Background of NEMO

Perinatal asphyxia occurs in approximately 20 per 1,000 live births. A proportion of these babies develop an early neonatal encephalopathy, or hypoxic ischaemic encephalopathy (HIE) is around 2-3/1000 births in the developed world and it's a major cause of both acute mortality and long-term neurodisability. The prognosis varies greatly from mild irritability to deep coma. Seizures are the hallmark of HIE and EEG studies have shown that many asphyxiated babies often have seizures that go unnoticed and which is not reduced by current antiepileptic drug therapy.

Data from both human and animal studies suggest that seizures amplify neonatal hypoxic-ischemic brain damage. In a recent study of term newborns with HIE, brain injury was independently associated with the severity of seizures. Prolonged seizures cause progressive cerebral hypoxia and changes in cerebral blood flow. These findings support the hypothesis based on data from animal models, that neonatal seizures are not only a manifestation of acute ischemic brain injury, but also exacerbate tissue damage and provide evidence for the conjecture that effective treatment of neonatal seizures could attenuate acute brain injury in this setting.

The clinical diagnosis of neonatal seizures is recognized to be difficult for a number of reasons:

• The neonatal brain is unable to express the clear seizure manifestations seen in older children and adults.
• Seizures in the babies can be clinically silent (i.e. electrographic only), and as a result the extent of the seizure burden may be greatly underestimated.
• EEG monitoring of treated neonatal seizures shows that current treatments often suppress clinical seizure manifestations, but are ineffective in suppressing the accompanying EEG seizure activity (electroclinical dissociation or uncoupling). Due to the ambiguity of clinical signs, effective seizure control in babies implies abolition (or reduction of >80%) of all seizure activity on the EEG.

Current AEDs for treatment of neonatal seizures have hardly changed over the last 50 years. There is an urgent need for consistent, evidence-based guidelines for the management (diagnosis and treatment) of neonatal seizures. The standard first line treatment for neonatal seizures worldwide is still phenobarbitone, despite evidence that it is only effective in 30-50% of babies. Furthermore, there is increasing concern about the potentially adverse effects of phenobarbitone on the developing nervous system.

Recent studies in rat pups indicate that the diuretic agent bumetanide (there is something missing) which will be assessed in NEMO.