Journal of
Clinical Medicine
Review
Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy in
Children—A Literature Review
Mitsumasa Fukuda 1, * , Takeshi Matsuo 2 , So Fujimoto 2 , Hirofumi Kashii 1 , Ai Hoshino 1 , Akihiko Ishiyama 1
and Satoko Kumada 1
Citation: Fukuda, M.; Matsuo, T.;
Fujimoto, S.; Kashii, H.; Hoshino, A.;
Ishiyama, A.; Kumada, S. Vagus
Nerve Stimulation Therapy for
Drug-Resistant Epilepsy in
Children—A Literature Review. J.
Clin. Med. 2024, 13, 780. https://
doi.org/10.3390/jcm13030780
Academic Editors: Umberto Aguglia
and Hideaki Kanemura
Received: 9 December 2023
Revised: 12 January 2024
Accepted: 27 January 2024
Published: 29 January 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
J. Clin. Med. 2024, 13, 780. https://doi.org/10.3390/jcm13030780
1 Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu 183-0042, Japan;
ocean.letter@gmail.com (H.K.); aizm0505@yahoo.co.jp (A.H.); akihiko_ishiyama@tmhp.jp (A.I.);
satoko_kumada@tmhp.jp (S.K.)
2 Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Fuchu 183-0042, Japan;
takeshi_matsuo@tmhp.jp (T.M.); sou_fujimoto@tmhp.jp (S.F.)
* Correspondence: mitsumasa_fukuda@tmhp.jp; Tel.: +81-42-323-5110
Abstract: Vagus nerve stimulation (VNS) is a palliative treatment for drug-resistant epilepsy (DRE)
that has been in use for over two decades. VNS suppresses epileptic seizures, prevents emotional
disorders, and improves cognitive function and sleep quality, a parallel effect associated with the
control of epileptic seizures. The seizure suppression rate with VNS increases monthly to annually,
and the incidence of side effects reduces over time. This method is effective in treating DRE in children
as well as adults, such as epilepsy associated with tuberous sclerosis, Dravet syndrome, and Lennox–
Gastaut syndrome. In children, it has been reported that seizures decreased by >70% approximately
8 years after initiating VNS, and the 50% responder rate was reported to be approximately 70%.
VNS regulates stimulation and has multiple useful systems, including self-seizure suppression using
magnets, additional stimulation using an automatic seizure detection system, different stimulation
settings for day and night, and an automatic stimulation adjustment system that reduces hospital
visits. VNS suppresses seizures and has beneficial behavioral effects in children with DRE. This
review describes the VNS system, the mechanism of the therapeutic effect, the specific stimulation
adjustment method, antiepileptic effects, and other clinical effects in patients with childhood DRE.
Keywords: vagus nerve stimulation; VNS; epilepsy; children; quality of life
1. Introduction
Vagus nerve stimulation (VNS) is a palliative therapy that stimulates the vagus nerves.
Implantable neurostimulators are an adjunct treatment to drug therapy for drug-resistant
epilepsy (DRE) and provide an alternative for patients who are not candidates for resective
surgery. Currently, three treatment methods are used in clinical practice: VNS, reactive
nerve stimulation, and deep brain stimulation. Among them, VNS is the first neuromod-
ulatory device approved for the treatment of epilepsy. VNS was approved in the United
States in 1997, and the number of implementations globally was approximately 125,000 in
2020, according to the manufacturing company. It has also been used in >35,000 pediatric
patients worldwide and is approved as a long-term treatment for DRE in children [1].
VNS suppresses epileptic seizures, prevents emotional disorders, and improves cog-
nitive function; further, it has a parallel effect associated with the control of epileptic
seizures. In Japan, there are no restrictions for its use related to age or seizure type for
children with DRE. Currently, it is an essential treatment method for patients who are
resistant to any anti-seizure medication and are unsuitable for open epilepsy surgery such
as corpus callosotomy or focal cortical resection or for patients for whom surgery is not
sufficiently effective.
https://www.mdpi.com/journal/jcm
 2. VNS Therapy Device
The VNS device comprises four devices: (1) An implantable pulse generator; (2) A
spiral‐implanted electrode; (3) A device that programs the stimulation conditions of the
subcutaneously implanted generator from outside the body: (4) An external magnet that
can initiate temporary stimulation using a self‐adjustment method (Figure 1a–c).
J. Clin. Med. 2024, 13, 780 2 of 11
The implantation procedure requires two incisions in the left chest for the generator
and in the left neck for the lead. The distal part of the lead is attached to the vagus nerve
via spiral tethers, and the other side is inserted subcutaneously into the upper chest using
Thistool
a tunneling review describesto
for connecting the VNS system,
a generator. the mechanism
Anatomically of therapeuticthe
and physiologically, effect,
rightthe specific
stimulation
vagus nerve mainlyadjustment
transmitsmethod,
downward antiepileptic effects,
impulses from and other
the center to the clinical effects in patients
heart’s sinoatrial
with
node. In childhood
fact, VNS doesDRE. affect the heart and is explored as a potential treatment for heart
conditions [2]. On the contrary, the left vagus nerve mainly transmits upward impulses
2. the
from VNS Therapy
internal Device
organs to the center rather than to the right [3]. Therefore, a spiral elec‐
trode is placed
The VNS to stimulate the vagus nerve
device comprises on the left(1)
four devices: side
Anofimplantable
the neck, which is unlikely
pulse generator; (2) A
to affect the heart. The stimulation is intermittent, and the parameters are programmable.
spiral-implanted electrode; (3) A device that programs the stimulation conditions of the
Thesubcutaneously
parameter setting is facilitated
implanted using a programming
generator from outsidewand connected
the body: (4) Anto aexternal
hand‐held magnet that
computer using radio frequencies (Figure 1d).
can initiate temporary stimulation using a self-adjustment method (Figure 1a–c).

