Neuroanatomical Features

The most critical neuroanatomical developmental processes of relevance to the manifestation of seizure activity in the newborn period are the organizational events (see Chapter 7 ) ( Table 12.2 ). The relevant events include the attainment of proper cellular orientation, alignment, and layering (i.e., lamination of cortical neurons); the elaboration of axonal and dendritic ramifications; and the establishment of synaptic connections. Only the first of these processes (lamination) is fully developed by the term equivalent in the human newborn. The latter two events (neurite outgrowth and synaptogenesis) required to provide the cortical connectivity to propagate and sustain a generalized seizure is rudimentary in the term newborn infant. In contrast, in the newborn monkey, the spread of seizure discharges is relatively rapid, and well-organized, synchronous, generalized seizures are readily apparent clinically and electroencephalographically. Such propagation of seizures appears related to the more advanced cortical organization and myelination of cortical efferent systems and interhemispheric commissures present in the newborn monkey. The relatively advanced cortical development apparent in limbic structures in the human newborn infant and the connections of these structures to the diencephalon and brain stem may underlie the frequency and dominance of oral-buccal-lingual movements (e.g., sucking, chewing, or drooling), oculomotor movements, and apnea as clinical manifestations of neonatal seizures.

Neurophysiological Features

The relation of excitatory to inhibitory synapses is important in determining the capacity of a focal discharge to both form and then to spread to contiguous and distant brain regions. Strong evidence indicates that the rates of development of the excitatory and inhibitory synaptic activities differ in the newborn cerebral cortex (see Table 12.2 ). Excitatory activity is mediated by glutamate through two key receptor types, N -methyl- d -aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). These two excitatory receptors are the predominant neurotransmitter receptors found in the immature brain, with a relative paucity of the principal inhibitory receptors for GABA. Indeed, the neonatal period is characterized by levels of excitatory neurotransmitter expression and function that exceed those observed in adult cortical neurons, while inhibition is not yet at adult levels ( Fig. 12.1 ). Moreover, properties of these two glutamate receptors enhance their excitatory function. NMDA receptors in the neonatal period exhibit prolonged duration of the NMDA-mediated excitatory postsynaptic potential, reduced ability of magnesium to block NMDA receptor activity, diminished inhibitory polyamine binding sites, and a greater sensitivity to glycine enhancement. Similarly, AMPA receptors in the neonatal period are deficient in the GluR2 subunit responsible for rendering the AMPA channel impermeable to calcium. Thus, these immature AMPA receptors are permeable to calcium and, as a consequence, enhanced excitation. In addition, early in development, the principal inhibitory neurotransmitter, GABA, acts at the major postsynaptic GABA _A receptor (GABA _A ) to produce excitation rather than inhibition, as occurs later in development. Consistent with these developmental phenomena, it is easier to produce epileptic activity in the immature animal than in the adult ( Fig. 12.2 ).

Schematic depiction of maturational changes in glutamate and GABA receptor function in the developing brain.

Equivalent developmental periods are displayed for rats and humans on the top and bottom axes, respectively. Activation of GABA receptors is depolarizing in rats early in the first postnatal week and in humans up to and including the neonatal period. Functional inhibition, however, is gradually reached overdevelopment in rats and humans. Before full maturation of GABA-mediated inhibition, the NMDA and AMPA subtypes of glutamate receptors peak between the first and second postnatal weeks in rats and in the neonatal period in humans. Kainate receptor binding is initially low and gradually rises to adult levels by the fourth postnatal week. AMPA , α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; GABA , γ-aminobutyric acid; NMDA , N -methyl- d -aspartate; P , postnatal day.

(From Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Med. 2009;5:380–391, with permission.)

Hypoxia-induced seizures in P10 rats and subsequent seizure activity.

Electroencephalographic recordings with representations of ictal discharges (A) during hypoxia, 0 to 2 days, 3 to 10 days, 14 to 21 days, 22 to 27 days, and 28 to 47 days following hypoxia. Abnormal activity was classified as seizures when activity was paroxysmal, rhythmic, increasing in amplitude, and greater than 3 seconds in duration. Electrographic seizures associated with abnormal behavioral automatisms were observed within the first 48 hours following hypoxia-induced seizures at P10. There was a decrease in the frequency (B) and duration (C) of the electrographic seizure activity between the ages of P13 and P20. The frequency (B and C) of electrographic seizures associated with abnormal behavior increased again in the animals at P24 to P31 and continued to increase into adulthood.

(From Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Med. 2009;5:380–391, with permission.)

Insights into the critical developmental relationship between neuronal chloride (Cl ⁻ ) levels and Cl ⁻ transport in the perinatal period have major implications for understanding the basis of GABA excitation, and thus key clinical and therapeutic aspects of neonatal seizures ( Table 12.3 ). GABA activation of the major postsynaptic GABA _A receptor causes Cl ⁻ flux. In the mature neuron, there is Cl ⁻ influx down an electrochemical gradient. However, in developing brain, at maturational stages comparable to the human perinatal period, GABA activation causes Cl ⁻ efflux, and GABA activation is therefore excitatory. The basis for this paradoxical effect relates to a developmental mismatch between the two Cl ⁻ transporters that determine neuronal Cl ⁻ levels . Thus, in the perinatal period, in the human cerebral cortex the expression of the Na ⁺ -K ⁺ -Cl ⁻ cotransporter (NKCC1) responsible for Cl ⁻ influx reaches a developmental peak, whereas the expression of the K ⁺ -Cl ⁻ cotransporter (KCC2) responsible for Cl ⁻ efflux is relatively low (see Fig. 12.1 ). The result is a high internal neuronal level of Cl ⁻ , so when the GABA _A receptor is activated there is efflux (rather than influx) of Cl ⁻ , resulting in depolarization and excitation. The later developmental upregulation of the KCC2 cotransporter extruding Cl ⁻ lowers the internal neuronal Cl ⁻ level. Thus, with GABA _A receptor activation there is Cl ⁻ influx with hyperpolarization and inhibition.

These findings may explain the therapeutic inconsistency of GABA agonists, such as phenobarbital and benzodiazepines, to be effective anticonvulsants in the newborn infant with seizures. This lack of anticonvulsant pharmacological efficacy is particularly apparent after neonatal hypoxic-ischemic insults, which, in an experimental model, are associated with the up-regulation of NKCC1. The NKCC1 inhibitor, bumetanide, has potent antiseizure properties by enhancing GABA-mediated inhibition through the blockage of Cl ⁻ uptake and the lowering of neuronal Cl ⁻ levels (see later). Moreover, because the maturation of the two cotransporters and neuronal Cl ⁻ levels occurs in a caudal-rostral direction, spinal cord and brain stem motor neurons would be expected to exhibit GABA-mediated inhibition before the cerebral cortical regions. This maturational process could explain the frequent occurrence of electroclinical uncoupling/dissociation in which antiseizure medications with GABA agonist mechanisms (i.e., phenobarbital and benzodiazepines) suppress motor manifestations of seizures (by spinal cord and brain stem inhibition) but not cortical electroencephalographic (EEG) manifestations (due to lack of cortex inhibition). The presence of a relative overexpression of NKCC1 versus KCC2 has been documented in postmortem human neonatal brain, and combined with the efficacy in rodent neonatal seizure models, a Phase 1 to 2 study has been initiated to examine the safety and pharmacokinetics of the use of bumetanide as a combination anticonvulsant in human infants suffering from acute neonatal seizures.

