Epilepsy & Behavior 39 (2014) 105110

Contents lists available at ScienceDirect

Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

A controlled trial of transcutaneous vagus nerve stimulation for the

treatment of pharmacoresistant epilepsy
Liu Aihua, Song Lu, Li Liping, Wang Xiuru, Lin Hua, Wang Yuping
The Department of Neurology, Xuanwu Hospital, Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing 100053, China

a r t i c l e

i n f o

Article history:
Received 28 May 2014
Revised 31 July 2014
Accepted 6 August 2014
Available online 18 September 2014
Keywords:
Transcutaneous vagus nerve stimulation
Parasympathetic nervous system
Refractory epilepsy
Seizure
Quality of life

a b s t r a c t
This study explored the efcacy and safety of transcutaneous vagus nerve stimulation (t-VNS) in patients with
pharmacoresistant epilepsy. A total of 60 patients were randomly divided into two groups based on the stimulation zone: the Ramsay-Hunt zone (treatment group) and the earlobe (control group). Before and after the
12-month treatment period, all patients completed the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Liverpool Seizure Severity Scale (LSSS), and the Quality of Life in Epilepsy Inventory
(QOLIE-31). Seizure frequency was determined according to the patient's seizure diary. During our study, the
antiepileptic drugs were maintained at a constant level in all subjects. After 12 months, the monthly seizure frequency was lower in the treatment group than in the control group (8.0 to 4.0; P = 0.003). This reduction in seizure frequency was correlated with seizure frequency at baseline and duration of epilepsy (both P N 0.05).
Additionally, all patients showed improved SAS, SDS, LSSS, and QOLIE-31 scores that were not correlated with
a reduction in seizure frequency. The side effects in the treatment group were dizziness (1 case) and daytime
drowsiness (3 cases), which could be relieved by reducing the stimulation intensity. In the control group, compared with baseline, there were no signicant changes in seizure frequency (P = 0.397), SAS, SDS, LESS, or
QOLIE-31. There were also no complications in this group.
2014 Published by Elsevier Inc.

1. Introduction
Epilepsy is a common and recurrent chronic central nervous system
disease [1] affecting approximately 50 million people worldwide according to World Health Organization (WHO) estimations [2]. However,
despite the advent of new antiepileptic drugs, seizures in approximately
one-third of patients with epilepsy are resistant to currently available
treatment [3,4]. Additionally, antiepileptic drugs (AEDs) have a variety
of side effects, such as cognitive and behavioral impairments as well
as endocrine disorders, that signicantly inuence the quality of life
(QOL) of patients with epilepsy. Although many patients have achieved
substantial benecial effects from various treatments, including
resective surgery, effective treatment measures are still lacking for
approximately 20% of patients [5].
Invasive vagus nerve stimulation (i-VNS) has provided a new
approach for the treatment of epilepsy that involves using surgically
implanted electrodes to stimulate the vagus nerve. In 1997, the US
Food and Drug Administration (FDA) approved i-VNS as an adjunct
therapy for adolescents and adults older than 12 years with
pharmacoresistant epilepsy, and to date, more than 100,000 people
worldwide have received this therapy [6]. Moreover, in addition to reduced seizure frequency and severity, there are reports of i-VNS
Corresponding author. Tel.: +86 10 83198899 8458; fax: +86 10 83157841.
E-mail address: wangyuping01@sina.cn (W. Yuping).

http://dx.doi.org/10.1016/j.yebeh.2014.08.005
1525-5050/ 2014 Published by Elsevier Inc.

