RESEARCH ARTICLE

Effect of Antiepileptic Drugs for Acute and

Chronic Seizures in Children with Encephalitis
Kuang-Lin Lin1,2*, Jainn-Jim Lin1,2,3,4, Shao-Hsuan Hsia2,3, Min-Liang Chou1,2, Po-
Cheng Hung1,2, Huei-Shyong Wang1,2, CHEESE Study Group2¶
1 Division of Pediatric Neurology, Chang Gung Children’s Hospital and Chang Gung Memorial Hospital, Chang
Gung University College of Medicine, Taoyuan, Taiwan, 2 Chang Gung Children’s Hospital Study Group for
Children with Encephalitis/Encephalopathy Related Status Epilepticus and Epilepsy (CHEESE), Taoyuan,
Taiwan, 3 Division of Pediatric Critical Care and Emergency Medicine, Chang Gung Children’s Hospital and
Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan, 4 Graduate
Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan

¶ Membership of the CHEESE Study Group is provided in the Acknowledgments.

* lincgh@cgmh.org.tw

Abstract
OPEN ACCESS
Background
Citation: Lin K-L, Lin J-J, Hsia S-H, Chou M-L, Hung
P-C, Wang H-S, et al. (2015) Effect of Antiepileptic Encephalitis presents with seizures in the acute phase and increases the risk of late unpro-
Drugs for Acute and Chronic Seizures in Children voked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs
with Encephalitis. PLoS ONE 10(10): e0139974. in pediatric patients with acute seizures due to encephalitis and epilepsy.
doi:10.1371/journal.pone.0139974

Editor: Giuseppe Biagini, University of Modena and Patients and Methods

Reggio Emilia, ITALY
Cases of acute pediatric encephalitis between January 2000 and December 2010 were
Received: June 11, 2015
reviewed. Clinical data, including onset at age, seizure type, seizure frequency, effects of
Accepted: September 18, 2015 antiepileptic drugs, and prognosis were analyzed.
Published: October 7, 2015

Copyright: © 2015 Lin et al. This is an open access

Results
article distributed under the terms of the Creative During the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them,
Commons Attribution License, which permits
44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251)
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with
credited. postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free
Data Availability Statement: The minimal dataset even after discontinuing the antiepileptic drugs. Among those with postencephalitic epi-
are within the paper and Supporting Information files. lepsy, 67% had favorable outcomes and were using <2 anti-epileptic drugs while 15% had
Additional data are available upon request from the intractable seizures and were using  2 antiepileptic drugs. After benzodiazepines, intrave-
Chang Gung Memorial Hospital Ethics Committee for
nous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures
researchers who meet the criteria for access to
confidential data or from the corresponding author in the acute phase. For refractory status epilepticus, high-dose topiramate combined with
(lincgh@cgmh.org.tw). intravenous high-dose phenobarbital or high-dose lidocaine had less side effects.
Funding: The work was supported by grants from
Chang Gung Memorial Hospital (grant: Conclusions
CMRPG4C0022), Taiwan(https://www.cgmh.org.tw/).
Children with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and
The funder had no role in study design, data
collection and analysis, decision to publish, or clonazepam are the most common drugs used, alone or in combination, for postencephalitic
preparation of the manuscript. epilepsy.

