Indian J Pediatr (September 2014) 81(9):917–925 DOI 10.1007/s12098-014-1540-2
REVIEW ARTICLE
Recent Advances in Neonatal Seizures Sujata Kanhere
Received: 6 May 2014 / Accepted: 9 July 2014 / Published online: 16 August 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Neonatal seizures are the most important indicators of underlying brain injury. Seizures in a neonate are different from seizures in older children in many aspects including clinical presentation and etiology. The neonatal brain is immature and tends to have a decreased seizure threshold. Neonatal seizures are classified, based on their presentation as, clinical seizures, electroclinical seizures and electroencephalographic seizures; based on the pathophysiology as epileptic and nonepileptic seizures; and also on the basis of the etiology. Hypoxic ischemic encephalopathy is the leading cause of neonatal seizures, followed by intracranial hemorrhage, metabolic causes such as hypoglycemia and hypocalcemia, intracranial infections and strokes. Neonatal epilepsy syndromes are rare. Electroencephalography (EEG) is the gold standard for diagnosis. Amplitude integrated EEG (aEEG) is also used for continuous monitoring. The approach to management consists of initial stabilization of the neonate followed by treatment of potentially correctable injurious processes such as hypocalcemia, hypoglycemia and electrolyte disturbances, etiology specific therapies and antiepileptic drug (AED) therapy. Phenobarbital remains the first line AED therapy. Pharmacokinetic data on newer drugs is limited. Prognosis depends on the etiology, seizure type, neurological e x a m i n a t i o n a t d i s c h a rg e a n d E E G . L o n g t e r m neurodevelopmental follow up is essential for babies with neonatal seizures.
Keywords Neonatal . Seizures . Etiology . Hypoxic-ischemic encephalopathy . EEG . Antiepileptic drug therapy
S. Kanhere (*) Division of Pediatric Neurology, Department of Pediatrics & Neonatology, K.J. Somaiya Medical College, Hospital & Research Centre, Mumbai, Maharashtra 400022, India e-mail: [email protected]
Introduction Seizures in the neonatal period are the most important symptoms of neurological dysfunction requiring urgent attention. Seizures occur most frequently in this period of life and 80 % of all neonatal seizures occur in the first week of life [1]. The etiology and clinical presentation of seizures in a neonate are distinct. Neonatal seizures are associated with high morbidity and mortality [2–6]. Research suggests that persistence of seizures may lead to brain injury and hence early recognition of neonatal seizures, determination of the etiology, particularly if treatable, and prompt treatment is critical.
Incidence The overall incidence of neonatal seizures reported is 1.8 to 3.5 / 1,000 live births [7]. Neonatal seizures occur in 57.5/ 1,000 live births in infants weighing 2,500 g [1, 8–10].
Definitions A neonatal seizure is a stereotypic, paroxysmal spell of altered neurologic function (behavior, motor, and / or autonomic function) [11], that is associated with or without an abnormal synchronous cortical discharge, occurring during the first 28 d (full term infants) or 44 wk gestational age (preterm). A neonatal electrographic seizure is defined as a sudden, repetitive, evolving and stereotyped event of abnormal electrographic pattern with amplitude of at least two microvolts and a minimum duration of ten seconds [12, 13].
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Pathophysiology The neonatal brain is immature and tends to have a decreased seizure threshold due to an excess of glutamergic synapses over inhibitory synapses. There is a delay in Na K -ATPase maturation, increased density of N-methyl-D-aspartate (NMDA) and α Amino-3 hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and those permeable to Calcium (GluR2 AMPA receptors) [14, 15]. This leads to increased excitability and long term consequences of seizures in perinatal hypoxia. Hypoxemia, ischemia and hypoglycemia can lead to a sharp fall in the production of ATP causing a failure of Na K pump and also cause a relative excess of excitatory neurotransmitters. Hypocalcemia leads to an increase in sodium influx and depolarization due to inhibition of sodium movement. There is delayed maturation of inhibitory GABAergic systems [14, 15]. As the chloride gradient is reversed, gammaaminobutyric acid (GABA) has an excitatory effect initially. Later, with maturation, KCC2 becomes predominant and activation of GABA A receptors leads to hyperpolarization.