resulting in signicant improvements in patients' psychological state,

cognitive ability, social skills, and quality of life [710].
However, the many side effects associated with i-VNS cannot be ignored. First, the implantation procedure is an invasive surgery typically
performed under general anesthesia. In addition to the initial operative
risk, the need for additional surgeries to change the battery makes this
therapy less than optimal [10]. Second, i-VNS can result in postoperative
complications including hoarseness and cough, with some patients also
suffering from nocturnal dyspnea [1113]. Of particular importance to
Chinese patients is that the devices must be imported, which increases
the economic burden of patients and their families.
The abovementioned problems have led to efforts to develop
alternative, nonsurgical methods to access the vagus nerve, including
transcutaneous stimulation. These have led to ndings that stimulation
of the rat auricular concha results in seizure inhibition [14]. The neuroanatomical rationale for stimulating this area is due to ndings that the
somatic sensory territory of the vagus nerve is primarily localized in the
Ramsay-Hunt zone of the ear, which includes the external auditory
canal and the conchal cavity [15,16]. Furthermore, there are projections
from the rat auricular concha area to the nucleus of the solitary tract
(NTS) [17]. From there, brous projections extend to the parabrachial
nucleus [18,19], which has a direct synaptic connection with afferent
pontine cholinergic bers [20]. Based on these preclinical studies, in
2000, Ventureyra proposed a new concept for the treatment of drug/
treatment-refractory epilepsy by stimulating the vagus nerve via

106

L. Aihua et al. / Epilepsy & Behavior 39 (2014) 105110

noninvasive transcutaneous stimulation in the ear, which he hypothesized would result in effective seizure control [21]. Afterward, a smallscale pilot study demonstrated that transcutaneous vagus nerve stimulation (t-VNS) can be used as an effective method for the treatment of
pharmacoresistant epilepsy [15].
The present study was a randomized controlled trial investigating the
efcacy and safety of t-VNS as a treatment option for pharmacoresistant
epilepsy. We hypothesized that t-VNS would signicantly reduce seizure
frequency and severity while improving patients' mood and QOL via a
mechanism of action similar to that of i-VNS.
2. Materials and methods
2.1. Patients and data collection
A total of 81 patients were initially selected for the present study,
which was conducted from November 2011 to July 2012 at Xuanwu
Hospital, Capital Medical University. Approval from the Institutional
Review Board was obtained prior to the initiation of this study, and all
patients or their guardians provided informed consent. The inclusion
criteria were as follows: N 4 years of age, with an average number of
monthly seizures N 4, taking two or more types of antiepileptic drugs

over 2 years with ineffective seizure control, and deemed not suitable
for surgical treatment or unwilling to take the risk of surgery. There
were 21 patients excluded because they were pregnant or lactating,
had serious heart, liver, or kidney disease, had pacemakers or other
implantable medical devices, or could not tolerate t-VNS for more
than 6 months. Patients who could not complete the questionnaires
due to impaired cognitive ability were also excluded (4 patients in the
treatment group and 9 patients in the control group, Fig. 1).
An interview was used to record general patient information including age, gender, duration of epilepsy, type of epilepsy, family history, the
number and dosage of AEDs, interictal EEG, MRI, and baseline seizure
frequency at the rst clinic visit. Seizure frequency at baseline was
calculated as the average monthly seizure frequency for 3 months
prior to t-VNS. The number of seizures per month was recorded according to the patient's seizure diary through telephone follow-up. The
questionnaires investigating the patient's psychological state, seizure
severity, and QOL were completed at baseline and at the end of a
12-month follow-up period.
The main study parameters were as follows: (1) the average number
of seizures per month during the different follow-up intervals; (2) the
reduction in seizure frequency, which was determined as the percentage
change in baseline seizure frequency over 6- and 12-month periods and

Fig. 1. Patient ow chart for this study showing inclusion and exclusion criteria. Dashed lines represent patients who dropped out from the study, while solid lines represent the patients in
the study. t-VNS: transcutaneous vagus nerve stimulation.