PLOS ONE | DOI:10.1371/journal.pone.0139974 October 7, 2015 1 / 11

 Seizures in Children with Encephalitis

Competing Interests: The authors have declared

that no competing interests exist. Introduction
Encephalitis is a common central nervous system disorder in children. It refers to inflamma-
tion and swelling of the brain often caused by either a direct viral infection or an immune-
mediated process. It is an important cause of acute symptomatic seizures and subsequent epi-
lepsy [1–3]. Previous epidemiologic studies have shown that 2.7–27% of epilepsies are second-
ary to previous central nervous system infections [4–7]. Encephalitis-related seizures may
present as a single seizure or as refractory status epilepticus, or even intractable epilepsy. But
few studies have reported on the efficacy and choice of antiepileptic drugs for acute seizures,
chronic seizures and epilepsy in children.
Acute central nervous system infections are most often evidenced in the first episode of sta-
tus epilepticus and appear to be markers for morbidity and mortality [8]. Based on the underly-
ing risk factors, optimal treatment should be given to minimize brain damage in the acute
phase. If management is not initiated promptly, refractory status epilepticus may develop, with
subsequent progression to intractable epilepsy. Postencephalitic epilepsy has been reported to
become intractable in 40–50% of children [9,10]. This study, therefore, aimed to report clinical
experience on the use of antiepileptic drugs in the management of acute and chronic seizures
in children with encephalitis. The outcomes were analyzed after at least one year of follow-up.

Materials and Methods

Data source
All case records from the Department of Pediatrics, Chang Gung Children’s Hospital coded
with the discharge diagnosis of acute encephalitis from January 2000 to December 2010 were
reviewed. Encephalopathy was defined as at least one symptom or sign of parenchymatous
brain dysfunction such as altered consciousness, personality or behavioral change, seizure,
paresis, or ataxia. Encephalitis was defined as the presence of encephalopathy plus at least two
of the following: (1) body temperature >38°C; (2) cerebrospinal fluid examination showing
increased protein content >40 mg/dL and/or pleocytosis >5 white blood cells/uL; (3) abnor-
mal electroencephalography (EEG) findings, such as diffuse or focal slow activity, or periodic
lateralized epileptiform discharge; and (4) abnormal neuroimaging results including computed
tomography (CT) and magnetic resonance imaging (MRI) [10–13]. Acute symptomatic sei-
zures in this study were defined as seizures occurring within 7 days (acute phase) after onset of
symptoms or signs of encephalitis. Unprovoked seizures were defined as seizures occurring in
the absence of a potentially responsible clinical condition or beyond the interval estimated for
the occurrence of acute symptomatic seizures [14]. The definition of postencephalitic epilepsy
was modified as two or more unprovoked seizures after acute phase of encephalitis or recurrent
seizures with abnormal EEG findings and/or MRI findings (high recurrence risk) at follow-up
that required antiepileptic drugs more than 6 months after encephalitis [15–17].

Patients
All of the children were previously healthy and none had prior seizures including febrile sei-
zures. The exclusion criteria were age >18 years, purulent meningitis, prior neurological insult,
progressive neurologic disorder, seizures due to electrolyte imbalance, or hypoglycemia. The
Chang Gung Memorial Hospital’s Institutional Review Board approved this study (103-
7263B). The need for informed consent was waived by the Institutional Review Board because
the study was an observational, retrospective study using a database from which the patients’
identification information had been removed.

PLOS ONE | DOI:10.1371/journal.pone.0139974 October 7, 2015 2 / 11

 Seizures in Children with Encephalitis

Data collection
By chart review, data were collected, including age at onset, sex, presence or absence of seizures
during the acute phase, initial seizure type, frequency of seizures (single, repetitive, status epi-
lepticus, and refractory status epilepticus), response to antiepileptic drugs, mortality, and sei-
zure outcomes of epilepsy. Repetitive seizures were defined as 2 seizures within the period of
the acute phase, with the interval of 2 seizures >30 min. Status epilepticus was defined as con-
tinuous seizure activity lasting 30 min, or two or more discrete seizures between which con-
sciousness was not fully regained [18]. Refractory status epilepticus was defined as seizures
lasting more than 2 h despite treatment with conventional antiepileptic drugs.
Patients with status epilepticus were treated with a protocol that included initial therapy
with a benzodiazepine, followed by therapeutic doses of phenytoin, phenobarbital, and/or val-
proic acid. If refractory status epilepticus was evident, the goal of treatment was to achieve
complete clinical seizure control or a burst suppression pattern on electroencephalography.
Treatment included multiple high-dose suppressive therapy of valproic acid, midazolam, pro-
pofol, thiopental, lidocaine, and high-dose phenobarbital [19]. The number of patients
responding to the first, second, third, and fourth antiepileptic drugs was recorded. For a single
seizure, repetitive seizures, or status epilepticus, the clinical cessation of convulsions was con-
sidered to be a therapeutic response. Mortality during the hospital stay and the causes were
recorded.
Seizure outcomes were assessed on the last clinical visit. All patients with postencephalitic
epilepsy with abnormal electroencephalography findings or recurrence of unprovoked seizures
were treated with antiepileptic drugs for 6 months. The patients were then classified into
three groups based on seizure outcomes after treatment at one year of follow-up: (1) intractable
postencephalitic epilepsy; (2) favorable outcome; and (3) successful antiepileptic drugs with-
drawal after 1 year of treatment. Intractable postencephalitic epilepsy was defined as more than
two seizures per month in patients receiving two or more antiepileptic drug treatments. Favor-
able outcome was defined as either seizure-free or fewer than two seizure episodes per month
after treatment. The follow-up period for the study group ranged from 1 year to 12 years and 5
months (mean±standard deviation (SD), 4.82±3.72 years).

