Incidence and Predictors of Later Epilepsy in Neonates with Encephalopathy: The Impact of Electrographic Seizures

Abstract

Objectives

To determine the incidence of later epilepsy in full‐term infants with neonatal encephalopathy (NE) who undergo continuous electroencephalography (cEEG) monitoring in the neonatal period and to identify potential predictors of later epilepsy both in infants with and without electrographic neonatal seizures (ENS).

Methods

This was a retrospective observational study performed at Cork University Maternity Hospital, Cork, Ireland, between 2003 and 2019. All term infants with NE had a minimum of 2 h of cEEG monitoring in the neonatal period. ENS were identified via cEEG monitoring. Pediatric medical charts were reviewed to determine if epilepsy developed after the neonatal period and to determine potential predictors of epilepsy in infants both with and without ENS.

Results

Two hundred and eighty infants were included. The overall incidence rate of epilepsy was 17.55 per 1000 person‐years (95% CI: 10.91 to 28.23). In infants with ENS (n = 82), the incidence rate was 39.27 per 1000 person‐years (95% CI: 22.30 to 69.16). In infants without ENS (n = 198), the incidence rate was 7.54 per 1000 person‐years (95% CI: 3.14 to 18.12). The incidence rate was significantly higher in the ENS group compared to the non‐ENS group (p‐value = 0.002). Several potential predictors for the development of later epilepsy were identified including infants delivered vaginally, low Apgar scores at 1 and 5 min, severe HIE diagnosis, presence of ENS, a severely abnormal EEG background and an abnormal brain MRI.

Significance

Following NE, term infants are at risk of epilepsy with a significantly higher incidence rate in infants who experience ENS compared to those who did not. Close follow‐up is required in both groups well into the childhood period.

Plain Language Summary

This study aimed to determine the occurrence of epilepsy in children who were monitored for seizures in the newborn period. The occurrence of epilepsy was higher in infants who experienced seizures in the newborn period compared to those who did not. Several potential predictors of later epilepsy were identified in both groups of infants (those with and without seizures in the newborn period). Both groups of infants require close follow‐up in childhood.

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Key Points

• Epilepsy is one of the most common neurological disorders in childhood.
• Infants with NE who experience ENS have a higher rate of later epilepsy in comparison to those who do not.
• All infants with NE require close follow-up and surveillance for later epilepsy.

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INTRODUCTION

Epilepsy is one of the most common neurological disorders of childhood.¹ It is a chronic disorder with a considerable burden of disease for both the child and their family; and is ranked globally as one of the top causes of years lived with a disability.^2,3 Childhood epilepsy often does not occur in isolation and can be associated with a constellation of co-morbidities including sensory impairment, sleep disturbance and neurodevelopmental issues.⁴ Epilepsy not only exerts a significant symptom burden on the individual child but it can have a huge effect on the family unit. It can lead to several hospital outpatient clinics annually, hospital admissions, inter-hospital transfers and restrictions in daily living. It may be attributed to a myriad of risk factors, or underlying conditions including a genetic predisposition, perinatal factors and structural brain abnormalities.⁵ Neonatal encephalopathy (NE) is an important contributing risk factor to later epilepsy. It is an umbrella term encompassing the syndrome of altered level of consciousness, inability to maintain normal respiration and abnormal tone and reflexes.^6,7 Published incidence rates of NE vary from 1 to 6 per 1000 live births.^8,9 Neonatal seizures (NS) are a common manifestation of NE and are the most frequent neurological emergency in the neonatal period. The incidence of epilepsy following NE is poorly cited as it is dependent on the presence or absence of NS which require electrographic confirmation; something that is not always possible, especially in earlier studies. No consensus yet exists as to whether NS are a manifestation of the underlying brain injury or whether they act to exacerbate brain injury further. There is, however, mounting experimental evidence that ongoing seizures can indeed, negatively impact the developing brain, by augmenting brain injury, mitigating normal brain growth and development, along with increasing the risk of later epilepsy.^10,11 Recent studies have shown an association with high total seizure burden (TSB) in infants and lower developmental scores.^12–14 Despite NS being the most common neurological emergency in the newborn period, they can be notoriously challenging to accurately detect due to the misclassification of normal neonatal physiological phenomena,¹⁵ electroclinical uncoupling¹⁶ and the high frequency of electrographic-only seizures in the neonatal period.^17,18 In older studies, the diagnosis of NS largely relied on clinical recognition with little reliance on EEG correlates. Clinical seizures themselves are often very subtle, reflective of an immature brain, characterized by incomplete myelination, axonal, dendritic and synaptic development.¹⁹ Such features can further impede accurate diagnosis of NS. Electrographic confirmation is now considered as gold standard in NS detection.^20–22 As diagnostic methods have improved, previous estimates of the incidence of NS and subsequent epilepsy may be incorrect. Estimation of the incidence of epilepsy aids in healthcare planning and identification of potential predictors of epilepsy may be helpful in prognostication and optimal therapy selection. Heightened awareness among parents and clinicians may lead to earlier presentations and ultimately better outcomes. We hypothesize that infants with NE, both in those, with and without electrographic neonatal seizures (ENS) are at risk of later epilepsy. The primary aim of our study is to establish the incidence of later epilepsy in these infants with a secondary aim to identify potential predictors of later epilepsy.

