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Purpose: Hypoxic ischemic encephalopathy (HIE) accounts for 60% of all neonatal seizures. There is emerging evidence that seizures cause additional injury to the developing brain that has sustained hypoxic ischemic injury. Temporal evolution of clinical seizure burden in HIE has been characterized, with maximum clinical seizure burden (the period of maximum seizure activity) being observed between 12 and 24 h of age. The purpose of our study was to investigate the distribution of electrographic seizure burden (the accumulated duration of seizures over a defined time period), following the initial hypoxic ischemic insult.
Methods: Fifteen full-term newborns with HIE and seizures, and a minimum of 48 h of continuous video–electroencephalography (EEG), were included in this retrospective study. Medical records of the infants were reviewed and details of clinical seizures and antiepileptic drugs were recorded. The time of maximum seizure burden was defined as the midpoint of an hour-long window, shifted in time by 1 s across the full EEG recording, which contained the maximum duration of seizures. The degree of temporal evolution of seizure burden within this period was tested. Temporal evolution was further analyzed by segmenting the time series into two periods; the time between the first recorded seizure and the maximum seizure burden (T1), and the time between the maximum seizure burden and the last recorded seizure (T2). Seizure burden, duration, and number of seizures per hour were analyzed within each time period.
Key Findings: EEG was commenced at a median of 14 h of age. Maximum electrographic seizure burden was reached at a median age of 22.7 h. Time from first recorded seizure to maximum seizure burden (T1) was significantly shorter than time from maximum seizure burden to last recorded seizure (T2) (p-value = 0.01). Median seizure burden during T1 was significantly higher than during T2 (p-value = 0.007). There is temporal evolution of electrographic seizure burden in full-term newborns with HIE. There is a short period of high seizure burden (T1) followed by a longer period of lower seizure burden (T2).
Significance: Understanding the temporal evolution of seizure burden in HIE contributes further to our understanding of neonatal seizures, helps identify an optimal therapeutic window for seizure treatment, and provides a benchmark against which to measure the efficacy of new and innovative forms of neuroprotection and antiepileptic medication.
Peripartum asphyxia affects approximately 3–5 per 1,000 live births, with approximately 0.5–1 per 1,000 infants subsequently developing symptoms of moderate or severe hypoxic ischemic encephalopathy (HIE) (Levene et al., 1985). The clinical manifestations of HIE evolve over time, and reflect the evolution of the underlying brain injury. Within the brain, following the initial hypoxic ischemic insult there is an immediate decline in the level of adenosine triphosphate (ATP), failure of the Na/K pump, cytoplasmic calcium accumulation, and cell death (Brillault et al., 2008). Activation of various proteins, and inflammatory mechanisms, leads to further cell death through necrosis and apoptosis in the following days and weeks (Volpe, 2008a).
The newborn brain is hyperexcitable, a feature important for synaptogenesis (Sarnat et al., 2010). This hyperexcitability predisposes the developing brain to seizures (Wirrell, 2005). γ-Aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the brain, but it is paradoxically excitatory in the newborn brain. This is because activation of GABAA receptors results in membrane depolarization as opposed to hyperpolarization seen in mature GABAergic synapses (Ben-Ari et al., 1997). This is as a result of elevated intracellular Cl−, facilitated by the Na+-K+-2Cl− cotransporter (NKCC1) (Dzhala et al., 2005). Animal studies show that seizures in addition to a hypoxic ischemic injury lead to depletion of high energy phosphates and induce high levels of glutamate (Yager et al., 2002). There is growing evidence that seizures in human newborns with HIE exacerbate the initial hypoxic ischemic injury (Miller et al., 2002; Glass et al., 2009; Ancora et al., 2010).
HIE grade reflects the degree of severity of the hypoxic ischemic injury, and is a predictor of long-term outcome. Newborns with grade 1 (mild) HIE are irritable and hyper alert. They do not develop seizures. Newborns with grade 2 (moderate) and grade 3 (severe) HIE may develop seizures (Sarnat & Sarnat, 1976; Levene et al., 1985). HIE accounts for approximately 60% of all neonatal seizures (Levene & Trounce, 1986). The evolution of clinical seizures over time, the temporal evolution (TE), in HIE has long been recognized. Rose & Lombroso (1970) described a peak incidence of clinical seizures in the first 24 h of age in newborns with presumed anoxic injury. Volpe (2008b) described clinical seizures in HIE as becoming more severe and frequent between 12 and 24 h of life, with status epilepticus often being observed, and seizure cessation by 72 h of age.
