Seizures are a common occurrence in both term and preterm neonates. Neonatal convulsion is a paroxysmal disturbance in the neurological function of neurons. They require immediate evaluation because the underlying condition might insult the developing and vulnerable neurons of neonates. Seizures are easily recognizable and require quick treatment. However, sometimes they can be missed. This review article focuses on a brief introduction, the aetiology and various types of seizures, and the clinical approach, different diagnostic methods and management of seizures due to the underlying condition. Hypoxic-ischemic encephalopathy is the most common cause of neonatal seizure. Other causes are metabolic, infectious (meningitis), intracranial haemorrhage, developmental defects, and other miscellaneous causes. Management depends on underlying causes.
A seizure is defined as a paroxysmal behaviour caused by hyper-synchronous discharge from a group of neurons. It is defined clinically as a paroxysmal alteration in neurologic function, i.e. motor, behaviour and/or autonomic function. There are many causes of neonatal seizures (NS), and they are usually due to an underlying injury or disorder. Hypoxic-ischemic encephalopathy (HIE) is responsible for most of the cases of neonatal seizure. Seizures occur more frequently in the neonatal period. Incidence of neonatal seizures range from 1 to 5/1,000 live births. In neonates, the majority of seizures are symptomatic of some underlying disorders. The occurrence of a seizure may be the first clinical indication of a neurologic disorder.
Four major types of NS have been identified:
- Subtle seizures: They are called subtle because the clinical manifestations are mild and sometimes they are missed. They are the commonest type, constituting about 50% of all seizures. Common examples of subtle seizures include:
- Ocular- Tonic horizontal deviation of eyes or sustained eye opening with ocular fixation or cycled fluttering
- Oro-facial-lingual movements – Tongue-thrusting, chewing, lip-smacking
- Limb movements – Paddling, cycling, boxing-jabs, etc.
- Autonomic phenomena – Tachycardia or bradycardia
- Apnea may be a rare manifestation of seizures, particularly in term infants. Apnea due to seizure activity has an accelerated or a normal heart rate when evaluated 20 seconds after onset. Bradycardia is not an early manifestation in convulsive apnea but may occur later due to prolonged hypoxemia.
- Clonic seizures: These are rhythmic movements of muscle groups. They have both fast and slow components, occur with a frequency of 1-3 jerks per second, and are commonly associated with electroencephalogram (EEG) changes. Focal clonic seizures have the best prognosis.
- Tonic seizures: There is sustained flexion or extension of axial or appendicular muscle groups. Seizures may be focal or generalized and may resemble decerebrate (tonic extension of all limbs) or decorticate posturing (flexion of upper limbs and extension of lower limbs). Usually there are no EEG changes in generalized tonic seizures.
- Myoclonic seizures: These manifest as single or multiple lightning-fast jerks of the upper or lower limbs and are usually distinguished from clonic movements because of the more rapid speed of myoclonic jerks. Common changes seen on the EEG include burst suppression pattern, focal sharp waves and hypsarrhythmia. Myoclonic seizures carry the worst prognosis in terms of neurodevelopmental outcome and seizure recurrence.
An epileptic seizure is a change in neurologic function (motor, sensory or autonomic) that is associated with an abnormal synchronous discharge of cortical neurons. These abnormal, electrical discharges are recorded by an EEG. The EEG usually demonstrates a rhythmic focal correlation associated with it, but typically of longer duration than the clinical event. With an EEG, we can also find the focus of origin and its subsequent spread to adjacent areas. Recent studies have suggested that higher degrees of seizure burden and neonatal status epilepticus may impact neurologic outcome as well as mortality.
Blood sugar, serum sodium and calcium, cerebrospinal fluid (CSF) examination should be done. CSF examination should be done in all cases, as the seizure may be the first sign of meningitis. It should not be neglected even if another aetiology such as hypoglycaemia is present. However, CSF study may be withheld temporarily if severe cardio-respiratory compromise is present or even omitted in some infants with severe birth asphyxia (documented abnormal cord pH/base excess and onset of seizures within 12-24 hrs of life).
Additional investigations may be considered in neonates who do not respond to a combination of phenobarbitone and phenytoin or earlier in neonates with specific features. These include screening for congenital TORCH infections which are Toxoplasmosis, Other (syphilis, parvovirus B19, varicella), Rubella, Cytomegalovirus, Herpes, and for inborn errors of metabolism (IEM). An arterial blood gas (ABG) may have to be performed if IEM is strongly suspected. Metabolic screening tests that include blood and urine ketones, urine reducing substances, blood ammonia, anion gap, urine and plasma amino-acidogram, serum and CSF lactate/ pyruvate ratio should be done if necessary.
