Chapter 11

Excessive newborn hyperbilirubinemia can cause permanent brain damage, that is, chronic bilirubin encephalopathy (BE), also known as kernicterus. The effort to understand and treat neonatal hyperbilirubinemia is for the most part an effort to prevent kernicterus and bilirubin-induced neurological dysfunction (BIND), the latter referring to subtle neurodevelopmental disabilities without classical findings of kernicterus.14 Kernicterus is a matter of concern for pediatricians and neonatologists. Historically, kernicterus caused a significant number of cases of cerebral palsy (CP), particularly the athetoid or dystonic type. Kernicterus remains a significant problem in underdeveloped countries where bilirubin screening and treatment of excessive hyperbilirubinemia is not routinely available as highlighted in Chapter 13 Neonatal Jaundice in Low-Middle-Income Countries. The “classic” literature on kernicterus evolved during an era when Rh disease was the main cause and therapeutic options for treatment were limited. The resulting acute bilirubin encephalopathy (ABE) was dramatic, with prominent central nervous system (CNS) signs of lethargy, ophthalmoplegia and setting sun sign (impairment of upward gaze), high-pitched cry, opisthotonus, and seizures.5 Both the basal ganglia, with yellow staining (icterus) of the deep nuclei or “kernel” of the brain, and brainstem auditory pathways were recognized as being particularly vulnerable.5,6

The association between high levels of unconjugated bilirubin in the blood and kernicterus was recognized7 in the 1950s. In newborns with Rh hemolytic disease (gestation not provided), Mollison and Cutbush8 described kernicterus in 1/13 or 8% of term infants with peak total serum bilirubin (TSB) levels of 19–24 mg/dL, 4/12 (33%) with TSB 25–29 mg/dL, and 8/11 (73%) with TSB 30–40 mg/dL. The authors note, however, that “in many cases only two blood samples were taken during the period of maximum jaundice …,” so it is likely that the maximum TSB concentrations were actually higher. As specific therapeutic criteria were developed first to treat and then to prevent severe hyperbilirubinemia and Rh disease, the incidence of kernicterus fell dramatically. However, the level of bilirubin that is regarded as safe in human infants cannot be determined in isolation from other important risk factors, because it is bilirubin in the CNS, not bilirubin in blood bound to albumin, that is neurotoxic.

While clearly the risk of kernicterus rises as TSB rises, other risk factors, including free bilirubin, pH, albumin binding, infection, inflammation, and gestational age, may be important in combination with TSB to better predict neurotoxicity.

### Pathology

Kernicterus is a pathological term originally used to describe the yellow staining (icterus) of the deep nuclei (kernel) of the brain, that is, the basal ganglia. More recently it has been used as a clinical term synonymous with chronic BE, the clinical syndrome encompassing long-term adverse neurodevelopmental sequelae corresponding to the pathological condition of kernicterus. The original pathological diagnosis included yellow staining and necrosis in the globus pallidus, subthalamic nucleus (STN), brainstem nuclei, hippocampal CA-2, and cerebellar Purkinje cells. Today, modern neuroimaging can identify characteristic, almost pathognomonic brain ...

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