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Vagus Nerve Stimulation
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Medical Policy
Title:
An independent licensee of the
Blue Cross Blue Shield Association
Vagus Nerve Stimulation
Professional
Original Effective Date: June 1, 1997
Revision Date(s): November 1, 1997;
July 1, 1998; January 1, 2006;
September 1, 2006; October 26, 2010;
March 3, 2011; January 1, 2012;
August 24, 2012; June 26, 2013;
November 24, 2015; April 25, 2016
Current Effective Date: November 24, 2015
Institutional
Original Effective Date: April 1, 2007
Revision Date(s): November 29, 2010;
March 3, 2011; January 1, 2012;
August 24, 2012; June 26, 2013;
November 24, 2015; April 25, 2016
Current Effective Date: November 24, 2015
State and Federal mandates and health plan member contract language, including specific
provisions/exclusions, take precedence over Medical Policy and must be considered first in
determining eligibility for coverage. To verify a member's benefits, contact Blue Cross and
Blue Shield of Kansas Customer Service.
The BCBSKS Medical Policies contained herein are for informational purposes and apply only
to members who have health insurance through BCBSKS or who are covered by a self-insured
group plan administered by BCBSKS. Medical Policy for FEP members is subject to FEP medical
policy which may differ from BCBSKS Medical Policy.
The medical policies do not constitute medical advice or medical care. Treating health care
providers are independent contractors and are neither employees nor agents of Blue Cross
and Blue Shield of Kansas and are solely responsible for diagnosis, treatment and medical
advice.
If your patient is covered under a different Blue Cross and Blue Shield plan, please refer to the
Medical Policies of that plan.
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Populations
Individuals:
 With seizures refractory to
medical treatment
Interventions
Interventions of interest
are:
 Vagus nerve stimulation
Comparators
Comparators of interest
are:
 Standard of care
Individuals:
 With treatment-resistant
depression
Interventions of interest
are:
 Vagus nerve stimulatio
Comparators of interest
are:
 Standard of car
Individuals:
 With chronic heart failure
 With upper-limb
impairment due to stroke
Individuals:
 With essential tremor,
obesity headache,
fibromyalgia, or tinnitus
Individuals:
 With epilepsy, depression,
schizophrenia, headache,
or impaired glucose
tolerance
Interventions of interest
are:
 Vagus nerve stimulation
Comparators of interest
are:
 Standard of car
Interventions of interest
are:
 Vagus nerve stimulation
Comparators of interest
are:
 Standard of care
Interventions of interest
are:
 Transcutaneous vagus
nerve stimulatio
Comparators of interest
are:
 Standard of car
Outcomes
Relevant outcomes include:
 Symptoms
 Change in disease status
 Functional outcomes
Relevant outcomes include:
 Symptoms
 Change in disease status
 Functional outcomes
Relevant outcomes include:
 Symptoms
 Change in disease status
 Functional outcomes
Relevant outcomes include:
 Symptoms
 Change in disease status
 Functional outcomes
Relevant outcomes include:
 Symptoms
 Change in disease status
 Functional outcomes
DESCRIPTION
Stimulation of the vagus nerve can be performed by means of an implantable stimulator
within the carotid artery sheath. This technique has been proposed as a treatment for
refractory seizures, depression and other disorders. There are also devices available that
are implanted at different areas of the vagus nerve. This evidence review also addresses
devices that stimulate the vagus nerve transcutaneously.
Background
Vagus Nerve Stimulation (VNS) was initially investigated as a treatment alternative in
patients with medically refractory partial-onset seizures for whom surgery is not
recommended or for whom surgery has failed. Over time, the use of VNS has expanded
to generalized seizures, and it has been investigated for a range of other conditions.
While the mechanisms for the therapeutic effects of VNS are not fully understood, the
basic premise of VNS in the treatment of various conditions is that vagal visceral
afferents have a diffuse central nervous system projection, and activation of these
pathways has a widespread effect on neuronal excitability. Electrical stimulus is applied
to axons of the vagus nerve, which have their cell bodies in the nodose and junctional
ganglia and synapse on the nucleus of the solitary tract in the brainstem. From the
solitary tract nucleus, vagal afferent pathways project to multiple areas of the brain.
There are also vagal efferent pathways that innervate the heart, vocal cords, and other
laryngeal and pharyngeal muscles, and provide parasympathetic innervation to the
gastrointestinal tract that may also be stimulated by VNS.
The type of VNS device addressed in this policy consists of an implantable,
programmable electronic pulse generator that delivers stimulation to the left vagus nerve
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Vagus Nerve Stimulation
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at the carotid sheath. The pulse generator is connected to the vagus nerve via a bipolar
electrical lead. Surgery for implantation of a vagal nerve stimulator involves implantation
of the pulse generator in the infraclavicular region and wrapping 2 spiral electrodes
around the left vagus nerve within the carotid sheath. The programmable stimulator may
be programmed in advance to stimulate at regular intervals or on demand by patients or
family by placing a magnet against the subclavicular implant site.
Various types of devices that stimulate the vagus nerve transcutaneously have been
developed as well. One device made by Cerbomed stimulates the auricular branch of the
vagus nerve. Some devices used in studies are not well characterized as to the specific
manufacturer or type of device used. The U.S. Food and Drug Administration has not
approved any transcutaneous VNS devices.
Other types of implantable vagus nerve stimulators are also available. The Maestro®
System (EnteroMedics, St. Paul, MN) consists of a subcutaneously implanted pulse
generator and electrodes that are placed in contact with the trunks of the vagus nerve at
the gastroesophageal junction. These types of stimulators differ in the location of the
pulse generator and electrodes and the stimulation programming settings, and are not
addressed in this evidence review.
VNS was originally approved for the treatment of medically refractory epilepsy.
