Published online August 1, 2007
PEDIATRICS Vol. 120 No. 2 August 2007, pp. e354-e363 (doi:10.1542/peds.2006-3007)
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ARTICLE

Neurodevelopmental Outcome in Term Infants With Status Epilepticus Detected With Amplitude-Integrated Electroencephalography

Linda G.M. van Rooij, MDa, Linda S. de Vries, MD, PhDa, Setyo Handryastuti, MDa, Dewi Hawani, MDa, Floris Groenendaal, MD, PhDa, Alexander C. van Huffelen, MD, PhDb and Mona C. Toet, MD, PhDa

a Departments of Neonatology
b Clinical Neurophysiology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, Netherlands


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. This study evaluated seizure, patient characteristics, and neurodevelopmental outcome of term newborns with amplitude-integrated electroencephalography–detected status epilepticus.

METHODS. Fifty-six term infants with status epilepticus were identified during a 12.5-year period. The time of onset of status epilepticus, background pattern before and after status epilepticus, success of controlling status epilepticus with antiepileptic drugs, and neurodevelopmental outcome were studied.

RESULTS. The incidence of status epilepticus in our population was 18%. Forty-two infants (75%) had a poor outcome and 14 were normal at follow-up. When all infants were studied as a single group, we found that not the duration, but the background pattern was correlated with neurodevelopmental outcome. In 50% of the infants with a poor outcome, the background pattern was abnormal before the status epilepticus and in 71% after the status epilepticus. Among infants with a good outcome, background pattern was normal in 14% before and 7% after the status epilepticus. In a subgroup of 48 infants with hypoxic-ischemic encephalopathy, there was a significant difference in background pattern, as well as in duration of the status epilepticus between infants with a poor outcome, compared with those with a good outcome. In 48% of the infants with a poor outcome, the background pattern was abnormal before, and in 75% after the status epilepticus, compared with 25% and 13%, respectively, for those with a good outcome. In 57% of the infants with a hemorrhage or perinatal arterial stroke, the status epilepticus was not controlled with antiepileptic drugs, compared with 21% in infants with hypoxic-ischemic encephalopathy (not significant).

CONCLUSIONS. The background pattern at the onset of status epilepticus was the main predictor of neurodevelopmental outcome. The duration of the status epilepticus was only of predictive value in the infants with hypoxic-ischemic encephalopathy. No association was found between the ability to control status epilepticus and subsequent neurodevelopmental outcome.

Key Words: hypoxic-ischemic encephalopathy • term newborn • status epilepticus • aEEG

Abbreviations: aEEG—amplitude-integrated electroencephalogram • HIE—hypoxic-ischemic encephalopathy • PAS—perinatal arterial stroke • BGP—background pattern • PNE—postneonatal epilepsy • SE—status epilepticus • AED—antiepileptic drug • FT—flat tracing • CLV—continuous low voltage • BS—burst suppression • DNV—discontinuous normal voltage • CNV—continuous normal voltage

Incidence of neonatal seizures is 3.5 per 1000 live births.1–4 Neonatal seizures are especially common in term infants with neurologic dysfunction. Recognition of neonatal seizures has improved since the increased use of continuous amplitude-integrated electroencephalogram (aEEG) monitoring. As a result, it is now known that a substantial part of the seizures are subclinical, also called silent seizures because of electroclinical dissociation.5–7 The most common etiology of seizures in term infants is hypoxic-ischemic encephalopathy (HIE). Other causes are hemorrhage, perinatal arterial stroke (PAS), infection of the central nervous system, metabolic disorders, and cerebral malformations.

