To assess early bilirubin toxicity, we have sutdied auditory brainstem responses (ABR) in relation to serum total bilirubin (TB) and unbound bilirubin(UB) levels in 66 non-asphyxiated full term infants at 3 to 5 days of age.Exchange transfusions(ET)were performed in 14 of the 66 infants and the measurements were done pre-ET and on consecutive 3 days of post-ET.ABR was measured with a Teledyne TA-1000 by stimuli of 85 dB and the latencies to wave I and V were averaged over two replications in each ear.TB and UB were determined by the peroxidase method using UB-Analyzer.Wave I latency increased significantly with the elevation of both TB and UB levels.Wave I-V interpeak latencies did not vary with the TB or UB Levels.Prolonged wave I latency pre-ET decreased remarkably at 24 to 48 hours of post-ET.UB levels decreased more rapidly than did the TB levels.These results suggest that the auditory nerve is reversibly damaged in the infants with hyperbilirubinemia.

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Auditory nerve and brainstem responses in newborn infants with hyperbilirubinemia

Bilirubin and brain injury

Neonatal hyperbilirubinemia is one of the most frequent diagnoses made in neonates. A high level of unconjugated bilirubin that is unbound to albumin is neurotoxic when the level exceeds age-specific thresholds or at lower levels in neonates with neurotoxic risk factors. Lower range of unbound bilirubin results in apoptosis, while moderate-to-high levels result in neuronal necrosis. Basal ganglia and various brain stem nuclei are more susceptible to bilirubin toxicity. Proposed mechanisms of bilirubin-induced neurotoxicity include excessive release of glutamate, mitochondrial energy failure, release of proinflammatory cytokines, and increased intracellular calcium concentration. These mechanisms are similar to the events that occur following hypoxic-ischemic insult in neonates. Severe hyperbilirubinemia in term neonates has been shown to be associated with increased risk for autism spectrum disorders. The neuropathological finding of bilirubin-induced neurotoxicity also includes cerebellar injury with a decreased number of Purkinje cells, and disruption of multisensory feedback loop between cerebellum and cortical neurons which may explain the clinical characteristics of autism spectrum disorders. Severe hyperbilirubinemia occurs more frequently in infants from low- and middle-income countries (LMIC). Simple devices to measure bilirubin, and timely treatment are essential to reduce neurotoxicity, and improve outcomes for thousands of neonates around the world.

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High unbound bilirubin for age: a neurotoxin with major effects on the developing brain.

Hyperbilirubinemia is one of the most common neonatal disorders. Delayed diagnosis and treatment of the pathologic and progressive indirect hyperbilirubinemia lead to neurological deficits, defined as bilirubin induced encephalopathy (BIE) (2). The incidence of this disorder in underdeveloped countries is much more than developed areas. All neonates with the risk factors for increased the blood level of indirect bilirubin are at risk for BIE, especially preterm neonates which are prone to low bilirubin kernicterus . BIE can be transient and acute (with early, intermediate and advanced phases)or be permanent, chronic and lifelong ( with tetrad of symptoms including visual (upward gaze palsy), auditory (sensory neural hearing loss), dental dysplasia abnormalities, and extrapyramidal disturbances (choreoathetosis cerebral palsy).Beside the abnormal neurologic manifestations of the jaundiced neonates ,brain MRI is the best imaging modality for the confirmation of the diagnosis. Although early treatment of extreme hyperbilirubinemia by phototherapy and exchange transfusion can prevent the BIE, unfortunately the chronic bilirubin encephalopathy does not have definitive treatment.

Bilirubin Induced Encephalopathy.

Early Amplitude-Integrated Electroencephalography Predicts Long-Term Outcomes in Term and Near-Term Newborns With Severe Hyperbilirubinemia.

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Udochukwu Michael Diala

Papers

Acute Bilirubin Encephalopathy and Its Progression to Kernicterus: Current Perspectives