Epidemiology and aetiology of neonatal seizures
Introduction
Seizures constitute the most frequent and distinctive manifestation of neurological disturbance in the neonatal period and have the highest incidence in the first month of life.1 They are a major risk for death or subsequent neurological disability and can independently confer an adverse neurodevelopmental outcome in high-risk neonates.2
It is important to determine the underlying aetiology of neonatal seizures in order to effectively treat the underlying cause and to offer a reasonably accurate prognosis to parents. Recent developments in neuroimaging techniques have decreased the incidence of seizures with unknown aetiology. In addition, techniques such as diffusion-weighted magnetic resonance imaging (MRI) have enhanced the diagnosis of focal ischaemic lesions. The development of newer neuroprotective strategies such as therapeutic hypothermia and the increasing recognition of continuous electroencephalography (EEG) monitoring as a gold standard for seizure detection have had significant impact on the incidence and severity of seizures.3
This review will explore the epidemiological and aetiological factors contributing to neonatal seizures in the context of advanced diagnostics and newer treatment modalities in neonatal neurology.
Section snippets
Incidence (Table 1)
The exact incidence of neonatal seizures in the general newborn population is difficult to estimate for a number of reasons. Although there is an increasing trend towards the diagnosis of seizures by electrodiagnostic techniques, traditionally the incidence of neonatal seizures has been estimated using clinical observation of abnormal movements. The clinical presentation of seizures in the neonatal period is subjective, with wide inter-observer variation.4 In preterm infants, presentation is
Aetiology of neonatal seizures
Neonatal seizures are a non-specific manifestation of many neurological and biochemical disorders.
The aetiological profile of neonatal seizures has changed over the past few decades.18 The factors that have contributed to the change include:
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Advances in obstetric/perinatal care that have altered the spectrum of brain injury.
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Increasing survival of extremely premature infants leading to a greater prevalence of infants with preterm brain injury.
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Developing neuroimaging techniques: MRI,
Hypoxic–ischaemic encephalopathy
This remains the most frequent underlying cause of seizures in term infants.1, 12, 13, 18 In various series, HIE contributes to 40–60% of seizures in term infants.1, 12 Seizures occur in ∼22–64% of term infants with moderate-to-severe HIE when diagnosed with routine EEG or with aEEG (also referred to as cerebral function monitoring).19 Seizures occurring in infants with HIE may contribute to a poor neurodevelopmental outcome20, 21 and early recognition and treatment of seizures is generally
Cerebrovascular disorders
Cerebrovascular disorders are the second most frequent cause of neonatal seizures.1, 13, 18 They comprise PAS and sino-venous thrombosis which is becoming increasingly recognized with better availability of MRI.
The incidence of PAS has been estimated to be 1 in 1600–5000 live births which predominantly includes arterial ischaemic stroke diagnosed in the neonatal period.28 Population-based studies have revealed an incidence of between 20 and 63 per 100 000 live births. The cause of focal
Central nervous system infections
Intracranial infections are present in about 5–10% of babies with neonatal seizures.1, 12 In the series reported by Tekgul et al.18 infections contributed to 3% of neonatal seizures. Infection most commonly takes the form of meningitis, but viral meningo-encephalitis particularly due to herpes simplex virus is also a well-recognised cause. Implicated organisms include bacteria such as Group B streptococcus and E. coli, viruses (herpes simplex virus and cytomegalovirus) as well as fungi and
Malformations of cortical development
Cortical malformations account for 5–9% of all causes of neonatal seizures.12, 18 Barkovich et al.40 offer a genetic and developmental classification for these disorders, which are being increasingly recognised as causes of neonatal seizures with advanced neuroimaging techniques. The more widespread malformations include tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly, lissencephaly, subcortical band heterotopia, periventricular nodular heterotopia, schizencephaly and
Hypoglycaemia
Hypoglycaemia is a major metabolic disturbance often noted in preterm or small-for-gestational age infants but also occurs in ill term infants, and in infants born to mothers with diabetes. Seizures represent acute neurological dysfunction in hypoglycaemia and are likely to be associated with adverse neurodevelopmental outcome.41 In the series reported by Tekgul et al.18 hypoglycaemia was thought to be the cause in 3% of neonates with neonatal seizures. The same authors comment on the fact that
Inborn errors of metabolism
Inborn errors of metabolism constitute a diverse group of disorders that usually present with poor feeding, lethargy, seizures, and are often associated with biochemical abnormalities including wide anion gap acidosis, hypoglycaemia, ketonuria, or hyperammonaemia. A prompt diagnosis is imperative in order to initiate treatment and prevent irreversible neurological and cognitive damage.
Van Hove et al.42 classify metabolic causes of epilepsy in neonates into three different categories:
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Benign idiopathic neonatal convulsions (fifth-day fits)
Benign idiopathic neonatal convulsions occur around the fifth day of life (day 1 to day 7, with 90% between day 4 and day 6) in otherwise healthy neonates. At present the aetiology is unknown. Seizures are clonic, mostly partial and/or apnoeic.51 The inter-ictal EEG shows characteristic sharpened theta activity in 60% of cases; in the remaining neonates the background activity is either discontinuous, with focal or multifocal abnormalities, or normal. Ictal recordings show unilateral or
Early myoclonic encephalopathy
Early myoclonic encephalopathy is a syndrome often associated with inborn errors of metabolism, but cerebral malformations have also been reported. Onset is nearly always in the first month of life and ictal manifestations are as follows: (i) partial or fragmented myoclonus; (ii) massive myoclonias; (iii) partial motor seizures; (iv) tonic spasms. Background EEG activity is abnormal consisting of complex bursts of spikes and sharp waves lasting for 1−5 s alternating with flat periods of 3−10 s
Neonatal abstinence syndrome
Neonatal seizures are reported in 2–11% of symptomatic infants with neonatal abstinence syndrome,58 often warranting treatment with anticonvulsants. Maternal use of the following substances may induce withdrawal symptoms in babies: narcotics (methadone, heroin, and morphine), sedatives, tricyclic antidepressants, cocaine and alcohol. Seizures occur within the first few days of life and are often associated with other symptoms of withdrawal. Early recognition of neonatal abstinence syndrome,
Conclusion
Seizures usually indicate serious neurological abnormality in newborn infants both term and preterm. As there may be a treatable cause they must always be carefully investigated. There is uncertainty about the true incidence of seizures during the neonatal period due to lack of population-based studies with EEG confirmation. As seizures themselves may cause further brain damage, identifying and treating seizures should be a priority when caring for a critically ill neonate. The need for further
Conflict of interest statement
None declared.
Funding sources
This work has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 241479 (The NEMO Project).
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