Energy Metabolism

The most prominent acute biochemical effects of seizures involve energy metabolism ( Fig. 12.3 ). Seizures are associated with a greatly increased rate of energy-dependent ion pumping, which is accompanied by a fall in the concentration of ATP and phosphocreatine, the storage form of high-energy phosphate in the brain. The resulting rise in adenosine diphosphate (ADP) has two major effects. First, the rise in ADP leads to the stimulation of glycolysis at the rate-limiting, phosphofructokinase step, which ultimately results in accelerated production of pyruvate (see Fig. 12.3 ). In the first minutes after the onset of seizure, there is a sharp increase in the rate of glucose utilization. In the absence of seizure, a major proportion of the pyruvate formed from glycolysis enters the mitochondrion, is oxidized to carbon dioxide, and is associated with the production of ATP. With seizure activity, however, a considerable proportion of pyruvate is converted in the cytoplasm to lactate in the presence of elevated levels of the reduced form of nicotinamide adenine dinucleotide (NADH). Second, the rise in ADP leads to a shift of the redox state in the cytoplasm toward reduction (i.e., NADH; see Fig. 12.3 ). The excess of lactate, specifically the associated hydrogen ion, has the beneficial effect of causing local vasodilation and a consequent increase in local blood supply and substrate influx. In addition, seizures are associated with elevated blood pressure, which contributes to increased cerebral blood flow (CBF) and substrate influx. This pressor effect is presumed to be a central autonomic component of the seizure because it can be interrupted by a section of the spinal cord or by administration of sympathetic ganglion-blocking agents. An impairment of cerebrovascular autoregulation with seizure causes the pressor response to result in increased CBF.

Biochemical effects of seizure.

The major effects are numbered. ADP , Adenosine diphosphate; ATP , adenosine triphosphate; NAD , nicotinamide adenine dinucleotide; NADH , reduced form of nicotinamide adenine dinucleotide; P _i , inorganic phosphate.

Despite these important compensatory factors, in experimental animals neonatal seizures are accompanied by reductions in brain glucose concentrations . In the neonatal rat, rabbit, dog, and monkey, despite normal or slightly elevated blood glucose concentrations, brain glucose concentrations fall dramatically within 5 minutes of onset of seizure to nearly undetectable levels after 30 minutes ( Table 12.4 and Fig. 12.4 ). Concomitant with the fall in brain glucose is a rise in brain lactate, which is used readily as a metabolic fuel in the neonatal brain. This fall in brain glucose concentration and rise in brain lactate are directly reminiscent of a hypoxic-ischemic brain insult and presumably relate to the accelerated rate of glucose utilization in an attempt to preserve supplies of phosphocreatine and ATP. Glucose conversion to lactate, which is accelerated with neonatal seizures, results in only two molecules of ATP for each molecule of glucose, as opposed to the 38 molecules of ATP generated when pyruvate enters the mitochondrion and is oxidized to carbon dioxide. Consistently, in vivo studies by magnetic resonance spectroscopy (MRS) of cerebral metabolites in newborn dogs subjected to convulsant-induced seizures demonstrated a prominent decrease in phosphocreatine (with which ATP is in equilibrium) and in intracellular pH. MRS studies by Younkin and colleagues in the human newborns demonstrate the relevance of these experimental data to the clinical situation ( Fig. 12.5 ). Four newborns had seizures during MRS imaging. The seizures resulted in substantial (~50%) decrease in the phosphocreatine to inorganic phosphate (PCr/Pi) ratio. One newborn’s seizures were successfully treated with intravenously administered phenobarbital, which caused an immediate increase in the PCr/Pi ratio. Furthermore, newborns had PCr/Pi ratios of less than 0.8 during seizures and developed long-term neurological sequelae, indicating that neonatal seizures may increase cerebral metabolic demands above energy supply, thereby causing or exacerbating injury. These observations indicate seizures may lead to secondary brain injury in an already injured neonatal brain and therefore have important implications for prognosis and therapy.

Decline in brain glucose concentration with seizure.

Ratio of brain glucose to blood glucose levels in convulsing neonatal rats as a function of duration of seizure activity. The shaded area represents mean control values ± SE. The asterisks indicate difference from controls at P < .01.

(From Wasterlain CG, Duffy TE. Status epilepticus in immature rats. Arch Neurol. 1976;33:821.)

Magnetic resonance (phosphorus-31) spectra from a full-term infant during subtle seizure activity (oral-buccal-lingual movements, i.e., lip smacking and chewing).

The electroencephalogram demonstrated seizure activity emanating from the left temporal region. The magnetic resonance spectrum from the nonictal hemisphere (dotted line) is normal. The spectrum from the ictal hemisphere (solid line) exhibits a marked decrease in phosphocreatine (PCr) and adenosine triphosphate (ATP) and a corresponding increase in inorganic phosphate (Pi). PDE , Phosphodiesters; PME , phosphomonoesters.

(Courtesy Dr. Donald Younkin.)

Prolonged Seizures

The best-documented mechanisms by which prolonged seizures may cause brain injury are depicted in Fig. 12.6 . Seizures may be accompanied by hypoventilation and apnea, which result in hypoxemia and hypercapnia. Hypoxemia may yield cardiovascular dysfunction and ischemic injury to brain, particularly in a newborn whose brain already has been compromised by an insult. Accentuation of the disturbance in cerebral energy metabolism when hypoxemia or hypoxemia-ischemia is combined with seizures has been shown in animal models.

Best-documented mechanisms for the occurrence of brain injury consequent to repeated seizures. ADP , Adenosine diphosphate; ATP , adenosine triphosphate; EAA , excitatory amino acids; P co ₂ , carbon dioxide pressure (especially glutamate); P o ₂ , oxygen pressure.

Hypercapnia may combine with seizure-induced adaptive elevations in arterial blood pressure and increased lactate to cause an abrupt increase in CBF in animal models and humans. ^a

a References .

Several lines of evidence indicate that elevations of arterial blood pressure and CBF also occur in the human newborn with seizures, as described in neonatal animal models. Studies using continuous monitoring of arterial blood pressure demonstrated sharp increases in mean arterial blood pressure during neonatal seizures, including subtle seizures, even in paralyzed patients ( Fig. 12.7 ). A study of Doppler ultrasound at the anterior fontanelle in 12 newborns demonstrated a sharp increase in CBF velocity during seizures, most of which were subtle in type. Moreover, the likelihood that this increase in CBF velocity is related to an increase in CBF was shown by the direct documentation of an increase in regional CBF by positron emission tomography during a subtle seizure in an infant. In a study of 12 newborns with seizures, ictal measurements of regional CBF by single photon emission computed tomography showed a 50% to 150% increase, and this increase occurred in newborns with subtle seizures and EEG-only seizures. Although the increase in CBF with seizure initially may be an adaptive response to increase substrate supply to the brain at a time of excessive metabolic demand, this response could become maladaptive in some newborns . For example, depending on such factors as the gestational age of the newborn or the neuropathological substrate for the seizures, some newborns may have highly vulnerable capillary beds, such as the germinal matrix in premature infants or the margins of ischemic lesions in premature infants or asphyxiated term newborns. Under these circumstances, an increase in CBF could rupture these capillary beds and cause intraventricular hemorrhage, hemorrhagic periventricular leukomalacia, or hemorrhagic infarction (see Fig. 12.6 ).

Increase in blood pressure with neonatal seizures.

Nine infants with subtle seizure phenomena were monitored during ictal episodes. Note the consistent increases in systemic blood pressure. In each infant, a simultaneous increase in cerebral blood flow velocity was documented by the Doppler ultrasound technique at the anterior fontanelle (not shown).

