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clearly defined epilepsy syndrome. Although many causes can give rise to neonatal seizures
(Table 1), although only a few of these conditions account for most seizures. Few seizures are
idiopathic. Several decades ago, late hypocalcaemia due to a low calcium:phosphate ratio in
baby formula was a frequent cause of neonatal seizures but this is very rare today. At term,
hypoxic ischaemic encephalopathy is the most common underlying factor, typically with onset
6–8 hours after the hypoxic insult but within the first 24 hours of life. In preterm infants,
cerebrovascular events are the most common cause. Meningitis, focal cerebral infarction,
metabolic disorders and congenital abnormalities of the brain can cause seizures at any
gestation.

Mechanism

The developing brain is particularly susceptible to developing seizures in response to injury;
several mechanisms are likely to be involved. Overall the hyperexcitable state of the immature
brain is based upon enhanced excitatory neurotransmission, paucity of inhibitory mechanisms,
developmental expression of neuronal ion channels, age-dependent modulation of
neuropeptides and age-dependent early microglial activation. In the immature brain there is a
relative excess of excitatory neurotransmitters and receptors6,7. The arborisation of axons and
dendritic processes as well as myelinisation are incomplete in the neonatal brain resulting in
weakly propagated, fragmentary seizures whose electrical activity may not spread to surface
EEG electrodes.

Generalised tonic-clonic seizures are rare in the first month of life and not seen in the preterm
infant. Neonatal seizures are usually focal, often short lasting (see EEG, Figure 1). The
development within the limbic system with connections to midbrain and brainstem is more
advanced than the cerebral cortical organisation, leading to a higher frequency of mouthing,
eye deviation, and apnoea in neonates than seizures in adults.

Clinical manifestation and classification

Even among trained observers, clinical neonatal seizures may be difficult to recognise and
differentiate from either normal behaviours or abnormal movements of non-epileptic origin8.
Additional problems arise when the relationship between clinical and electroencephalographic
seizures is considered. At times, there is temporal overlap of the two (so-called ‘electroclinical
seizures’). However, in some clinical settings up to 85% of electrographic seizures are
clinically silent (i.e. only electroencephalographic seizure activity present with no clinical
accompaniment, referred to as ‘electrical only seizures’), leading to significant underestimation
of seizure burden9. For these reasons, in the broadest terms a seizure in this age group is best
defined either in clinical terms as an abnormal paroxysmal event (with or without EEG seizure
activity) or electrographically as a sustained epileptiform change in the EEG, which may or
may not be accompanied by paroxysmal alteration in neurological function.

As aetiology and presentation of neonatal seizures is different to seizures in older children
and adults, they do not easily fit into the 1981 ILAE classification of epileptic seizure types
or the 1989 ILAE classification of epilepsy syndromes and epilepsies62. While this continues
to be a widely accepted view, the most recently proposed ILAE (The International League
Against Epilepsy)55 classification suggested that neonatal seizures should not be considered a
distinct seizure type, but could be classified within its more general, universal scheme –
which would classify all neonatal seizures as either ‘focal seizures’ or ‘other’55. Several
classifications have been proposed, of which the classifications by Volpe3 (according to
clinical features only) and by Mizrahi and Kellaway4,10 (according to pathophysiology:
epileptic or non-epileptic origin) are more widely used (Table 2).