The complex cascade of molecular and cellular events leading to bilirubin-induced neurotoxicity remains incompletely delineated. This new review in our Medical Progress series discusses bilirubin-induced brain damage and recent insights into its pathogenesis and prevention.
Neonatal unconjugated hyperbilirubinemia and resultant clinical jaundice affect up to approximately 85% of newborns. Although this condition is generally a benign, transitional phenomenon, unconjugated bilirubin levels that can pose a direct threat of serious brain injury develop in a small proportion of neonates.
• What is kernicterus?
Acute bilirubin encephalopathy may ensue and progress to kernicterus (chronic bilirubin encephalopathy), a permanent disabling neurologic condition that is classically characterized by the extrapyramidal movement disorders of dystonia, choreoathetosis, or both; hearing loss due to auditory neuropathy spectrum disorders; and oculomotor pareses. These central nervous system (CNS) sequelae reflect the regional topography of bilirubin-induced neuropathology, which involves the globus pallidus, subthalamic nucleus, brain-stem nuclei, hippocampal CA2 neurons, and cerebellar Purkinje’s cells.
• What factors contribute to the incidence of kernicterus in developing nations?
Factors that contribute to the incidence of kernicterus in developing nations include inadequate screening for neonatal jaundice; the inability to measure total serum bilirubin levels easily; and a high prevalence of medical conditions that increase the risk of severe hyperbilirubinemia or bilirubin neurotoxicity, such as glucose-6-phosphate dehydrogenase deficiency, Rh isoimmunization, and sepsis. These factors also include delays in referral of neonates with jaundice to treatment facilities; the challenge of implementing phototherapy in settings that often lack effective light sources and electricity; and the limited availability of whole blood, safe blood-banking practices, or both to support exchange transfusion in infants who have critically high bilirubin levels or signs of acute bilirubin toxicity.
Morning Report Questions
Q: What type of bilirubin is neurotoxic?
A: The decision to treat an infant who has marked hyperbilirubinemia with the aim of preventing acute bilirubin toxicity is conventionally based primarily on the total serum bilirubin level. This level alone, however, is of limited value in predicting neurologic impairment and kernicterus in newborns with hyperbilirubinemia. The total serum bilirubin level is the level of albumin-bound bilirubin. The small circulating fraction that is not bound to albumin or other serum proteins is indexed according to the level of unbound, or free, circulating bilirubin. This level should be a more reliable index of the risk of neurotoxicity than the level of total serum bilirubin.
Even though unbound circulating bilirubin has biologic effects in the brain, the level alone does not dictate the risk of bilirubin encephalopathy. Bilirubin-induced neurotoxicity depends on a complex interaction between the level and duration of CNS exposure to unbound bilirubin and the innate cellular characteristics of the developing CNS that may confer either a predisposition to or protection against bilirubin-induced neuronal injury.
Q: What are the mainstays of treatment in newborns with hyperbilirubinemia?
A: Phototherapy and exchange transfusion remain the mainstays of therapy. Their effectiveness is based on limiting or reducing unconjugated bilirubin concentrations to nontoxic levels. Improvements in phototherapy have markedly reduced the need for exchange transfusion. Although phototherapy is generally considered a benign intervention and has been in clinical use for decades, studies have raised concerns about the potential toxicity of intensive phototherapy in preterm neonates with extremely low birth weight. The American Academy of Pediatrics recommends immediate exchange when signs of an intermediate-to-advanced stage of acute bilirubin encephalopathy (hypertonia, arching, retrocollis, opisthotonos, fever, and high-pitched cry) are present in an infant with jaundice, regardless of the total serum bilirubin level, and even if the total serum bilirubin level is decreasing.