Medical Policy


Subject:  Vagus Nerve Stimulation
Policy #:  SURG.00007Current Effective Date:  10/14/2014
Status:RevisedLast Review Date:  08/14/2014

Description/Scope

This document addresses the indications for use of an implantable vagus nerve stimulation (VNS) device, the electronic analysis of the implanted neurostimulator pulse generator system, and non-implantable (transcutaneous) VNS devices for the treatment of medically and surgically refractory seizures associated with intractable epilepsy and as a treatment of other conditions.

Position Statement

Medically Necessary:

Implantation of a vagus nerve stimulation device is considered medically necessary in an individual with medically and surgically refractory seizures as evidenced by:

Electronic analysis of an implanted neurostimulator pulse generator system for vagus nerve stimulation is considered medically necessary when the implantation occurred because the above criteria were met.

Investigational and Not Medically Necessary:

Implantation of a vagus nerve stimulation device is considered investigational and not medically necessary as a treatment for all other conditions not listed as medically necessary, including, but not limited to:

Electronic analysis of an implanted neurostimulator pulse generator system for vagus nerve stimulation is considered investigational and not medically necessary when the medically necessary criteria for device implantation are not met.

Non-implantable vagus nerve stimulation devices are considered investigational and not medically necessary for all indications.

Rationale

Implantable VNS as Treatment of Medically and Surgically Refractory Seizures

In 1997, the U.S. Food and Drug Administration (FDA) approved a VNS device called the NeuroCybernetic Prosthesis (NCP®) system through the premarket approval (PMA) process. The device was approved 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." In April 1999, the Centers for Medicare and Medicaid Services (CMS) issued a national coverage determination (NCD 160.18) for implantable VNS as an effective treatment for medically refractory partial onset seizures when surgery is not recommended or has failed.

Published evidence from well-designed multimember trials with long-term follow-up demonstrates the use of VNS as an adjunct to optimal use of antiepileptic drugs in the treatment of medically refractory individuals with at least six partial onset seizures per month reduces seizure frequency by approximately 25% after three months of treatment (Morris, 1999; Murphy, 1999). In individuals who achieve an initial reduction in seizure frequency, the beneficial treatment effect appears to be maintained and may increase with time. Appropriate candidate selection for implantable VNS is based on the presence of seizures that are refractory to medical therapy, either in terms of persistence of seizures, or due to intolerable side effects of drug therapy, and not on the number of seizures alone (Fisher, 1999).

The long-term efficacy and safety of VNS therapy in children with medically refractory seizures, including those with Lennox-Gastaut Syndrome (LGS), has been reported in numerous retrospective case series, multicenter and observational studies, and randomized controlled trials (Alexopoulos, 2006; Benifla, 2006; De Herdt, 2007; Elliott, 2011c; Healy, 2013; Klinkenberg, 2012; Kostov, 2009; Tecoma, 2006; You, 2007; You, 2008). Additional retrospective case series measuring the long term effects of VNS for medically and surgically refractory seizures in adults and the pediatric population have been published in the peer-reviewed medical literature. Significant reductions in seizure frequency with possible cumulative effect are reported along with a reduction in surgical complications and untoward side effects with chronic VNS therapy (Coykendall, 2010; Elliott, 2011a; Elliott, 2011b; Ghaemi, 2010; Kabir, 2009; Siddiqui, 2010; Vale, 2011). Englot and colleagues (2011) performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 participants with intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS implantation, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after greater than 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the individuals, and VNS predicted a ≥ 50% reduction in seizures (main effects, odds ratio of 1.83; 95% confidence interval 1.80-1.86). Individuals with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. The authors concluded that VNS is an effective and relatively safe adjunctive therapy in individuals with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that approximately 25% of individuals do not receive any benefit from therapy.

In 2013, the American Academy of Neurology (AAN) (Morris, 2013) released an updated guideline evaluating the evidence regarding the efficacy and safety of VNS for epilepsy. The guidelines states that VNS may be considered for seizures (both partial and generalized) in children, for LGS [Lennox-Gastaut-syndrome]-associated seizures. VNS may also improve mood when used in the treatment of adults with epilepsy although this should be considered a secondary reason for VNS.

Implantable VNS as Treatment of Refractory Depression

In July 2005, Cyberonics, Inc. (Houston, TX, USA) received FDA premarket approval for the VNS TherapySystem "…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 episode and have not had an adequate response to four or more adequate antidepressant treatments." The data presented to the FDA consisted of a case series of 60 individuals receiving VNS (Study D-01), a short-term (3-month) randomized sham-controlled clinical trial of 221 individuals (Study D-02), and an observational study comparing 205 individuals on VNS therapy to 124 individuals receiving ongoing treatment for depression (Study D-04) (George, 2005; Rush, 2000). Individuals who responded to sham treatment in the short-term randomized, controlled trial (approximately 10%) were excluded from the long-term observational study.

