ABSTRACT We examined neonatal predictors of epilepsy in term newborns with neonatal encephalopathy (NE) by studying children enrolled in a longitudinal, single center cohort study. Clinical

data were obtained through chart review, and MRI was performed in the neonatal period. We administered a seizure questionnaire to parents of children aged ≥12 mo (range, 12 mo to 16.5 y) to

determine the outcome of epilepsy. The association between clinical predictors and time to onset of epilepsy was assessed using Cox proportional hazards regression. Thirteen of 129 children

developed epilepsy: all had neonatal seizures and brain injury on neonatal MRI. Of the newborns with neonatal seizures, 25% (15.8/1000 person-years) developed epilepsy, with the highest

was independently associated with epilepsy. These data add to information regarding epilepsy pathogenesis and further aid clinicians to counsel parents regarding the likelihood that a

newborn with NE will develop epilepsy. SIMILAR CONTENT BEING VIEWED BY OTHERS ADVERSE SHORT- AND LONG-TERM OUTCOMES AMONG INFANTS WITH MILD NEONATAL ENCEPHALOPATHY Article 23 August 2022

NEONATAL BRAIN MRI AND SHORT-TERM OUTCOMES AFTER ACUTE PROVOKED SEIZURES Article Open access 15 July 2023 NEONATAL ENCEPHALOPATHY AND HYPOXIC-ISCHEMIC ENCEPHALOPATHY: THE STATE OF THE ART

Article Open access 24 March 2025 MAIN The incidence of neonatal encephalopathy (NE) is about 1 to 2.5 per 1000 live term births, mostly as a result of perinatal asphyxia (1–3). NE is a

significant cause of neonatal death and adverse neurodevelopmental outcome such as cerebral palsy, developmental delay, and epilepsy. The reported rate of epilepsy after NE due to

hypoxic-ischemic encephalopathy ranges from 9 to 33% (4–6), and in one study, children with a history of hypoxic-ischemic encephalopathy had five times the risk of developing epilepsy when

compared with those without (7). Although children with NE are known to be at risk for epilepsy, there are few studies examining the neonatal risk factors for developing seizures beyond the

newborn period. Past studies in small cohorts have examined severity of encephalopathy, neonatal seizures, and MRI as risk factors with conflicting results. Pisani _et al_. (4) found that

severe (but not moderate) encephalopathy was associated with later epilepsy, whereas van Kooij _et al_. (6) found a 10% prevalence of epilepsy among a cohort of children who suffered

moderate encephalopathy. Neonatal seizures were a risk factor in one study, although the effect was not significant after adjusting for the degree of encephalopathy (4). MRI injury is also

risk factor for epilepsy (5,6). Small cohort size, inadequate neonatal imaging, or lack of long-term outcome data limit these studies, and counseling for parents of children with NE remains

a challenge. The objective of this study was to evaluate the neonatal clinical and imaging risk factors for childhood epilepsy in a single center cohort of children with a history of NE. All

children were imaged using high-resolution MRI according to a standardized research protocol in the newborn period and evaluated longitudinally through childhood. MATERIALS AND METHODS This

is a longitudinal cohort study of neonates who were admitted to the Intensive Care Nursery at the University of California San Francisco. Newborns met inclusion criteria of GA ≥36 wk at

birth and any one of the following: umbilical cord arterial blood pH <7.1, umbilical cord arterial blood base excess >−10, or 5-min Apgar score ≤5. These broad inclusion criteria were

chosen to encompass newborns with a wide range of injury and neurodevelopmental outcome and have been used in previous publications by our group (8–14). Newborns were excluded if there was

evidence of intrauterine or perinatal infection, major anomalies of the brain or other major organ system, or evidence of congenital metabolic disease. From December 1993 to June 2009, 234

infants ≥36 wk GA at birth were enrolled and imaged according to protocol. Thirty-one children were excluded for the following reasons: deceased during the birth admission (17 children) or

withdrew from the study (14 children), leaving 203 subjects. CLINICAL DATA. Trained neonatal research nurses extracted birth delivery data including GA at birth, birth weight, and Apgar

scores from medical records. Clinical seizures (spells identified by the attending physician as seizures and treated using anticonvulsant medication), electrographic seizures (events

identified by the attending neurophysiologist as seizures), and status epilepticus (recurrent electrographic seizures considered by the neurophysiologist as “status epilepticus,”

