Neonatal Seizures

Clinical note

Neonatal seizures or neonatal convulsions are epileptic fits occurring from birth to the end of the neonatal period. ^1–18 The neonatal period is the most vulnerable of all periods of life for developing seizures, particularly in the first 1–2 days to the first week from birth. They may be short-lived events lasting for a few days only. However, they often signify serious malfunction of or damage to the immature brain and constitute a neurological emergency demanding urgent diagnosis and management.

Clinical Manifestations

Neonatal seizures, as with any other type of seizure, are paroxysmal, repetitive and stereotypical events. They are usually clinically subtle, inconspicuous and difficult to recognise from the normal behaviours of the inter-ictal periods or physiological phenomena. There is no recognisable post-ictal state. Generalised tonic clonic seizures (GTCS) are exceptional. The most widely used scheme is by Volpe²⁰ of five main types of neonatal seizure.

• Subtle seizures (50%)
• Tonic seizures (5%)
• Clonic seizures (25%)
• Myoclonic seizures (20%)
• Non-paroxysmal repetitive behaviours

Useful Definitions

The neonatal period is defined as the first 28 days of life of a full-term infant.

Neonatal seizures are those that occur from birth to the end of the neonatal period.

Gestational age is defined as the duration of pregnancy.

Chronological age is the actual legal age of the infant from the time of birth.

Conceptional age is the combined gestational and chronological ages.

Full-term infants are those of 40 weeks gestational age.

ILAE Classification and Definitions

The ILAE Commission (1989)¹⁹ broadly classifies neonatal seizures amongst ‘epilepsies and syndromes undetermined as to whether they are focal or generalised’ under the subheading ‘with both generalised and focal seizures’.

Neonatal seizures differ from those of older children and adults. The most frequent neonatal seizures are described as subtle because the clinical manifestations are frequently overlooked. These include tonic, horizontal deviation of the eyes with or without jerking, eyelid blinking or fluttering, sucking, smacking or other oral–buccal–lingual movements, swimming or pedalling movements and, occasionally, apnoeic spells. Other neonatal seizures occur as tonic extension of the limbs, mimicking decerebrate or decorticate posturing. These occur particularly in premature infants. Multifocal clonic seizures characterised by clonic movements of a limb, which may migrate to other body parts or other limbs or focal clonic seizures, which are much more localised, may occur. In the latter, the infant is usually not unconscious. Rarely, myoclonic seizures may occur and the EEG pattern is frequently that of suppression–burst activity. The tonic seizures have a poor prognosis because they frequently accompany intraventricular haemorrhage. The myoclonic seizures also have a poor prognosis because they are frequently a part of the early myoclonic encephalopathy syndrome.¹⁹

In another scheme by Mizrahi¹² neonatal seizures are classified as follows: focal clonic, focal tonic, generalised tonic, myoclonic, spasms and motor automatisms (which include occular signs, oral–buccal–lingual movements, progression movements and complex purposeless movements).

Nearly one-quarter of infants experience several seizure types and the same seizure may manifest with subtle, clonic, myoclonic, autonomic or other symptoms (Figure 5.1).

Figure 5.1

Ictal EEG patterns in a 2-day-old boy with right middle cerebral artery thrombosis Top and middle: Apnoeic, myoclonic, clonic and subtle seizure of motor automatisms associated with various ictal EEG patterns and locations.

Subtle Seizures

Subtle seizures are far more common than other types of neonatal seizures. They are described as subtle because the clinical manifestations are frequently overlooked. They imitate normal behaviours and reactions. These include the following.

1. Ocular movements, which range from random and roving eye movements to sustained conjugate tonic deviation with or without jerking. Eyelid blinking or fluttering, eyes rolling up, eye opening, fixation of a gaze or nystagmus may occur alone or with other ictal manifestations.
2. Oral–buccal–lingual movements (sucking, smacking, chewing and tongue protrusions).
3. Progression movements (rowing, swimming, pedalling, bicycling, thrashing or struggling movements).
4. Complex purposeless movements (sudden arousal with episodic limb hyperactivity and crying).¹⁵

Motor Seizures

Clonic seizures are rhythmic jerks that may localise in a small part of the face or limbs, axial muscles and the diaphragm or be multifocal or hemiconvulsive. Todd’s paresis follows prolonged hemiconvulsions.