The primary efficacy outcome was the relief of depression symptoms, assessed by any one of many different depression symptom rating scales. A 50% reduction from baseline score was considered to be a reasonable measure of treatment response. In the studies evaluating VNS therapy, the four most common instruments used were the Hamilton Rating Scale for Depression (HAMD), Clinical Global Impression, Montgomery and Åsberg Depression Rating Scale (MADRS), and the Inventory of Depressive Symptomatology Self-Related (IDS-SR). The case series data reported rates of improvement, as measured by a 50% improvement in depression score of 31% at 10 weeks to greater than 40% at 1 to 2 years. This appeared to stabilize out to 2 years, but there were substantial losses to follow-up (n=42 at 2 years vs. original sample of 59) (Marangell, 2002; Rush, 2000; Sackeim, 2001). Natural history, placebo effects, and the expectations of the individual and their medical practitioner make it difficult to infer efficacy from this case series data.

The D-02 randomized trial (Rush, 2000; Rush, 2005a) compared VNS therapy to a sham control, (implanted but inactivated VNS), reporting a non-statistically significant result for the principal outcome at 3 months. A total of 15% of VNS subjects responded versus 10% of control subjects (p=0.31). The IDS-SR was considered a secondary outcome, showing a difference that was statistically significant in favor of VNS (17.4% vs. 7.5%, p=0.04). All other outcomes assessed in the trial did not show statistically significant differences between groups.

The observational study comparing subjects participating in the randomized clinical trial and a separately recruited control group (D-04 vs. D-02) evaluated VNS therapy out to 1 year, showing a statistically significant difference in the rate of change of depression score (p<0.001) (George 2005; Rush, 2000). This study was conceived after the results of the randomized clinical trial were known. The outcomes of this study, however, may have been confounded by issues such as unmeasured differences between subjects, nonconcurrent controls, differences in sites of care between subjects with VNS therapy and controls, and differences with regard to concomitant therapy changes. Analyses performed on subsets of subjects cared for in the same sites and censoring observations after treatment changes, generally showed diminished differences in apparent treatment effectiveness of VNS with almost no statistically significant differences. Considering these concerns about the quality of the observational data, these results lack strong evidence to support the effectiveness of VNS therapy as a treatment for refractory depression.

Nahas and colleagues (2005) evaluated the safety and effectiveness of VNS in an acute phase pilot study of 59 individuals with treatment-resistant major depressive episode (MDE). They examined the effects of adjunctive VNS over 24 months in this adult population. Adults treated in the outpatient setting 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 ≥ 50% reduction from the baseline 28-item Hamilton Rating Scale for Depression (HAMD-28) total score, and remission was defined as a HAMD-28 score ≤ 10. Based on last observation carried forward analyses, HAMD-28 response rates were 31% (18 of 59) after 3 months, 44% (26 of 59) after 1 year, and 42% (25 of 59) after 2 years of adjunctive VNS. Remission rates were 15% (9 of 59) at 3 months, 27% (16 of 59) at 1 year, and 22% (13 of 59) at 2 years. By 2 years, 2 deaths (unrelated to VNS) had occurred, 4 participants had withdrawn from the study, and 81% (48 of 59) were still receiving VNS. Longer-term VNS was generally well tolerated, however, at 24 months; the accumulated serious adverse events affected 42% of the participants. The investigators concluded that their findings suggest that individuals with chronic or recurrent, treatment-resistant MDE may show long-term benefit when treated with VNS. However, the number of responders and the degree of their improvement fluctuated over the 2 year study. Since there was no control group, it is difficult to determine if this was due to the VNS or the natural course of chronic depression. There was no information on whether any subjects failed to respond to either electroconvulsive therapy (ECT) or details about antidepressant augmentation strategies utilized prior to being accepted into this study.

An open-label, uncontrolled, unblinded, industry-sponsored study of VNS therapy, in addition to concomitant treatment with antidepressant medications (stable for 4 weeks prior to study entry, during the recovery period and the acute study phase), enrolled individuals with treatment-resistant depression (TRD) or bipolar I or II disorder at 9 European sites (D03) (Schlaepfer, 2008). The study protocol was similar to the D01 study conducted in the Unite States, except that: (1) the study inclusion required a score ≥ 20 on the HAMD-24 scale in the D03 study, as opposed to ≥ 20 on the HAMD-28 scale in the D01 study, (2) the maximum age at entry was 80 in the D03 study and 70 in the D01 study, and (3) the number of failed adequate medication trials was ≥ 2 but < 6 in the D03 study versus ≥ 2 in the D01 study. During the long-term follow-up period, adjustments in stimulation parameters and medications were permitted. Of the 74 participants implanted with the device, 4 withdrew during the acute study period. Seven participants dropped out during the first-year long-term study period, 5 participants due to adverse events or lack of efficacy, and 2 participants committed suicide. Primary outcomes were reported as a reduction in the severity of depression as measured by the HAMD-24, but HAMD-28 was assessed and used for comparison of results to the D01 study. The baseline HAMD-28 score averaged 34. After 3 months of VNS, response rates (≥50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1-year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of participants met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). Comparing results of this study to the D01 study results, the investigators reported a decrease in severity of depression after 3-, 6-, 9-, and 12-months compared to baseline HAMD-28 score, reaching significance in both samples over time, with higher efficacy in the D03 study compared to the D01 study. This was attributed to the lower measures of baseline depression in the D01 study. The investigators, however, reported "a major shortcoming" of this study, as in the United States D01 study, was that effectiveness was not assessed in a sham controlled design, "limiting interpretations on clinical utility." In addition, the authors suggest in future trials of VNS for depression, "it might therefore be valuable to study the specific characteristics of personality of a patient population with treatment resistance interested in this procedure (VNS) to judge whether personality features contribute differentially to treatment effects" (Schlaepfer, 2008).

