Bilirubin-Induced Neurotoxicity in the Preterm Neonate

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Key points

  • Bilirubin-induced neuronal injury likely reflects the adverse nature of hazardous unbound unconjugated bilirubin on plasma membranes and resultant excitotoxicity, neuroinflammation, oxidative stress, and perturbed cell cycle kinetics, including cell cycle arrest.

  • Hazardous hyperbilirubinemia leading to acute bilirubin encephalopathy is increasingly recognized to adversely impact neural respiratory drive and manifest clinically as recurrent symptomatic central, mixed, and obstructive apnea events.

Neuropathology of kernicterus

The neuropathology of bilirubin-induced brain damage is (i) remarkably similar across preterm and term neonates, and murine animal models; (ii) distinct from hypoxic-ischemic neonatal CNS injury; and (iii) notable in sparing the neocortex.1, 3 Classic kernicterus at postmortem in the preterm neonate is characterized by both (i) intense yellow staining of neurons in selected brainstem nuclear clusters and (ii) histopathologic evidence of neuronal damage in these stained regions. However,

Neuroimaging of kernicterus

MRI of the infant with kernicterus mirrors the distinct regional nature of bilirubin-induced neuropathology demonstrating abnormal bilateral, symmetric, high-intensity signals in the globus pallidus and subthalamic nuclei and on occasion the internal capsule and thalamus (Fig. 1).4, 5 Chronic bilateral, symmetrically increased T2-signal (or T2-FLAIR [fluid attenuated inversion recovery] signal) in the globus pallidus and subthalamic nuclei of an infant with a history of hyperbilirubinemia

Molecular and cellular mechanisms of bilirubin neurotoxicity

The complex cascades of molecular and cellular events that underlie bilirubin-induced neurotoxicity remain incompletely understood, but involve regional and cell-specific responses.8 Fig. 2 highlights the multiple reported effects of bilirubin on neurons and glia cells.8 Which of these effects constitute the “core” processes or molecular triggers that ultimately lead to bilirubin neurotoxicity is unclear.8, 9, 10, 11, 12 Nevertheless, the pathogenesis of bilirubin-induced neuronal cell injury

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    Disclosure Statement: Dr J.F. Watchko reports serving as a consultant in legal cases related to neonatal jaundice. No other potential conflict of interest relevant to this article was reported.

    Support: The Mario Lemieux Foundation and The 25 Club of Magee-Womens Hospital.

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