Epilepsy Currents
2022, Vol. 22(1) 11–17
© The Author(s) 2021
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DOI: 10.1177/15357597211065587
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Neuromodulation for Refractory Epilepsy

Philippe Ryvlin1* and Lara E. Jehi2

1Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne,
Switzerland

2Epilepsy Center, Cleveland Clinic, Cleveland, OH, USA
*Correspondence: Philippe Ryvlin, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of
Lausanne (UNIL), BH10/137, CHUV, Rue du Bugnon 46, Lausanne 1011, Switzerland. Email: Philippe.Ryvlin@chuv.ch

Abstract
Three neuromodulation therapies, all using implanted device and electrodes, have been approved to treat adults with drug-resistant
focal epilepsy, namely, the vagus nerve stimulation in 1995, deep brain stimulation of the anterior nucleus of the thalamus (ANT-
DBS) in 2018 (2010 in Europe), and responsive neurostimulation (RNS) in 2014. Indications for VNS have more recently extended
to children down to age of 4. Limited or anecdotal data are available in other epilepsy syndromes and refractory/super-refractory
status epilepticus. Overall, neuromodulation therapies are palliative, with only a minority of patients achieving long-term seizure
freedom, justifying favoring such treatments in patients who are not good candidates for curative epilepsy surgery. About half of
patients implanted with VNS, ANT-DBS, and RNS have 50% or greater reduction in seizures, with long-term data suggesting
increased efficacy over time. Besides their impact on seizure frequency, neuromodulation therapies are associated with various
benefits and drawbacks in comparison to antiseizure drugs. Yet, we lack high-level evidence to best position each neuromodulation
therapy in the treatment pathways of persons with difficult-to-treat epilepsy.

Keywords
neuromodulation, vagus nerve stimulation, responsive neurostimulation, deep brain stimulation, drug-resistant epilepsy

Introduction

It has been almost 50 years since the first attempt to control
seizures with chronic electrical stimulation of the nervous
system.1 Yet, the first appropriately powered and designed
randomized controlled trial (RCT) of neuromodulation for
epilepsy, targeting the left vagus nerve, was only published in
1995,2 leading to the approval by the U.S. Food and Drug
Administration (FDA) of vagus nerve stimulation (VNS) as an
adjunctive treatment for drug-resistant focal epilepsy in 1997.
Since then, only 2 other neuromodulation therapies benefited
from appropriate pivotal RCTs and were subsequently approved
by the FDAwithin the last decade, deep brain stimulation of the
anterior nucleus of the thalamus (ANT-DBS) and responsive
neurostimulation of the epileptogenic zone(s) (RNS).3,4 In
parallel, an upgraded VNS device, offering closed-loop

tachycardia-responsive stimulation, has been made available
in the last 5 years.5,6 Approved neuromodulation therapies are
all indicated in adults with drug-resistant focal epilepsy,7 de-
fined as the failure of adequate trials of 2 tolerated and ap-
propriately chosen and used antiseizure medications (ASMs) to
achieve sustained seizure freedom.8 Yet, ANT-DBS requires the
failure of 3 ASMs, and VNS benefits from broader indications
in children down to age of 4 7. VNS is approved in much of the
world; RNS only in the United States; and ANT-DBS in North
America, Europe, and a few other countries.7

Vagus Nerve Stimulation

In 2017, the indications of VNS were extended by the FDA to
children ≥ 4 years old,9 in agreement with the upgraded rec-
ommendations of the American Academy of Neurology (AAN)

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EPILEPSY CURRENTS

Current Review
in Clinical Research

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which reported a 50% responder rate (50%-RR) of 55% in this
age group.10 Accordingly, a recent systematic review covering
more than 100 pediatric VNS studies reported a pooled prev-
alence estimate for 50%-RR and seizure freedom of 56% and
12%, respectively.11 Yet, the only double-blind RCT conducted
in children aged 3 to 17 years was negative.12 The AAN
guidelines also concluded that VNS shows increasing efficacy
over time.10 A review of the literature and VNS registry data
collating 8423 patients reported consistent long-term 50%-RR
increasing up to 63%, and seizure freedom rate up to 8%.13

