Epilepsy Research 164 (2020) 106354

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Epilepsy Research
journal homepage: www.elsevier.com/locate/epilepsyres

Epidemiology of traumatic brain injury-associated epilepsy in western T

China: An analysis of multicenter data
Xue-ping Wanga, Jie Zhongb, Ting Leic, Hai-jiao Wanga, Li-na Zhua, Shanshan Chua, Ling Liua,*
a
Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China
b
Department of Ophthalmology, Sichuan Provincial People’s Hospital, No. 32 West Second Section First Ring Road, Chengdu, Sichuan, China
c
Department of Neurosurgery, Shang Jin Nan Fu Hospital of West China Hospital, Sichuan University, No. 253, Shang Jin Road, Chengdu, 610041, Sichuan Province,
China

A R T I C LE I N FO A B S T R A C T

Keywords: Objectives: This study aims to explore the probability of developing posttraumatic epilepsy (PTE) in the fol-
Posttraumatic lowing 8 years after traumatic brain injury (TBI), the risk factors associated with PTE and its cumulative pre-
Epilepsy valence.
Traumatic brain injury Methods: This is a retrospective follow-up study of patients with traumatic brain injury (TBI) discharged from
Incidence
the West China Hospital between January 1, 2011 and December 31, 2017, Chengdu Shang Jin Nan Fu Hospital
Risk factors
and Sichuan Provincial People’s Hospital from January 1, 2013 to March 1, 2015. We used forward stepwise
method to build the final multivariate cox proportional hazard regression model to obtain estimates of hazard
ratio (HR) of PTE and 95% confidence intervals (CI). We also conducted Kaplan–Meier survival analysis to
investigate the cumulative prevalence of PTE.
Results: The cumulative incidence of PTE rose from 6.2% in one year to 10.6% in eight years. There were more
male patients in PTE group and generally older. Besides, patients with PTE tended to have abnormal CT scan
results. The risk factors of PTE were male (HR = 1.6, 95% CI: 1.1−2.2, P = 0.009), early posttraumatic seizures
(HR = 2.9, 95% CI: 2.2−4.1, P < 0.001), TBI severity (moderate TBI: HR = 3.0, 95% CI: 1.8−5.0, P = 0.001;
severe TBI: HR = 4.3, 95% CI: 2.3−7.6, P < 0.029), loss of consciousness (LOC) more than 30 min (30
min–24 h: HR = 1.8, 95% CI: 1.02−3.1, P = 0.041; > 24 h: HR = 2.4, 95% CI: 1.4−2.4, P = 0.001), subdural
hematoma (SDH) (HR = 1.9, 95% CI: 1.4−2.5, P < 0.001), brain contusion sites (frontal–temporal lobe:
HR = 2.7, 95% CI: 1.9−3.9, P < 0.001; other sites: HR = 1.5, 95% CI: 1.01−2.3, P = 0.042) and cranial
surgery (HR = 1.7, 95% CI: 1.3−2.3, P < 0.001).
Significance: The probability of developing PTE increased during the study period. In addition, the risk of de-
veloping PTE was significantly associated with gender, EPTS, LOC time, SDH, brain contusion sites, surgery and
TBI severity. However, further researches may be needed to predict the risk of PTE in combination with
quantitative factors.

1. Introduction
Traumatic brain injury (TBI) is a major cause of morbidity and
mortality, with a decline in quality of life and serious consequences for
many survivors, especially younger children and the elderly
(Pickelsimer et al., 2006). Seizure is known to be a common sequela of
traumatic brain injury and can even occur for many years after injury in
all age groups (Frey, 2003; Statler, 2006). With the rapid development
of China’s economy and health concerns, traumatic brain injury is be-
coming more and more common, so are posttraumatic seizures (PTS).
Therefore, some patients and their caregivers are beginning wonder:
How likely am I to have PTE?

Abbreviation: TBI, traumatic brain injury; PTE, posttraumatic epilepsy; PTS, posttraumatic seizure; IPTS, immediate posttraumatic seizure; EPTS, early posttrau-
matic seizure; LPTS, late posttraumatic seizure; ICD, International Classification of Diseases; LOH, length of hospital stay; CT, computed tomography; MRI, magnetic
resonance imaging; MVA, motor vehicle accident; SDH, subdural hematoma; EDH, epidural hematoma; ICH, intracranial hemorrhage; SAH, subarachnoid hemor-
rhage; DAI, diffuse axonal injury; LOC, loss of consciousness; GCS, Glasgow Coma Scale; ILAE, International League Against Epilepsy; IBE, International Bureau for
Epilepsy; EEG, electroencephalogram; SD, standard deviation; CI, confidence intervals; RR, risk ratio; IQR, interquartile range
⁎
Corresponding author.
E-mail address: zjllxx1968@163.com (L. Liu).