L. Aihua et al. / Epilepsy & Behavior 39 (2014) 105110

calculated as ( seizure frequency / baseline seizure frequency) 100%;

(3) the Liverpool Seizure Severity Scale score; (4) the Self-Rating Anxiety
and Self-Rating Depression Scale scores; and (5) the Quality of Life in
Epilepsy Inventory (QOLIE-31).
All patients underwent bilateral t-VNS using a transcutaneous vagus
nerve stimulator (TENS-200, Hua Tuo brand). The patients were
randomly divided into two groups: a control group stimulated on the
earlobe (n = 30) and a treatment group stimulated in the RamsayHunt zone (n = 30) as shown in Fig. 2. The number of patients was
determined by a power analysis that determined that a minimum of
30 patients was needed for this study. The stimulation frequency was
20 Hz, with a pulse width of 0.2 s. Intensity was gradually increased in
steps of 2 mA as directed by the patient. The stimulation was
maintained at a stable level below the point where the patients felt
pain or at the level at which seizures disappeared. All stimulations
were administered by the patients or their guardians who were
instructed on the proper use of the equipment prior to treatment,
which consisted of continuous stimulation lasting for 20 min, 3 times
per day for a total of 12 months. Throughout this study, the type and
dose of AEDs remained the same as those at baseline.
The outcome was assessed at regular outpatient visits. Before and
after t-VNS, parameters 1, 3, 4, and 5 were compared in each group. Parameters 1 and 2 were compared between the two groups at 6 and
12 months of follow-up. Further analysis was performed to determine
whether the reduction in seizure frequency was correlated with age,
duration of epilepsy, type of epilepsy, the number of AEDs, interictal
EEG, MRI, baseline seizure frequency, or baseline stimulation intensity.

2.2. Statistical analysis

Categorical variables with nonnormal distributions (age, number of
antiepileptic drugs [AEDs], seizure frequency, and stimulation intensity)
are expressed by count (percentage) or median range between the
25th and the 75th percentile (IQRs). The continuous variables with
normal distribution are expressed as mean standard deviation (SD).
Differences between categorical variables were compared using a
chi-square test or Fisher's exact test with Yates' correction if any cell
number was less than ve or close to zero. Differences between the
nonnormally distributed continuous variables were compared using
the nonparametric MannWhitney U test, while the normally distributed continuous variables were compared using an independent twosample t-test. Differences between baseline and 12-month follow-up
for continuous variables were compared using the paired t-test. Multiple linear regressions were used to analyze any association between
treatment efcacy and independent variables. The variance ination
factor (VIF) test was performed to verify the severity of multicollinearity
in the multiple linear regression models. All statistical assessments were
two-sided, and a P value of 0.05 was considered signicant. Statistical

Fig. 2. Location of stimulation for treatment and control groups. The treatment group was
stimulated in the Ramsay-Hunt zone, while the control group was stimulated on the earlobe.

107

analyses were performed with the SPSS software for Windows, version
18.0 (SPSS Inc., Chicago, IL, USA).
3. Results
Patient demographics are shown in Table 1. There were no signicant differences in age (34.5 years [IQR: 26.5 to 41.3] vs. 29.0 years
[IQR: 24.5 to 42.0]; P = 0.668) and duration of epilepsy (19.7
11.1 years vs. 17.6 9.6 years; P = 0.943) between the treatment
and control groups. However, a signicant difference was found
between the treatment and control groups in the Self-Rating Anxiety
Scale (SAS) scores (43.3 8.5 vs. 38.1 7.0; P = 0.031).
As shown in Fig. 1, 7 cases in the control group quit voluntarily because of no signicant seizure reduction, increased seizures, or individual
reasons, with 2 cases lost during the follow-up period. In the treatment
group, 4 cases removed themselves from the study; among them was 1
case presenting with severe dizziness after the use of t-VNS, while the
other 3 cases were lost during follow-up. At the end of treatment, a
total of 47 cases (22 men, 25 women) with a mean age of 32.4 years
remained. No patients reported symptoms of parasympathetic over
activity.
As shown in Fig. 3, the median monthly seizure frequency was signicantly reduced in the treatment group compared with baseline
after 6 (5.5 [IQR: 3.0 to 12.0] vs. 6.0 [IQR: 4.8 to 25.0]; P b 0.001) and
12 months (4.0 [IQR: 2.8 to 8.3] vs. 6.0 [IQR: 4.8 to 25.0]; P b 0.001) of
t-VNS therapy. However, the median seizure frequency in the treatment
group was not signicantly lower than that in the control group until
12 months of treatment (4.0 [IQR: 2.8 to 8.3] vs. 8.0 [IQR: 4.5 to 12.0];
P b 0.001). The percentage of patients in six categories of seizure reduction after 6 and 12 months of t-VNS therapy is shown in Fig. 4.
For patients in the treatment group, SAS, SDS, LSSS, and QOLIE-31
scores were all signicantly improved after 12 months compared with
baseline (P = 0.017, 0.018, b0.001, and 0.001, respectively). Additionally,
Table 1
Demographic characteristics of the treatment and control groups.

