Severe neonatal hyperbilirubinemia and the brain: the old but still evolving story

Aetiology and Pathophysiology of Cerebral Palsy

“…Severe unconjugated hyperbilirubinaemia remains a significant perinatal/postnatal aetiological factor for CP in LMICs of sub-Saharan Africa and south Asia due to suboptimal management of neonatal jaundice [56,57]. However, in HICs, kernicterus spectrum disorder (KSD) also occurs especially in preterm/low birth weight babies where brain damage may be present at levels of total serum bilirubin (TSB) below the "safe level" or without signs of acute bilirubin encephalopathy (ABE) (the so-called "low bilirubin kernicterus") [56].…”

“…Severe unconjugated hyperbilirubinaemia remains a significant perinatal/postnatal aetiological factor for CP in LMICs of sub-Saharan Africa and south Asia due to suboptimal management of neonatal jaundice [56,57]. However, in HICs, kernicterus spectrum disorder (KSD) also occurs especially in preterm/low birth weight babies where brain damage may be present at levels of total serum bilirubin (TSB) below the "safe level" or without signs of acute bilirubin encephalopathy (ABE) (the so-called "low bilirubin kernicterus") [56]. Some causes of unconjugated hyperbilirubinaemia that manifest as ABE and KSD include Rhesus and ABO incompatibilities, G6PD deficiency, prematurity/low birth weight and Crigler-Najjar syndrome type 1 while the risk factors for KSD are: asphyxia, prematurity, low birth weight, acidosis, sepsis, hypoalbuminaemia, hyperthermia and respiratory distress [56][57][58].…”

“…However, in HICs, kernicterus spectrum disorder (KSD) also occurs especially in preterm/low birth weight babies where brain damage may be present at levels of total serum bilirubin (TSB) below the "safe level" or without signs of acute bilirubin encephalopathy (ABE) (the so-called "low bilirubin kernicterus") [56]. Some causes of unconjugated hyperbilirubinaemia that manifest as ABE and KSD include Rhesus and ABO incompatibilities, G6PD deficiency, prematurity/low birth weight and Crigler-Najjar syndrome type 1 while the risk factors for KSD are: asphyxia, prematurity, low birth weight, acidosis, sepsis, hypoalbuminaemia, hyperthermia and respiratory distress [56][57][58]. The latter are factors that facilitate bilirubin neurotoxicity (BNTx) by making it easier for the hydrophobic, lipid soluble free or unconjugated bilirubin to cross the blood brain barrier (BBB) to damage specific regions of the brain (selective bilirubin neurotoxicity) [56,57].…”

“…Some causes of unconjugated hyperbilirubinaemia that manifest as ABE and KSD include Rhesus and ABO incompatibilities, G6PD deficiency, prematurity/low birth weight and Crigler-Najjar syndrome type 1 while the risk factors for KSD are: asphyxia, prematurity, low birth weight, acidosis, sepsis, hypoalbuminaemia, hyperthermia and respiratory distress [56][57][58]. The latter are factors that facilitate bilirubin neurotoxicity (BNTx) by making it easier for the hydrophobic, lipid soluble free or unconjugated bilirubin to cross the blood brain barrier (BBB) to damage specific regions of the brain (selective bilirubin neurotoxicity) [56,57].…”

“…The neuropathology of ABE and KSD comprises bilirubin (yellow) staining of brainstem nuclei ("kernicterus") and neuronal necrosis, loss and gliosis in the basal ganglia/nuclei (Globus pallidus & subthalamic nucleus) and hippocampus [56][57][58]. Thus, the major areas of neuronal damage (selective bilirubin neurotoxicity) are basal nuclei/ganglia (globus pallidus), subthalamic nucleus of thalamus, oculomotor and cochlear (auditory) brainstem nuclei and the cerebellar dentate and Purkinje cells of the cerebellum in preterm infants [8,[56][57][58]. On MRI, the main findings in ABE are bilateral and symmetrical abnormalities (hyperintensities) of Globus pallidus and subthalamic nucleus (rarely hippocampus) on T 1 and T 2 -weighted images [4].…”