https://doi.org/10.1016/j.eplepsyres.2020.106354
Received 30 December 2019; Received in revised form 17 April 2020; Accepted 4 May 2020
Available online 11 May 2020
0920-1211/ © 2020 Elsevier B.V. All rights reserved.
X.-p. Wang, et al.
The epidemiology of seizures and epilepsy after traumatic brain
injury has been studied in different countries and some risk factors are
thought to be correlated with PTS and posttraumatic epilepsy (PTE),
such as gender, history of alcohol abuse, posttraumatic amnesia, focal
neurologic signs, loss of consciousness, skull fracture, midline shift,
brain contusion, subdural hemorrhage, intracranial hemorrhage, clin-
ical severity of TBI and acute symptomatic seizure as concluded by a
meta-analysis (Xu et al., 2017). Prior literatures also reported some
other risk factors, like older age (Annegers et al., 1998; DeGrauw et al.,
2018), cranial surgery (Ritter et al., 2016a, 2016b, 2016c, Chen et al.,
2017), simple partial seizures (Chen, Li et al. 2017). So far, there have
been some studies on PTS in China, but either these studies have a
relatively short follow up time, about 2–3 years (Wang et al., 2008;
Zhao et al., 2012; Wang et al., 2013) or they are single- center studies
(Chen et al., 2017), and the risk factors are not consistent. At present,
there is no long-term follow-up studies on PTS in China. As studies
indicate the cumulative incidence of PTE increase with length of follow-
up, we are the first to investigate the incidence and risk factors of PTE
in a large cohort with all age groups patients hospitalized at three
medical centers in China.
In this study, our goal is to assess the incidence of PTE after TBI and
to investigate characteristics related to demographic, clinical pre-
sentation and image results to identify independent risk factors that can
help predict epileptic events after TBI.
2. Methods
This study was approved by the West China Hospital of Sichuan
University Ethics Committee. And the subjects or their agents agreed to
participate in this study.
2.1. Patient material and data collection
West China Hospital’s (a tertiary referral center in Sichuan province,
China) electronic medical record database was retrospectively queried
for patients hospitalized between January 1, 2011 and December 31,
2017 with a diagnosis of TBI, which was defined as any hospital dis-
charge with a primary or secondary diagnosis of trauma to the head,
according to the International Classification of Diseases (ICD-10), pa-
tients diagnosed as traumatic brain injury (S06.902), cerebral concus-
sion (S06.001), subdural hematoma (SDH) (S06.501), epidural hema-
toma (EDH) (S06.401), subarachnoid hemorrhage (SAH) (S06.601),
skull fracture (liner or depressed fracture) (S02.902), intracranial he-
morrhage (S06.806), brain contusion (S06.201), diffuse axonal injury
(S06.204) and open or closed TBI (S06.911) were extracted from the
electronic medical record database. The other two hospitals’ (Chengdu
Shang Jin Nan Fu Hospital and Sichuan Provincial People’s Hospital)
electronic medical records were also extracted from January 1, 2013 to
March 1, 2015. The inclusion criteria were: (1) the injury of the brain
was caused by external force and clinical diagnosis of TBI, (2) the
traumatic incident occurred at West China Hospital between January 1,
2011 and December 31, 2017, and Chengdu Shang Jin Nan Fu Hospital
and Sichuan Provincial People’s Hospital between January 1, 2013, and
March 1, 2015, (3) there was unabridged trauma-related data in med-
ical records, and (4) the patients or their relatives agreed to participate
in this study. The following patients were excluded: (1) Patients who
were known to have epilepsy or seizures before TBI. (2) Patients who
had TBI before, or have second or subsequent episodes of TBI. (3)
Patients who had previously suffered from other diseases that may lead
to seizure, such as cerebrovascular disease, brain tumors, encephalitis,
brain surgery and other chronic diseases, (4) Patients whose general
condition was poor or with other conditions that may result in epileptic
seizures before the PTS or PTE came out during follow-up. (Patients
selection of three hospitals was listed in Supplementary Fig. 1).
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Epilepsy Research 164 (2020) 106354
2.2. Investigation content and procedures
Formally trained neurologists filled out the designed forms of TBI-
related information according to the hospital records of the patients.
The survey included the demographic data (age, gender, length of
hospital stay, previous history), the circumstance of TBI (mechanism of
injury, severity of TBI, clinical manifestations, treatments, computed
tomography (CT) or magnetic resonance imaging (MRI) studies per-
formed at initial presentation), and the seizure onset information
during their hospitalization (EPTS and IPTS). We characterized the
mechanism of injury as four levels: motor vehicle accident (MVA),
violence, fall from height ≤1 m, fall from height > 1 m (Ferguson et al.,
2010; Wang et al., 2013; Ritter et al., 2016a, 2016b, 2016c). We ex-
amined case records for clinical and neurological assessment at arrival,
whether this patient had neurological deficits on arrival. The treat-
ments of TBI are divided into conservative treatment, surgery (in-
