Seizure 55 (2018) 66–69

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Seizure
journal homepage: www.elsevier.com/locate/yseiz

The effect of vagus nerve stimulator in controlling status epilepticus in

children
Satyanarayana Gedelab , Bilal Sitwata , William P. Welcha , Robert T. Kraftyc,
Yoshimi Sogawaa,*
a
Division of Pediatric Neurology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
b
Division of Pediatric Neurology, Nationwide Children’s Hospital, Columbus, OH, United States
c
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, United States

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: This study explores the effect of Vagus Nerve Stimulator (VNS) on Status Epilepticus (SE) in
Received 6 April 2017 children with medically intractable epilepsy.
Received in revised form 5 October 2017 Methods: Retrospective review was conducted in children with a history of at least two SE, who had VNS
Accepted 13 January 2018
implantation and had at least one year follow up after the procedure.
Results: Sixteen patients met inclusion/exclusion criteria. The median age of seizure onset and surgery
Keywords: was 1.3 years and 9.0 years, respectively. Prior to VNS implantation, 81% (13/16) of patients had one
Vagus Nerve Stimulator
seizure per month when all seizure types were combined. 75% (12/16) of patients experienced one
Status Epilepticus
Children
generalized convulsive seizure per month. The median number of SE prior to VNS was three (2–9), and
Intractable epilepsy 63% (10/16) had at least one SE during a year prior to implantation. The proportion of patients who did not
have any SE one year after VNS implantation increased compared to the year prior (75% vs. 37%, p = 0.07).
The seizure frequency decreased in a minority of patients when all seizure types were combined (20% at
one year, p = 1.00, 44% at the last follow up, p = 0.55), but generalized convulsive seizure decreased in 69%
of patients at one year (p = 0.01) and 75% of patients at last follow up (p = 0.01).
Conclusion: VNS appears to have favorable impact on SE and generalized convulsive seizures in children
with medically intractable epilepsy.
© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction 2. Material and methods

Vagus Nerve Stimulator (VNS) has been used as an adjunctive
treatment for intractable epilepsy in adults and children, has been
reported as an effective acute treatment for refractory Status
Epilepticus (SE), which is the most common pediatric neurological
emergency with morbidity and mortality ranging from 1 to 16%
[1,2] [3,4]. The actual mechanism of action of VNS remains unclear,
but the thalamus and the limbic system are thought to be
important based on changes in regional cerebral blood flow study
during VNS stimulation [5]. This study explores the effect of VNS on
SE and generalized convulsive seizures in children with medically
intractable epilepsy.
Abbreviations: SE, Status Epilepticus; VNS, Vagus Nerve Stimulator; AED, anti-
epileptic drug.
* Corresponding author at: 4401 Penn Avenue, Faculty Pavilion 8F, The Children’s
Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, United States.
E-mail address: Yoshimi.Sogawa@chp.edu (Y. Sogawa).
Retrospective review was conducted in children, who had VNS
implantation between 2011 and 2014 and had at least one year
follow up after the procedure. The patients in this study had
history of at least two SE prior to VNS implantation.
The Children’s Hospital of Pittsburgh is the tertiary children’s
hospital with level 4 comprehensive epilepsy center. The primary
outcome was the presence or absence of SE during one year post-
VNS implantation, which was compared to one year prior to VNS
implantation. SE was defined as either 1) a seizure documented as
status epilepticus by physicians, 2) a seizure persisting upon arrival
to ED, or 3) a seizure longer than 10 min with active motor
manifestations [3,6,7]. The patients were typically followed every
two to four weeks for the initial three months and every one to
three months thereafter for VNS adjustments. The change in
seizure frequency was our secondary outcome and was analyzed at
group level as well as at each patient level. Seizure frequency was
collected as: 1) one seizure per week; 2) <one per week,
but one per month; 3) <one seizure per month, but two per

https://doi.org/10.1016/j.seizure.2018.01.010
1059-1311/© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
 S. Gedela et al. / Seizure 55 (2018) 66–69 67