Repeated prolonged seizures may be deleterious for the brain, even in the absence of prominent disturbances of ventilation or perfusion (see Fig. 12.6 ). The deleterious effects of hypoventilation and apnea can be controlled by prompt and vigorous support of ventilation. However, studies of paralyzed and well-ventilated, primarily adult animals subjected to repeated seizures indicate that eventually adaptive compensatory increases in substrate supply to brain experiencing seizures can no longer adequately compensate for the increase in energy expenditure and the resulting fall in energy reserves. Thus, decreases in brain ATP and phosphocreatine concentrations become progressive and irreparable brain injury may result. ^a

a References .

Effect of phenobarbital on the depressed ratio of phosphocreatine (PCr) to inorganic phosphorus (Pi) in an infant with seizure emanating from the left hemisphere.

Note the immediate and then sustained improvement in cerebral energy state (i.e., increase in PCr/Pi ratio) after treatment with phenobarbital.

(Courtesy Dr. Donald Younkin.)

Work with newborn animals indicates that glucose administration just before seizures prevents the fall in brain glucose level that occurs with status epilepticus and also markedly reduces mortality and brain cell loss. This protective effect of glucose was substantially greater in neonatal than in older animals ( Fig. 12.9 ). The precise beneficial effect of the glucose did not seem to relate to brain ATP and phosphocreatine concentrations because neither concentration in the whole brain was altered in these experiments. However, the glucose did appear to serve as a carbon source because DNA, RNA, protein, and cholesterol concentrations were relatively spared in the glucose-treated animals. In a study with potential clinical relevance, glucose administered early during seizures in neonatal rats subjected to hypoxia-ischemia led to decreased mortality but no change in the extent of ischemic brain injury. The potential for important interactions between glucose homeostasis and seizures is raised further by MRS studies of neonatal dogs, which showed that levels of hypoglycemia that do not result in alterations in levels of high-energy phosphates are accompanied by distinct decreases in such levels when seizures occur in addition to hypoglycemia. These data indicate the importance of careful attention to glucose homeostasis in the management of the newborns with seizures, and they raise the possibility that administration of glucose may be a useful adjunct to the therapy of some newborns with seizures.

Age-dependent protective effect of glucose on mortality from repetitive seizures in the rat.

The percentage of protection by glucose equals the number of saline-treated rats minus the number of glucose-treated rats: number of saline treated, dead × 100.

(Courtesy Dr. Claude Wasterlain.)

An additional mechanism for the genesis of brain injury with severe seizures relates to excitatory amino acids . ^a

a References .

Recurrent Seizures

Although most evidence does not suggest serious structural or functional defects from a single neonatal seizure, recurrent seizures , even if not prolonged, are associated with long-term functional, morphological, and physiological deficits ( Table 12.6 ). The most consistent functional disturbance involves deficits in cognition . Visual-spatial memory and learning have been particularly involved, and these deficits are consistent with the locus of the principal structural deficits in the hippocampus. The morphological correlates of the functional disturbances involve neuronal developmental abnormalities rather than neuronal cell loss . The most severe disturbances occur in the hippocampus and include dendritic spine loss in CA3 pyramidal cells, and a distinctive pattern of synaptic reorganization of axons and terminals of the dentate granule cells (i.e., mossy fibers). The degree of this “sprouting” of mossy fibers correlates with the severity of the cognitive deficits. In addition, dentate granule cell neurogenesis, which, unlike in other cortical areas, persists in the neonatal period, is impaired after recurrent seizures.

Recurrent seizures also lead to physiological and molecular alterations that favor subsequent neuronal excitability and therefore epileptogenesis , as well as the occurrence of neuronal injury with subsequent insults. Alterations include increases in excitatory amino acid receptors (NMDA and AMPA/kainate), decreases in GABA receptors, posttranslational alterations in AMPA receptors (resulting in a decrease in the GluR2 subunit) that render them permeable to calcium, imbalanced excitatory and inhibitory systems, and altered intrinsic neuronal membrane properties—all of which favor excitation. Recent data from animal models show that brief episodes of neonatal seizure, produced in particular by hypoxia or hypoxia ischemia, can result in long-term alterations in AMPA receptor subunit composition that can predispose to subsequent spontaneous seizure activity. Importantly, in a rodent model, the alterations in AMPA receptor subunit composition, and later spontaneous seizures could be reversed by early posttreatment with the AMPA receptor antagonist NBQX. These data provide evidence that early postseizure treatment may have clinical potential to mitigate some of the deleterious long-term consequences of neonatal seizures, particularly the later development of epilepsy. Consistent with the deleterious effect of recurrent seizures, an observational study of neonatal electrophysiological monitoring of seizures in term infants with hypoxic-ischemic brain injury targeting anticonvulsants to reduce seizure burden was associated with a lower rate of postneonatal epilepsy.

In addition to the modifications of neurotransmitter expression and function, changes in ion channels and metabolic pathways have been suggested to contribute to permanent changes in excitability . KCNQ potassium channels play a very important role in controlling excitation in early-life. The human KCNQ2 and KCNQ3 channel loss-of-function phenotype, benign familial neonatal seizures, suggests these channels are present, active, and important during the neonatal period. A number of medications including flupirtine, a KCNQ channel opener, has been shown to be effective in preventing chemo-convulsant seizures in the neonatal rodent.

Recently, an important regulator of protein translation and synthesis, the mTOR (mammalian target of rapamycin) pathway, has been implicated in epileptogenesis in a number of adult seizure models, and overactivation of mTOR is the hallmark defect of the disease tuberous sclerosis (see Chapter 5 ), which has a high incidence of epilepsy. Similar to adult experimental models, it appears that mTOR upregulation occurs in models of neonatal seizures, and the mTOR inhibitor rapamycin has been shown to prevent acute hypoxia-induced neonatal and convulsant-induced seizures.

Taken together, emerging evidence from many experimental models suggests a series of changes that occur in the immature brain in response to early postnatal seizures. First, changes in immediate early genes and posttranslational modifications of existing proteins occur within minutes to hours, whereas transcriptional events and the onset of inflammatory signaling occur within hours to days. Cell death is minimal following seizures in the immature brain compared to the adult. Later changes include gliosis and axonal sprouting, which may contribute to overall network excitability and dysfunction. These changes are outlined in Fig. 12.10 , and each represents a separable opportunity to discover novel therapeutic targets that are unique and age-specific to the immature brain.

Time course of epileptogenesis.

An initial insult, such as traumatic brain injury and/or status epilepticus, is followed by a latent period lasting weeks to months or even years before the onset of spontaneous seizures. During this latent period, a cascade of molecular and cellular events occurs that alters the excitability of the neuronal network, ultimately resulting in spontaneous epileptiform activity. The alterations that occur during the latent period might provide a good opportunity for biomarker development and therapeutic intervention. The cascade of events that are presently suggested by experimental evidence can be classified temporally following the initial insult. Early changes, including the induction of immediate early genes and posttranslational modification of receptor and ion-channel related proteins, occur within seconds to minutes. Within hours to days, there can be neuronal death, inflammation, and altered transcriptional regulation of genes, such as those encoding growth factors. A later phase, lasting weeks to months, includes morphological alterations, such as mossy fiber sprouting, gliosis, and neurogenesis.

(From Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Med. 2009;5:380–391, with permission.)

A critical question, of course, is the extent to which these changes occur in the human newborn who experiences recurrent seizures, and what seizure burden may produce such adverse neurobiological consequences. Although this question remains unanswered, there is mounting evidence that seizures are associated with less favorable neurobehavioral outcomes (see later).