METHODS

Patients and methods

This was a retrospective observational study performed at Cork University Maternity Hospital, Cork, Ireland, including infants that were previously enrolled in research studies in our center between 2003 and 2019.^23–35 This study was approved by the local ethics board—Clinical Research Ethics Committee of Cork Teaching Hospitals (CREC). For our study, infants with NE were included if; ≥37 weeks' gestation, with ≥2 h of continuous EEG (cEEG) monitoring and available follow-up data after the neonatal period. Exclusion criteria included infants with neonatal onset epilepsy, NE secondary to a genetic or metabolic condition, infants with perinatal asphyxia in the absence of clinical encephalopathy, or if death occurred in the neonatal period or prior to follow-up. Infants' main diagnoses were grouped as: HIE (mild, moderate, severe), stroke/intracranial hemorrhage (ICH), sepsis/meningitis. Infants with encephalopathy who did not have any of those diagnoses were grouped as “other.” Neonatal MRI brain injury was classified as normal or abnormal based on written radiology reports at the time. Clinical birth characteristics were recorded in the original databases of the included historical studies. Written pediatric medical notes were reviewed to ascertain later pediatric data in relation to epilepsy and outcome.

EEG

All infants had cEEG monitoring in the neonatal intensive care unit for a minimum of 2 h in the neonatal period. EEG was commenced in infants at risk of HIE or where there was a clinical concern for seizures.^23–35 EEG electrodes were applied to the scalp at F3/FP3, F4/FP4, C3, C4, T3, T4, O1, O2, and CZ and additionally PZ in later studies; 2017–2019 (according to the international 10–20 system of electrode placement, as modified for neonates). All EEGs were reviewed in entirety for the presence of seizures. An ENS was defined as a sudden repetitive, stereotyped discharge of minimum 10 s duration on one or more EEG channels with evolving frequency, amplitude and morphology.^32,36 The EEG background was graded as severe background pattern yes/no in all infants. A severe background pattern included Grade 3–4 background abnormalities in HIE infants²⁵ or the presence of widespread high-amplitude multifocal sharp waves, burst suppression, persistent discontinuity ≥10 s or isoelectric activity in the non-HIE group as per current EEG guidelines.^20,22 In infants with HIE, EEG background was graded at 24 h of age or the nearest 1-h epoch. For infants with a diagnosis other than HIE, the earliest 2 h of good-quality EEG recording was graded, as often EEG monitoring was not performed at 24 h of age for those infants due to varying age at presentation.

Outcome

Written pediatric medical charts were reviewed for all infants to determine if epilepsy developed after the neonatal period. Duration of follow-up was defined as the interval in months between the end of the neonatal period and the date of epilepsy diagnosis (for those diagnosed with epilepsy) or the date of the last medical appointment (for those not diagnosed with epilepsy). Age in months at final clinical encounter was also recorded for all infants. Epilepsy was defined in accordance with ILAE guidelines; ≥2 unprovoked (or reflex) seizures occurring >24 h apart or one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures, or an epilepsy syndrome.³⁷ In addition, a diagnosis of epilepsy was considered when anti-seizure medications (ASMs) were commenced by a pediatric neurologist on the basis of strong clinical history and semiology suggestive of epilepsy with an abnormal EEG. When epilepsy was present, epilepsy onset, type, seizure type, pediatric EEG details, treatment, and related co-morbidities were recorded. All pediatric EEGs were reported by an experienced consultant neurophysiologist in line with standard international recommendations.³⁸ Drug-resistant epilepsy was defined as failure of adequate trials of two tolerated and appropriately chosen and used ASM schedules to achieve sustained seizure freedom.³⁹ Epilepsy type was categorized as focal, generalized, combined (focal and generalized), epilepsy syndrome, and unknown following chart review.⁴⁰ Seizure type was categorized as focal, generalized, combined, or unknown.⁴¹