Age (years)1
16302
3145
4660
Duration of epilepsy (years)3
102
1120
2130
31
Epilepsy type2
Simple partial seizure
Complex partial seizure
Generalized seizures
MRI2
Normal
Abnormal
EEG2
Normal
Abnormal
The number of AEDs1
Seizure frequency1
Stimulation intensity (mA)1
SAS scores3
SDS scores3
LSSS scores3
QOLIE-31 scores3

Treatment group
(n = 26)

Control group
(n = 21)

P-value

34.5 (26.5, 41.3)

12 (46.2)
8 (30.8)
6 (23.1)
19.7 11.1
5 (19.2)
11 (42.3)
6 (23.1)
4 (15.4)

29.0 (24.5, 42.0)

11 (52.4)
5 (23.8)
5 (23.8)
17.6 9.6
5 (19.0)
10 (47.6)
5 (23.8)
2 (9.5)

0.668
0.862

17 (65.4)
3 (11.5)
6 (23.1)

15 (71.4)
3 (14.3)
3 (14.3)

17 (65.4)
9 (34.6)

13 (61.9)
8 (38.1)

10 (38.5)
16 (61.5)
3.0 (2.0, 3.0)
6.0 (4.8, 25.0)
6.0 (5.0, 6.3)
43.3 8.5
49.2 7.3
13.9 3.9
109.2 11.8

10 (47.6)
11 (52.4)
3.0 (2.0, 3.0)
7.0 (4.0, 11.5)
6.0 (5.0, 6.5)
38.1 7.0
48.1 7.2
14.8 4.4
111.4 10.4

0.496
0.943

0.741

0.805

0.528

0.981
0.829
0.918
0.031
0.581
0.471
0.492

Values are expressed as 1median (IQR), 2count (percentage), and 3mean standard deviation. P-values are based on the 1MannWhitney U test, 2chi-square test/Fisher's exact
test, and 3t-test. AEDs: antiepileptic drugs, EEG: electroencephalograph, LSSS: Liverpool
Seizure Severity Scale, MRI: magnetic resonance image, QOLIE-31: Quality of Life in Epilepsy Inventory, SAS: Self-Rating Anxiety Scale, SDS: Self-Rating Depression Scale, t-VNS:
transcutaneous vagus nerve stimulation.
P b 0.05 indicates a signicant difference between the two groups.

108

L. Aihua et al. / Epilepsy & Behavior 39 (2014) 105110

Table 2
Multiple linear regression analysis of t-VNS efcacy.

Age (years)
Duration of epilepsy (years)
Seizure type
Simple partial seizure
Complex partial seizure
Generalized seizures
MRI
Normal
Abnormal
EEG
Normal
Abnormal
The number of AEDs
Seizure frequency
Stimulation intensity (mA)
Fig. 3. Monthly seizure frequency at baseline and at 6 and 12 months after t-VNS in the
treatment group and the control group. Signicant difference (P b 0.05) compared with
baseline. Signicant difference (P b 0.05) between the two groups. P-values are based
on the Wilcoxon signed-rank test.