“continuous,” or “near continuous” seizures) were determined from chart review. Before 2008, video-EEG monitoring was performed at the discretion of the attending neurologist and

neonatologist and performed as standard of care in all children with clinical seizures (minimum duration 30 min). Since 2008, video-EEG has been performed for all newborns treated with

therapeutic hypothermia from the time of admission until 6–12 h after rewarming and at least 24 h after the last recorded EEG seizure. A pediatric neurologist measured the degree of

encephalopathy in the first 3 d of life on a scale of 0–6, which considers feeding, alertness, tone, respiratory status, reflexes, and seizures (12). MRI. All neonates were imaged with MRI

using a specialized neonatal head coil on a 1.5-Tesla Signa EchoSpeed system (GE Medical Systems) and using imaging sequences optimized for the neonatal brain (14,15). In cases where more

than one MRI was performed during the hospital stay, the MRI closest to day of life 3 to 5 was used for analysis. A pediatric neuroradiologist blinded to the neonatal course prospectively

scored the imaging as previously described (8). Injury was scored using a system that is strongly predictive of neurodevelopmental outcome after NE (8). The pattern of injury was described

as “basal ganglia/thalamus predominant,” “watershed predominant,” or “normal” (11). We defined “mild-moderate injury” as a basal ganglia/thalamus score of 1 or 2 (abnormal signal in the

thalamus and/or lentiform nucleus) or watershed score of 1–4 (abnormal signal in the anterior and/or posterior watershed zones), and “severe injury or near-total injury” as a basal

ganglia/thalamus score ≥3 or a watershed score of 5 (more extensive involvement in either territory). EPILEPSY INTERVIEW. The parents of enrolled subjects were contacted by telephone in June

2010, and administered a structured seizure questionnaire that was developed for the purpose of this study. For the children with postneonatal seizures, parents were asked to provide

information regarding age of seizure onset, frequency, and medication use. Epilepsy was defined as recurrent, unprovoked seizures, or a single seizure in the setting of abnormal EEG and

initiation of medication. For the children who died after hospital discharge, the medical records were reviewed to complete the standardized seizure questionnaire. Epilepsy was graded

according to modified Engel classification (class 0 = seizure free and off seizure medications for at least 6 mo; class 1 = seizure free for at least 6 mo while on medication or seizure-free

off medication for fewer than 6 mo; class 2 = fewer than one seizure per month on medication; class 3 = one to four seizures a month on medication; class 4 = five to thirty seizures per

month on medication; class 5 = thirty or more seizures a month) (16). NEURODEVELOPMENTAL FOLLOW-UP. A pediatric neurologist and a developmental psychologist who were blinded to the neonatal

course examined the children at ages 3–6 mo, 1 y, 2.5 y, 4 y, and 8 y. Neuromotor function was evaluated using the neuromotor score, a 5-point scale where 0 is normal and 5 is spastic

quadriparesis (8). The neuromotor score was classified as follows: 0 or 1 normal, 2 borderline, ≥3 abnormal. An age-appropriate neuropsychological test was administered to the child at each

follow-up appointment. The Bayley Scales of Infant Development were used to test children at 1 y and 2.5 y (Bayley-II before 2008) (17,18). At the age of 4, the Wechsler Preschool and

