Neonatal Kernicterus

Neonatal kernicterus is the chronic and permanent form of bilirubin neurotoxicity, with basal ganglia, brainstem nuclei and cerebellar injury. It follows acute bilirubin encephalopathy, the acute form seen in the first weeks of life, and is largely preventable.

It is now rare in settings with bilirubin screening and treatment, but persists in places with delayed recognition of jaundice, G6PD deficiency, haemolytic disease and unmonitored discharge. Preterm infants have injury at lower bilirubin levels.

Risk factors are haemolysis (Rh and ABO disease, G6PD deficiency), prematurity, sepsis, acidosis, low albumin, asphyxia and delayed feeding. Bilirubin over 425 micromol/L (25 mg/dL) in term infants carries high risk, and the threshold falls with each risk factor.

Pathophysiology.

Unconjugated bilirubin bound to albumin is safe, but free bilirubin crosses the blood brain barrier. It is deposited in the globus pallidus, subthalamic nucleus, hippocampus, cerebellum and brainstem auditory and oculomotor nuclei.

Free bilirubin damages neuronal membranes and mitochondria and causes neuronal death. Risk factors that lower albumin binding or open the blood brain barrier (acidosis, sepsis, prematurity) lower the threshold for injury.

• Acute phase 1: lethargy, poor suck, hypotonia and a weak cry.
• Acute phase 2: irritability, high pitched cry, hypertonia with arching of the neck (retrocollis) and trunk (opisthotonos), and fever.
• Acute phase 3: deep retrocollis and opisthotonos, apnoea, seizures, coma and death.
• Chronic kernicterus: athetoid or dystonic cerebral palsy, sensorineural hearing loss or auditory neuropathy spectrum disorder, upward gaze palsy and dental enamel dysplasia, with usually preserved intellect.

Red flags.

• Hypertonia, arching or high pitched cry in a jaundiced infant: a medical emergency whatever the bilirubin level.
• Bilirubin near or over the exchange transfusion threshold, rising over 8.5 micromol/L/h or with albumin under 30 g/L.

• Total and conjugated bilirubin, albumin, full blood count, reticulocyte count, blood group, direct antiglobulin test, G6PD enzyme assay, glucose and blood gas.
• Sepsis screen, thyroid function and urine for reducing substances.
• Brainstem auditory evoked response (abnormal early, even with normal otoacoustic emissions).
• MRI brain: high T1 signal in the globus pallidus in the acute phase, and high T2 signal in the globus pallidus and subthalamic nuclei in the chronic phase.

Differential diagnosis. Hypoxic ischaemic encephalopathy, sepsis and meningitis, hypoglycaemia, kernicterus mimics such as mitochondrial disease and other causes of dystonic cerebral palsy.

Prevention.

• Visual and bilirubin assessment of every jaundiced infant, with bilirubin measurement within 6 hours for jaundice in the first 24 hours.
• Follow gestation specific and age specific treatment charts. Start intensive phototherapy at the threshold.

Acute bilirubin encephalopathy or bilirubin at the exchange threshold.

• Intensive phototherapy at once, with exposure of the maximum skin area.
• Urgent double volume exchange transfusion (160 to 180 mL/kg), without waiting for repeat levels, when signs of encephalopathy are present or bilirubin reaches the exchange threshold. The exchange threshold for term infants without risk factors is about 430 micromol/L (25 mg/dL), and is lower with haemolysis, sepsis, acidosis, low albumin or prematurity.
• IV albumin 1 g/kg before exchange when albumin is low. IV immunoglobulin 500 mg/kg over 4 hours in immune haemolysis.
• Rehydrate, feed and correct acidosis. Stop drugs that displace bilirubin (sulphonamides, ceftriaxone, salicylates). Treat sepsis.

Chronic kernicterus.

• Multidisciplinary rehabilitation, and management of dystonia with baclofen (0.3 mg/kg/day orally in 3 divided doses, titrated to a maximum of 2 mg/kg/day), trihexyphenidyl and botulinum toxin under neurology direction.
• Hearing assessment with hearing aids or cochlear implants, ophthalmology and dental review, and gastrostomy for dysphagia.

Monitoring. Bilirubin every 4 to 6 hours during treatment, hearing and neurodevelopment for at least 2 years.

Referral and escalation. Immediate transfer to a centre able to perform exchange transfusion. Refer for hearing and neurodevelopmental follow up.

Special groups. Preterm infants have exchange thresholds that fall with gestational age and need gestation specific charts.