Long-term outcome of infants with neonatal seizures depends on the underlying etiology. The severity of the underlying problem is reflected in the aEEG background pattern (BGP), which in itself has been shown to be of predictive value of subsequent neurodevelopmental outcome.8,9 Recent studies suggest an adverse effect of neonatal seizures on neurodevelopmental outcome. Neonatal seizures are reported to predispose to later problems in cognition, behavior, and development of postneonatal epilepsy (PNE).10–12 Animal studies also suggest adverse effects of neonatal seizures on brain development.13–16 Status epilepticus (SE) in neonates is relatively rare, and there are limited data available in the literature for this age group.10,17–19

The aim of this study was to retrospectively evaluate the seizure and patient characteristics and subsequent neurodevelopmental outcomes of term infants with aEEG-detected SE. We hypothesized that a longer duration of and the inability to control SE would have an adverse effect on subsequent neurodevelopmental outcome.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During the period June 1992 to January 2005, 428 term neonates who were at high risk for developing seizures were monitored using aEEG. Information on all of the infants who were monitored was collected in our neonatal aEEG database.

For this study we selected all of the infants, born between June 1992 and January 2005, with a gestational age ≥37 weeks, who developed a SE (both clinical and subclinical) that was detected with aEEG. The medical charts and aEEG recordings of these infants were carefully reviewed. Infants with congenital malformations, chromosomal abnormalities, or inborn errors of metabolism were excluded.

Both clinical and subclinical seizures were treated with antiepileptic drugs (AEDs). Before 1998, a regimen of phenobarbital, phenytoin, clonazepam, and lidocaine (as a rescue drug) was used. After 1998, this regimen was changed into phenobarbital, lidocaine and/or midazolam, and clonazepam as a fourth-line antiepileptic drug. For seizures not responding to this regimen, pyridoxin was used in selected cases.20

Infants diagnosed with HIE were classified as mild (grade 1), moderate (grade 2), and severe (grade 3) according to the criteria of Sarnat and Sarnat.21

aEEG
The aEEG was recorded with the cerebral function monitor (CFM 4640; Lectromed Devices Ltd, Herts, United Kingdom) and, since 2003, also with Olympic 6000 (Olympic Medical, Seattle, WA) and BRM2 Brain Monitor (BrainZ Instruments Ltd, Auckland, New Zealand). The aEEG recorded a single-channel amplitude-integrated electroencephalogram from 2 parietal needle electrodes (corresponding with P3 and P4 according to the international electroencephalogram 10–20 classification, ground Fz). A second tracing continuously recorded the electrode impedance. The more recent machines (Olympic 6000 or BRM2 brain monitor) also allowed us to assess the raw electroencephalogram in the review mode. In both machines, the filtered signal is rectified, smoothed, and amplitude integrated before it is written out at slow speed (6 cm/hour) at the cot side.22,23

For pattern recognition the following criteria were used24,25: (1) flat tracing (FT), which is very low voltage, mainly inactive (isoelectric) tracing with activity below 5 µV; (2) continuous low voltage (CLV), which is continuous BGP of very low voltage (approximately or less than 5 µV); (3) burst suppression (BS), which is discontinuous BGP periods of very low voltage (inactivity) intermixed with bursts of higher amplitude; (4) discontinuous normal voltage (DNV), which is a discontinuous trace, where the voltage is predominantly >5 µV; and (5) continuous normal voltage (CNV), which is continuous activity with voltage 10 to 25 µV (–50 µV).

Epileptiform activity (characteristic pattern, with a sudden increase of lower and upper margin of the recorded signal because of increased amplitude during epileptic seizure activity and lower voltage in the postictal period) was classified as follows: (1) single seizure; (2) repetitive seizures, ≥3 discharges during a 30-minute period; (3) and SE, continuous discharges for ≥30 minutes, which can present as a "sawtooth pattern" or as continuous increase of the lower and upper margin (Fig 1).


Figure 1
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  		FIGURE 1 Two examples of SE patterns on aEEG (Olympic 6000).

 
The time interval from birth to the first seizure and from birth to onset of SE was calculated. Total duration was calculated counting the subsequent number of 10-minute epochs. We considered that the SE was not controlled if the SE was still present after administration of 4 different AEDs. The BGP before and after SE was noted, and administered AEDs were also noted.