cluding craniotomy, decompressive craniectomy, removal of brain
tissue, etc., that is, the cranium is opened, intracranial foreign body or
brain tissue is removed, and the cranium is not closed) and puncture
(borehole drainage, place intracranial pressure monitor, that is, the
cranium is closed).
We coded CT or MRI scan results into the following groups: SDH,
EDH, SAH, fracture (liner or depressed fracture), ICH, cerebral contu-
sion load (with their locations), DAI and open or closed TBI. Contusion
load was calculated by adding the number of contusion areas estab-
lished in the CT/MRI images. These regions were represented by cor-
tical areas or non-cortical local contusion, such as frontal, temporal,
parietal, occipital, and local non-cortical contusion, if only one region
had contusion, the contusion load was 1(Ritter et al., 2016a, 2016b,
2016c). If a patient had both frontal and temporal lobe contusion, then
it was defined as frontal–temporal lobe contusion. While if he had ei-
ther frontal, temporal or other-site lobe, it was defined as other sites
contusion (Wang et al., 2013).
Loss of consciousness (LOC) was obtained and further categorized
into three levels according to duration: 0−30 min, 31 min to 24 h, and
more than 24 h.
Brain injury severity stratification was identified based on the
Glasgow Coma Scale (GCS) Rating (Mena et al., 2011). The GCS score
ranges were used to classify TBI severity as follows: 3–8, “severe’’;
9–12, “moderate’’; and 13–15, “mild.’’ GCS was measured upon ad-
mission to the hospital.
2.3. Definition of PTS
According to the new definition of epilepsy proposed by the
International League Against Epilepsy (ILAE) and the International
Bureau for Epilepsy (IBE), epilepsy is a disorder of the brain char-
acterized by an enduring predisposition to generate epileptic seizures
(Fisher et al., 2014). The definition of epilepsy requires at least two
unprovoked (or reflex) seizures occurring > 24 h apart (Fisher et al.,
2014). PTS was defined as a single, non-recurrent convulsive episode,
and it can be divided into three categories according to the time of
seizure onset, as follows: immediate PTS (IPTS) as a seizure occurring
within the first 24 h after injury (Iudice and Murri, 2000), early post-
traumatic seizure (EPTS) was defined that seizures occurred within 1–7
days of injury (Yablon, 1993; Agrawal et al., 2006), and late PTS (LPTS)
occur more than a week after trauma. PTE usually refers to 2 or more
relapses, unprovoked, late (i.e., occurring more than 1 week after TBI)
posttraumatic seizures.
2.4. Prospective data collection and outcome
From July 2018 to March 2019, researchers followed patients with
complete information via telephone. All participants were followed up
at least one year to detect seizures. Among the participants who were
unable to understand the survey, we interviewed their close relatives
X.-p. Wang, et al.
and their nursing staff or general practitioner. The follow-up survey
contains the general condition of the patient (whether he had cachexia,
whether he had some other diseases before PTS or PTE which can lead
to seizures), the occurrence of seizures (when did the first seizure attack
appeared after discharge from hospital), the type and frequency of
seizures (the clinical manifestations and frequency of epileptic sei-
zures), and the treatment condition (whether he took anti-epileptic
drugs and the drug dosage). Positive answers were determined by the
definition of PTE, underwent an electroencephalogram (EEG), diag-
nosed and treated by a neurologist.
The main outcome measure was the incidence of epilepsy after TBI,
which was defined as two or more unprovoked seizure episodes after
one week of TBI.
2.5. Statistical analysis
A database was created in Excel, and statistical analysis was per-
formed using SPSS 22.0 (SPSS Inc., Chicago, IL, USA). The numeric
variables are presented as mean and standard deviation (SD), inter-
quartile range (IQR). The incidence rates are expressed in percentile, to
examine associations of categorical and quantitative prognostic factors
with the development of PTE, the Fisher exact test and Mann-Whitney
U test were applied, respectively. To study the risk factors causing PTE,
21 factors thought to possibly associate with PTE entered to a uni-
variate cox regression analysis firstly. The factors included such as age,
gender, LOH, GCS score, severity, LOC, LOC time, neurological deficits,
CT founding (SDH, EDH, SAH, skull fracture, ICH, DAI, open TBI,
contusion sites, contusion load), the mechanism of injury, treatment,
IPTS and EPTS.
The multivariate cox proportional hazards regression model was
conducted to identify the risk factors of PTE using a forward stepwise
method, which included all variables with a P value < 0.05 in the
univariate cox regression analysis. PTE was represented by the depen-
dent variable (Y), and the factors affecting PTE were designated as the
independent variable (X). Statistical analyses were 2-tailed and sig-
nificance was set to a P value < 0.05. The cumulative probability of
posttraumatic epilepsy after traumatic brain injury was estimated with
the use of the Kaplan–Meier method.
3. Results
3.1. Demographic information
A total of 5389 TBI cases were admitted into our study from three
