CEREBRAL PALSY: WHAT RESEARCH IS BEING DONE?

Investigators from many arenas of medicine and health are using their expertise to help improve treatment and prevention of cerebral palsy. Much of their work is supported through NINDS, the National Institute of Child Health and Human Development, other agencies within the Federal Government, nonprofit groups such as the United Cerebral Palsy Research Foundation, and private institutions.

The ultimate hope for overcoming cerebral palsy lies with prevention. In order to prevent cerebral palsy, however, scientists must first understand the complex process of normal brain development and what can make this process go awry.

Between early pregnancy and the first months of life, one cell divides to form first a handful of cells, and then hundreds, millions, and, eventually, billions of cells. Some of these cells specialize to become brain cells. These brain cells specialize into different types and migrate to their appropriate site in the brain. They send out branches to form crucial connections with other brain cells. Ultimately, the most complex entity known to us is created: a human brain with its billions of interconnected neurons.

Mounting evidence is pointing investigators toward this intricate process in the womb for clues about cerebral palsy. For example, a group of researchers has recently observed that more than one-third of children who have cerebral palsy also have missing enamel on certain teeth. This tooth defect can be traced to problems in the early months of fetal development, suggesting that a disruption at this period in development might be linked both to this tooth defect and to cerebral palsy.

As a result of this and other research, many scientists now believe that a significant number of children develop cerebral palsy because of mishaps early in brain development. They are examining how brain cells specialize, how they know where to migrate, how they form the right connections — and they are looking for preventable factors that can disrupt this process before or after birth.

Scientists are also scrutinizing other events — such as bleeding in the brain, seizures, and breathing and circulation problems — that threaten the brain of the newborn baby. Through this research, they hope to learn how these hazards can damage the newborn's brain and to develop new methods for prevention.

Some newborn infants, for example, have life-threatening problems with breathing and blood circulation. A recently introduced treatment to help these infants is extracorporeal membrane oxygenation, in which blood is routed from the patient to a special machine that takes over the lungs' task of removing carbon dioxide and adding oxygen. Although this technique can dramatically help many such infants, some scientists have observed that a substantial fraction of treated children later experience long-term neurological problems, including developmental delay and cerebral palsy. Investigators are studying infants through pregnancy, delivery, birth and infancy, and they are tracking those who undergo this treatment. By observing them at all stages of development, scientists can learn whether their problems developed before birth, result from the same breathing problems that made them candidates for the treatment, or spring from errors in the treatment itself. Once this is determined, they may be able to correct any existing problems or develop new treatment methods to prevent brain damage.

Other scientists are exploring how brain insults like hypoxic-ischemic encephalopathy (brain damage from a shortage of oxygen or blood flow), bleeding in the brain, and seizures can cause the abnormal release of brain chemicals and trigger brain damage. For example, research has shown that bleeding in the brain unleashes dangerously high amounts of a brain chemical called glutamate. While glutamate is normally used in the brain for communication, too much glutamate overstimulates the brain's cells and causes a cycle of destruction. Scientists are now looking closely at glutamate to detect how its release harms brain tissue and spreads the damage from stroke. By learning how such brain chemicals that normally help us function can hurt the brain, scientists may be equipped to develop new drugs that block their harmful effects.

In related research, some investigators are already conducting studies to learn if certain drugs can help prevent neonatal strokes. Several of these drugs seem promising because they appear to reduce the excess production of potentially dangerous chemicals in the brain and may help control brain blood flow and volume. Earlier research has linked sudden changes in blood flow and volume to stroke in newborns.

Low birthweight itself is also the subject of extensive research. In spite of improvements in health care for some pregnant women, the incidence of low birth-weight babies born each year in the United States remains at about 7.5 percent. Some scientists currently investigating this serious health problem are working to understand how infections, hormonal problems and genetic factors may increase a woman's chances of giving birth prematurely. They are also conducting more applied research that could yield new drugs that can safely delay labor, new devices to further improve medical care for premature infants, and new insight into how smoking and alcohol consumption can disrupt fetal development.

While this research offers hope for preventing cerebral palsy in the future, ongoing research to improve treatment brightens the outlook for those who must face the challenges of cerebral palsy today. An important thrust of such research is the evaluation of treatments already in use so that physicians and parents have the information they need to choose the best therapy. A good example of this effort is an ongoing NINDS-supported study that promises to yield new information about which patients are most likely to benefit from selective dorsal root rhizotomy, a recently introduced surgery that is becoming increasingly in demand for reduction of spasticity.