However, duration of seizure-free periods remains unclear in
most reports. Recent controlled and uncontrolled studies have
confirmed the positive impact of VNS on quality of life (QoL).
An open-label randomized trial showed that VNS therapy with
best medical practice (BMP) was associated with a significantly
greater improvement of QoL than BMP alone, with a mean gain
of 5.5 points at 12 months.14 A survey from 5000 VNS-treated
epilepsy patients also suggested self-reported benefits in
alertness, post-ictal state, cognition, and school or professional
achievements.15 In contrast, controlled studies failed to show a
significant effect of VNS on comorbid depression in compar-
ison to controls.14,16-18

The closed-loop VNS (AspireSR), which triggers vagus
nerve stimulation upon detection of pre-defined (supposedly
ictal) changes in heart rate, has now largely replaced standard
VNS. Yet, true ictal tachycardia, defined as > 100 bpm with at
least 55% increase or 35 bpm increase from baseline, was only
observed in 16%-17% of seizures recorded with this device.5,6

When using a more liberal threshold of ≥ 20% increase in heart
rate, up to 66% of seizures could be detected but at the cost of 7
false detections per hour.5,6 There is no controlled study
comparing closed-loop to standard VNS. Yet, several uncon-
trolled studies reported improved seizure control following
replacement of the latter by the former in 31% to 41% of ca-
ses.19-21 Furthermore, one- to two-thirds of non-responders to
standard VNS responded to the AspireSR.19-21

VNS has been used off-label in several epileptic disorders, in
particular, generalized epilepsies. The AAN has recommended
that VNS may be considered for Lennox-Gastaut syndrome
(LGS),10 where the 50%-RR was estimated at 55%.10,22

Comparable benefits were reported in Dravet syndrome,23 re-
fractory idiopathic/primary generalized epilepsies,24-29 and
CDKL5 disorder.30 VNS has also been claimed to effectively
control atonic seizures as an alternative to corpus callosotomy.
However, a recent meta-analysis of 31 studies involving 533
children showed that callosotomy was more effective than VNS
at a cost of greater adverse events, including twice as many
reoperations and a 14% rate of symptomatic disconnection
syndrome.31 A recent meta-analysis reported 38 cases with
refractory (RSE) or super-refractory (SRSE) status epilepticus,
where limited or no alternative treatments was available, who
were treated with VNS, including 28 whose status was con-
trolled. However, RSE/SRSE ceased more than 10 days after
implantation in half of these patients, calling into question the
role of VNS in controlling status.32

The cost-effectiveness of VNS has been confirmed in several
studies showing decreased hospitalization and emergency
visits,33-38 status epilepticus,34,35 intensive care unit costs,33 and
antiseizure drugs’ prescription,37 but increased outpatient re-
source use.36,38 Overall, most studies reported decreased direct
healthcare costs following VNS therapy.33-35,38,39 Yet, cost-
savings largely vary between series and countries, with aver-
age direct costs of VNS treatment ranging as much as from 75 to
2333 dollars per month.35,36,38

While no new VNS-related side-effect has been reported,
more evidence was collected regarding the significant risk of de-
novo or aggravating sleep breathing disorders in up to 57% of
patients.40-42

Deep Brain Stimulation of the Anterior
Nucleus of the Thalamus (ANT-DBS)

Following a positive pivotal RCT performed in 109 adult pa-
tients with drug-resistant focal epilepsy (SANTE trial), ANT-
DBS was approved in Europe in 2010 and in the USA in 2018.3

The long-term open-label extension study of the SANTE trial
has shown improving efficacy in patients continuing ANT-
DBS.43 At 7 years of follow-up, the median reduction in seizure
frequency and the proportion of 50% responders reached �70%
and 74%, respectively.43 In addition, 16% of patients enjoyed a
seizure-free period ≥ 6 months during follow-up, but no long-
term seizure freedom was observed.44 Yet, 34% of patients
discontinued ANT-DBS at the longest follow-up, with another
21% considered not evaluable due to missing data. If one con-
siders all discontinuations and lack of evaluable data as treatment
failures, the proportion of 50%-RR remains stable over time and
is closer to 40% than 74%. Previous treatment with VNS does not
seem to influence the chances of responding to ANT-DBS.3,45 A
few case reports have found ANT-DBS to be effective in con-
trolling RSE46,47 and antiGAD-associated TLE.48