hospitals between the defined time before. Of these, 3869 cases were
extracted after discharge, 412 patients died, and 1108 cases were in
other situations (Supplementary Fig. 1). According to the exclusion
criteria, we attempted to contact the 3549 discharged patients by tel-
ephone, 501 died from other diseases or accidents, and 908 unreach-
able, 5 with other diseases that might lead to epilepsy or progressive
diseases. Finally, 2135 patients were successfully followed-up.
Complete demographic and hospitalization data, injury details are
listed in Table 1. The average age at admission was 38.72 ± 23.32
years (IQR: 20–57 years), and more than half of patients were male
(1577 male, 73.9%). The mean follow-up term was 67.23 ± 19.01
months after brain injury (IQR: 57–81.07 months). The average LOH
was 14.36 ± 20.6 days (IQR: 5–16 days). The average GCS score was
12.3 ± 3.5 (range 3–15), 1407 (65.9%), 339 (15.9%) and 389 (18.2%)
patients were considered suffering from mild, moderate and severe TBI
based on GCS score at arrival. 1055 (49.4%) patients lost consciousness
after TBI, of which 510 (23.9%) patients lost consciousness for more
than 24 h. MVA was the most common cause of injury, 816 injuries
(38.2%) were caused by MVA, 681 patients (31.9%) fall from a height
≤ 1 m, and 401 (18.8%) fall from a height > 1 m. 493 (23.1%) patients
had some degree of neurological deficits, either movement disorder or
aphasia. 814 (38.1%) patients suffered injuries that required
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Epilepsy Research 164 (2020) 106354
neurological surgery and 127 (6%) patients underwent puncture. 32
(1.5%), 124 (5.8%) and 9 (0.4%) patients had IPTS, EPTS and LPTS,
respectively.
A total of 226 PTE cases were recorded after the brain injury, with
an incidence rate of 10.6% (95% CI: 9.3%–11.9%). Among the PTE
patients, there were 187 (82.7%) males, which was higher than that in
the non-PTE group. PTE patients were older than the non-PTE patients
(41.79 ± 18.22 vs 38.35 ± 23.83, P = 0.036). The average hospital
stay of PTE cases was also longer than that of non-PTE cases
(27.84 ± 28.45 vs 12.77 ± 18.84, P < 0.001). Compared with non-PTE
subjects, more PTE subjects had neurological deficits and loss of con-
sciousness [neurological deficits: 126 (55.8%) vs 367 (19.2%),
P < 0.001; LOC: 168 (74.3%) vs 887 (46.5%), P < 0.001). (Table 1)].
There were more severe patients in PTE group than in non-PTE group
[severe TBI: 140 (61.9%) vs 249 (13%), P < 0.001]
3.2. CT imaging features
After reviewing CT/MRI scan images at admission, 928 (43.5%)
subjects were found to have SDH, 747 (35%) cases had EDH and 643
(30.1%) patients had ICH. Evidence of SAH and DAI was present in 606
(28.4%) and 228 (10.7%) patients, and 414 (19.4%) patients had
frontal–temporal contusion, while 555 (25.9%) TBI patients had other
sites contusion. 147 (6.9%) patients were considered open TBI. CT
scans of 828 (38.8%) patients were interpreted as having liner fracture
while 189 (8.9%) subjects as depressed fracture (Table 1).
PTE patients were more likely to have abnormal CT scan images
than non-PTE patients (including SDH, EDH, ICH, SAH, DAI, brain
contusion, fracture and open TBI, both P value < 0.005) (Table 1).
3.3. Incidence of seizure and epilepsy
Of the 2135 TBI patients, 165 (7.7%) were diagnosed with post-
traumatic seizures and 32 (1.5%) cases were diagnosed with immediate
posttraumatic seizures (IPTS), 124 (5.8%) suffered from early-stage
seizures (EPTS) and 9 (0.4%) suffered from late-stage seizures (LPTS),
226 (10.6%) were diagnosed with posttraumatic epilepsy. A total of
132 (6.2%) PTE occurred within 1 year after brain trauma. At the end of
5 years, this number reached about 207 (9.7%), and the final PTE pa-
tients with the longest follow up term at 100.52 months (about 8 years)
were 226 (10.6%). About 36 (1.7%) PTE occurred with mild TBI, 50
(2.3%) with moderate TBI and 140 (6.6%) cases with severe TBI
(Table 1).
3.4. Factors affecting PTE
3.4.1. Univariate analysis
To study the risk factors causing PTE, 21 factors which were thought
to possibly associate with PTE entered to a univariate cox regression
analysis firstly. Those factors are listed in Table 1. These factors include
gender, age, severity of TBI (Initial GCS value), LOH, LOC, LOC time,
neurological deficits, surgical intervention, contusion load, contusion
sites, SDH, EDH, SAH, DAI, skull fracture and EPTS between the groups
were statistically significant (both P < 0.01) (Table 2).
3.4.2. Multivariate analysis
Multivariate cox proportional hazards regression analysis was per-
formed on factors with P < 0.05 by univariate cox analysis using for-
ward stepwise (P < 0.05) to identify independent risk factors for PTE
(Table 2). We found 7 factors that contributed to PTE. Gender (Male:
HR = 1.6, 95% CI: 1.1−2.2, P = 0.009) and EPTS (EPTS: HR = 2.9,
95% CI: 2.2−4.1, P < 0.001) were risk factors for PTE. In addition,
frontal–temporal lobe contusion and other sites contusion had 2.7 times
(frontal–temporal lobe contusion: HR = 2.7, 95% CI: 1.9−3.9,
P < 0.001) and 1.5 times (Other sites contusion: HR = 1.5, 95% CI:
1.01−2.3, P = 0.042) more likely to develop PTE compared to those
X.-p. Wang, et al. Epilepsy Research 164 (2020) 106354