Follow-up and Outcome
All of the survivors were seen in our outpatient clinic. Neurodevelopmental outcome was assessed using the Griffiths Mental Developmental Scale at postnatal ages of ≥18 months.26 A full neurologic assessment was performed at each visit to the follow-up clinic, and cerebral palsy was classified according to the criteria of Hagberg et al27 Global delay was considered if there was a developmental quotient <85, obtained at 18 to 24 months of age, using the Griffiths Mental Developmental Scale.

Analysis
For analysis of duration and onset of SE, ability to control SE, BGP before and after SE, and number of used AEDs, we compared different groups. First we compared infants with a poor outcome with infants with a good outcome irrespective of the underlying diagnosis. Subsequently, we restricted the analysis to infants with HIE, comparing those with a poor outcome with infants with a good outcome, and finally we compared infants with HIE with those with other diagnoses.

Statistics
Statistical analysis was performed by using SPSS 12.0 for Windows (SPSS Inc, Chicago, IL). Comparisons of continuous variables were made with Mann-Whitney U test, and for categorical variables, Fisher's exact or {chi}2 tests were used. The level of significance was set at .05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 311 neonates who were monitored using aEEG developed seizures. Fifty six (18%) of these infants developed a SE during the neonatal period. In 15 infants, a SE was immediately recognized at the start of the aEEG recording. In most infants, the SE appeared as a sawtooth pattern with 2 to 6 discharges in a 10-minute period without evidence of recovery in between the discharges. In only 3 subjects, the SE appeared as a continuous increase of the lower and upper margin.

Most infants were treated with phenobarbital in the referral hospital for clinically suspected seizures. In 28 infants (50%), the SE was completely subclinical. Five infants showed clinical seizures at the onset of the SE, but after administration of AEDs, the SE became subclinical. In 15 infants, there were sporadic clinical manifestations during the SE, most of the time subtle (apnea with drop of saturation) or clonic jerks. Eight infants showed more clinical seizures of different types, but not continuously during the total duration of electrographic SE. Eleven ventilated infants were given vecuronium to differentiate between muscle artifacts and real discharges on the aEEG.

Forty two (75%) of the infants had a poor outcome (35 died and 7 survived with a severe disability), and 14 (25%) were normal or mildly abnormal at follow-up. Of the 42 infants with a poor outcome, 40 (95%) were diagnosed to have HIE, grade 2 or 3, 6 of whom had, in addition, an intracranial hemorrhage or PAS. One infant had a posterior fossa hemorrhage, and 1 infant had seizures associated with hypoglycemia. Among the 14 infants with a normal outcome, 8 infants (57%) were diagnosed to have HIE (all grade 2), and 2 of them also developed a hemorrhage or PAS. Six infants had a hemorrhage or PAS without HIE. Clinical characteristics are shown in Table 1.


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  		TABLE 1 Clinical Characteristics of the 56 Infants With SE

 
Of the 14 infants with a good outcome, 12 were normal and 2 infants had a mild disability: 1 had a mild hemiplegia with a normal developmental quotient, and 1 had a delay in speech and language development.

Of the 42 infants with a poor outcome, 35 died during the neonatal period. In 32 infants, intensive care was withdrawn because of an expected poor prognosis. This decision was based on multiple factors, including a neurologic examination, aEEG BGP, and occurrence of seizures and neuroimaging findings (cranial ultrasound and/or MRI). The 7 survivors all developed a severe disability: 2 developed a global delay in development and PNE. The other 5 infants all developed cerebral palsy and mental retardation, and 2 of them also developed PNE. Thus, in total, 4 infants developed PNE: 2 of them developed PNE during the first year of life, 1 at the age of 4 years, and 1 at 5 years.

