Published online April 3, 2006
PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1270-1280 (doi:10.1542/peds.2005-1178)
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The Current Etiologic Profile and Neurodevelopmental Outcome of Seizures in Term Newborn Infants

Hasan Tekgul, MDa,b, Kimberlee Gauvreau, ScDc, Janet Soul, MD, CM, FRCPCa, Lauren Murphy, PhDd, Richard Robertson, MDe, Jane Stewart, MDc, Joseph Volpe, MDa, Blaise Bourgeois, MDa and Adré J. du Plessis, MBChB, MPHa

a Departments of Neurology
c Pediatrics
d Psychiatry
e Radiology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
b Department of Neurology, Ege University Hospital, Izmir, Turkey


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVES. The objectives of this study were to delineate the etiologic profile and neurodevelopmental outcome of neonatal seizures in the current era of neonatal intensive care and to identify predictors of neurodevelopmental outcome in survivors.

METHODS. Eighty-nine term infants with clinical neonatal seizures underwent neurologic examination, electroencephalography (EEG), neuroimaging, and extensive diagnostic tests in the newborn period. After discharge, all infants underwent regular neurologic evaluations and, at 12 to 18 months, formal neurodevelopmental testing. We tested the prognostic value of seizure etiology, neurologic examination, EEG, and neuroimaging.

RESULTS. Etiology was found in 77 infants. Global cerebral hypoxia-ischemia, focal cerebral hypoxia-ischemia, and intracranial hemorrhage were most common. Neonatal mortality was 7%; 28% of the survivors had poor long-term outcome. Association between seizure etiology and outcome was strong, with cerebral dysgenesis and global hypoxia-ischemia associated with poor outcome. Normal neonatal period/early infancy neurologic examination was associated with uniformly favorable outcome at 12 to 18 months; abnormal examination lacked specificity. Normal/mildly abnormal neonatal EEG had favorable outcome, particularly if neonatal neuroimaging was normal. Moderate/severely abnormal EEG, and multifocal/diffuse cortical or primarily deep gray matter lesions, had a worse outcome.

CONCLUSIONS. Mortality associated with neonatal seizures has declined although long-term neurodevelopmental morbidity remains unchanged. Seizure etiology and background EEG patterns remain powerful prognostic factors. Diagnostic advances have changed the etiologic distribution for neonatal seizures and improved accuracy of outcome prediction. Global cerebral hypoxia-ischemia, the most common etiology, is responsible for the large majority of infants with poor long-term outcome.

Key Words: neonatal seizures • outcome • developmental delay • cerebral palsy • postneonatal seizures

Abbreviations: EEG—electroencephalography • CT—computed tomography • HI—hypoxia-ischemia • ADC—apparent diffusion coefficient • BSID-II—Bayley Scales of Infant Development II • MDI—Mental Development Index • ECMO—extracorporeal membrane oxygenation

Seizures are the most common and distinctive clinical manifestation of neurologic dysfunction in the newborn infant.1 Newborn infants with seizures are at risk for neonatal death and survivors at risk for neurologic impairment, developmental delay, and later epilepsy.1–5 Despite increasingly sophisticated neonatal intensive care, clinicians managing seizures remain challenged by difficult prognostic and therapeutic questions.1, 6

The changing etiologic profile of neonatal seizures over the years7–10 can be ascribed to advances in several areas. Among these are significant developments in obstetric and neonatal management that have changed the spectrum of insults to which the immature brain is exposed. In addition, more accurate etiologic diagnosis has been facilitated by advances in neurodiagnostic technology, particularly brain imaging.11–14

The mortality of infants developing seizures during the neonatal period has shown a decreasing trend over time. In earlier studies, the mortality was as high as 40% but decreased in subsequent reports to ~20%.1, 2, 15–18 As opposed to this increase in survival, the prevalence of long-term neurodevelopmental sequelae in survivors has remained unchanged at ~30%.1, 15, 19

Previous studies have sought to define predictors of long-term outcome in newborn infants developing seizures.20–24 The most reliable early predictors of later neurologic outcome have been the underlying etiology of the seizures and specific electroencephalography (EEG) background patterns.4, 5, 7, 20–22, 25, 26