Seizure Types

A seizure is defined clinically as a paroxysmal alteration in neurological function (i.e., behavioral, motor, or autonomic function). Such a definition includes clinical phenomena that are associated temporally with seizure activity identifiable on an EEG and, therefore, are clearly epileptic (i.e., related to hypersynchronous electrical discharges that may spread and activate other brain structures). The clinical seizure definition also includes paroxysmal clinical phenomena that are not consistently associated temporally with EEG seizure activity; how many of these clinical phenomena without identifiable EEG correlates are epileptic and just not identifiable on surface-recorded EEG and how many are nonepileptic is not resolved (see later discussion). The classification of neonatal seizures presented here categorizes clinical seizures and designates those clinical seizures likely to be associated with EEG seizure activity.

The classification schemes for neonatal seizures have varied over time ( Table 12.7 ). A consensus statement on neonatal EEG terminology by the American Clinical Neurophysiology Society defined three types of neonatal seizures: (1) clinical-only seizures in which there is a sudden paroxysm of abnormal clinical change that does not correlate with a simultaneous EEG seizure, (2) electroclinical seizures in which there is a clinical seizure coupled with an associated EEG seizure, and (3) EEG-only seizures in which there is an EEG seizure that is not associated with any outwardly visible clinical signs. EEG-only seizures are also referred to as subclinical, nonconvulsive, or occult seizures ( Table 12.8 ). Neonatal EEG seizures are described as having (1) a sudden EEG change; (2) repetitive waveforms that evolve in morphology, frequency, and/or location; (3) an amplitude of at least 2 µV; and (4) a duration of at least 10 seconds ( Table 12.9 ).

Electrographic seizure definitions were provided earlier and are summarized in Table 12.9 . It is important to distinguish between electrographic seizures and other related EEG patterns. Although a seizure on EEG is composed of an evolving pattern of epileptiform discharges, not all epileptiform discharges are seizures. Epileptiform dischar ges are brief abnormalities that stand out from the EEG background, usually due to a peaked or sharp appearance. They are sometimes referred to as “sharp waves” or “spikes” because of this EEG appearance. It is normal for newborns to have some sharp waves, and many newborns with epileptiform discharges do not experience seizures. However, epileptiform discharges that occur in runs or are clustered in one brain region are associated with an increased risk of seizure occurrence. In particular, brief rhythmic discharges (BRDs) are EEG patterns that meet the criteria for neonatal seizures (sudden, abnormal, evolving) but are shorter in duration than 10 seconds. BRDs have also been referred to as brief intermittent/ictal/interictal rhythmic discharges (BIRDs) or brief electroencephalographic rhythmic discharges (BERDs). BRDs are associated with underlying brain pathology and are associated with the occurrence of seizures, as well as an increased risk of future developmental delay, cerebral palsy, and mortality. Further, some BRDs are associated with clinical signs, including focal clonic activity. Indicating that the exact separation between seizures and shorter rhythmic discharges may be less distinct. Clearly the 10-second rule is largely arbitrary, and electrographic events with a clinical correlate are generally considered electroclinical seizures even if they last less than 10 seconds.

For those seizures with a clinical correlate, the most recent International League Against Epilepsy seizure classification report classifies neonatal seizures according to the same descriptors as seizures at later ages, rather than as a separate entity as had occurred in prior seizure classification systems. However, the organization of this chapter will retain emphasis of the classification of clinical seizures noted in Table 12.7 .

Despite great efforts to carefully describe the appearance of neonatal seizures, inter-rater agreement in neonatal seizure identification by clinical observation is suboptimal . Malone and colleagues presented clinical data and video clips of abnormal neonatal movements from 20 newborns to 137 observers, including 91 physicians from seven neonatal intensive care units. Observers classified the movements as seizure or nonseizure. The average number of correctly classified events was only 50%, compared to the gold standard of EEG classification. Further, interobserver agreement was poor for both physicians and other health care professionals. Similarly, in a study of staff observing high-risk newborns, only 9% of 526 electrographic seizures were identified by clinical observation, indicating that an underdiagnosis of seizures occurred. In addition, 78% of 177 nonictal events were incorrectly identified as seizures, indicating that an overdiagnosis of seizures occurred. Problematically, the more difficult to diagnose seizure types tend to occur more often than the more readily diagnosed seizure types in newborns. A study of 61 seizures in 24 newborns classified seizures by their most prominent clinical features. Clonic and tonic seizures, which might be more readily identified, only occurred in 20% and 8%, respectively, while orolingual, ocular, and autonomic features, which might be more difficult to identify, were the main features in 55%.

Despite the limitations in clinical recognition of seizures discussed previously, attempts at clinical recognition and classification of neonatal seizures are critical to diagnose seizures and differentiate them from nonictal events. Four essential clinically evident seizure types can be recognized: subtle, clonic, tonic, and myoclonic (see Table 12.7 ). Subtle seizures do not have a clear position in the most recent International League Against Epilepsy seizure classification report, but they are very common in newborns and the term is used frequently throughout the literature. Thus, the term is retained as part of the categorization system in this chapter. As discussed further on, a critical fifth seizure type to consider in newborns is seizures with no observable clinical correlate, which have been referred to as EEG-only seizures, subclinical seizures, nonconvulsive seizures, and occult seizures . In the terminology used later, multifocal refers to clinical activity that involves more than one site, is asynchronous, and, usually, is migratory, whereas generalized refers to clinical activity that is diffusely bilateral, synchronous, and nonmigratory.

An important initial distinction in classifying a seizure is whether it has a generalized or focal mechanism of onset . Focal seizures have a defined region of onset, and electrical activity initially spreads through neural networks in that region, although the seizure may spread within the hemisphere or to the contralateral hemisphere with time. Generalized seizures may begin from a specific point, but almost immediately involve bilateral neural networks, such that electrical activity appears on both sides of the brain simultaneously on EEG. In the vast majority of neonatal seizures, onset is focal or multifocal . Spread of the seizure within one hemisphere and secondary generalization to the contralateral hemisphere are less common in newborns than in older children, presumably because the network connections in the newborn brain are not as fully developed (discussed earlier).

Electroencephalographic-Only (Subclinical, Nonconvulsive, Occult) Seizures

A major issue with clinical diagnosis of seizures in newborns is the high incidence of EEG-only seizures in newborns. ^a

a References .

Total recorded electrographic seizure activity measured in seconds, versus total clinical seizure manifestations in nine patients with electrographic seizures recorded on continuous video electroencephalography (EEG) during the first 72 hours of life.

(From Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed. 2008;93:F187–F191, with permission.)

In newborns with clinically evident seizures, the administration of antiseizure medications may lead to termination of the clinically evident seizures while electrographic seizures persist, which is an occurrence referred to as electromechanical uncoupling or electromechanical dissociation. In the study by Clancy and colleagues, 79% of 393 electrical seizures recorded were not accompanied by clinical seizure activity monitored by direct observation; 88% of the total population of patients had been treated with one or more antiseizure medications. Thus, when clinically evident electroclinical seizures terminate following antiseizure medication administration, EEG monitoring may be needed to assess for ongoing EEG-only seizures.