year; 4) <two seizures per year. For statistical analysis at group Table 1
Clinical characteristics (N = 16).
level, seizure frequency was dichotomized between one per
month and <one per month. This cutoff was chosen based on our Median or N IQR or %
typical practice to offer VNS [8]. Seizure frequency in each patient Gender (male) 9 56.3
was classified as decreased, unchanged, or increased based on the Seizure Onset (years) 1.3 0.8–9.5
change in category of seizure frequency. One year was chosen VNS implant (years) 9.0 2.2–15.5
Follow up (years) 2.7 1.1–5.5
because VNS adjustment typically occurs over three to six months
[2]. Seizure types were combined to determine total seizure Etiology
frequency and were collected on each visit after VNS implantation. Known 14 87.5
Generalized convulsive seizures and SE were collected and Congenital brain malformation (4)
analyzed separately. Etiology was dichotomized into ‘known’ Acquired brain insult (3)
Genetic w/o Brain Malformation (4)
and ‘unknown’ based on the revised ILAE Classification [9]. Patients
Known Etiology Not Otherwise Specified* (3)
were classified as cognitively impaired if full scale IQ was <70. Unknown 2 12.5
Epilepsy type was dichotomized between focal and generalized/ Abnormal Brain MRI 9 56.3
mixed/non-localizable [9]. Regarding VNS parameters, duty cycle Cognitive impairment 11 68.8
(%) and output current (mA) were analyzed [2]. Data analysis was
Epilepsy Syndrome
performed with Stata software version 10 (StataCorp LP, College Generalized/mixed/non-localizable 10 62.5
Station, TX). A two-sided P value of <0.05 was considered Focal 6 37.5
statistically significant. Nonparametric tests were used due to
small sample size: the primary outcome was analyzed using exact Treatment prior to VNS implant
Total AED 4 2–8
McNemar’s test for comparing matched proportions, secondary
Epilepsy Surgery 1
outcomes were analyzed using the exact sign test for paired ordinal
outcomes and Fisher’s exact test for analyzing patient level Total AED after VNS implant
characteristics. The association between seizure frequency change 1 year after VNS 3 1–5
and these clinical variables were analyzed in binary fashion. This The last follow up 3 1–6

study was approved by our Institutional Review Board. VNS: Vagus Nerve Stimulator.
AED: Anti-epileptic drug.
*
Children with abnormal neurological examination or development prior to
3. Results
epilepsy onset, or with genetic or MRI brain abnormalities of unclear significance.

3.1. Clinical characteristics (Table 1)

18/81(22%) patients, who had VNS implantation between year
2011 and 2014, had history of at least two SE. Two patients did not
reach one year follow up; VNS was turned off within one month
because of discomfort in one patient, and VNS was explanted
secondary to infection in another. The final cohort consists of 16
patients (9 male). Two of them have been published previously
[10]. The median age of seizure onset and surgery was 1.3 years and
9.0 years, respectively. The median follow up duration was 2.7
years. The majority (88%) had a known etiology, and cognitive
impairment was common (69%). Over half of them (62.5%) were
classified as having generalized/mixed/non-localizable epilepsy at
the time of surgery. One patient had resective surgery prior to VNS.
A median of four anti-epileptic drugs (AEDs) were trialed prior to
VNS implantation .
3.2. Seizure frequency prior to implantation (Table 2)
Prior to VNS implantation, 81% (13/16) of patients had one
seizure per month (all seizure types combined). 75% (12/16) of
patients experienced one generalized convulsive seizure per
month. The median number of SE prior to VNS was three (2 to 9),
and 63% (10/16) had at least one SE in the year prior to VNS
implantation .
3.3. Seizure frequency after implantation (Table 2)
At one year after VNS implantation and at the last follow up, the
median output current was 1.75 mA (0.5–2.25 mA) and 2 mA (1.5–
3 mA), median duty cycle was 25% (10–44%) and 44% (25–44%)
respectively. There was a non-statistically significant decrease in
the proportion of patients who had at least one SE within a year
after VNS implantation relative to the year prior to VNS
implantation (63% vs. 25%, p = 0.07): 3 of the 10 patients who
had at least one SE in the year prior to VNS implantation
experienced SE in the year after implantation, compared to 1 of the
6 who had no SE one year prior. The percentage of patients having
 one generalized convulsive seizure per month decreased at one
year (p = 0.01) and at last follow up (p = 0.01) (75% vs. 19% vs. 19%).
Similar trend was also observed at individual patient level. The
generalized convulsive seizure decreased in 69% of patients at one
year (p = 0.01) and 75% of patients at last follow up (p = 0.01). This
change in generalized convulsive seizure frequency was not
associated with normal MRI (p = 0.84), etiology (p = 0.31), epilepsy
classification (p = 0.33), cognitive impairment (p = 0.61), or VNS
settings (output current z = 0.6, Duty cycle z = 0.24).
4. Discussion
Large cohorts of children with VNS therapy have been
published, yet efficacy of VNS on specific seizure type and epilepsy
syndrome remains limited [2,11]. Among seizure types, general-
ized convulsive seizures and SE are especially important due to
higher mortality and morbidity [6,12]. Orosz et al reported
improvement of 21.7% at 12 months and 29.3% at 24 months
post-VNS in subset analysis of about 100 patients with predomi-
nantly generalized tonic-clonic seizures [11]. Our results cannot be
directly compared with this study as they used a different
definition for seizure improvement, but showed a similar trend
of improvement at one year (69%) and at the last follow up (75%).
The impact of VNS on status epilepticus was specifically studied on
one study [4]. They reported eight adult patients with history of
multiple episodes of SE with reduction of SE in 75% (6/8) of patients
over a mean follow-up duration of four years. Our result showed a
similar trend. Ten patients had SE within one year prior to VNS, and
only three of them experienced SE within one year after VNS
implantation. The study by Orosz et al reported the mean duration
of epilepsy prior to VNS implantation in children was 8.3 years and
were tried on mean of 6.9 AEDs prior to VNS implant [11]. Although
not statistically significant, our result of decrease in the proportion
of patients with SE after VNS implantation may suggest that VNS
could be considered at an earlier stage in selected patients with
68 S. Gedela et al. / Seizure 55 (2018) 66–69