Clinical Features and Classification Neonatal seizures present differently because the immature brain cannot sustain a well organized synchronized generalized seizure. Neonatal seizures are classified based on (a) the presentation, as Clinical seizures, Electroencephalographic seizures and Electroclinical seizures; (b) the pathophysiology, as epileptic and nonepileptic seizures; and (c) the etiology [16–18]. The recently proposed ILAE classification suggests that neonatal seizure should not be considered a distinct seizure type but as part of the general scheme as focal seizures and others. Neonatal seizure syndromes are rare and classified separately [19]. Clinical seizures are classified as Subtle, Clonic- focal or multifocal, Tonic- focal or generalized, Myoclonic- focal/ multifocal or generalized and Spasms as shown in Table 1.
Subtle Seizures (Motor Automatisms) Subtle seizures are now described as motor automatisms (Table 1). About 50 % of seizures in term and preterm neonates are subtle seizures and are often seen with other seizures. The manifestations of subtle seizures are lip smacking, sucking, drooling, blinking, vacant staring, nystagmus, cycling, pedaling, tonic posturing of a limb, chewing movements, yawning or rhythmic changes in vitals - apnea or color change. The electroencephalograph (EEG) may be normal. Response to antiepileptic drugs (AEDs) is inconsistent.
Indian J Pediatr (September 2014) 81(9):917–925 Table 1 Clinical and pathophysiological classification • Clinical seizures with epileptic seizures (Electroclinical) Focal clonic : Unifocal, multifocal, hemiconvulsive, axial Focal tonic : Asymmetrical truncal posturing, limb posturing, sustained eye deviation Myoclonic : Generalized, focal Spasms : Flexor, extensor, mixed flexor / extensor • Clinical seizures without epileptic seizures (Clinical) Myoclonic : Generalized, focal, fragmentary Generalized tonic : Flexor, extensor, mixed flexor / extensor Motor automatisms : Ocular signs, oral-buccal-lingual movements, progression movements, complex purposeless movements • Electrical seizures without clinical seizures (Electrographic)
Clonic Seizures These seizures are characterized by well localized clonic jerking movements which can be focal or multifocal but there is no loss of consciousness. Focal clonic seizures are seen in localized structural lesions or in infections, subarachnoid hemorrhage, focal traumatic injury or focal infarcts. Stroke is the most common cause of focal clonic seizures. The EEG shows unifocal abnormality and the prognosis of focal clonic seizures is good. In multifocal clonic seizures, multiple muscle groups are affected frequently, simultaneously or in sequence. The migration is non-ordered. These random clonic movements of limbs are similar to those seen in normal infants less than 34 wk of gestation. The EEG shows multifocal abnormality.
Tonic Seizures These seizures can be focal or more often, generalized. They may be accompanied by tonic eye deviation or clonic movements or apnea and lethargy between seizures. Preterms with intraventricular hemorrhage or diffuse CNS disease present with tonic seizures. EEG shows multifocal abnormality or burst suppression pattern or extremely attenuated amplitude bilaterally or unilaterally (Fig. 1). Generalized tonic seizures resemble decorticate or decerebrate posturing and are not accompanied by EEG seizures. Prognosis is poor but better when the seizure occurs soon after an apneic or hypoxic episode.
Spasms These are sudden generalized jerks lasting 1–2 s which may be flexor, extensor or mixed. Spasms are shorter than generalized tonic spells. The EEG shows a single very brief generalized discharge.
Indian J Pediatr (September 2014) 81(9):917–925
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Fig. 1 Neonatal EEG showing asymmetry of background activity with attenuation over the right hemisphere
Myoclonic Seizures
Etiology [20–24]
These are brief, focal or generalized jerks of extremities or body affecting single or multiple distal muscle groups seen in diffuse CNS pathology such as asphyxia, inborn errors of metabolism (IEM), dysgenesis or major trauma. Focal and multifocal myoclonic seizures may be accompanied by focal sharp transient waves. EEG shows burst suppression pattern with generalized myoclonic seizures. The prognosis is poor.