Tonic seizures manifest with sustained contraction of facial, limb, axial and other muscles. They may be focal, multifocal or generalised, symmetrical or asymmetrical. Truncal or limb tonic extension imitates decerebrate or decorticate posturing.

Myoclonic seizures are rapid, single or arrhythmic repetitive jerks. They may affect a finger, a limb or the whole body. They may mimic the Moro reflex and startling responses. They are more frequent in pre-term than full-term infants indicating, if massive, major brain injury and poor prognosis. Myoclonic seizures are associated with the most severe brain damage.²¹ However, healthy pre-term and rarely full-term neonates may have abundant myoclonic movements during sleep. Neonates have cortical, reticular and segmental types of myoclonus, similar to adult forms.²²

Spasms producing flexion or extension similar to those of West syndrome are rare. They are slower than myoclonic seizures and faster than tonic seizures.

Autonomic Ictal Manifestations

Autonomic ictal manifestations commonly occur with motor manifestations in 37% of subtle seizures.^23,24 These are paroxysmal changes of heart rate, respiration and systemic blood pressure.^25,26 Apnoea as an isolated seizure phenomenon unaccompanied by other clinical epileptic features is probably exceptional.²⁶ Salivation and pupillary changes are common.

Duration of Neonatal Seizures

The duration of neonatal seizures is usually brief (10 s to 1–2 min) and repetitive with a median of 8 min in between each seizure. Longer seizures and status epilepticus develop more readily at this age, but convulsive neonatal status epilepticus is not as severe as that of older infants and children.

Non-Epileptic Neonatal Seizures

By definition all neonatal seizures are epileptic in origin, generated by abnormal, paroxysmal and hypersynchronous neuronal discharges characteristic of epileptogenesis.

The characterisation of neonatal seizures as epileptic and non-epileptic by Kellaway and Mizrahi^4,10,27 is a topic of considerable debate.

Epileptic Neonatal Seizures

Focal clonic, focal tonic and some types of myoclonic jerks are genuine epileptic seizures documented with ictal EEG changes and they have a high correlation with focal brain lesions and a favourable short-term outcome.^4,10,27

Non-Epileptic Neonatal Seizures

Many of the subtle seizures, generalised tonic posturing and some myoclonic symptoms may be non-epileptic seizures. These show clinical similarities to reflex behaviours of the neonates, they are not associated with ictal EEG discharges and are commonly correlated with diffuse abnormal brain processes such as hypoxic–ischaemic encephalopathy and a poor short-term outcome.^4,10,27 They are considered as exaggerated reflex behaviours due to abnormal release of brain stem tonic mechanisms from cortical control. Hence, the term brain stem release phenomena:^4,27 “They most typically occur in neonates with clinical and EEG evidence of forebrain depression that may release brain stem facilitatory centres for generating reflex behaviours without cortical inhibition”.^4,10,27

The argument to support the non-epileptic nature of these episodic clinical events is that they have the following characteristics.^4,10,27

• They are suppressed by restraint or repositioning of the infant.
• They are elicited by tactile stimulation and their intensity is proportional to the rate, intensity and number of sites of stimulation. Stimulation at one site can provoke paroxysmal movements at another site.
• They are not associated with ictal EEG discharges.

Reservations about these features are based on the following reasons.

• The electrical seizure activity may occur deep within brain structures that are inaccessible to an EEG. This is well documented in neurosurgical patients with simultaneous surface and deep EEG recordings.
• The responses to stimulation and restraint are also well-known phenomena of genuine epileptic seizures (see photic and tactile stimulation and inhibition).

Aetiology

Aetiology of neonatal seizures is extensive and diverse (Table 5.1). Severe causes predominate. The prevalence and significance of aetiological factors are continuously changing and differ between developed and developing countries depending on available improved neonatal and obstetric care.

