Early posttraumatic seizures in pediatric traumatic brain injury: a multicenter analysis

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  • 1 Department of Emergency Medicine, KK Women’s and Children’s Hospital, Singapore;
  • | 2 SingHealth Duke-NUS Global Health Institute, Duke-NUS Medical School, Singapore;
  • | 3 Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China;
  • | 4 Centre for Quantitative Medicine, Duke-NUS, Singapore;
  • | 5 Department of Pediatric Intensive Care Unit, Children’s Hospital of Chongqing Medical University, Chongqing, China;
  • | 6 Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong;
  • | 7 Department of Pediatric Intensive Care Unit, Children’s Hospital of Fudan University, Shanghai, China;
  • | 8 Department of Paediatrics, University Malaya Medical Centre, Kuala Lumpur, Malaysia;
  • | 9 Khoo Teck Puat National University Children’s Medical Institute, National University Hospital, Singapore;
  • | 10 Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;
  • | 11 Department of Pediatric Critical Care Medicine, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan; and
  • | 12 Children’s Intensive Care Unit, KK Women’s and Children’s Hospital, Singapore
Open access

OBJECTIVE

Early posttraumatic seizures (EPTSs) in children after traumatic brain injury (TBI) increase metabolic stress on the injured brain. The authors sought to study the demographic and radiographic predictors for EPTS, and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes among children with moderate to severe TBI in Asia.

METHODS

A secondary analysis of a retrospective TBI cohort among participating centers of the Pediatric Acute & Critical Care Medicine Asian Network was performed. Children < 16 years of age with a Glasgow Coma Scale (GCS) score ≤ 13 who were admitted to pediatric intensive care units between January 2014 and October 2017 were included. Logistic regression analysis was performed to study risk factors for EPTS and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes. Poor functional outcomes were defined as moderate disability, severe disability, and coma as defined by the Pediatric Cerebral Performance Category scale.

RESULTS

Overall, 313 children were analyzed, with a median age of 4.3 years (IQR 1.8–8.9 years); 162 children (51.8%) had severe TBI (GCS score < 8), and 76 children (24.3%) had EPTS. After adjusting for age, sex, and the presence of nonaccidental trauma (NAT), only younger age was significantly associated with EPTS (adjusted odds ratio [aOR] 0.85, 95% CI 0.78–0.92; p < 0.001). Forty-nine children (15.6%) in the cohort died, and 87 (32.9%) of the 264 surviving patients had poor functional outcomes. EPTS did not increase the risk of death. After adjusting for age, sex, TBI due to NAT, multiple traumas, and a GCS score < 8, the presence of EPTS was associated with poor functional outcomes (aOR 2.08, 95% CI 1.05–4.10; p = 0.036).

CONCLUSIONS

EPTSs were common among children with moderate to severe TBI in Asia and were associated with poor functional outcomes among children who survived TBI.

ABBREVIATIONS

AED = antiepileptic drug; aOR = adjusted odds ratio; EEG = electroencephalography; EPTS = early posttraumatic seizure; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; ICP = intracranial pressure; MVC = motor vehicle collision; NAT = nonaccidental trauma; PACCMAN = Pediatric Acute & Critical Care Medicine Asian Network; PCPC = Pediatric Cerebral Performance Category; PICU = pediatric intensive care unit; TBI = traumatic brain injury.

OBJECTIVE

Early posttraumatic seizures (EPTSs) in children after traumatic brain injury (TBI) increase metabolic stress on the injured brain. The authors sought to study the demographic and radiographic predictors for EPTS, and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes among children with moderate to severe TBI in Asia.

METHODS

A secondary analysis of a retrospective TBI cohort among participating centers of the Pediatric Acute & Critical Care Medicine Asian Network was performed. Children < 16 years of age with a Glasgow Coma Scale (GCS) score ≤ 13 who were admitted to pediatric intensive care units between January 2014 and October 2017 were included. Logistic regression analysis was performed to study risk factors for EPTS and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes. Poor functional outcomes were defined as moderate disability, severe disability, and coma as defined by the Pediatric Cerebral Performance Category scale.

RESULTS

Overall, 313 children were analyzed, with a median age of 4.3 years (IQR 1.8–8.9 years); 162 children (51.8%) had severe TBI (GCS score < 8), and 76 children (24.3%) had EPTS. After adjusting for age, sex, and the presence of nonaccidental trauma (NAT), only younger age was significantly associated with EPTS (adjusted odds ratio [aOR] 0.85, 95% CI 0.78–0.92; p < 0.001). Forty-nine children (15.6%) in the cohort died, and 87 (32.9%) of the 264 surviving patients had poor functional outcomes. EPTS did not increase the risk of death. After adjusting for age, sex, TBI due to NAT, multiple traumas, and a GCS score < 8, the presence of EPTS was associated with poor functional outcomes (aOR 2.08, 95% CI 1.05–4.10; p = 0.036).