Figure 1. Vagus nerve stimulation (VNS) therapy device.: (a) The implanted VNS device consists
Figure
of a1.pulse
Vagus nerve stimulation
generator (AspireSR (VNS)
Modeltherapy
106) device.: (a) The
and a spiral implanted
electrode VNSaround
wrap device consists
the left of
vagus nerve.
a pulse generator (AspireSR Model 106) and a spiral electrode wrap around the left vagus nerve. (b)
(b) The VNS device comprises a pulse generator (SenTiva Model 1000), a programming wand, and a
The VNS device comprises a pulse generator (SenTiva Model 1000), a programming wand, and a
notepad.
notepad. (c) magnet
(c) The The magnet is as
is used used as an external
an external magnetmagnet
that can that cantemporary
initiate initiate temporary
stimulationstimulation
using using
a self-adjustment method. (d) Parameter setting is facilitated using a programming
a self‐adjustment method. (d) Parameter setting is facilitated using a programming wand connected wand connected
to atohand‐held
a hand-heldcomputer usingusing
computer radio radio
frequencies. AspireSR
frequencies. and Sentiva
AspireSR andare supplied
SenTiva areby LivaNova
supplied by LivaNova
PLC—London, United Kingdom.
PLC—London, United Kingdom.

3. Anatomy
The of the Vagus Nerve
implantation and Mechanism
procedure of Antiepileptic
requires two Action
incisions in the leftof VNSfor the generator
chest
Theinvagus
and nerve
the left is afor
neck complex nerve
the lead. The that is both
distal efferent
part of theandleadafferent; approximately
is attached to the vagus nerve
90% of the nerves are afferent, transmitting information from each thoracic
via spiral tethers, and the other side is inserted subcutaneously into the and abdominal
upper chest using
organ to the central
a tunneling toolnervous system. The
for connecting toafferent fibers ofAnatomically
a generator. the vagus nerveand ascend and are
physiologically, the
relayed to the nucleus tractus solitarius (NTS) on both sides of the
right vagus nerve mainly transmits downward impulses from the center tomedulla oblongata. Thethe heart’s
sinoatrial node. In fact, VNS does affect the heart and is explored as a potential treatment
for heart conditions [2]. On the contrary, the left vagus nerve mainly transmits upward
impulses from the internal organs to the center rather than to the right [3]. Therefore, a
spiral electrode is placed to stimulate the vagus nerve on the left side of the neck, which
is unlikely to affect the heart. The stimulation is intermittent, and the parameters are
programmable. The parameter setting is facilitated using a programming wand connected
to a hand-held computer using radio frequencies (Figure 1d).

3. Anatomy of the Vagus Nerve and Mechanism of Antiepileptic Action of VNS

The vagus nerve is a complex nerve that is both efferent and afferent; approximately
90% of the nerves are afferent, transmitting information from each thoracic and abdominal
organ to the central nervous system. The afferent fibers of the vagus nerve ascend and are
relayed to the nucleus tractus solitarius (NTS) on both sides of the medulla oblongata. The
output from the NTS is further divided into three routes: (1) Somatic motor nerves of the
medulla oblongata (regulating breathing, heart rhythm, and blood pressure); (2) Medullary
reticular formation (involved in respiratory reflexes); (3) The third cerebrum pathway is
divided into two pathways—one that connects directly to the hypothalamus, amygdala,
 J. Clin. Med. 2024, 13, x FOR PEER REVIEW 3 of 12

J. Clin. Med. 2024, 13, 780 output from the NTS is further divided into three routes: (1) Somatic motor nerves of the 3 of 11
medulla oblongata (regulating breathing, heart rhythm, and blood pressure); (2) Medul‐
lary reticular formation (involved in respiratory reflexes); (3) The third cerebrum pathway
is divided into two pathways—one that connects directly to the hypothalamus, amygdala,
and limbic system from the NTS and the other that connects mainly to the intralaminal
and limbic system from the NTS and the other that connects mainly to the intralaminal
nucleiofofthe
nuclei thethalamus
thalamus through
through the parabrachial
the parabrachial nucleus
nucleus and reaches
and reaches the cerebral
the cerebral cortex cortex
through the midline nuclei [4,5] (Figure 2). The presumed mechanism
through the midline nuclei [4,5] (Figure 2). The presumed mechanism of VNS therapy of VNS is therapy
that upward activity induced by VNS broadly affects the limbic system and cortex, sup‐ cortex,
is that upward activity induced by VNS broadly affects the limbic system and
suppressing
pressing generalized
generalized epilepticepileptic
waves inwaves
clinicalin clinical physiology
physiology and local
and local cerebral bloodcerebral
flow blood
flow
in in functional
functional imagingimaging
[6,7]. [6,7].