while 2 patients showed no obvious seizure reduction, both continued

to use t-VNS, citing improvements in mood and reduced seizure severity. At the end of this study, the SAS, SDS, LSSS, and QOLIE-31 scores had
improved insignicantly for these two patients. In the control group,
while there was a decline in the SAS scores from baseline (38.14) to
the 12-month follow-up (36.95), this difference was not signicant
(P = 0.186). Similarly, the control group showed no signicant
differences between baseline and the 12-month follow-up examinations for SDS and LSSS scores (P = 0.053 and 0.421, respectively),
while there was a signicant increase in QOLIE scores (111.43 vs.
115.52, P = 0.038). We did nd a signicant interaction between the
reduction in seizure frequency and both seizure frequency at baseline
(P b 0.05) and duration of epilepsy prior to treatment (P b 0.05). However age, duration of epilepsy, seizure type, the number of AEDs, EEG,
MRI, and stimulation intensity at baseline did not show signicant associations with the efcacy of t-VNS (Table 2).
In the treatment group, 1 patient quit because of severe dizziness
after the intensity of t-VNS reached 6 mA, and adjusting the intensity
did not relieve the dizziness. Additionally, 3 patients receiving 8 mA
reported obvious drowsiness during the day, which was alleviated
immediately by reducing the stimulation intensity (the intensity was
reduced to 6 mA, 7 mA, and 7 mA, respectively). No complications
were seen in the control group.

Fig. 4. Percentage of patients in six categories of monthly seizure reduction after 6 and
12 months of t-VNS therapy.

Coefcient (95% CI)

P-value

0.45 (1.45, 0.55)

1.36 (0.21, 2.52)

0.372
0.022

Ref.
17.61 (52.69, 17.48)
12.35 (15.65, 41.35)

0.316
0.377

Ref.
8.11 (16.99, 33.21)

0.517

Ref.
2.20 (26.71, 22.32)
6.60 (12.70, 25.90)
1.41 (0.46, 2.36)
3.78 (12.77, 5.22)

0.857
0.493
0.005
0.400

Adjusted R2 = 0.158. There is no multicollinearity in the multiple linear regression. AEDs:

antiepileptic drugs, EEG: electroencephalograph, MRI: magnetic resonance image, t-VNS:
transcutaneous vagus nerve stimulation.
P b 0.05 indicates a signicant difference.

4. Discussion
The present study was a randomized controlled trial of t-VNS for the
treatment of pharmacoresistant epilepsy. While other trials of t-VNS for
treatment of epilepsy have been published recently [15,2224], these
studies only examined the effects for 69 months and studied patients
with higher seizure frequency. For example, Rong et al. [24] used a
lower, xed level of stimulation (1 mA) rather than the variable
stimulation levels used here and treated patients with a mean baseline
seizure frequency of about 65 per month. The results of this study
suggest that t-VNS can effectively reduce seizure frequency and severity
as well as signicantly improve the mood and QOL in patients with
pharmacoresistant epilepsy without severe complications.
After 12 months, seizure frequency was reduced in the treatment
group by approximately 40%, while in the control group, seizure
frequency increased by 0.85%, suggesting that the efcacy of t-VNS
increases with treatment time. This increase in antiseizure effect over
time is similar to what has been found in other t-VNS studies [24].
However, in our study, the physician tended to increase the stimulation
intensity over the course of treatment, which may have enhanced the
reduction of seizure frequency. Therefore, we cannot conclude whether
the improvement in our study is due to the longer stimulation time or
the higher stimulation intensity. Our improvement was slightly better
than what was found by other studies [11,25]. It is possible that this outcome was most likely associated with our bilateral stimulation method,
whereas those other studies were associated with the stimulation of the
left vagus nerve during i-VNS. Furthermore, our reduction of seizure frequency at 6 months was lower than what was found in other t-VNS
studies at that time point [22,23]. However, our study used patients
with lower baseline seizure frequency, which we found to be correlated
with treatment efcacy, so this may account for our lower effect.
Interestingly, we found that the seizure reductions in many patients
tended to uctuate rather than maintain a sustained ascending or
descending trend throughout treatment. Also of note, the stimulation
intensity was not altered in 2 patients who were seizure-free at
6 months, as per our protocol. Two months later, the seizures recurred
in both patients and could not be controlled with increased intensity.
However, in another case of seizure disappearance after t-VNS, the
patient worried about seizure recurrence and the physician continued
to increase the stimulation intensity up to 8 mA until the end of the
12-month follow-up period. In this case, the patient remained seizurefree at 12 months. To a certain extent, this result suggests that we can
continue to increase the stimulation intensity (based on patient
tolerance) after seizures are reduced by 100% to ensure the efcacy of
t-VNS, and further research should focus on this point.