Electrographic neonatal seizures have been defined as clear ictal events characterized by the appearance of sudden, repetitive, evolving, stereotyped waveforms that have a definite beginning, middle, and end, and last for a minimum of 10 s (Clancy & Legido, 1987). It is recognized that neonatal seizures can be difficult to diagnose using clinical features alone in term neonates (Mizrahi & Kellaway, 1987; Scher et al., 1993; Murray et al., 2008a). Amplitude integrated EEG (aEEG) is a useful tool in seizure detection. However, neonatal seizures can be difficult to assess using this modality, particularly when they are infrequent, brief, or of low amplitude (Frenkel et al., 2011; Shellhaas et al., 2007; Rennie et al., 2004).
The temporal behavior of electrographic neonatal seizures across a diverse group of newborns with varying gestational ages and seizure etiologies were investigated by Clancy & Legido (1987) using EEG recordings ranging in duration from 27 min to 3 h. Seizures were recurrent, but brief, with a mean seizure duration of 137 s and mean interictal duration of 480 s. A study by McBride et al. (2000) using continuous multichannel video–electroencephalography (EEG) from as soon as possible after birth in a high risk group of newborns identified electrographic seizures within 1 h in 65% of newborns monitored. All infants who developed seizures did so within 21 h of commencement of monitoring. In newborns with HIE, mean seizure duration was 93 s, and electrographic seizures had ceased by 73 h of age. Newborns with HIE had more seizures and a higher seizure burden (the accumulated duration of seizures over a defined time period) over the duration of the recording, when compared to those with seizures secondary to stroke.
Treatment of neonatal seizures is difficult and controversial, as there is evidence that traditional first- and second-line antiepileptic drugs (AEDs), phenobarbital and phenytoin, are poorly effective (Booth & Evans, 2004; Painter et al., 1999). With increasing evidence that high seizure burden is detrimental to the developing brain, a greater understanding of temporal evolution would be extremely valuable (Miller et al., 2002; Glass et al., 2009; Björkman et al., 2010; Ancora et al., 2010; Glass et al., 2011).
Given the unreliability of clinical signs associated with electrographic seizures, and because neonatal seizures can be difficult to detect using aEEG, continuous multichannel video-EEG remains the gold standard for monitoring seizures in the newborn (Shah et al., 2012). Continuous EEG is not, however, available in most neonatal intensive care units (NICUs). As a result, there is relatively little information regarding the temporal evolution of electrographic seizure burden in newborns who have sustained a hypoxic ischemic injury. In our institution, infants with neonatal encephalopathy have continuous video-EEG monitoring for a minimum of 48 h, from as soon as possible after birth, allowing us to analyze the evolution of seizure burden over time.
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From 2003 to 2010, 107 newborns with HIE had continuous video-EEG monitoring. The modified Sarnat score for HIE was assigned as mild in 43, moderate in 34, and severe in 30 newborns. Among the 64 newborns with moderate or severe HIE, 31 received therapeutic hypothermia. These infants were excluded from this study. In the remaining 33 newborns, who had moderate or severe HIE, 18 developed seizures. Three infants were excluded due to EEG recordings of <48 h duration and, therefore, 15 newborns were included in this study. Clinical characteristics of these infants are described in Table 1. Thirteen of 15 infants were recruited prior to 2006, when TH was introduced in our institution. Nine of 15 infants had an instrumental delivery (vacuum or forceps), two of 15 were delivered by emergency caesarean section, three of 15 had standard vaginal deliveries, and one infant had shoulder dystocia. All of the infants required resuscitation at birth. Placental histology information was not available for any of the infants. None of the infants developed hypoglycemia, severe electrolyte imbalance, or sepsis during the EEG monitoring period. Six infants had moderate HIE (grade 2) and nine had severe HIE (grade 3) (Table 1).