Significant advances have been made since then in the surgical and medical treatment of
epilepsy, and newer, more recently approved medications are available. Despite these
advances, however, 25% to 50% of patients with epilepsy experience breakthrough
seizures or suffer from debilitating adverse effects of antiepileptic drugs. For patient such
as these, VNS therapy has been used as an alternative to or adjunct to epilepsy surgery
or medications.
Based on observations that patients treated with VNS experience improvements in mood,
VNS has been evaluated for the treatment of refractory depression. VNS has been
investigated for multiple other conditions which may be affected by either the afferent or
efferent stimulation of the vagus nerve, including headaches, tremor, obesity, heart
failure, fibromyalgia, tinnitus, and traumatic brain injury.
Regulatory Status
In 1997, the NeuroCybernetic Prosthesis (NCP®) System (Cyberonics), a vagus nerve
stimulation (VNS) device, was approved by the U.S. Food and Drug Administration (FDA)
through the premarket approval (PMA) process for use in conjunction with drugs or
surgery “…as an adjunctive treatment of adults and adolescents over 12 years of age
with medically refractory partial onset seizures.”
On July 15, 2005, Cyberonics received PMA supplement approval by FDA for the VNS
Therapy™ System “…for the adjunctive long-term treatment of chronic or recurrent
depression for patients 18 years of age or older who are experiencing a major depressive
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episode and have not had an adequate response to four or more adequate
antidepressant treatments.”
Cerbomed has developed a transcutaneous VNS (t-VNS®) system that uses a combined
stimulation unit and ear electrode to stimulate the auricular branch of the vagus nerve,
which supplies the skin over the concha of the ear. Patients self-administer electric
stimulation for several hours a day; no surgical procedure is required. The device
received the CE mark in Europe in 2011, but has not been FDA approved for use in the
United States. ElectroCore Medical has developed a noninvasive VNS system
(gammaCore®) that is currently being investigated for headache; the device has not
been FDA approved.
POLICY
A.
Vagus nerve stimulation may be considered medically necessary as a treatment
of medically refractory seizures.
B.
Vagus nerve stimulation is considered experimental / investigational as a
treatment of other conditions, including but not limited to heart failure,
fibromyalgia, depression, essential tremor, obesity, headaches, tinnitus, and
traumatic brain injury.
C.
Nonimplantable vagus nerve stimulation devices are considered experimental /
investigational for all indications.
Policy Guidelines
Medically refractory seizures are defined as seizures that occur in spite of therapeutic
levels of antiepileptic drugs or seizures that cannot be treated with therapeutic levels of
antiepileptic drugs because of intolerable adverse effects of these drugs.
RATIONALE
The most recent update covered the period through January 20, 2016. The review of evidence in
the first several sections will pertain to implantable vagus nerve stimulators. The evidence on
transcutaneous vagus nerve stimulators will be discussed separately in the last section.
Treatment of Seizures
Vagus Nerve Stimulation for Adult Partial-Onset Seizures
The evidence review on treatment of seizures has expanded the indications over time, but was
originally based, in part, on a 1998 TEC Assessment that offered the following conclusions.1
 Published evidence from 2 large, well-designed multicenter randomized trials involving
over 300 patients demonstrates that the use of vagus nerve stimulation (VNS) as an
adjunct to optimal use of antiepileptic drugs in the treatment of medically refractory
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

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patients with at least 6 partial-onset seizures/month reduces seizure frequency by
approximately 25% after 3 months of treatment. In patients who achieve an initial
reduction in seizure frequency, the beneficial treatment effect appears to be maintained
and may increase with time.
Adverse effects are mild and consist primarily of hoarseness or voice change during “on”
periods of stimulation.
There is limited information about the use of VNS in patients with other types of seizure
disorders.
Based on this TEC Assessment, earlier versions of this evidence review supported the use of VNS
for partial-onset seizures for patients older than 12 years of age. A randomized controlled trial
(RCT) published in 2014 reported long-term quality of life outcomes for 112 patients with
pharmaco-resistant focal seizures, which supported the beneficial effects of VNS for this group.2
VNS for Adult Generalized Seizures
Tecoma and Iragui observed in a 2006 review that since the approval of VNS for partial-onset
seizures, a number of case series including patients with generalized seizures have been
published. These series report seizure reduction rates similar to or greater than those reported in
partial epilepsy and note that “…this body of evidence suggests that VNS has broad antiepileptic
efficacy.”3 The authors suggest that these results may be particularly important since resective
epilepsy surgery is generally not feasible in these patients.
Other reports published since the review by Tecoma and Iragui are consistent with the authors’
observations. In a French study of 50 consecutive refractory adolescents and adults who were
not eligible for surgery, 11 of whom had generalized epilepsy, 58% were classified as responders
to VNS at 3 year follow-up.4 Generalized epilepsy was predictive of a better outcome than partial
epilepsy. Seizure reduction of 61% was also reported in a case series of 12 patients with drugresistant idiopathic generalized epilepsy.5 Garcia-Navarrete et al evaluated outcomes after 18
months of follow-up for a prospectively followed cohort of 43 patients with medication-resistant
epilepsy who underwent VNS implantation.6 Subjects’ seizure types were heterogeneous, but
52% had generalized epilepsy. Pharmacotherapy was unchanged during the course of the study.
Twenty-seven subjects (63%) were described as “responders,” defined as having a 50% or
greater reduction in seizure frequency compared with the year prior to VNS implantation. The
difference in reduction of seizure frequency was not statistically significant between subjects with
generalized and focal epilepsy.
