KERNICTERUS YELLOW KERN PATHOPHYSIOLOGY

Traditionally, the term kernicterus (literally yellow kern, with kern indicating the most commonly afflicted region of the brain, ie, the nuclear region) refers to an anatomic diagnosis made at autopsy based on a characteristic pattern of staining found in babies who had marked hyperbilirubinemia before they died. Regions most commonly affected include the basal ganglia; hippocampus; geniculate bodies; and cranial nerve nuclei, such as the oculomotor, vestibular, and cochlear. The cerebellum can also be affected. Acute bilirubin encephalopathy, which refers to the clinical signs associated with bilirubin toxicity, ie, hypotonia followed by hypertonia, opisthotonus or retrocollis, or both, is usually synonymous with kernicterus.

Prevalent in the 1950s and 1960s, kernicterus had virtually disappeared from the clinical scene, only to reappear during the 1990s. Early discharge of term infants (before their bilirubin peaks) may be a factor in the reemergence of this devastating neurologic affliction.

Much of the traditional teaching regarding hyperbilirubinemia is now being questioned as more is learned about bilirubin metabolism and neurologic injury. Kernicterus is now recognized to occur in the premature infant and very rarely in the term infant in the absence of profound hyperbilirubinemia. Conversely, physiologic jaundice (sometimes to levels previously thought to be universally dangerous) has been recognized to be within the reference range in the first week of life in healthy term babies, particularly those who are breastfed. Jaundice of this type resolves spontaneously, without sequelae.

Despite the lack of a clear-cut cause-and-effect relationship between kernicterus and hyperbilirubinemia, laboratory investigations have demonstrated that bilirubin is neurotoxic at a cellular level. Other in vitro studies have shown bilirubin to have more antioxidant capability than vitamin E, which is commonly assumed to be the most potent antioxidant in the human system. This possible role of bilirubin in early protection against oxidative injury, coupled with identification of multiple neonatal mechanisms to preserve and potentiate bilirubin production, has led to speculation about an as-yet-unrecognized beneficial role for bilirubin in the human neonate.

Pathophysiology: Bilirubin staining can be noted on autopsy of fresh specimens in the regions of the basal ganglia, hippocampus, substantia nigra, and brainstem nuclei. Such staining can occur in the absence of severe hyperbilirubinemia; in this situation, factors influencing permeability of the blood-brain barrier (eg, acidosis, infection) and the amount of unbound (versus albumin-bound) bilirubin may play a role. Characteristic patterns of neuronal necrosis leading to the clinical findings consistent with chronic bilirubin encephalopathy are also essential in the pathophysiology of this entity. Bilirubin staining of the brain without accompanying neuronal necrosis can be observed in babies who did not demonstrate clinical signs of bilirubin encephalopathy but who succumbed from other causes. This staining is thought to be a secondary phenomenon, dissimilar from the staining associated with kernicterus.

Frequency:
• In the US: The exact incidence of kernicterus is unknown. A pilot kernicterus registry following the cases of babies with kernicterus in the United States reports 80 babies with chronic kernicterus enrolled in the registry from 1984-1998. All babies reported in the registry had been discharged from the hospital fewer than 72 hours after birth. Most of these babies (60%) were term infants. Total serum bilirubin levels at the time of presentation with the classic physical signs of kernicterus ranged from 26-50 mg/dL. Sixty-seven percent of the patients were male, 54% were white, and 95% were breastfed. Severe hemolytic processes were identified in 19 out of 80 babies; glucose-6-phosphate dehydrogenase (G6PD) deficiency was diagnosed in 18 out of 80, galactosemia occurred in 2 out of 80, and Crigler-Najjar syndrome type I occurred in 1. Nine babies were diagnosed with sepsis. In 21 out of 74 infants, no etiology for the severe hyperbilirubinemia was discovered. Three out of 80 infants died.

Mortality/Morbidity: Classic kernicterus has been defined in the term infant. Increasing experience with premature babies indicates that the clinical presentation in premature infants may be somewhat different. Especially in the premature infant with significant hyperbilirubinemia, concomitant ongoing pathologies may make identifying the cause of death specifically as kernicterus difficult. Neurologic sequelae of bilirubin encephalopathy are variable, and correctly attributing some long-term neurologic deficits to kernicterus as opposed to other neonatal conditions may be difficult.

• In the kernicterus registry mentioned previously, 3 out of 80 patients died (3.75%). How many other patients died without being reported to the registry is unknown, as is the experience in countries other than the United States, especially countries with a high prevalence of hereditary hemolytic disorders.

• Of those patients reported to the kernicterus registry, 66 out of 77 (86%) had chronic kernicterus, 61 of which had severe disease. Ten out of 77 (13%) had no discernible sequelae when older than 1 year.

Race: Asian and Hispanic babies born either in their native countries or in the United States and Native American and Eskimo infants have higher production levels of bilirubin than white infants. African American infants have lower production levels. The reasons for these racial differences have not been fully elucidated.

Sex: Male infants have consistently higher levels of serum bilirubin than do female infants.

Age: Acute bilirubin toxicity appears to occur in the first few days of life of the term infant. Preterm infants may be at risk of toxicity for slightly longer than a few days. If injury has occurred, the first phase of acute bilirubin encephalopathy appears within the first week of life.