Cranial ultrasound was performed in all of the infants. MRI was performed as well in 12 of the 35 infants who died and in 20 of the 21 survivors. All of the infants who died showed areas of increased echogenicity in the basal ganglia on cranial ultrasound, and most of them also showed increased echogenicity in the subcortical white matter. In 6 infants, these findings were confirmed with MRI and postmortem examination, in 6 infants only with MRI, and in 9 infants only with postmortem examination. In the 15 infants in whom postmortem examination was performed, severe ischemic damage was seen in the brain, as well as in almost all of the other organs. In the survivors, different abnormalities were seen on MRI. Table 2 shows the MRI findings, as well as the data regarding neurodevelopmental outcome. Table 3 shows aEEG characteristics of all of the different groups.


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  		TABLE 2 Diagnosis, MRI Findings, and Outcome of the 21 Survivors

 

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  		TABLE 3 aEEG Characteristics of the Different Groups

 
Complete Cohort
The exact duration of SE could only be calculated in 41 infants (30 poor outcome and 11 normal outcome), because in the other 15 infants, a SE was already present at the start of the aEEG recording. The total duration of SE in these 41 individuals ranged from 35 to 1350 minutes (Fig 2). The median duration of the SE in infants with poor outcome was 200 minutes compared with 240 minutes in the infants with a good outcome (P = .61).


Figure 2
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  		FIGURE 2 The distribution of the total duration of SE for 41 infants in whom the duration could be calculated with certainty.

 
When the 15 infants who showed a SE at the beginning of the registration were also included in the analysis, assuming that the duration of the SE was underestimated in those infants, we still did not find a significant difference in duration (205 vs 158 minutes; P = .24). In 11 (26%) of the infants with poor outcome, the SE was refractory to AEDs compared with 3 (21%) of the infants with a good outcome. Ten of these 11 infants with a poor outcome were diagnosed with HIE, and 1 had a posterior fossa hemorrhage. All 3 with a good outcome had an intraventricular hemorrhage (last seen between 22 months and 5 years).

There was a difference in BGP between infants with a poor and good outcome. Figure 3 shows the percentage of infants with CNV/DNV, BS, or CLV/FT BGP for both groups before and after SE. In the infants with a poor outcome, a BS or CLV/FT BGP was seen more often before and the SE compared with those with a good outcome (P < .05). Twenty three (55%) of the 42 infants with a poor outcome had an initial DNV pattern (none of the infants had a real CNV pattern). In 11 of them (48%), the pattern deteriorated to a BS, CLV, or FT pattern after the SE. In contrast, in the good outcome group, 12 (86%) of the 14 infants initially had a CNV/DNV pattern, and only 2 had a BS pattern; none of them showed a deterioration of the BGP after the SE (P < .05), and 2 infants even showed an improvement of the BG pattern after the SE. Figure 4 shows an example of a long-lasting SE refractory to AEDs, and Fig 5 shows an example of a SE on a poor BGP.


Figure 3
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  		FIGURE 3 Distribution of different BGP in both groups before and after SE.

 

Figure 4
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  		FIGURE 4 Example of a SE refractory to AEDs (Olympic 6000). The total duration is 300 minutes. After the SE, the BGP showed a BS for a short period and then returned to a DNV pattern. This infant had a normal outcome.

 

Figure 5
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  		FIGURE 5 Example of a SE refractory to AEDs (BRM2). The total duration was 1350 minutes. After the SE, the BGP shows a BS without subsequent recovery. The infant died 2 days after the SE.

 
All of the infants received ≥1 AED for both clinical and subclinical seizures. Most of the infants (n = 51; 91%) received ≥3 AEDs. Phenobarbital was given in all of the infants as a first-line drug. In 5 infants it was given as prophylaxis immediately after birth. Thirty eight (90%) of the infants with poor outcome received ≥3 AEDs, compared with 93% of the infants with a good outcome (not significant).

