clinical policy bulletin: vagus nerve stimulation...treatment. vagus nerve stimulation (vns) using...
TRANSCRIPT
Vagus Nerve Stimulation Page 1 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
Clinical Policy Bulletin: Vagus Nerve Stimulation
Revised February 2015
Number: 0191
Policy
Aetna considers vagus nerve electrical stimulators medically necessary durable medical
equipment (DME) for shortening the duration or reducing the severity of seizures in members
with partial onset seizures who remain refractory to optimal anti-epileptic medications and/or
surgical intervention, or who have debilitating side effects from anti-epileptic medications. (Note:
Electronic analysis of an implanted neurostimulator pulse generator system for vagus nerve
stimulation is considered medically necessary when criteria are met).
Aetna considers transcutaneous vagus nerve stimulation experimental and investigational for the
treatment of seizures and all other indications (see below) because the effectiveness of this
approach has not been established.
Aetna considers vagus nerve electrical stimulators and transcutaneous vagus nerve
stimulation experimental and investigational for the treatment of all other indications because its
effectiveness for these indications has not been established (not an all inclusive list):
Addictions
Anxiety disorders
Autism
Bipolar disorders
Cerebral palsy
Chronic headaches
Cognitive impairment associated with Alzheimer’s disease
Coma
Depression
Eating disorders (e.g., anorexia and bulimia)
Essential tremor
Fibromyalgia
Generalized epilepsy syndromes
Generalized treatment-resistant epilepsy
Heart failure
Hemicrania continua
Impaired glucose tolerance/Pre-diabetes
Juvenile myoclonic epilepsy
Migraine headaches
Mood disorders
Narcolepsy
Obesity
Obsessive-compulsive disorder
Vagus Nerve Stimulation Page 2 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
Sleep disorder
Stroke
Tinnitus
Tourette's syndrome
Traumatic brain injury (TBI) including post-TBI pneumonia
See also CPB 0221 - Quantitative EEG (Brain Mapping), CPB 0226 - Hospitalization for the
Initiation of Ketogenic Diet for the Treatment of Intractable Seizures, CPB 0279 - Magnetic
Source Imaging/Magnetoencephalography, CPB 0322 - Electroencephalographic (EEG) Video
Monitoring, CPB 0394 - Epilepsy Surgery, CPB 0425 - Ambulatory Electroencephalography, and
CPB 0406 - Tinnitus Treatments.
Background
Approximately 1.7 millions Americans suffer from epilepsy. The vast majority of these patients
can be controlled by conventional drug therapy. Despite the availability of new anti-epileptic
medications and advances in surgical therapy, more than 200,000 people remain refractory to
treatment. Vagus nerve stimulation (VNS) using the NeuroCybernetic Prosthesis (NCP) System
has been shown to shorten the duration and reduce the severity of seizures in certain patients
who remain refractory despite optimal drug therapy or surgical intervention or in those with
debilitating side effects of anti-epileptic medications.
The NCP System, approved by the Food and Drug Administration (FDA) on July 16, 1997, is a
pacer-like device implanted under the skin in the upper left chest area. It is connected by wire to
a lead that is wrapped around the left vagus nerve in the neck. Through the vagus nerve, it
delivers intermittent electrical pulses 24 hours a day to the brain. When a patient senses the
impending onset of a seizure, he/she can activate the device through a hand-held magnet to
deliver an additional dose of stimulation. Treatment with the vagus nerve stimulator is not free of
side effects. Patients have experienced cough, hoarseness, alterations in their voice, and
shortness of breath.
Recent studies have established vagus nerve stimulation to be a viable option for improving
seizure control in difficult to treat pediatric patients with epilepsy (Zamponi et al, 2002; Murphy et
al, 2003; Smyth et al, 2003; and Buoni et al, 2004). An assessment of VNS in children by the
National Institute for Clinical Excellence (NICE, 2004) reached the following conclusion:
"Current evidence on the safety and efficacy of vagus nerve stimulation for refractory epilepsy in
children appears adequate to support the use of this procedure, provided that the normal
arrangements are in place for consent, audit and clinical governance".
It has been reported that VNS in patients with epilepsy is associated with an improvement in
mood. Approximately 1/3 of patients with major depressive disorder fail to experience sufficient
symptom improvement despite adequate treatment. Management of patients with treatment
resistant depression (TRD) usually consists of pharmacological or non-pharmacological
methods. The former approach entails switching to another anti-depressant monotherapy, and
augmentation or combination with 2 or more antidepressants or other agents. The latter
approach includes psychotherapy, electroconvulsive therapy, and VNS. Although VNS is
associated with mood improvements in patients with epilepsy, randomized, controlled studies
with long-term follow-up are needed to confirm its effect on TRD. In this regard, Kosel and
Schlaepfer (2003) stated that recent data from an open-label, multi-center pilot study involving 60
patients (Goodnick et al, 2001) suggested a potential clinical usefulness in the acute and
maintenance treatment of TRD. However, definite therapeutic effects of clinical significance
remain to be confirmed in large placebo-controlled trial. This is in agreement with the
observation of George et al (2000) who noted that additional research is needed to clarify the
mechanisms of action of VNS and its potential clinical utility in the management of patients with
TRD. Because of the lack of well-designed controlled clinical trials, VNS for refractory
Vagus Nerve Stimulation Page 3 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
depression is considered experimental and investigational. Long-term data regarding tolerability
as well as symptomatic and functional outcomes of depressed patients receiving VNS are
needed to ascertain the effectiveness of this procedure for treating refractory depression. An
assessment by the Institute for Clinical Systems Improvement (ICSI, 2004) stated that VNS for
depression “cannot be considered evidence-based.”
In an acute phase pilot study (n = 59), Nahas et al (2005) evaluated the safety and effectiveness
of VNS for patients with treatment-resistant major depressive episode (MDE). They examined
the effects of adjunctive VNS over 24 months in this patient population. Adult outpatients with
chronic or recurrent major depressive disorder or bipolar (I or II) disorder and experiencing a
treatment-resistant, non-psychotic MDE (DSM-IV criteria) received 2 years of VNS. Changes in
psychotropic medications and VNS stimulus parameters were allowed only after the first 3
months. Response was defined as greater than or equal to 50 % reduction from the baseline 28-
item Hamilton Rating Scale for Depression (HAM-D-28) total score, and remission was defined
as a HAM-D-28 score less than or equal to 10. Based on last observation carried forward
analyses, HAM-D-28 response rates were 31 % (18/59) after 3 months, 44 % (26/59) after 1
year, and 42 % (25/59) after 2 years of adjunctive VNS. Remission rates were 15 % (9/59) at 3
months, 27 % (16/59) at 1 year, and 22 % (13/59) at 2 years. By 2 years, 2 deaths (unrelated to
VNS) had occurred, 4 participants had withdrawn from the study, and 81 % (48/59) were still
receiving VNS. Longer-term VNS was generally well- tolerated. These investigators concluded
that their findings suggest that patients with chronic or recurrent, TRD may show long-term
benefit when treated with VNS.
George et al (2005) stated that previous reports had described the effects of VNS plus treatment
as usual (VNS+TAU) during open trials of patients with TRD. To better understand these effects
on long-term outcome, these researchers compared 12-month VNS+TAU outcomes with those of
a comparable TRD group. Admission criteria were similar for those receiving VNS+TAU (n =
205) or only TAU (n = 124). In the primary analysis, repeated-measures linear regression was
used to compare the VNS+TAU group (monthly data) with the TAU group (quarterly data)
according to scores of the 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR
(30)). The 2 groups had similar baseline demographic data, psychiatric and treatment histories,
and degrees of treatment resistance, except that more TAU participants had at least 10 prior
major depressive episodes, and the VNS+TAU group had more electroconvulsive therapy before
study entry. The VNS+TAU group was associated with greater improvement per month in IDS-
SR(30) than the TAU group across 12 months (p < 0.001). Response rates according to the 24-
item Hamilton Rating Scale for Depression (last observation carried forward) at 12 months were
27 % for the VNS+TAU group and 13 % for the TAU group (p < 0.011). Both groups received
similar TAU (drugs and electroconvulsive therapy) during follow-up. These investigators
concluded that this comparison of 2 similar but non-randomized TRD groups showed that
VNS+TAU was associated with a greater anti-depressant benefit over 12 months. These
preliminary findings by Nahas et al (2005) as well as George as et (2005) need to be validated by
prospective, randomized placebo-controlled studies.
In a randomized controlled 10-week study, Rush and colleagues (2005a) compared adjunctive
VNS with sham treatment in 235 outpatients with non-psychotic major depressive disorder (n =
210) or non-psychotic, depressed phase, bipolar disorder (n = 25). Subjects had not responded
adequately to between 2 to 6 research-qualified medication trials. A 2-week, single-blind recovery
period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation.
Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was
based on response rates (greater than or equal to 50 % reduction from baseline on the 24-item
Hamilton Rating Scale for Depression [HRSD(24)]). At 10-weeks, HRSD(24) response rates
were 15.2 % for the active (n = 112) and 10.0 % for the sham (n = 110) groups (p
= 0.251). Response rates with a secondary outcome, the Inventory of Depressive
Symptomatology - Self-Report (IDS-SR(30)), were 17.0 % (active) and 7.3 % (sham) (p =
0.032). Vagal nerve stimulation was well-tolerated; 1 % (3/235) of subjects left the study
because of adverse events. These investigators concluded that this study did not yield definitive
evidence of short-term effectiveness of adjunctive VNS in TRD.
Vagus Nerve Stimulation Page 4 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
Rush et al (2005b) described follow-up of outpatients with non-psychotic major depressive (n =
185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of
active (n = 110) or sham VNS (n = 95). The initial active group received another 9 months, while
the initial sham group received 12 months of VNS. Participants received anti-depressant
treatments and VNS, both of which could be adjusted. The primary analysis (repeated measures
linear regression) revealed a significant reduction in HRSD(24) scores (average improvement,
.45 points [SE = .05] per month (p < 0.001). At exit, HRSD(24) response rate was 27.2 %
(55/202); remission rate (HRSD(24) less than or equal to 9) was 15.8 % (32/202). Montgomery
Asberg Depression Rating Scale (28.2 % [57/202]) and Clinical Global Impression-Improvement
(34.0 % [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were
the most frequently reported adverse events. These researchers concluded that these 1-year
open trial data found VNS to be well-tolerated, suggesting a potential long-term, growing benefit
in TRD, albeit in the context of changes in depression treatments. Comparative long-term data
are needed to determine whether these benefits can be attributed to VNS.
Furthermore, the BlueCross BlueShield TEC assessment on VNS for TRD (2005) stated that this
method does not meet the TEC criteria. The TEC assessment stated that the available evidence
is insufficient to permit conclusions of the effect of VNS therapy on health outcomes. According
to the TEC assessment, “the available evidence consists of a case series of 60 patients receiving
VNS, a short-term (i.e., 3-month) randomized, sham-controlled clinical trial of 221 patients, and
an observational study comparing 205 patients on VNS therapy compared to 124 patients
receiving ongoing treatment for depression. Patients who responded to sham treatment in the
short-term randomized, controlled trial (approximately 10%) were excluded from the long-term
observational study. Patient selection was a concern for all studies. 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 defined by thorough state-of-the-art psychiatric evaluation and
management”.
The BlueCross BlueShield Association updated their assessment in August 2006, and concluded
that VNS does not meet the TEC criteria. The assessment explained that, "[s]ince the last TEC
Assessment, there have been no studies reporting clinical outcomes on any new or different
patients. Data from the case series and clinical trials have been reanalyzed to show what
proportions of patients who respond at one time are still responders at a subsequent time point.
However, this information by itself does not provide evidence of the efficacy of VNS beyond that
provided by the original observational comparison of VNS versus treatment as usual."
An assessment of VNS for severe depression by the Aggressive Research Intelligence Facility
(ARIF, 2005) stated: "To conclude, this is an experimental and as yet unproven method of
treatment for severe depression. If this treatment is utilized, patients should be advised of the
experimental nature of the treatment and should be assessed by an expert in the field, who is
familiar with the treatment. The treatment should ideally be given as part of a robust evaluation
of clinical effectiveness and safety in order to add to the current evidence base". Furthermore,
an assessment by the California Technology Assessment Forum (CTAF, 2006) concluded that
the use of VNS for the treatment of resistant depression does not meet CTAF's technology
assessment criteria for safety, effectiveness, and improvement in health outcomes.
George et al (2007) stated that VNS is a new approach in treating neuropsychiatric diseases
within the class of brain-stimulating devices known as neuromodulators. Although VNS has
received FDA approval for the treatment of medication-resistant depression. there is a lack of
Class I evidence of effectiveness in treating depression. The authors concluded that much more
research is needed regarding exactly how to refine and deliver the electrical pulses and how this
differentially affects brain function in health and disease.
The Centers for Medicare & Medicaid Services (CMS, 2007) stated that there is sufficient
evidence to conclude that VNS is not reasonable and necessary for the treatment of resistant
Vagus Nerve Stimulation Page 5 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
depression. Thus, CMS has announced a national non-coverage determination for this
indication.
In a systematic review on the safety and effectiveness of VNS in the management of patients
with TRD, Daban and colleagues (2008) concluded that VNS seems to be an interesting new
approach to treating TRD. However, despite the promising results reported mainly in open
studies, further clinical trials are necessary to confirm its effectiveness in major depression.
Moreover, studies on its mechanism of action and cost-effectiveness are also needed to better
understand and develop VNS therapy for affective disorder. This is in agreement with the
observation of Fitzgerald and Daskalakis (2008) who stated that given the invasive nature of
VNS and potential side effects, further research on its use for the treatment of depression is
urgently needed. This should include the development of predictors of clinical response and
definition of stimulation parameters with enhanced effectiveness.
An Agency for Healthcare Research and Quality's review (Gaynes et al, 2011) reported that there
is insufficient evidence to evaluate whether non-pharmacological treatments are effective for
TRD. The review summarized evidence of the effectiveness of 4 non-pharmacological
treatments: (i) electroconvulsive therapy (ECT), (ii) repetitive transcranial magnetic stimulation
(rTMS), (iii) VNS, and (iv) cognitive behavioral therapy (CBT) or interpersonal psychotherapy.
With respect to maintaining remission (or preventing relapse), there were no direct comparisons
(evidence) involving ECT, rTMS, VNS, or CBT. With regard to indirect evidence, there were 3
fair trials compared rTMS with a sham procedure and found no significant differences, however,
too few patients were followed during the relapse prevention phases in 2 of the 3 studies (20-
week and 6-month follow-up) and patients in the 3rd study (3-month follow-up) received a co-
intervention providing insufficient evidence for a conclusion. There were no eligible studies for
ECT, VNS. or psychotherapy.
The review concluded that that comparative clinical research on non-pharmacologic interventions
in a TRD population is early in its infancy, and many clinical questions about efficacy and
effectiveness remain unanswered. Interpretation of the data is substantially hindered by varying
definitions of TRD and the paucity of relevant studies. The greatest volume of evidence is for
ECT and rTMS. However, even for the few comparisons of treatments that are supported by
some evidence, the strength of evidence is low for benefits, reflecting low confidence that the
evidence reflects the true effect and indicating that further research is likely to change our
confidence in these findings. This finding of low strength is most notable in 2 cases: ECT and
rTMS did not produce different clinical outcomes in TRD, and ECT produced better outcomes than
pharmacotherapy. No trials directly compared the likelihood of maintaining remission for
non-pharmacologic interventions. The few trials addressing adverse events, subpopulations,
subtypes, and health-related outcomes provided low or insufficient evidence of differences
between non-pharmacologic interventions. The most urgent next steps for research are to apply
a consistent definition of TRD, to conduct more head-to-head clinical trials comparing non-
pharmacologic interventions with themselves and with pharmacologic treatments, and to
delineate carefully the number of treatment failures following a treatment attempt of adequate
dose and duration in the current episode.
Recently, VNS has been used to treat patients with autism, obesity, Alzheimer’s disease, and
obsessive-compulsive disorder. Results from pilot studies suggested that VNS might induce
weight loss in obese individuals and improve cognitive function in patients with Alzheimer’s
disease. However, these findings need to be validated in large randomized placebo-controlled
studies with long-term outcomes.
In an open-label study, Camilleri and associates (2008) evalauted the effects of vagal blocking by
means of a new medical device that uses high-frequency electrical algorithms to create
intermittent vagal blocking (VBLOC therapy) on excess weight loss (EWL). Electrodes were
implanted laparoscopically on both vagi near the esophago-gastric junction to provide electrical
block. Patients (obese subjects with body mass index [BMI] of 35 to 50 kg/m(2)) were followed
for 6 months for body weight, safety, electrocardiogram, dietary intake, satiation, satiety, and
plasma pancreatic polypeptide (PP) response to sham feeding. To specifically assess device
Vagus Nerve Stimulation Page 6 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
effects alone, no diet or exercise programs were instituted. A total of 31 patients (mean BMI,
41.2 +/- 1.4 kg/m(2)) received the device. Mean EWL at 4 and 12 weeks and 6 months after
implant was 7.5 %, 11.6 %, and 14.2 %, respectively (all p < 0.001); 25 % of patients lost over 25
% EWL at 6 months (maximum, 36.8 %). There were no deaths or device-related serious
adverse events (AEs). Calorie intake decreased by greater than 30 % at 4 and 12 weeks and 6
months (all p < or = 0.01), with earlier satiation (p < 0.001) and reduced hunger (p = 0.005). After
12 weeks, plasma PP responses were suppressed (20 +/- 7 versus 42 +/- 19 pg/ml). Average
percent EWL in patients with PP response less than 25 pg/ml was double that with PP response
greater than 25 pg/ml (p = 0.02). Three patients had serious AEs that required brief
hospitalization, 1 each for lower respiratory tract, subcutaneous implant site seroma, and
clostridium difficile diarrhea. The authors concluded that VBLOC therapy is associated with
significant EWL and a desirable safety profile. They noted that these findings have resulted in
the design and implementation of a randomized, double-blind, prospective, multi-center trial in an
obese subject population.