VNS for Childhood Seizures
Since publication of the 1998 TEC assessment, there has been interest in expanding the use of
VNS to younger patients. Several studies have reported results that support the safety and
efficacy of the device in children with refractory seizures.7 For example, 60 pediatric patients
were treated as part of the double-blind clinical trials conducted to support the U.S. Food and
Drug Administration (FDA) application.8 At 18 months, the median reduction in seizure frequency
with VNS was 50%, similar to the results achieved in adults. Adverse events were also similar to
those recently reported in adults,9 and none resulted in termination of stimulation. Hornig et al
reported on a case series of 19 pediatric patients, with observation periods ranging up to 30
months.10 Overall, 50% of patients had a 50% reduction in seizure frequency. Patwardhan et al
reported that among 38 patients aged 11 months to 16 years with medically refractory seizures,
both generalized and partial-onset, 29% had a greater than 90% reduction in seizure frequency
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after VNS implantation, while 39% had 50% to 90% reduction.11 Healy et al reported that among
16 patients younger than 12 years of age who underwent VNS implantation at a single center, 9
(56%) experienced a reduction in their seizure frequency of 50% or more.12 Results from an addon study to an RCT designed to compare high-output with low-output VNS stimulation among 41
children with medically refractory epilepsy suggest that VNS does not have adverse effects on
cognitive or psychosocial outcomes.13 Other studies of pediatric patients that included patients
with generalized and partial-onset seizures have supported the use of VNS in reducing seizure
frequency. These have included a series of 41 children treated with VNS, randomized to a highor low-dose stimulation protocol,14 a retrospective case-control study with 36 patients treated
with VNS compared with 72 age- and sex-matched controls with refractory epilepsy not treated
with VNS,15 a retrospective cohort study including 252 pediatric patients with a variety of seizure
types treated with VNS,16 and a retrospective cohort study of 347 children with a variety of
seizure types treated with VNS followed for up to 2 years.17
Similar to studies in adults, pediatric studies suggest that VNS improves seizure frequency in
generalized epilepsy syndromes. In a multicenter study of 28 children with refractory seizures,
You et al reported that 15 (53.6%) children showed a greater than 50% reduction in seizure
frequency and 9 (32.1%) had a greater than 75% reduction, and there were no significant
differences when groups were compared by seizure type or etiology.18 Tecoma and Iragui cite a
multicenter retrospective analysis of 50 children with Lennox-Gastaut syndrome (LGS) treated
with VNS.3 Median seizure reduction at 6 months was 88% for tonic seizures and 81% for
atypical absence seizures. You et al compared VNS and total corpus callosotomy for LGS.19 Of the
14 patients who underwent a corpus callosotomy, 9 (64%) had a greater than 50% reduction in
seizure frequency and 5 (36%) had a greater than 75% reduction. Of the 10 patients who
underwent VNS implantation, 7 (70%) had a greater than 50% reduction in seizure frequency
and 2 (20%) had a greater than 75% reduction. For 24 children with LGS or LGS-like syndrome
who underwent VNS implantation, Cukiert et al reported that at least a 50% seizure frequency
decrease was seen for 35 different seizure types.20
VNS generally does not completely eliminate seizures, and it is not possible to predict which
patients will respond. One meta-analysis that included 74 retrospective and prospective studies
assessing VNS efficacy in seizures found that predictors of efficacy included generalized epilepsy
or mixed seizure types (compared with partial-onset seizures) and age younger than 18 years.21
In 2014, Arya et al reported results of a single-center retrospective chart review that included 43
pediatric patients who underwent VNS implantation over a 5-year period; the authors found that
absence of a lesion on MRI predicted a good outcome.22 These studies support the use of VNS in
children, in patients with generalized epilepsy, and in those who are not candidates for surgery.
Section Summary: Treatment of Seizures
The evidence on the efficacy of VNS for treatment of medically refractory seizures consists of 2
RCTs and numerous uncontrolled studies. The RCTs both reported a significant reduction in
seizure frequency with VNS for patients with partial-onset seizures. The uncontrolled studies have
consistently reported large reductions for a broader range of seizure types in both adults and
children. The large reduction in seizures includes substantial numbers of patients who achieve a
greater than 50% reduction in seizure frequency.
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Treatment-Resistant Depression
Interest in the application of VNS for treatment of treatment-resistant depression is related to
reports of improvement in depressed mood among epileptic patients undergoing VNS.23 TEC
Assessments written in 2005 and updated in 2006 concluded that evidence was insufficient to
permit conclusions of the effect of VNS therapy on depression.24,25 The available evidence for
these TEC Assessments included study groups assembled by the manufacturer of the device
(Cyberonics) and have since been reported on in various publications.26,27 Analyses from these
study groups were presented for FDA review and consisted of a case series of 60 patients
receiving VNS (study D-01), a short-term (ie, 3-month) sham-controlled RCT of 221 patients
(study D-02), and an observational study comparing 205 patients on VNS therapy with 124
patients receiving ongoing treatment for depression (study D-04).28 Patients who responded to
sham treatment in the short-term RCT (10%) were excluded from the long-term observational
study.
The primary outcome evaluated was the relief of depression symptoms that can usually be
assessed by any one of many different depression symptom rating scales. A 50% reduction from
baseline score is considered to be a reasonable measure of treatment response. An improvement
in depression symptoms may allow reduction of pharmacologic therapy for depression, with a
reduction in adverse effects related to that form of treatment. In the studies evaluating VNS
therapy, the 4 most common instruments used were the Hamilton Rating Scale for Depression,
Clinical Global Impression, Montgomery and Asberg Depression Rating Scale, and the Inventory
of Depressive Symptomatology (IDS).
Several case series published before the randomized trial showed rates of improvement with
VNS, as measured by a 50% improvement in depression score, of 31% at 10 weeks to greater
than 40% at 1 to 2 years, but there are some losses to follow-up.29-31 Natural history, placebo
effects, and patient and provider expectations make it difficult to infer efficacy from case series
data.
The randomized study (D-02) that compared VNS therapy with a sham control (implanted but
inactivated VNS) showed a nonstatistically significant result for the principal outcome.27,28 Fifteen
percent of VNS subjects responded versus 10% of control subjects (p=0.31). The Inventory for
Depressive Symptomatology Systems Review (IDS-SR) score was considered a secondary
outcome and showed a difference in outcome that was statistically significant in favor of VNS
compared with sham treatment (17.4% vs 7.5%, respectively, p=0.04).