Figure
Figure2.2.TheThe
vagal efferent
vagal fibersfibers
efferent send thesendsignals
the “down”
signals from the brain,
“down” from which account
the brain, for ap‐
which account for
proximately 10% of all fibers, and the vagal afferents “up” from the intestinal wall to the brain,
approximately 10% of all fibers, and the vagal afferents “up” from the intestinal wall to the brain,
accounting for 90% of all fibers. Afferent fibers from the NTS project most densely to the PBNP, with
accounting
the NTS also for 90% oftoallnoradrenergic
projecting fibers. Afferent
(LC) andfibers from the NTS
serotonergic (RN) project most densely
neuromodulatory to the PBNP,
systems.
with the
Vagal NTS alsoisprojecting
information to noradrenergic
relayed to several (LC) and
mostly subcortical serotonergic
structures, (RN)the
including neuromodulatory
hypothalamus, systems.
the nucleus
Vagal of the amygdala,
information is relayedthe
tonucleus
severalof the stria
mostly terminalis,structures,
subcortical and the intralaminar
including thethalamic nu‐
hypothalamus, the
cleus. Vagal
nucleus of afferent information
the amygdala, the is also sentoftothe
nucleus anterior
thestria insular cortex
terminalis, and (Ins), which communicates
the intralaminar thalamic nucleus.
with more rostral regions of the cortex (O/VPC) and PFC. NTS, nucleus tractus solitarius; PBNP,
Vagal afferent
parabrachial information
nucleus is also
of the pons; LC, sent
locusto the anterior
coeruleus; insular
RN, raphe cortexInsC,
nucleus; (Ins),insular
whichcortex;
communicates
with more
O/VPC rostral
orbital regions of prefrontal
and ventrolateral the cortexcortex;
(O/VPC) and PFC.cortex
PFC, prefrontal NTS, [8].
nucleus tractus solitarius; PBNP,
parabrachial nucleus of the pons; LC, locus coeruleus; RN, raphe nucleus; InsC, insular cortex;
O/VPCNeuroendocrinologically,
orbital and ventrolateral VNS is thought
prefrontal to cause
cortex; PFC,changes in cortex
prefrontal the gamma‐aminobu‐
[8].
tyric acid (GABA) system nerve activity, norepinephrine system nerve activity, and amino
Neuroendocrinologically,
acid metabolism. VNS
In addition, basic is thought
research to cause
on this changes
treatment in the
method hasgamma-aminobutyric
reported in‐
acid (GABA) system nerve activity, norepinephrine system nerve activity,
creases in GABA in the piriform cortex and prolonged amygdala kindling timeand amino acid
[9,10].
Neuroimmunologically, a previous report using pro‐ and anti‐inflammatory
metabolism. In addition, basic research on this treatment method has reported cytokines in increases
peripheral blood indicated that VNS causes rebalancing of the immune system,
in GABA in the piriform cortex and prolonged amygdala kindling time [9,10]. Neuroim- reducing
neurotoxins,
munologically,increasing neuroprotective
a previous report usingkynurenine
pro- andmetabolites, and normalizing
anti-inflammatory cytokines cortisol
in peripheral
levels
blood indicated that VNS causes rebalancing of the immune system, reducingcells
[11]. Another study using gene expression in peripheral blood mononuclear neurotoxins,
indicated that VNS suppressed epileptic seizures through anti‐inflammatory effects [12].
increasing neuroprotective kynurenine metabolites, and normalizing cortisol levels [11]. An-
In neurophysiological studies, VNS suppresses seizures by regulating cerebral blood flow
other study using gene expression in peripheral blood mononuclear cells indicated that VNS
and desynchronizing paroxysmal electroencephalogram (EEG) patterns
suppressed epileptic seizures through anti-inflammatory effects [12]. In neurophysiological
studies, VNS suppresses seizures by regulating cerebral blood flow and desynchronizing
paroxysmal electroencephalogram (EEG) patterns neurophysiologically [7,13]. The effects
of VNS appeared slowly over time, suggesting the involvement of multiple mechanisms as
described above.