Statistical analysis
Statistical analysis was performed using the SPSS statistical software, version 12.0 (SPSS, Inc.,
Chicago, IL). Independent t test or one-way analysis of variance was used for continuous vari-
ables, and the χ2 or Fisher’s exact test was used for categorical variables. Statistical significance
was set at p<0.05. All statistical tests were two-tailed.

Results
Demographic data
During the study period, 1138 patients were discharged with a diagnosis of acute encephalitis.
After excluding 100 patients with underlying neurologic diseases, 1038 previously healthy
patients diagnosed with acute encephalitis were enrolled in the study. There were 450 (43.4%)
girls and 588 (56.6%) boys. Their mean age at onset of acute encephalitis was 6.07±4.47 years
(range, 2 months to 18 years). Among them, 469 (45.2%) patients were aged 4 years, 288
(27.7%) were 5–8 years old, 163 (15.7%) were 9–12 years old, and 118 (11.4%) were 13–17
years old. The highest incidence of encephalitis was in the group aged 4 years. Most patients
(n = 759, 72.9%) had encephalitis before the age of 8 years. The presumed infectious pathogens
of children with acute seizures were showed in Table 1.

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 Seizures in Children with Encephalitis

Table 1. The infectious pathogens of 463 children with different seizure frequency in acute phase.

presumed infectious pathogens (n)

Seizure frequency in acute phase M. pneumonia enterovirus HSV influenza viruses VZV unknown
Single seizure 13 3 11 12 7 37
Repetitive seizures 26 27 10 4 0 160
Status epilepticus 11 2 15 3 1 68
Refractory status epilepticus 11 0 5 2 0 35
Total (n) 61 32 41 21 8 300

M. pneumonia: mycoplasma pneumonia; HSV: herpes simplex virus; VZV: varicella-zoster virus

doi:10.1371/journal.pone.0139974.t001

Seizure profiles
During the acute phase of encephalitis, 463 of 1038 (44.6%) patients had acute seizures. The
initial seizure types were categorized into focal seizures (n = 125/463, 27%), generalized tonic-
clonic seizures (n = 149/463, 32.2%), myoclonic seizures (n = 56/463, 12.1%), and secondarily
generalized seizures (n = 133/463, 28.7%). The frequency of seizures was classified into single
seizure (n = 83/463, 17.9%), repetitive seizures (n = 227/463, 49%), status epilepticus (n = 100/
463, 21.6%), and refractory status epilepticus (n = 53/463, 11.4%).