Vagal nerve stimulation is also being studied for treating chronic headaches; however, its value for
this indication has yet to be established. Mauskop (2005) reported that VNS was implanted in
4 men and 2 women with disabling chronic cluster and migraine headaches. In 1 man and 1
woman with chronic migraines, VNS produced dramatic improvement with restoration of ability to
work. Two patients with chronic cluster headaches had significant improvement of their
headaches. Treatment was well-tolerated in 5 patients, while 1 developed nausea even at the
lowest current strength. The author concluded that VNS may be an effective therapy for
intractable chronic migraine and cluster headaches and deserves further trials.
Ansari et al (2007) noted that a possible role of VNS in the treatment of severe refractory
headache, intractable chronic migraine and cluster headache has been suggested. Clinical trials
are ongoing to examine VNS as a potential treatment for essential tremor, cognitive deficits in
Alzheimer's disease, anxiety disorders, and bulimia. Furthermore, VNS has also been studied in
the treatment of resistant obesity, addictions, sleep disorders, narcolepsy, coma, as well as
memory and learning deficits.
In a review on current and future treatments for chronic migraine, Mathew (2009) stated that
larger and more accurate studies are needed to further evaluate the usefulness of VNS as a
preventive migraine treatment.
In a pilot study, Schwartz et al (2008) examined the feasibility and safety and tested possible
efficacy of chronic VNS in patients with heart failure (HF). A total of 8 patients (mean age of 54
years) were included in this study. CardioFit (BioControl Medical), a vagal
stimulation implantable system delivering pulses synchronous with heart beats through a multiple
contact bipolar cuff electrode, was used. Vagus nerve stimulation was started 2 to 4 weeks after
implant, slowly raising intensity; patients were followed 1, 3 and 6 months thereafter. All
procedures were successful: as sole surgical side effect, 1 patient had transient hoarseness.
Vagal stimulation was well-tolerated, with only mild side effects (cough and sensation of electrical
stimulation). There was a significant improvement in NYHA class, Minnesota quality of life (from
52 +/- 14 to 31 +/- 18, p < 0.001), left ventricular end-systolic volume (from 208 +/- 71 to 190 +/-
83 ml, p = 0.03), and a favorable trend toward reduction in end-diastolic volume. The authors
concluded that this novel approach in treating patients with HF is feasible, and appears safe and
tolerable. They stated that the preliminary efficacy results appear promising, and that these
findings suggest the opportunity to proceed with a larger multi-center study.
Rosenberg et al (2009) stated that treatment of mood disorders is one of the most challenging
territories in the elderly. Effectiveness of different treatment strategies could be related to age,
sex and physical conditions. The side effect profile in this population also affects pharmacological
interventions. These investigators reviewed the neurostimulative treatment strategies in this
population of patients. However, possible treatment strategies such as electroconvulsive
therapy, transcranial magnetic stimulation (TMS), VNS and deep brain stimulation (DBS) were
less studied in the elderly. Electroconvulsive therapy was found to be an
effective treatment procedure in mood disorders. Few double-blind sham controlled studies were
Vagus Nerve Stimulation Page 7 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
conducted and demonstrated effectiveness of TMS; and DBS has lack of double-blind studies.
Electroconvulsive therapy appears to be the golden standard for the treatment resistant elderly
patients despite its side effects. The authors stated that double-blind, sham, controlled studies
with larger samples are needed to confirm preliminary results with transcranial direct current
stimulation, magnetic seizure therapy, DBS as well as VNS.
Jaseja (2008) stated that cerebral palsy (CP) continues to pose a cause for major socio-
economic concern and medical challenge worldwide. It is associated with a multi-faceted
symptomatology warranting a multi-dimensional management-approach. Recent recognition of
neurocognitive impairment and its hopefully possible treatment has opened up a new dimension
in its management to the neurologists. Vagal nerve stimulation technique is presently emerging
as an effective alternative anti-epileptic therapeutic measure in intractable epilepsy. Vagus nerve
stimulation has recently been shown to possess a suppressive effect also on interictal
epileptiform discharges (IEDs) that are now being widely accepted as established associates of
neurocognitive impairment. The author proposed VNS technique implantation in CP patients on
account of its dual therapeutic effectiveness, i.e., anti-epileptic and IED-suppression. These 2
effects are likely to control seizures that are quite often drug-resistant and also improve
neurocognition in CP patients, thus hoping for a better overall prognostic outcome and an
improved quality of life of the CP patients by VNS.
Kraus et al (2007) stated that direct VNS has proved to be an effective treatment for seizure
disorder. However, since this invasive technique implies surgery, with its side-effects and
relatively high financial costs, a non-invasive method to stimulate vagal afferences would be a
great step forward. These researchers studied effects of non-invasive electrical stimulation of
the nerves in the left outer auditory canal in healthy subjects (n = 22), aiming to activate vagal
afferences transcutaneously (tVNS). Short-term changes in brain activation and subjective well-
being induced by tVNS were investigated by functional magnetic resonance imaging (fMRI) and
psychometric assessment using the adjective mood scale (AMS), a self-rating scale for current
subjective feeling. Stimulation of the ear lobe served as a sham control. Functional MRI showed
that robust tVNS induced blood oxygenation level dependent (BOLD)-signal decreases in limbic
brain areas, including the amygdala, hippocampus, para-hippocampal gyrus and the middle and
superior temporal gyrus. Increased activation was seen in the insula, precentral gyrus and the
thalamus. Psychometric assessment revealed significant improvement of well-being after tVNS.
Ear lobe stimulation as a sham control intervention did not show similar effects in either fMRI or
psychometric assessment. No significant effects on heart rate, blood pressure or peripheral
microcirculation could be detected during the stimulation procedure. The authors concluded that
these findings showed the feasibility and beneficial effects of tVNS in the left auditory canal of
healthy subjects.
Dietrich and colleagues (2008) stated that left cervical VNS using the implanted NCP can reduce
epileptic seizures. To address a disadvantage of this device, the use of an alternative
transcutaneous electrical nerve stimulation technique, designed for muscular stimulation, was
studied. Functional MRI has been used to test non-invasively access nerve structures
associated with the vagus nerve system. The results and their impact were unsatisfying due to
missing brainstem activations. These activations, however, are mandatory for reasoning, higher
subcortical and cortical activations of vagus nerve structures. The objective of this study was to
test a new parameter setting and a novel device for performing specific tVNS at the inner side of
the tragus. This study showed the feasibility of these and their potential for brainstem and
cerebral activations as measured by BOLD fMRI. In total, 4 healthy male adults were scanned
inside a 1.5-Tesla MR scanner while undergoing tVNS at the left tragus. These investigators
ensured that their newly developed tVNS stimulator was adapted to be an MRI-safe stimulation
device. In the experiment, cortical and brainstem representations during tVNS were compared to
a baseline. A positive BOLD response was detected during stimulation in brain areas associated
with higher order relay nuclei of vagal afferent pathways, the left locus coeruleus, the thalamus,
the left prefrontal cortex, the right and the left postcentral gyrus, the left posterior cingulated
gyrus and the left insula, respectively. Deactivations were found in the right nucleus accumbens
Vagus Nerve Stimulation Page 8 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
and the right cerebellar hemisphere. The authors concluded that this method and device are
feasible and appropriate for accessing cerebral vagus nerve structures.
Xiong et al (2009) stated that post-operative cognitive dysfunction (POCD) is a decline in cognitive
function for weeks or months after surgery. It may affect the patients' length of hospital stay,
quality of life, the rehabilitation process, and work performance. Prolonged POCD occurs
frequently after cardiac surgery, and the risk of POCD increases with age. The pathophysiology
of POCD is not well-understood. However, emerging evidences indicate that various inflammatory
mediators are involved in the pathophysiology of POCD and inflammatory response may be a
potential pathogenic factor. Vagus nerve stimulation has been shown to decrease production and
release of pro-inflammatory cytokines through the cholinergic anti-inflammatory pathway (CAP) in
both animal model and human. Considering that inflammation plays a definite role in the
pathogenesis of POCD and the vagus nerve can mediate inflammation via CAP, these
researchers hypothesized that transcutaneous VNS may attenuate POCD by reducing
inflammatory response in elderly patients.
Hemicrania continua is a rare, relentless, constant, 1-sided headache that is accompanied at
times by mild symptoms related to dysfunction of the autonomic nervous system in the face --
small pupil, drooping eyelid, red or watering eye, stuffy or runny nose -- similar to the symptoms of
a cluster headache, but much less dramatic. The pain is usually dull but can wax and wane in
severity. These headaches often subside entirely with prescription anti-inflammatory medication.