The observational study that compared patients participating in the RCT and a separately
recruited control group (D-04 vs D-02, respectively) evaluated VNS therapy out to 1 year and
showed a statistically significant difference in the rate of change of depression score.26,28
However, issues such as unmeasured differences among patients, nonconcurrent controls,
differences in sites of care between VNS therapy patients and controls, and differences on
concomitant therapy changes raise concern about this observational study. Analyses performed
on subsets of patients cared for in the same sites, and censoring observations after treatment
changes, generally showed diminished differences in apparent treatment effectiveness of VNS
and almost no statistically significant differences.28 Patient selection for the randomized trial and
the observational comparison trial may be of concern. VNS is intended for treatment-refractory
depression, but the entry criteria of failure of 2 drugs and a 6-week trial of therapy may not be a
strict enough definition of treatment resistance. Treatment-refractory depression should be
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defined by thorough psychiatric evaluation and comprehensive management. It is important to
note that patients with clinically significant suicide risk were excluded from all VNS studies. Given
these concerns about the quality of the observational data, these results did not provide strong
evidence for the effectiveness of VNS therapy.
In addition to the results of the TEC Assessments, several systematic reviews and meta-analyses
have addressed the role of VNS in treatment-resistant depression. A systematic review of the
literature for VNS of treatment-resistant depression identified the randomized trial previously
described among the 18 studies that met the study’s inclusion criteria.32 VNS was found to be
associated with a reduction in depressive symptoms in the open-label studies. However, results
from the only double-blind trial were considered to be inconclusive.27,28 Daban et al concluded
that further clinical trials are needed to confirm efficacy of VNS in treatment-resistant depression.
In a meta-analysis that included 14 studies, Martin and Martin-Sanchez reported that among the
uncontrolled studies included in their analysis, 31.8% of subjects responded to VNS treatment.33
However, results from a meta-regression to predict each study’s effect size suggested that 84%
of the observed variation across studies was explained by baseline depression severity. Berry et
al34 reported results from a meta-analysis of 6 industry-sponsored studies of safety and efficacy
for VNS in treatment-resistant depression, which included the D-01, D-02, Bajbouj et al35 (D-03),
D-04, and Aaronson et al (D-21) study results.36 In addition, the meta-analysis used data from a
registry of patients with treatment-resistant depression (335 patients receiving VNS and
treatment as usual and 301 patients receiving treatment as usual only) that were unpublished at
the time of the meta-analysis publication (NCT00320372). The authors report that adjunctive
VNS was associated with a greater likelihood of treatment response (odds ratio, 3.19; 95%
confidence interval [CI], 2.12 to 4.66). However, the meta-analysis did not have systematic study
selection criteria, limiting the conclusions that can be drawn from it.
In 2014, Liu et al conducted a systematic review of brain stimulation treatments, including deep
brain stimulation, electroconvulsive therapy, transcranial magnetic stimulation, and VNS, for
mental illnesses other than nonpsychotic unipolar depression in adults aged 65 years or older.37
The authors identified 2 small studies that evaluated the effect of VNS on cognition in patients
with Alzheimer disease, 1 with 10 subjects and 1 with 17 subjects, which were mixed in
demonstrating clinical improvements.
In 2013, Aaronson et al reported results from an active-controlled trial in which 331 patients with
a history of chronic or recurrent bipolar disorder or major depressive disorder, with a current
diagnosis of a major depressive episode, were randomized to 1 of 3 VNS current doses (high,
medium, low).36 Patients had a history of failure to respond to at least 4 adequate dose/duration
of antidepressant treatment trials from at least 2 different treatment categories. After 22 weeks,
the current dose could be adjusted in any of the groups. At follow-up visits at weeks 10, 14, 18,
and 22 after enrollment, there was no statistically significant difference between the dose groups
for the study’s primary outcome, change in IDS score from baseline. However, the mean IDS
score improved significantly for each group from baseline to the 22-week follow-up. At 50-week
follow-up, there were no significant differences between the treatment dose groups for any of
the depression scores used. Most patients completed the study; however, there was a high rate
of reported adverse events, including voice alteration in 72.2%, dyspnea in 32.3%, and pain in
31.7%. Interpretation of the IDS improvement over time is limited by the lack of a no-treatment
control group. Approximately 20% of the patients included had a history of bipolar disorder; as
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such, the results may not be representative of most patients with treatment-resistant unipolar
depression.
Other case series do not substantially strengthen the evidence supporting VNS. A case series by
Bajbouj et al that followed patients for 2 years showed that 53.1% (26/49) patients met criteria
for a treatment response and 38.9% (19/49) met criteria for remission.35 A small study of 9
patients with rapid-cycling bipolar disorder showed improvements in several depression rating
scales over 40 weeks of observation.38 Another case series by Cristancho et al that followed
patients for 1 year showed that 4 of 15 responded and 1 of 15 remitted according to the principal
response criteria.39 In a 2014 case series that included 27 patients with treatment-resistant
depression, 5 patients demonstrated complete remission after 1 year and 6 patients were
considered responders.40
Adverse effects of VNS therapy included voice alteration, headache, neck pain, and cough, which
are known from prior experience with VNS therapy for seizures. Regarding specific concerns for
depressed patients (eg, those with mania, hypomania, suicide, or worsening depression), there
does not appear to be a greater risk of these events during VNS therapy.28
Section Summary: Treatment-Resistant Depression
There is 1 RCT evaluating the efficacy of VNS for treatment-resistant depression. This study
reported only short-term results and found no significant improvement for the primary outcome
with VNS. Other available studies, which include nonrandomized comparative studies and case
series, are limited by relatively small sample sizes and the potential for selection bias; the case
series are further limited by the lack of a control group. Given the limitations of this literature,
combined with the lack of substantial new clinical trials, the scientific evidence is considered to be
insufficient to permit conclusions on the effect of this technology on major depression.