Antiepileptic drugs for encephalitis-related acute symptomatic seizures

There were 463 patients with acute symptomatic seizures in the acute phase of encephalitis,
including 330 patients who received antiepileptic drugs after admission. Of patients with single
seizure (n = 83), 53 did not receive any antiepileptic drugs and 30 received antiepileptic drugs.
All responded to diazepam or lorazepam. For patients with repetitive seizures (n = 227), 147
were treated with antiepileptic drugs. As regards initial antiepileptic drugs, 17 of 147 patients
(11.6%) were controlled after diazepam or lorazepam, while 130 patients were treated with sec-
ond-line antiepileptic drugs. Sixteen patients were initially treated with oral antiepileptic drugs
as second-line for seizure control, including oral carbamazepine (n = 10), clonazepam (n = 3),
lamotrigine (n = 1), carbamazepine plus clonazepam (n = 1), and carbamazepine plus lamotri-
gine (n = 1). The remaining 114 patients received intravenous antiepileptic drugs as second-
line treatment.
Of the 114 patients, 96 (84.2%) responded to the second-line drugs. Phenytoin was adminis-
tered to 61 patients and phenobarbital was administered to 51 patients, which resulted in the
cessation of clinical seizures in 46 (75.4%) and 48 (94.1%) of patients, respectively. Phenobarbi-
tal was more effective than phenytoin (p = 0.009). In all of the refractory patients, phenobarbi-
tal and valproic acid were effective as a third choice of drug. However, there were no
statistically significant differences between the types of drugs. The order and effectiveness of
each intravenous antiepileptic drug used were summarized in Table 2.
All of the patients with status epilepticus and refractory status epilepticus (n = 153) were
treated with intravenous antiepileptic drugs after initial diazepam or lorazepam. Seventy-four
(48.4%) of the 153 patients were controlled after a second antiepileptic drug. Phenytoin was
administered to 104 patients and phenobarbital was administered to 49 patients, which
resulted in the cessation of clinical seizures in 49 (47.1%) and 25 (51%) of the patients, respec-
tively. Phenobarbital was more effective than phenytoin, but not statistically significant
(p = 0.056).
In the refractory patients, phenytoin was effective as a third choice in six of 17 patients
(35.3%), phenobarbital was effective in 13 of 47 patients (27.6%), valproic acid was effective in

PLOS ONE | DOI:10.1371/journal.pone.0139974 October 7, 2015 4 / 11

 Seizures in Children with Encephalitis

Table 2. Sequence and efficacy of intravenous antiepileptic drugs in patients with acute symptomatic seizures after pediatric encephalitis
(n = 330).

Treatment */*, (* 1st 2nd 3rd 4th 5th 6th 7th 8th Cumulative
%) efficacy
Single seizure (n = 30)
Benzodiazepines 30/30 30/30 (100%)
(100%)
Repetitive seizures (n = 147)
Benzodiazepines 17/147 17/147 (11.6%)
(11.6%)
Phenytoin 46/61 46/61 (75.4%)
(75.4%)
Phenobarbital 48/51 9/9 (100%) 57/60 (95%)
(94.1%)
Valproic acid 2/2 (100%) 1/1 (100%) 3/3 (100%)
Total 47/177 96/114 10/10
(26.6%) (84.2%)a (100%)b
Status epilepticus or refractory status epilepticus(n = 153)
Benzodiazepines 0/153 (0%)
Phenytoin 49/104 6/17 55/121 (45.4%)
(47.1%) (35.3%)
Phenobarbital 25/49 (51%) 13/47 38/96 (39.5%)
(27.6%)
Valproic acid 5/13 4/23 4/7 13/43 (30.2%)
(38.5%) (17.4%) (57.1%)
Midazolam CIV 1/2 (50%) 15/24 0/16 (0%) 16/42 (38.1%)
(62.5%)
Propofol CIV 1/1 (100%) 3/3 2/4 (50%) 6/8 (75%)
(100%)
Thiopental CIV 2/2 (100%) 1/1 (100%) 0/1 (0%) 1/1 4/5 (80%)
(100%)
TPM+Lidocaine 7/11 0/2 (0%) 7/13 (53.8%)
(63.6%)
TPM+HD-PB 2/2 1/1 (100%) 2/3 0/2 (0%) 5/8 (62.5%)
(100%) (66.7%)
Total 0/153 (0%) 74/153 25/79 22/50 9/28 11/17 2/6 1/3
(48.4%) (31.6%)c (44%) (32.1%) (64.7%)d (33.3%)e (33.3%)