Table 1. Clinical characteristics of neonates included in the study (n = 15)
|Gestational age (weeks)||40.7 (40.4–40.9)|
|Birth weight (kg)||3.3 (3.08–3.66)|
|Age at NICU admission (mins)||25 (20–50)|
|Clinical HIE score|| |
|5-min Apgar score||6 (2–7)|
|First pH (n = 12)||7.06 (7.02–7.18)|
|Lactate (mMol/L) (n = 12)||10.8 (8.5–12.8)|
|Base excess (mEq/L) (n = 13)||−12.2 (−16.8 to −11.8)|
Thirteen of 15 infants had an MRI scan of the brain within the first 2 weeks of birth. None of the MRI scans showed evidence of chronic injury. Six MRI scans were reported as normal, two infants had basal ganglia abnormalities, and five infants had abnormalities consistent with watershed injury.
A total of 1,635 seizures were recorded in the 15 infants. Figure 1 illustrates the variability in seizure burden between infants. In many of the infants, there are prolonged periods of quiescence that were not accounted for by missing data, and do not appear to be temporally related to AED administration. The time of the first recorded clinical seizure was available in 12 of 15 infants. In 11 of 12 infants the first recorded clinical seizure consisted of apnea, lip smacking, or limb cycling. In one infant, clonic limb jerking was recorded. The first clinical seizure was recorded before the start of EEG monitoring in 9 of 12 infants. The median time from first recorded clinical seizure to commencement of EEG recording was 1.8 h (IQR −2.0 to 6.0). The median time from first recorded clinical seizure to first recorded EEG seizure was 2.8 h (IQR 0.8–5.3).
Figure 1. A graphical representation of the seizure time series combined with clinical information. The start and end of EEG monitoring are denoted by blue triangles. Annotated seizures are denoted by a vertical black line. The time of first recorded clinical seizure is denoted by a blue circle. Missing data are denoted by a red cross. Phenobarbital loading dose administration is denoted by a vertical red line, phenytoin loading dose administration by a vertical magenta line, and first dose of midazolam by a vertical green line. The maximum seizure burden (peak in seizure burden) is denoted by a blue cross.
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EEG studies commenced as soon as possible after the infants were identified as meeting inclusion criteria for our institution’s EEG research studies and parental consent had been obtained. As represented in Figure 1, EEG monitoring was commenced at between 2 and 26 h of age and a median age of 14 h (IQR 6–20). EEG monitoring continued for a median of 70.7 h (IQR 62.9–81.9). In 7 of 15 infants, electrographic seizures were ongoing at the start of EEG monitoring.
The summary statistics for seizure burden are shown in Table 2. Seizures continued over a median period of 36.6 h from first recorded seizure to last recorded seizure (IQR 17.8–52.7). The median age at first recorded electrographic seizure was 17.1 h (IQR 12.5–21.3). There was time variability across which maximum seizure burden occurred (between 13 and 42 h of age). The median age at which maximum electrographic seizure burden was reached was 22.7 h (IQR 19.0–29.9). In 11 of 15 infants (four moderate and seven severe) the maximum seizure burden was in excess of 30 min of seizure per hour. This corresponds to a definition of neonatal status epilepticus (Lawrence & Inder, 2010). The median age at which the last electrographic seizure was recorded was 55.5 h (IQR 41.4–64.0).
Table 2. Comparison of timing, seizure burden, duration and frequency overall and during T1 and T2 (n = 15)
| ||T1 + T2||T1||T2||p-value (from Sign test)|
|Median (IQR)||Median (IQR)||Median (IQR)|
|Seizure period (h)||36.6 (17.8–52.7)||5.9 (3.4–9.6)||29.0 (14.5–44.7)||0.01|
|Total seizure burden (min)||206 (152–413)||92 (50–133)||108 (66–336)||0.30|
|Seizure number||84 (41–190)||22 (8–48)||48 (22–124)||0.42|
|Missing data (%)||11.7 (1.4–24.1)||0 (0–8.4)||4.8 (0–17.5)||0.15|
|Seizure burden (min/h)||8.9 (4.1–14.6)||17.1 (9.6–26.5)||6.3 (3.7–13.7)||0.007|
|Mean seizure duration (s)||206 (98–331)||306 (192–484)||177 (88–404)||0.12|
|Number of seizures (per h)||2.7 (1.9–4.1)||4.2 (2.3–5.9)||2.2 (1.4–4.2)||0.12|
|Skewness*||0.62 (−0.09 to 1.28)||–||–||0.02*|
Figure 2A illustrates the nonuniformity of distribution of seizure burden, and the temporal evolution of seizure burden in this cohort of infants with HIE. The median of the skewness coefficient was positive and statistically significant (coefficient 0.62, p-value = 0.02, Table 2), indicating an accumulation of seizures near the first recorded seizure. The time from first recorded seizure to maximum seizure burden (T1) was significantly shorter than time from maximum seizure burden to last recorded seizure (T2) (p-value = 0.01, Table 2). Figure 1 illustrates that maximum seizure burden occurs closer to the start of EEG recording than to the end of EEG recording, as confirmed by a positive skewness coefficient. The median time from first recorded seizure to maximum seizure burden was 5.9 h.