Table 1
Comparison of demographic data between the PTE and non-PTE patients.
Items Total (n = 2135) Non-PTE (n = 1909) PTE (n = 226) P value

Demographic data
Gender (Male, n, %) 1577 (73.9%) 1390 (72.8%) 187 (82.7%) 0.001
Age (year, mean ± SD) 38.72 ± 23.32 38.35 ± 23.83 41.79 ± 18.22 0.036
Follow up (months) 67.23 ± 19.01 67.66 ± 18.56 63.6 ± 22.14 0.08
Clinical characteristics
GCS score 12.3 ± 3.5 12.78 ± 3.18 8.23 ± 3.40 < 0.001
13−15 1407 (65.9%) 1371 (71.8%) 36 (15.9%) < 0.001
9−12 339 (15.9%) 289 (15.1%) 50 (22.1%)
3−8 389 (18.2%) 249 (13%) 140 (61.9%)
LOH (days) 14.36 ± 20.6 12.77 ± 18.84 27.84 ± 28.45 < 0.001
Neurological deficits 493 (23.1%) 367 (19.2%) 126 (55.8%) < 0.001
LOC 1055 (49.4) 887 (46.5%) 168 (74.3%) < 0.001
LOC time < 0.001
0−30 min 1409 (65.9%) 1367 (71.6%) 42 (18.6%)
31min-24 h 216 (10.1%) 192 (10.1%) 24 (10.6%)
> 24 h 510 (23.9%) 350 (18.3%) 160 (70.8%)
Etiology of TBI < 0.001
MVA 816 (38.2%) 696 (36.5%) 120 (53.1%)
Violence 238 (11.1%) 221 (11.6%) 17 (7.5%)
Fall ≤1 m 680 (31.9%) 629 (32.9%) 51 (22.6%)
Fall > 1 m 401 (18.8%) 363 (19%) 38 (16.8%)
Treatment < 0.001
Conservative 1194 (55.9%) 1122 (58.8%) 72 (31.9%)
Neurological Surgery 814 (38.1%) 670 (35.1%) 144 (63.7%)
Puncture 127 (6%) 117 (6.1%) 10 (4.4%)
Neuroimaging abnormal
SDH 928 (43.5%) 760 (39.8%) 168 (74.3%) < 0.001
EDH 747 (35%) 616 (32.3%) 131 (58%) < 0.001
ICH 643 (30.1%) 594 (31.1%) 49 (21.7%) 0.001
SAH 606 (28.4%) 523 (27.4%) 83 (36.7%) 0.004
DAI 228 (10.7%) 87 (4.6%) 141 (62.4%) < 0.001
Contusion sites < 0.001
No 1166 (54.6%) 1116 (58.5%) 50 (22.1%)
*Frontal–temporal lobe 414 (19.4%) 289 (15.1%) 125 (55.3%)
*Other sites 555 (25.9%) 504 (26.4%) 51 (22.6.8%)
Fracture 0.002
No 1118 (52.3%) 1024 (53.6%) 94 (41.6%)
Liner 828 (38.8%) 716 (37.5%) 112 (49.6%)
Depressed 189 (8.9%) 169 (8.9%) 20 (8.8%)
Open 147 (6.9%) 110 (5.8%) 37 (16.4%) < 0.001
PTS and PTE
IPTS 32 (1.5%) 26 (1.4%) 6 (2.7%) 0.142
EPTS 124 (5.8%) 64 (3.4%) 60 (26.5%) < 0.001
LPTS 9 (0.4%) 9 (0.5%) – –
PTE 10.6% (9.3%–11.9%) – – –
Risk of PTE within 1 year 132 (6.2%) – –
Risk of PTE within 5 year 207 (9.7%) – –
Risk of PTE within 8 year 226 (10.6%) – –
PTE in mild TBI 36 (1.7%) – –
PTE in moderate TBI 50 (2.3%) – –
PTE in severe TBI 140 (6.6%) – –