*/*: number of seizure termination/number of trial

(*):(efficacy, %)
Benzodiazepines: diazepam or lorazepam
CIV: continuous intravenous administration; TPM: high-dose topiramate; HD-PB: high-dose phenobarbital
Seizures were not clearly terminated but gradually subsided after treatment with other oral antiepileptic drugs in (a) 16 patients, (b) 8 patients, (c) 4
patients, (d) 1 patient, and (e) 1 patient.

doi:10.1371/journal.pone.0139974.t002

five of 13 patients (38.5%), and midazolam was more effective in one of two patients (50%).
However, there were no statistically significant differences among the types of drug. The
sequence and effectiveness of each of the intravenous antiepileptic drugs used were summa-
rized in Table 2.
Fifty-three patients did not respond to any of the third-line drugs and developed refractory
status epilepticus. Seizures were stopped by multiple high-dose suppressive therapy in 45 chil-
dren, including thiopental (n = 4/5, 80%), propofol (n = 6/8, 75%), high-dose topiramate com-
bined with high-dose phenobarbital (n = 5/8, 62.5%), high-dose topiramate combined with

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 Seizures in Children with Encephalitis

high-dose lidocaine (n = 7/13, 53.8%), midazolam (n = 15/40, 37.5%), and valproic acid (n = 8/
30, 26.7%). However, the relative risk for respiratory depression and hypotension was higher in
the use of thiopental or propofol than in high-dose topiramate combined with high-dose lido-
caine or high-dose phenobarbital for seizure control (10/13 vs. 12/21, p = 0.030).
All of the patients in this study who developed respiratory depression required ventilatory
support. Six of eight (75%) patients who used thiopental and five (100%) who used propofol
developed hypotension. Six of 13 (46.2%) who used high-dose topiramate combined with high-
dose lidocaine and three of eight (37.5%) patients who used high-dose phenobarbital also
developed hypotension. Seizures gradually subsided after a ketogenic diet in three patients.
Five of 53 (9.4%) patients did not respond to any antiepileptic drugs.

Mortality and outcomes

Fifteen patients were discharged against medical advice while 33 died during their hospital stay
due to uncal herniation (n = 16), sepsis (n = 11), thiopental- or propofol-induced profound
hypotension (n = 5), and ventricular fibrillation/ventricular tachycardia (n = 1). Mortality was
related to poor control of status epilepticus. Fourteen of 53 (26.4%) patients with refractory sta-
tus epilepticus died, but only 19 of 971 (2.0%) with non-refractory status epilepticus died
(p<0.001).

Antiepileptic drugs and postencephalitic epilepsy at one year of follow-

up
A total of 990 survivors were discharged, including 268 (27.1%) who were discharged with anti-
epileptic drug treatment (Fig 1). Excluding 23 patients who were lost to follow-up and excluded
from the analysis, 251 of the 967 (26%) patients developed postencephalitic epilepsy. Of the
251, 46 (18.3%) successfully stopped taking antiepileptic drugs within one year, while 205
(78.7%) continued to receive antiepileptic drugs. Among them, 138 (54.9%) received a single
antiepileptic drug for seizure control, 30 (11.9%) received two antiepileptic drugs, and 37
(14.7%) received more than two antiepileptic drugs. Phenobarbital and clonazepam were the
most common drugs used in combination therapy for postencephalitic epilepsy. Of the 251
patients, 214 (85.3%) had favorable outcomes and 37 (14.7%) had intractable seizures. The
antiepileptic drugs used for postencephalitic epilepsy were summarized in Table 3.
A total of 990 survivors were enrolled, including 268 (27.1%) who were discharged with
antiepileptic drugs (AEDs) treatment. Thirty-seven children (37/251, 15%) with intractable
epilepsy received more than two AEDs at one year of follow-up.