Other Conditions
Treatment of Chronic Heart Failure
VNS has been investigated for treatment of chronic heart failure in some case series. A case
series phase 2 trial of VNS therapy for chronic heart failure reported improvements in New York
Heart Association class quality of life, 6-minute walk test, and left ventricular (LV) ejection
fraction.41 The ANTHEM-HF study is also a case series study, but patients were randomized to
either right- or left-sided vagus nerve implantation (but there was no control group).42 Overall,
from baseline to 6-month follow-up, LV ejection fraction improved by 4.5% (95% CI, 2.4 to 6.6),
LV end systolic volume improved by -4.1 mL (95% CI, -9.0 to 0.8), LV end-diastolic diameter
(LVESD) improved by -1.7 mm (95% CI, -2.8 to -0.7), heart rate variability improved by 17
milliseconds (95% CI, 6.5 to 28), and 6-minute walk distance improved by 56 meters (95% CI,
37 to 75).
In 2015, Zannand et al reported results from the NECTAR-HF trial, a randomized, shamcontrolled trial, with outcomes from VNS in patients with severe LV dysfunction, despite optimal
medical therapy.43 Ninety-six patients were implanted with a vagal nerve stimulator and
randomized in a 2:1 manner to active therapy (VNS ON) or control (VNS OFF) for 6 months.
Programming of the generator was performed by a physician unblinded to treatment assignment,
while all other investigators and site study staff involved in end point data collection were blinded
to randomization. Sixty-three patients were randomized to the intervention, of whom 59 had
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paired pre-post data available, while 32 were randomized to control, of whom 28 had paired data
available. The analysis was a modified intention-to-treat. For the primary end point of change in
LVESD from baseline to 6 months, there were no significant differences between groups (p=0.60
between-group difference in LVESD change). Other secondary efficacy end points related to LV
remodeling parameters, ie, LV function and circulating biomarkers of heart failure, did not differ
between groups, with the exception of 36-Item Short-Form Health Survey Physical Component
score, which showed greater improvement in the VNS ON group than in the control group (from
36.3 to 41.2 in the VNS ON group vs from 37.7 to 38.4 in the control group; p=0.02). Subject
blinding was found to be imperfect, which may have biased the subjective outcome data
reporting.
Treatment of Upper-Limb Impairment Due to Stroke
Dawson et al conducted a randomized pilot trial of VNS in patients with upper-limb dysfunction
after ischemic stroke.44 Twenty-one subjects were randomized to VNS plus rehabilitation or
rehabilitation alone. Mean change in the outcome as assessed by a functional assessment score
was +8.7 in the VNS group versus +3.0 in the control group (p=0.064). Six patients in the VNS
group achieved clinically meaningful response versus 4 in the control group (p=0.17).
Essential Tremor, Obesity, Headache, Fibromyalgia, and Tinnitus
VNS has been investigated with small pilot studies or studies evaluating mechanism of disease for
several conditions. These conditions include essential tremor,45 obesity,46 fibromyalgia,47
headache,48,49 and tinnitus.50 None of these studies are sufficient to make conclusions on the
effect of VNS on these conditions. Only conditions for which at least 1 randomized trial has been
reported will be detailed.
Section Summary: Other Conditions
In other conditions evaluated with RCTs (heart failure, upper-limb impairment), the trials did not
show efficacy of VNS for the primary outcome. Other conditions (essential tremor, obesity,
headache, fibromyalgia, tinnitus) have only been investigated with case series, which are not
sufficient to make conclusions on the effect of VNS.
Transcutaneous VNS
Only conditions for which there is at least 1 RCT will be discussed, as case series are inadequate
to determine the effect of the technology.
Transcutaneous VNS for Epilepsy
Aihua et al reported results from a series of 60 patients with pharmaco-resistant epilepsy treated
with a transcutaneous VNS (t-VNS) device, who were randomly assigned to receive stimulation
over the earlobe (control group) or the Ramsay-Hunt zone (treatment group), which includes the
external auditory canal and the conchal cavity and is considered to be the somatic sensory
territory of the vagus nerve.51 Thirty patients were randomized to each group; 4 subjects from
the treatment group were excluded from analysis due to loss to follow-up (n=3) or adverse
effects (n=1), while 9 subjects from the control group were excluded from analysis due to loss to
follow-up (n=2) or increase or lack of decrease in seizures or other reasons (n=7). In the
treatment group, compared with baseline, the median monthly seizure frequency was
significantly reduced after 6 months (5.5 vs 6.0; p<0.001) and 12 months (4.0 vs 6.0; p<0.001)
of t-VNS therapy. At 12-month follow-up, t-VNS group subjects had a significantly lower median
monthly seizure frequency compared with the control group (4.0 vs 8.0; p<0.001).
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Two small case series were identified that used a t-VNS device for treatment of medicationrefractory seizures. In a small case series of 10 patients with treatment-resistant epilepsy, Stefan
et al reported that 3 patients withdrew from the study, while 5 of 7 patients reported a reduction
in seizure frequency.52 In another small case series, He et al reported that among 14 pediatric
patients with intractable epilepsy who were treated with bilateral t-VNS, of the 13 patients who
completed follow-up, mean reduction in self-reported seizure frequency was 31.8% after 8
weeks, 54.1% from week 9 to 16, and 54.2% from week 17 to 24.53
Transcutaneous VNS for Psychiatric Disorders
Hein et al reported results of 2 pilot RCTs of a t-VNS device for the treatment of depression, 1
which included 22 subjects and 1 with 15 subjects.54 In the first study, 11 subjects each were
randomized to active or sham t-VNS. At 2 weeks follow-up, Beck Depression Inventory (BDI) selfrating scores in the active-stimulation group decreased from 27.0 to 14.0 points (p<0.001), while
the sham-stimulated patients did not show significant reductions in the BDI (31.0 to 25.8 points).