HIE Group
In 13 of the 48 infants with HIE, the SE was present at the beginning of the aEEG recording. The exact duration of the SE could, therefore, only be calculated in 35 infants, and there was no difference in duration between the 30 infants with a poor outcome and the 5 infants with a good outcome (200 vs 100 minutes; P = .211). When the 13 infants who showed a SE at the beginning of the registration were also included in the analysis, assuming that the duration of the SE was underestimated in those 13 infants, a significant difference in duration was found between the infants with a poor outcome and those with a good outcome (215 vs 85 minutes; P = .04).

The SE could be controlled with AEDs in all 8 of the HIE infants with a good outcome compared with 30 of the 40 infants with a poor outcome. This difference did not reach statistical significance (P = .18).

Twenty one (53%) of the 40 infants with a poor outcome had a CNV or DNV pattern before the start of the SE compared with 6 (75%) of the 8 infants with a good outcome (P = .06). In the infants with a poor outcome, 15 of them with an initially normal BGP showed deterioration of the BGP after the SE. In the infants with a good outcome, no deterioration of the BGP was seen. (P = .04). In the HIE group there was also no difference in time of onset of seizures and SE between those with a poor and those with a good outcome (6 vs 5 hours [P = .81] and 19 vs 9 hours [P = .31], respectively). Thirty six of the 40 infants with a poor outcome received >3 AEDs compared with 7 of the 8 infants with a good outcome.

Comparison of Infants With HIE With Infants With Other Diagnoses
When comparing the 35 infants with HIE and 6 infants with other causes of seizures (hemorrhage 6, PAS 1, and hypoglycemia 1) for whom the duration of SE could be calculated exactly, no difference in duration was found (P = .60). Also, when comparing all 56 infants, there was no significant difference between both groups (180 vs 220 minutes; P = .72).

In 3 (43%) of 7 infants with a hemorrhage or PAS (without asphyxia), the SE was stopped after administration of AEDs compared with 38 (79%) of the 48 infants with HIE (P = .06). Of the 4 infants with a hemorrhage in whom SE was not controlled, 1 died and 3 were normal at follow-up. All 10 of the infants with HIE and drug-resistant SE died.

When infants with HIE were compared with infants with other underlying problems, there was also a difference in BGP. In the HIE group before and after the SE, more infants had a BS or CLV/FT BGP (P < .05). Fifteen of the infants with HIE showed deterioration of the initially normal BGP after the SE compared with none in the infants with other diagnoses (P = .09).

In infants with HIE, the median time of onset of seizures was 3.5 hours after birth, with a median onset of SE of 16 hours. In infants with hemorrhage, PAS, or hypoglycemia, these median onset times were, respectively, 13.5 and 26 hours (P = .01 and .06). When comparing the HIE group with infants with other diagnoses, no significant difference was found in number of AEDs.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In the present study, we report 56 term infants with a SE detected with aEEG. Approximately 38% of these infants survived the neonatal period, and 57% of the survivors had a normal outcome. The most important finding was that the BGP on which the SE arises was the best predictor of subsequent neurodevelopmental outcome. An unexpected finding in our study was that the duration of the SE did not correlate with neurodevelopmental outcome. In the subgroup of infants with HIE, there was also no significant difference in duration of SE when excluding the infants who showed a SE at the beginning of the aEEG registration. Quite a number of HIE infants (n = 13) showed a SE at the beginning of their aEEG registration, suggestive of an even longer duration of the SE. When these infants were included in the analysis, the duration of the SE was significantly longer in the infants with a poor outcome.

The main causes of neonatal seizures in our group were HIE, hemorrhage, and PAS. In 11 of the 42 infants with a poor outcome, a deterioration of the initial discontinuous normal BGP was seen after SE, whereas in the survivors with a good outcome, the BGP did not change after SE, though they received the same number of AEDs to control their SE. Although it was not significant (probably because of small groups), we found that in 57% of the infants with a hemorrhage or PAS, the SE was not controlled compared with 21% in infants with HIE.