The reasons for electroclinical dissociation/uncoupling are probably multiple, but data concerning the development of Cl ⁻ transporters in perinatal human brain provide a rational explanation . As discussed earlier, a developmental mismatch occurs between the transporter responsible for Cl ⁻ influx (NKCC1) and the transporter responsible for Cl ⁻ efflux (KCC2), so that, in the human perinatal brain, neuronal Cl ⁻ levels are likely to be high. Thus, GABA activation results in Cl ⁻ efflux with resulting depolarization, and thus excitation. Therefore, with treatment with common anticonvulsant medications, such as phenobarbital and benzodiazepines, which are principally GABA agonists, electrographic seizures are not consistently terminated. However, because the maturation of the transporters occurs in a caudal-to-rostral direction, neuronal Cl ⁻ levels in the brain stem and spinal cord motor systems would be expected to decrease to normal levels before cortical neuronal levels. Thus, GABA activation induced by antiseizure medications would eliminate the motor phenomena of the seizure, but not the cortical electrographic component, resulting in electroclinical dissociation/uncoupling.

The findings described earlier have led to an increased reliance on EEG monitoring with either conventional EEG or aEEG for three main reasons. First, many newborns experience only EEG-only seizures, and EEG-only seizures constitute the majority of neonatal seizures. Second, even in newborns with clinically evident electroclinical seizures, the administration of antiseizure medications may induce electromechanical dissociation/uncoupling with the termination of clinically evident seizures but persisting EEG-only seizures. Third, clinical events may be difficult to distinguish as seizure based on clinical observation, which potentially leads to unnecessary exposure of newborns to antiseizure medications for nonepileptic events. As a result, many neonatal intensive care units place increased importance on EEG monitoring, either using conventional EEG or aEEG, to identify neonatal seizures ; and, as noted earlier, an expanded role for EEG monitoring has been advocated by recent guidelines, consensus statements, and committee reports (see later discussion).

Nonepileptic Movements

Nonepileptic neonatal movements can be difficult to distinguish from seizures by appearance alone, and EEG assessment may be required. Some nonictal movements are benign events while others, although not seizures, are nonetheless abnormal and indicative of underlying brain injury or dysfunction.

Does Absence of Electroencephalographic Seizure Activity Indicate That a Clinical Event Is Nonepileptic?

Central to the concept that certain neonatal clinical events are nonepileptic (e.g., brain stem release phenomena) is the lack of a consistent EEG seizure accompaniment. Does the absence of EEG seizure activity rule out an epileptic origin for the clinical activity? Data from older children and adults, as well as in newborns, indicate that epileptic phenomena can occur in the absence of surface-recorded EEG discharges, and such phenomena can be generated at subcortical (i.e., deep limbic, diencephalic, brain stem) levels ( Table 12.18 ).

Particularly strong support for the notion that neonatal seizures may originate from brain stem structures is provided by rodent studies. Investigators showed that stimulation of the inferior colliculus of the adult rat caused a persistent electrical discharge accompanied by wild running behavior. However, stimulation of this midbrain region in the neonatal rat produced less complex movement such as “forelimb paddling, hind limb treading, and rolling-curling movements of the torso.” These may be analogous to the “boxing,” “bicycling,” and similar movements of the human newborn. Moreover, the sensitivity of the inferior colliculus for the development of the electrical and clinical seizure activity was considerably greater in the newborn than in the older animal. In addition, it is noteworthy that the inferior colliculus of the newborn is particularly sensitive to hypoxic-ischemic brain injury, the most common cause of neonatal seizures.

Several studies of more than 100 newborns with EEG-confirmed seizures have helped to clarify the relationship between subtle seizures and electrographic seizures. First, the proportion of newborns who exhibited subtle clinical seizures was nearly identical among newborns who either did or did not exhibit simultaneous electrographic discharges. Thus, there was no overrepresentation of subtle seizures in the newborns who did not exhibit an EEG correlate. Second, the groups with and without EEG accompaniments to the subtle seizures were clinically similar and had similar neurological outcomes. Thus, there was no indication that the newborns without consistent EEG correlates to the subtle movements were more likely to have cerebral destruction with resulting “release” phenomena. Third, newborns with subtle seizures sometimes exhibited or did not exhibit concomitant EEG seizures. Finally, the clinical phenomena often began seconds before the electrographic discharges. Together, these data indicate that some subtle clinical seizures may originate from subcortical structures and only sometimes propagate to the cortex to produce surface-recorded EEG seizures. This mechanism would account for inconsistent electroclinical correlations and for the fact that the initial EEG change may occur after the initial clinical manifestation.

More data are needed regarding the pathophysiology of subtle seizures. Of particular importance is whether such “surface EEG-silent” seizures have the potential to result in brain injury, whether they can be eliminated by conventional antiseizure medication therapy, and whether elimination of the events is associated with more favorable neurobehavioral outcomes.

Hypoxic-Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy is the most common cause of neonatal seizures in both full-term and premature infants accounting for close to one-half of the causes (see Chapters 16 and 18 ). ^a

a References .

Electrographic seizure frequency from day 1 to 4 after birth.

Seizure frequency was classified according to sporadic (gray) , frequent (light blue) , and status epilepticus (dark blue) .

(From Shah DK, Wusthoff CJ, Clarke P, et al. Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2014;99:F219–F224, with permission.)

There is some evidence that therapeutic hypothermia may reduce electrographic seizure exposure in newborns . However, comparing seizure incidence on studies conducted before and after therapeutic hypothermia utilization may not reflect a reduction in seizures because most studies performed initially relied on clinical observation for seizure identification while most studies performed later used EEG monitoring for seizure identification. Data obtained before the implementation of therapeutic hypothermia as a neuroprotective strategy reported EEG seizures in 22% to 64% of newborns. In newborns with moderate to severe hypoxic-ischemic encephalopathy managed with therapeutic hypothermia, seizures were identified in 30% to 65%. A single-center study did note a significant reduction in EEG seizure burden in newborns with moderate (but not severe) hypoxic-ischemic encephalopathy who underwent therapeutic hypothermia compared with those who did not receive this treatment, after controlling for degree of magnetic resonance imaging (MRI)–assessed injury, suggesting that therapeutic hypothermia had anticonvulsant therapeutic impact. Similarly, a retrospective study of 107 newborns with hypoxic-ischemic encephalopathy identified seizures in 37 with EEG monitoring. The EEG tracings could be analyzed in 31 newborns, including 15 who received therapeutic hypothermia and 16 who did not receive therapeutic hypothermia. EEG monitoring was initiated earlier in newborns who received therapeutic hypothermia, and despite that group having a longer opportunity for seizure identification with EEG monitoring, the recorded electrographic seizure burden in the cooled group was significantly lower than in the noncooled group (60 vs. 203 minutes). However, this difference was only apparent in those with moderate hypoxic-ischemic encephalopathy.

As described earlier, multiple animal and human studies suggest that seizures exacerbate existing cerebral injury. Thus, most clinicians aim to identify and manage seizures in these newborns. A statement from the American Academy of Pediatrics recommends that centers performing therapeutic hypothermia in newborns with hypoxic-ischemic encephalopathy have either aEEG or conventional EEG available for seizure identification .

Ischemic Stroke

Ischemic stroke is the second most common cause of neonatal seizures in full-term newborns, accounting for between 10% and 20% of cases (see Chapter 21 ). The incidence of perinatal arterial stroke is approximately 1 in 1600 to 5000. At least half of neonatal stroke cases are not recognized in the neonatal period, but for those that are diagnosed in the neonatal period, up to 97% present with seizures and 50% have seizures as the only recognized sign. Compared to newborns with more diffuse brain injury, such as hypoxic-ischemic encephalopathy, those with neonatal stroke as a cause of seizures are more likely to appear active and alert between seizures. In addition, seizures due to arterial ischemic stroke tend to occur after the first 12 hours of life; that is, somewhat later than those due to hypoxic-ischemic encephalopathy (see Chapter 22 ). The risk of developing subsequent epilepsy ranges from approximately 10% to 50%, depending on time to follow-up and inclusion criteria.