Table 5.1

Main causes of neonatal seizures

By far the commonest cause is hypoxic–ischaemic encephalopathy. It may be responsible for 80% of all seizures in the first 2 days of life.²⁸ Brain damage due to prenatal distress and malformations of cortical development is being increasingly recognised. Intracranial haemorrhage and infarction, stroke²⁹ and prenatal and neonatal infections are common. Most previously common acute metabolic disturbances such as electrolyte and glucose abnormalities have been minimised because of improved neonatal intensive care and awareness of nutritional hazards. Late hypocalcaemia is virtually eliminated, while electrolytic derangement and hypoglycaemia are now rare.

Inborn errors of metabolism such as urea cycle disorders are rare.^10,20,30,31

Pyridoxine dependency, with seizures in the first days of life (which are reversible with treatment), is exceptional.

Exogenous causes of neonatal convulsions may be iatrogenic or due to drug withdrawal in babies born to mothers on drugs.²⁴

In most cases, the neonate may present with a combination of different neurological disturbances, each of which can cause seizures.

Diagnostic Procedures

Neonatal seizures represent one of the very few emergencies in the newborn. Abnormal, repetitive and stereotypic behaviours of neonates should be suspected and evaluated as possible seizures. Polygraphic video–EEG recording of suspected events is probably mandatory for an incontrovertible seizure diagnosis. Confirmation of neonatal seizures should initiate urgent and appropriate clinical and laboratory evaluation for the aetiological cause (Table 5.1) and treatment. Family and prenatal history is important. A thorough physical examination of the neonate should be coupled with urgent and comprehensive biochemical tests for correctable metabolic disturbances. Although rare, more severe inborn errors of metabolism should be considered for diagnosis and treatment.

Brain Imaging

Cranial ultrasonography, brain imaging with X-ray computed tomography (CT) scan and preferably magnetic resonance imaging (MRI)³⁷ should be used for the detection of structural abnormalities such as malformations of cortical development, intracranial haemorrhage, hydrocephalus and cerebral infarction.

Cranial ultrasonograghy is the main imaging modality of premature neonates and well suited for the study of neonates in general. It is performed at the bedside and provides effective assessment of ventricular size and other fluid-containing lesions as well as effective viewing of haemorrhagic and ischaemic lesions and their evolution. Cranial ultrasonography is limited in resolution and the type of lesions that it can identify.

A CT brain scan is often of secondary or adjunctive importance to ultrasound. Last-generation CT brain scan images are of high resolution, can be generated within seconds and can accurately detect haemorrhage, infarction, gross malformations and ventricular and other pathological conditions. A CT scan has low sensitivity in many other brain conditions such as abnormalities of cortical development where MRI is much superior. However, MRI interpretation should take into consideration the normal developmental and maturational states of neonates and infants. In infants younger than 6 months, cortical abnormalities are detected with T2-weighted images, whereas T1-weighted images are needed for the evaluation of brain maturation.³⁷

Electroencephalography

The neonatal EEG is probably one of the best and most useful of EEG applications.^10,38–45 However, neonatal EEG recordings and interpretations require the special skills of well-trained technologists and physicians. Polygraphic studies with simultaneous video–EEG recording are essential.⁴⁶

Only 10% of neonates with suspected seizures have EEG confirmation. Suspected clonic movements have the highest yield of 44% but this is only 17% for ‘subtle’ movements.⁴⁷

Inter-Ictal EEG

Inter-ictal EEG epileptogenic spikes or sharp slow wave foci are not reliable markers at this age.

Certain inter-ictal EEG patterns may have diagnostic significance (Figure 5.2 and 5.3.)^4,10

Figure 5.2

Zip-like electrical discharges Top and middle: Continuous recording in a neonate with severe brain hypoxia. Zip-like electrical discharges consist of high frequency rapid spikes of accelerating and (more...)

Figure 5.3

Inter-ictal EEG in a neonate with benign neonatal (non-familial) seizures. The theta pointu alternant pattern is usually associated with a good prognosis.

• Electrocerebral inactivity of a flat or near-flat EEG of severe brain damage.
• The suppression–burst pattern of neonatal epileptic encephalopathies (Figure 5.4).
• Theta pointu alternant of benign neonatal convulsions (Figure 5.3).
• Persistently focal sharp or slow waves in localised lesions.
• Quasi-periodic focal or multifocal pattern in neonatal herpes simplex encephalitis.⁴⁸
• Periodic complexes in glycine encephalopathy.^31,49
• Inter-hemispheric or intra-hemispheric abnormalities.