CONCLUSIONS

EPTSs were common among children with moderate to severe TBI in Asia and were associated with poor functional outcomes among children who survived TBI.

ABBREVIATIONS

AED = antiepileptic drug; aOR = adjusted odds ratio; EEG = electroencephalography; EPTS = early posttraumatic seizure; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; ICP = intracranial pressure; MVC = motor vehicle collision; NAT = nonaccidental trauma; PACCMAN = Pediatric Acute & Critical Care Medicine Asian Network; PCPC = Pediatric Cerebral Performance Category; PICU = pediatric intensive care unit; TBI = traumatic brain injury.

In Brief

The authors sought to study predictors for early posttraumatic seizures (EPTSs) in children with moderate to severe traumatic brain injury (TBI), the association between EPTSs and death, and the association between EPTSs and poor functional outcomes. EPTSs occurred more commonly in younger children with TBI and were associated with poor functional outcomes among children who survived TBI. The authors’ findings have validated those of other single-center studies on the association between EPTSs and poor outcomes in children with TBI.

Pediatric traumatic brain injury (TBI) causes death and deprives those who survive of optimal neurocognitive development, educational opportunities, and quality of life.1–3 Management of pediatric TBI includes strategies that reduce or prevent secondary insults to the brain.4 Because posttraumatic seizures increase the metabolic demands of the brain, it is essential to identify and manage these seizures promptly to mitigate the risk of hypoxia and secondary brain damage.5 Specifically, early posttraumatic seizures (EPTSs), defined as seizures occurring in the first 7 days after injury, have been the object of many single-center studies.6–8

Children with TBI who are at risk of EPTS include children < 2 years of age, those with severe TBI (defined by a Glasgow Coma Scale [GCS] score < 8), and those who experience nonaccidental trauma (NAT).7,8 EPTSs also occur more commonly in the presence of cerebral edema, intraparenchymal hemorrhage, and depressed skull fracture.9 Investigators have proposed that electroencephalography (EEG) monitoring may benefit these high-risk groups through early identification of subclinical seizures.7 Risk factors reported from these single-center studies require validation in larger and more varied multicenter study populations for generalizability and translation of study findings.

While EPTSs have been associated with longer stays in the intensive care unit and hospital,7,10 the associations between EPTSs and functional or neurocognitive outcomes are less understood, with some reporting that children with EPTSs have poorer outcomes as measured by the Glasgow Outcome Scale (GOS), ranging from severe disability to a persistent vegetative state to death.9,11 A better understanding of the impact of EPTS on long-term outcomes for children with TBI is necessary for accurate prognostication.

The current evidence is synthesized largely from data coming from North America and Europe.4 The incidence and risk factors of EPTS, as well as the availability and use of EEG in Asian trauma centers and pediatric intensive care units (PICUs), are not well reported. Therefore, we sought to study the demographic and radiographic predictors for EPTS, and to investigate the association between EPTS and mortality, and between EPTS and poor functional outcomes among children with moderate to severe TBI, in a multicenter Asian PICU cohort.

Methods

Study Design

We performed a secondary analysis of the retrospective Pediatric Acute & Critical Care Medicine Asian Network (PACCMAN) TBI data set. This was a retrospective chart review performed for patients admitted to 8 PICUs in Asia between January 2014 and October 2017.12 All sites have access to neuroimaging, EEG monitoring, and neurosurgical expertise. Intracranial pressure (ICP) monitoring was routinely available in all centers. Indications for ICP monitoring included a decrease in GCS score with concerns of raised ICP or postsurgical intervention, and the decision to monitor ICP was generally made by the primary team at each site. Normothermia is routinely recommended at all participating sites.

Children < 16 years of age who presented within 24 hours of head injury with a GCS score ≤ 13 (constituting moderate and severe TBI) were included in this study. We also included patients with TBI in the presence of multiple trauma (e.g., intrathoracic, intraabdominal, and long-bone injuries) and documented these injuries. Children with trivial injuries and those with low GCS scores due to non-intracranial causes were excluded.

Study Variables

Data were collected using a standardized electronic data form (REDCap, Vanderbilt University). Variables included in the primary analysis were patient demographics, mechanism of injury, and the physical examination findings (including the presenting GCS score). We included the head CT results and PICU management pertaining to the use of ICP monitoring, mechanical ventilation, hyperosmolar therapy, and temperature control, as well as whether and what type of neurosurgical interventions were performed.

For the secondary analysis, we collected additional data on the following variables: presence of EEG monitoring (including the use of EEG for all children with TBI vs only for those suspected of having seizures), date of the first seizure (where relevant), type and semiology of the seizure (generalized tonic-clonic vs focal seizure), and frequency of seizures. We also clarified whether antiepileptic drugs (AEDs) were used and, if so, whether they were used prophylactically or only on clinical suspicion of seizures.