The incidence of neonatal SE is not exactly known. We found an incidence of 18% in a group of term infants with neonatal seizures. Our data are in agreement with the aEEG study of Hellström-Westas et al,7 who reported that in 14 (16%) of 87 infants with electrographic seizures, the "sawtooth pattern" lasted >1 hour. In 2 electroencephalogram studies, different percentages were found. Scher et al28 reported that electrographic SE was found in 33% of their term infants. McBride et al10 found an even higher incidence of electrographic SE, 43% in a group of both preterm and term infants. In both studies, SE was defined as continuous seizure activity for ≥30 minutes or recurrent seizures for >50% of the recording time. Our study is an aEEG study, recording from 2 parietal electrodes. It is well recognized that, with this technique, focal seizures and seizures with low voltage and short duration can be missed.29,30 Further studies with continuous monitoring with more channels would be useful to define the amount of seizure activity missed with this type of recording. On the other hand, continuous monitoring is very useful in long-lasting SE, especially to see the therapeutic effect of AEDs.

Because this study was retrospective, we have no detailed information about clinical seizure types in the infants. In the medical charts and on aEEG registrations, we found enough information, however, about clinical signs before and during aEEG recording. In 28 infants, the SE was subclinical, and in 5 infants, clinical seizures stopped after administration of AEDs whereas on aEEG recording, the SE continued. It should be noted that 8 of the infants with subclinical SE were paralyzed. In our group of 56 infants with SE, we found 59% of electrographic SE. This is in agreement with data from Scher et al,6 who found dissociation of electrical and clinical expression of seizures in 58% of their study population.

No conclusive data exist regarding association of duration of seizures and neurodevelopmental outcome. In most reports, duration does not seem to correlate with outcome.9,10 Prolonged or poorly controlled neonatal seizures have been associated with a worse outcome, but the severity of the underlying disorder may be responsible for both poor seizure control and adverse outcome.9,29 In our infants with SE, seizure control was successful in <50% of the infants with a hemorrhage or PAS. In 3 infants with an intraventricular hemorrhage, the uncontrolled SE was superimposed on a normal BGP, and all 3 had a normal outcome. Another infant with a posterior fossa hemorrhage died. Postmortem examination showed that this lesion was associated with a tentorial tear. An MRI, performed a few days after the onset of the SE, also showed extensive cortical necrosis, possibly associated with the long-lasting SE. Somatosensory and visual-evoked potentials were absent, and because of the poor prognosis, intensive care treatment was withdrawn.