Cranial ultrasound is an excellent tool for detection of intraventricular and parenchymal haemorrhage but is unable to detect subarachnoid haemorrhage (SAH) and subdural haemorrhage. It should be done in all infants with seizures. Neuroimaging such as computed tomography (CT) scan and magnetic resonance imaging (MRI) can be done in certain cases. CT should be done in all infants where an aetiology is not available after the ﬁrst line of investigations. It can be diagnostic in subarachnoid haemorrhage and developmental malformations. MRI is indicated only if investigations do not reveal any aetiology and seizures are resistant to the usual anti-epileptic therapy. It can be diagnostic in cerebral dysgenesis, lissencephaly, and other neuronal migration disorders.
AMPLITUDE INTEGRATED EEG (aEEG):
This new method provides continuous monitoring of cerebral electrical activity at the bedside in critically sick newborns. 24-hour aEEG is helpful in evaluating the background as well as in the identiﬁcation of seizure activity.
Aetiology of NS :[1-6]
The most common causes of seizures as per the recently published studies from the country are hypoxic-ischemic encephalopathy, metabolic disturbances (hypoglycaemia and hypocalcaemia), and meningitis.[5,6]
Hypoxic-ischemic encephalopathy (HIE):
Hypoxic-ischemic encephalopathy secondary to perinatal asphyxia is the commonest cause. Most seizures due to HIE (about 50-65%) start within the ﬁrst 12 hrs of life while the rest manifest by 24-48 hours of age. Subtle seizures are the most common type of seizures that occur in HIE. Earlier the onset of seizures in HIE portends a poorer prognosis.
Common metabolic causes of seizures include hypoglycaemia, hypocalcaemia, and hypomagnesemia. Other rare causes include pyridoxine dependency and inborn errors of metabolism (IEM).
Meningitis should be excluded in all neonates with seizures. Meningo-encephalitis secondary to intrauterine infections (TORCH) may also present as seizures in the neonatal period.
Seizures due to subarachnoid, intra-parenchymal or subdural haemorrhage occur more often in term neonates, while seizures secondary to intra-ventricular haemorrhage (IVH) occur in preterm infants. Most seizures due to intracranial haemorrhage occur between 2 and 7 days of age. Seizures occurring in a term
‘well baby’ on day 2-3 of life is often due to subarachnoid haemorrhage.
Cerebral dysgenesis and neuronal migration disorders are rare causes of seizures in the neonatal period.
They include polycythaemia, maternal narcotic withdrawal, drug toxicity (e.g. theophylline) local anaesthetic injection into scalp, and phacomatosis (e.g. tuberous sclerosis, incontinentia pigmenti). Accidental injection of local anaesthetic into scalp may be suspected in the presence of ﬁxed and dilated pupil and absence of doll’s eye reﬂex.
- 1. Initial medical management: The ﬁrst step in successful management of seizures is to maintain the thermo-neutral environment of baby and to ensure airway, breathing, and circulation (ABC). Oxygen should be started, intravenous (IV) access should be secured, and blood should be collected for glucose and other investigations. A brief relevant history should be obtained and quick clinical examination should be performed.
- Correction of hypoglycaemia and hypocalcemia: If glucometer shows hypoglycaemia or if there is no facility to test blood sugar immediately, 2 ml/kg of 10% dextrose should be given stat as a bolus injection followed by a continuous infusion of 6-8 mg/kg/min. If hypoglycaemia has been treated or excluded as a cause of convulsions, the neonate should receive 2 ml/kg of 10% calcium gluconate IV over 10 minutes under strict cardiac monitoring. If serum calcium levels are suggestive of hypocalcaemia, the neonate should receive calcium gluconate at 8 ml/kg/day for 3 days. If seizures continue despite correction of hypocalcaemia, 0.25 ml/kg of 50% magnesium sulphate should be given intramuscularly.
- Anti-epileptic drug therapy (AED) should be considered in the presence of even a single clinical seizures facilities for continuous EEG monitoring are not easily available. AED should be given if seizures persist even after correction of hypoglycaemia/ hypocalcaemia.
Phenobarbitone: Based on available evidence, the WHO guidelines on neonatal seizures recommend phenobarbitone as the ﬁrst-line agent for management of neonatal seizures. It is the drug of choice in neonatal seizures. The dose is 20 mg/kg IV given slowly over 20 minutes (not faster than 1 mg/kg/min). If seizures persist after completion of this loading dose, additional doses of phenobarbitone 10 mg/kg may be used every 20-30 minutes until a total dose of 40 mg/kg has been given. The maintenance dose is 5 mg/kg/day in 2 divided doses, started 12 hours after the loading dose.
Phenytoin is the second-line agent in neonates with seizures. Phenytoin is indicated if the maximal loading dose of phenobarbitone (40 mg/kg) fails to resolve seizures or is given earlier if adverse eﬀects like respiratory depression, hypotension or bradycardia ensue with phenobarbitone. The dose is 20 mg/kg IV at a rate of not more than 1 mg/kg/min under cardiac monitoring. Phenytoin should be diluted in normal saline as it is incompatible with dextrose solution. A repeat dose of 10 mg/kg may be given in refractory seizures. It also causes hypotension and cardiac abnormalities.
