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Pediatrics and Neonatology xxx (xxxx) xxx

Available online at www.sciencedirect.com

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journal homepage: http://www.pediatr-neonatol.com

Original Article

Therapeutic effects of children with

refractory epilepsy after vagus nerve
stimulation in Taiwan
Sung-Tse Li a,b,c, Nan-Chang Chiu c,d,*, Kun-Long Hung e,f,g,
Che-Sheng Ho c,d, Yung-Ting Kuo h,i, Wen-Hsiang Wu b on behalf
of the VNS TCNS j

a
Department of Pediatrics, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan
b
Department of Healthcare Management, Yuanpei University of Medical Technology, Hsinchu, Taiwan
c
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
d
Department of Pediatrics, MacKay Children’s Hospital, Taipei, Taiwan
e
Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan
f
Department of Pediatrics, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan
g
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
h
Department of Pediatrics, Shuang Ho Hospital, Ministry of Health and Welfare, Taipei Medical
University, New Taipei City, Taiwan
i
Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taiwan
j
Vagus Nerve Stimulation Study Group of Taiwan Child Neurology Society, Taiwan

Received Dec 5, 2019; received in revised form May 7, 2020; accepted Jul 10, 2020
Available online - - -

Key Words Background: Vagus nerve stimulation (VNS) is used as an add-on treatment for epilepsy. This
children; study aimed to use Taiwanese nationwide registry data to analyze the therapeutic effects of
refractory epilepsy; VNS in children with refractory epilepsy (RE) and try to explore predictive factors of VNS treat-
vagus nerve ment effectiveness.
stimulation Methods: This retrospective study collected data from December 2007 to December 2014. Pa-
tient variables included gender, age, VNS implantation date, epilepsy duration, seizure fre-
quency, seizure type, etiology, and antiepileptic drug (AED) history. We divided patients
into three groups: Group I as seizure frequency >80 times per month, Group II as seizure fre-
quency 24e80 times per month, and Group III as seizure frequency <24 times per month. Multi-
variate regression analysis was performed to determine predictors of seizure frequency
reduction after VNS treatment.
Results: A total of 80 patients were included in this study. Three or more AED types were pre-
scribed for 61 (77.1%) patients. Seizure frequency decreased significantly at 12 and 24 months

* Corresponding author. Department of Pediatrics, MacKay Children’s Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei City, 10449,
Taiwan. Fax: þ886 2 2543 3642.
E-mail address: ncc88@mmh.org.twv (N.-C. Chiu).

https://doi.org/10.1016/j.pedneo.2020.07.010
1875-9572/Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Li S-T et al., Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan,
Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.010
 + MODEL
2 S.-T. Li et al

after VNS treatment. The mean seizure reduction rates were 44.6% and 50.1% at 12 and 24
months after VNS treatment, with the difference between them reaching statistical signifi-
cance (p Z 0.001). In multivariate linear regression, high seizure frequency (Group I) was a
positive predictor of seizure frequency reduction (p < 0.001). The most common complication
was coughing (eight patients, 10%) and no patient had early withdrawal or premature termina-
tion of VNS use due to complications.
Conclusion: VNS is an effective palliative treatment for children with RE for different seizure
types. Seizure reduction rate at 24 months after VNS was better than at 12 months after VNS.
High seizure frequency can be regarded as a positive predictor for seizure frequency reduction
in children with RE treated with VNS.
Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