Primary Scale of Intelligence-Revised (WPPSI-R) was used (19,20). The Wechsler Intelligence Scale for Children IV (WISC-IV) (21) was administered for the 8-y follow-up. Scores from

standardized tests (all with a mean of 100 and a SD of 15) were used to classify cognitive outcomes as follows: ≥85 on all subscales was considered normal, 70–84 on one or more subscales was

considered borderline, and <70 (_i.e_. 2 SDs below the mean) on one or more subscales was considered abnormal. Comorbidities and most recent neurological and neurodevelopmental

examinations were extracted from medical records and the structured seizure questionnaire. ANALYSIS. Data analyses were conducted using statistical software Stata 10 (StataCorp LP, College

Station, TX). The association of clinical predictors with time to onset of epilepsy was assessed using Cox proportional hazards regression and graphically displayed using Kaplan-Meier

curves. Data were censored at the time of onset of epilepsy or at the time of the telephone interview in children without epilepsy. Differences between children with and without follow-up

were assessed using two-tailed _t_ test for continuous variables, Wilcoxon rank sum for nonparametric data, and χ2 or Fisher's exact test for categorical variables. Multivariable model

included those predictors with _p_ ≤ 0.1 in the univariable analysis. The _p_ values <0.05 were considered significant. The Committee on Human Research at the University of California,

San Francisco, approved the protocol. Infants were studied only after informed voluntary parental consent. RESULTS Of the 203 subjects included in the study, we successfully contacted 127

families by telephone and were able to complete adequately adjudicate outcome based on medical records for 2 deceased children, for an overall follow-up rate of 64%. The study subjects are

presented in Table 1. The children whose parents were not available to complete the survey were similar to those whose parents did complete the survey with no differences in sex, GA at

birth, birth weight, cord gas pH or base excess, NE score, and MRI injury scores. However, those whose parents responded were significantly more likely to have had neonatal seizures (40%

_versus_ 25%, _p_ = 0.04) and have been enrolled in the study more recently (median year of enrollment 2004 _versus_ 1997, _p_ < 0.00005). The median age of surviving study participants

at the time of the follow-up survey was 73 mo (6 y; range, 12 mo to 16.5 y). EPILEPSY FEATURES AND OUTCOME. Of the 129 evaluated subjects, 13 (10%) developed epilepsy, 7 had febrile

seizures, and 1 child had a single spell at age of 2 mo that was not clearly a seizure. The age of epilepsy onset ranged from 0 to 5 y; 7 (54%) had onset within the first year of life.

Eleven children had abnormal neurodevelopmental outcome, one had borderline outcome and one was not assessed. The clinical characteristics of the 13 study subjects with epilepsy are

presented in Table 2. PERINATAL RISK FACTORS FOR EPILEPSY. Degree of encephalopathy was the only clinical feature associated with epilepsy (Table 3). NEONATAL SEIZURES AND RISK OF EPILEPSY.

All 13 children with epilepsy had a history of clinical and/or electrographic neonatal seizures. The frequency of epilepsy among the 52 children with a history of neonatal seizures was 25%

(or 15.7 per 1000 person years). Among children with neonatal seizures, those with status epilepticus were most likely to develop epilepsy (5/6, 83% or 1237.1/1000 person-years). The single

child who had not developed epilepsy was 21 mo at the time of the evaluation and had been treated with therapeutic hypothermia. Those children without status, but whose neonatal seizures EEG

confirmed, were more likely to develop epilepsy when compared with those who had only clinical seizures [5/19, 26% or 93.5/1000 person-years _versus_ 3/28, 11% or 14.5/1000 person-years;

hazard ratio (HR), 4.0; 95% CI, 0.9–17.3]. The epilepsy-free survival data in those children with and without a history of neonatal seizures are presented in Figure 1. BRAIN INJURY AND

EPILEPSY. All children with epilepsy had injury on neonatal MRI, and the severity of injury was associated with epilepsy. The children with severe or near-total brain injury were more likely

to develop epilepsy (8/22, 36% or 54.7/1000 person-years) _versus_ 5/65 (8% or 11.5/1000 person-years) for those with mild or moderate injury. Of the 16 children with severe or near-total

brain injury and neonatal seizures, half developed epilepsy. Pattern of injury was also important: of the 30 children with basal ganglia/thalamus predominant pattern of injury, six (20% or