Cerebral sinus venous thrombosis occurs less frequently than arterial stroke in newborns, affecting approximately 1 in 8 to 38,000 children per year; 42% to 78% of these newborns have experienced a venous infarct. Seizures are the presenting symptom or a complication of cerebral sinus venous thrombosis in 55% to 80% of the cases, but affected newborns usually also manifest diffuse and focal neurological deficits.

Intracranial Hemorrhage

Intracranial hemorrhage may be difficult to establish conclusively as a cause of seizures distinct from hypoxic-ischemic or traumatic injury because of the frequent association of one or both of these factors with the hemorrhage. Nevertheless, approximately 15% of term infants have intracranial hemorrhage as the primary cause of their seizure, and this incidence is higher in premature infants. In the contemporary multicenter neonatal seizure registry study described earlier, intracranial hemorrhage was the etiology in 12% of newborns with seizures, and in the large previously described single-center cohort, 12% had intracranial hemorrhage as the etiology.

Intracerebral hemorrhage often presents with seizures in newborns. In one prospective study of newborns and children with intracerebral hemorrhage, 60% of 20 newborns with intracerebral hemorrhage presented with seizures. In addition, 18 subjects underwent EEG during the acute period, including EEG monitoring in 13, and EEG-only seizures were identified in 25% of the 20 newborns.

Primary subarachnoid hemorrhage , although very common, is usually not of major clinical significance. Nevertheless, seizures can occur secondary to subarachnoid hemorrhage in the full-term infant, and in that context the spells most often have their onset on the second postnatal day. Newborns with subarachnoid hemorrhage in association with hypoxic-ischemic encephalopathy usually exhibit seizures on the first postnatal day, probably as a result of the encephalopathy rather than the hemorrhage. In the interictal period, newborns with seizures secondary to uncomplicated subarachnoid hemorrhage often appear remarkably well.

Germinal matrix-intraventricular hemorrhage , emanating from small blood vessels in the subependymal germinal matrix, is principally a lesion of the premature infants, occurring in the first 3 days of life (see Chapter 24 ). Seizures in association with this type of hemorrhage usually occur with severe lesions or with accompanying parenchymal involvement or both. In one series of EEG-confirmed seizures, 28 of 62 (45%) of preterm newborns had severe intraventricular hemorrhage with or without periventricular hemorrhagic infarction. More recent studies have documented a high incidence of seizures in the preterm infant in the first 72 hours of life, and these were strongly associated with the presence of intraventricular hemorrhage (IVH). In one study, 95 very preterm infants (<30 weeks gestational age) underwent aEEG monitoring during the first 72 hours of life. The overall incidence of seizures in this sample was 48%. High seizure burden was associated with increased risk of IVH throughout each of the 3 days of monitoring. The seizures observed in this very preterm cohort demonstrated a similar evolution in time line to the seizures of a term infant suffering from HIE with the highest median seizure burden during the 0- to 24-hour period. These observations support the potential role of perinatal asphyxia in the pathway to IVH.

Subdural hemorrhage is often associated with a traumatic event, and it is probably the associated cerebral contusion that results in the convulsive phenomena (see Chapter 22 ). The most common variety of subdural hemorrhage is the convexity type, and the seizures in this setting are often focal. Historically, in one large series, convulsive phenomena occurred in 50% of newborns with subdural hemorrhage and appeared in the first 48 hours of life. However, in more recent series with less severe hemorrhages, the vast majority of subdural hemorrhages were asymptomatic. In most newborns with extra-axial hemorrhage, no neurosurgical intervention is required, and following resolution of the acute symptomatic seizures, the prognosis is excellent.

Intracranial Infection

Intracranial bacterial and nonbacterial infections are not uncommon causes of neonatal seizures (see Chapters 34 and 35 ). In the contemporary multicenter neonatal seizure registry study described earlier, infection was the etiology in 4% of newborns with seizures. There is an equal incidence in preterm and term infants. Infections can include congenital infections (such as TORCH [ T oxoplasmosis, O ther, R ubella, C ytomegalovirus, and H erpes infections] infection) or acute CNS infections. Of the bacterial infections, meningitides secondary to Group B streptococci and Escherichia coli are the most common pathogens. The onset of seizures in these instances is usually in the latter part of the first week and subsequent to that period. The relevant nonbacterial infections include the various neonatal encephalitides: toxoplasmosis, herpes simplex, coxsackievirus B infection, rubella, and cytomegalovirus infection. In intrauterine toxoplasmosis or cytomegalovirus infection that is severe enough to result in neonatal seizures, the episodes occur in the first 3 days of life. Seizures associated with herpes simplex encephalitis tend to occur after 7 days of life. Early-onset disseminated herpes simplex virus (HSV) disease does not usually present with seizures. Seizures are more common in term infants with localized CNS rather than disseminated disease. The infant with this variety of neonatal HSV infection usually has been discharged from the hospital before the illness begins. The usual signs are stupor and irritability, which evolve to seizures (often focal) and, perhaps, coma.

Developmental Defects

Many aberrations of brain development can result in seizures, which begin at any time during the neonatal period. In the contemporary multicenter neonatal seizure registry study described previously, brain malformations were the etiology in 4% of newborns with seizures. Similarly, in prior studies malformations of cortical development accounted for 5% to 9% of neonatal seizures. Common malformations include tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly, lissencephaly, subcortical band heterotopia, periventricular nodular heterotopia, schizencephaly, and polymicrogyria (see Chapters 5 and 6 ). Though these disorders may be the cause of a substantial percent of neonatal seizures, most patients with these malformations do not have seizures in the neonatal period. In tuberous sclerosis, only 5% of children develop seizures in the neonatal period. Outcomes depend primarily on the type and severity of malformation.

Metabolic Disturbances

This category includes abnormalities in the levels of glucose, calcium, magnesium, electrolytes, amino acids, organic acids, blood ammonia, and other metabolites; certain intoxications, especially with local anesthetics; mitochondrial or peroxisomal disturbance; pyridoxine and folinic acid responsive seizures (FARS); and glucose transporter deficiency ( Table 12.20 ). The aberrations in levels of glucose and divalent cations are the most frequent. In the contemporary multicenter neonatal seizure registry study described earlier, the etiology was a transient metabolic disturbance in 4% and an inborn error of metabolism in 3% of newborns with seizures.

Other Metabolic Disturbances.

Metabolic disturbances other than hypoglycemia and deficiency of divalent cations are uncommon causes of seizures in the newborn (see Table 12.20 ). Worthy of note are hyponatremia and hypernatremia, hyperammonemia, other amino acid and organic acid abnormalities, mitochondrial disturbances, peroxisomal disorders, pyridoxine dependency, FARS, and glucose transporter deficiency. These metabolic disturbances are all discussed much more extensively in Chapter 27 , Chapter 28 , Chapter 29 .

Hyponatremia may result in seizures and often occurs with inappropriate antidiuretic hormone secretion in the context of bacterial meningitis, intracranial hemorrhage, hypoxic-ischemic encephalopathy, or excessive intake of water. The latter may occur in a child with minor gastrointestinal difficulties with inappropriate dilution of formula or excess water (in place of formula) intake. Hypernatremia occurs primarily in severely dehydrated infants or as a complication of overly vigorous use of sodium bicarbonate for the correction of acidosis. Seizures often result during the correction of hypernatremia if markedly hypotonic solutions are used, perhaps secondary to the development of intracellular edema. Seizures are most likely to arise in the setting of overly rapid correction with hypotonic fluids.