Abbreviation: LOH = length of hospital stay, GCS = Glasgow Coma Scale, LOC = loss of consciousness, MVA = motor vehicle accident, SDH = subdural hematoma,
EDH = epidural hematoma, ICH = intracranial hemorrhage, SAH = subarachnoid hemorrhage, DAI = diffuse axonal injury, IPTS = immediate posttraumatic
seizure, EPTS = early posttraumatic seizure, LPTS = late posttraumatic seizure, PTE = posttraumatic epilepsy.
* Frontal–temporal lobe contusion = patients had both frontal and temporal lobe contusion; Other sites = contusion don’t involve both frontal and temporal lobe
or just subcortex contusion. LPTS means patients had only one seizure attack after 7 days of TBI.

who did not have, respectively. SDH was also a predictor for PTE
(HR = 1.9, 95% CI: 1.4−2.5, P < 0.001). The severity of injury
measured by the initial GCS score was also correlated with the occur-
rence of PTS. The moderate (GCS 9−12) and severe (GCS 3−8) TBI
patients were 3.0 (HR = 3.0, 95% CI: 1.8−5.0, P = 0.001) and 4.3
(HR = 4.3, 95% CI: 2.3−7.6, P < 0.001) times more likely to have
PTE compared to the mild TBI patients (GCS 13−15), respectively.
Subjects who lost consciousness more than 30 min were also at higher
risk to develop PTE than those whose LOC time less than 30 min (LOC
time =30 min–24 h, HR 1.8, 95% CI: 1.02−3.1, P = 0.042; LOC
time > 24 h: HR 2.4, 95% CI: 1.4−2.4, P = 0.001). Furthermore, pa-
tients who underwent neurological surgery were approximately 1.7
(HR = 1.7, 95% CI: 1.3−2.3, P < 0.001) times more likely to develop
PTE than conservative treatment.
3.5. Cumulative probability of PTE
Fig. 1A–H shows the cumulative probability of PTE in the entire
cohort and which is based on the severity of TBI, EPTS, LOC time,
gender, contusion sites, SDH and treatment of the traumatic brain in-
jury. As Fig.1A showed the cumulative probability of PTE in the entire
cohort increases over time. Fig. 1B–H showed that the cumulative
probability of PTE also increased with the extension of follow-up time
as stratification of seven independent risk factors.