Statistical analysis

For statistical analysis, IBM SPSS Statistics 26.0 (IBM Corporation, Armonk, NY, USA) and Stata 17.0 (StataCorp, LP College Station, TX, USA) were used. Cumulative incidences were calculated as the number of infants with epilepsy onset during follow-up divided by the number of infants included in the study and multiplied by 100. Incidence rates for epilepsy (per 1000 person-years) overall and by group were calculated as the number of infants with epilepsy onset divided by the observed time at risk and multiplied by 1000. Time at risk was defined as the interval in months between the end of the neonatal period and the date of epilepsy diagnosis (for those diagnosed with epilepsy) or the date of the last medical appointment (for those not diagnosed with epilepsy). Follow-up for infants who developed epilepsy continued beyond their diagnosis to monitor additional outcomes. Incidence rates and their corresponding 95% confidence intervals (CIs) are presented. Categorical variables are described using frequencies and percentages, and continuous variables are described using medians and interquartile ranges (IQRs). Differences between infants with epilepsy and those without were investigated using the Mann–Whitney U test when the variable was continuous and Fisher's exact test when the variable was categorical. Univariable logistic regression models were used to investigate potential predictors of epilepsy. For all potential predictors investigated, the unadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) are presented. When there was separation, penalized maximum likelihood logistic regression was used as it can produce finite coefficient estimates when there is perfect prediction. Multivariable analysis was not performed due to the small number of infants diagnosed with epilepsy.⁴² Additionally, subgroup analyses were performed separately for infants with ENS and those without ENS.

RESULTS

Five hundred and twelve infants were recruited to historical studies and two hundred and eighty infants were included in this study (Figure 1). Overall, children were followed up to a median age of 30 months, IQR (24 to 60 months). Those who were not diagnosed with epilepsy were followed up until a median age of 29 months (IQR: 23 to 58 months; range: 5 to 196 months) and 95% (250/263) of them were ≥12 months old at final clinical encounter. Those who were diagnosed with epilepsy were followed up until a median age of 84 months (IQR: 24 to 123 months; range: 7 to 200 months) and 88% (15/17) of them were ≥12 months old at final clinical encounter. The most common underlying diagnosis in all infants who underwent EEG monitoring was HIE (238/280, 85%), followed by stroke/ICH (26/280, 9%).

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Epilepsy

Epilepsy was diagnosed in 17 (out of 280) infants with an incidence rate of 17.55 per 1000 person-years (95% CI: 10.91 to 28.23). In the ENS group (n = 82), 12 infants were diagnosed with epilepsy with an incidence rate of 39.27 per 1000 person-years (95% CI: 22.30 to 69.16) and in the non-ENS group (n = 198), 5 infants were diagnosed with epilepsy with an incidence rate of 7.54 per 1000 person-years (95% CI: 3.14 to 18.12). The incidence rate was significantly higher in the ENS group compared to the non-ENS group (p-value = 0.002).

Epilepsy onset

Overall, the median age at onset of epilepsy was 7.0 months (IQR: 3.5 to 40.5 months; range: 1 to 115 months). For the ENS group (n = 12) and the non-ENS group (n = 5) the median (IQR) was 6.5 (3.3 to 34.3) months and 9.0 (3.5 to 65.5) months, respectively. Epilepsy occurred in the first year of age in 59% (10/17) of all cases (7/12 in ENS group and 3/5 in non-ENS group). Of the seven children (4 female, 3 male), who developed epilepsy after the first year; 5 had ENS (all moderate–severe HIE). Of the two who developed epilepsy after the first year in the absence of ENS, one had mild HIE (did not receive therapeutic hypothermia (TH)) and one had moderate HIE (received TH) during the neonatal period. The latest onset of epilepsy described in our cohort occurred at approximately 115 months of age in a male child who experienced ENS and who underwent TH for moderate HIE. He was treated with Phenobarbital and Phenytoin in the neonatal period. This child presented with Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS) on the background of spastic quadriparesis.

