Bilirubin and Brain Toxicity

More than a century has passed since Hervieux first described yellow staining of the basal ganglia in association with neonatal jaundice (1). The term kernicterus was, however, first used by Schmorl in 1904 to describe the post-mortem finding of yellow staining of the basal ganglia in term infants whose cause of death was probably feto-maternal iso-immunization (2). This term has since been used to describe both the acute, often fatal condition in the newborn with substantial elevation of serum bilirubin levels, seizures, opisthotonus, and bleeding tendency, as well as the neurologic sequelae in survivors, consisting of choreoathetosis, asymmetric spasticity, paresis of upward gaze, and neurogenic hearing loss (3-7). Yellow staining of the brain has, in recent years, also been observed in infants dying without the clinical symptoms of kernicterus, and in whom only moderately elevated serum bilirubin values had been noted (8-10). Bilirubin has, in addition, been implicated in damage to cognitive functions (11, 12), but consensus is lacking regarding permanent damage to such functions (13, 14). The terms kernicterus and bilirubin encephalopathy have often been used interchangably, and without any clear definition of the terms. We suggest that bilirubin encephalopathy should be used in a broader sense so as to include all conditions in which bilirubin is known, or thought to be, the cause of brain toxicity. The term kernicterus would be reserved for cases exhibiting the classical acute symptoms described above, or surviving with the typical neurologic sequelae. During the past thirty years, considerable research has been carried out regarding the causes of hyperbilirubinemia and the mechanisms underlying bilirubin toxicity. Despite these efforts the basic mechanisms remain elusive. This research has been concentrated on three main areas. Firstly, the binding of bilirubin to albumin has been investigated in detail. Secondly, a number of studies have addressed the toxicity of bilirubin both in nervous tissue, and in other cell and organ systems. Finally, the mode of entry of bilirubin into the central nervous system has been examined.