4. Specific Basic Stimulus Adjustment of VNS

According to the research at the beginning of VNS therapy, two pivotal trials indicated
that device settings of 30 s on/5 min off are safe and effective [14,15]. After VNS implanta-
 cated that device settings of 30 s on/5 min off are safe and effective [14,15]. After VNS
implantation surgery, stimulation is started at a low intensity and gradually increased
while paying attention to the appearance of side effects. In the normal mode, it starts with
an output current of 0.25 mA, a signal frequency of 20 Hz, a pulse width of 250 μs, a signal
J. Clin. Med. 2024, 13, 780 ON time of 30 s, and a signal OFF time of 5 min. It gradually increases while the effect on 4 of 11
seizures is observed, as long as no adverse effects appear. If there is no effect, the duty
cycle increases the ON time proportion in one cycle. The optimal conditions vary depend‐
ingsurgery,
tion on the patient and require
stimulation trial at
is started and errorintensity
a low to determine in each case
and gradually [16] (Figure
increased 3a,c,d).
while paying
In a recent
attention to study to identify of
the appearance anside
appropriate
effects. target
In the dose for VNS
normal mode, therapy in with
it starts epilepsy, the
an output
target output
current of 0.25 current and duty
mA, a signal cycle were
frequency of 20identified
Hz, a pulseas 1.61
widthmAofand
25017.1%, respectively
µs, a signal ON time
of[17].
30 s, and a signal OFF time of 5 min. It gradually increases while the effect on seizures is
The as
observed, magnet mode
long as normallyeffects
no adverse sets the outputIf0.25
appear. mA
there is higher than
no effect, thetheduty
normal mode.
cycle If
increases
patients
the ON timeareproportion
adults and in
feel ancycle.
one epileptic
Theaura, theyconditions
optimal can start the magnet
vary mode on
depending by the
placing
patient
it directly
and require above theerror
trial and pulsetogenerator
determine forin>1each
s but <3 s.
case Even
[16] children
(Figure withIndevelopmental
3a,c,d). a recent study to
delays may use the magnet mode when their parents and guardians
identify an appropriate target dose for VNS therapy in epilepsy, the target notice warning
outputsigns
current
or when they have repeated seizures within a short period.
and duty cycle were identified as 1.61 mA and 17.1%, respectively [17]. (Figure 3b,c).

Figure3.3. VNS
Figure VNS parameter
parametersetting.
setting.(a)(a)
Basic VNS
Basic stimulation
VNS parameters:
stimulation signal signal
parameters: ON time,ONsignal
time,OFF
signal
time,
OFF plusplus
time, frequency, plus width,
frequency, and output
plus width, current.current.
and output (b) The (b)
magnet
The mode
magnetnormally sets the output
mode normally sets the
0.25 mA
output higher
0.25 than the
mA higher normal
than mode. Ifmode.
the normal patients feel an epileptic
If patients aura or their
feel an epileptic aura parents and
or their guard‐and
parents
ians notice warning signs or repeated seizures within a short period, they hold the magnet over the
guardians notice warning signs or repeated seizures within a short period, they hold the magnet over
plus generator for >1 s but <3 s. (c) Normal mode: 0.25 mA steps up to the therapeutic effect. Magnet
the plusnormal
mode: generator
modefor+ >1 s but
0.25 mA <3 s. (c)mode.
magnet Normal mode: mode:
Autostim 0.25 mA stepsmode
normal up to+ the therapeutic
0.125 mA. (d) Dutyeffect.
Magnet mode: normal
cycle: Increase the dutymode
cycle + 0.25time
over mAandmagnet
assessmode.
clinicalAutostim
outcomes.mode: normaltomode
Adjustments + 0.125
the duty cyclemA.
should
(d) Duty be less Increase
cycle: frequent (3–6 months).
the duty cycle over time and assess clinical outcomes. Adjustments to the
duty cycle should be less frequent (3–6 months).
5. Seizure Suppression Effect
The
VNS magnet
reduces mode normally seizure
and improves sets thefrequency
output 0.25 mA
over higher
time. Thethan the normal
McHugh mode. If
classification
patients
has five levels of seizure frequency reduction: 80–100% (class I), 50–79% (class II), less placing
are adults and feel an epileptic aura, they can start the magnet mode by than
it 50%
directly
(classabove the pulse
III), only generator
the effect for use
of magnet >1 s(class
but <3 s. and
IV), Evennochildren withV).
effect (class developmental
The repre‐
delays mayindicator
sentative use the magnet
using themode when
McHugh their parents
classification and50%
is the guardians notice
responder ratewarning
(the rate signs
of
orpatients
when they
whose have repeated
seizures haveseizures within abyshort
been reduced ≥50%,period. (Figure 3b,c).
corresponding to classes 1 and 2)

5. Seizure Suppression Effect

VNS reduces and improves seizure frequency over time. The McHugh classification
has five levels of seizure frequency reduction: 80–100% (class I), 50–79% (class II), less
than 50% (class III), only the effect of magnet use (class IV), and no effect (class V). The
representative indicator using the McHugh classification is the 50% responder rate (the
rate of patients whose seizures have been reduced by ≥50%, corresponding to classes 1
and 2) [18]. In a large-scale study focusing on adult epilepsy in the early stages of VNS
initiation, the average seizure control rate was 20% at 3 months, 35% at 1 year, and 45%
at 2 years after initiating stimulation. Furthermore, the 50% responder rate was 23% at
3 months, 37% at 1 year, and 44% at 2 years after initiating stimulation, confirming that
seizures decreased over time [19]. Another study that followed 44 adults and 21 children
over a long period reported that the 50% responder rate gradually increased and reached
approximately 75% (Figure 4) [20]. Furthermore, a recent meta-analysis study indicated
 [18]. In a large‐scale study focusing on adult epilepsy in the early stages of VNS initiation,
the average seizure control rate was 20% at 3 months, 35% at 1 year, and 45% at 2 years
after initiating stimulation. Furthermore, the 50% responder rate was 23% at 3 months,
37% at 1 year, and 44% at 2 years after initiating stimulation, confirming that seizures
decreased over time [19]. Another study that followed 44 adults and 21 children over a
J. Clin. Med. 2024, 13, 780 5 of 11
long period reported that the 50% responder rate gradually increased and reached ap‐
proximately 75% (Figure 4) [20]. Furthermore, a recent meta‐analysis study indicated that
seizure reduction (50% responder rate) for the VNS devices at years one, two, and three
werethat
VNSseizure
32.9%,reduction
44.4%, and(50% responder
53.5%, rate)[21].
respectively for the VNS devices
As described at years
below, one, two,
the efficacy andand three
were VNS 32.9%, 44.4%, and 53.5%, respectively [21]. As described below,
safety reported for children are approximately the same as those for adults. Convention‐ the efficacy and
safety reported for children are approximately the same as those for adults. Conventionally,
ally, the Engel classification has been used to evaluate seizure improvement after epilepsy
the Engel
surgery; classification
however, the treatmenthasoutcome
been used to evaluate
classification seizurebyimprovement
proposed McHugh et al.after
is of‐epilepsy
surgery; however, the treatment outcome classification proposed
ten used to determine the seizure improvement effect after VNS [18]. by McHugh et al. is often
used to determine the seizure improvement effect after VNS [18].