Discussion
Central nervous system infections are a known risk factor for the development of acute symp-
tomatic seizures and represent a major risk factor for acquired epilepsy [20]. In a recent study
of acute seizures in central nervous system infections, 23% of patients have acute seizures and
73% have encephalitis, which is a significantly more frequent etiology than meningitis. Viral
encephalitis has been shown to result in a 14-fold increase in the risk of acute seizures [21]. In
the present study, 463 (44.6%) children with encephalitis have had seizures in the acute phase,
suggesting that encephalitis leads to a high percentage of the presentation of acute seizures,
especially in pediatric encephalitis. In this cohort, 153 (33%) patients with acute seizures have
status epilepticus, including 53 (34.6%) who developed refractory status epilepticus. Thus, once
seizures develop in the acute phase of pediatric encephalitis, clinicians should be aware of the
possible development of refractory status epilepticus.

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 Seizures in Children with Encephalitis

Encephalitis is most often evidenced in first episode of status epilepticus and appears to be a
marker for morbidity and mortality [8]. In the present study, 14/53 (26.4%) of patients with
refractory status epilepticus died, whereas only 19/971 (2.0%) of patients with non-refractory
status epilepticus died (p<0.001). Therefore, mortality is significantly related to the presence of
refractory status epilepticus in the pediatric patients with encephalitis. The underlying cause is
well known to be the influential factor on the outcome of status epilepticus [22,23]. Therefore,
clinicians should do their best to treat the underlying disease and provide effective antiepileptic
drugs for the best possible outcomes.

Fig 1. Flow diagram of children with postencephalitic epilepsy.

doi:10.1371/journal.pone.0139974.g001

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 Seizures in Children with Encephalitis

Table 3. Choice of antiepileptic drugs for postencephalitic epilepsy in 205 children.

AED Number (%) PB BZD VPA CBZ TPM OXC LEV PHT LA VGB LTG AZA GBP
Single AED 138 (67.3%) 72 16 13 19 7 3 5 2 1
Multiple AEDs
2 AEDs 30 (14.6%) 15 12 10 8 6 2 2 3 1 1
3 AEDs 24 (11.7%) 10 11 11 7 11 3 7 2 2 5 3
4 AEDs 8 (3.9%) 6 6 4 1 3 1 2 4 1
5 AEDs 4 (2.0%) 4 4 3 1 3 2 1 1 1
6 AEDs 1 (0.5%) 1 1 1 1 1 1
Total 205 (100%) 108 49 41 37 31 11 10 9 9 9 7 2 1

AED: antiepileptic drugs; PB: phenobarbital; BZD: benzodiazepines (diazepam or lorazepam); VPA: valproic acid; CBZ: carbamazepine; TPM: topiramate;
OXC: oxcarbazepine; LEV: levetiracetam; PHT: phenytoin; LA: phenytoin+phenobarbital; VGB: vigabatrin; LTG: lamotrigine; AZA: acetazolamide; GBP:
gabapentin