Seizures due to hypoxic-ischemic encephalopathy occur within first 2 d and those due to hypoglycemia are usually seen after the first 2 d. The commonest cause of seizures in full term and preterm neonates is hypoxic-ischemic encephalopathy (25–50 %) followed by transient metabolic causes (5–30 %), intracranial hemorrhage (15–20 %) and intracranial infections (5–15 %) (Table 2). When seizures present after the first 48 h in an initially well neonate, infection and metabolic disorders are likely causes. Inborn errors of metabolism (IEM) are rare and may present after feeds are introduced. Late onset seizures (>10 d of life) are often related to hypocalcemia, malformations or neonatal seizure syndromes. In practice, more than one etiology may be identified in a neonate with seizures, requiring appropriate treatment.
Relation of Seizure to EEG in a Neonate Epileptic and non-epileptic seizures Clinical events that cannot be provoked by stimulation and cannot be suppressed by restraint of the neonate and are associated with EEG seizure activity are clearly epileptic in origin : focal clonic, focal tonic, some types of myoclonic seizures and spasms. The ‘electrical only’ seizures are obviously epileptic. The others are considered nonepileptic in nature (Table 1). Is a clinical seizure without EEG seizure nonepileptic? These may be either Brain stem release phenomena or Epileptic seizures which originate from electrical discharges in deep cerebral structures (limbic regions), or in diencephalon, or brain stem structures and thus are either not detected by surface-recorded EEG or inconsistently propagated to the surface.
Hypoxic Ischemic Encephalopathy (HIE) HIE is the leading cause of neonatal seizures. Seizures occur within first 24 h and 50 % within 12 h of life accompanied by early depression of sensorium. The seizures are frequent, short and focal or multifocal. In arterial strokes, focal seizures are seen and the neonate appears well. Asymmetry, if at all, develops only later. Venous sinus thrombosis can also present with multifocal seizures and encephalopathy. Neuroimaging studies are required for diagnosis of vascular lesions.
920 Table 2 Etiology of neonatal seizures • Hypoxic Ischemic Encephalopathy • Strokes: Focal ischemic injury, Neonatal arterial stroke, Cerebral vein thrombosis • Intracranial Hemorrhage and CNS Trauma • Metabolic Problems: Hypoglycemia (Blood glucose level
REVIEW ARTICLE
Recent Advances in Neonatal Seizures Sujata Kanhere
Received: 6 May 2014 / Accepted: 9 July 2014 / Published online: 16 August 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Neonatal seizures are the most important indicators of underlying brain injury. Seizures in a neonate are different from seizures in older children in many aspects including clinical presentation and etiology. The neonatal brain is immature and tends to have a decreased seizure threshold. Neonatal seizures are classified, based on their presentation as, clinical seizures, electroclinical seizures and electroencephalographic seizures; based on the pathophysiology as epileptic and nonepileptic seizures; and also on the basis of the etiology. Hypoxic ischemic encephalopathy is the leading cause of neonatal seizures, followed by intracranial hemorrhage, metabolic causes such as hypoglycemia and hypocalcemia, intracranial infections and strokes. Neonatal epilepsy syndromes are rare. Electroencephalography (EEG) is the gold standard for diagnosis. Amplitude integrated EEG (aEEG) is also used for continuous monitoring. The approach to management consists of initial stabilization of the neonate followed by treatment of potentially correctable injurious processes such as hypocalcemia, hypoglycemia and electrolyte disturbances, etiology specific therapies and antiepileptic drug (AED) therapy. Phenobarbital remains the first line AED therapy. Pharmacokinetic data on newer drugs is limited. Prognosis depends on the etiology, seizure type, neurological e x a m i n a t i o n a t d i s c h a rg e a n d E E G . L o n g t e r m neurodevelopmental follow up is essential for babies with neonatal seizures.
Keywords Neonatal . Seizures . Etiology . Hypoxic-ischemic encephalopathy . EEG . Antiepileptic drug therapy
S. Kanhere (*) Division of Pediatric Neurology, Department of Pediatrics & Neonatology, K.J. Somaiya Medical College, Hospital & Research Centre, Mumbai, Maharashtra 400022, India e-mail: [email protected]
Introduction Seizures in the neonatal period are the most important symptoms of neurological dysfunction requiring urgent attention. Seizures occur most frequently in this period of life and 80 % of all neonatal seizures occur in the first week of life [1]. The etiology and clinical presentation of seizures in a neonate are distinct. Neonatal seizures are associated with high morbidity and mortality [2–6]. Research suggests that persistence of seizures may lead to brain injury and hence early recognition of neonatal seizures, determination of the etiology, particularly if treatable, and prompt treatment is critical.