In the second study, 7 patients were randomized to active t-VNS and 8 patients were randomized
to sham t-VNS. In this study, BDI self-rating scores in the active stimulation group decreased
from 29.4 to 17.4 points (p<0.05) after 2 weeks, while the sham-stimulated patients did not
show significant change in BDI (28.6 to 25.4 points). The authors do not report direct
comparisons in BDI change between the sham- and active-stimulation groups.
Hasan et al reported a randomized trial of t-VNS for the treatment of schizophrenia.55 Twenty
patients were assigned either to active t-VNS or to sham treatment for 12 weeks. There was no
statistically significant difference in the improvement of schizophrenia status during the
observation period.
Shiozawa et al conducted a systematic review of studies evaluating the evidence related to
transcutaneous stimulation of the trigeminal or vagus nerve for psychiatric disorders.56 They
found 4 studies that addressed t-VNS for psychiatric disorders and included a total of 84 subjects.
Three of the 4 studies evaluated physiologic parameters in healthy patients and 1 evaluated
pharmaco-resistant epilepsy (Stefan et al, previously described52). The authors also include a fifth
study in a data table, although not in their text or reference list (Hein et al, previously
described54) Overall, the studies included were limited by small size and poor generalizability.
Transcutaneous VNS for Headache
Gaul et al reported the results of a randomized open-label study of t-VNS for the treatment of
chronic cluster headache.57 Forty-eight patients with chronic cluster headache were randomized
to either t-VNS or to individualized standard of care. Transcutaneous VNS was to be used twice
daily with the option of additional treatment during headaches. At 4 weeks, the t-VNS group had
a greater reduction in the number of headaches than the control group, resulting in a mean
therapeutic gain of 3.9 fewer headaches per week (p=0.02). In terms of response rate, defined
as a 50% or more reduction in headaches, the t-VNS group had a 40% response rate versus
8.3% in the control group (p<0.001). The study lacked a sham placebo control group, which may
result in placebo response in the t-VNS group.
Goadsby et al reported results from an open-label pilot study of t-VNS for the treatment of
migraine with or without aura.58 Eighty migraine attacks were self-treated by 27 patients, of an
initial sample of 30 patients (2 patients treated no migraine attacks with the device, 1 patient
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Page 12 of 22
treated only an aura). Of 54 moderate or severe attacks treated, 12 subjects (22%) were painfree at 2 hours posttreatment. Thirteen subjects reported adverse events, which were all
considered mild or moderate.
Transcutaneous VNS for Impaired Glucose Tolerance
Huang et al reported results of a pilot RCT of a t-VNS device that provides stimulation to the
auricle for the treatment of impaired glucose tolerance.59 The study included 70 patients with
impaired glucose tolerance who were randomized to active or sham t-VNS, along with 30 controls
who received no t-VNS treatment. After 12 weeks of treatment, patients who received active tVNS were reported to have significantly lower 2-hour glucose tolerance test results than those
who received sham t-VNS (7.5 mmol/L vs 8 mmol/L; p=0.004).
Section Summary: Transcutaneous VNS
Transcutaneous VNS has been investigated with small randomized trials for several conditions.
Some evidence for the efficacy of t-VNS for epilepsy comes 1 small RCT, which reported lower
seizure rates for active t-VNStreated patients compared with sham controls; however, the high
dropout rates in this study are problematic. In the study of depression, 1 small RCT that
compared treatment with t-VNS with sham stimulation demonstrated some improvements in
depression scores with t-VNS; however, the lack of comparisons between groups limits
conclusions that may be drawn. An RCT for cluster headache showed a reduction in headache
frequency, but did not have a sham treatment group. A sham-controlled pilot RCT for impaired
glucose tolerance showed some effect on glucose tolerance tests.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.
Table 1. Summary of Key Trials
NCT No.
Ongoing
NCT02089243
Unpublished
NCT01958125a
NCT01792817a
Trial Name
Planned
Completion
Enrollment
Date
Prospective Randomized Controlled Study of Vagus
Nerve Stimulation Therapy in the Patients With
Medically Refractory Medial Temporal Lobe Epilepsy;
Controlled Randomized Vagus Nerve Stimulation Versus
Resection (CoRaVNStiR)
40
Jul 2017
A Randomized, Multicentre, Double-blind, Parallel,
Sham-controlled Study of GammaCore®, a Noninvasive Neurostimulator Device for the Acute Relief of
Episodic and Chronic Cluster Headache.
Non-invasive Neurostimulation of the Vagus Nerve With
the GammaCore Device for the Treatment of Cluster
Headache
120
Jan 2015
150
Oct 2014
NCT: national clinical trial.
a
Denotes industry-sponsored or cosponsored trial.
Summary of Evidence
The evidence for vagus nerve stimulation (VNS) in individuals who have seizures refractory to
medical treatment includes randomized controlled trials (RCTs) and multiple observational
studies. Relevant outcomes are symptoms, change in disease status, and functional outcomes.
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The RCTs reported a significant reduction in seizure frequency for patients with partial-onset
seizures. The uncontrolled studies have consistently reported large reductions for a broader
range of seizure types in both adults and children. The evidence is sufficient to determine
qualitatively that the technology results in a meaningful improvement in the net health outcome.
The evidence for VNS in individuals who have treatment-resistant depression includes 1 RCT and
other nonrandomized comparative studies and case series. Relevant outcomes are symptoms,
change in disease status, and functional outcomes. The RCT reported only short-term results and
found no significant improvement for the primary outcome. Other available studies are limited by
small sample sizes, potential selection bias, and lack of a control group in the case series. The
evidence is insufficient to determine the effects of the technology on health outcomes.