Figure 4. Seizure suppression effect. A study that followed 44 adults and 21 children over a long
Figure 4. Seizure suppression effect. A study that followed 44 adults and 21 children over a long
period reported that the mean reductions in seizures at 6 months and 1, 2, 4, 6, 8, and 10 years were
period reported that the mean reductions in seizures at 6 months and 1, 2, 4, 6, 8, and 10 years were
35.7, 35.7, 52.1, 60.4,
52.1, 58.3, 58.3,65.7,
60.4,75.5,
65.7,and
75.5, and 75.5%,
75.5%, respectively.
respectively. The control
The seizure seizureratecontrol rate increased
increased slowly. slowly.
FigureFigure
4 was4created
was created
by theby the authors
authors based
based on the on the research
research results
results of ElliotofetElliot et al. [20].
al. [20].

6. VNS Device with an Automatic Seizure Control System Based on Heart

6. VNS Device with an Automatic Seizure Control System Based on Heart
Rate Fluctuations
Rate Fluctuations
This automatic seizure control function was included in the previous generation
This automatic seizure control function was included in the previous generation
model, AspireSR (Figure 1a), and the current model, the SenTiva model manufactured
model, AspireSR (Figure 1a), and the current model, the SenTiva model manufactured by
by LivaNova, PLC in the London, UK, which has self-adjustment and automatic seizure
LivaNova, PLC in the London, UK, which has self‐adjustment and automatic seizure ad‐
adjustment functions based on heart rate fluctuations (Figure 1b). This model has been
justment functions based on heart rate fluctuations (Figure 1b). This model has been ap‐
approved for use in the United States, Europe, China (from 2023), and Japan. The automatic
proved for use in the United States, Europe, China (from 2023), and Japan. The automatic
seizure adjustment function identifies sudden tachycardia immediately before or during
seizure adjustment function identifies sudden tachycardia immediately before or during
a seizure, identifies it as a seizure, automatically applies additional stimulation, and is
a seizure, identifies it as a seizure, automatically applies additional stimulation, and is
expected to have a greater seizure suppression effect. As an effect of AutoStim mode,
expected to have a greater seizure suppression effect. As an effect of AutoStim mode,
tachycardia, in which the heart rate increases by more than 50% during an attack, is
tachycardia, in which the heart rate increases by more than 50% during an attack, is ob‐
servedobserved
in only in only approximately
approximately 15% of seizures,
15% of seizures, and it isand it is necessary
necessary to lowertothe
lower the threshold
threshold
for a heart rate increase. It has been reported that this treatment not
for a heart rate increase. It has been reported that this treatment not only suppresses sei‐ only suppresses
zuresseizures
but alsobut also improves
improves QOL in approximately
QOL in approximately one‐thirdone-third
of patientsof[22].
patients [22].
If the patients have a cardiac arrhythmia the automatic stimulationstimulation
If the patients have a cardiac arrhythmia the automatic feature is notfeature
suit‐ is not
able. This includes heart conditions or treatments that do not allow necessary changes inchanges
suitable. This includes heart conditions or treatments that do not allow necessary
in the patient’s
the patient’s heart
heart rate, suchrate, suchfibrillation,
as atrial as atrial fibrillation,
pacemakerpacemaker
dependency, dependency,
implantableimplantable
de‐
defibrillator, or cardiac medications such as beta
fibrillator, or cardiac medications such as beta blockers [23]. blockers [23].

7. Clinical Effects and Benefits Other Than Seizures

In addition to seizure suppression, various other clinical benefits have been reported.
Reducing the number of hospitalizations, anti-seizure medications, and dosage is possible;
therefore, it may be possible to reduce the side effects of anti-seizure medications. Moreover,
a reduction in injuries due to a decrease in drop attacks and a decline in sudden unexpected
death in epilepsy (SUDEP) due to a decrease in status attacks and a reduction in the burden
on the cardiopulmonary system have been reported [24]. Furthermore, even in cases where
seizures do not improve, improved emotional stability and sociability are often observed,
especially by parents, resulting in positive outcomes for the child’s development and
quality of life (QOL) (Figure 5) [25].