Incidence The overall incidence of neonatal seizures reported is 1.8 to 3.5 / 1,000 live births [7]. Neonatal seizures occur in 57.5/ 1,000 live births in infants weighing 2,500 g [1, 8–10].
Definitions A neonatal seizure is a stereotypic, paroxysmal spell of altered neurologic function (behavior, motor, and / or autonomic function) [11], that is associated with or without an abnormal synchronous cortical discharge, occurring during the first 28 d (full term infants) or 44 wk gestational age (preterm). A neonatal electrographic seizure is defined as a sudden, repetitive, evolving and stereotyped event of abnormal electrographic pattern with amplitude of at least two microvolts and a minimum duration of ten seconds [12, 13].
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Pathophysiology The neonatal brain is immature and tends to have a decreased seizure threshold due to an excess of glutamergic synapses over inhibitory synapses. There is a delay in Na K -ATPase maturation, increased density of N-methyl-D-aspartate (NMDA) and α Amino-3 hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and those permeable to Calcium (GluR2 AMPA receptors) [14, 15]. This leads to increased excitability and long term consequences of seizures in perinatal hypoxia. Hypoxemia, ischemia and hypoglycemia can lead to a sharp fall in the production of ATP causing a failure of Na K pump and also cause a relative excess of excitatory neurotransmitters. Hypocalcemia leads to an increase in sodium influx and depolarization due to inhibition of sodium movement. There is delayed maturation of inhibitory GABAergic systems [14, 15]. As the chloride gradient is reversed, gammaaminobutyric acid (GABA) has an excitatory effect initially. Later, with maturation, KCC2 becomes predominant and activation of GABA A receptors leads to hyperpolarization.
Clinical Features and Classification Neonatal seizures present differently because the immature brain cannot sustain a well organized synchronized generalized seizure. Neonatal seizures are classified based on (a) the presentation, as Clinical seizures, Electroencephalographic seizures and Electroclinical seizures; (b) the pathophysiology, as epileptic and nonepileptic seizures; and (c) the etiology [16–18]. The recently proposed ILAE classification suggests that neonatal seizure should not be considered a distinct seizure type but as part of the general scheme as focal seizures and others. Neonatal seizure syndromes are rare and classified separately [19]. Clinical seizures are classified as Subtle, Clonic- focal or multifocal, Tonic- focal or generalized, Myoclonic- focal/ multifocal or generalized and Spasms as shown in Table 1.
Subtle Seizures (Motor Automatisms) Subtle seizures are now described as motor automatisms (Table 1). About 50 % of seizures in term and preterm neonates are subtle seizures and are often seen with other seizures. The manifestations of subtle seizures are lip smacking, sucking, drooling, blinking, vacant staring, nystagmus, cycling, pedaling, tonic posturing of a limb, chewing movements, yawning or rhythmic changes in vitals - apnea or color change. The electroencephalograph (EEG) may be normal. Response to antiepileptic drugs (AEDs) is inconsistent.
Indian J Pediatr (September 2014) 81(9):917–925 Table 1 Clinical and pathophysiological classification • Clinical seizures with epileptic seizures (Electroclinical) Focal clonic : Unifocal, multifocal, hemiconvulsive, axial Focal tonic : Asymmetrical truncal posturing, limb posturing, sustained eye deviation Myoclonic : Generalized, focal Spasms : Flexor, extensor, mixed flexor / extensor • Clinical seizures without epileptic seizures (Clinical) Myoclonic : Generalized, focal, fragmentary Generalized tonic : Flexor, extensor, mixed flexor / extensor Motor automatisms : Ocular signs, oral-buccal-lingual movements, progression movements, complex purposeless movements • Electrical seizures without clinical seizures (Electrographic)
Clonic Seizures These seizures are characterized by well localized clonic jerking movements which can be focal or multifocal but there is no loss of consciousness. Focal clonic seizures are seen in localized structural lesions or in infections, subarachnoid hemorrhage, focal traumatic injury or focal infarcts. Stroke is the most common cause of focal clonic seizures. The EEG shows unifocal abnormality and the prognosis of focal clonic seizures is good. In multifocal clonic seizures, multiple muscle groups are affected frequently, simultaneously or in sequence. The migration is non-ordered. These random clonic movements of limbs are similar to those seen in normal infants less than 34 wk of gestation. The EEG shows multifocal abnormality.