The evidence for VNS in individuals who have chronic heart failure or upper-limb impairment due
to stroke includes RCTs and case series. Relevant outcomes are symptoms, change in disease
status, and functional outcomes. The RCTs for both conditions did not show significant
improvements in the primary outcomes. The evidence is insufficient to determine the effects of
the technology on health outcomes.
The evidence for VNS in individuals who have essential tremor, obesity, headache, fibromyalgia,
or tinnitus includes case series. Relevant outcomes are symptoms, change in disease status, and
functional outcomes. Case series are insufficient to make conclusions regarding efficacy. The
evidence is insufficient to determine the effects of the technology on health outcomes.
The evidence for transcutaneous VNS stimulation in individuals who have epilepsy, depression,
schizophrenia, headache, or impaired glucose tolerance includes at least 1 RCT and case series
for some of the conditions. Relevant outcomes are symptoms, change in disease status, and
functional outcomes. The RCTs are all small and have various methodologic problems. None
shows definitive efficacy of transcutaneous VNS in improving outcomes among patients. The
evidence is insufficient to determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
American Academy of Neurology
In 1999, the American Academy of Neurology (AAN) released a consensus statement on the use
of VNS in adults that stated, “VNS is indicated for adults and adolescents over 12 years of age
with medically intractable partial seizures who are not candidates for potentially curative surgical
resections, such as lesionectomies or mesial temporal lobectomies.”60 AAN released an update to
these guidelines in 2013 that stated, “VNS may be considered for seizures in children, for LGS
[Lennox-Gastaut syndrome]-associated seizures, and for improving mood in adults with epilepsy
(Level C). VNS may be considered to have improved efficacy over time (Level C).”61
American Psychiatric Association
The American Psychiatric Association guidelines on the treatment of major depressive disorder in
adults, updated in November 2010, includes the following statement on the use of VNS: “Vagus
nerve stimulation (VNS) may be an additional option for individuals who have not responded to at
least four adequate trials of antidepressant treatment, including ECT [electroconvulsive therapy],”
with a level of evidence III (may be recommended on the basis of individual circumstances).62
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European Headache Federation
In 2013, the European Headache Federation issued a consensus statement on neuromodulation
treatments for chronic headaches, which makes the following statement about the use of VNS:
“Due to the lack of evidence, VNS should only be employed in chronic headache sufferers using a
randomized, placebo controlled trial design.”63
U.S. Preventive Services Task Force Recommendations
Not applicable.
CODING
The following codes for treatment and procedures applicable to this policy are included below
for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s)
does not constitute or imply member coverage or provider reimbursement. Please refer to the
member's contract benefits in effect at the time of service to determine coverage or noncoverage of these services as it applies to an individual member.
CPT/HCPCS
61885
61886
64553
64568
64569
64570
95974
95975
L8680
L8681
L8685
L8686
Insertion or replacement of cranial neurostimulator pulse generator or receiver,
direct or inductive coupling; with connection to a single electrode array
Insertion or replacement of cranial neurostimulator pulse generator or receiver,
direct or inductive coupling; with connection to 2 or more electrode arrays
Percutaneous implantation of neurostimulator electrode array; cranial nerve
Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator
electrode array and pulse generator
Revision or replacement of cranial nerve (eg, vagus nerve) neurostimulator
electrode array, including connection to existing pulse generator
Removal of cranial nerve (eg, vagus nerve) neurostimulator electrode array and
pulse generator
Electronic analysis of implanted neurostimulator pulse generator system (eg, rate,
pulse amplitude and duration, configuration of wave form, battery status, electrode
selectability, output modulation, cycling, impedance and patient compliance
measurements); complex cranial nerve neurostimulator pulse generator/transmitter,
with intraoperative or subsequent programming, with or without nerve interface
testing, first hour
Electronic analysis of implanted neurostimulator pulse generator system (eg, rate,
pulse amplitude and duration, configuration of wave form, battery status, electrode
selectability, output modulation, cycling, impedance and patient compliance
measurements); complex cranial nerve neurostimulator pulse generator/transmitter,
with intraoperative or subsequent programming, each additional 30 minutes after
first hour (List separately in addition to code for primary procedure)
Implantable neurostimulator electrode, each
Patient programmer (external) for use with implantable programmable
neurostimulator pulse generator, replacement only
Implantable neurostimulator pulse generator, single array, non-rechargeable,
includes extension
Implantable neurostimulator pulse generator, single array, non-rechargeable,
includes extension
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Vagus Nerve Stimulation
L8687
L8688
L8689

Page 15 of 22
Implantable neurostimulator pulse generator, dual array, rechargeable, includes
extension
Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes
extension
External recharging system for battery (internal) for use with implantable
neurostimulator, replacement only
VNS requires not only the surgical implantation of the device, but also subsequent
neurostimulator programming, which occurs intraoperatively and typically during additional
outpatient visits. There are CPT codes that specifically describe the neurostimulator
programming and analysis of cranial nerve stimulation (ie, vagus nerve) as follows: 95974,
95975.