32.3/1000 person-years) developed epilepsy, whereas only seven (12%, 17.7/1000 person years) with watershed predominant pattern of injury developed epilepsy (_p_ = 0.005). When compared with

those children with mild/moderate brain injury, those with severe or near-total injury had a higher rate of epilepsy (HR, 5.5; 95% CI, 1.8–16.8; _p_ = 0.003). Epilepsy-free survival by

severity of brain injury is presented in Figure 2. ADJUSTED ANALYSIS. In a multivariable analysis among those with moderate or severe encephalopathy, neonatal seizures and MRI injury,

adjusting for NE, status epilepticus remained a highly significant risk factor for epilepsy (HR, 17.3; 95% CI, 2.7–110.0; _p_ = 0.003), whereas severe/near-total injury (HR, 2.4; 95% CI,

0.7–8.4; _p_ = 0.2) was not (Table 4). DISCUSSION In this longitudinal sample of 129 newborns with NE, neonatal seizures and brain injury on MRI were strong risk factors for epilepsy, and

the children with epilepsy all had adverse neurodevelopmental outcome. These results support previous studies suggesting that epilepsy occurs in children with a more severe spectrum of NE.

The 25% frequency of epilepsy after neonatal seizures is similar to previous contemporary cohorts that used broad clinical and/or electrographic definitions for neonatal seizures and lower

than studies that required EEG confirmation of seizures (22–25). Although duration of follow-up is variable across studies, highest risk within the first year of life is a common feature, as

is the high rate of associated neurodevelopmental disabilities (23,25–28). Animal studies have begun to elucidate mechanisms by which neonatal seizures can induce persistent enhanced

neocortical excitability (29). Our data also support evidence that severity of seizures is important, which is in keeping with studies by Clancy and Legido (22), who showed in a mixed cohort

that a higher burden of neonatal seizures was a risk factor for epilepsy, and Pisani _et al_., (30) who showed a higher rate of epilepsy after status epilepticus when compared with

recurrent seizures. Severity and pattern of MRI injury are known risk factors for neonatal seizures (6,11), and we also show a clear relationship with epilepsy. Children with severe basal

ganglia/thalamus pattern of injury and cortical involvement were at highest risk of developing epilepsy. There is controversy from animal studies regarding whether neuronal injury is

required for acquired epileptogenesis in the immature brain, or whether seizures alone without neuronal injury can cause changes in excitability sufficient to result in unprovoked seizures

beyond the neonatal period (31). Our finding, that epilepsy occurred only in those children with apparent brain injury on MRI, supports, but does not prove, the hypothesis that neuronal

injury is, in fact, required to develop epilepsy. Although our findings do not support a reduced risk of epilepsy in the cooled subjects, the data we present do not exclude this possibility.

Since fall 2007, we have treated most newborns at risk for hypoxic-ischemic injury and moderate-severe encephalopathy with therapeutic hypothermia using whole body cooling. Therapeutic

hypothermia, which has been shown to reduce death and disability at 18–22 mo in several randomized, controlled trials (32–35) also has an antiseizure effect in animal models (36,37),

although its effect on seizures in human newborns is not clear. Among newborns treated with therapeutic hypothermia at our center, electrographic seizures are present in >30%. If neonatal

seizures are suppressed in human newborns treated with hypothermia and neonatal seizures enhance long-term epileptogenesis, the risk of epilepsy in the cooled population may ultimately be

reduced. The question of whether hypothermia reduces neonatal seizure burden and/or epileptogenesis should be further explored in larger data sets. Although this is a large cohort with

high-quality neonatal imaging and long-term follow-up, the data are limited in several ways. First, the survey response rate was only 64%. This limitation may have led to an overestimate of

the prevalence of epilepsy, because the rate of neonatal seizures was higher in those children whose parents responded to the interview. However, response rate should not affect the