Similarly, although physical therapy programs are a popular and widespread approach to managing cerebral palsy, little scientific evidence exists to help physicians, other health professionals and parents determine how well physical therapy works or to choose the best approach among many. Current research on cerebral palsy aims to provide this information through careful studies that compare the abilities of children who have had physical and other therapy with those who have not.

As part of this effort, scientists are working to create new measures to judge the effectiveness of treatment, as in ongoing research to precisely identify the specific brain areas responsible for movement may yield one such approach. Using magnetic pulses, researchers can locate brain areas that control specific actions, such as raising an arm or lifting a leg, and construct detailed maps. By comparing charts made before and after therapy among children who have cerebral palsy, researchers may gain new insights into how therapy affects the brain's organization and new data about its effectiveness.

Investigators are also working to develop new drugs — and new ways of using existing drugs — to help relieve cerebral palsy's symptoms. In one such set of studies, early research results suggest that doctors may improve the effectiveness of the anti-spasticity drug called baclofen by giving the drug through spinal injections, rather than by mouth.

In addition, scientists are also exploring the use of tiny implanted pumps that deliver a constant supply of anti-spasticity drugs into the fluid around the spinal cord, in the hope of improving these drugs' effectiveness and reducing side effects such as drowsiness. Other experimental drug development efforts are exploring the use of minute amounts of the familiar toxin called botulinum. Ingested in large amounts, this toxin is responsible for botulism poisoning, in which the body's muscles become paralyzed. Injected in tiny amounts, however, this toxin has shown early promise in reducing spasticity in specific muscles.

A large research effort is also directed at producing more effective, nontoxic drugs to control seizures. Through its Antiepileptic Drug Development Program, the NINDS screens new compounds developed by industrial and university laboratories around the world for toxicity and anticonvulsant activity and coordinates clinical studies of efficacy and safety. To date, this program has screened more than 13,000 compounds and, as a result, five new antiepileptic drugs — carbamazepine, clonazepam, valproate, clorazepate, and felbamate — have been approved for marketing. A new project within the program is exploring how the structure of a given antiseizure medication relates to its effectiveness. If successful, this project may enable scientists to design better antiseizure medications more quickly and cheaply.

As researchers continue to explore new treatments for cerebral palsy and to expand our knowledge of brain development, we can expect significant medical advances to prevent cerebral palsy and many other disorders that strike in early life.

Research Regarding Very Low Birthweight Babies

Research conducted and supported by NINDS continuously seeks to uncover new clues about cerebral palsy. Investigators from NINDS and the California Birth Defects Monitoring Program (CBDMP) presented data suggesting that very low birthweight babies have a decreased incidence of cerebral palsy when their mothers are treated with magnesium sulfate soon before giving birth. The results of this study, which were based on observations of a group of children born in four Northern California counties, were published in the February 1995 issue of Pediatrics.*

Low birthweight babies are 100 times more likely to develop cerebral palsy than normal birthweight infants. If further research confirms the study's findings, use of magnesium sulfate may prevent 25 percent of the cases of cerebral palsy in the approximately 52,000 low birthweight babies born each year in the United States.

Magnesium is a natural compound that is responsible for numerous chemical processes within the body and brain. Obstetricians in the United States often administer magnesium sulfate, an inexpensive form of the compound, to pregnant women to prevent preterm labor and high blood pressure brought on by pregnancy. The drug, administered intravenously in the hospital, is considered safe when given under medical supervision. Scientists speculate that magnesium may play a role in brain development and possibly prevent bleeding inside the brains of preterm infants. Previous research has shown that magnesium may protect against brain bleeding in very premature infants. Animal studies have demonstrated that magnesium given after a traumatic brain injury can reduce the severity of brain damage.

Despite these encouraging research findings, pregnant women should not change their magnesium intake because the effects of high doses have not yet been studied and the possible risks and benefits are not known.

Researchers caution that more research will be required to establish a definitive relationship between the drug and prevention of the disorder. Clinical trials now underway, one of them a collaboration between NINDS and the National Institute of Child Health and Human Development, are evaluating magnesium for the prevention of cerebral palsy in prematurely born babies.