Epilepsy types

Generalized epilepsy did not occur in any infants. Focal epilepsy occurred in all but two cases. The infants who did not have focal epilepsy were both diagnosed with Infantile Epileptic Spasms Syndrome (IESS). Overall, six infants (35%) were diagnosed with IESS; moderate HIE (n = 1), severe HIE (n = 3); stroke (n = 1); NE of unknown etiology (n = 1). Of those with HIE, only one infant was born following the introduction of TH and was subsequently cooled. All infants who developed IESS following HIE died by the age of seven years. Lennox–Gastaut syndrome was also diagnosed in one infant in addition to IESS with moderate HIE.

Epilepsy treatment

Drug-resistant epilepsy occurred in 9 of the 17 infants with epilepsy. Levetiracetam was the most common ASM prescribed (12/17), followed by Sodium Valproate (8/17) at any time of the child's epilepsy treatment. The median number of ASMs during childhood was 3 (IQR: 1 to 5). One case is now off all ASMs; an infant with severe HIE treated with Phenobarbitone for focal epilepsy and another declined to commence ASMs.

Co-morbidities and mortality associated with PNE

Eleven infants with epilepsy also had cerebral palsy (CP). Other common co-morbidities included developmental delay, visual impairment, and a requirement for enteral feeding (Table S2). Six infants with epilepsy (5 of those also had CP) died at a median age of 2.7 years (IQR: 1.5 to 7.8 years).

Investigation of potential predictors of epilepsy

Infants with low Apgar scores at 1 and 5 min, delivered vaginally (compared to those with an assisted delivery), a diagnosis of severe HIE (compared to those with mild HIE, moderate HIE or stroke/ICH), a diagnosis of “other” (compared to mild HIE), presence of ENS, a severely abnormal EEG background and an abnormal brain MRI were significantly more likely to be diagnosed with later epilepsy (Table 1). The strongest predictor of later epilepsy was a severely abnormal neonatal EEG background (AUC(95% CI): 0.85(0.72 to 0.98)), followed by underlying diagnosis (AUC(95% CI): 0.83(0.72 to 0.94)) and presence of ENS (AUC(95% CI): 0.72(0.59 to 0.85)). The presence of a severely abnormal EEG background conferred an odds ratio of 52.5 (95% CI: 15.0 to 183.8) and having ENS conferred an odds ratio of 6.6 (95% CI: 2.3 to 19.5) of later epilepsy. The cumulative incidence by diagnosis was: HIE 6.3% (mild 0.9%, moderate 4.0%, severe 40.0%), stroke/ICH 3.8%, sepsis/meningitis 0% and other 14.3%.

TABLE 1 Investigation of potential predictors of epilepsy in all infants who had EEG monitoring (n = 280).