ICD-9 Diagnoses
345.00-345.91
Epilepsy, code range
ICD-10 Diagnoses (Effective October 1, 2015)
G40.001
G40.009
G40.011
G40.019
G40.101
G40.109
G40.111
G40.119
G40.201
G40.209
G40.211
G40.219
G40.301
G40.309
G40.311
Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes
with seizures of localized onset, not intractable, with status epilepticus
Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes
with seizures of localized onset, not intractable, without status epilepticus
Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes
with seizures of localized onset, intractable, with status epilepticus
Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes
with seizures of localized onset, intractable, without status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with simple partial seizures, not intractable, with status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with simple partial seizures, not intractable, without status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with simple partial seizures, intractable, with status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with simple partial seizures, intractable, without status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with complex partial seizures, not intractable, with status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with complex partial seizures, not intractable, without status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with complex partial seizures, intractable, with status epilepticus
Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes
with complex partial seizures, intractable, without status epilepticus
Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with
status epilepticus
Generalized idiopathic epilepsy and epileptic syndromes, not intractable, without
status epilepticus
Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status
epilepticus
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Vagus Nerve Stimulation
G40.319
G40.401
G40.409
G40.411
G40.419
G40.501
G40.509
G40.801
G40.802
G40.811
G40.812
G40.813
G40.814
G40.821
G40.822
G40.823
G40.824
G40.A01
G40.A09
G40.A11
G40.A19
G40.B01
G40.B09
G40.B11
G40.B19
Page 16 of 22
Generalized idiopathic epilepsy and epileptic syndromes, intractable, without status
epilepticus
Other generalized epilepsy and epileptic syndromes, not intractable, with status
epilepticus
Other generalized epilepsy and epileptic syndromes, not intractable, without status
epilepticus
Other generalized epilepsy and epileptic syndromes, intractable, with status
epilepticus
Other generalized epilepsy and epileptic syndromes, intractable, without status
epilepticus
Epileptic seizures related to external causes, not intractable, with status epilepticus
Epileptic seizures related to external causes, not intractable, without status
epilepticus
Other epilepsy, not intractable, with status epilepticus
Other epilepsy, not intractable, without status epilepticus
Lennox-Gastaut syndrome, not intractable, with status epilepticus
Lennox-Gastaut syndrome, not intractable, without status epilepticus
Lennox-Gastaut syndrome, intractable, with status epilepticus
Lennox-Gastaut syndrome, intractable, without status epilepticus
Epileptic spasms, not intractable, with status epilepticus
Epileptic spasms, not intractable, without status epilepticus
Epileptic spasms, intractable, with status epilepticus
Epileptic spasms, intractable, without status epilepticus
Absence epileptic syndrome, not intractable, with status epilepticus
Absence epileptic syndrome, not intractable, without status epilepticus
Absence epileptic syndrome, intractable, with status epilepticus
Absence epileptic syndrome, intractable, without status epilepticus
Juvenile myoclonic epilepsy, not intractable, with status epilepticus
Juvenile myoclonic epilepsy, not intractable, without status epilepticus
Juvenile myoclonic epilepsy, intractable, with status epilepticus
Juvenile myoclonic epilepsy, intractable, without status epilepticus
REVISIONS
10-08-2008
Revised title from Vagal Nerve Stimulator to Vagus Nerve Stimulation
Added Rationale section
In Coding section:
▪ Added L8689
Added Revisions section
10-26-2010
Description section updated
In Policy section:
▪ Policy language liberalized from:
"Vagal nerve stimulation is medically necessary for:
1. Patient not responding to anticonvulsant medications with multiple
medications tried
2. Patient not a candidate for a surgical procedure
3. Medically refractory seizures (i.e. Lennox-Gastaut) in children under 12 years"
Current Procedural Terminology © American Medical Association. All Rights Reserved.
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Vagus Nerve Stimulation
03-03-2011
01-01-2012
08-24-2012
Page 17 of 22
to: "A. Vagus nerve stimulation may be considered medically necessary as a
treatment of medically refractory seizures.
▪ Policy language liberalized from:
"Vagal nerve stimulation is experimental / investigational because effectiveness
has not been established for all other indications including:
1. Autism,
2. Obesity,
3. Refractory depression,
4. Obsessive-compulsive disorder,
5. Cognitive impairment associated with Alzheimer’s disease, and
6. Depression"
to: "B. Vagus nerve stimulation is considered experimental / investigational as a
treatment of other conditions." with the reference to indications being removed as
the list was not all inclusive.
Added Policy Guidelines section and the following wording:
▪ "Medically refractory seizures are defined as seizures that occur in spite of
therapeutic levels of antiepileptic drugs or seizures that cannot be treated
with therapeutic levels of antiepileptic drugs because of intolerable adverse
effects of these drugs."
Updated Rationale section
In Coding section:
▪ Updated wording for CPT/HCPCS codes: 61886, L8681, L8689
Updated References section
In Coding section:
▪ Added CPT codes: 64568, 64569, 64570
Rationale section updated.
Reference section updated.
In Coding section:
 Revised CPT nomenclature for the following code: 64553
 Removed CPT code: 64573
 Removed the following CPT guidelines:
“95974: Electronic analysis of implanted neurostimulator pulse generator
system (e.g., rate, pulse amplitude and duration, configuration of wave form,
battery status, electrode selectability, output modulation, cycling, impedance,
and patient compliance measurements); complex cranial nerve
neurostimulator pulse generator/transmitter, with intraoperative or
subsequent programming, with or without nerve interface testing, first hour.
95975: complex cranial nerve neurostimulator pulse generator/transmitter,
with intraoperative or subsequent programming, with or without nerve
interface testing, each additional 30 minutes.”
 Added the following CPT guidelines:
“95974: use modifier 52, if less than 31 minutes in duration.”
Description section updated.
In the Policy section:
 In Item B, added "including, but not limited to heart failure, fibromyalgia,
depression, essential tremor, obesity, and headaches." to read "Vagus nerve
stimulation is considered experimental / investigational as a treatment of
other conditions, including, but not limited to heart failure, fibromyalgia,
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Vagus Nerve Stimulation
06-26-2013
11-24-2015
04-25-2016
Page 18 of 22
depression, essential tremor, obesity, and headaches."
Rationale section updated.
Reference section updated.
Rational section updated.
In Coding section:
 Added ICD-10 Diagnoses (Effective October 1, 2014)
Description section updated
In Policy section:
 In Item B removed “and” and added “tinnitus, and traumatic brain injury” to
read, “Vagus nerve stimulation is considered experimental / investigational as a
treatment of other conditions, including but not limited to heart failure,
fibromyalgia, depression, essential tremor, obesity, headaches, tinnitus, and
traumatic brain injury.”
Rationale section updated
In Coding section:
 Updated Coding notations.
References updated
Description section updated
Rationale section updated
References updated
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