The aims of the current study were to describe the etiologic profile of neonatal seizures, the neurodevelopmental outcome, and reliable prognostic indicators of outcome for infants surviving neonatal seizures in the modern era.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Our study population included all newborn infants admitted to the NICUs of Children's Hospital and Brigham and Women's Hospital in Boston, between January 1, 1997, and March 1, 2000. Eligibility criteria were a birth gestational age ≥37 weeks, clinical seizures in the neonatal period diagnosed by a child neurologist, EEG and neuroimaging (computed tomography [CT] and/or magnetic resonance imaging [MRI]) studies in the neonatal period, and at least 12 months of follow-up in our Neonatal Neurology Program. The diagnosis of neonatal seizures by the child neurologist is based either on direct observation of the clinical and/or EEG events in question or on the review of observations made by the neonatologists. Because we have a neurology consultation service dedicated to the NICU, the neurologists are called at the first suspicion of seizures. We identified cases through the careful review of our neonatology and neurology databases. During the clinical evaluation of suspected seizures, it is standard practice for the child neurologist to exclude phenomena that mimic seizures in the newborn using widely accepted criteria.1 For example, in cases in which myoclonic events were confined to sleep, benign neonatal sleep myoclonus was specifically excluded by clinical and EEG criteria1 before infants were considered eligible for the study. We obtained prenatal, perinatal, and neonatal data by detailed review of the maternal and infant's medical charts. This study was approved by the Institutional Review Boards of Brigham and Women's Hospital and Children's Hospital Boston.

At our center, neurologists with special expertise in neonatal neurologic conditions are involved from the outset in the diagnosis and acute management of all infants with seizures. Diagnosis of clinical neonatal seizures is based on observations by the NICU staff and confirmed by the neurologist. Clinical seizures are classified according to Volpe1 as subtle, clonic, tonic, and myoclonic. Although many infants had more than 1 seizure type, we assigned the single most prominent seizure type to the infant in each case. In cases in which myoclonic seizures occurred only during sleep, benign neonatal sleep myoclonus was excluded by widely accepted criteria.1 The attending neurologist performs daily neurologic examinations during the newborn period. For this study, we documented the most abnormal neurologic examination during the neonatal period.

A consistent institutional management protocol was used for neonatal seizures based on published guidelines.1 Specifically, the first-line agent was intravenous phenobarbital, increased as needed to a maximum cumulative loading dose of 40 to 50 mg/kg. For refractory seizures, defined as persistent seizures despite a phenobarbital blood level of 40 to 50 mg/dL, we used intravenous phenytoin to a maximum of 20 mg/kg. As a third-line agent for persistent seizures, we used doses of 0.05 mg/kg lorazepam. When these measures failed to control seizure activity, 100 mg intravenous pyridoxine was administered with EEG monitoring.1

Etiologic Classification
We made an etiologic diagnosis based on the clinical history and examination and a uniform protocol of special laboratory tests and imaging studies. All infants with neonatal seizures undergo early EEG and neuroimaging studies (mostly MRI). We use a consistent protocol of MRI techniques for all neonatal studies, which include conventional T1/T2-weighted studies as well as diffusion-weighted sequences. These imaging studies not only enhance the accuracy of the etiologic diagnosis, but also allow inferences about the timing of the insults. Laboratory studies included serum glucose and electrolyte levels, cerebrospinal fluid studies, and arterial blood gas and acid-base analysis. When indicated, we also measured serum ammonia, urine and serum organic and amino acid analysis, lactate and pyruvate levels. Infants with thromboembolic or hemorrhagic lesions were evaluated by a battery of coagulation studies, and if thromboembolic lesions remained unexplained, these infants underwent echocardiography.

We assigned each infant to 1 of the following 9 etiologic categories: global cerebral hypoxia-ischemia (HI), focal cerebral HI, trauma/hemorrhage, cerebral dysgenesis, transient metabolic disturbances, infection/inflammation, inborn errors of metabolism, toxins, and familial/genetic syndromes. In cases in which this comprehensive diagnostic evaluation revealed no etiology, infants were assigned to an "etiology unknown" category.