Figure 2. Median seizure burden over time with and without temporal evolution (TE). Graph (A) represents the entire cohort of newborns (moderate and severe HIE). The solid blue line represents evolution in seizure burden over time (temporal evolution). The broken red line represents how seizure burden would evolve if there were uniformity of seizure burden across time, with no temporal evolution. Graph (B) compares distribution of seizure burden in the newborns with severe HIE and moderate HIE. The solid red line represents temporal evolution in severe HIE, and the broken red line represents how seizure burden would evolve if there were no temporal evolution. The solid blue line represents temporal evolution in moderate HIE. The broken blue line represents how seizure burden would evolve if there were no temporal evolution.
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Median seizure burden during T1 was significantly higher than median seizure burden during T2 (p-value = 0.007, Table 2). There was no significant difference in the number of seizures per h between the two time periods.
Infants with severe HIE had a longer seizure period (p-value = 0.007), as illustrated in Figure 2B. This arose from a significantly longer T2 period in severe HIE (p-value = 0.01). Median seizure burden was significantly higher during T1 versus T2 in newborns with severe HIE (p-value = 0.004, Table 3), whereas the difference in seizure burden during T1 versus T2 in moderate HIE was not significant. Median seizure duration was significantly longer during T1 than during T2 in infants with severe HIE (p-value = 0.04, Table 3).
Table 3. Comparison of timing, seizure burden, duration, and frequency over the two time periods by HIE grading
| ||T1 + T2||T1||T2||p-value (from Sign test)|
|Median (IQR)||Median (IQR)||Median (IQR)|
|Moderate (n = 6)|| || || || |
| Time (h)||17.7 (10.8–34.6)||4.8 (2.5–10.8)||10.1 (4.6–28.8)||0.69|
| Seizure burden (min/h)||13.0 (4.1–16.6)||14.9 (8.8–33.6)||10.5 (3.3–27.8)||0.69|
| Seizure duration (s)||362 (168–513)||395 (181–779)||423 (149–650)||1|
| Number of seizures (per h)||2.5 (1.2–3.8)||3.7 (1.5–5.6)||1.8 (1.0–5.0)||0.22|
|Severe (n = 9)|| || || || |
| Time (h)||47.4 (35.4–60.6)||8.6 (3.8–11.4)||36.0 (26.7–56.1)||0.004|
| Seizure burden (min/h)||7.4 (5.2–14.0)||17.1 (9.5–25.0)||6.1 (4.3–10.5)||0.004|
| Seizure duration (s)||126 (97–295)||306 (156–377)||101 (84–280)||0.04|
| Number of seizures (per h)||2.9 (2.0–4.8)||4.4 (2.6–6.9)||2.7 (1.8–5.1)||0.51|
The use of AEDs was reviewed. Two infants, with subclinical seizures only, received no medication. Thirteen of 15 infants received phenobarbital, at a median age of 12.3 h (IQR 10.2–19.2). Eleven of 13 infants received phenobarbital before maximum seizure burden was reached. Nine infants received phenytoin as a second-line AED, at a median age of 29.5 h (IQR 27.6–33.4). All nine received phenytoin after maximum seizure burden had been reached. Eight continued to have electrographic seizures following its administration. Three infants received midazolam as a third-line AED. All continued to have seizures following midazolam administration. There was no association between time of drug administration and time that maximum seizure burden was reached (Spearman’s correlation coefficient [p-value] = −0.17 [0.58] and −0.17 [0.67] for phenobarbital and phenytoin, respectively).
Other medications that can influence the EEG and seizure activity were reviewed. Two infants received magnesium sulfate because of low magnesium levels—infant 4 (Fig. 1) at 45 h of age and infant 15 at 15 h of age. Two infants received pyridoxine—infant 12 at 26 h of age and infant 6 at 80 h of age. Five infants received morphine at a median age of 4 h.