Inborn errors of metabolism may also present with neonatal seizures, and these conditions are discussed in much more detail in Chapters 27 and 28 . Disturbances of amino acid or organic acid metabolism may result in neonatal seizures, virtually always in the context of other neurological features. The most common of these associated with neonatal seizures are nonketotic hyperglycinemia, sulfite oxidase deficiency, multiple carboxylase deficiency, multiple acyl-coenzyme A dehydrogenase deficiency (glutaric aciduria, type II), and urea cycle defect. Hyperammonemia or acidosis (or both) most commonly accompanies these disturbances. Transient disturbance of the glycine cleavage enzyme may cause neonatal seizures; the diagnosis can be missed if CSF glycine levels are not determined because plasma glycine levels may be normal. The process resolves spontaneously after approximately 6 weeks of age.

Additional unusual causes of neonatal seizures in this context include mitochondrial or peroxisomal disturbance (see Chapter 29 ). Of the former, pyruvate dehydrogenase deficiency and cytochrome c oxidase deficiency, with elevated lactate in blood and CSF, are the most common. Although not strictly a “metabolic” disturbance, peroxisomal disease, especially Zellweger syndrome or neonatal adrenoleukodystrophy, associated with elevations of blood levels of very-long-chain fatty acids and other biochemical changes, is associated with severe neonatal seizures, caused by associated cerebral neuronal migrational defects.

Pyridoxine dependency , a disturbance in pyridoxine metabolism, may produce severe seizures that are recalcitrant to usual therapy (see Chapter 29 ). Onset is usually in the first hours of life, but intrauterine seizures as well as onset after the neonatal period have been observed. Seizures are usually multifocal clonic and recalcitrant to all therapeutic modalities. There is an associated newborn encephalopathy, which may manifest as hyperalertness, tremulousness, or hypothermia. A prodrome of restlessness, irritability, and emesis preceding seizures has been described. A progressive encephalopathy and ultimately death ensue if treatment is not initiated.

Generalized tonic-clonic seizures, a rare form of neonatal seizure, have been described in newborns with pyridoxine dependency. However, the clinical presentation may be varied. Clinical studies also indicate that the disorder may begin after days or weeks; that the seizures may respond initially to anticonvulsant medications; and that doses of pyridoxine greater than 100 mg may be necessary to stop the seizures.

Any suspicion of the disorder should lead to a therapeutic trial of pyridoxine (see later). The diagnosis may be suspected from the EEG that usually shows an unusual paroxysmal pattern consisting of generalized bursts of bilaterally synchronous high-voltage 1- to 4-Hz activity with intermixed spikes or sharp waves ( Fig. 12.13 ). Diagnosis is supported by documentation of cessation of seizures and normalization of the EEG findings within minutes after intravenous injection of 50 to 100 mg of pyridoxine. The EEG findings may not normalize for several hours, even when a prompt seizure response is observed. Subsequently complete control of seizures on pyridoxine monotherapy and recurrence on withdrawal established the diagnosis.

Pyridoxine response in an infant with pyridoxine dependency.

(A) Before the injection of pyridoxine, the electroencephalogram shows disorganized background with generalized bursts of irregular spikes and sharp–slow wave complexes without clinical accompaniments. Vitamin B ₆ was injected 30 seconds later. (B) Ten minutes after vitamin B ₆ injection. The discharges have subsided (4 minutes earlier), and the patient shows normal sleep background with early sleep spindles appearing in the tracing.

(From Mikati MA, Trevathan E, Krishnamoorthy KS, Lombroso CT. Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up. Electroencephalogr Clin Neurophysiol. 1991;78:215–221.)

Most infants have exhibited subsequent intellectual disability despite therapy from the first days of life. Nevertheless, early therapy may decrease the likelihood or severity, or both, of intellectual deficit; indeed, 8 of the 10 reported infants with normal intellect were identified and treated in the first month of life. However, many infants treated in the first month still exhibit cognitive deficits later. Intrauterine therapy by maternal pyridoxine supplementation may be necessary to prevent fetal brain injury.

The molecular defect involves the active form of pyridoxine, pyridoxal-5-phosphate, necessary for the action of GAD, which leads to the synthesis of the inhibitory neurotransmitter GABA. This formulation is supported by the finding of low GABA levels as well as elevated glutamate levels in CSF. The disturbance of pyridoxal-5 phosphate results because of its inactivation by alpha-amino adipic semialdehyde (AASA), an intermediate in the degradation of lysine. AASA accumulates because of a defect in its degradation by AASA dehydrogenase (antiquitin), the result of a mutation in the ALDH7A1 gene. Elevated urinary AASA is a reliable biomarker for the diagnosis of antiquitin deficiency and, hence, pyridoxine-dependent seizures. The major structural features in pyridoxine-dependent seizures include evidence for both neuronal and white matter injury, with diffuse cortical atrophy, callosal thinning, and impaired cerebral myelination. These findings may relate to the elevation in CSF and brain of glutamate, caused by the molecular defect. Glutamate may lead to neuronal injury by excitotoxic mechanisms and to oligodendroglial injury by free radical mechanisms. Intrauterine onset of anatomical disturbance is suggested by the fetal imaging finding of partial hypoplasia of the corpus callosum.

Pyridoxamine phosphate oxidase deficiency (PNPO) is a related neonatal epileptic disorder involving synthesis of pyridoxal-5-phosphate. The molecular defect involves PNPO, which is required for synthesis of pyridoxal-5-PO ₄ . The clinical presentation often includes fetal seizures, and infants are often premature and exhibit an encephalopathy as well as seizures. The disorder requires treatment with pyridoxal-5 phosphate; pyridoxine, not unexpectedly, is not effective therapy. Folinic acid-responsive seizures refer to a clinical syndrome of neonatal seizures with onset as early as the first hours of life, responsiveness to oral administration of folinic acid, and the presence on CSF analysis for monoamine neurotransmitters of two unknown metabolic peaks (see Chapter 29 ). The disorder is accompanied by a discontinuous EEG pattern with multifocal sharp waves and progressive cerebral cortical and white matter atrophy. The seizures respond to oral folinic acid at doses ranging from 2 to 20 mg twice daily; the lowest doses have been used in the neonatal period. At least 50% of the infants have had subsequent cognitive deficits. Recent data indicate that FARS and pyridoxine-dependent seizures are syndromes caused by the same genetic defects (see Chapter 29 ).

A disorder of glucose transport from blood to brain is important to recognize because prompt treatment can lead to the cessation of seizures and to improved neurological development. This disorder is caused by an autosomal dominant, heterozygous mutation in the GLUT1 transporter (SLC2A1 gene) (see Chapter 29 ). Approximately 25% of cases have had onset of seizures in the first 2 months of life. The mean age of onset of seizures is 5 months. The striking metabolic findings are low glucose concentrations in CSF with normal blood glucose concentration. The mean ratio of CSF to blood glucose has been 37%. That the hypoglycorrhachia was not the result of increased glycolysis, but rather of impaired glucose transport, is shown by the consistent finding of a low (rather than high) lactate level in CSF. The impaired glucose transport is related to a defect of the glucose transporter (Glut1) responsible for the facilitative diffusion of glucose across the blood-brain endothelial barrier and across the neuronal plasma membrane. Treatment with a ketogenic diet, which supplies usable metabolic fuel for brain energy metabolism not transported by the glucose transporter, is generally effective in leading to seizure control and may blunt the impaired neurological development that is a consistent feature of the disease. However, in general, the beneficial effect of the ketogenic diet is most apparent for seizure control.