Outcomes were defined as mortality and the functional outcome at the time of PICU discharge. We chose to report mortality and functional outcomes separately rather than as a composite outcome because we recognized that children with severe TBI may die soon after arrival, and, therefore, may not have time to develop or exhibit EPTSs. We used the Pediatric Cerebral Performance Category (PCPC) scale for functional outcomes, which is a qualitative assessment of function among surviving patients in the following 5 categories: good, mild disability, moderate disability, severe disability, and vegetative state or coma.13,14 We defined poor outcomes as moderate disability, severe disability, and vegetative state or coma.12

Statistical Analysis

Categorical variables are reported as frequencies and percentages and continuous variables as the mean with standard deviation or median (IQR), depending on the normality of their distribution. A priori, we set a threshold of 5% for missing data to perform multiple imputation; thus, imputation was not warranted in our data set.

We performed a logistic regression analysis to identify risk factors for EPTS and to study the association between EPTS and mortality as well as poor functional outcomes. Variables that entered the regression were determined based on univariate significance (p < 0.2) as well as clinical factors that are known to increase the risk for poor outcomes in children with TBI.15 These included the age and sex of the child, and the presence of severe TBI (defined by a GCS score < 8), NAT, and presence of multiple trauma. We presented unadjusted and adjusted odds ratios (aORs) with their 95% confidence intervals. All analyses were performed using IBM SPSS Statistics version 26 (IBM Corp.). Statistical significance was set at p < 0.05 for all tests.

Ethics approval for this study was given by SingHealth Centralised Institutional Review Board E, Singapore, with waiver of informed consent.

Results

Overall, 313 children were analyzed, with a median age of 4.3 years (IQR 1.8–8.9 years); 214 patients (68.4%) were male and 162 patients (51.8%) had severe TBI (GCS score < 8). The most common cause of injury was a fall (137, 43.8%), followed by motor vehicle collisions (MVCs; 136, 43.5%) and NAT (23, 7.3%). Our study population had 179 children (57.2%) who presented with multiple trauma. Of those patients, 130 (72.6%) had intrathoracic injuries, 63 (35.2%) had long-bone injuries, and 57 (31.8%) had intraabdominal injuries.

Seventy-six children (24.3%) had EPTSs, among whom 75 (98.7%) had clinical seizures and 1 child had subclinical seizures detected on EEG. This was an 11-year-old child who sustained a subdural hemorrhage, cerebral edema, and midline shift, and underwent a decompressive craniectomy. Forty-six (60.5%) and 28 (36.8%) children had generalized tonic-clonic and focal seizures, respectively. Children with EPTS were younger (median age 2.2 years [IQR 0.6–4.8 years]) compared with those without EPTS (median 4.8 years [IQR 2.4–9.5 years], p < 0.001) (Table 1). There was a greater proportion of children with EPTS who had NAT (12/76, 15.8%) compared with those without EPTS (11/237, 4.6%), while the proportion of patients with EPTS who were injured due to MVCs was lower (21/76, 27.6% vs 115/237, 48.5%; p = 0.001).

TABLE 1.

Patient demographics and clinical characteristics

CharacteristicEPTS (n = 76)No EPTS (n = 237)p Value
Median age, yrs2.2 (0.6–4.8)4.8 (2.4–9.5)<0.001
Male sex48 (63.2)166 (70.0)0.261
Baseline PCPC0.394
 Good72 (98.6)221 (96.5)
 Mild disability0 (0)6 (2.6)
 Moderate disability1 (1.4)1 (0.4)
 Severe disability0 (0)1 (0.4)
 Vegetative state or coma0 (0)0 (0)
Mechanism of injury0.001
 MVC21 (27.6)115 (48.5)
 Fall40 (52.6)97 (40.9)
 NAT12 (15.8)11 (4.6)
 Other3 (3.9)14 (5.9)
Median GCS score7 (5–10)7 (3–12)0.545
GCS score <842 (55.3)120 (50.8)0.503
ICP monitoring14 (18.4)52 (21.9)0.513
Median highest ICP, mm Hg
 Day 125.5 (18.3–35.0)20.0 (13.0–29.5)0.151
 Day 226.0 (20.0–35.3)21.0 (15.3–25.8)0.038
 Day 325.0 (20.0–31.0)18.0 (12.0–26.3)0.042
CT findings*
 Subarachnoid hemorrhage28 (37.8)79 (35.6)0.727
 Subdural hemorrhage29 (39.2)63 (28.4)0.082
 Extradural hemorrhage10 (13.5)63 (28.4)0.010
 Intraparenchymal bleed14 (18.9)55 (24.8)0.302
 Diffuse axonal injury5 (6.8)22 (9.9)0.415
 Cerebral edema16 (21.6)54 (24.3)0.636
Multiple trauma37 (48.7)142 (60.2)0.078

Values represent the number of patients (%) or median (IQR) unless indicated otherwise. Boldface type indicates statistical significance.