In the global cerebral HI group, we included infants with evidence for a diffuse cerebral HI insult occurring in the neonatal, intrapartum, or antepartum periods. Infants were assigned to the neonatal cerebral HI group if seizures developed after an identified postnatal acute hypoperfusion insult. The diagnosis of intrapartum cerebral HI required that 4 specific criteria be met: (1) severe metabolic acidemia (pH ≤ 7.0) on the umbilical cord or first neonatal blood sample, (2) 5-minute Apgar score of ≤6, (3) fetal distress (abnormal fetal heart rate and/or meconium-stained amniotic fluid), and (4) neonatal seizures within the first 24 hours after delivery. Fetal heart rate patterns considered abnormal were loss of variability with late decelerations and/or prolonged bradycardia. For the purposes of this study, we diagnosed antepartum cerebral HI when infants had MRI patterns typical for cerebral HI,27–30 failed to meet our criteria for intrapartum asphyxia or neonatal HI, and had other etiologies excluded. For infants with the diagnosis of global cerebral HI, the associated encephalopathy was graded as mild, moderate, or severe.31 In the focal cerebral HI group, we included infants with evidence on neuroimaging studies of vascular territory infarction(s).

The intracranial hemorrhage group included infants with extra-axial (epidural, subdural, and subarachnoid) hemorrhage or intraparenchymal hemorrhage. We did not distinguish in this classification between the various causes of hemorrhage (eg, coagulopathic, parturitional, traumatic, or idiopathic).

EEG Studies
All EEG studies were recorded at the bedside using a digital portable EEG machine (Nicolet Voyageur, Nicolet Biomedical Inc, Madison, WI). All studies used the 10/20 international system of electrode placement both bipolar and referential electrode montages, recording through 17 to 21 channels for a minimum duration of 30 minutes. Infants with abnormal EEG recordings on initial studies underwent at least 1 follow-up EEG examination during the neonatal period.

All initial and follow-up EEG recordings were reviewed by 2 child neurologists (H.T. and B.B.) without knowledge of the neonatal and subsequent long-term outcome data. We graded the interictal EEG background into 4 categories of abnormality using previously published criteria22, 32: Normal studies had preserved sleep state modulation and transitions; voltage, synchrony, and symmetry appropriate for age; and age-appropriate patterns (eg, {delta} brushes and frontal sharp transients). Mildly abnormal recordings had preserved sleep state modulation and transitions but excessive sharp wave activity and decrease or absence of normal patterns. Moderately abnormal recordings had low voltage background activity; "dysmaturity" of more than 2 weeks for conceptional age; asymmetric voltage or frequency; excessive asynchrony for postconceptional age; and/or markedly excessive discontinuity for age. Severely abnormal recordings included those with low-voltage undifferentiated patterns; markedly discontinuous and nonreactive tracings; burst-suppression pattern, or electrocerebral inactivity. Single recordings with elements of more than 1 grade of abnormality were assigned the highest grade. Not all patients underwent prolonged recordings; therefore, to avoid bias, we did not consider electrographic seizures in our analysis.

We examined the prognostic use of the EEG background patterns by comparing long-term outcome with the worst neonatal EEG background, with the EEG background during the first 3 days (early EEG), and with the EEG background between 5 and 9 days after the onset of seizures (later EEG).

Neuroimaging Studies
All MRI was performed on either a GE 1.5-Tesla 5X or LX (GE Medical Systems, Milwaukee, WI) magnetic resonance scanner using a standard quadrature head coil. Anatomic magnetic resonance was performed using sagittal and/or axial conventional spin echo T1-weighted imaging (TR/TE = 300/14; 4-mm slice thickness/1-mm gap) and axial fast spin echo T2-weighted imaging (TR/TE/etl = 3000/126/16; 4-mm slice thickness/1-mm gap) in all neonates. Axial line scan diffusion imaging (LSDI) (TR/TE/b factor = 1258/63/750; nominal 7-mm slice thickness/0-mm gap) was also obtained. Isotropic diffusion-weighted images and apparent diffusion coefficient (ADC) maps were generated for each examination.