L. Aihua et al. / Epilepsy & Behavior 39 (2014) 105110

Determining the factors that can predict the antiepileptic efcacy of

t-VNS will help doctors to choose the most suitable candidates for t-VNS
in addition to enabling patients who are unsuitable for this treatment to
choose other therapies in a timely manner. We found that the reduction
in seizure frequency observed with t-VNS was correlated with seizure
frequency and duration of epilepsy but not with age, seizure type, the
number of AEDs, family history of epilepsy, MRI and EEG abnormalities,
or the initial stimulation intensity. This suggests that t-VNS would be
most suitable for those with higher seizure frequency and those who
have had epilepsy for a long time. However, more trials consisting of
patients with a greater range of seizure frequency and duration would
be necessary to conrm this. This outcome is different than what has
been seen in other i-VNS trials [26,27], which did not show any
correlation of therapeutic efcacy with baseline factors.
In the present study, many patients in the treatment group who
experienced a reduction in seizure frequency showed increased QOL
scores compared with baseline, with 2 patients continuing to use
t-VNS because they felt that their mood, sleep, and seizure severity
were improved, despite demonstrating no signicant reduction in seizure frequency. However, the overall increase in patients' QOL scores
had no correlation with seizure reduction (P = 0.149), suggesting that
the positive effect of t-VNS on QOL is independent of its antiepileptic effect. Additionally, some studies have found that the QOL of patients with
drug/treatment-refractory epilepsy is primarily correlated with seizure
disappearance rather than merely a reduction in seizure frequency [28].
This is similar to what we have found here where the QOL scores increased substantially for the 2 patients in the present study who experienced seizure disappearance after the use of t-VNS. However, we
could not determine whether there was a correlation between seizure
disappearance and improvement in QOL because of the limited sample.
While a recent study utilizing t-VNS for the treatment of refractory depression achieved good results [29], in the present study, there was a
signicant difference in the SDS scores of patients in the treatment
group between baseline and the 12-month follow-up (P = 0.018). We
believe that this difference might have been caused by the lower depression severity in our patients. Importantly, the LSSS scores were signicantly lower at the end of the study compared with baseline
(P b 0.001), indicating that t-VNS can signicantly reduce seizure
severity.
In the treatment group, 4 patients reported an improvement in
daytime drowsiness after the use of t-VNS. On the one hand, this
might be a result of an improvement in the patients' depression and
anxiety, which had a direct positive inuence on the patients' difculty
in falling sleep during the night enabling them to maintain vigorous
activity during the day. However, this effect might be associated with
a functional change in brainstem structures due to t-VNS, resulting in
the modulation of the sleepwake and REM/NREM sleep cycles. As
mentioned previously, t-VNS indirectly stimulates neurons in both the
LC and the parabrachial nucleus [18,19], which produce norepinephrine
and acetylcholine, respectively [20]. Since both acetylcholine and norepinephrine can effectively improve patients' alertness [30], we believe
that the improvement in drowsiness during the daytime may be at least
partially caused by increased acetylcholine and norepinephrine levels.
Our ndings are similar to what has been found using i-VNS, which
can signicantly improve alertness during the day, reducing patients'
daytime sleep [31]. It is extremely important to improve the alertness
of patients with epilepsy because this can signicantly inuence their
mental state and QOL.
While the patients in the control group did not report any obvious
discomfort, in the treatment group, one patient withdrew from the
study because of severe dizziness at a stimulation intensity of 8 mA,
which could not be relieved by adjusting the intensity, and the
symptoms only disappeared after suspending t-VNS. Three patients
(stimulated at 8 mA) presented with daytime drowsiness that was relieved by reducing the intensity to 4 mA. This side effect of drowsiness
attracted our attention because it conicted with the improvement in