relationships between perinatal risk factors, including seizures and MRI findings, and epilepsy. Second, it is possible that there was bias toward diagnosis of epilepsy in some cases of

children with ambiguous spells and severe developmental impairment. This may have falsely increased the relationship between MRI injury and neonatal seizures and epilepsy. Third, since the

study's inception in 1993, we have changed the guidelines for monitoring and treating newborns with encephalopathy. Before 2008, video-EEG was used at the discretion of the attending

neurologist, usually for 30–60 min routine recordings. Since 2008, we have monitored all children with NE using continuous video-EEG for the duration of hypothermia and rewarming. To

understand the true relationship between clinical _versus_ electrographic seizures and epilepsy, we will need to examine a larger cohort of subjects with long-term conventional video-EEG

monitoring. CONCLUSIONS Epilepsy is an outcome following brain injury and neonatal seizures in the setting of severe hypoxic-ischemic brain injury. These data add to our understanding of the

pathogenesis of epilepsy after seizures in the newborn period and provide information for clinicians and parents planning long-term care for children with NE. For term infants with NE, but

without both neonatal seizures and brain injury on MRI, parents can be reassured that the child is unlikely to develop epilepsy. Children with electrographic seizures (especially status

epilepticus) and severe brain injury have a high risk of adverse neurodevelopmental outcome, including epilepsy. This high-risk population will be important for future studies examining

neuroprotective and antiepileptic agents. Neonatal seizures and status epilepticus are potentially modifiable risk factors, and there is urgent need for studies to examine whether early

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seizure attack, and learning memory deficits in the kainic acid treated rats. _CNS Neurosci Ther [Epub ahead of print]_ Download references ACKNOWLEDGEMENTS We thank Dr. Charles E.

McCullough, the study nurses from the NCRC, project coordinators Veronica de Santiago, and Laurel Haeusslein, as well as the participants of the KL2 Works in Progress program. Amy Markowitz

provided editorial support. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Neurology, University of California at San Francisco, San Francisco, 94143, California Hannah C Glass,

 Joseph E Sullivan & Donna M Ferriero * Department of Pediatrics, University of California at San Francisco, San Francisco, 94143, California Elizabeth E Rogers & Sonia L Bonifacio *

Department of Radiology, University of California at San Francisco, San Francisco, 94143, California A James Barkovich * Department of Clinical & Translational Science

Institute-Pediatric Clinical Research Center, University of California at San Francisco, San Francisco, 94143, California Rita J Jeremy * University of Washington School of Medicine,

Seattle, 98195, Washington Karen J Hong Authors * Hannah C Glass View author publications You can also search for this author inPubMed Google Scholar * Karen J Hong View author publications

You can also search for this author inPubMed Google Scholar * Elizabeth E Rogers View author publications You can also search for this author inPubMed Google Scholar * Rita J Jeremy View

author publications You can also search for this author inPubMed Google Scholar * Sonia L Bonifacio View author publications You can also search for this author inPubMed Google Scholar *

Joseph E Sullivan View author publications You can also search for this author inPubMed Google Scholar * A James Barkovich View author publications You can also search for this author

inPubMed Google Scholar * Donna M Ferriero View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Hannah C Glass.

ADDITIONAL INFORMATION Supported by the NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131 and NIH/NINDS grant numbers 5P50NS035902 and NS40117. NIH/NINDS K23NS066137 and the Neonatal Brain

Research Institute at UCSF support HCG. The authors report no conflicts of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Glass, H., Hong, K.,

Rogers, E. _et al._ Risk Factors for Epilepsy in Children With Neonatal Encephalopathy. _Pediatr Res_ 70, 535–540 (2011). https://doi.org/10.1203/PDR.0b013e31822f24c7 Download citation *

Received: 18 February 2011 * Accepted: 26 May 2011 * Issue Date: November 2011 * DOI: https://doi.org/10.1203/PDR.0b013e31822f24c7 SHARE THIS ARTICLE Anyone you share the following link with

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