Magis et al (2011) stated that cluster headache is well known as one of the most painful primary
neurovascular headache. Since 1 % of chronic cluster headache patients become refractory to
all existing pharmacological treatments, various invasive and sometimes mutilating procedures
have been tried in the last decades. Recently, neurostimulational approaches have raised new
hope for drug-resistant chronic cluster headache patients. The authors reviwed the evidence on
stimulation of the great occipital nerve, which has been the best evaluated peripheral nerve
stimulation technique in drug-resistant chronic cluster headache, providing the most convincing
results so far. Other peripheral nerve stimulation approaches used for this indication were also
reviewed in detail. They noted that "[a]lthough available studies are limited to a relatively small
number of patients and placebo-controlled trials are lacking .... More studies are needed to
evaluate the usefulness of supraorbital nerve stimulation and of vagus nerve stimulation in
management of cluster headaches".
Martin and Martin-Sanchez (2012) evaluated the effectiveness of VNS for treatment of
depression. These researchers conducted a systematic review and meta-analysis of analytical
studies. Effectiveness was evaluated according to severity of illness and percentage of
responders. They identified 687 references. Of these, 14 met the selection criteria and were
included in the review. The meta-analysis of effectiveness for uncontrolled studies showed a
significant reduction in scores at the Hamilton Depression Rating Scale endpoint, and the
percentage of responders was 31.8 % ([23.2 % to 41.8 %], p < 0.001). However, the randomized
controlled trial that covered a sample of 235 patients with depression, reported no statistically
significant differences between the active intervention and placebo groups (odds ratio [OR] =
1.61 [95 % confidence interval [CI]: 0.72 to 3.62]; p = 0.25). To study the cause of this
heterogeneity, a meta-regression was performed. The adjusted co-efficient of determination (R2
(Adj)) was 0.84, which implies that an 84 % variation in effect size across the studies was
explained by baseline severity of depression (p < 0.0001). The authors concluded that currently,
insufficient data are available to describe VNS as effective in the treatment of depression. In
addition, it cannot be ruled out that the positive results observed in the uncontrolled studies might
have been mainly due to a placebo effect.
In a pilot study, Lehtimaki et al (2013) examined if transcutaneous VNS (tVNS) combined with
sound therapy (ST) would reduce the severity of tinnitus and tinnitus-associated distress. The
objectives were to study whether tVNS has therapeutic effects on patients with tinnitus and,
additionally, if tVNS has effects on acoustically evoked neuronal activity of the auditory cortex.
The clinical efficacy was studied by a short-term tVNS plus ST trial in 10 patients with tinnitus
using disease-specific and general well-being questionnaires. Transcutaneous VNS was
Vagus Nerve Stimulation Page 9 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
delivered to the left tragus. The acute effects of tVNS were evaluated in 8 patients in the MEG
study in which the N1m response was analyzed in terms of source level amplitude and latency in
the presence or absence of tVNS. The treatment with tVNS plus ST produced improved mood
and decreased tinnitus handicap scores, indicating reduced tinnitus severity. The application of
tVNS decreased the amplitude of auditory N1m responses in both hemispheres. The results of
this pilot study need to be validated by well-designed studies.
Straube et al (2012) stated that chronic migraine (CM) was first defined in the second edition of
the International Headache Society (IHS) classification in 2004. The definition currently used
(IHS 2006) requires the patient to have headache on more than 15 days/month for longer than 3
months and a migraine headache on at least 8 of these monthly headache days and that there is
no medication overuse. In daily practice the majority of the patients with CM also report
medication overuse but it is difficult to determine whether the use is the cause or the
consequence of CM. Most the patients also have other co-morbidities, such as depression,
anxiety and chronic pain at other locations. Therapy has to take this complexity into
consideration and is generally multi-modal with behavioral therapy, aerobic training and
pharmacotherapy. The use of analgesics should be limited to fewer than 15 days per month and
use of triptans to fewer than 10 days per month. Drug treatment should be started with
topiramate, the drug with the best scientific evidence. If there is no benefit, onabotulinum toxin A
(155 to 195 Units) should be used. There is also some limited evidence that valproic acid and
amitriptyline might be beneficial. Moreover, the authors stated that neuromodulation by
stimulation of the greater occipital nerve or vagal nerve is being tested in studies and is so far an
experimental procedure only.
On behalf of the Guideline Development Subcommittee of the American Academy of Neurology
(AAN), Morris et al (2013) evaluated the evidence since the 1999 assessment regarding safety
and effectiveness of (VNS for epilepsy, currently approved as adjunctive therapy for partial-onset
seizures in patients greater than 12 years of age. These investigators reviewed the literature and
identified relevant published studies. They classified these studies according to the AAN
evidence-based methodology. Vagal nerve stimulation is associated with a greater than 50 %
seizure reduction in 55 % (95 % CI: 50 % to 59 %) of 470 children with partial or generalized
epilepsy (13 Class III studies). Vagal nerve stimulation is associated with a greater than 50 %
seizure reduction in 55 % (95 % CI: 46 % to 64 %) of 113 patients with Lennox-Gastaut
syndrome (LGS) (4 Class III studies). Vagal nerve stimulation is associated with an increase in
greater than or equal to 50% seizure frequency reduction rates of approximately 7 % from 1 to 5
years post-implantation (2 Class III studies). Vagal nerve stimulation is associated with a
significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies).
Infection risk at the VNS implantation site in children is increased relative to that in adults (OR =
3.4, 95 % CI: 1.0 to 11.2). Vagal nerve stimulation is possibly effective for seizures (both partial
and generalized) in children, for LGS-associated seizures, and for mood problems in adults with
epilepsy; it may have improved efficacy over time. The authors concluded that VNS may be
considered for seizures in children, for LGS-associated seizures, and for improving mood in
adults with epilepsy (Level C); it may be considered to have improved efficacy over time (Level
C). Children should be carefully monitored for site infection after VNS implantation. Moreover,
these researchers noted that some reports have discussed VNS use in small numbers of patients
with juvenile myoclonic epilepsy (JME); they stated that larger reports would help substantiate
whether VNS is appropriate in medically refractory JME.
McClelland et al (2013) stated that eating disorders (ED) are chronic and sometimes deadly
illnesses. Existing treatments have limited proven efficacy, especially in the case of adults with
anorexia nervosa. Emerging neural models of ED provide a rationale for more targeted, brain-
directed interventions. In a systematic review, these investigators examined the effects of
neuromodulation techniques on eating behaviors and body weight and assessed their potential
for therapeutic use in ED. All articles in PubMed, PsychInfo and Web of Knowledge were
considered and screened against a priori inclusion/exclusion criteria. The effects of repetitive
transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, VNS and deep
brain stimulation (DBS) were examined across studies in ED samples, other psychiatric and
Vagus Nerve Stimulation Page 10 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
neurological disorders, and animal models. A total of 60 studies were identified. There is
evidence for ED symptom reduction following rTMS and DBS in both anorexia nervosa and
bulimia nervosa. Findings from studies of other psychiatric and neurological disorders and from
animal studies demonstrated that increases in food intake and body weight can be achieved
following DBS and that VNS has potential value as a means of controlling eating and inducing
weight loss. The authors concluded that neuromodulatory tools have potential for reducing ED
symptomatology and related behaviors, and for altering food intake and body weight. They
stated that more research is needed to evaluate the potential of neuromodulatory procedures for
improving long-term outcomes in ED.
Elliott et al (2011a) evaluated the safety and effectiveness of VNS in a consecutive series of
adults and children with treatment-resistant epilepsy (TRE). In this retrospective review of a
prospectively created database of 436 consecutive patients who underwent VNS implantation for
TRE between November 1997 and April 2008, there were 220 (50.5 %) females and 216 (49.5
%) males ranging in age from 1 to 76 years at the time of implantation (mean of 29.0 ± 16.5).
Thirty-three patients (7.6 %) in the primary implantation group had inadequate follow-up (less
than 3 months from implantation) and 3 patients had early device removal because of infection
and were excluded from seizure control outcome analyses. Duration of VNS treatment varied
from 10 days to 11 years (mean of 4.94 years). Mean seizure frequency significantly improved
following implantation (mean reduction of 55.8 %, p < 0.0001). Seizure control greater than or
equal to 90 % was achieved in 90 patients (22.5 %), greater than or equal to 75 % seizure control
in 162 patients (40.5 %), greater than or equal to 50 % improvement in 255 patients (63.75 %),
and less than 50 % improvement in 145 patients (36.25 %). Permanent injury to the vagus nerve
occurred in 2.8 % of patients. The authors concluded that VNS is a safe and effective palliative
treatment option for focal and generalized TRE in adults and children. When used in conjunction
with a multi-disciplinary and multi-modality treatment regimen including aggressive anti-epileptic
drug regimens and epilepsy surgery when appropriate, more than 60 %
of patients with TRE experienced at least a 50 % reduction in seizure burden. Good results were
seen in patients with non FDA-approved indications. Moreover, they stated that prospective,
randomized trials are needed for patients with generalized epilepsies and for younger children to
potentially expand the number of patients who may benefit from this palliative treatment. The
authors also noted the following drawbacks of the study: (i) although patients were entered
prospectively into the database, this study was performed via retrospective query. Follow-up
was unavailable in 8 % of patients, providing a small margin of error in the estimates of VNS
efficacy. Determination of seizure frequency and use and efficacy of magnetic swiping relied on
the report of patients or caretakers and is inherently subject to error, (ii) a design limitation
inherent to all retrospective, non-randomized studies on VNS is the lack of a control group, and
(iii) a potential confound is the effect of AED (anti-epileptic drug) regimen changes on seizure
frequency over time in the setting of VNS. Many office visits were accompanied by VNS setting
changes and, much more frequently, by AED regimen adjustments (medication and/or dosage
changes). The complexity and frequency of such changes (often multiple changes in a single
visit) proved too difficult to incorporate into a meaningful analysis. The authors could not control
for all of these changes but believe AED treatment plays a major role in the success of any
treatment plan that includes long-term VNS therapy. In fact, the increase in VNS efficacy over
time reported by numerous centers may be due to alteration in device parameters, changes in
AED regimen, or an undefined, synergistic effect of both.