ANT-DBS is associated with the classic risks of implant site
infection and pain, the latter being reported in up to 20% of
patients.44 During RCT, stimulation of ANTwas associated with
significantly more frequent mood and memory complaints (15%
and 13%, respectively) than sham stimulation (1.8%). At 7 years
of follow-up, more than 30% of patients reported mood or
memory disorders, with 10% expressing suicidality, two-third of
whom had a past-history of depression prior to ANT-DBS
treatment.43 Yet, objective assessments do not necessarily sup-
port patients’ subjective complaints,49 and some improvement is
reported over time44 or with reduction in stimulation intensity.50

Responsive Neurostimulation (RNS)

Following a positive pivotal RCT performed in 191 adult pa-
tients with drug-resistant focal epilepsy,4 RNS was approved by
the FDA in 2014. The long-term open-label extension study has
reported up to 9 years of follow-up, showing a progressive
increase in seizure control over time. In patients continuing
RNS, the median reduction in seizure frequency and proportion

12 Epilepsy Currents 22(1)



of 50%-RR reached�72% and 73%, respectively, while 28% of
patients enjoyed seizure-free periods > 6 months.51,52 Yet, 37%
of patients discontinued RNS at the longest follow-up, with
another 6% considered not evaluable due to missing data. As for
ANT-DBS, if one considers all discontinuations and lack of
evaluable data as treatment failures, the proportion of 50%-RR
remains stable over time and closer to 40% than 73%. Im-
provement in QoL was also observed with RNS, including on
cognitive and seizure worry subscores.4,51

While RNS typically targets cortical epileptogenic zone(s), it
was also used successfully in a few patients to stimulate the
thalamus, including the centromedian/ventrolateral thalamus
bilaterally in a patient with drug-refractory Jeavons syndrome,53

and the right anterior nucleus of the thalamus in an adult with
childhood onset genetic generalized epilepsy.54 Positive out-
come of RNS was also reported in 4 patients with anti-GAD-
associated TLE55 and in 1 patient with SRSE.56

RNS provides unique intracerebral EEG data which can
reliably give information on the epileptic activity of the
recorded brain regions and offer additional benefits. In par-
ticular, RNS might demonstrate that some patients with sus-
pected bitemporal epilepsy primarily suffer from a single or
predominant seizure-onset zone, leading to successful uni-
lateral temporal lobe epilepsy surgery.57,58 Another applica-
tion lies in the possibility to delineate patient’s specific seizure
cycles, which could enable clinically relevant seizure fore-
casting.59,60 RNS-recorded data might also help to predict the
long-term response to antiseizure drug shortly after its
initiation.61

Infection at the RNS implant site amounts to 4% per surgical
procedure and 12% of patients overall after 9 years of follow-
up.51 It usually only involves soft tissue, but still requires
explantation in half of cases. Intracranial hemorrhage was re-
ported in 3% of patients, with 1% associated with neurologic
sequelae. In contrast with ANT-DBS, no cognitive side-effect
was reported with RNS. On the contrary, some improvement
was observed in neuropsychological performances, in relation
to the brain regions stimulated.62 Suicidality was reported in
10% of patients, 86% of which had a past history of mood
disorders prior to RNS treatment.51 This is to compare with the
prevalence of suicidality reported in epilepsy in general, which
often ranges between 20% and 35%.63-65

Areas for Future Research

Despite the wealth of data collected through observational
studies or clinical trials, several unanswered questions remain.

Impact on SUDEP Risk

Two underpowered and 1 large-scale VNS studies, providing
6170 and 277,661 patient-years (PYs) of follow-up, respec-
tively, investigated the evolution of the SUDEP rate as a
function of the duration of VNS treatment.66-68 Only the large-
scale study reported a significant decrease of SUDEP rate over
time.68 However, due to the lack of appropriate controls, one

cannot assess the proper role of VNS in mediating the reduction
in SUDEP incidence. In a nationwide population-based case-
control study, VNS treatment was associated with a significantly
lower risk of SUDEP as compared to no such treatment with an
odds ratio of .41 (95% CI: .17–.98).69 As for other forms of
neurostimulation therapy, the rate of probable or definite SU-
DEP in patients undergoing ANT-DBS and RNS was calculated
at 2.9/1000 PYs (95% CI: .3-10.4) and 2.8/1000 PYs (95% CI:
1.2-6.7),51 respectively, corresponding to the lower margin of
the SUDEP figures reported in drug-resistant epilepsy.