1. Introduction to use nationwide data from Taiwan to analyze the thera-

In approximately 65e75% of children newly diagnosed with
epilepsy, seizure-free status can be achieved by treatment
with low to moderate doses of antiepileptic drugs (AEDs).1
However, despite the availability of a variety of AEDs,
seizures cannot be well controlled in approximately
30e40% of children with epilepsy; these cases are consid-
ered to have refractory epilepsy (RE).1e3 Epileptic surgery
is considered a safe and effective treatment method for
patients with RE.4 For patients with RE who are not can-
didates for epileptic surgery, vagus nerve stimulation (VNS)
provides another non-pharmacological treatment op-
tion.5,6 In 1997, the US Food and Drug Administration
approved VNS as an adjuvant treatment for adult and
adolescent patients over 12 years with RE.7 VNS was also
approved by the Taiwan Food and Drug Administration
(TFDA) in 2006. After one year of VNS treatment, patients
experienced 30e60% seizure reduction rate.8e10 A clinical
trial later demonstrated no difference in efficacy or com-
plications of VNS in children aged 1e12 years vs. 12e18
years, indicating suitability in both groups.11 Although VNS
treatment is effective, the treatment is expensive and
there are no predictive factors that indicate the likelihood
of benefit from treatment.12 Under economic consider-
ations, it is difficult to decide whether families of children
with RE should receive VNS treatment. A meta-analysis
conducted by Englot et al found generalized epilepsy and
childhood age group to be positive factors in treatment
with VNS.13 Many studies have been conducted to establish
predictors that influence the efficacy of VNS treatment,
including age, gender, seizure frequency before VNS
treatment, duration of epilepsy prior to VNS, types or
numbers of AEDs before VNS treatment, epilepsy etiology
and seizure types, etc.14e22 There is still no consensus on
these potential predictors at present.
The Taiwan Child Neurology Society (TCNS) VNS Study
Group first published a preliminary study on the effective-
ness of VNS treatment in eight patients with RE in
Taiwan.23,24 Subsequent papers investigated the impact of
VNS on neuropsychological outcome in children with RE and
parenting stress experienced by their families.25e27 Studies
on the clinical outcomes of VNS therapy in Asia are
extremely limited.28 Therefore, the purpose of this study is
peutic effects of VNS and to explore factors that may pre-
dict the effectiveness of VNS treatment.
2. Methods
The present study followed a retrospective design and
involved fifteen secondary and tertiary hospitals. The study
was implemented from December 2007 to December 2014.
The enrollment inclusion criteria for review of patient
medical records were as follows: (1) the patient was diag-
nosed as RE by a pediatric neurologist, underwent follow-
up every 1e3 months at an outpatient clinic, and the
seizure frequency was recorded in the medical record by
the pediatric neurologist; (2) the patient was treated with
VNS (pulse model 102 or demipulse model 103, LivaNova
Inc., London, UK, formerly Cyberonics Inc.) and followed up
for at least two years; and (3) the patient was 1e18 years
old. The variables collected in this study included gender,
age, vagus nerve stimulator implantation date, duration
from epilepsy to VNS, seizure frequency before and after
VNS treatment, seizure type, etiology of epilepsy, compli-
cations after VNS, and history of AEDs before and after VNS
treatment. After removing the identifiable variables, the
data were collected by the TCNS. After this study was
approved by each hospital’s institutional review board, the
authors and co-authors began to review the patients’
medical records (IRB number: 14MMHIS197).
VNS treatment regimen was as follows. The initial
standard setting was as the suggestion of LivaNova Inc.:
output current: 0.25 mA, signal frequency: 20e30 Hz, pulse
width: 250e500 ms, on time: 30 s, off time: 5 min. The first
follow-up after initial settings was one month later. Ac-
cording to the change of seizure frequency, pediatric
neurologist may increase output current by increments of
0.25 mA/month up to patient’s tolerability. Finally, output
current was increased to 1.5e2.25 mA, or as tolerated.
Seizure frequency before VNS treatment was divided
into three groups. We adapted the “classification” method
of “data mining” to explore the correlation between the
pre-VNS seizure frequency and change of seizure frequency
after VNS. Pre-VNS seizure frequency was divided into the
three groups after CART (classification and regression trees)
analysis. Group I comprised patients with seizure frequency

