K.B. "Maternal Infection and Cerebral Palsy in Infants of Normal Birth Weight." Journal of the American Medical Association, July 16, 1997, Vol. 278, No. 3, pp. 207-211.