	All infants (n = 280)a % (n)	Epilepsy (n = 17)a % (n)	No epilepsy (n = 263)a % (n)	p-valueb	OR (95% CI)	AUC (95% CI)	p-valuec
Sex				0.443		0.55 (0.41 to 0.69)	0.482
Male	63 (175)	53 (9)	63 (166)		1
Female	38 (105)	47 (8)	37 (97)		1.5 (0.6 to 4.1)
Mode of Delivery				0.021		0.69 (0.56 to 0.82)	0.008
SVD	25 (69)	53 (9)	23 (60)		1
Assisted	41 (115)	18 (3)	43 (112)		0.2 (0.0 to 0.7)
Elective Caesarean Section	3 (7)	6 (1)	2 (6)		1.1 (0.1 to 10.3)
Emergency Caesarean Section	32 (89)	24 (4)	32 (85)		0.3 (0.1 to 1.1)
Diagnosis				<0.001		0.83 (0.72 to 0.94)	<0.001
Mild HIE	40 (112)	6 (1)	42 (111)		1k
Moderate HIE	36 (101)	24 (4)	37 (97)		3.4 (0.5 to 22.2)
Severe HIE	9 (25)	59 (10)	6 (15)		50.4 (8.4 to 302.0)
Stroke/ICH	9 (26)	6 (1)	10 (25)		4.4 (0.4 to 43.8)
Sepsis/Meningitis	3 (9)	0 (0)	3 (9)		3.9 (0.1 to 102.8)
Otherd	3 (7)	6 (1)	2 (6)		17.2 (1.6 to 188.6)
Therapeutic Hypothermia				0.799		0.52 (0.38 to 0.66)	0.787
No	63 (175)	59 (10)	63 (165)		1
Yes	38 (105)	41 (7)	37 (98)		1.2 (0.4 to 3.2)
Electrographic Neonatal Seizures				<0.001		0.72 (0.59 to 0.85)	0.002
No	71 (198)	29 (5)	73 (193)		1
Yes	29 (82)	71 (12)	27 (70)		6.6 (2.3 to 19.5)
Severely Abnormal Neonatal EEG Backgrounde				<0.001		0.85 (0.72 to 0.98)	<0.001
No	91 (249)	25 (4)	95 (245)		1
Yes	9 (26)	75 (12)	5 (14)		52.5 (15.0 to 183.8)
Neonatal MRI Brain Imagingf				0.002		0.70 (0.59 to 0.81)	0.011
Normal	43 (84)	7 (1)	46 (83)		1
Abnormal	57 (110)	93 (14)	54 (96)		12.1 (1.6 to 94.0)
	median (IQR)	median (IQR)	median (IQR)	p-valuec
Gestational Age (Weeks)g	40 (39 to 41)	40 (39 to 40)	40 (39 to 41)	0.953	1.1 (0.7 to 1.6)	0.50 (0.37 to 0.64)	0.954
Birth Weight (grams)	3455 (3140 to 3758)	3620 (3325 to 3810)	3450 (3140 to 3750)	0.363	1.0 (1.0 to 1.0)	0.57 (0.44 to 0.69)	0.363
Apgar at 1 minuteh	3 (2 to 6)	2 (0 to 4)	3 (2 to 6)	0.004	0.7 (0.5 to 0.9)	0.71 (0.60 to 0.83)	0.004
Apgar at 5 minutesi	6 (4 to 8)	3 (2 to 6)	6 (4 to 8)	0.004	0.7 (0.6 to 0.9)	0.71 (0.59 to 0.84)	0.004
Apgar at 10 minutesj	6 (5 to 8)	5 (4 to 7)	7 (5 to 8)	0.073	0.8 (0.6 to 1.0)	0.68 (0.51 to 0.84)	0.076

Subgroup analyses: Investigation of potential predictors of epilepsy by ENS seizure group

The results of the subgroup analyses are presented in Table 2 for infants who had ENS and in Table S1 for infants who did not have ENS.

TABLE 2 Investigation of potential predictors of epilepsy following ENS (n = 82).

	All infants (n = 82)a % (n)	Epilepsy (n = 12)a % (n)	No epilepsy (n = 70)a % (n)	p-valueb
Sex				0.751
Male	63 (52)	58 (7)	64 (45)
Female	37 (30)	42 (5)	36 (25)
Mode of Delivery				0.046
SVD	23 (19)	50 (6)	19 (13)
Instrumental	39 (32)	17 (2)	43 (30)
Elective Section	4 (3)	8 (1)	3 (2)
Emergency Section	34 (28)	25 (3)	36 (25)
Diagnosis				0.003
Mild HIE	5 (4)	0 (0)	6 (4)
Moderate HIE	39 (32)	17 (2)	43 (30)
Severe HIE	21 (17)	67 (8)	13 (9)
Stroke/ICH	28 (23)	8 (1)	31 (22)
Sepsis/Meningitis	2 (2)	0 (0)	3 (2)
Otherd	5 (4)	8 (1)	4 (3)
Therapeutic Hypothermia				1
No	61 (50)	58 (7)	61 (43)
Yes	39 (32)	42 (5)	39 (27)
Severely abnormal Neonatal EEG Backgrounde				<0.001
No	75 (61)	18 (2)	84 (59)
Yes	25 (20)	82 (9)	16 (11)
Neonatal MRI Brain Imagingf				0.109
Normal	19 (13)	0 (0)	22 (13)
Abnormal	81 (56)	100 (11)	78 (45)
	median (IQR)	median (IQR)	median (IQR)	p-valuec
Gestational Age (Weeks)	40 (39 to 41)	40 (40 to 41)	40 (39 to 41)	0.312
Birth Weight (grams)	3520 (3223 to 3743)	3633 (3453 to 3815)	3455 (3160 to 3725)	0.114
Apgar at 1 minuteg	4 (2 to 8)	2 (1 to 4)	4 (2 to 8)	0.018
Apgar at 5 minutes	7 (3 to 9)	3 (2 to 7)	7 (4 to 9)	0.011
Apgar at 10 minutesh	5 (4 to 7)	4 (3 to 7)	5 (4 to 7)	0.647
Number of neonatal ASMs	1 (1 to 2)	3 (1 to 5)	1 (1 to 1)	0.001

Electrographic neonatal seizures (n = 82)

ENS occurred in 82 (29%) infants, 12 (15%) of whom later developed epilepsy.