Please cite this article as: Li S-T et al., Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan,
Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.010
 + MODEL
VNS for children with refractory epilepsy 3

more than 80 times per month. Group II was frequency had early withdrawal or premature termination of VNS use
between 24 and 80 times per month. Group III was fre- due to these complications or other reasons.
quency less than 24 times per month. The etiology of epi- The median (range) seizure frequencies 12 and 24
lepsy was divided into two groups: symptomatic and months after VNS treatment were 14.5 (0e280) and 13.5
idiopathic/cryogenic. Seizure frequency reduction was (0e201), respectively. Compared to before treatment,
calculated as post-VNS seizure episodes per month minus seizure frequency decreased significantly both at 12 and 24
pre-VNS seizure episodes. Seizure reduction rate was the months (Fig. 1). Twelve months and 24 months after VNS
reduced seizure frequency divided by seizure frequency treatment, the mean seizure reduction rates were 44.6%
before VNS treatment. The seizure frequency 12 months and 50.1%, reaching statistical significance (p Z 0.001).
after VNS treatment was calculated as the mean frequency At twelve months after VNS treatment, 37 (46.3%) pa-
of seizures from the 10th to 12th month.29 The seizure tients experienced a seizure reduction rate of S50%, 18
frequency 24 months after VNS treatment was calculated as (22.5%) experienced a reduction rate of S75%, nine (11.3%)
the mean frequency of seizures from the 22nd to 24th experienced a reduction rate of S90%, and four (5%)
month. The mean will be rounded to an integer. If seizures reached seizure-free status. At 24 months after VNS treat-
reappeared in seizure-free patient, the outcome was ment, 45 (56.3%) patients experienced a seizure reduction
defined as non-seizure-free.20 rate of S50%, 24 (30%) experienced a reduction rate of
Statistical analysis was conducted using SPSS software S75%, 10 (12.5%) experienced a reduction rate of S90%,
version 21 on Windows 10 (IBM Corp., Armonk, NY, USA). and five (6.3%) reached seizure-free status (Fig. 2). There is
Descriptive statistics included numbers, percentages, me- an increased trend in the percentage of patients with seizure
dians, range, mean, and standard deviation (SD). Contin- reduction rate of S50%, 75%, 90% and 100% between 12 and
uous variable data were analyzed using the ShapiroeWilk 24 months, but it did not reach statistical significance.
test for normal distribution. Category variable data based Twelve (15%) patients increased seizure frequency after 12
on data characteristics were analyzed using the chi-square months of VNS treatment and 7 (8.8%) patients increased
test, Fisher’s exact test, or McNemar’s test. Continuous seizure frequency after 24 months of VNS treatment.
variable data based on data characteristics were analyzed After 24 months of VNS treatment, 11 (13.6%) patients
using the Student’s t-test, one-way analysis of variance changed from using S3 types of AEDs to 1e2 AED types.
(ANOVA), ManneWhitney U test, or KruskaleWallis test.
Paired variables were analyzed using the paired-sample
Wilcoxon signed-rank test. Univariate and multivariate
regression analyses were performed to determine the Table 1 Demographic data of children with refractory
impact of the following independent variables on seizure epilepsy.
frequency reduction (dependent variable): gender, age, Parameter Variable N (%)
seizure frequency, etiology, seizure type, epilepsy duration
Gender
prior to VNS and types of AEDs. Comparisons with a p
Male 43 (53.8)
value < 0.05 were considered statistically significant.
Female 37 (46.2)
Age (years)
1e6 15 (18.8)
3. Results
7e12 27 (33.8)
13e18 38 (47.4)
Demographic data for the 80 patients (43 males and 37 fe- Seizure frequency groupa
males) who met the inclusion criteria are listed in Table 1. Group I 25 (31.3)
The mean age (SD) of patients was 10.8  4.0 years, with a Group II 21 (26.3)
median of 11.3 years. The median monthly seizure fre- Group III 34 (42.4)
quency before treatment was 30 times per month, and the Etiology
seizure frequency ranged from 1 to 900 times per month Symptomatic 34 (42.5)
before VNS treatment. The patient’s numbers in Group I, Idiopathic/Cryptogenic 46 (57.5)
Group II, and Group III were 25 (31.3%), 21 (26.3%), and 34 Seizure type
(42.4%). There were 34 (42.5%) patients with symptomatic Partial seizure 30 (37.5)
etiology, which included central nervous system infection in Generalized seizure 12 (15.0)
11 (13.7%), brain malformation in 10 (12.5%), genetic dis- S2 patterns 38 (47.5)
order in five (6.3%), hypoxic ischemic encephalopathy in Duration of epilepsy prior to VNS
four (5%), brain vascular lesion in two (2.5%), and brain <12 months 25 (31.2)
tumor in two (2.5%). In terms of seizure type, more than two 12e36 months 29 (36.3)
seizure types occurred in 38 (47.5%) patients. When patients S36 months 26 (32.5)
were divided into groups based on duration of epilepsy prior AED types
to VNS treatment of less than 12 months, 12e36 months, or 1e2 types 19 (23.8)
more than 36 months, each group represented approxi- S3 types 61 (77.1)
mately one third of patients. In terms of AED history, 61
(77.1%) patients had been prescribed three or more types of AED: antiepileptic drug; VNS: vagus nerve stimulation.
a
Group I: seizure frequency S80 per months; Group II:
AEDs. The most common complication was coughing (eight
seizure frequency 24e80 per month; Group III: seizure fre-
patients, 10%) and followed by hoarseness (6.3%). Pain,
quency <24 per month.
vomiting and infection each accounted for 1.3%. No patient

