The first description of kernicterus (or brain jaundice) in newborns was provided by Hervieux in 1847 (1) and in
1875, Orth (36) observed bilirubin pigment at autopsy in the brains of infants who were severely jaundiced. Schmorl (37) subsequently described two forms of “brain icterus,” the first “characterized by a diffuse yellow coloration of the entire brain substance,” and a second form in which “the jaundiced coloration appears to be completely circumscribed and…limited to the so-called ‘kern’ or nuclear region of the brain.”

Full-term infants who die of kernicterus demonstrate bilirubin staining in a characteristic distribution (Table 35-4), although a variety of patterns have been described, grossly and microscopically (38). Kernicteric premature infants and Gunn rats with inherited UGT deficiency display a similar topography of neuronal damage (see Table 35-4) (39). Those regions most commonly affected are the basal ganglia, particularly the subthalamic nucleus and the globus pallidus; the hippocampus; the geniculate bodies; various brainstem nuclei, including the inferior colliculus, oculomotor, vestibular, cochlear, and inferior olivary nuclei; and the cerebellum, especially the dentate nucleus and the vermis (39,40). Ahdab-Barmada has provided a detailed review of the neuropathology of kernicterus, and its anatomic, cytologic, and histologic characteristics (41).

Yellow staining of the brain occurs when it is exposed to elevated levels of bilirubin. Table 35-5 lists the three patterns of bilirubin staining of the brain seen in the newborn (41).

Table 35-6 summarizes the neuropathologic findings of kernicterus. There can be some confusion regarding the diagnosis of kernicterus in the presence of yellow discoloration of the central nervous system. Ahdab-Barmada emphasizes that the diagnosis of kernicterus should only be applied to the incorporation of bilirubin pigment into gangliosides or phospholipids of mature neurons with subsequent damage to the neuron, depending on the amount of pigment trapped within the cell (41). The unique topographic pattern of nuclear involvement is described above (see Topography) and the combination of the bright yellow-orange staining of these brain nuclei, together with evidence of neuronal damage and degeneration within the nuclei, is necessary before a diagnosis of kernicterus can be made (41).

Autopsies on jaundiced infants reveal bilirubin staining of the aorta, pleural fluid, and ascitic fluid, or a generalized yellow cast throughout the viscera. The staining usually is not considered a sign of tissue damage unless other cytologic changes are found (38). Bilirubin staining also can be found in necrotic tissue anywhere in the body and has been described in the gastrointestinal tract, lungs (hyaline membranes) (42), kidney, adrenals, and gonads. In infants with hemolytic disease, bile plugs commonly are found in the canaliculi between the hepatocytes, especially in the periportal areas. The kidneys may show bilirubin-stained tubular casts, bilirubin crystals in the small vessels or in edematous interstitium, and renal tubular necrosis. The bilirubin infarcts (i.e., patches of yellow staining in the renal medulla) are probably the result of focal areas of acute tubular necrosis that have been stained by bilirubin (38).

Neuronal necrosis is the dominant histopathologic feature after 7 to 10 days of postnatal life (see Table 35-6). For the most part, its distribution corresponds with the distribution of bilirubin staining, although there are some exceptions to this rule. For example, intense staining develops in the olivary and dentate nuclei, but there is little neuronal necrosis in these regions. The important areas of neuronal injury (as opposed to staining) include the basal ganglia, brainstem oculomotor nuclei, and brainstem auditory (cochlear) nuclei (40). The involvement of these regions explains some of the clinical sequelae of bilirubin encephalopathy (see Clinical Features of Bilirubin Encephalopathy below).

Originally a pathologic diagnosis and later a well-defined acute and chronic neurologic syndrome, kernicterus or bilirubin encephalopathy appears to be a less-well-circumscribed entity that includes nuclear bilirubin staining of very-low-birth-weight infants who died of other causes and, possibly, a subtle chronic encephalopathy in which extrapyramidal motor disturbances and sensorineural hearing deficit are not the predominant features.

Most, but not all, full-term infants seen today with the pathologic changes described manifest the clinical symptomatology of this disorder, including very high serum bilirubin levels (commonly higher than 30 mg/dL [513 μmol/L]). Exceptions have been described. Perlman and associates (43) recently reported kernicterus at autopsy in two very sick near-term infants with maximum TSB levels of 5.2 and 14.4 mg/dL (89 to 246 μmol/L).

Yellow staining of the brain also has been observed in premature infants who manifested none of the clinical signs of kernicterus during life and in whom TSB levels remained low (44,45). Turkel and colleagues (46) identified 32 infants with kernicterus at autopsy and compared them with 32 control infants of similar gestational ages without kernicterus. In the kernicteric infants, although the gross pattern of staining followed that of classic kernicterus, the typical histologic changes characteristic of kernicterus were found in only three patients. These authors suggest that the bilirubin staining they observed probably was not the same clinicopathologic entity as the kernicterus of posticteric encephalopathy. Instead of the neuronal degeneration typically seen, they found spongy change and gliosis, which both imply nonspecific damage to the brain. This suggests that prior diffuse injury may predispose the brain to bilirubin deposition at relatively low levels of serum bilirubin.

Ahdab-Barmada and Moossy (39) found kernicterus in 97 autopsies of neonates (95 younger than 36 weeks of gestation)
The neuropathology in these infants was strikingly similar to that of classic kernicterus in the full-term neonate and in the Gunn rat (see Table 35-4). In the National Institute of Child Health and Human Development (NICHHD) cooperative phototherapy study, four low-birth-weight infants had autopsy-proven kernicterus (47). The neuropathologic findings in these infants were those of classic kernicterus. As Table 35-7 shows, the neuropathology of kernicterus is different from that of hypoxic ischemic encephalopathy. Even though hypoxic ischemic insults may predispose the brain to bilirubin deposition in some low-birth-weight infants, in others the typical histologic features of kernicterus will be found.

As discussed in Formation, Structure, and Properties of Bilirubin above, the polar groups of the bilirubin molecule, in its most stable conformation, are involved in intramolecular hydrogen bonding that restricts solvation and renders the pigment nearly insoluble in water at pH 7.4. When doubly ionized in alkaline medium, the molecule is much more soluble. The low water solubility of bilirubin and its tendency to aggregate and precipitate at physiologic pH, particularly acid pH, have long been thought to be key factors in its toxicity. Thus, when the concentration of bilirubin acid exceeds its solubility, bilirubin may gradually aggregate and precipitate from solution (17). Bilirubin crystals have been found in the brain cells of infants who died from kernicterus, and bilirubin concentrations of 2 mg/dL (34 μmol/L) have been observed in kernicteric brains (52). It is likely that even higher local concentrations of pigment exist in the brain in kernicterus and may occur when aggregates precipitate within brain cells (53,54). Wennberg (55) suggested that formation of reversible complexes between bilirubin monoanion and membranes is also important in the development of bilirubin encephalopathy.

Although it is known that bilirubin uncouples oxidative phosphorylation and inhibits cellular respiration and protein phosphorylation, there is no agreement that these are the key mechanisms of bilirubin toxicity in vivo (see Fig. 35-8). Bilirubin also inhibits mitochondrial enzymes, interferes with DNA and protein synthesis (56), and alters cerebral glucose metabolism (49,57). Unconjugated bilirubin will initiate a mitochondrial pathway of apoptosis in developing brain neurons (58) and it inhibits the function of Nmethyl-aspartate-receptor ion channels (59). Bilirubin also binds to lysine sites on albumin and ligandin, proteins that are essential for bilirubin transport and metabolism (49). Consequently, lysine binding may have a role in the pathogenesis of bilirubin toxicity.