In this group, infants delivered vaginally (compared to those with an assisted delivery) a diagnosis of severe HIE (compared to those with moderate HIE or stroke/ICH), a severely abnormal EEG background, more ASMs in the neonatal period or low Apgar scores at 1 and 5 min were significantly more likely to be diagnosed with later epilepsy (Table 2).

The presence of a severely abnormal EEG background conferred an odds ratio of 24.1 (95% CI: 4.6 to 127.2) of developing later epilepsy. All infants who developed epilepsy with available brain imaging had abnormal findings.

Infants without electrographic neonatal seizures (n = 198)

Epilepsy occurred in 5 (3%) of the 198 infants who did not have ENS. Infants with a severely abnormal EEG background and low Apgar score at 1 min were significantly more likely to be diagnosed with later epilepsy (Table S1). A severely abnormal EEG background was noted in 3 infants with later epilepsy, while the other two infants had Grade 1 EEG backgrounds; (moderate HIE; n = 1 and mild HIE; n = 1). Despite, these infants not having ENS, 3 of the 5 received ASMs in the neonatal period which may have eliminated seizures before the onset of EEG monitoring. All but one infant with epilepsy who had neonatal brain imaging had an abnormal result, characterized by predominantly gray matter brain injury. This child had repeat imaging at the time of epilepsy diagnosis and a small right sided focus of increased signal intensity likely representative of gliosis was identified (Tables S1 and S2).

DISCUSSION

The incidence rate of later epilepsy in full term infants with neonatal encephalopathy who underwent EEG monitoring in the neonatal period was 17.55 per 1000 person-years. The incidence rate was significantly higher in the ENS group compared to the non-ENS group (p-value = 0.002). Overall, ENS conferred an odds ratio of 6.6 (95% CI: 2.3 to 19.5) in developing later epilepsy. Several potential predictors of later epilepsy were identified including infants delivered vaginally, low Apgar scores at 1 and 5 min, severe HIE diagnosis, presence of ENS, a severely abnormal EEG background, and an abnormal brain MRI.

In both groups of infants, a severely abnormal EEG background was a significant risk factor for the development of later epilepsy. Several groups have previously reported the association of an abnormal EEG background with later epilepsy.^43–45 Glass et al. reported a non-significant association of an abnormal EEG background with later epilepsy.⁴⁵ Others have described an abnormal EEG characterized by isoelectric or low-voltage activity, burst-suppression pattern, permanent discontinuous or depressed activity to be associated with later epilepsy following acute symptomatic seizures.^43,44 Persistently abnormal EEG background patterns in the neonatal period can also increase the risk of later epilepsy, in particular, the presence of a burst-suppression pattern.⁴⁶ The rate of amplitude-integrated (aEEG) recovery in moderate and severe HIE, specifically the absence of signs of recovery within 24 h of age has also been found to be associated with increased risk.^47,48 While we only reviewed particular epochs; specifically 24 h of age in HIE and the earliest 2 h of EEG recording available in non-HIE infants, the former timepoint has been previously demonstrated to be predictive of outcome.⁴⁹ In the ENS group, additional potential predictors of PNE included increasing number of ASM in the newborn period and lower Apgar scores at 1 and 5 min. Treatment response in the newborn period has also been previously cited as a risk factor for later epilepsy, with time to seizure control and number of ASMs required to achieve seizure control being important determinants for later outcomes.^43,44,50 Pisani et al. reported response to treatment as the single independent risk factor for later epilepsy in a cohort of 85 pre-term and term infants with NS.⁴⁴ In addition, in large studies with over 200 infants, both Toet et al. and Shellhass et al. reported that infants who developed epilepsy tended to require more ASMs compared to those who did not.^43,50

HIE was the most common diagnosis associated with later epilepsy in our cohort, though our numbers are limited with a likely over-representation of HIE in comparison to other diagnoses such as stroke. IESS occurred in 27% (4/15) of cases of HIE with epilepsy, with all but one case occurring in the pre-therapeutic hypothermia era. Of note, the cumulative incidence of epilepsy in the pre-TH era was 10% (95% CI: 3% to 21%) in comparison to 5% (95% CI: 3% to 9%) post its introduction though this was not significant; p-value = 0.207. Our analysis, however, is limited by the small numbers included, and larger studies investigating the impact of TH on epileptogenesis are required.