MRI studies were obtained using a departmental protocol of conventional T1/T2 techniques, proton density, and diffusion-weighted imaging. At our center, neonatal CT scan is used only when the critical clinical condition of the infant demands more rapid scanning or when MRI is not available. If the seizure etiology was identified by standard CT scan, infants did not always undergo MRI studies. All neuroimaging studies were interpreted by a single pediatric neuroradiologist (R.R.) without knowledge of the neonatal and subsequent long-term outcome data. We categorized CT and/or MRI examinations as normal or abnormal, and if abnormal, into extra- and/or intraparenchymal lesions. The MRI findings were also classified according to the predominant pattern of abnormality, as follows: normal, extra-axial hemorrhage only, focal cortical abnormality, multifocal or diffuse cortical abnormality, and primarily deep gray matter abnormality with or without white matter abnormality.

Outcome Measures
At our center, all infants with a history of neonatal seizures are followed for at least the first year of life in the Neonatal Neurology Program where they are evaluated by a multidisciplinary team of experienced child neurologists, developmental psychologists, and physical therapists. In this study, we evaluated outcome by neurologic examination, developmental progress, and the presence of seizures after NICU discharge. All infants with neonatal seizures were evaluated on at least 3 occasions (ie, around 2 months, between 6 and 9 months, and between 12 and 18 months of age) in the Neonatal Neurology Program at Children's Hospital. At each visit, infants underwent a full neurologic examination by 1 of 2 child neurologists (A.d.P., J.S.) as well as a developmental assessment.

Neurologic Examination
During each of the neurologic examinations, we measured the head circumference, cranial nerve function, motor function, auditory function, and visual function.33 Motor function was assessed by testing muscle strength, tone, posture, coordination, and reflexes (deep tendon, primitive, and postural). Motor skills were compared with those expected for age. In cases of suspected visual dysfunction, formal ophthalmology consultation was obtained. Visual impairment was diagnosed only if confirmed by ophthalmologic consultation. Neurologic function was categorized as follows: normal, if no abnormalities were identified; mild deficit, if abnormalities were present on examination but had little or no functional significance; moderate deficit, if abnormalities caused functional impairment; or severe deficit, if full-time special assistance was required.

Developmental Testing
After the first year of life, all infants underwent formal testing by an experienced developmental psychologist using the Bayley Scales of Infant Development II (BSID-II). Specifically, we used the Mental Developmental Index (MDI) of the BSID-II to measure cognitive development. We categorized MDI scores below 85 on BSID-II as indicative of delayed cognitive development.34

Postneonatal seizures were diagnosed if >1 afebrile and unprovoked seizures occurred after the neonatal period.

Statistical Analysis
The primary outcome variable for this study was overall outcome defined as "poor" if an infant had at least 1 of the following: moderate to severe motor deficit and/or visual impairment at the 12- to 18-month visit, significantly delayed mental performance (BSID MDI score <70), or postneonatal seizures. All other infants were considered to have a "favorable" outcome.

Patient characteristics, including EEG background activity, CT, and MRI, were compared for infants experiencing poor versus favorable outcome by using Fisher's exact test.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Population
Over the 38-month study period, 116 infants developed neonatal seizures. Of these, we excluded 16 preterm infants from the study based on our entry criteria. Seven of the remaining 100 term infants died during the acute neonatal illness. Four infants left the Boston area and were lost to follow-up, precluding reliable long-term evaluation. The study therefore focused on the 89 surviving term infants (41 girls and 48 boys), ranging in gestational age from 37 to 42 weeks (median: 40 weeks), with a history of clinical seizures in the newborn period, followed in our Neonatal Neurology Program for at least 12 months. Birth weight in these infants ranged from 2050 to 4536 g (median: 3400 g). Although all infants were ≥37 weeks in gestation at birth, 5 infants met criteria for intrauterine growth retardation. Sixty-three infants (71%) were in-born at the Brigham and Women's Hospital; of the remaining 26 infants, who were referred from surrounding centers to Children's Hospital, 7 underwent extracorporeal membrane oxygenation (ECMO) for meconium aspiration and/or persistent pulmonary hypertension.