Tonic Seizures These seizures can be focal or more often, generalized. They may be accompanied by tonic eye deviation or clonic movements or apnea and lethargy between seizures. Preterms with intraventricular hemorrhage or diffuse CNS disease present with tonic seizures. EEG shows multifocal abnormality or burst suppression pattern or extremely attenuated amplitude bilaterally or unilaterally (Fig. 1). Generalized tonic seizures resemble decorticate or decerebrate posturing and are not accompanied by EEG seizures. Prognosis is poor but better when the seizure occurs soon after an apneic or hypoxic episode.
Spasms These are sudden generalized jerks lasting 1–2 s which may be flexor, extensor or mixed. Spasms are shorter than generalized tonic spells. The EEG shows a single very brief generalized discharge.
Indian J Pediatr (September 2014) 81(9):917–925
919
Fig. 1 Neonatal EEG showing asymmetry of background activity with attenuation over the right hemisphere
Myoclonic Seizures
Etiology [20–24]
These are brief, focal or generalized jerks of extremities or body affecting single or multiple distal muscle groups seen in diffuse CNS pathology such as asphyxia, inborn errors of metabolism (IEM), dysgenesis or major trauma. Focal and multifocal myoclonic seizures may be accompanied by focal sharp transient waves. EEG shows burst suppression pattern with generalized myoclonic seizures. The prognosis is poor.
Seizures due to hypoxic-ischemic encephalopathy occur within first 2 d and those due to hypoglycemia are usually seen after the first 2 d. The commonest cause of seizures in full term and preterm neonates is hypoxic-ischemic encephalopathy (25–50 %) followed by transient metabolic causes (5–30 %), intracranial hemorrhage (15–20 %) and intracranial infections (5–15 %) (Table 2). When seizures present after the first 48 h in an initially well neonate, infection and metabolic disorders are likely causes. Inborn errors of metabolism (IEM) are rare and may present after feeds are introduced. Late onset seizures (>10 d of life) are often related to hypocalcemia, malformations or neonatal seizure syndromes. In practice, more than one etiology may be identified in a neonate with seizures, requiring appropriate treatment.
Relation of Seizure to EEG in a Neonate Epileptic and non-epileptic seizures Clinical events that cannot be provoked by stimulation and cannot be suppressed by restraint of the neonate and are associated with EEG seizure activity are clearly epileptic in origin : focal clonic, focal tonic, some types of myoclonic seizures and spasms. The ‘electrical only’ seizures are obviously epileptic. The others are considered nonepileptic in nature (Table 1). Is a clinical seizure without EEG seizure nonepileptic? These may be either Brain stem release phenomena or Epileptic seizures which originate from electrical discharges in deep cerebral structures (limbic regions), or in diencephalon, or brain stem structures and thus are either not detected by surface-recorded EEG or inconsistently propagated to the surface.
Hypoxic Ischemic Encephalopathy (HIE) HIE is the leading cause of neonatal seizures. Seizures occur within first 24 h and 50 % within 12 h of life accompanied by early depression of sensorium. The seizures are frequent, short and focal or multifocal. In arterial strokes, focal seizures are seen and the neonate appears well. Asymmetry, if at all, develops only later. Venous sinus thrombosis can also present with multifocal seizures and encephalopathy. Neuroimaging studies are required for diagnosis of vascular lesions.
920 Table 2 Etiology of neonatal seizures • Hypoxic Ischemic Encephalopathy • Strokes: Focal ischemic injury, Neonatal arterial stroke, Cerebral vein thrombosis • Intracranial Hemorrhage and CNS Trauma • Metabolic Problems: Hypoglycemia (Blood glucose level