In similarly designed studies, the highest rate of epilepsy has been reported following stroke.^50,51 Notably, many of the infants included in our study were recruited to historical studies that focused on infants with perinatal asphyxia, so infants with neonatal stroke and etiologies other than HIE may be under-represented. The latency period for epileptogenesis following neonatal stroke can be considerably longer than other etiologies and the median follow-up in this study may have been insufficient.^52,53

A latent period exists between acute provoked seizures and recurrent unprovoked seizures whereby a process of structural and metabolic change takes place, causing a permanent hyper-excitable state leading to recurrent seizures.⁵⁴ While the first year of life is the most common period for the development of epilepsy, longer latency periods have been described.^44,45,52,55 For infants with ENS, epilepsy developed after the first year of life in 42% (5/12), with the latest at 115 months. In the absence of ENS in at risk infants in the newborn period (non-seizure group), later epilepsy still remains a considerable risk. In our study, 2.5% (5/198) of infants developed epilepsy in the absence of ENS. The latest onset for epilepsy in this group was 72 months. This underscores the need for long-term follow-up of at-risk infants in the neonatal period, particularly, even in the absence of ENS.

Infants at risk of seizures are not only at risk of later epilepsy but also of other co-morbidities and mortality. Eleven infants (65%) with epilepsy in our cohort also had cerebral palsy. Furthermore, early drug-resistant epilepsy was common in this cohort, occurring in over 50%. Follow-up duration varied in our cohort, so not all children had a prolonged follow-up period, so length of the follow-up for some infants may increase over time. In addition, over one-third of infants with epilepsy died in childhood, however, not from a direct cause of their underlying epilepsy but from their associated neuro-disabilities.

Our study has several strengths; it includes a large study population with a median follow-up period of 29 months, IQR (23 to 59 months). In total, 95% of included infants were ≥12 months of age at their final clinical encounter. However, we do acknowledge that the epileptogenic period following perinatal brain injury can be longer.⁵⁵ All neonatal seizures were confirmed electrographically as per current guidelines.^20–22 A detailed description is provided on all 17 children who developed epilepsy, including neonatal history and pediatric treatment. Pediatric EEGs were reviewed by an experienced consultant neurophysiologist. Infants were included in this study if they had NE irrespective of the presence of electrographic seizures which is an added value in comparison to other studies. We equally acknowledge our study's limitations. Neonatal EEG background was graded only at one specific timepoint and background grade may have fluctuated over time. EEGs were not all graded by the same grading system or at the same postnatal age as standardized EEG grading schemes do not exist for infants with non-HIE causes of NE. Typically, infants with other causes of NE present at a later age, and subsequently grading at 24 h of age was not always possible. Though an abnormal EEG background was associated with epilepsy, some of these abnormalities may have been exacerbated by ASMs and sedative drugs. This was a retrospective study which involved chart review and the quality of recording of medical information did vary, in particular the description of later epilepsy as current classification systems were not routinely used in earlier cases.^40,41,56 Also, pediatric EEGs were performed at the discretion of the referring clinician. In the case of a strong clinical history indicative of epilepsy with underlying potential predictors, not all children had EEGs coinciding at the exact timing of diagnosis. Extensive statistical analysis was limited due to the small number of infants who ultimately developed epilepsy, particularly, when undertaking sub-group analyses.

Further studies are required including a larger and more heterogenous group of infants, more representative of those with NE and at risk of later epilepsy. More extensive analysis is required to evaluate in more detail specific clinical and EEG risk factors for the development of later epilepsy, including extended seizure characterization, and this will be the focus of further study.

Following NE, term infants are at risk of PNE; 15% of infants following acute provoked seizures and 3% of those who did not experience ENS developed later epilepsy. Close follow-up is required in both groups well into the childhood period.

FUNDING INFORMATION

CMS is a PhD candidate funded by the Health Research Board (CDA-2018-008). This research was also supported by a Wellcome Trust Innovator Award (209325/Z/17) and partly supported by Merck's Life Science Community Engagement Programme—Scientific Research. No role was played by the funder/sponsor in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to disclose.

DATA AVAILABILITY STATEMENT

Research data are not shared.

ETHICS STATEMENT

This study was approved by the local ethics board—Clinical Research Ethics Committee of Cork Teaching Hospitals (CREC). We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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