CHAPTER THREE
PERINATAL ISCHEMIA AND STROKE

BILIRUBIN ENCEPHALOPATHY

Kernicterus (Bilirubin encephalopathy) is an acquired metabolic encephalopathy of the neonatal period. Its etiology and pathogenesis overlap to some extent with HIE. Kernicterus is caused by unconjugated hyperbilirubinemia that develops either as a result of hemolytic disease (Rh incompatibility, hereditary spherocytosis, other hemolytic disorders) or because of inability of the liver to conjugate bilirubin. The latter is seen in a rare defect of glucuronyl transferase, the Crigler-Najjar syndrome, and in premature babies in whom this enzyme is not fully functional. Unconjugated (indirect) bilirubin in serum is bound to albumin. Unbound unconjugated bilirubin crosses the blood-brain barrier and, because it is lipid soluble, it penetrates neuronal and glial membranes. Hypoalbuminemia, low pH, which weakens the albumin-bilirubin bond, and drugs (salicylates, sulfonamides) that compete with bilirubin for albumin binding, increase the amount of unconjugated unbound bilirubin.

Kernicterus

Bilirubin has a special affinity for the hippocampus, globus pallidus and subthalamic nucleus. The striatum, thalamus, inferior olives and dentate nucleus of the cerebellum are also but less frequently involved. In severe kernicterus, affected structures have a bright yellow color (kernicterus means nuclear jaundice). Microscopically, they show neuronal necrosis (eosinophilic neurons similar to HIE) and, in burned-out cases, neuronal loss, gliosis and atrophy. Bilirubin is thought to be toxic to nerve cells. It causes mitochondrial damage and inhibits oxidative phosphorylation in vitro. The mechanism of neurotoxicity and the reason for the topography of the lesions are not known. Immaturity of the blood-brain barrier probably plays a role in kernicterus. Infusion of bilirubin in experimental animals, after "opening" of the barrier by injecting hypertonic solutions, causes bilirubin staining. Bilirubin encephalopathy affects parts of the brain that are also involved in perinatal HIE. According to one school of thought, kernicterus is simply due to leakage of bilirubin in areas where the blood-brain barrier has been damaged by HIE.

Patients surviving kernicterus have severe permanent neurologic symptoms (choreoathetosis, spasticity, muscular rigidity, ataxia, mental retardation). Kernicterus as a result of Rh incompatibility is now rare. Rh isoimmunization can be prevented if an Rh negative mother is given an intramuscular injection of anti Rho(D) immune globulin within 72 hours of the birth of an Rh positive baby or in any situation in which significant fetal maternal hemorrhage may have occurred. Some cases of kernicterus are seen in premature babies with relatively modest levels of bilirubin. These babies often also have GMH-IVH and PVL.