Table 2
Seizure frequency pre/post VNS implant.

Seizure frequency as a group

Status epilepticus
Prior to VNS overall (%) 1 year prior to VNS (%) 1 year post VNS (%) last FU (%)
No SE 0 6 (37.5) 12 (75) 9 (56.3)
Single SE 0 4 (25) 3 (18.8) 2 (12.5)
No SEMultiple SE 16 (100) 6 (37.5) 1 (6.3) 5 (31.3)
No SEPatients with SE 10 (62.5) 4 (25.1), p = 0.07

All seizure combined

At surgery (%) 1 year post VNS (%) last FU (%)
1/week or more 7 (43.8) 5 (33.3) 8(50)
Less than 1/week, > = 1/month 6 (37.5) 8 (53.3) 0 (0)
Less than 1/month, > = 2/year 3 (18.8) 1 (6.7) 6 (37.5)
Less than 2/year 0 1 (6.7) 2 (12.5)
Patients with >= 1/month 13 (81) 13 (81), p = 1.0 8 (50), p = 0.13

Generalized convulsive seizures

At surgery (%) 1 year post VNS (%) last FU (%)
1/week or more 2 (12.5) 0 1(6.3)
Less than 1/week, > = 1/month 10 (62.5) 3(18.8) 2 (12.5)
Less than 1/month, > = 2/year 3 (18.8) 7 (43.8) 2 (12.5)
Less than 2/year 1 (6.3) 6 (37.5) 11 (68.8)
Patients with > = 1/month 13 (75) 3 (19), p = 0.01 3 (19), p = 0.01

Seizure frequency at individual patient level

At surgery (%) 1 year post VNS (%) last FU (%)

Status epilepticus comparing 1 year pre/post VNS (n = 10)
Decreased 9
Unchanged 0
Increased 1

All seizure combined

Decreased 3(20) 7 (43.8)
Unchanged 9(60) 5 (31.3)
Increased 3 (20) 4 (25)
p = 1.00 p = 0.55

Generalized convulsive seizures

Decreased 11 (68.8) 12 (75)
Unchanged 4 (25) 2 (12.5)
Increased 1 (6.3) 2 (12.5)
p = 0.01 p = 0.01

VNS: Vagus Nerve Stimulator.

SE: Status Epilepticus.
FU: Follow Up.

intractable epilepsy. The strength and limitation of our study needs
to be addressed. Our study has relatively long and consistent follow
up. None of 18 eligible patients were excluded because of lack of
sufficient follow up. The number of patients, who had multiple SE
prior to VNS implantation, was higher (22%) at our institution than
the general epilepsy population. However, this is clearly too small
to explore the relation between clinical variables and VNS efficacy,
or to evaluate true decrease in SE. Seizure frequency was collected
categorically in our study, not as 50% or 90% reduction as in
conventional clinical trials. We thought our approach was more
practical in this patient population, as many of them had difficult-
to-count seizure types (e.g. absence and myoclonic). Our study was
not controlled; therefore, we cannot exclude the possibility that
concurrent AED adjustments would have impacted the outcome.
However, this is less likely as patients had failed multiple AEDs
before VNS implantation and we typically avoid AED adjustments
during the first six months of VNS adjustment. It is also possible
that seizure frequency was under-reported over time, including
status epilepticus, although we assert that the treating epileptol-
ogist was aware of most, if not all, prolonged seizures or episodes of
status epilepticus given more frequent and regular clinical follow
up for VNS adjustment.
5. Conclusion
VNS appears to have favorable impact on SE and generalized
convulsive seizures. This may be an area of further study in
patients with intractable epilepsy, as these seizure types are
associated with higher mortality and morbidity.
Author disclosures
The authors have no conflict of interest. We confirm that we
have read the Journal's position on issues involved in ethical
publication and affirm that this report is consistent with those
guidelines.
Acknowledgements
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors. The
statistical analysis service was provided by the Clinical and
Translational Science Institute (CTSI) at the University of Pitts-
burgh, supported by the National Institutes of Health through
Grant Number UL1 TR001857.
 S. Gedela et al. / Seizure 55 (2018) 66–69
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