109

daytime drowsiness observed in the previously mentioned cases. We

hypothesized that drowsiness might be correlated with the high
stimulation intensity. The previously discussed study that examined
the relationship between i-VNS and sleep also found a decreased
Multiple Sleep Latency Test (MSLT) score of patients with high stimulation intensity (N 1.5 mA), indicating increased daytime sleepiness [31].
Another study observed decreased REM sleep with high stimulation intensity (N 1.5 mA), although this effect was not observed when the intensity was lower than 1.5 mA [32]. As poor sleep during the night
might also cause daytime drowsiness, more attention should be given
to stimulation parameters that might negatively inuence a patient's
sleep.
There are some limitations of our study. Firstly, we used earlobe
stimulation rather than sham stimulation as the control treatment.
This was because the patients brought the instruments home for daily
use and might have realized that they were in a sham stimulation
group, eliminating the blind control. Second, our sample was too small
to allow us to analyze the correlation between the efcacy of t-VNS
and the type of AED used, which might also affect the efcacy of t-VNS
because of the potential synergistic effect between t-VNS and certain
AEDs. Additionally, as this study focused on seizure frequency, there
was no comparison of different seizure syndromes. Further study
would be needed to determine if t-VNS affects the various syndromes
differently. Lastly, there should be further study of the interictal and
ictal EEGs performed before and after t-VNS.

5. Conclusion
In view of the signicant reduction in seizure frequency and severity
along with the improvement in the patients' mental states and QOL, we
feel that t-VNS is an effective and safe therapy for pharmacoresistant
epilepsy. Furthermore, we found that t-VNS may be most effective in
those with high seizure frequency and a long history of epilepsy.
Adverse effects included drowsiness and dizziness, which were relieved
by either reducing stimulus intensity or discontinuing the stimulus.

Acknowledgments
This study was supported by Beijing Key Laboratory of
Neuromodulation (BZ0098).
Conict of interest
The authors declare that they have no conicts of interest for any
information or equipment used in this manuscript.

References
[1] Stedman's Medical Dictionary. Stedman's medical dictionary for health professions
and nursing. 5th ed. New York: Lippincott Williams and Wilkins; 2005.
[2] The global campaign against epilepsy. Geneva: World Health Organization; 2000
[Information Pack for the launch of the Global Campaign's Second Phase, 1213
2001].
[3] Mohanraj R, Brodie MJ. Determining pharmacological intractability in epilepsy
surgery principles and controversies. In: Miller JW, Stilbergeld DL, editors. 1st ed.
New York: Taylor & Francis; 2006. p. 319.
[4] Kwan P, Brodie MJ. Early identication of refractory epilepsy. N Engl J Med 2000;
342:3149.
[5] Smith JR, Flanigin HF, King DW. Surgical management of epilepsies. South Med J
1989;82:73642.
[6] Mller K, Fab D, Entz L, Kelemen A, Halsz P, Rsonyi G, et al. Outcome of vagus
nerve stimulation for epilepsy in Budapest. Epilepsia 2010;51(Suppl. 3):98101.
[7] Ben-Menachem E, Maon-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, Mirza W,
et al. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled
study of effect on seizures. First International Vagus Nerve Stimulation Study
Group. Epilepsia 1994;35(3):61626.
[8] Ardesch JJ, Buschman HP, Wagener-Schimmel LJ, van der Aa HE, Hageman G. Vagus
nerve stimulation for medically refractory epilepsy: a long-term follow-up study.
Seizure 2007;16(7):57985.

