March 2010 Fact Sheet

Leading neuroscientists, clinicians, radiologists, neurobiologists, and pediatric neurologists came together for a symposium  entitled “Injury to the Preterm Brain and Cerebral Palsy” in conjunction with the 37th Annual Meeting of the Child Neurology Society on November 5th, 2008.  The symposium  was supported by the National Institutes of Health, the Child Neurology Society, the Kennedy Krieger Institute, and the Cerebral Palsy International Research Foundation. Recently a summary of the symposium was published in the Journal of Child Neurology by Michael Babcock, Felina Kostova and Drs. Donna Ferriero, Michael Johnson, Jan Brunstrom, Henrik Hagberg and Bernard Maria. The first session was on clinical aspects of injury to the preterm brain.

Current Knowledge of Preterm Injury

Dr. Joseph Volpe of the Children’s Hospital in Boston discussed the current state of knowledge regarding injury to the preterm brain. Of the 60,000 infants born each year in the US weighing less than 1,500 grams, up to 10% develop motor dysfunction and up to 50% have cognitive, behavioral and social deficits. Due to advances in neonatal care, 90% of these extremely low birthweight infants survive.  Periventricular leukomalacia (PVL) is the most common pathology, occurring in up to 50 % of these infants.  PVL has two components, one being a focal component, the other being a diffuse cell-specific  component characterized by injury to the preoligodendrocyte (precursor of the cell responsible for myelinating the neuronal axon), and the occurrence of astrocytosis, and microgliosis (nerve cells that are activated after a CNS injury).  Injury to preoligodendrocytes can result in cell death or loss of cell processes.  After insult, there is a replenishment of preoligodendrocytes that are unable  to mature into oligodendrocytes capable of myelination.

It is believed that there are interacting factors that contribute to PVL  in the premature infant . They include cerebral ischemia, infection and inflammation and a maturation dependent vulnerability of the preoligodendrocyte. Premature infants are susceptible to ischemia because of impaired vascular autoregulation, generating reactive oxygen and nitrogen species. These reactive species accumulate and cause injury in the preoligodendrocytes as they have not yet acquired an antioxidant defense system.  In addition, there is also clearly a link between infection/inflammation and PVL.  Infection and inflammation are associated with release of pathogen-associated molecular products that activate microglia. These activated microglia lead to production of free-radicals that cause injury to the preoligodendrocyte as well.

Thus there are upstream mechanisms of ischemia, reperfusion, and inflammation that activate downstream mechanisms of excitotoxicity (pathological process by which nerve cells are damaged and killed by glutamate and similar substances) and free radical attack that can all potentially be targeted for prevention of injury.  There are many animal studies demonstrating efficacy of various compounds blocking action of reactive species thus preventing injury and many of these appear to be ready for trials in premature infants.

Neuroimaging in Cerebral Palsy

Dr. David Edwards of the Hammersmith Hospital in London, England discussed recent technological advances and clinical usefulness of imaging.  He stated that conventional MRI does not have a lot of value in predicting health outcomes in premature infants.  Another type of imaging, called diffusion tensor imaging (DTI) has shown promise in that it can reveal  the structural integrity of white matter as well as white matter tracts throughout the brain demonstrating connections between various  regions.  Using DTI and tract-based spatial statistics, researchers have demonstrated a good correlation between health outcomes of 2 years old with white matter lesions and measures of microscopic white matter integrity.  DTI has revealed that in children with white matter lesions, not only is there decreased volume of the thalamus, but there is decreased connectivity between the thalamus and the cortex.  It is believed that use of DTI with functional MRI can be combined to give very precise structure-function relationships of various regions of the brain.

Fetal Inflammatory Response

Dr. Olaf Dammann of the University of Hanover in Germany discussed the fetal inflammatory response and brain injury.  It is now believed that premature birth is sometimes the result of some exposure during pregnancy (such as intrauterine infection) and that this exposure causes white matter damage in the infant.  Thus prematurity and cerebral palsy are associated but not necessarily causal in some instances.  In addition, it is now believed that it is not exposure to the pathogen itself that causes the damage, but rather exposure to substances produced by the fetal inflammatory response to the pathogen.

Further, Dr Dammann stated that it is likely that fetal white blood cells are involved in brain injury by going through the fetal blood-brain barrier once activated by cytokines, which in turn, activate microglia and astrocytes that damage the preoligodendrocytes.  He also suggested that brain injury and long-term disability results not just from a single event, but from an ongoing exposure to persistent inflammation as evidenced by the presence of a marker of inflammation present in the blood of children with cerebral palsy at age 10.