CT was performed in 74 patients with EPTSs and 222 patients without EPTSs.

We found that the maximum ICPs on day 2 (median 26.0 mm Hg vs 21.0 mm Hg, p = 0.038) and day 3 (median 25.0 mm Hg vs 18.0 mm Hg, p = 0.042) of hospitalization were significantly higher in the patients with EPTS than in those without EPTS, but not on day 1 of arrival (Table 1 and Fig. 1). The only difference found on CT was a smaller proportion of children with extradural hemorrhage in the patients with EPTS compared with those without (10/76, 13.5% vs 63/237, 28.4%; p = 0.010) (Table 1). After adjusting for age, sex, and NAT, only younger age was significantly associated with EPTS (aOR 0.85, 95% CI 0.78–0.92; p < 0.001).

FIG. 1.
FIG. 1.

Boxplot showing the daily maximum ICP reading by absence (n = 14) and presence (n = 52) of EPTSs. Circles and plus signs indicate outliers in the absent and present groups, respectively. Diamonds indicate the means and thick black lines indicate the medians. Figure is available in color online only.

Specific to seizure monitoring, 124 (39.6%) of 313 patients had EEG monitoring, and 73 (58.9%) of these 124 patients had EEG monitoring performed before the onset of suspected seizures. Among the 76 children with EPTS, EEG monitoring was used in 50 (65.8%); 19 (38.0%) of those children had EEG monitoring prior to onset of suspected seizures. Overall, 134 children (42.8%) received AEDs, with prophylactic AED use in 63 children (20.1%). Children who received prophylactic AEDs were older (median age 8.2 years [IQR 3.0–11.4 years]) compared with those who did not (median age 3.8 years [IQR 1.7–7.8 years], p < 0.001). Eleven (17.5%) of the 63 children who received prophylactic AEDs developed EPTS, compared with 65 (26.0%) of 250 children who did not receive prophylactic AEDs (p = 0.158). The most common prophylactic AED administered was phenytoin (23/63, 36.5%), followed by levetiracetam (16/63, 25.4%) and sodium valproate (11/63, 17.5%). We found that a greater proportion of children with EPTS received hypothermia treatment compared with those without EPTS (14/76, 18.4% vs 18/237, 7.6%; p = 0.042). There was no statistical difference in the proportion of patients who received neurosurgical interventions, except that a smaller proportion required evacuation of an intracranial bleed among those with EPTSs compared with those without (1/76, 1.3% vs 31/237, 13.1%; p = 0.003) (Table 2).

TABLE 2.

Management strategies stratified by the presence of EPTS

ManagementEPTS (n = 76)No EPTS (n = 237)p Value
AEDs69 (90.8)65 (27.4)<0.001
Hyperosmolar therapy29 (38.2)85 (35.9)0.718
Tracheal intubation w/in 24 hrs60 (78.9)172 (72.9)0.292
Temperature control w/in 24 hrs0.042
 ≥35°C29 (38.2)98 (41.5)
 34°C9 (11.8)9 (3.8)
 33°C5 (6.6)9 (3.8)
 No temperature control33 (43.4)120 (50.8)
Hyperventilation6 (7.9)14 (5.9)0.544
Neurosurgical intervention27 (35.5)92 (39.0)0.589
 Decompressive craniectomy8 (10.5)20 (8.4)0.579
 Craniotomy8 (10.5)32 (13.5)0.499
 ICP monitoring14 (18.4)52 (21.9)0.513
 Evacuation of intracranial bleed1 (1.3)31 (13.1)0.003
 Elevation of depressed skull fracture4 (5.3)8 (3.4)0.456

Values represent the number of patients (%) unless indicated otherwise. Boldface type indicates statistical significance

Forty-nine patients (15.6%) died. Among the 264 patients who survived, 8 (3.0%) did not have a PCPC assigned at discharge. As assessed by the PCPC on hospital discharge, 102 patients (38.6%) had good ability, 67 patients (25.4%) had mild disability, 37 patients (14.0%) had moderate disability, 30 patients (11.4%) had severe disability, and 20 patients (7.6%) were in a vegetative state or coma. Poor outcomes occurred in 87 (32.9%) of the patients who survived. The presence of EPTS was not associated with a higher risk for mortality (9/76, 11.8% vs 40/237, 16.9%; p = 0.293). However, among surviving patients, more patients with EPTS had poor functional outcomes (29/65, 44.6% vs 58/191, 30.4%; p = 0.036) (Table 3). After adjusting for age, sex, TBI due to NAT, multiple trauma, and severity of TBI (GCS score < 8), the presence of EPTS remained a significant predictor for poor functional outcomes (aOR 2.08, 95% CI 1.05–4.10; p = 0.036) (Table 4).