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To our knowledge, this is the first quantitative description of the temporal evolution of electrographic seizure burden in full-term newborns with HIE. Electrographic seizure data provide a more accurate picture of the true seizure burden in newborns who often have subclinical or subtle seizures. Recognition of a pattern of temporal evolution of seizure burden in this historical cohort of newborns establishes a benchmark against which to compare seizure burden in newborns with HIE who receive therapeutic hypothermia, and/or other novel forms of neuroprotection or antiepileptic therapy.
The distribution of seizure burden is not uniform. The time from first recorded seizure to maximum seizure burden (T1) is significantly shorter than the time from maximum seizure burden to last recorded seizure (T2), and the median seizure burden during T1 is significantly higher than the median seizure burden during T2. This indicates a short period of high seizure burden followed by a longer period of low seizure burden.
Hypoxic ischemic brain injury in the peripartum period results in an evolving process of brain injury. The combination of reduced oxygen delivery and reduced blood flow results in rapid depletion of energy metabolites, leading to the failure of the ATP-dependent Na/K pump resulting in Na+ influx and leading to cell death by necrosis (Volpe, 2008a). Animal studies have shown that following the initial insult, there is a latent phase during which oxidative metabolism normalizes, followed by a secondary failure of oxidative metabolism (Gunn & Bennet, 2009). This corresponds with an apparent clinical improvement in newborns with a hypoxic ischemic injury. In our cohort, the median time of first electrographic seizure recording is 17.1 h. This correlates with Volpe’s described onset of secondary energy failure, which is usually apparent by 8–16 h of age and maximal at 24–48 h (Volpe, 2008a). The median age at maximum electrographic seizure burden in our cohort was 22.7 h. The time of seizure onset we report corresponds closely to the findings of Filan et al. (2005) (18–20 h) and is earlier than reported in Scher et al. (2008) (34.8 h). TH may alter the time of seizure onset. Wusthoff et al. (2011) investigated the incidence and timing of electrographic seizures in term newborns who were undergoing TH. The mean time of first seizure onset was 35 h in these infants. Future studies may help to clarify whether time of seizure onset is related to time of initial injury. The focus of our study was the evolution of seizure burden over time once seizures begin.
The temporal and spatial characteristics of neonatal seizures have been studied previously. Bye & Flanagan (1995) quantified characteristics of 1,420 seizures in a cohort of 32 newborns and found that seizure variables were relatively stable over time. Seizures in this cohort had a variety of etiologies, however, with 9 of 32 infants having seizures secondary to HIE. Shellhaas & Clancy (2007) analyzed 851 seizures from a cohort of 121 newborns. Seizure burden was quantified as a percentage of an infant’s EEG recording with ictal activity, and was high, at 24.8%. Seizures were found to be numerous but brief (mean 132 s). However, these data were obtained from short EEG recordings of 23–145 min. Newborns in this cohort were of various gestational ages, with a range of seizure etiologies. Analysis of temporal evolution of seizure burden is possible only with long-term continuous EEG. Our EEG monitoring periods were a minimum of 48 h, allowing us to specifically investigate evolution in seizure burden over time in full-term newborns with HIE. As in these previous studies, seizure burden was calculated as a total of seizures recorded from any channel. We did not calculate seizure burden per EEG channel. It is recognized that prolonged seizures and high seizure burden are damaging to the brain regardless of whether seizures are focal or generalized (Holmes, 2002; Nagarajan et al., 2011). However, further analysis of the spatial evolution of seizures in conjunction with analysis of temporal evolution will add important new information to our understanding of neonatal seizures. In our cohort, seizure burden was high, with infants having a median of 2.7 seizures per hour and 8.9 min of seizure per hour (Table 2). Seizure duration was longer than that found in other studies (206 s). In these studies, seizure duration ranges from 93–137 s. (Clancy & Legido, 1987; McBride et al., 2000; Shellhaas & Clancy, 2007). There is a trend toward seizure duration being shorter during T2.