Elliott et al (2011b) analyzed the effectiveness of VNS in a large consecutive series of children
18 years of age and younger with TRE and compared the safety and effectiveness in children
under 12 years of age with the outcomes in older children. These researchers retrospectively
reviewed 141 consecutive cases involving children (75 girls and 66 boys) with TRE in whom
primary VNS implantation was performed by the senior author between November 1997 and
April 2008 and who had at least 1 year of follow-up since implantation. The patients' mean age
at VNS insertion was 11.1 years (range of 1 to 18 years). Eighty-six children (61.0 %) were
younger than 12 years at time of VNS insertion (which constitutes off-label usage of this device).
Follow-up was complete for 91.8 % of patients and the mean duration of VNS therapy in these
patients was 5.2 years (range of 25 days to 11.4 years). Seizure frequency significantly
Vagus Nerve Stimulation Page 11 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
improved with VNS therapy (mean reduction of 58.9 %, p < 0.0001) without a significant reduction
in anti-epileptic medication burden (median number of anti-epileptic drugs taken 3, unchanged).
Reduction in seizure frequency of at least 50 % occurred in 64.8 % of patients and
41.4 % of patients experienced at least a 75 % reduction. Major (3) and minor (6) complications
occurred in 9 patients (6.4 %) and included 1 deep infection requiring device removal, 1
pneumothorax, 2 superficial infections treated with antibiotics, 1 seroma/hematoma treated with
aspiration, persistent cough in 1 patient, severe but transient neck pain in 1 patient, and
hoarseness in 2 patients. There was no difference in efficacy or complications between children
12 years of age and older (FDA-approved indication) and those younger than 12 years of age (off
-label usage). Linear regression analyses did not identify any demographic and clinical variables
that predicted response to VNS. The authors concluded that VNS is a safe and effective
treatment for TRE in young adults and children. Over 50 % of patients experienced at least 50 %
reduction in seizure burden. Children younger than 12 years had a response similar to that of
older children with no increase in complications. Moreover, they stated that given the efficacy of
this device and the devastating effects of persistent epilepsy during critical developmental
epochs, randomized trials are needed to potentially expand the indications for VNS to include
younger children. Moreover, the authors stated that this study was limited by the retrospective
query into a prospective database and was subject to biases inherent to such methodology.
Nearly 8 % of patients were unavailable for follow-up. Determination of seizure frequency relied
on the reports of patients or caretakers and is inherently subject to error and bias. This limitation
is common to many studies measuring seizure frequency and treatment outcomes. These
researchers tried to improve their estimates by using LVCF (last value carried forward) analysis
instead of declining-n analysis, which is prone to non-responder attrition. Detailed information on
the effects of VNS on mood, quality of life, and qualitative aspects of seizures (duration, severity,
clustering, postictal period, and magnet usage) were either not systematically reported or could
not be derived from this retrospective analysis. Moreover, these investigators did not determine
if a mean reduction in seizures of nearly 50 % translates into caretaker and patient satisfaction
and overall improvements in quality of life. They stated that future prospective studies are needed
to better ascertain baseline mood assessments, quality-of-life metrics, and caretaker satisfaction
and to determine the impact of VNS on these parameters and their relation to seizure control.
Another confound concerns the unknown impact that changes in AED regimens have on seizure
frequency over time in the setting of VNS. Many office visits were accompanied by VNS setting
changes and, more frequently, by AED regimen adjustments. The authors could not control for
these changes but believe AED treatment plays a major role in the success of any treatment plan,
including long-term VNS therapy. They stated that further study is needed to better understand
the relative contributions of effective VNS therapy, AED regimen adjustments,
and regression to the mean.
The study by Elliott et al (2011b) (effects of VNS on children) appeared to be a sub-analysis of
the study by Elliott et al 2011a) (effects of VNS on adults and children).
An UpToDate review on “Vagus nerve stimulation therapy for the treatment of epilepsy” (Karceski
and Schachter, 2014) states that “The Food and Drug Administration (FDA) has approved vagus
nerve stimulator (VNS) therapy as adjunctive treatment for adults and adolescents over 12 years
of age whose partial-onset seizures were refractory to antiepileptic drugs. Since the approval of
VNS therapy for epilepsy, clinicians have actively debated its role. While further controlled
studies are needed to more fully understand the safety, tolerability, and efficacy profile of VNS in
children and in patients with generalized seizures, VNS is often used in these cases as well ….
Case series suggest that VNS is also effective in generalized epilepsy syndromes. While some
studies found that symptomatic generalized epilepsy is more responsive to VNS than idiopathic
syndromes, others have reported the opposite or found no difference”.
Huang et al (2014) noted that impaired glucose tolerance (IGT) is a pre-diabetic state of
hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and
cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve
activity may be the underlying mechanism of metabolic syndrome including obesity, elevated
glucose levels, and high blood pressure (BP). In this pilot randomized clinical trial (RCT), these
Vagus Nerve Stimulation Page 12 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
researchers compared the effectiveness of transcutaneous auricular VNS (taVNS) and sham-
taVNS on patients with IGT. A total of 72 participants with IGT were single-blinded and were
randomly allocated by computer-generated envelope to either taVNS or sham-taVNS treatment
groups. In addition, 30 IGT adults were recruited as a control population and not assigned
treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All
treatments were self-administered by the patients at home after training at the hospital. Patients
were instructed to fill in a patient diary booklet each day to describe any side effects after each
treatment. The treatment period was 12 weeks in duration. Baseline comparison between
treatment and control group showed no difference in weight, BMI, or measures of systolic BP,
diastolic BP, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated
hemoglobin (HbAlc). A total of 100 participants completed the study and were included in data
analysis. Two female patients (1 in the taVNS group, 1 in the sham-taVNS group) dropped out of
the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping
treatment. Compared with sham-taVNS, taVNS significantly reduced the 2-hour glucose tolerance
(F(2) = 5.79, p = 0.004). In addition, these investigators found that taVNS significantly decreased
(F(1) = 4.21, p = 0.044) systolic BP over time compared with sham-taVNS. Compared with the no-
treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) =
10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the
course of the 12-week treatment period. The authors concluded that the findings of this study
suggested that taVNS is a promising, simple, and cost-effective treatment for IGT/ pre-
diabetes with only slight risk of mild side-effects.
Cai et l (2014) stated that because of its ability to regulate mechanisms well-studied in
neuroscience, such as norepinephrine and serotonin release, the vagus nerve may play an
important role in regulating cerebral blood flow, edema, inflammation, glutamate excito-toxicity,
and neurotrophic processes. There is strong evidence that these same processes are important
in stroke pathophysiology. These investigators reviewed the literature for the role of VNS in
improving ischemic stroke outcomes by performing a systematic search for publications in Medline
(1966 to 2014) with keywords "VNS AND stroke" in subject headings and key words with no
language restrictions. Of the 73 publications retrieved, these researchers identified 7 studies from
3 different research groups that met the final inclusion criteria of research studies
addressing the role of VNS in ischemic stroke. Results from these studies suggested that VNS
has promising efficacy in reducing stroke volume and attenuating neurological deficits in
ischemic stroke models. Given the lack of success in phase III trials for stroke neuroprotection, it
is important to develop new therapies targeting different neuroprotective pathways. The authors
concluded that further studies of the possible role of VNS, through normally physiologically active
mechanisms, in ischemic stroke therapeutics should be conducted in both animal models and
clinical studies. In addition, recent advent of a non-invasive, transcutaneous VNS could provide
the potential for easier clinical translation.
Hall et al (2104) stated that nosocomial infections, pneumonia in particular, are well-known
complications of traumatic brain injury (TBI), which are associated with a worse neurological
outcome. These researchers explored the role of vagus nerve activity in immunomodulation as a
causative factor. A MEDLINE search revealed numerous reports published over the last decade
describing the "cholinergic anti-inflammatory pathway" between the vagus nucleus and leukocyte
activity. Using a combination of lipopolysaccharide stimulation and vagotomy, it has been shown
that the parasympathetic fibers terminating in the spleen reduce tumor necrosis factor (TNF)
production. Further pharmacological and receptor knockout studies have identified the α7 subtype
of nicotinic receptors as the likely target for this. Vagal activity also induces changes in neutrophil
chemotaxis through altered expression of the CD11b integrin which is abolished by splenectomy.