TABLE 3.

Summary of clinical outcomes stratified by the presence of EPTS

Clinical OutcomeEPTS, n (%)No EPTS, n (%)p Value
Overall hospital mortality9/76 (11.8)40/237 (16.9)0.293
Surviving pts, n*65191
Discharge PCPC0.119
 Good20 (30.8)82 (42.9)
 Mild disability16 (24.6)51 (26.7)
 Moderate disability11 (16.9)26 (13.6)
 Severe disability13 (20.0)17 (8.9)
 Vegetative state or coma5 (7.7)15 (7.9)
Poor outcome PCPC29 (44.6)58 (30.4)0.036

Pts = patients.

Boldface type indicates statistical significance.

Among surviving patients, 2 children with EPTS and 6 children without EPTS did not have a documented discharge PCPC.

Poor functional outcomes are defined as a PCPC of moderate disability, severe disability, and vegetative state or coma.

TABLE 4.

Independent risk factors for poor functional outcomes among patients who survived TBI

VariableUnadjusted OR (95% CI)Unadjusted p ValueaOR (95% CI)Adjusted p Value
Age1.04 (0.97–1.10)0.2681.07 (0.99–1.15)0.109
Male sex0.71 (0.41–1.24)0.2360.70 (0.38–1.29)0.248
NAT1.05 (0.40–2.74)0.9202.20 (0.69–6.99)0.182
GCS score <84.75 (2.70–8.33)<0.0014.40 (2.43–7.97)<0.001
Multiple trauma2.47 (1.43–4.27)0.0012.21 (1.18–4.15)0.014
EPTS1.85 (1.04–3.29)0.0372.08 (1.05–4.10)0.036

Poor functional outcomes are defined as a PCPC of moderate disability, severe disability, and vegetative state or coma. Boldface type indicates statistical significance.

Discussion

In our retrospective multicenter cohort of pediatric patients with moderate to severe TBI, we report an EPTS rate of 24.3%. We found younger age to be an independent risk factor for EPTS. Children with EPTSs experienced higher ICP (daily highest ICP) on day 2 and day 3 after admission to the hospital compared with those without EPTSs. We did not find an association between the presence of EPTS and mortality. However, among surviving patients, we found that the presence of EPTS was associated with poor functional outcomes (aOR 2.08, 95% CI 1.05–4.10; p = 0.036) even after adjusting for age, sex, TBI from NAT, multiple trauma, and severity of TBI (GCS score < 8). This is in keeping with two other single-center studies that found worse outcomes using the GOS among children with EPTS compared with those without.9,11

Our rate of EPTS at 24.3% for moderate to severe TBI is higher than that reported in the literature. EPTS rates between 6.9% and 12% have been reported depending on the severity of TBIs reported in various single-center studies.8,16,17 In our cohort of patients with moderate to severe TBI, slightly more than half had severe TBI with a GCS score < 8 (51.8%), and we reported a mortality rate of 15.6%. Thus, our high EPTS rate could reflect severe injury within our cohort. Since EPTSs are known to further damage the already injured brain through increased metabolism and cerebral hypoxia,5 this highlights an important area of study for children with TBI, especially in Asia.

Our findings reinforce the reported literature that younger age is a strong independent risk factor for EPTSs.7,17 As young children undergo periods of rapid brain growth with great neuroplasticity, they are at risk of EPTS as well as secondary brain damage due to EPTS.18 While NAT was more likely to occur in children with EPTS compared with those without, we did not find this association significant after adjusting for age and sex. This could be accounted for by the relatively small number of patients experiencing child abuse in our study. However, the absence of robust multidisciplinary assessment teams in many countries in Asia could impact accurate reporting, potentially resulting in child abuse being underreported in our part of the world.12 This vulnerable patient population will benefit from better case definitions and further study.

We did not find an association between the type of intracranial lesion on head CT and the presence of EPTS. While subdural hematomas have specifically been reported to be associated with posttraumatic seizures,17 we did not find a significant difference in the proportion of these in patients with EPTS compared with those without EPTS (29, 39.2% vs 63, 28.4%; p = 0.082) in our cohort. Future studies that focus on the epileptogenic potential of specific brain injuries may provide insight on the link between specific lesions and the likelihood of developing EPTSs.