Figure 5.4

The burst–suppression pattern in a neonate with severe hypoxic encephalopathy.

Background EEG activity, mainly in serial EEGs, often provides objective evidence of the degree and severity of the underlying cause.^4,10,31,49

Important Note on the Suppression–burst Pattern

The suppression–burst pattern is relatively frequent in the neonatal period. It is associated with heterogeneous seizures and can be induced by drugs.^50,51 It is common in neonatal ischaemic encephalopathy where it is usually transient and short lived.⁵⁰ Conversely, the suppression–burst pattern is relatively stable lasting for more than 2 weeks in Ohtahara syndrome and early myoclonic encephalopathy.⁵²

Ictal EEG

Documentation of seizures with an ictal EEG is often mandatory in view of the subtle clinical seizure manifestations (Figures 5.1 and 5.2). EEG ictal activity may be focal or multifocal appearing in a normal or abnormal background. The electrical ictal seizure EEG patterns of neonatal seizures vary significantly even in the same neonate and in the same EEG recording (Figure 5.1). The same EEG may show focal or multifocal ictal discharges that may occur simultaneously or independently in different brain locations.

Ictal EEG paroxysms consist of repetitive waves with a predominant beta, alpha, theta and delta range or a mixture of all that may accelerate in speed, decelerate in speed or both (Figures 5.1 and 5.2). These are spikes, sharp or saw tooth or sinusoidal waves (monomorphic or polymorphic) ranging in amplitude from very low to very high. The patterns may be synchronous or asynchronous, focal or multifocal and, less frequently, generalised. They may appear and disappear suddenly or build up from accelerating localised repetitive waves. Ictal discharges may gradually or abruptly change in frequency, amplitude and morphology in the course of the same or subsequent seizures. Conversely, they may remain virtually unchanged from onset to termination. The background EEG may be normal or abnormal.

Definition of Zips

Zips. This is a descriptive term I coined for a common ictal EEG pattern in neonates which consists of localised episodic rapid spikes of accelerating and decelerating speed that look like zips (Figure 5.2). Zips may be associated with subtle and focal clonic/tonic seizures or remain clinically silent. Zips of subtle seizures are often multifocal and of shifting localisation.

Focal EEG ictal discharges are usually associated with subtle, clonic or tonic seizures. The most common locations are the centrotemporal followed by the occipital regions. Midline (Cz) and temporal regions may be involved but frontal localisations are exceptional. The same infant may have unifocal or multifocal ictal discharges that may be simultaneous, develop one from the other or occur independently in different brain sites. Neonates do not show the clinical or EEG Jacksonian march of older children. There may be abrupt changes of location in the progress of the seizure.

Seizures with consistently focal EEG paroxysms are highly correlated with focal brain lesions. Seizures that lack or have an inconstant relationship with EEG discharges correlate with diffuse pathological conditions.

Generalised manifestations are more likely to occur with myoclonic jerks and neonatal spasms.

Two specific electrical seizure patterns of neonates usually carry a poor prognosis because they are ‘typically associated with severe encephalopathies’.^10,27,53,54

1. Alpha seizure discharges are characterised by sustained and rhythmic activity of 12 Hz and 20–70 μV in the centrotemporal regions.
2. Electrical seizure activity of the depressed brain is of low voltage and long duration. It is highly localised on one side and shows little tendency to spread.

Post-Ictal EEG

Post-ictally, the EEG usually returns to the pre-ictal state immediately (Figure 5.1). Transient slowing or depression of EEG activity may occur following frequent or prolonged seizures.

Stimulus-Evoked Electrographic Patterns

Stimulus-evoked electrographic patterns with or without concomitant clinical ictal manifestations usually occur in pre-term neonates or neonates with significant diffuse or multifocal brain damage.⁵⁵ The electrographic seizures are elicited by tactile or painful stimulation. The majority of neonates die or have significant neurological handicaps.