The onset of seizures was the first day of life in 57 infants (64%), the second or third day in 18 (20%), and after 3 days in 14 (16%). Distribution of the predominant clinical seizure type was as follows: clonic (54 [61%]), tonic (17 [19%]), subtle (12 [13%]), and myoclonic (6 [7%]). Eighty-five neonates (96%) were treated with anticonvulsant medications; all 85 infants received phenobarbital, whereas 20 infants (22%) with refractory seizures received additional phenytoin or lorazepam. Anticonvulsant medication was started before the onset of EEG recording in 67 infants and after the initial EEG in 18 cases. In our NICUs, the standard protocol is to follow a loading dose of phenobarbital with maintenance doses of 3 to 5 mg/kg per day; both the onset and dosing of maintenance phenobarbital therapy are based on measured blood levels. In addition, infants are discharged on maintenance phenobarbital with decisions for ongoing therapy based on the clinical findings at 6- to 12-week neurology follow-up.

Etiologic Classification
The distribution of etiologies for the neonatal seizures in our 89 term infants is presented in Table 1. The most common etiologies for neonatal seizures were global cerebral HI, cerebral vaso-occlusive lesions, and intracranial hemorrhage. Of note, none of our infants had toxin exposure; drug withdrawal; or familial, genetic, or syndromic causes for their seizures.


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  		TABLE 1. Etiologic Distribution of Clinical Neonatal Seizures (n = 89)

 
Among the 23 infants with intrapartum asphyxia, 10 had moderate and 13 had severe encephalopathy. By definition, no infant had mild encephalopathy because seizures placed infants in at least the moderate level of encephalopathy. The median 5-minute Apgar score was 5 (range: 0–6). Seventeen neonates had an umbilical cord blood pH ≤ 7.00. Neonatal cerebral HI occurred in 3 infants after circulatory insufficiency secondary to severe congenital heart disease, severe respiratory failure, or cardiac arrest.

Infants with vaso-occlusive lesions or unexplained hemorrhage were evaluated for coagulopathy. The only case of suspected thrombophilia (ie, protein C deficiency) occurred in an infant with arterial stroke. Diagnoses of extraparenchymal hemorrhage included subdural (4), subarachnoid (3), and combined (4). Among infants with no identified etiology, 6 infants had seizures around the third day, whereas in the remaining 5 infants, seizures occurred after the fifth day of life. None of these infants had a known family history of neonatal seizures, and chromosomal studies for benign familial neonatal seizures were not performed.

Overall Neurologic Outcome
By definition, the overall outcome was considered poor at the ≥12-month follow-up evaluation if significant abnormalities were present on neurologic examination or cognitive testing, or if seizures recurred after NICU discharge. Table 2 summarizes the neurologic outcome of our overall group. Among the infants with a favorable outcome, 41 (64%) infants were considered normal in all areas evaluated, whereas 23 (36%) had neurologic abnormalities on examination without apparent functional impact. Among the infants with overall poor neurologic outcome, 20 had severe and 5 had moderate neurologic impairment. Details of the neurologic findings are shown in Table 2.


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  		TABLE 2. Summary of Neurologic Outcome at 1 Year of Age (n = 89)

 
Factors Associated With Outcome
Etiologic Classification and Outcome
Table 3 summarizes the neurologic impairment by seizure etiology. The statistical relationship between neonatal seizure etiology and poor outcome was highly significant (P < .001).


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  		TABLE 3. Outcome by Etiology of Neonatal Seizures

 
Seizure Classification and Outcome
The relationship between the type of neonatal seizure and overall outcome did not achieve statistical significance (P = .12). Poor outcome occurred in 8 of 17 infants (47%) with predominantly tonic seizures, 15 of 54 infants (28%) with clonic seizures, and 2 of 12 infants (17%) with predominantly subtle seizures. None of the 6 infants with predominantly myoclonic seizures had poor outcome.