J. Clin. Med. 2024, 13, 780
ble; therefore, it may be possible to reduce the side effects of anti‐seizure medications.
Moreover, a reduction in injuries due to a decrease in drop attacks and a decline in sudden
unexpected death in epilepsy (SUDEP) due to a decrease in status attacks and a reduction
in the burden on the cardiopulmonary system have been reported [24]. Furthermore, even
in cases where seizures do not improve, improved emotional stability and sociability are
often observed, especially by parents, resulting in positive outcomes for the child’s devel‐6 of 11
opment and quality of life (QOL) (Figure 5) [25].

Figure
Figure Clinical
5. 5. Clinicaleffects
effectsand
and benefits otherthan
benefits other thanseizures:
seizures:(a)(a) Mean
Mean change
change in Quality
in the the Quality of in
of Life Life in
Epilepsy
EpilepsyInventory-89
Inventory‐89(QOLIE-89)
(QOLIE‐89) overall scorefrom
overall score frombaseline
baseline(Month
(Month0; n0;=n96)
= 96) to months
to months 3 (n =394),
(n = 94),
6 (n6 =(n68),
= 68),
andand1212
(n (n = 60).The
= 60). TheQOLIE-89 scoreover
QOLIE‐89score over time
time showed
showed a significant
significantdifference
differencebetween
between the
the VNS+BMP
VNS+BMP and BMP‐only
and BMP-only groups,
groups, with awith a greater
greater improvement
improvement in patients
in patients allocated
allocated to the
to the VNS+BMP
VNS+BMP group. (b) Change from baseline to month 12 in subscales QOLIE‐89 scores. The differ‐
group. (b) Change from baseline to month 12 in subscales QOLIE-89 scores. The differences were
ences were insignificant: epilepsy‐targeted score (p = 0.06), cognitive (p = 0.20), mental health (p =
insignificant: epilepsy-targeted
0.33), and physical score
health (p = 0.17). (p =best
BMP: 0.06), cognitive
medical (p VNS:
practice, = 0.20), mental
vagus nervehealth (p = 0.33),
stimulation. Fig‐ and
physical health
ure 5 was (p =by
created 0.17). BMP: best
the authors medical
based practice,results
on the research VNS: of vagus nerve
Ryvlin et al.stimulation.
[25]. Figure 5 was
created by the authors based on the research results of Ryvlin et al. [25].
Furthermore, the 22 patients with DRE who underwent VNS were reported to have
Furthermore,
a significant the 22
decrease patientsand
in seizures with DRE who
interictal underwent
epileptiform VNS were
discharges reported
on their EEGs,to ashave
well as significantly
a significant decreaseimproved
in seizures sleep
andquality, compared
interictal to the control
epileptiform dischargesgroupon [26].
their EEGs, as
well as significantly improved sleep quality, compared to the control group [26].
8. Side Effects
8. SideThe
Effects
most problematic side effect of VNS is wound infection. In a previous study of
808The
patients, it was observed
most problematic sideineffect
12 patients
of VNS(1.5%), and the
is wound mean (±standard
infection. deviation)
In a previous study of
time from the most recent VNS‐related surgeries to infection was 42 (±27) days
808 patients, it was observed in 12 patients (1.5%), and the mean (±standard deviation) [27]. Fur‐ time
thermore,
from the most side effects
recent include reactive
VNS-related coughing,
surgeries voice was
to infection changes,
42 (±paresthesia, pain
27) days [27]. in the
Furthermore,
back of the head, nausea, and salivation. However, they tend to subside over time
side effects include reactive coughing, voice changes, paresthesia, pain in the back of the and canhead,
be alleviated by changing the stimulation settings. Care must be taken in rare cases, as
nausea, and salivation. However, they tend to subside over time and can be alleviated by
J. Clin. Med. 2024, 13, x FOR PEER REVIEWpain, scarring, and wound infection at the surgical site can sometimes cause irritation
7 of 12(Fig‐
changing the stimulation settings. Care must be taken in rare cases, as pain, scarring, and
ure 6) [28,29].
wound infection at the surgical site can sometimes cause irritation (Figure 6) [28,29].

Figure 6. Side effects include voice changes, reactive coughing, and paresthesia pain in the back of
Figure 6. Side effects include voice changes, reactive coughing, and paresthesia pain in the back of
the
the head,
head, butbut these
these gradually
gradually improve.
improve. FigureFigure
6 was 6created
was created by the authors
by the authors based onbased on the research
the research
results of Morris et al. [28].
results of Morris et al. [28].