We also wanted to understand the practice of EEG monitoring in Asian centers. In our study population, approximately 40% of patients received EEG monitoring; however, only 23.3% of all injured children had EEG monitoring performed before the onset of suspected seizures. Among children who experienced NAT (n = 23), EEG monitoring was performed in only 5 patients (21.7%) and only after the onset of suspected seizures. This highlights that routine continuous EEG monitoring is not practiced for many children with moderate to severe TBI among participating sites in our Asian cohort, and such monitoring may not be feasible in many settings. Therefore, we recommend that resources be focused on young children and those with suspected or confirmed NAT wherever possible, for early detection of EPTS.8

Prophylactic AEDs have not been proven to be protective against EPTS, and their use is still debated.6,8,19 Given the lack of well-controlled studies, the most recent Brain Trauma Foundation guidelines recommended only level III evidence for the use of prophylactic AEDs in pediatric patients with TBI.4,6,8,20,21 Although the proportion of children with EPTS among those who received prophylactic AEDs was smaller than the proportion with EPTS among those who did not receive prophylactic AEDs (17.5% vs 26.0%, p = 0.158), we were not able to establish the protective effect of prophylactic AEDs given our retrospective study design. Future prospective TBI research should focus on the impact of prophylactic AEDs on EPTS rates and clinical outcomes among high-risk groups, particularly young children.

We recognize the limitations of our study. The retrospective design mandates a cautious interpretation of our findings. Causation cannot be established between EPTS and poor functional outcomes, and future trials are needed to understand 1) if prophylactic AEDs can indeed reduce the incidence of or prevent EPTS, and 2) if this practice translates into better patient outcomes. Next, assessment of severity of injury using the presenting GCS score has limitations. The underlying specific brain injury may vary from a focal bleed to cerebral contusions, diffuse axonal injuries, and cerebral edema;22 therefore, future research on EPTSs should look into specific pathophysiology mechanisms and their epileptogenic potential. This may provide guidance on which child will truly benefit from seizure prophylaxis. We also recognize that although all sites had EEG monitoring, the lack of standardized practices for EEG monitoring had implications on potential missed nonconvulsive seizures. We found deviations from the standard TBI guidelines in our cohort. For example, there was a greater proportion of children with EPTS who underwent hypothermia treatment compared with those without EPTS (18.4% vs 7.6%, p = 0.042). Since hypothermia treatment is not routine and not recommended for children with TBI,4 this was likely due to individual physician practices. Finally, we recognize that being a multicenter study, interventional strategies vary, and some confounders may not be known or measurable. Nevertheless, by including 8 Asian centers in this study we were better able to understand the prevalence of EPTS and obtain an overview of physician practices in our part of the world.

Conclusions

Approximately 25% of children with moderate to severe TBI had EPTSs in our study. Younger age was an independent predictor for EPTSs, and the presence of EPTSs was associated with poor functional outcomes among patients who survived TBI. We highlight that routine EEG monitoring may be beneficial for specific high-risk groups. Future prospective research is needed to validate the impact of EEG monitoring and early seizure management on long-term patient outcomes in these vulnerable pediatric populations.

Acknowledgments

This study was funded by a SingHealth Foundation research grant (no. SHF/FG670P/2017). The grant was awarded to Dr. Shu-Ling Chong. The funding organization had no role in the design of the study, collection, analysis, interpretation of data, or in writing the manuscript.

We would like to thank Ms. Dianna Sri, Ms. Tan Sili, Dr. Sheng Fu (KK Women’s and Children’s Hospital), and Ms. Patricia Tay (Singapore Clinical Research Institute) for their coordination and contributions to this manuscript.

We would also like to acknowledge the following PACCMAN members: Ji Jian (Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China) and Lijia Fan (Khoo Teck Puat National University Children’s Medical Institute, National University Hospital, Singapore).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Chong, Qian, Lee. Acquisition of data: Chong, Qian, Yao, Dang, Chan, Ming, Gan, Ong, Kurosawa. Analysis and interpretation of data: Chong, Qian, Yao, Allen, Lee. Drafting the article: Chong, Allen, Dang, Chan, Ming, Gan, Ong, Kurosawa. Critically revising the article: Chong, Yao, Allen, Gan, Lee. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Chong. Statistical analysis: Chong, Allen. Study supervision: Lee.

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    Liesemer K, Bratton SL, Zebrack CM, Brockmeyer D, Statler KD. Early post-traumatic seizures in moderate to severe pediatric traumatic brain injury: rates, risk factors, and clinical features. J Neurotrauma. 2011;28(5):755762.

    • Search Google Scholar
    • Export Citation
  • 9

    Ateş O, Ondül S, Önal C, Büyükkiraz M, Somay H, Cayli SR, et al. Post-traumatic early epilepsy in pediatric age group with emphasis on influential factors. Childs Nerv Syst. 2006;22(3):279284.

    • Search Google Scholar
    • Export Citation
  • 10

    Arndt DH, Lerner JT, Matsumoto JH, Madikians A, Yudovin S, Valino H, et al. Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort. Epilepsia. 2013;54(10):17801788.