Neurologic Examination and Outcome
Next we assessed the ability of the neurologic examination performed at different ages (ie, neonatal, 2 months, and 6–9 months) to predict long-term outcome at 12 to 18 months. We found the neurologic examination to have 100% sensitivity and negative predictive value at each of these time points. Specifically, any infant with a normal neurologic examination performed by a child neurologist at these times had a favorable long-term outcome. However, the converse was not true, ie, the specificity and positive predictive values of the neurologic examination in the newborn period (39% and 39%), at 2 months age (61% and 51%), and at 6 to 9 months (62% and 52%) were all low.

Neonatal EEG Studies and Outcome
The relationship between the most abnormal neonatal EEG studies and neurologic outcome is summarized in Tables 4 and 5. All infants with clinical neonatal seizures underwent EEG recordings between 1 and 14 days of age (median: 2 days). Of the 89 infants, 55 (62%) had at least 1 follow-up EEG during the neonatal period. Seventy-three patients (82%) had at least 1 abnormal EEG recording. Twenty-nine infants (33%) had electrographic seizures on at least 1 EEG.


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  		TABLE 4. Relationship Among Neonatal EEG, Neuroimaging (CT, MRI), and Overall Outcome at 1 Year of Age

 

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  		TABLE 5. Outcome After Global Cerebral HI (n = 36): Predictive Value of EEG Background (Most Abnormal EEG and After 1 Week) and MRI Findings

 
The EEG background activity on the most abnormal neonatal study was a powerful predictor of overall outcome (P < .001). Normal or mildly abnormal EEG background was associated with a favorable outcome in 42 of 47 infants (89%), whereas 36% of infants with a moderately abnormal background and 82% with severely abnormal EEG background had a poor outcome. Interestingly, 18% of infants with severely abnormal EEG background had favorable outcomes. Conversely, in 3 of 4 infants with normal EEG background patterns but poor outcome, MRI studies showed injury confined to the deep gray matter. When comparing normal/mildly abnormal versus moderate/severe EEG background abnormality, we found that EEG predicted outcome with a sensitivity of 80% and specificity of 66%.

Next we performed stratified analyses by etiologic classification to determine the added prognostic value of EEG background for each etiologic subgroup. The relationship between EEG background activity on the most abnormal neonatal study and outcome was examined for each etiologic class separately and was statistically significant for global HI only (83% poor outcome if moderate/severe background vs 17% if normal/mild; P = .02). Within the focal HI, intracranial hemorrhage, and unknown categories, the prognosis was good regardless of EEG background; other categories contained few infants.

Within the global HI group, we also compared the prognostic use of background EEG activity on early (days 1–3) EEG studies (n = 33); later (5–9 days) studies (n = 27); and the study with the most abnormal neonatal EEG background (n = 36). We found the most abnormal EEG recording to be predictive of the overall outcome in these infants (P = .02); we found no difference in prognostic value between the early and later EEG studies.

Neonatal Neuroimaging and Outcome
The relationship between the neonatal neuroimaging studies and neurologic outcome is summarized in Tables 4 and 5. All 89 infants underwent brain imaging studies (CT and/or MRI) in the acute period (median age: 5 days). Seventy-three (82%) had at least 1 MRI, whereas 16 (18%) required only CT scans. Imaging studies were normal in 19 infants (21%), 2 of whom had only CT scans. Eleven infants (12%) had extraparenchymal lesions only, whereas 59 infants (66%) had parenchymal lesions.