Please cite this article as: Li S-T et al., Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan,
Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.010
 + MODEL
4 S.-T. Li et al

Figure 1 Seizure frequency per month before, 12 months and 24 months after VNS treatment. Seizure frequency decreased
significantly at 12 months after VNS, 24 months after VNS and between 12 months and 24 months after VNS. The thick line in the
middle of box is the median. Outliers (B) are at least 1.5 box lengths from the median and extremes (A) are at least three.
*p < 0.05 between two groups.

Figure 2 Percentage of patients with seizure reduction rate S50% and more after 12 and 24 months of vagus nerve stimulation
treatment. Though they did not reach statistical significance, the different percentages at 24 months after VNS were all higher than
at 12 months after VNS.

However, four (5%) patients changed from using 1e2 AED
types to S3 AED types. Sixty (75%) patients did not change
the number of AED types. Changes in AED types did not
reach statistical significance after analysis by McNemar’s
test (p Z 0.118).
The results of each variable before and after two years of
VNS treatment are shown in Table 2. The change in seizure
frequency reached statistical significance in each variable.
Results of univariate linear regression and multivariate
linear regression of these variables are shown in Table 3. In

Please cite this article as: Li S-T et al., Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan,
Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.010
 + MODEL
VNS for children with refractory epilepsy 5