110

L. Aihua et al. / Epilepsy & Behavior 39 (2014) 105110

[9] Erdem A, Acik V, Leventolu A, Sarilar C, Cansu A. Effect of vagal nerve stimulation in
DykeDavidoffMasson syndrome with refractory generalized seizures case
report. Turk Neurosurg 2009;19(2):1979.
[10] Kostov K, Kostov H, Taubll E. Long-term vagus nerve stimulation in the treatment
of LennoxGastaut syndrome. Epilepsy Behav 2009;16(2):3214.
[11] Morris III GL, Mueller WM. Long-term treatment with vagus nerve stimulation in
patients with refractory epilepsy. Neurology 1999;53:17315.
[12] A randomized controlled trial of chronic vagus nerve stimulation for treatment of
medically intractable seizures. Neurology 1995;45(2):22430.
[13] Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES,
et al. Vagus nerve stimulation therapy for partial onset seizures: a randomized,
active control trial. Neurology 1998;51(1):4855.
[14] Wei H. Research on auriculo-vagus-reex and mechanisms of the antiseizure effect
by auricular acupuncture; 2008 [Doctoral dissertations].
[15] Stefan H, Kreiselmeyer G, Kerling F, Kurzbuch K, Rauch C, Heers M, et al. Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of
concept trial. Epilepsia 2012;53(7):e1158. http://dx.doi.org/10.1111/j.1528-1167.
2012.03492.x.
[16] Xi YG. Ear acupuncture therapy and earvagus nerveviscera reex; 2005 [Doctoral
dissertations].
[17] Liu D, Hu Y. The central projections of the great auricular nerve primary afferent
bers an HRP transganglionic tracing method. Brain Res 1988;445(2):20510.
[18] Ramani R. Vagus nerve stimulation therapy for seizures. J Neurosurg Anesthesiol
2008;20(1):2935.
[19] Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and
glutamate transmission in nucleus tractus solitarius. Epilepsia 1999;40(8):10517.
[20] Quattrochi J, Datta S, Hobson JA. Cholinergic and noncholinergic afferents of the
caudolateral parabrachial nucleus: a role in the long-term enhancement of rapid
eye movement sleep. Neuroscience 1998;83:112336.

[21] Ventureyra EC. Transcutaneous vagus nerve stimulation for partial onset seizure
therapy. A new concept. Childs Nerv Syst 2000;16:1012.
[22] He W, Jing X, Wang X, Rong P, Li L, Shi H, et al. Transcutaneous auricular vagus nerve
stimulation as a complementary therapy for pediatric epilepsy: a pilot trial. Epilepsy
Behav 2013;28(3):3436. http://dx.doi.org/10.1016/j.yebeh.2013.02.001.
[23] Rong P, Liu A, Zhang J, Wang Y, Yang A, Li L, et al. An alternative therapy for drugresistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J
(Engl) 2014;127(2):3004.
[24] Rong P, Liu A, Zhang J, Wang Y, He W, Yang A, et al. Transcutaneous vagus nerve
stimulation for refractory epilepsy: a randomized controlled trial; 2014.
[25] Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet
Neurol 2002;1:47782.
[26] Scherrmann J, Hoppe C, Kral T, Schramm J, Elger CE. Vagus nerve stimulation. Clinical
experience in a large patient series. J Clin Neurophysiol 2001;18:40814.
[27] Nakken KO, Henriksen O, Roste GK, Lossius R. Vagal nerve stimulation the
Norwegian experience. Seizure 2003;12:3741.
[28] Birbeck GL, Hays RD, Cui X, Vickrey BG. Seizure reduction and quality of life
improvements in people with epilepsy. Epilepsia 2002;43:5358.
[29] Hein E, Nowak M, Kiess O, Biermann T, Bayerlein K, Kornhuber J, et al. Auricular
transcutaneous electrical nerve stimulation in depressed patients: a randomized
controlled pilot study. J Neural Transm 2013;120(5):8217.
[30] Schachter S, Saper C. Vagus nerve stimulation. Epilepsia 1998;39:67786.
[31] Malow BA, Edwards J, Marzec M, Sagher O, Ross D, Fromes G. Vagus nerve stimulation reduces daytime sleepiness in epilepsy patients. Neurology 2001;57(5):87984.
[32] Rizzo P, Beelke M, De Carli F, Canovaro P, Nobili L, Robert A, et al. Chronic vagus
nerve stimulation improves alertness and reduces rapid eye movement sleep in
patients affected by refractory epilepsy. Sleep 2003;26(5):60711.