Neonatal Encephalopathy

Neonatal encephalopathy is a clinical syndrome of disturbed neurological function in the first days of life in an infant born at or near term, with difficulty initiating and maintaining breathing, depressed tone and reflexes, reduced consciousness and often seizures. It is a description, not a diagnosis, and has many causes.

It affects about 1 to 3 in 1000 term births in high income settings and more in low income settings. Hypoxic ischaemic injury is the commonest cause, but not the only one.

Causes include hypoxic ischaemic injury, neonatal stroke, infection (sepsis, meningitis, herpes simplex), metabolic disease (hypoglycaemia, urea cycle and organic acid disorders, nonketotic hyperglycinaemia), intracranial haemorrhage, genetic epilepsies and brain malformations, kernicterus and maternal drugs.

Pathophysiology.

After a hypoxic ischaemic insult, primary energy failure causes cell depolarisation and excitotoxic cell death. A latent phase of partial recovery of 1 to 6 hours is followed by secondary energy failure at 6 to 48 hours, with seizures and apoptosis.

Cooling in the latent phase reduces secondary injury, which is why early recognition within 6 hours matters. Other causes injure the brain through toxins, inflammation, metabolic failure or vascular occlusion.

• Staging into mild, moderate or severe encephalopathy by level of consciousness, tone, posture, primitive reflexes, autonomic function and seizures.
• Mild: hyperalertness, irritability, normal or increased tone, no seizures, resolves within 24 hours.
• Moderate: lethargy, hypotonia, weak suck, seizures, and autonomic features such as bradycardia.
• Severe: stupor or coma, flaccid tone, absent reflexes, apnoea, seizures and abnormal pupils.
• Multi-organ dysfunction (kidney, liver, heart, haematological and gut) with hypoxic ischaemic injury.

Red flags.

• Seizures, or persistent encephalopathy beyond 24 hours.
• Fever, bulging fontanelle or vesicles suggesting herpes simplex infection.
• Persistent hypoglycaemia, acidosis, hyperammonaemia or odour suggesting metabolic disease.
• Encephalopathy with a normal birth history.

• Cord or first neonatal blood gas (pH under 7.0 and base deficit of 12 mmol/L or more support a hypoxic ischaemic cause), glucose, lactate, ammonia, electrolytes, calcium, magnesium, full blood count, coagulation, liver function and creatinine.
• Blood culture, CRP and lumbar puncture when stable. Herpes simplex PCR on blood, cerebrospinal fluid and surface swabs.
• Amplitude integrated or full EEG for seizures and background activity.
• Cranial ultrasound early, and MRI at 4 to 7 days of age (diffusion weighted imaging in the first week).
• Plasma amino acids, urine organic acids and acylcarnitines, when metabolic disease is possible. Genetic panels in persistent seizures.

Differential diagnosis. Neonatal sepsis and meningitis, herpes simplex encephalitis, stroke, intracranial haemorrhage, hypoglycaemia, inborn errors of metabolism, neonatal epilepsy syndromes, kernicterus and drug withdrawal or toxicity.

Immediate.

• Resuscitate, secure ventilation, avoid hyperoxia and hypocapnia, and maintain normal blood pressure and glucose of 2.6 to 8 mmol/L.
• Therapeutic hypothermia for infants of 36 weeks or more with moderate or severe encephalopathy and evidence of perinatal hypoxia ischaemia: cool to 33.5 degrees Celsius (rectal or oesophageal) for 72 hours, started within 6 hours of birth, then rewarm at 0.5 degrees Celsius each hour or slower. Cool in a centre able to monitor the infant.
• Restrict fluids to 40 to 60 mL/kg/day initially with glucose 10%, adjusting to urine output and electrolytes, because of the risk of fluid overload and syndrome of inappropriate antidiuresis.
• Start antibiotics for suspected sepsis: benzylpenicillin or ampicillin with gentamicin, adjusted to age and local policy. Start aciclovir 20 mg/kg IV every 8 hours until herpes simplex is excluded.

Seizures.

• Phenobarbital 20 mg/kg IV over 20 minutes as first line. Repeat 10 mg/kg once or twice, to a maximum of 40 mg/kg.
• Second line: levetiracetam 40 to 60 mg/kg IV loading, or phenytoin 20 mg/kg IV (or the equivalent dose of fosphenytoin), or midazolam 0.05 to 0.15 mg/kg IV, then infusion 0.05 to 0.2 mg/kg/h.
• Refractory seizures: pyridoxine 100 mg IV as a single test dose with EEG and cardiorespiratory monitoring, then pyridoxine 15 to 30 mg/kg/day orally in 3 divided doses if there is a response.
• Drug clearance is reduced during cooling, so monitor levels and sedation.

Supportive care. Correct metabolic acidosis, coagulopathy, hypotension (dopamine 5 to 10 micrograms/kg/min or adrenaline 0.05 to 0.3 micrograms/kg/min) and organ dysfunction. Treat the specific cause when found (glucose, metabolic rescue, antibiotics, stroke management).

Monitoring. Continuous EEG or amplitude integrated EEG, temperature, heart rate, blood pressure, glucose, gases, electrolytes, urine output and liver and renal function. MRI at 4 to 7 days for prognosis. Hearing, vision and neurodevelopmental follow up to at least 2 years of age.

Referral and escalation. Early referral for therapeutic hypothermia centre transfer within 6 hours when not available locally. Refer to paediatric neurology for seizures, and to metabolic services for suspected inborn errors.

Special groups. Infants under 36 weeks are not routinely cooled and need individual assessment. Infants with mild encephalopathy need close observation, as some progress.