By extrapolating this evidence these investigators suggested a possible mechanism for
immunosuppression following TBI, which also has the potential to be targeted to reduce the
incidence of pneumonia. The authors concluded that while there is strong supporting evidence for
the role of vagal nerve over-activity in post-TBI pneumonia, there have yet to be any clinical
investigations and further study is needed.
Vagus Nerve Stimulation Page 13 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
Zhou et al (2014) noted that previous studies have shown that VNS can improve the prognosis of
TBI. These researchers examined the mechanism of the neuroprotective effects of VNS in rabbits
with brain explosive injury. Rabbits with brain explosive injury received continuous stimulation (10
V, 5 Hz, 5 ms, 20 minutes) of the right cervical vagus nerve. Tumor necrosis factor-α, interleukin
(IL)-1β and IL-10 concentrations were detected in serum and brain tissues, and water content in
brain tissues was measured. Results showed that VNS could reduce the degree of brain edema,
decrease TNF-α and IL-1β concentrations, and increase IL-10 concentration after brain explosive
injury in rabbits. The authors concluded that these data suggested that VNS may exert
neuroprotective effects against explosive injury via regulating the
expression of TNF-α, IL-1β and IL-10 in the serum and brain tissue.
Howland (2014) noted that right cervical VNS is effective for treating heart failure in pre-clinical
studies and a phase II clinical trial. The effectiveness of various forms of non-invasive
transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not
been investigated beyond small pilot studies. The relationship between depression,
inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve.
The author concluded that VNS deserves further study for its potentially favorable effects on
cardiovascular, cerebrovascular, metabolic, and other physiological biomarkers associated with
depression morbidity and mortality.
Appendix
Exclusion Criteria for VNS Therapy of Partial Onset Seizures:
VNS can not be used in persons with left or bilateral cervical vagotomy
VNS is not indicated for persons with other types of seizures.
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
61885 Insertion or replacement of cranial neurostimulator pulse generator or
receiver, direct or inductive coupling; with connection to a single electrode
array
64553 Percutaneous implantation of neurostimulator electrode array; cranial
nerve
64568 Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator
electrode array and pulse generator
64569 Revision or replacement of cranial nerve (eg, vagus nerve)
neurostimulator electrode array, including connection to existing pulse
generator
64570 Removal of cranial nerve (eg, vagus nerve) neurostimulator electrode
array and pulse generator
95970 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); simple or complex
brain, spinal cord, or peripheral (i.e., cranial nerve, peripheral nerve, sacral
nerve, neuromuscular) neurostimulator pulse generator/transmitter,
without reprogramming
Vagus Nerve Stimulation Page 14 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
95974 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, each additional 30 minutes
after first hour (List separately in addition to code for primary procedure)
CPT codes not covered for indications listed in the CPB:
0312T Vagus nerve blocking therapy (morbid obesity); laparoscopic implantation
of neurostimulator electrode array, anterior and posterior vagal trunks
adjacent to esophagogastric junction (EGJ), with implantation of pulse
generator, includes programming
0313T Vagus nerve blocking therapy (morbid obesity); laparoscopic revision or
replacement of vagal trunk neurostimulator electrode array, including
connection to existing pulse generator
0317T Vagus nerve blocking therapy (morbid obesity); neurostimulator pulse
generator electronic analysis, includes reprogramming when performed
64550 Application of surface (transcutaneous) neurostimulator [not covered for
transcutaneous vagus nerve stimulation]
Other CPT codes related to the CPB:
0314T Vagus nerve blocking therapy (morbid obesity); laparoscopic removal of
vagal trunk neurostimulator electrode array and pulse generator
0315T Vagus nerve blocking therapy (morbid obesity); removal of pulse generator
0316T Vagus nerve blocking therapy (morbid obesity); replacement of pulse
generator
HCPCS codes covered if selection criteria are met:
C1767 Generator, neurostimulator (implantable), nonrechargeable
C1778 Lead, neurostimulator (implantable)
C1816 Receiver and/or transmitter, neurostimulator (implantable)
C1883 Adaptor/ extension, pacing lead or neurostimulator lead (implantable)
L8680 Implantable neurostimulator electrode, each
L8681 Patient programmer (external) for use with implantable programmable
neurostimulator pulse generator, replacement only
L8682 Implantable neurostimulator radiofrequency receiver
L8683 Radiofrequency transmitter (external) for use with implantable
neurostimulator radiofrequency receiver
L8685 Implantable neurostimulator pulse generator, single array, rechargeable,
includes extension
L8686 Implantable neurostimulator pulse generator, single array, non-
rechargeable, includes extension
Vagus Nerve Stimulation Page 15 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
L8687 Implantable neurostimulator pulse generator, dual array, rechargeable,
includes extension
L8688 Implantable neurostimulator pulse generator, dual array, non-
rechargeable, includes extension
L8689 External recharging system for battery (internal) for use with implanted
neurostimulator, replacement only
L8695 External recharging system for battery (external) for use with implantable
neurostimulator, replacement only
ICD-9 codes covered if selection criteria are met:
345.40 - 345.41 Localization-related (focal) (partial) epilepsy and epileptic syndromes with
complex partial seizures [not covered for transcutaneous vagus nerve
stimulation]
345.50 - 345.51 Localization-related (focal) (partial) epilepsy and epileptic syndromes with
simple partial seizures [not covered for trancutaneous vagus nerve
stimulation]
ICD-9 codes not covered for indications listed in the CPB:
278.00 - 278.01 Obesity
291.82 Alcohol-induced sleep disorders
292.85 Drug-induced sleep disorders
296.00 - 296.99 Episodic mood disorders
298.0 Depressive type psychosis
299.00 - 299.01 Autistic disorder
300.00 - 300.09 Anxiety states
300.3 Obsessive-compulsive disorders
300.4 Dysthymic disorder
301.11 Chronic hypomanic personality disorder
303.00 - 303.93 Alcohol dependence syndrome
304.00 - 304.93 Drug dependence
305.00 - 305.93 Nondependent abuse of drugs
307.1 Anorexia nervosa
307.23 Tourette's disorder
307.40 - 307.49 Specific disorders of sleep of nonorganic origin
307.50 - 307.59 Other and unspecified disorders of eating
307.81 Tension headache
311 Depressive disorder, not elsewhere classified
327.19 Other organic hypersomnia
Vagus Nerve Stimulation Page 16 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
327.30 - 327.39 Circadian rhythm sleep disorder
327.40 - 327.49 Organic parasomnia
327.51 - 327.59 Organic sleep related movement disorders
327.8 Other organic sleep disorders
331.0 Alzheimer's disease
333.1 Essential and other specified forms of tremor
339.10 Tension type headache, unspecified
339.41 Hemicrania continua
343.0 - 343.9 Infantile cerebral palsy
345.00 - 345.3
345.60 - 345.91
Epilepsy [other than partial onset]
346.00 - 346.93 Migraine
347.00 - 347.11 Cataplexy and narcolepsy
388.30 - 388.32 Tinnitus
398.91 Rheumatic heart failure (congestive)
402.01 Hypertensive heart disease, malignant, with heart failure
402.11 Hypertensive heart disease, benign, with heart failure
402.91 Hypertensive heart disease, unspecified, with heart failure
404.01 Hypertensive heart and chronic kidney disease, malignant, with heart
failure and with chronic kidney disease stage I through stage IV, or
unspecified
404.03 Hypertensive heart and chronic kidney disease, malignant, with heart
failure and chronic kidney disease stage V or end stage renal disease
404.11 Hypertensive heart and chronic kidney disease, benign, with heart failure
and with chronic kidney disease stage I through stage IV, or unspecified
404.13 Hypertensive heart and chronic kidney disease, benign, with heart failure
and chronic kidney disease stage V or end stage renal disease
404.91 Hypertensive heart and chronic kidney disease, unspecified, with heart
failure and with chronic kidney disease stage I through stage IV, or
unspecified
404.93 Hypertensive heart and chronic kidney disease, unspecified, with heart
failure and chronic kidney disease stage V or end stage renal disease
428.0 - 428.9 Heart failure
729.1 Myalgia and myositis, unspecified [fibromyalgia]
780.01 Coma
780.39 Other convulsions [seizure NOS]
Vagus Nerve Stimulation Page 17 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
780.50 - 780.59 Sleep disturbances
783.6 Polyphagia
784.0 Headache
The above policy is based on the following references:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Landy HJ, Ramsay RE, Slater J, et al. Vagus nerve stimulation for complex partial
seizures: Surgical technique, safety, and efficacy. J Neurosurg. 1993;78(1):26-31.
Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. Vagus nerve stimulation for
treatment of partial seizures: A controlled study of effect on seizures. First International
Vagus Nerve Stimulation Study Group. Epilepsia. 1994;35(3):616-626.
The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus
nerve stimulation for treatment of medically intractable seizures. Neurology. 1995;45
(2):224-230.
Salinsky MC, Uthman BM, Ristanovic RK, et al. Vagus nerve stimulation for the treatment
of medically intractable seizures. Results of a 1-year open-extension trial. Vagus Nerve
Stimulation Study Group. Arch Neurol. 1996;53(11):1176-1180.