    • Search Google Scholar
    • Export Citation
  • 11

    Chiaretti A, De Benedictis R, Polidori G, Piastra M, Iannelli A, Di Rocco C. Early post-traumatic seizures in children with head injury. Childs Nerv Syst. 2000;16(12):862866.

    • Search Google Scholar
    • Export Citation
  • 12

    Chong SL, Dang H, Ming M, Mahmood M, Zheng CQS, Gan CS, et al. Traumatic brain injury outcomes in 10 Asian pediatric intensive care units: a Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) retrospective study. Pediatr Crit Care Med. 2021;22(4):401411.

    • Search Google Scholar
    • Export Citation
  • 13

    Fiser DH, Long N, Roberson PK, Hefley G, Zolten K, Brodie-Fowler M. Relationship of pediatric overall performance category and pediatric cerebral performance category scores at pediatric intensive care unit discharge with outcome measures collected at hospital discharge and 1- and 6-month follow-up assessments. Crit Care Med. 2000;28(7):26162620.

    • Search Google Scholar
    • Export Citation
  • 14

    Fiser DH, Tilford JM, Roberson PK. Relationship of illness severity and length of stay to functional outcomes in the pediatric intensive care unit: a multi-institutional study. Crit Care Med. 2000;28(4):11731179.

    • Search Google Scholar
    • Export Citation
  • 15

    Chong SL, Ong GYK, Zheng CQ, Dang H, Ming M, Mahmood M, et al. Early coagulopathy in pediatric traumatic brain injury: a Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) retrospective study. Neurosurgery. 2021;89(2):283290.

    • Search Google Scholar
    • Export Citation
  • 16

    Lewis RJ, Yee L, Inkelis SH, Gilmore D. Clinical predictors of post-traumatic seizures in children with head trauma. Ann Emerg Med. 1993;22(7):11141118.

    • Search Google Scholar
    • Export Citation
  • 17

    Rumalla K, Smith KA, Letchuman V, Gandham M, Kombathula R, Arnold PM. Nationwide incidence and risk factors for posttraumatic seizures in children with traumatic brain injury. J Neurosurg Pediatr. 2018;22(6):684693.

    • Search Google Scholar
    • Export Citation
  • 18

    Kuluz J. Posttraumatic seizures in children with severe traumatic brain injury. Pediatr Crit Care Med. 2017;18(1):8788.

  • 19

    Kolf MJ, McPherson CC, Kniska KS, Luecke CM, Lahart MA, Pineda JA. Early post-traumatic seizure occurrence in pediatric patients receiving levetiracetam prophylaxis with severe traumatic brain injury. J Pediatr Pharmacol Ther. 2020;25(3):241245.

    • Search Google Scholar
    • Export Citation
  • 20

    Pearl PL, McCarter R, McGavin CL, Yu Y, Sandoval F, Trzcinski S, et al. Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy. Epilepsia. 2013;54(9):e135e137.

    • Search Google Scholar
    • Export Citation
  • 21

    Young KD, Okada PJ, Sokolove PE, Palchak MJ, Panacek EA, Baren JM, et al. A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Ann Emerg Med. 2004;43(4):435446.

    • Search Google Scholar
    • Export Citation
  • 22

    Appavu B, Foldes ST, Adelson PD. Clinical trials for pediatric traumatic brain injury: definition of insanity?. J Neurosurg Pediatr. 2019;23(6):661669.

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  • View in gallery

    Boxplot showing the daily maximum ICP reading by absence (n = 14) and presence (n = 52) of EPTSs. Circles and plus signs indicate outliers in the absent and present groups, respectively. Diamonds indicate the means and thick black lines indicate the medians. Figure is available in color online only.

  • 1

    Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation. 2007;22(5):341353.

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  • 2

    Prasad MR, Swank PR, Ewing-Cobbs L. Long-term school outcomes of children and adolescents with traumatic brain injury. J Head Trauma Rehabil. 2017;32(1):E24E32.

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  • 3

    Sariaslan A, Sharp DJ, D’Onofrio BM, Larsson H, Fazel S. Long-term outcomes associated with traumatic brain injury in childhood and adolescence: a nationwide Swedish cohort study of a wide range of medical and social outcomes. PLoS Med. 2016;13(8):e1002103.

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  • 4

    Kochanek PM, Tasker RC, Carney N, Totten AM, Adelson PD, Selden NR, et al. Guidelines for the management of pediatric severe traumatic brain injury. Pediatr Crit Care Med. 2019;20(3S):S1S82.

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    • Export Citation
  • 5

    Zimmermann LL, Diaz-Arrastia R, Vespa PM. Seizures and the role of anticonvulsants after traumatic brain injury. Neurosurg Clin N Am. 2016;27(4):499508.