4
X.-p. Wang, et al. Epilepsy Research 164 (2020) 106354

Table 2 multicenter study was 9.8% within 2 years (Wang et al., 2013), since
Univariable and multivariable cox proportional hazards analysis of predictors our research was based on multicenter data and the follow-up period
associated with PTE in the multicenter cohort. was longer (median 6 years). A meta-analysis reported the pooled
Items Univariable Multivariable prevalence of PTE after TBI was 15% (95% CI 14–17%) (Xu et al.,
2017), and studies in other countries estimated that the incidence was
HR 95% CI P value HR 95% CI P value about 13–37% (Armstrong et al., 1990; De Santis et al., 1992; Haltiner
et al., 1997; Asikainen et al., 1999; Englander et al., 2003a, 2003b). The
Gender (male) 1.7 1.2−2.4 0.002 1. 6 1.1−2.2 0.009
Age group incidence of PTE among civilians is 1.8–5% (Frey, 2003; Chen et al.,
≤15 1 – – 1 – – 2014), while the incidence of war-induced patients was around 53%
16−40 2.9 1.8−4.5 < 0.001 1.2 0.6−2.2 0.637 (Chen et al., 2014), which was higher than our study. Because these
41−64 2.8 1.7−4.6 0.001 1.1 0.5−2.6 0.874
studies focused on different TBI patients (some studies just included
≥65 0.7 0.3−1.6 0.412 0.4 0.1−1.6 0.199
LOH (days) 1.1 1.01−1.15 0.001 0.99 0.93−1.01 0.385
moderate and severe patients), longer follow up time (up to 30 years),
Etiology different PTE definitions (PTE was defined as one or more seizure one
Fall > 1 m 1 – – 1 – – week after TBI) and severity definitions (some used GCS scores and
Fall ≤1 m 0.8 0.5−1.3 0.251 1.1 0.7−1.5 0.754 others used the clinical manifestations and CT/MRI results). Our study
Violence 0.7 0.4−1.3 0.300 0.9 0.5−1.7 0.800
reported 6-year cumulative PTE probability was 1.7% for mild, 2.3%
MVA 1.6 1.1−2.3 0.015 1.2 0.7−1.8 0.506
LOC 3.1 2.3−4.2 < 0.001 0.8 0.6−1.2 0.299 for moderate, and 6.6% for severe TBI, similar to a study in the US,
LOC time which reported 5-year cumulative PTE probability was 0.7% for mild,
< 30 min 1 – – 1 – 1.2% for moderate, and 10% for severe TBI (Chen et al., 2014). Zhao
30 min–24 h 3.9 2.4−6.5 < 0.001 1.8 1.02−3.1 0. 041
et al. reported the prevalence of PTE was 3.6%, 6.9% and 17.0% in
> 24 h 12.5 8.9−17.6 < 0.001 2.4 1.4−2.4 0.001
Neurological 4.7 3.6−6.2 < 0.001 1.2 0.9−1.7 0.263
mild, medium and severe TBI, based on the GCS classification. This
deficit incidence rates were higher than our study, since they defined those
GCS 0.8 0.73−0.78 < 0.001 0.99 0.9−1.1 0.911 patients whose GCS was 8 as moderate TBI and their sample size was
Severity larger (Zhao et al., 2012). Considering the above discrepancies between
Mild 1 – – 1 – –
studies, our study included TBI patients of all ages, three level of TBI
Moderate 6.1 3.9−9.4 < 0.001 3.0 1.8−5.0 0.001
Severe 17.5 12.1−25.3 < 0.001 4.3 2.3−7.6 < 0.001 severity (based on the most often used and easier classification), and
SDH 2.1 1.5−2.6 < 0.001 1.9 1.4−2.5 < 0.001 patients from three hospitals, which made this research even more
EDH 1.7 1.2−2.3 0.001 1.3 0.9−1.8 0.193 significant.
Contusion site
A lot of studies have identified some risk factors for PTE, such as
No 1 – – 1 – –
Other sites 2.2 1.5−3.2 0.001 2.7 1.9−3.9 < 0.001
age > 65 years, penetrating injuries, TBI severity, abnormal CT/MR
Frontal–temporal 8.1 5.9−11.3 < 0.001 1.5 1.01−2.3 0.042 scan (e.g. SDH, intracranial hemorrhage, greater than 5 mm midline
lobe* shift, biparietal or multiple brain contusion, liner skull fracture), loss of
ICH 3.4 2.6−4.5 < 0.001 0.9 0.7−1.3 0.797 consciousness > 24 h, posttraumatic amnesia lasted more than 24 h,
Contusion load
craniocerebral surgery, early posttraumatic seizure, family history of
0 1 – – 1 – –
1 1.7 1.1−2.8 0.020 1.6 0.95−2.6 0.072 epilepsy, history of mental illness (Agrawal et al., 2006; Lowenstein,
≥2 6.4 4.6−8.8 < 0.001 1.7 1.01−2.9 0.045 2009; Christensen, 2012; Da Silva and Willmore, 2012; Pitkänen and
Fracture Bolkvadze, 2012). However, in addition to the severity of TBI, other
No 1 – – 1 – – studies have not reached consensus on other risk factors, because these
Liner 1.6 1.2−2.2 0.003 0.9 0.7−1.3 0.637
Depressed 1.2 0.7−2.0 0.376 1.1 0.6−1.9 0.636
studies had some differences in statistical methods, the definition of risk
SAH 1.5 1.1−2.0 0.003 0.8 0.6−1.03 0.089 factors and the study population. By retrieving previous researches on
DAI 3.5 2.5−5.1 < 0.001 1.1 0.8−1.7 0.540 risk factors, our study used the most commonly and easily operated
Open TBI 1.3 0.8−2.2 0.219 NA# NA NA classification methods and we finally found 7 risk factors for PTE,
IPTS 1.9 0.9−4.3 0.116 NA NA NA
gender (especial male), loss consciousness more than 30 min, EPTS,
EPTS 7.9 5.9−10.6 < 0.001 2.9 2.2−4.1 < 0.001
Treatment craniocerebral surgery, severity of TBI, brain contusion sites and SDH,
Conservative 1 – – 1 – all these factors were reported by other studies.
Surgery 3.2 2.4−4.2 < 0.001 1.6 0.9−3.4 0.110 EPTS was a crucial predictor of PTE. It was reported that individuals
Puncture 1.3 0.7−2.6 0.414 1.7 1.3−2.3 < 0.001 with early seizures had a 36.8 times higher risk of developing PTE than
those without early seizure (DeGrauw et al., 2018). Early seizures were
Abbreviation: LOH = length of hospital stay, GCS = Glasgow Coma Scale,
LOC = loss of consciousness, MVA = motor vehicle accident, SDH = subdural considered to be provoked, but some researchers argued that “seizure
hematoma, EDH = epidural hematoma, ICH = intracranial hemorrhage, begets seizure” (Scharfman, 2007), early seizure may damage the
SAH = subarachnoid hemorrhage, DAI = diffuse axonal injury, neuroregulatory system after injury and alter glutamate management
IPTS = immediate posttraumatic seizure, EPTS = early posttraumatic seizure, and inflammatory response to promote TBI-induced excitatory and
PTE = posttraumatic epilepsy, NA = not available, RR = risk ratio, enable seizure-prone systems (Bratton et al., 2007; Sofroniew, 2009).
CI = confidence interval. Some studies defined severity of TBI based on the time of un-
* Frontal–temporal lobe contusion = patients had both frontal and temporal consciousness, the longer the time of unconsciousness, the worse the
lobe contusion; Other sites = contusion do not involve both frontal and tem- TBI [Serious traumatic brain injuries were characterized by one or more
poral lobe or just subcortex contusion.
#
of the following features: brain contusion (diagnosed on the basis of
NA, these two variables had no significant in univariable cox regression
observation during surgery or focal neurologic symptoms), intracranial
(P > 0.05), they did not enter into the multivariable cox proportional hazard
hematoma, or loss of consciousness or post-traumatic amnesia for more
regression.
than 24 h. Moderate traumatic brain injuries were characterized by one
or more of the following features: loss of consciousness or post-trau-
4. Discussion
matic amnesia lasting 30 min to 24 h or a skull fracture. Mild traumatic
brain injuries were characterized by an absence of fracture and a loss of
We found the prevalence of PTE was 10.6%, which was higher than
consciousness or post-traumatic amnesia for less than 30 min (Annegers
another two studies in China, one retrospective single center study was
et al., 1998). Cranial surgeries were also a PTS predictor in our models,
5% within 3 years (Zhao et al., 2012) and the other prospective
as confirmed by previously published findings (Englander et al., 2003a,