Clarke BM, Upton AR, Griffin H, et al. Seizure control after stimulation of the vagus nerve:
Clinical outcome measures. Can J Neurol Sci. 1997;24(3):222-225.
Bryant J, Stein K. Vagus nerve stimulation in epilepsy. DEC Report No. 82. Southampton,
UK: Wessex Institute for Health Research and Development, University of Southampton;
1998.
Alberta Heritage Foundation for Medical Research (AHFMR). Vagus nerve stimulation for
refractory epilepsy. Technote TN 19. Edmonton, AB: AHFMR; 1998.
George MS, Sackeim HA, Marangell LB, et al. Vagus nerve stimulation. A potential
therapy for resistant depression? Psychiatr Clin North Am. 2000;23(4):757-783.
George MS, Sackeim HA, Rush AJ, et al. Vagus nerve stimulation: A new tool for brain
research and therapy. Biol Psychiatry. 2000;47(4):287-295.
Rush AJ, George MS, Sackheim HA, et al. Vagus nerve stimulation for treatment resistant
depression: A multicenter study. Biol Psychiatry. 2000;47(4):276-286.
Rosenbaum JF, Heninger G. Vagus nerve stimulation for treatment-resistant depression.
Biol Psychiatry. 2000;47(4):273-275.
Alberta Heritage Foundation for Medical Research (AHFMR). Vagus nerve stimulation.
Emerging Technology Report. Edmonton, AB: AHFMR; 2000.
Goodnick PJ, Rush AJ, George MS, et al. Vagus nerve stimulation in depression. Expert
Opin Pharmacother. 2001;2(7):1061-1063.
Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-
resistant depression: Efficacy, side effects, and predictors of outcome.
Neuropsychopharmacology. 2001;25(5):713-728.
Sjogren MJ, Hellstrom PT, Jonsson MA, et al. Cognition-enhancing effect of vagus nerve
stimulation in patients with Alzheimer's disease: A pilot study. J Clin Psychiatry. 2002;63
(11):972-980.
Koutroumanidis M, Binnie CD, Hennessy MJ, et al. VNS in patients with previous
unsuccessful resective epilepsy surgery: Antiepileptic and psychotropic effects. Acta
Neurol Scand. 2003;107(2):117-121.
Cohen-Gadol AA, Britton JW, Wetjen NM, et al. Neurostimulation therapy for epilepsy:
Current modalities and future directions. Mayo Clin Proc. 2003;78(2):238-248.
Murphy JV, Patil A. Stimulation of the nervous system for the management of seizures:
Current and future developments. CNS Drugs. 2003;17(2):101-115.
Kosel M, Schlaepfer TE. Beyond the treatment of epilepsy: New applications of vagus
nerve stimulation in psychiatry. CNS Spectr. 2003;8(7):515-521.
Privitera MD, Welty TE, Ficker DM, Welge J. Vagus nerve stimulation for partial
seizures. Cochrane Database Syst Rev. 2002;(1):CD002896.
Vagus Nerve Stimulation Page 18 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
Corabian P, Leggett P. Vagus nerve stimulation for refractory epilepsy. Health Technology
Report. HTA 24: Series A. Edmonton, AB: Alberta Heritage Foundation for Medical
Research (AHFMR); March 2001. Available at: http://www.ahfmr.ab.ca/hta/hta-
publications/reports/vagus_nerve.pdf. Accessed June 15, 2004.
Topfer L A, Hailey D. Vagus nerve stimulation (VNS) for treatment-resistant depression.
Issues in Emerging Health Technologies. Issue 25. Ottawa, ON: Canadian Coordinating
Office for Health Technology Assessment (CCOHTA); October 2001. Available at:
http://www.ccohta.ca/. Accessed June 15, 2004.
Zamponi N, Rychlicki F, Cardinali C, et al. Intermittent vagal nerve stimulation in
paediatric patients: 1-year follow-up. Childs Nerv Syst. 2002;18(1-2):61-66.
Chapell R, Reston J, Snyder D, et al. Management of treatment-resistant epilepsy.
Volume 1: Evidence report and appendices. Volume 2: Evidence tables. Evidence
Report/Technology Assessment No. 77. Rockville, MD: Agency for Healthcare Research
and Quality (AHRQ); 2003.
Murphy JV, Torkelson R, Dowler I, et al. Vagal nerve stimulation in refractory epilepsy:
The first 100 patients receiving vagal nerve stimulation at a pediatric epilepsy center. Arch
Pediatr Adolesc Med. 2003;157(6):560-564.
Smyth MD, Tubbs RS, Bebin EM, et al. Complications of chronic vagus nerve stimulation
for epilepsy in children. J Neurosurg. 2003;99(3):500-503.
Buoni S, Mariottini A, Pieri S, et al. Vagus nerve stimulation for drug-resistant epilepsy in
children and young adults. Brain Dev. 2004;26(3):158-163.
National Institute for Clinical Excellence (NICE). Vagus nerve stimulation for refractory
epilepsy in children. Interventional Procedure Guidance 50. London, UK: NICE; March
2004. Available at: http://www.nice.org.uk. Accessed June 15, 2004.
National Institute for Clinical Excellence (NICE), Interventional Procedures Programme.
Interventional procedure overview of vagus nerve stimulation for refractory epilepsy in
children. London, UK: NICE; October 2002. Available at:
http://www.nice.org.uk/page.aspx?o=66545. Accessed June 15, 2004.
Elger G, Hoppe C, Falkai P, et al. Vagus nerve stimulation is associated with mood
improvements in epilepsy patients. Epilepsy Res. 2000;42(2-3):203-210.
Carpenter LL, Friehs GM, Price LH. Cervical vagus nerve stimulation for treatment-
resistant depression. Neurosurg Clin N Am. 2003;14(2):275-282.
National Institute for Clinical Excellence (NICE), National Collaborating Centre for Primary
Care. The epilepsies. The diagnosis and management of the epilepsies in adults and
children in primary and secondary care. Clinical Guideline 20. London, UK: NICE; October
2004.
Klein N, Sacher J, Wallner H, et al. Therapy of treatment resistant depression: Focus on
the management of TRD with atypical antipsychotics. CNS Spectr. 2004;9(11):823-832.
Husted DS, Shapira NA. A review of the treatment for refractory obsessive-compulsive
disorder: From medicine to deep brain stimulation. CNS Spectr. 2004;9(11):833-847.
Pallanti S, Hollander E, Goodman WK. A qualitative analysis of nonresponse:
Management of treatment-refractory obsessive-compulsive disorder. J Clin Psychiatry.
2004;65 Suppl 14:6-10.
Institute for Clinical Systems Improvement (ICSI). Major depression in adults for mental
health care. ICSI Health Care Guideline. Bloomington, MN: ICSI; May 2004.
Institute for Clinical Systems Improvement (ICSI). Major depression in adults in primary
care. ICSI Health Care Guideline. 10th ed. Bloomington, MN: ICSI; May 2007.
Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of
epilepsy in adults. A national clinical guideline. SIGN Publication No. 70. Edinburgh,
Scotland: SIGN; April 2003.
Nahas Z, Marangell LB, Husain MM, Two-year outcome of vagus nerve stimulation (VNS)
for treatment of major depressive episodes. J Clin Psychiatry. 2005;66(9):1097-1104.
George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve
stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry.
2005;58(5):364-373.
Vagus Nerve Stimulation Page 19 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-
resistant depression: A randomized, controlled acute phase trial. Biol Psychiatry.
2005a;58(5):347-354.
Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of vagus nerve
stimulation in treatment-resistant depression: A naturalistic study. Biol Psychiatry.
2005b;58(5):355-363.
Parrella A, Mundy L, Hiller J. VNS Therapy System for the treatment of chronic or
recurrent treatment-resistant depression in adults. Horizon Scanning Prioritising Summary
- Volume 11. Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of
National Horizon Scanning Unit (HealthPACT and MSAC); 2004.
BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Vagus
nerve stimulation for treatment-resistant depression. TEC Assessment Program. Chicago,
IL: BCBSA; August 2005; 20(8). Available at: http://www.bcbs.com/tec/vol20/20_08.html.
Accessed February 6, 2006.
Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster
headaches. Cephalalgia. 2005;25(2):82-86.
United States Senate, Committee on Finance. Review of the FDA's approval process for
the vagus nerve stimulation therapy system for treatment-resistant depression. Committee
Staff Report to the Chairman and Ranking Member. 109th Congress, 2nd Session. S. Prt.
109-45. Washington, DC: U.S. Government Printing Office; 2006. Available at:
http://finance.senate.gov/press/Gpress/02_2006%20report.pdf. Accessed June 12, 2006.
Aggressive Research Intelligence Facility (ARIF). Vagus nerve stimulation. Persistent
severe depression. Requests for Information -- Completed. Birmingham, UK: University of
Birmingham; October 2005. Available at: http://www.bham.ac.uk/arif/tvt.htm. Accessed
January 29, 2007.