doi:10.1371/journal.pone.0139974.t003

In general, seizures are initially treated with boluses of intravenous lorazepam or diazepam
as first-line drugs, followed by intravenous infusions of phenytoin and/or phenobarbital as sec-
ond-line drugs. Phenytoin is reported to be ineffective for febrile status epilepticus [24,25].
Sugai suggests that pentobarbital is effective for prolonged status epilepticus whereas phenytoin
is for cluster convulsive status epilepticus [26]. In this study, phenobarbital (97.5%) is more
effective than phenytoin (75.4%) for controlling repetitive seizures (p = 0.009). Phenobarbital
may therefore be a suitable second-line antiepileptic drug for seizures in pediatric encephalitis.
In the current study, 53 patients did not respond to the initial antiepileptic drug and devel-
oped refractory status epilepticus. They responded to high-dose suppressive therapy that
included intravenous thiopental (80%), propofol (75%), high-dose topiramate combined with
high-dose phenobarbital (62.5%), or high-dose lidocaine (53.8%). In addition, three patients
responded to a ketogenic diet combined with antiepileptic drugs. In terms of adverse effects, 5
of 13 (38.5%) patients died due to thiopental- (n = 4) or propofol-induced (n = 1) profound
hypotension. Therefore, we suggest that high-dose topiramate combined with intravenous
high-dose phenobarbital or high-dose lidocaine may be considered as an alternative third-line
treatment for refractory status epilepticus due to encephalitis [19,27,28]. A ketogenic diet may
also be considered [29–31].
Regarding the long-term management of postencephalitic epilepsy, it is reported that high-
dose phenobarbital is the most effective agent for seizure control during the recovery phase
and chronic phase of acute encephalitis with refractory repetitive partial seizures [26,27]. In the
current study (n = 205, 1 year follow-up), 168 (82%) patients with postencephalitic epilepsy
have favorable outcomes and 37 (18%) have intractable epilepsy. Phenobarbital and clonaze-
pam are the most common drugs used alone or in combination for postencephalitic epilepsy,
followed by valproic acid and carbamazepine. The role of new antiepileptic drugs in posten-
cephalitic epilepsy warrants further research.
The present study has some limitations. First, there was no routine electroencephalogram
monitoring for every patient. Thus, the subgroup of non-convulsive status epilepticus is not
identified. Second, bias may exist in the selection of antiepileptic drugs because this is a retro-
spective study. Third, the definitions of acute symptomatic seizure and postencephalitic epi-
lepsy are modified from those proposed by the International League Against Epilepsy
Epidemiology Commission. Fourth, this is not a population-based study. Further prospective
studies are necessary.

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 Seizures in Children with Encephalitis

Conclusions
Children with encephalitis may have a high rate (26%) of postencephalitic epilepsy, 15% of
them having intractable epilepsy. The mortality rate is significantly high when they develop
refractory status epilepticus. Based on the findings here, the recommended treatment for acute
seizures or status epilepticus in pediatric encephalitis should include several considerations.
First, phenobarbital is preferred over phenytoin as a second-line agent in treatment. Second,
high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lido-
caine may be considered third-line treatment for refractory status epilepticus.

Supporting Information
S1 File. The demographic data of 1038 encephalitic children. During the study period, 1138
patients were discharged with a diagnosis of acute encephalitis. After excluding 100 patients
with underlying neurologic diseases, 1038 previously healthy patients diagnosed with acute
encephalitis were enrolled in the study.
(XLS)

Acknowledgments
The authors thank Drs. Kuang-Lin Lin, Jainn-Jim Lin, Shao-Hsuan Hsia, Huei-Shyong Wang,
and the CHEESE (Children with Encephalitis/Encephalopathy Related Status Epilepticus and
Epilepsy) study group for providing clinical information on their patients; Dr. Huei-Shyong
Wang for reviewing the manuscript; and M.S. Yun-Tong Lin for helping in the clinical data
collection.

Contributors
Members of the CHEESE Study Group are: Kuang-Lin Lin (lead author, Division of Pediatric
Neurology, Chang Gung Children’s Hospital, lincgh@cgmh.org.tw); Huei-Shyong Wang, Min-
Liang Chou, Po-Cheng Hung, Meng-Ying Hsieh, I-Jun Chou, Shih-Yun Lan (Division of Pedi-
atric Neurology, Chang Gung Children’s Hospital); Jainn-Jim Lin, Shao-Hsuan Hsia (Division
of Pediatric Critical Care and Emergency Medicine, Chang Gung Children’s Hospital); Alex
Mun-Ching Wong (Department of Medical Imaging and Intervention, Chang Gung Memorial
Hospital); Cheng-Hsun Chiu (Molecular Infectious Disease Research Center, Division of Pedi-
atric Infection, Chang Gung Children’s Hospital and Chang Gung University); Wen-I Lee
(Department of Pediatric Allergy, Immunology, and Rheumatology, Chang Gung Children's
Hospital).

Author Contributions
Conceived and designed the experiments: KLL JJL. Performed the experiments: JJL SHH MLC
PCH. Analyzed the data: KLL JJL HSW. Contributed reagents/materials/analysis tools: JJL
HSW. Wrote the paper: KLL JJL.

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