Biomarkers Predicting Response to Therapy

Reliable predictors of therapeutic response are lacking across
neuromodulation options. Non-lesional epilepsy and general-
ized seizure type were found associated with greater VNS ef-
ficacy but with a very modest odds ratio,13 while the role of age
remains debated.12,70-72 Several neurophysiological and neu-
roimaging predictors are being investigated but are not yet
validated in clinical practice.73-76 Similarly, we lack biomarkers
to predict response to ANT-DBS, with some reports suggesting
the potential value of temporal theta-band desynchronization,77

hippocampal-evoked potentials,78 and increased functional
connectivity between ANTand the default mode network.79 The
exact position of ANT-DBS electrodes might also prove im-
portant, with some data suggesting better seizure control when
stimulating the anterior half of ANT80,81 or its junction with the
mammillothalamic tract.82,83 The transventricular lead trajec-
tory appears more effective than the extraventricular one to
reach the appropriate target, without difference in safety be-
tween the 2 methods.84,85 No biomarker exists either to predict
the clinical response to RNS.

Comparative Effectiveness

No robust observational data or RCT data exist to meaningfully
compare effectiveness across neuromodulation therapies. Two
uncontrolled retrospective studies compared the effectiveness of
RNS and VNS in a total of 53 patients, showing no significant
difference in patients’ profiles, median reduction in seizure
frequency, and seizure-free rates.86,87 Also, of interest is the
proportion of patients who responded to ANT-DBS or RNS
after having failed VNS. In the SANTE trial, 45% of patients
had been previously treated with VNS, and these were found to
equally benefit from ANT-DBS than the other patients.3 An-
other series of 7 patients who failed VNS and were subsequently
treated with ANT-DBS reported a 71% RR.45 Similarly, patients
who failed VNS demonstrated a similar response to RNS as
those not previously treated with VNS.4,51

Seizure freedom Versus Remission

Reported rates of seizure freedom in neuromodulation studies
actually refer to periods of seizure-remission of varying du-
ration, typically between 6 and 12 months, observed by the
date of last follow-up during open-label extension phases of

Ryvlin and Jehi 13



clinical study. Considering that the estimated cumulative
probability of 12-month seizure-remission is 33.4% at 7 years
in patients with drug-resistant epilepsy using medical therapy
alone88 and that surgical series typically report complete
seizure freedom since surgery (for example, an Engel score
of 1 is equivalent to sustained seizure freedom since surgery
and not terminal remission), ascertaining the true contribu-
tion of neuromodulation to observed remission 7 or 9 years
after device implantation is difficult and will require further
evaluation.

Conclusion

Many neuromodulation therapies and brain targets have been
proposed for epilepsy, but only 4 appropriately designed
RCTs have been performed in the field.2-4,89 Furthermore,
these RCTs concentrated on demonstrating the antiseizure
efficacy of active vs sham stimulation, with no evidence
gathered to delineate the optimal timing for offering such
therapies during the course of drug-resistant epilepsy or
guide the choice or order of the different neuromodulation
methods. Accordingly, neuromodulation should be currently
primarily offered to patients with refractory epilepsy who are
not, or who are poor candidates for curative epilepsy surgery.
Decision regarding the type of neuromodulation should be
discussed with patients and caregivers based on a fair pre-
sentation of the expected risks and benefits associated with
each type of therapy.

Acknowledgments

We wish to thank Lawrence Hirsch, Sylvain Rheims, and Arseny
Sokolov for providing suggestions for this review.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
This work was supported by EU’s Horizon 2020 Research and
Innovation Programme; 785907 (HBP SGA2); 945539 (HBP
SGA3).

ORCID iD

Philippe Ryvlin  https://orcid.org/0000-0001-7775-6576

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https://orcid.org/0000-0001-7775-6576
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https://doi.org/10.1212/WNL.0000000000012030


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Ryvlin and Jehi 17


	Neuromodulation for Refractory Epilepsy
	Introduction
	Vagus Nerve Stimulation
	Deep Brain Stimulation of the Anterior Nucleus of the Thalamus (ANT-DBS)
	Responsive Neurostimulation (RNS)
	Areas for Future Research
	Impact on SUDEP Risk
	Biomarkers Predicting Response to Therapy
	Comparative Effectiveness
	Seizure freedom Versus Remission

	Conclusion
	Acknowledgments
	Declaration of Conflicting Interests
	Funding
	ORCID iD
	References