California Technology Assessment Forum (CTAF). Vagus nerve stimulation for treatment
resistant depression. Technology Assessment. San Francisco, CA: CTAF; February 15,
2006. Available at: http://ctaf.org/ass/viewfull.ctaf?id=65198186099. Accessed June 6,
2006.
George MS, Nahas Z, Borckardt JJ, et al. Vagus nerve stimulation for the treatment of
depression and other neuropsychiatric disorders. Expert Rev Neurother. 2007;7(1):63-74.
Centers for Medicare & Medicaid Services (CMS). Decision memo for vagus nerve
stimulation for treatment of resistant depression (TRD) (CAG-00313R). Baltimore, MD:
CMS; May 4, 2007. Available at: http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?
id=195. Accessed May 14, 2007.
Suchman M. Approving the vagus-nerve stimulator for depression. N Engl J Med.
2007;356(16):1604-1607.
BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Vagus
nerve stimulation for treatment-resistant depression. TEC Assessment Program. Chicago,
IL: BCBSA; August 2006; 21(7). Available at:
http://www.bcbs.com/betterknowledge/tec/vols/21/21_07.html. Accessed May 14, 2007.
Pichon Riviere A, Augustovski F, Alcaraz A, et al. Vagus nerve stimulation for refractory
epilepsy [summary]. Report IRR No. 90. Buenos Aires, Argentina: Institute for Clinical
Effectiveness and Health Policy (IECS); 2006.
Diamond A, Kenney C, Jankovic J. Effect of vagal nerve stimulation in a case of Tourette's
syndrome and complex partial epilepsy. Mov Disord. 2006;21(8):1273-1275.
Ansari S, Chaudhri K, Al Moutaery KA. Vagus nerve stimulation: Indications and
limitations. Acta Neurochir Suppl. 2007;97(Pt 2):281-286.
Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety and efficacy of vagus nerve
stimulation in treatment-resistant depression. A systematic review. J Affect Disord.
2008;110(1-2):1-15.
Fitzgerald PB, Daskalakis ZJ. The use of repetitive transcranial magnetic stimulation and
vagal nerve stimulation in the treatment of depression. Curr Opin Psychiatry. 2008;21
(1):25-29.
Camilleri M, Toouli J, Herrera MF, et al. Intra-abdominal vagal blocking (VBLOC therapy):
Clinical results with a new implantable medical device. Surgery. 2008;143(6):723-731.
Vagus Nerve Stimulation Page 20 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
Schwartz PJ, De Ferrari GM, Sanzo A, et al. Long term vagal stimulation in patients with
advanced heart failure: First experience in man. Eur J Heart Fail. 2008;10(9):884-891.
Mathew NT. Dynamic optimization of chronic migraine treatment: Current and future
options. Neurology. 2009;72(Suppl 1):S14-S20.
Kennedy SH, Milev R, Giacobbe P, et al; Canadian Network for Mood and Anxiety
Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT)
Clinical guidelines for the management of major depressive disorder in adults. IV.
Neurostimulation therapies. J Affect Disord. 2009;117 Suppl 1:S44-S53.
Rosenberg O, Shoenfeld N, Kotler M, Dannon PN. Mood disorders in elderly population:
Neurostimulative treatment possibilities. Recent Pat CNS Drug Discov. 2009;4(2):149-
159.
Kraus T, Hösl K, Kiess O, et al. BOLD fMRI deactivation of limbic and temporal brain
structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J
Neural Transm. 2007;114(11):1485-1493.
Jaseja H. Vagal nerve stimulation: Exploring its efficacy and success for an improved
prognosis and quality of life in cerebral palsy patients. Clin Neurol Neurosurg. 2008;110
(8):755-762.
Dietrich S, Smith J, Scherzinger C, et al. A novel transcutaneous vagus nerve stimulation
leads to brainstem and cerebral activations measured by functional MRI. Biomed Tech
(Berl). 2008;53(3):104-111.
Xiong J, Xue FS, Liu JH, et al. Transcutaneous vagus nerve stimulation may attenuate
postoperative cognitive dysfunction in elderly patients. Med Hypotheses. 2009;73(6):938-
941.
Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation.
J Clin Neurophysiol. 2010;27(2):130-138.
Lund C, Kostov H, Blomskjøld B, Nakken KO. Efficacy and tolerability of long-term
treatment with vagus nerve stimulation in adolescents and adults with refractory epilepsy
and learning disabilities. Seizure. 2011;20(1):34-37.
Magis D, Schoenen J. Peripheral nerve stimulation in chronic cluster headache. Prog
Neurol Surg. 2011;24:126-312.
Gaynes BN, Lux L, Lloyd S, et al. Nonpharmacologic interventions for treatment-resistant
depression in adults. Comparative effectiveness review No. 33. (Prepared by RTI
International-University of North Carolina (RTI-UNC) Evidence based Practice Center
under Contract No. 290-02-0016I). AHRQ Publication No. 11-EHC056-EF. Rockville, MD:
Agency for Healthcare Research and Quality. September 2011. Available at:
http://www.effectivehealthcare.ahrq.gov/ehc/products/76/792/TRD_CER33_20111110.pdf.
Accessed January 24, 2012.
Herremans SC, Baeken C. The current perspective of neuromodulation techniques in the
treatment of alcohol addiction: A systematic review. Psychiatr Danub. 2012;24 Suppl
1:S14-S20.
Rong PJ, Fang JL, Wang LP, et al. Transcutaneous vagus nerve stimulation for the
treatment of depression: A study protocol for a double blinded randomized clinical trial.
BMC Complement Altern Med. 2012;12:255.
Martin JL, Martin-Sanchez E. Systematic review and meta-analysis of vagus nerve
stimulation in the treatment of depression: Variable results based on study designs. Eur
Psychiatry. 2012;27(3):147-155.
Hein E, Nowak M, Kiess O, et al. Auricular transcutaneous electrical nerve stimulation in
depressed patients: A randomized controlled pilot study. J Neural Transm. 2013;120
(5):821-827.
Lehtimaki J, Hyvarinen P, Ylikoski M, et al. Transcutaneous vagus nerve stimulation in
tinnitus: A pilot study. Acta Otolaryngol. 2013;133(4):378-382.
Straube A, Gaul C, Forderreuther S, et al; German Migraine and Headache Society;
German Society for Neurology; Austrian Headache Society; Swiss Headache Society.
Therapy and care of patients with chronic migraine: Expert recommendations of the
German Migraine and Headache Society/German Society for Neurology as well as the
Vagus Nerve Stimulation Page 21 of 21
http://qawww.aetna.com/cpb/medical/data/100_199/0191_draft.html 04/15/2015
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
Austrian Headache Society/Swiss Headache Society. Nervenarzt. 2012;83(12):1600-
1608.
Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: Vagus
nerve stimulation for the treatment of epilepsy: Report of the Guideline Development
Subcommittee of the American Academy of Neurology. Neurology. 2013;81(16):1453-
1459.
McClelland J, Bozhilova N, Campbell I, Schmidt U. A systematic review of the effects of
neuromodulation on eating and body weight: Evidence from human and animal studies.
Eur Eat Disord Rev. 2013;21(6):436-455.
Elliott RE, Morsi A, Kalhorn SP, et al. Vagus nerve stimulation in 436 consecutive patients
with treatment-resistant epilepsy: Long-term outcomes and predictors of response.
Epilepsy Behav. 2011a;20(1):57-63.
Elliott RE, Rodgers SD, Bassani L, et al. Vagus nerve stimulation for children with
treatment-resistant epilepsy: A consecutive series of 141 cases. J Neurosurg Pediatr.
2011b;7(5):491-500.
Karceski S, Schachter SC. Vagus nerve stimulation therapy for the treatment of epilepsy.
UpToDate Inc., Waltham, MA. Last reviewed October 2014.
Huang F, Dong J, Kong J, et al. Effect of transcutaneous auricular vagus nerve stimulation
on impaired glucose tolerance: A pilot randomized study. BMC Complement Altern Med.
2014;14:203.
Cai PY, Bodhit A, Derequito R, et al. Vagus nerve stimulation in ischemic stroke: Old wine
in a new bottle. Front Neurol. 2014;5:107.
Hall S, Kumaria A, Belli A. The role of vagus nerve overactivity in the increased incidence
of pneumonia following traumatic brain injury. Br J Neurosurg. 2014;28(2):181-186.
Zhou L, Lin J, Lin J, et al. Neuroprotective effects of vagus nerve stimulation on traumatic
brain injury. Neural Regen Res. 2014;9(17):1585-1591.
Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014;1(2):64-73.
Kreuzer PM, Landgrebe M, Resch M, et al. Feasibility, safety and efficacy of
transcutaneous vagus nerve stimulation in chronic tinnitus: An open pilot study. Brain
Stimul. 2014;7(5):740-747.
Premchand RK, Sharma K, Mittal S, et al. Autonomic regulation therapy via left or right
cervical vagus nerve stimulation in patients with chronic heart failure: Results of the
ANTHEM-HF Trial. J Card Fail. 2014;20(11):808-816.
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in
private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for
medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
CPT only copyright 2008 American Medical Association. All Rights Reserved.