9. Effect on Pediatric Drug‐Resistant Epilepsy

Similar to adults, 70–80% of childhood epilepsy cases are benign and progress spon‐
taneously. However, 20–30% of cases are resistant to anti‐seizure medications, and persis‐
tent seizures and abnormal brain waves seriously affect a child’s development. VNS has
certain suppressive effects on childhood DRE, the same as adults in the open‐label multi‐
center study report of the analysis population, which included 347 children (aged 6
J. Clin. Med. 2024, 13, 780 7 of 11

9. Effect on Pediatric Drug-Resistant Epilepsy

Similar to adults, 70–80% of childhood epilepsy cases are benign and progress sponta-
neously. However, 20–30% of cases are resistant to anti-seizure medications, and persistent
seizures and abnormal brain waves seriously affect a child’s development. VNS has certain
suppressive effects on childhood DRE, the same as adults in the open-label multicenter
study report of the analysis population, which included 347 children (aged 6 months to
17.9 years at the time of implant). It indicated that at 6, 12, and 24 months after implanta-
tion 32.5%, 37.6%, and 43.8% of patients, respectively, had a 50.0% responder rate in the
baseline seizure frequency of the predominant seizure type. And, 19 patients (5.5%) were
rendered seizure-free. A subset analysis using an age cut-off of <12 years at the initiation of
VNS therapy demonstrated a 50% responder rate of 36.3%, 43.0%, and 50% at 6, 12, and
24 months, respectively, including 7.0%, 7.8%, and 11.3% of patients who were rendered free
of the predominant seizure type. [30]. The efficacy rates in patients with childhood-onset
epilepsy based on characteristic diseases are shown in Table 1.

Table 1. Efficacy of VNS for childhood DRE.

Underlying Disease Typical Age of Epilepsy Onset 50% Responder Rate

<1 year old [31]
Tuberous sclerosis 50–90% [32,33]
(1 year old on average)
Lennox–Gastaut syndrome Median age 4 years [34] 50–65% [34–36]
Dravet syndrome <1 year old [37,38] 36–63% [39,40]
Rett syndrome
6–18 months old [41,42] 86% [43]
(MECP2 genetic mutation)

Tuber sclerosis complex (TSC) is an autosomal dominant multisystem disorder that affects
1 in 6000 individuals [31]. Major et al. reported that the average age at VNS implantation was
15 years (range: 2–44; SD: 12.5), and the average duration of follow-up on VNS was 4 years
(range: 0.5–8.6; SD: 2.3). The outcomes were rated as class I (>80% seizure frequency reduction)
in three (19%), class II (50–79% reduction) in five (31%), class III (<50% reduction) in two
(13%), class IV (magnet benefit only) in one (6%), and class V (no improvement) in five (31%)
patients. Intermittent magnet use was effective in aborting seizures in eight patients (50%).
Five patients (31%) reported improved functioning. Parain et al. reported that 10 patients with
TSC with medically refractory epilepsy were treated using vagal nerve stimulation. Nine of
them experienced at least a 50% reduction in seizure frequency, and five had a ≥90% reduction
in seizure frequency. No adverse events were encountered [32,33].
Lennox–Gastaut syndrome (LGS) is a severe type of childhood epilepsy with an onset
typically occurring before 8 years of age; it is almost always pharmacologically resistant.
It has been reported that the 50% responder rate for LGS is >50%, and effects other than
the seizure suppression mentioned above have also been confirmed [34,35]. In another
report, a meta-analysis of 480 patients with LGS indicated that 54% of patients responded
to adjunctive VNS therapy and that the treatment option was safe and well-tolerated [36].
Moreover, Dravet syndrome, a common childhood DRE, presents within the first
year of life in a normal child with prolonged, febrile and afebrile, focal clonic (usually
hemiclonic), or generalized clonic seizures. Seizures are usually intractable, and children
demonstrate cognitive and behavioral impairments from the second year of life [37,38].
Recent studies about the effects of VNS on Dravet syndrome indicated that a more than
50% reduction in seizure frequency was observed in 36.4% (8/22), 54.5% (12/22), and 63.2%
(12/19) of the patients at 12, 24, and 36 months, respectively [39], and another meta-analysis
study indicated that 52.9% of Dravet syndrome patients experienced a ≥50% reduction in
seizures [40].
MECP2 mutations in female patients are the primary cause of Rett syndrome, which is
a rare and severe X-linked neurodevelopmental disease caused by the gain of function of
J. Clin. Med. 2024, 13, 780 8 of 11

the MECP2 gene. Seizures occur in 47% of the cases with MECP2 mutations around 1 year
of age, usually as part of a developmental and epileptic encephalopathy [41,42]. In a study
of seven children with Rett syndrome who had DRE, five of the seven female patients had
experienced at least a 50% reduction in seizure frequency at 3 months. At 12 months, six
female patients had experienced at least a 50% reduction in seizure frequency. Four out of
seven patients had at least a 90% reduction at 12 months. The two patients with 24 months
of follow-up maintained more than a 90% reduction in seizure frequency from baseline [43].
Moreover, several studies have reported the effectiveness of DRE for childhood
autism [44]. However, cases in which implantable devices cannot be tolerated also need to
be considered. Regarding clinical effects other than seizures, a study of pediatric epileptic
encephalopathy also reported that patients whose seizure frequency was reduced by at
least 50% had significantly improved neuropsychological performance and QOL [45].
VNS is strictly a palliative treatment option for DRE. It is particularly recommended for
cases in which the indications for epilepsy surgery are unknown, sufficient effects have not
been obtained via surgery, or ketogenic diet therapy has not been effective. Symptomatic
childhood epilepsy is the main target disease. However, for Dravet syndrome it is essential
to first try anti-seizure medications such as Stiripentol and Fenfluramine hydrochloride [46].
Care must be taken not to include atypical self-remitting childhood epilepsy as an indication,
such as self-limited epilepsy with centrotemporal spikes (SeLECTS).