In both electroencephalogram and aEEG studies, the BGP is a significant characteristic in predicting neurologic outcome after HIE.8,22,23,30–34 In our present study, the BGP in most of the poor-outcome infants was abnormal, especially after the SE, whereas in infants with a good outcome, only 2 had an abnormal BGP. Eleven of the 42 infants with a poor outcome had a DNV pattern at onset and showed deterioration of this BGP to an abnormal BGP. In our survivors with a good outcome, in the whole group, as well as in the infants with HIE, the BGP did not deteriorate after administration of a similar number of AEDs to control their SE. Although AEDs can depress EEG background activity, this depression depends mainly on the severity of the underlying HIE. Such a depression is not common with an initially normal BGP and if it occurs is most of the time transient.35–38 One could assume that the presence of a poor BGP after interruption of the SE led to withdrawal of intensive care. In 3 of the infants, the SE was still present on the aEEG when treatment was withdrawn. However, in the other infants, the aEEG was continued for a median time of 23 hours after interruption of the SE to allow recovery of the BGP, but this did not occur in any of the infants. In 32 of the infants for whom care was withdrawn, this was based on multiple factors, such as clinical history, neurologic examination, and neuroimaging findings. MRI was available in 12 of the infants who died, mainly showing extensive injury of the deep gray nuclei. In another 15 infants, postmortem examination confirmed the extent of the damage. Whether seizures damage the developing brain is still a matter of debate.14,15,39–41 In recent years there is more evidence, in both animal studies and clinical observations, that seizures in the immature brain are harmful,13,39,40,42,43 especially after hypoxic-ischemic brain damage.11,16 Our observation that in our group of infants with HIE there is a significant difference in duration of SE and in deterioration of BGP between those with a poor and those with a good outcome could indicate that the brain of an infant with moderate-to-severe HIE might be more susceptible to seizure-induced injury. In these infants, cerebral energy metabolism has been compromised by the hypoxic-ischemic insult. After the occurrence of seizures, the brain is not able to recover from this cerebral metabolic compromise.44,45 Seizures can also be a sign of secondary energy failure, which also can contribute to more brain damage.46 Because this is a clinical study, we can not say with certainty that the SE by itself caused brain damage, but previous animal and human studies have shown that the combination of hypoxia and seizures produces more profound changes in the brain than either factor alone.10,11,16 This observation could imply that controlling seizures is especially of great importance after a hypoxic-ischemic insult and could possibly reduce the severity of brain damage. Although there is no agreement in the literature that the treatment of subclinical seizures is of benefit to the infant, most leaders in the field would try to control a clinical or subclinical SE. It is both of interest and concern that our small number of infants with a SE, not because of HIE, but rather because of intraventricular hemorrhage, were difficult to treat effectively. However, despite the long duration of their SE, they showed a good short-term outcome. No difference in time interval was found from birth to the onset of seizures and the onset of SE between survivors and nonsurvivors. In 50 of the 56 infants, seizures started in the first 24 hours after birth. Legido et al9 found a significant difference in global neurologic outcome between infants who had seizures before or at 24 hours after birth. Regarding the etiology of seizures in their study, early onset of seizures was observed after acute fetal distress and the onset of seizures was delayed in cases of metabolic disturbance, withdrawal syndromes, intraventricular and periventricular hemorrhages, and sepsis.

It is known that seizures because of hypoxia-ischemia tend to occur within 24 hours after birth. If the origin of cerebral injury is antenatal, seizures can occur within a few hours after birth.47 Seizures because of hemorrhage, PAS, metabolic disturbances, or infections occur later, that is, within the first 2 to 3 days after birth.4 We found a significant difference in time of onset of seizures between the newborns with HIE compared with those with vascular incidents and hypoglycemia, though in most of the infants the seizures started within the first 24 hours of life.

All of the survivors had a follow-up of ≥18 months. Four infants (19% of survivors) developed PNE. Two of them developed PNE in the first year of life and the other 2 at the ages of 4 and 5 years. This cumulative incidence is higher than the 9.5% that we reported previously,48 which is probably because of the fact that, in this study, all of the infants had severe neonatal seizures resulting in SE. PNE is significantly related to cerebral palsy and mental retardation.49 From our 7 survivors with a poor outcome, the youngest is now 3 years of age and the other 6 are at least 4 years of age.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The incidence of neonatal SE among term infants who present with neonatal seizures was 18%. BGP on which SE presented was predictive of neurodevelopmental outcome. There was no association between duration of SE and neurodevelopmental outcome, except for a subgroup of infants with HIE. Especially in infants with SE because of hemorrhage, controlling SE can be difficult. In a substantial part of the infants with moderate-to-severe HIE, an initial DNV BGP deteriorated to BS or CLV/FT after SE.


   ACKNOWLEDGMENTS
 
Dr van Rooij was supported by Dutch Epilepsy Foundation grant NEF 3–15.


   FOOTNOTES
 
Accepted Jan 26, 2007.

Address correspondence to Linda S. de Vries, MD, PhD, Department of Neonatology, Wilhelmina Children's Hospital, KE 04.123.1, PO Box 85090, 3508 AB Utrecht, Netherlands. E-mail: l.s.devries{at}umcutrecht.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.

Dr Handryastuti's current affiliation is Department of Child Health, Neurology Division, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.

Dr Hawani's current affiliation is Department of Child Health, Neurology Division, Hasan Sadikin Hospital, Bandung, Indonesia.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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