In this retrospective study, we found that there is a trend toward a higher seizure burden among infants with severe HIE due to a high seizure burden during T1 and a longer seizure period. This is in contrast to findings in previous studies (Sarnat & Sarnat, 1976), which suggest that infants with severe HIE have fewer seizures in the context of a severely suppressed or isoelectric EEG. This may be explained by brief recordings in other studies during the period that we have identified as T2, where there are fewer minutes of seizure per hour, but seizures continue over many hours. However, the small number of infants in each subgroup (six moderate vs. nine severe HIE) limits the statistical analysis. This observation warrants further investigation.
Despite the small sample size, we have demonstrated a consistent, statistically significant temporal evolution of electrographic seizure burden. This pattern of evolution has not been described previously and has not been studied in animals or in humans. High initial seizure burden may be explained by the excitability of the newborn brain and its predisposition to seizures. The subsequent decline in seizure activity may represent depletion of existing neurotransmitters and the inability of the injured brain to replenish depleted stores (Sarnat et al., 2010). It may also correspond to the onset of apoptosis in previously epileptogenic neurons. These findings warrant further animal studies and observational studies in humans.
Not all infants were undergoing EEG monitoring when the first clinical seizure was recorded. However, the first clinical seizure is an unreliable time point, given that abnormal movements are often misinterpreted as seizures, and true seizures are frequently unrecognized (Murray et al., 2008a). Furthermore, the median time from first recorded clinical seizure to commencement of EEG recording was short, at 1.8 h, and electrographic seizure burden in all cases increased following start of EEG recording, implying that maximum seizure burden was recorded in all infants, and that the temporal evolution we report is accurate.
Some infants had periods of missing EEG data during recordings either because of delayed application of EEG leads or because of a temporary cessation in EEG acquisition during the recording period. Missing data in an observational study of this kind are difficult to avoid in the context of ill newborns receiving intensive care in the NICU, who require multiple interventions and investigations.
Although we cannot discount the possibility that some of the newborns in this cohort had a suboptimal in utero environment or experienced a degree of hypoxia in the antepartum period that predisposed them to perinatal brain injury, their clinical presentation and subsequent investigations indicate that there was significant peripartum injury. The majority of infants were of normal birth weight, born by either instrumental delivery or emergency caesarean section, and required resuscitation and immediate admission to NICU. There was a predominance of metabolic acidosis and elevated lactate, which are associated with significant peripartum morbidity (Toh, 2000; Malin et al., 2010; da Silva et al., 2000). Our findings are concordant with those of Cowan et al. (2003), which suggest that events in the immediate perinatal period are most important in neonatal brain injury.
In this cohort, overall seizure burden may have been influenced by the administration of phenobarbital, or second-line AEDs. Given that AED administration is considered part of standard care for neonatal seizures, it is not possible or ethical to study the temporal evolution of seizure burden in the absence of medication in human newborns. The majority of infants in this cohort received AEDs but the number of AEDs administered and the time of administration varied greatly. However, the timing of AED administration in these infants does not correspond with the time points of interest in this study, in particular the time at which maximum seizure burden was reached, as indicated by weak and statistically insignificant correlation coefficients. This may imply that the temporal evolution of seizure burden is independent of timing of AED administration. Several studies, using both continuous EEG and aEEG have illustrated inconsistent reduction of seizure burden following administration of phenobarbital and other second-line AEDs (Connell et al., 1989; Boylan et al., 2002; Painter et al., 1999). Five infants received morphine. There is no evidence to suggest that morphine affects the incidence of seizures in newborns, although it is recognized as having an effect on EEG background (Bye et al., 1997).
We have illustrated that a period of maximum seizure burden is reached within a median of 5.9 h of the first recorded seizure. This suggests a narrow window for optimizing therapy aimed at reducing seizure burden. This study also provides reference data for the temporal evolution of seizures in HIE. Recognition of a consistent pattern of temporal evolution may help confirm the diagnosis of HIE, and rule out neonatal seizures due to other etiologies such as neonatal stroke, and inborn errors of metabolism, more quickly than neuroimaging, which is not usually performed within the first 72 h of life. The identification of temporal evolution in this cohort of infants with HIE and seizures serves to emphasize the importance of early, and continuous long-term EEG monitoring of neonatal seizures.
Assessment of all aspects of seizure burden, and the effect of medication or therapies on reducing this burden is important, given the growing body of evidence showing that a high seizure burden in HIE is associated with further brain injury, independent of the initial hypoxic insult (Miller et al., 2002; Glass et al., 2009; Ancora et al., 2010).