10. Clinical Efficacy of the Latest Model SentTiva: An Illustrative Report

An 8-year-old boy with autism spectrum disorder presented with a 5-year history of
drug-resistant tonic and myoclonic seizures with a drop attack. Notably, many anti-seizure
medications could not suppress the seizures, and he was diagnosed with Lennox–Gastaut
syndrome based on the seizure type and EEG findings. He was referred to our hospital and
underwent a total corpus callosotomy when he was 5 years old. However, the drop seizures
were not suppressed, and VNS placement (SenTiva Model 1000) was performed when he was
7 years old. The number of seizures, especially drop attacks, was reduced by approximately
80%
J. Clin. Med. 2024, 13, byPEER
x FOR adjusting
REVIEWthe VNS stimulation, and the level of alertness was also improved using 9 of 12
pharmacological therapy. As his seizures occurred only during the day when he was awake, we
used the day/night mode to lower the stimulation intensity during sleep (Figure 7). Besides
this day/nightModel
setting1000
function, the SenTiva
has a schedule Model 1000
programming has a schedule
function programming
that allows function
patients to adjust their stim‐
ulationtowithout
that allows patients visiting
adjust their the hospital.
stimulation without visiting the hospital.

Figure 7. VNS Figure

parameter
7. VNSinparameter
a case study. Asstudy.
in a case his seizures only occurred
As his seizures during
only occurred the the
during daydaywhen
whenhehe was
was awake, weawake,
used the day/night
we used mode to
the day/night lower
mode the stimulation
to lower intensity
the stimulation during
intensity duringsleep.
sleep.VNS
VNS sup‐
pressed
suppressed seizures byseizures by approximately
approximately 80%;by
80%; further, further, by reducing
reducing the dosethe
of dose of anti‐seizure
anti-seizure medications,
medications,
VNS efficacy
VNS efficacy significantly significantly
improved improved
daytime daytime
alertness alertness and
and insomnia. PHT,insomnia.
phenytoin;PHT,VPA,phenytoin;
valproic VPA,
valproic acid; LTG, lamotrigine; RFN, rufinamide; LCM, lacosamide.
acid; LTG, lamotrigine; RFN, rufinamide; LCM, lacosamide.
11. Future Perspectives
VNS is essentially a palliative therapy, and its main limitation is that it cannot entirely
suppress seizures. However, there is potential for various improvements that may in‐
crease the utility of VNS. One is to identify biomarkers that indicate the efficacy of pre‐
operative VNS. There are reports that predict the effects of VNS using resting‐state mag‐
netoencephalography (rMEG) and resting‐state functional MRI [47,48]. In addition, the
J. Clin. Med. 2024, 13, 780 9 of 11

11. Future Perspectives

VNS is essentially a palliative therapy, and its main limitation is that it cannot entirely
suppress seizures. However, there is potential for various improvements that may increase
the utility of VNS. One is to identify biomarkers that indicate the efficacy of preoperative
VNS. There are reports that predict the effects of VNS using resting-state magnetoen-
cephalography (rMEG) and resting-state functional MRI [47,48]. In addition, the effects of
VNS can be predicted via the analysis of scalp EEGs, which are commonly performed, but
this prediction method may be more difficult [49–51]. The second is to clarify the seizure
types (e.g., focal vs. generalized) and epilepsy syndromes for which VNS is effective and to
clarify the optimal dose setting for each. Furthermore, it was reported that the use of VNS
earlier during the course of epilepsy was significantly related to responder status and QOL
improvement [52,53]. However, there are still too few clinical trials of prognostic factors
for VNS therapy in children. Future studies should aim to address these questions and
improve the technology used in VNS to further expand the role of VNS therapy for DRE
in children.

12. Conclusions
VNS affects seizure control; however, other benefits, such as improved sleep quality
and emotional stability, fewer hospitalizations, and the possibility of reducing or discontin-
uing medication, have been reported. The VNS stimulation intensity can be adjusted while
monitoring seizure suppression and side effects. VNS treatment is useful when combined
with anti-seizure medications, as the stimulation intensity can be changed during the day
and night, and additional stimulation can be performed during or just before seizures.
VNS is extremely useful because it positively affects the development and QOL of children
with DRE.

Author Contributions: Conceptualization, M.F.; Data Acquisition, H.K., A.H. and A.I.; Writing—Original
Draft Preparation, M.F., T.M. and S.F.; Writing—Review and Editing, Supervision, S.K. All authors have
read and agreed to the published version of the manuscript.
Funding: This research was funded by a Grant-in-Aid for Scientific Research (C) (20K08223) and a
Grant-in-Aid for Early-Career Scientists (18K15700), Japan.
Institutional Review Board Statement: The case report and data were approved by the Institutional
Review Board of the Tokyo Metropolitan Neurological Hospital (TS-H31-042 and was approved on
18 May 2020).
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest.

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