All is not well: the continual challenges of bilirubin encephalopathy.

impression that kernicterus has virtually " become extinct " with the near elimination of Rh disease is incorrect. In fact, this neurological condition is experiencing a re-emergence, likely due to earlier hospital discharge and a " more lax " approach to the treatment of neonatal hyperbilirubinemia. 1 Up to one in 700 healthy term newborns may be at risk of kernicterus due to severe hyperbilirubinemia, as defined by total serum bilirubin greater than 250 mg/L or 428 µmol/L. 2 Risk factors for hyperbilirubinemia include onset of jaundice within 24 hours of age, ABO and Rh incompatibility, or other hemolytic diseases such as glucose-6-phosphate dehydrogenase (G6PD) deficiency. Preterm or sick infants have increased susceptibility to bilirubin toxicity. In this issue, AlOtaibi et al 3 retrospectively reviewed the outcome of 12 neonates admitted to the Hospital for Sick Children with kernicterus over a ten-year period. The majority of cases (58%) were attributed to G6PD deficiency. Seven out of ten patients reportedly had abnormal neurodevelopmental outcome. In neonates, serum bilirubin is comprised mainly of the unconjugated form, which is bound to albumin. When the blood binding capacity is exceeded, free unconjugated bilirubin then enters brain tissue and leads to neurotoxicity by a number of possible mechanisms. Bilirubin depletes cellular energy reserves by uncoupling oxidative phosphorylation and impairing mitochondrial function. Hyperbilirubinemia in a rodent model has also been shown to inhibit calcium and calmodulin-dependent protein kinase II, leading to alterations in both calcium-regulated ion conductance and neurotransmitter release, a situation which may lead to excitotoxic cell death. 4 Finally, in in vitro studies on rat neurons and astroglia, bilirubin was found to induce apoptosis and inhibit uptake of glutamate by astrocytes. 5,6 Thus, neuronal loss in bilirubin encephalopathy is due to both apoptosis and necrosis. Pathologically, the globus pallidus and subthalamic nuclei show neuronal loss, demyelination and gliosis. Other affected areas include the cerebellum, particularly Purkinje cells, and the CA2 region of the hippocampus. In the auditory system, central auditory pathways including cochlear nuclei, the superior olivary complex, nuclei of the lateral lemniscus and inferior colliculi are affected but the eighth nerve and inner ear structures are relatively spared. Infants with acute bilirubin encephalopathy initially present with lethargy, hypotonia, and poor feeding. If hyperbilirubinemia is untreated, additional symptoms such as fever, seizures, high-pitched cry, retrocollis, and opisthotonus may develop. The classic tetrad of athetoid cerebral palsy, deafness, upward gaze palsy and dental enamel hypoplasia …