DEND refers to a syndrome characterized by developmental delay, epilepsy, and neonatal diabetes. Characteristic features are a severe neonatal-onset epileptic encephalopathy and diabetes mellitus, associated with a channelopathy involving the endocrine pancreas and the brain. The molecular defect involves an ATP-dependent potassium channel (KATP), responsive to the ratio of intracellular ATP/ADP concentrations. This channel normally closes when the ATP/ADP ratio rises; that is, in association with increased blood glucose. Thus, potassium remains intracellular, and the cell depolarizes. The depolarization leads to Ca ²⁺ influx and thereby to physiological insulin release. This mechanism serves to regulate insulin release moment-by-moment in response to blood glucose. In DEND, the channels are unable to close properly. Treatment with insulin is inadequate and does not ameliorate the neurological manifestations. However, sulfonylurea, an oral hypoglycemic agent, binds to the channel, promoting closure and physiological insulin release. Prompt recognition and treatment of this syndrome with oral hypoglycemic agents and not systemic insulin administration are essential for a good neurological outcome.

The HI/HA syndrome (hyperinsulinism/hyperammonemia syndrome) also involves regulation of insulin secretion and is associated with neonatal and infantile seizures. The median age of presentation is 4 to 5 months, although approximately 20% exhibit seizures in the first 72 hours of life in association with hypoglycemia. The hypoglycemia is caused by hyperinsulinism. The molecular defect involves glutamate dehydrogenase (GDH), which generates ATP through the oxidation of glutamate. The rise in ATP to ADP ratio results in closure of K _ATP channel and insulin secretion, as discussed re: DEND syndrome. The mutation in the responsible gene ( GLUD1 ) impairs its normal inhibition by GTP. Leucine, an endogenous activator of GDH, then operates unopposed to activate GDH and leads to the molecular events described previously for insulin release. Management of the hyperinsulinism in this disorder is accomplished with diazoxide, which promotes the opening of the K _ATP channel, thereby inhibiting insulin release. Protein restriction is also useful. The hyperammonemia is mild, is related primarily to upregulated GDH in kidney, and is unrelated to the neurological phenomena. On follow-up, affected infants later exhibit principally atypical absence seizures, learning disabilities, and behavioral problems.

Drug Withdrawal

A rare cause of seizures is passive addiction of the newborn and drug withdrawal. The drugs particularly involved are narcotic-analgesics (e.g., methadone), sedative-hypnotics (e.g., shorter-acting barbiturates), propoxyphene, tricyclic antidepressants, cocaine, and alcohol (see Chapter 38 ). The usual time of onset of seizures in this setting is the first several days of life.

Neonatal Epilepsy Syndromes

As described earlier, most neonatal seizures represent acute symptomatic (provoked) seizures, but there are rare newborns with epilepsy. Several neonatal syndromes are principally distinguished according to their clinical features (see Tables 12.19 and 12.21 ). The current International League Against Epilepsy classification system defines several electroclinical syndromes with onset in the neonatal and infantile periods. An epilepsy syndrome was defined as “a complex of clinical features, signs, and symptoms that together define a distinctive, recognizable clinical disorder.” These distinctive disorders are identifiable on the basis of a typical age of onset, specific EEG characteristics, seizure types, and other factors which, when taken together, permit a specific diagnosis. The classification and terminology used to describe these syndromes have evolved over time. The five major neonatal epilepsy syndromes are discussed next.

Electroencephalogram and Electroencephalographic Monitoring

EEG provides important diagnostic and prognostic information. Moreover, increasingly, continuous EEG monitoring is performed in neonatal intensive care facilities for several important reasons. EEG data can assist in the determination of whether clinical events are correlated with electrical seizures requiring anticonvulsant medication or with nonepileptic events in which anticonvulsant medication administration can be avoided. As discussed earlier, some seizures have readily identifiable clinical manifestations (i.e., clonic or tonic components), while many seizures have more subtle manifestations (i.e., orolingual, ocular, or autonomic). Thus, clinical diagnosis of seizures may be difficult and unreliable. As described earlier, when compared to the gold standard of EEG data, observers only classify clinical events correctly as seizures about half of the time, and there is poor interobserver agreement. As a result, many nonictal events are classified as seizures, potentially leading to unnecessary exposure to anticonvulsant medications. Second , many newborns experience clinically silent seizures, which can only be identified with EEG. In many clinical settings the majority of electrographic seizures are not accompanied by clinically evident seizures, and the majority of time spent having electrographic seizures is not accompanied by clinically evident seizure activity. Third, in newborns with clinically evident seizures and administration of anticonvulsant medications, EEG-only seizures may persist (electromechanical uncoupling or dissociation). Thus, even if management is initiated based on identification of clinically evident seizures, EEG monitoring may be required to fully assess the impact of management on seizure cessation. Fourth, assessment of the EEG background may provide important prognostic information (discussed later).

As a result of these data, there is increasing emphasis on continuous EEG monitoring to aid in management of seizures in newborns . Many neonatal intensive care units report using EEG monitoring, with conventional EEG or aEEG, to identify and manage neonatal seizures. In addition, recent guidelines and consensus statements have advocated for EEG monitoring. This recommendation has included the need for confirmation of seizures by EEG in specialized settings before therapy and the need for continuous electrophysiological monitoring in the setting of therapeutic hypothermia.

The most comprehensive guideline on continuous EEG monitoring in the newborn was produced in 2011 by the American Clinical Neurophysiology Society. The guideline was created to standardize care and define best neuromonitoring practices in the neonatal population, while recognizing that not all recommendations would be feasible or applicable across institutions. The guideline recommendations included that (1) electrodes be placed using the International 10 to 20 system with additional electrocardiogram, respiratory, eye, and electromyography leads; (2) at least 1 hour of recording be assessed to adequately assess cycling through wakefulness and sleep; (3) high-risk newborns be monitored for at least 24 hours to screen for the presence of electrographic seizures; and (4) in newborns with seizures, monitoring occur during seizure management and for an additional 24 hours after the last electrographic seizure. Video EEG recording was recommended for 24 hours rather than a briefer EEG recording because many newborns will not have seizures in the first hour of recording but will experience electrographic seizures within the first day. Studies in high-risk newborns indicate that the majority of acute seizures occur within 48 hours of the brain insult.

Accurate delineation of seizure phenomena by EEG in the newborn requires experienced electroencephalographers with training in the normal developmental features of EEG in the newborn and skilled EEG technologists for the application of the EEG. A recent report on Standardized EEG Terminology and Categorization for the Description of Continuous EEG Monitoring in Newborns was developed by the American Clinical Neurophysiology Society summarizing the many reports of the EEG accompaniments of neonatal seizures. As summarized earlier (see Table 12.9 ), an electrographic seizure is defined as “a sudden, abnormal electroencephalogram (EEG) event defined by a repetitive and evolving pattern with a minimum 2 microvolt voltage and duration of at least 10 seconds.” The major EEG correlates of neonatal seizures thus consist of focal or multifocal spikes or sharp waves or both and focal rhythmic discharges, occurring as a distinct change from background. These discharges may spread to adjacent cortical regions or to homotypic areas of the contralateral hemisphere. Such discharges are distinguished from normal sharp “transients,” which are random rather than localized, are not rhythmic, do not spread, and are not followed by voltage suppression. Two general points concerning identification of electrical seizure activity in the newborn should be emphasized. First, neonatal seizures tend to be brief, usually lasting less than 2 minutes ( Fig. 12.14 ). Second, electrographic seizures tend to be focal and well localized, arising most commonly from temporal and central regions, less commonly from occipital regions, and least commonly from frontal regions.

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