Not unexpectedly, infants with abnormal neuroradiologic studies (CT/MRI) were more likely to have a poor outcome than those with normal studies (36% vs 1%; P = .001). Only 1 infant with normal brain imaging had a poor outcome. Furthermore, infants with parenchymal brain injury were more likely to have poor outcome than those with normal studies or those with extraparenchymal injury (41% vs 0% and 9%; P < .001). The predictive value of MRI abnormalities was evaluated in the 73 infants with such studies. Multifocal/diffuse cortical lesions or primarily deep gray matter involvement on MRI were strongly associated with poor outcome. Outcome was favorable in infants with MRI studies that either were normal or showed extraparenchymal or focal cortical lesions.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Important diagnostic and therapeutic advances have entered the practice of neonatal intensive care in recent years. The principal aim of this study was to assess the impact of these advances on the etiology and outcome of neonatal seizures. We found certain striking differences between our population and those from previous studies, whereas in other respects, there was little if any change. The mortality associated with neonatal seizures in our infants was substantially lower than in earlier studies; in fact, the 7% mortality in our study is less than half that reported 2 decades ago.1, 3, 18 The improved survival of infants with neonatal seizures in our study likely reflects advances in neonatal critical care over time, including the advent of life-support techniques such as ECMO, a rescue technique used in 7 (7.8%) of our infants. Conversely, the 28% prevalence of adverse long-term outcome and the 20% rate of later seizure recurrence35 in our survivors are essentially unchanged from earlier studies.1, 3, 18

The large majority of seizures in our population was symptomatic of an identifiable cause from a broad spectrum of etiologies. In fact, the number of infants without identified etiologies was significantly lower than in previous studies.8, 24 In addition, there were clear differences in the relative distribution of seizures in the various etiologic categories.7, 10, 24

Cerebral HI has been the leading cause for neonatal seizures in most previous studies, although the incidence has varied, likely as a result of the inconsistent diagnostic criteria used. Although global cerebral HI remains the most common etiology for seizures in our study, there are distinct differences from previous reports.1, 8, 9, 36, 37 First, intrapartum asphyxia was less frequently implicated in our study,1, 3, 14, 18, 38, 39 possibly because of improved obstetric management and the relatively more stringent diagnostic criteria for intrapartum asphyxia in our study.31 Second, we diagnosed antepartum HI in a number of our infants, a diagnosis facilitated by the superior tissue resolution of MRI that allowed detection of topographic patterns of injury14, 27, 28, 40–46 typical for global cerebral HI insults in animals47, 48 and at autopsy.49 Infants were diagnosed with antepartum HI if they had these characteristic MRI patterns but failed to meet our criteria for intrapartum asphyxia, and no other cause was identified. In these infants, it is assumed that a transient global cerebral HI insult in the late antepartum period had resolved with sufficient time for recovery of, for example, metabolic acidosis before delivery.

The increased sensitivity of recent neuroimaging techniques has had other important repercussions.50, 51 In addition to reducing the frequency of seizures with unknown etiology, techniques such as diffusion-weighted MRI have enhanced the diagnosis of focal cerebral HI, particularly during the early stages of infarction when techniques such as CT scan, and even conventional MRI, may fail to identify the lesion. As experience accrues with other in vivo techniques such as proton magnetic resonance spectroscopy (1H-MRS), the accuracy of diagnosis for cerebral HI and certain metabolic diseases is likely to be enhanced further.12, 52–54

In our study, acute transient metabolic disturbances and central nervous system infections were less commonly implicated as the cause of neonatal seizures than in earlier studies.8, 55–57 In fact, seizures caused by transient metabolic disturbances (eg, hypoglycemia and electrolyte disturbances) show a 10-fold decrease compared with other reports over the past 30 years.55–57 It is likely that improved neonatal intensive care is at least partly responsible for this trend, just as improved maternal and neonatal antimicrobial strategies are likely a reason for the marked decrease in seizures resulting from central nervous system infections.

As in earlier reports, the strongest early predictors of long-term outcome in our study were the underlying seizure etiology and EEG background patterns.1, 10, 24, 58 Etiologies associated with poor outcome included cerebral dysgenesis, global cerebral HI, and central nervous system infection. Conversely, infants with focal cerebral HI, transient metabolic disturbances, or idiopathic seizures had an almost universally favorable outcome. The more favorable outcome in our infants with posthemorrhagic seizures may reflect the exclusion of premature infants from our study. We found no significant relationship between the predominant clinical seizure type and outcome. This finding differs from other reports in which generalized tonic19, 59 and subtle seizures9 have been associated with a worse outcome. The reasons for this are not certain, but one important difference between our study and these others is the fact that our study was confined to term infants, whereas these others included both preterm and term infants. Not only are generalized tonic seizures more common in the preterm infant, but they are also associated with major structural lesions such as severe intraventricular hemorrhage and hence with a worse outcome.