Electroclinical Dissociation or Decoupling Response

Only one-fifth (21%) of electrical ictal EEG patterns (electrical or electrographic seizures) associate with distinctive clinical manifestations (electroclinical seizures). All others are occult, that is they are clinically silent or subclinical.⁵⁶

Electrographic or electrical seizures, namely EEG electrical seizure activity without apparent clinical manifestations, are more common after initiation of anti-epileptic drugs (AEDs). This is because AEDs may suppress the clinical manifestations of seizures but not the EEG ictal discharge. This phenomenon is named the ‘decoupling response’ ^10,27,53 or ‘electroclinical dissociation’.^57,58 Electroclinical dissociation may arise from foci not consistently reflected in surface electrodes.⁵⁷

Neonates with electrographic seizures do not differ from those with exclusively electroclinical seizures regarding peri-natal factors, aetiology or outcome, though the background EEG is more abnormal in the electrographic group.⁵⁷ Movements of the limbs occur at a statistically significant higher rate during electroclinical seizures. Electrographic seizures, like electroclinical seizures, are also associated with disturbed cerebral metabolism.⁵⁹

Prognosis

This is cause dependent because the main factor that determines outcome is the underlying cause and not the seizures themselves. Despite high mortality (approximately 15%) and morbidity (approximately 30%), one-half of neonates with seizures achieve a normal or near normal state. One-third of the survivors develop epilepsy.⁶⁰ Table 5.2 provides indicators of good, bad or intermediate prognosis.

Table 5.2

Indicators of prognosis

Neonatal Syndromes

Despite the high prevalence of neonatal seizures, epileptic syndromes in neonates are rare. Four syndromes have been recognised by the ILAE.^19,75

• Benign familial neonatal seizures
• Benign neonatal seizures (non-familial)
• Early myoclonic encephalopathy
• Ohtahara syndrome

Benign Familial Neonatal Seizures

Benign familial neonatal seizures ^76–80 constitute a rare autosomal dominant epileptic syndrome characterised by frequent brief seizures within the first days of life.

Differential Diagnosis

A family history of similar convulsions, a prerequisite for the diagnosis of benign familial neonatal seizures, eliminates the possibility of other diseases. However, other causes of neonatal seizures should be excluded.

Despite artificially similar names^3,75 benign familial neonatal seizures are entirely different from benign neonatal seizures (non-familial) (Table 5.3).

Table 5.3

Benign (non-familial) neonatal seizures versus benign familial neonatal seizures

Benign Neonatal Seizures (Non-Familial)

Benign neonatal seizures (non-familial)^{76,79,104–106} constitute a short-lived and self-limited benign epileptic syndrome. It manifests with a single episode of repetitive lengthy seizures, which constitutes clonic status epilepticus.

Early Myoclonic Encephalopathy

Early myoclonic encephalopathy is a dreadful but fortunately rare epileptic encephalopathy of the first days and weeks of life. ^{50,52,110–113}

Ohtahara Syndrome

Ohtahara syndrome^{52,112,113,124,125} is a rare and devastating form of severe epileptic encephalopathy of very early life.

Differential Diagnosis

The main differential diagnosis of Ohtahara syndrome is from early myoclonic encephalopathy (Table 5.4).^52,130

Table 5.4

Early myoclonic encephalopathy versus Ohtahara syndrome

Non-Epileptic Movement Disorders in Neonates and Infants Imitating Seizures

Non-epileptic movement disorders in neonates and infants may be misdiagnosed as epileptic seizures. The commoner of these are:

• Benign neonatal sleep myoclonus
• Benign non-epileptic myoclonus of early infancy (benign non-epileptic infantile spasms)
• Hyperekplexia (familial startle disease)

Benign Neonatal Sleep Myoclonus

Benign neonatal sleep myoclonus^133–136 is a common non-epileptic condition misdiagnosed as epileptic seizures and even as infantile spasms.

Benign Non-Epileptic Myoclonus of Early Infancy

Hyperekplexia

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Footnotes

*

Note on a recent development

‘Benign familial neonatal–infantile seizures’ is a newly described clinically intermediate variant between benign familial neonatal seizures and benign familial infantile seizures. The disorder can now be strongly suspected clinically and the families can be given an excellent prognosis.^94,95