    • Search Google Scholar
    • Export Citation
  • 6

    Chung MG, O’Brien NF. Prevalence of early posttraumatic seizures in children with moderate to severe traumatic brain injury despite levetiracetam prophylaxis. Pediatr Crit Care Med. 2016;17(2):150156.

    • Search Google Scholar
    • Export Citation
  • 7

    O’Neill BR, Handler MH, Tong S, Chapman KE. Incidence of seizures on continuous EEG monitoring following traumatic brain injury in children. J Neurosurg Pediatr. 2015;16(2):167176.

    • Search Google Scholar
    • Export Citation
  • 8

    Liesemer K, Bratton SL, Zebrack CM, Brockmeyer D, Statler KD. Early post-traumatic seizures in moderate to severe pediatric traumatic brain injury: rates, risk factors, and clinical features. J Neurotrauma. 2011;28(5):755762.

    • Search Google Scholar
    • Export Citation
  • 9

    Ateş O, Ondül S, Önal C, Büyükkiraz M, Somay H, Cayli SR, et al. Post-traumatic early epilepsy in pediatric age group with emphasis on influential factors. Childs Nerv Syst. 2006;22(3):279284.

    • Search Google Scholar
    • Export Citation
  • 10

    Arndt DH, Lerner JT, Matsumoto JH, Madikians A, Yudovin S, Valino H, et al. Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort. Epilepsia. 2013;54(10):17801788.

    • Search Google Scholar
    • Export Citation
  • 11

    Chiaretti A, De Benedictis R, Polidori G, Piastra M, Iannelli A, Di Rocco C. Early post-traumatic seizures in children with head injury. Childs Nerv Syst. 2000;16(12):862866.

    • Search Google Scholar
    • Export Citation
  • 12

    Chong SL, Dang H, Ming M, Mahmood M, Zheng CQS, Gan CS, et al. Traumatic brain injury outcomes in 10 Asian pediatric intensive care units: a Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) retrospective study. Pediatr Crit Care Med. 2021;22(4):401411.

    • Search Google Scholar
    • Export Citation
  • 13

    Fiser DH, Long N, Roberson PK, Hefley G, Zolten K, Brodie-Fowler M. Relationship of pediatric overall performance category and pediatric cerebral performance category scores at pediatric intensive care unit discharge with outcome measures collected at hospital discharge and 1- and 6-month follow-up assessments. Crit Care Med. 2000;28(7):26162620.

    • Search Google Scholar
    • Export Citation
  • 14

    Fiser DH, Tilford JM, Roberson PK. Relationship of illness severity and length of stay to functional outcomes in the pediatric intensive care unit: a multi-institutional study. Crit Care Med. 2000;28(4):11731179.

    • Search Google Scholar
    • Export Citation
  • 15

    Chong SL, Ong GYK, Zheng CQ, Dang H, Ming M, Mahmood M, et al. Early coagulopathy in pediatric traumatic brain injury: a Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) retrospective study. Neurosurgery. 2021;89(2):283290.

    • Search Google Scholar
    • Export Citation
  • 16

    Lewis RJ, Yee L, Inkelis SH, Gilmore D. Clinical predictors of post-traumatic seizures in children with head trauma. Ann Emerg Med. 1993;22(7):11141118.

    • Search Google Scholar
    • Export Citation
  • 17

    Rumalla K, Smith KA, Letchuman V, Gandham M, Kombathula R, Arnold PM. Nationwide incidence and risk factors for posttraumatic seizures in children with traumatic brain injury. J Neurosurg Pediatr. 2018;22(6):684693.

    • Search Google Scholar
    • Export Citation
  • 18

    Kuluz J. Posttraumatic seizures in children with severe traumatic brain injury. Pediatr Crit Care Med. 2017;18(1):8788.

  • 19

    Kolf MJ, McPherson CC, Kniska KS, Luecke CM, Lahart MA, Pineda JA. Early post-traumatic seizure occurrence in pediatric patients receiving levetiracetam prophylaxis with severe traumatic brain injury. J Pediatr Pharmacol Ther. 2020;25(3):241245.

    • Search Google Scholar
    • Export Citation
  • 20

    Pearl PL, McCarter R, McGavin CL, Yu Y, Sandoval F, Trzcinski S, et al. Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy. Epilepsia. 2013;54(9):e135e137.

    • Search Google Scholar
    • Export Citation
  • 21

    Young KD, Okada PJ, Sokolove PE, Palchak MJ, Panacek EA, Baren JM, et al. A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Ann Emerg Med. 2004;43(4):435446.

    • Search Google Scholar
    • Export Citation
  • 22

    Appavu B, Foldes ST, Adelson PD. Clinical trials for pediatric traumatic brain injury: definition of insanity?. J Neurosurg Pediatr. 2019;23(6):661669.

    • Search Google Scholar
    • Export Citation

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