The prognostic value of the neurologic examination in infants is difficult to evaluate across studies because of inconsistencies in examiner expertise, diagnostic criteria, and timing of the examinations.4, 5, 18, 20, 35, 60–62 In our study, all neonatal examinations were performed daily by the attending neurologist. After ICU discharge, a consistent team of neurologists, physical therapists, and developmental psychologists in our Neonatal Neurology Program performed comprehensive evaluations at regular intervals. With this approach, we found that a normal neurologic examination during the neonatal period and early infancy predicted a uniformly favorable outcome between 12 and 18 months; conversely, an abnormal examination at these times was an unreliable predictor. Background EEG abnormalities of moderate to severe grades were strong predictors of poor outcome, as in earlier reports.20, 22, 32 However, in our study, these background EEG patterns provided significant added value to prognostic power over etiology only in the global HI group, in which the most abnormal EEG background regardless of its postnatal timing was the best predictor. In fact, unlike previous reports, we found no use in considering rate of EEG recovery in infants with seizures after global HI; specifically, there was no difference in prognostic value between the early and late studies. All but 1 infant with normal neonatal brain imaging and all infants with focal cortical infarcts had a favorable long-term outcome, whereas infants with deep gray matter lesions or multifocal/diffuse cortical lesions invariably had a poor outcome.

Our findings raise several important questions. First, although our data suggest that recent advances in neonatal care are associated with a promising decrease in the mortality of infants with neonatal seizures, the long-term neurologic morbidity in survivors remains substantial and unchanged from earlier studies. Potentially, this trend is the result of sicker infants with previously lethal insults now surviving the acute illness only to manifest adverse neurologic sequelae later. Another possibility is that seizures themselves are causing brain injury despite improved overall life-support measures. Whether seizures cause additional injury to the immature brain over that attributable to the underlying etiology remains controversial.63–71 Some studies have suggested that the immature brain is remarkably resistant to injury by even prolonged seizures.63–68, 72 Conversely, others have shown that when cerebral energy metabolism has previously been compromised by, for example, cerebral HI, ongoing seizures may contribute directly to the ultimate brain injury.73–78 The enormous importance of this latter finding relates to our findings not only that cerebral HI insults are the leading cause of neonatal seizures, but also that 70% of infants with adverse long-term outcome had cerebral HI as the cause of neonatal seizures. This would suggest that particular urgency is warranted in controlling seizures after global HI insults. Unfortunately, it is well known that post-HI seizures in the newborn are particularly refractory to conventional anticonvulsant agents,6 even at high doses.79 Recent data suggest that induced moderate hypothermia80 may provide effective neuroprotection against cerebral HI injury. However, in animal studies, this neuroprotection depends on the initiation of hypothermia before the onset of seizures, which may herald closure of the therapeutic window.81 For all of these reasons, the future reduction of long-term neurologic deficits in this population will require rapid and accurate diagnostic evaluation to identify the asphyxiated fetus and newborn followed by urgent treatment with agents that demonstrate neuroprotective efficacy in clinical trials.


   ACKNOWLEDGMENTS
 
Dr Tekgul is a recipient of grant in scope of the North Atlantic Treaty Organization Science Fellowship Program by the Scientific and Technical Research Council of Turkey. We thank the LifeBridge Fund for support of this work.


   FOOTNOTES
 
Accepted Sep 22, 2005.

Address correspondence to Adré J. du Plessis, MD, Fegan 11, Department of Neurology, Children's Hospital, 300 Longwood Ave, Boston MA 02115. E-mail: adre.duplessis{at}childrens.harvard.edu, hasantekgul{at}hotmail.com

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


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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