5
X.-p. Wang, et al.
Fig. 1. Kaplan–Meier estimate of cumulative probability of PTE in the cohort.
(A) Cumulative Probability of PTE in the overall cohort. (B–H) Kaplan–Meier estimate according to seven risk factors that had significant difference in the multi-
variable cox proportional hazards regression model. PTE = posttraumatic epilepsy, TBI = traumatic brain injury, EPTS = early posttraumatic seizure, LOC = loss of
consciousness, SDH = subdural hematoma, HR = hazard ration.
2003b, Walker et al., 2015; Ritter et al., 2016a, 2016b, 2016c). Sur-
geries may bring more damage to brain tissue and result in some
complications, thereby increasing the risk of late seizure (Honeybul and
Ho, 2014). In addition, the study also pointed out that more severe TBI
patients would require surgery rather than conservative treatment
(Fisher et al., 2012), which means that if the patient undergone surgical
treatment, to some extent, it indicated that his TBI was more severe
than those who received conservative treatment, surgery might be a
sign of severe TBI. Almost all studies found that severe TBI was a risk
factor for PTE, and this conclusion indirectly support our result that
surgery was a risk factor for PTE.
As for neuroimaging data, SDH was a significant risk factor of PTE,
consistent with many studies (Englander et al., 2003a, 2003b, Walker
et al., 2015; Ritter et al., 2016a, 2016b, 2016c). We also noticed that
patients with contusion, especially those with frontal–temporal lobe,
were more likely to develop PTE, which was reported in some studies
that PTE was most often in the temporal lobe (57%), then in the frontal
lobe (35%), and rarely in the occipital and parietal lobes (Gupta et al.,
2014; Tubi et al., 2019). SDH regions had a tendency to temporal glial
scarring, which is the mechanism of epilepsy formation (Sills, 2007;
Sofroniew, 2009). Both human and animal studies have shown that the
temporal lobe structure had a higher risk of atrophy and a lower seizure
threshold and susceptibility (Vespa et al., 2010; Gupta et al., 2014;
Mamad et al., 2018). These findings imply that future research should
focus on the temporal lobe to assess the genesis and progression of PTE.
Epidemiological studies have found that the latency between TBI
and PTE attacks varies greatly. Researches documented the risk of
epilepsy after brain injury was highest in the first few years after injury
(Christensen et al., 2009; Zhao et al., 2012; Wang et al., 2013). A po-
pulation-based case–control study found that the risk of PTE was
greatest in the first 6 months after severe TBI or mild TBI, and the risk
of PTE remained elevated even in 10 years after any TBI (Mahler et al.,
2015). Recent data indicate that the majority (86%) of the subsequent
unprovoked seizure considered to be associated with brain trauma
would occur within 2 years (Haltiner et al., 1997) and remain high for
more than 10 years after the injury. Compared with people without TBI
(Christensen et al., 2009). Our study showed that 60.2% of PTE oc-
curred within 1 year after brain injury and the rate increased as the
follow-up time extended, which was consistent with previous studies.
6
Epilepsy Research 164 (2020) 106354
The K–M survival curve showed that the cumulative prevalence of PTE
increased with time. After stratified by the independent risk factors, the
K–M survival curve showed a similar trend.
We are the first multi-center study on PTE in China with a longer
follow-up period, and our study has the advantage of being demo-
graphically heterogeneous. Before extracting data, we reviewed all re-
levant researches, including the most frequently reported risk factors,
which can be obtained from clinical practice. Otherwise we used the
K–M survival analysis to show the cumulative prevalence of PTE in
overall cohort and that according to different risk factors. However, our
study was a retrospective analysis of database, so it was inevitable that
there may be flaws in the design of such studies, as well as the inability
to obtain certain data, for example, whether the patient suffered from
mental illness and the time of amnesia. Nowadays, continuous EEG
monitoring studies found that epileptiform abnormalities during the
acute period following traumatic brain injury independently predict
post-traumatic epilepsy in 1 years after TBI (Kim et al., 2018), and the
advanced MR technology indicated the gliomesenchymal sequelae of
focal brain lesions (subdural hematomas/contusions) that required
surgical treatment were a PTE risk factor (Messori et al., 2005).
Therefore, in the future, we can diagnose whether posttraumatic epi-
lepsy will occur in patients based on more quantitative indicators, so as
to take appropriate intervention measures as soon as possible, which
will help to improve the accuracy and predictability of decision-
making.
5. Conclusion
Our study focuses on the epidemiologic features and risk factors for
PTE after brain injury. Due to the longer follow-up time in our study
and the multi-center cohort, we found a higher risk of PTE (10.6%) than
the other two studies in China. The development of PTE was related to
gender, loss of consciousness for more than 30 min, EPTS, craniocer-
ebral surgery, the severity of TBI, brain contusion sites and SDH. Most
PTE occurred within 1 year after TBI and the K–M survival curve in-
dicated that the cumulative prevalence of PTE increased with the time
extending.
X.-p. Wang, et al.
Author contributions
Dr Ling Liu had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analysis.
Concept and design: Ling Liu, Jie Zhong, Ting Lei, Xueping Wang.
Acquisition, analysis, or interpretation of data: Xueping Wang,
Haijiao Wang, Shanshan Chu, Lina Zhu.
Drafting of the manuscript: Xueping Wang.
Critical revision of the manuscript for important intellectual con-
tent: Ling Liu.
Funding
This study was funded by 1·3·5 project for disciplines of excellence –
Clinical Research Incubation Project, West China Hospital, Sichuan
University (2019HXFH048).
Disclosure
The authors report no disclosures relevant to the manuscript.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.eplepsyres.2020.
106354.
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