univariate linear regression, high seizure frequency (Group I) of VNS patients had a change in AEDs at 12 months, 59% at 24
(p < 0.001) and less than 12 months before VNS implantation months, and 81% at 36 months (these changes were mainly a
(p Z 0.015) were positive predictors for seizure frequency dose increase).33 In our study, the adjustment of AEDs was
reduction. However, in multivariate linear regression, only done by patients’ own pediatric neurologists. Only 11.3% and
high seizure frequency (Group I) was a positive predictor for 25% of patients changed the number of anticonvulsants at 12
seizure frequency reduction (p < 0.001). and 24 months. Since VNS treatment is expensive, both
doctors and families may be more conservative about
changing the AEDs. After all, VNS should be considered as a
4. Discussion palliative treatment and cannot replace AEDs.
High seizure frequency before VNS treatment was iden-
In 1997, the US FDA approved VNS for adults or adolescents tified by Labar et al as a positive predictor of VNS effec-
over the age of 12 years; however, additional data have tiveness,14 but it was found not to be a predictor in other
indicated that VNS has a good effectiveness when used to studies.11,18 In our study, high seizure frequency was
treat RE in children <12 years of age.28 Furthermore, good revealed to be a predictor of VNS effectiveness by univar-
results have been achieved in children under the age of six.13 iate and multivariate analysis. We suppose that because the
VNS treatment has even been found to be effective and VNS treatment response fluctuates,34 the lower seizure
tolerable in children <3 years of age.30 In this study, four frequency groups may be more strongly affected by fluc-
children aged 2e3 years were treated with and tolerated VNS. tuations in VNS effectiveness statistics, whereas the high
In our study, the mean seizure reduction rate reached a seizure frequency group may be less affected. Thus, the
statistical significance level between 12 and 24 months VNS reduction in seizure frequency in the high frequency group
implantation. A previous study by Ryzı́ et al, who analyzed would be more obvious.
15 children with intractable epilepsy, obtained a mean Some previous studies have suggested that long epilepsy
seizure reduction rate of 42.5% at 12 months and 54.9% at duration was a negative predictor for the effectiveness of
24 months.31 In one nationwide multicenter registry study VNS. Renfroe and Wheless reported that 15.0% of the
in Japan, which included 362 patients of all ages, the me-
dian seizure reduction rates were 53.3% and 60% at 12 and
24 months after VNS treatment.28 Our results are consistent Table 2 Seizure frequency before and 24 months after
with previous studies, indicating that VNS is an effective vagus nerve stimulation.
palliative treatment for children with RE and also has Parameter Pre-VNS Post-VNS P
benefit even one year after implantation. Gender
Among patients <12 years old with RE in Orosz et al’s Male 30 (1e625) 11 (0e122) <0.001*
study, 43.0% and 50.0% achieved S50% seizure reduction Female 30 (1e900) 15 (0e201) <0.001*
rate at 12 and 24 months, respectively.10 Kuba et al Age (years)
demonstrated that 44% and 58.9% of patients experienced a 1e6 21 (2e900) 14 (0e201) 0.008*
S50% seizure reduction rate at 12 and 24 months.29 Kawai 7e12 40 (3e266) 16 (0e71) <0.001*
et al showed S50% seizure reduction rates of 55.8% and 13e18 26 (1e625) 11 (0e131) <0.001*
57.7%, and seizure-free rates of 5.9% and 6.9%, at 12 and 24 Seizure frequency
months.28 In our study, we found that S50% seizure group
reduction rates were 46.3% and 56.3%, and seizure-free Group I 134 (81e900) 54 (0e201) <0.001*
rates were 5.0% and 6.3% at 12 and 24 months. As Fig. 2 Group II 35 (24e78) 17 (0e68) <0.001*
shows, longer VNS treatment time makes a trend of more Group III 8.5 (1e22) 4 (0e23) <0.001*
patients will reach S50% or even higher seizure reduction Etiology
rates, though it did not show statistical significance. Symptomatic 29 (2e900) 10.5 (1e201) <0.001*
In previous TCNS study, Chen et al enrolled eight pa- Idiopathic/ 30.5 (1e625) 15 (0e131) <0.001*
tients and found five patients (62.5%) had S50% seizure Cryptogenic
reduction rate, without seizure-free patients.23 Tsai et al Seizure type
enrolled 37 patients and found seizure reduction rates of Partial seizure 17.5 (2e900) 9.5 (0e117) <0.001*
45.9% at 12 months and 43.2% at 24 months, with one Generalized 11 (1e305) 5 (0e81) 0.007*
seizure-free patient (2.7%).25 Li et al enrolled 30 patients seizure
and found seizure reduction rate of 42.6%, and 15 patients S 2 patterns 39 (3e690) 21.5 (0e201) <0.001*
(50%) had S50% seizure reduction rate, with one seizure- Duration of epilepsy
free patient (3.3%).26 Although the studies of Tsai et al prior to VNS
and Li et al aimed to investigate the impact of VNS on <12 months 28 (4e900) 15 (0e201) <0.001*
neuropsychological outcome in children with RE and 12e36 months 40 (1e390) 13 (0e131) <0.001*
parenting stress, their seizure reduction outcomes are S36 months 23 (2e225) 11 (1e117) <0.001*
consistent with our study. AED types
There are controversies of whether AEDs should be 1e2 types 21 (1e390) 11 (0e113) 0.001*
adjusted after VNS treatment. De Herdt et al reported that S3 types 34 (1e900) 15 (0e201) <0.001*
the mean numbers of AEDs remained unchanged even after
Data presented as median (range); AED: antiepileptic drug;
many years of VNS stimulation.32 Kuba et al found that
VNS: vagus nerve stimulation.
treatment was increased or additional AED therapy was
p value analyzed using the Wilcoxon signed-rank test; *p < 0.05.
added in 76.7% of patients.29 In the study by Arcand et al, 33%

Please cite this article as: Li S-T et al., Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan,
Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.010
 + MODEL
6 S.-T. Li et al

Table 3 Regression analysis of potential predictors of change in seizure frequency.