Fosphenytoin, the prodrug of phenytoin, does not cause the same degree of hypotension or cardiac abnormalities, is highly water soluble and can be given intramuscular (IM), and is less likely to lead to soft-tissue injury when compared with phenytoin. Dose is 1.5 mg/kg of Fosphenytoin is equivalent to 1 mg/kg of phenytoin.
Benzodiazepines: This group of drugs may be required in up to 15-20% of neonatal seizures. The commonly used benzodiazepines are lorazepam (0.05-0.1 mg/kg IV bolus) and midazolam. Diazepam is generally avoided in neonates because of its short duration of antiepileptic eﬀect but very prolonged sedative eﬀect, narrow therapeutic index, and the presence of sodium benzoate as a preservative. Lorazepam is preferred over diazepam as it has a longer duration of action and results in less adverse eﬀects (sedation and cardiovascular eﬀects). Midazolam (0.15 mg/kg IV bolus followed by infusion of 0.1 to 0.4 mg/kg/hour) is faster acting than lorazepam and may be administered as an infusion. It causes less respiratory depression and sedation than lorazepam. However, when used as continuous infusion, the infant must be monitored for respiratory depression, apnea, and bradycardia so equipment for resuscitation and assisted ventilation should be available at the bedside of all neonates.
Antiepileptic drugs for seizures refractory to above treatment, the following drugs might be tried:
Lidocaine: It is administered as a bolus dose of 4 mg/kg IV followed by an infusion rate of 2 mg/kg/hr. It is tapered over several days. Adverse eﬀects include hypotension, seizures and arrhythmias.
Paraldehyde: A dose of 0.1-0.2 mL/kg/dose may be given IM or 0.3 mL/kg/dose mixed with coconut oil in 3:1 may be used by per rectal route. Additional doses may be used after 30 minutes and then every 4-6 hourly. Adverse eﬀects include hypotension, pulmonary oedema, pulmonary haemorrhage and liver injury.
Sodium Valproate: Per rectal or IV route may be used. The dose is 20-25 mg/kg/d followed by 5-10 mg/kg every 12 hours. Adverse eﬀects include hepatotoxicity; hence it should be used with caution in newborns.
Vigabatrin: is used in neonates with infantile spasms. e dose is 50 mg/kg/day.
Topiramate: It has potential neuroprotective eﬀect against injury caused by seizures in neonates. It has been used for refractory infantile spasms in infants. It has higher volume of distribution compared with other drugs requires higher initial and maintenance doses of approximately 3 mg/kg.
- Other therapies
Pyridoxine: A therapeutic trial of pyridoxine is used as a last resort in refractory seizures. Intravenous route is the preferred method; however, suitable IV preparations are not universally available and hence intramuscular (IM) route may have to be used. Neurobion vial of 1mL has 50 mg pyridoxine and 1 mL may be administered on both the sides in either the gluteal region or anterolateral aspect of thigh. Its side eﬀects include hypotension and apnea.
Exchange transfusion: This is indicated in life-threatening metabolic disorders, trans-placental transfer of maternal drugs (e.g. chlorpropamide), bilirubin encephalopathy and accidental injection of local anaesthetic.
MAINTENANCE ANTIEPILEPTIC THERAPY:
Monotherapy is the main strategy to control seizures. Attempts should be made to stop all anti-epileptic drugs and wean the baby to only phenobarbitone at 3-5 mg/kg/day. If seizures are uncontrolled or if clinical toxicity appears, a second AED may be added.
WHEN TO DISCONTINUE AED:
There are no speciﬁc guidelines available for discontinuation of AED. The goal is to discontinue phenobarbitone as early as possible. We usually try to discontinue all medications at discharge if clinical examination is normal, irrespective of aetiology and EEG. If neurological examination is persistently abnormal at discharge, AED is continued and baby is reassessed at one month. If the baby is normal on examination and seizure free at 1 month, phenobarbitone is discontinued gradually over 2 weeks. If neurological assessment is not normal, an EEG is obtained. If EEG is normal, then phenobarbitone is tapered and stopped. If EEG is overtly abnormal, the infant is reassessed in the same manner at 3 months and then every 3 months till 1 year of age.
Advances in obstetric management and in neonatal intensive care have caused a reduction in mortality in infants with neonatal seizures from about 40% to less than 20%, with less than 10% mortality in term infants. Morbidity rates are not much changed, due to increased numbers of survivors among ill premature newborns who have a greater risk of neurologic sequelae. Long- term sequelae in infants with neonatal seizures, including cerebral palsy and intellectual disabilities, occur at a high rate of up to 30%, with post-neonatal seizures occurring in up to 20%.
Normal development can be expected in infants with benign idiopathic neonatal seizures and in 90% of those with primary subarachnoid haemorrhage. Whereas only 50% of those with HIE, and even fewer with a brain malformation, will have normal outcome. Hence the most important factor affecting outcome for infants with neonatal seizures is the underlying aetiology. Useful clinical indicators for a good outcome include a normal neonatal neurologic exam, normal or mildly abnormal neonatal EEG activity, and normal neuroimaging or abnormalities limited to extra-parenchymal injury.
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