Univariate Multivariate
b T p b t p
Gender
Maleb e e e e e e
Female 0.025 0.221 0.826 0.047 0.446 0.657
Age (years)
1e6 0.146 1.151 0.253 0.144 1.244 0.218
7e12b e e e e e e
13e18 0.016 0.123 0.903 0.148 1.295 0.200
Seizure frequency groupa
Group I 0.59 5.762 <0.001* 0.622 5.647 <0.001*
Group II 0.056 0.543 0.589 0.105 0.942 0.349
Group IIIb e e e e e e
Etiology
Symptomatic 0.031 0.276 0.783 0.085 0.83 0.409
Idiopathic/Cryptogenicb e e e e e e
Seizure type
Partial seizure 0.077 0.638 0.525 0.083 0.776 0.441
Generalized seizure 0.098 0.817 0.417 0.092 0.795 0.429
S2 patternb e e e e e e
Duration of epilepsy prior to VNS
<12 months 0.315 2.484 0.015* 0.237 1.928 0.058
12e36 months 0.084 0.658 0.512 0.052 0.461 0.646
S36 monthsb e e e e e e
AED types
1e2 typesb e e e e e e
S3 types 0.101 0.898 0.372 0.088 0.921 0.360
*p < 0.05.
AED: antiepileptic drug; VNS: vagus nerve stimulation.
a
Group I: seizure frequency S80 per months; Group II: seizure frequency 24e80 per month; Group III: seizure frequency <24 per
month.
b
Reference group.

patients with an <5 years epilepsy duration became
seizure-free at three months of VNS treatment, while only
4.4% of the patients with longer duration became seizure-
free.16 In the study by Englot et al of 5554 patients, a trend
was found in which patients with an epilepsy duration of
<10 years before VNS implantation had a higher rate of
seizure-free status than those with epilepsy of longer
duration before implantation (10.4% vs. 7.3%), but this
difference was not significant.35 On the contrary, Labar
found that longer epilepsy duration was associated with
improved VNS effectiveness.18 Furthermore, some studies
found that epilepsy duration was not associated with the
efficacy of VNS treatment.11,15,20,36 In our study, duration
of epilepsy of less than 12 months prior to VNS was a sig-
nificant negative predictor in univariate analysis, but it was
not significant in multivariate analysis. Among our sample,
there were 54 (67.5%) patients with epilepsy duration of <3
years, whereas only 18 (22.5%) patients had epilepsy
duration of >5 years. When we further divided a group of
duration longer than 5 years, there was still no significant
difference in multivariate analysis. We consider duration of
epilepsy is not a good predictor of VNS effectiveness. Other
patient variables, such as gender, patient age, etiology,
seizure type, and number of AED types, were not predictors
of VNS effectiveness in our study.
The source of this research data was medical records
obtained from the TCNS, which were provided by individual
pediatric neurologists in Taiwan. One limitation of our
study is that each pediatric neurologist may have individual
difference in the determination of epilepsy type, etiology,
seizure frequency recording method, adjustment of AEDs,
methods of follow-up, etc. A prospective registry study
with more precise seizure frequency recording methods,
more parameter settings of VNS and more enrolled patients
is warranted in future.
In conclusion, based on clinical data from TCNS, VNS is
an effective palliative treatment for children with RE
across all analysis groups. Seizure reduction rate at 24
months after VNS is better than at 12 months after VNS.
High seizure frequency can be regarded as a positive pre-
dictor for reduction of seizure frequency in children with RE
treated with VNS.
Declaration of Competing Interest
The authors declare no potential conflicts of interest with
respect to the research, authorship, or publication of this
article.

Please cite this article as: Li S-T et al., Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan,
Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.010
 + MODEL
VNS for children with refractory epilepsy
Acknowledgments
The study was supported by Taiwan Child Neurology Society
(TCNS-2014-001).
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