Bajbouj and colleagues (2010) reported 2-year follow-up data on individuals with TRD in a small open label, longitudinal cohort study. The results indicated that 53.1% (26 of 49) of individuals met the treatment response criteria (≥50% reduction in the HAMD-28 scores from baseline) and 38.9% (19 of 49) fulfilled the remission criteria (HAMD-28 scores ≤10) while on VNS. These results are limited in demonstrating improved health outcomes due to the small study population and lack of a comparison group. Cristancho and colleagues (2011) followed participants with major depressive disorder (n=10) and with bipolar disorder (n=5) at 6 and 12 months post-VNS implantation. At the 12 month follow-up, 4 of 15 participants responded and 1 of 15 participants remitted according to the principal response criteria. These outcomes are comparable to those observed in previous VNS efficacy studies and with a similar side effect profile, however, the small sample size, lack of a comparison group, and short-term outcome measurements limit this study in drawing conclusions concerning the net health benefit of VNS for this group of individuals.

In a multicenter double-blind study, Aaronson and colleagues (2013) compared the safety and effectiveness of different stimulation levels of VNS therapy as adjuvant treatment in 331 individuals with a history of chronic or recurrent bipolar disorder or a current episode of major depressive disorder. The intent of the trial was to show that "high" and "medium" electrical "doses" (charge) would produce superior clinical outcomes relative to a "low" electrical dose. Participants with a history of failure to respond to at least 4 adequate dose/duration antidepressant treatment trials from at least 2 different treatment categories were randomized to 1 of 3 dose groups. After 22 weeks, the current stimulation 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 treatment groups in comparison of the primary outcome measure, a change in IDS-Clinician Administered (IDS-C) score from baseline. The mean IDS-C score improved significantly for each of the groups from baseline to 22-week follow-up. At 50 weeks of follow-up, the proportion of the small number of 22 week responders with a durable outcome was greater in the "high" and "medium" electrical "dose" groups than in the "low" dose group. Most participants 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%. Limitations of this study include the interpretation of improvement in IDS-C scores over time due to the lack of a controlled (no treatment) comparator group and, that approximately 20% of the participants had a history of bipolar disorder. Therefore, the results may not be representative of a homogeneous group of individuals with treatment-resistant unipolar depression. 

In April 1999, CMS determined that implantable VNS was not medically reasonable and necessary for TRD. On July 15, 2005, the FDA granted premarket approval to Cyberonics, Inc. for their VNS Therapy System for the adjunctive long-term treatment of chronic or recurrent depression for individuals 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to 4 or more antidepressant treatments. CMS subsequently initiated a national coverage analysis (NCA) to reconsider resistant depression as an additional indication for implantable VNS (CMS, 2007). After a review of the evidence, CMS concluded in a national non-coverage determination (effective May 4, 2007) that VNS is not reasonable and necessary for individuals with TRD.

A guideline statement from the Canadian Network for Mood and Anxiety Treatments includes a review of the literature on VNS for depression, concluding that there is a lack of substantive evidence for short-term and long-term efficacy in acute severe depression, and that the appropriate place of VNS remains to be determined (Kennedy, 2009).

An American Psychiatric Association (APA) workgroup's third edition of the Practice Guideline for the Treatment of Patients with Major Depressive Disorder states:

Vagus nerve stimulation is approved for use in patients with treatment-resistant depression on the basis of its potential benefit with long-term treatment. There is no indication for the use of VNS in acute phase treatment of depression, as data showed no evidence for acute efficacy (Rush, 2005a; Sackeim, 2001).

For individuals "whose symptoms have not responded adequately to medication, ECT remains the most effective form of therapy and should be considered." However, for those individuals with TRD, "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" (Level of Clinical Confidence III: May be recommended on the basis of individual circumstance) (Gelenberg, 2010).

An Agency for Healthcare Research and Quality's (AHRQ) comparative effectiveness review (Gaynes, 2011) summarized the evidence concerning the effectiveness of 4 treatments in the clinical management of TRD, including ECT, repetitive transcranial magnetic stimulation (rTMS), VNS, and cognitive behavioral therapy (CBT) or interpersonal psychotherapy (IPT). The following is a summary of the findings on the efficacy and safety of VNS for adult TRD:

The review concluded that many clinical questions about efficacy and effectiveness remain unanswered. Comparative clinical research on nonpharmacologic interventions in a TRD population is in its infancy. Comparison of any of the potential interventions in the treatment of TRD, nonpharmacologic or otherwise, is hampered by variable definitions of TRD, heterogeneity of study participants, and lack of clinically meaningful interpretation of pertinent outcome measures as relevant studies did not assess both response and remission rates.

The available evidence in the peer-reviewed medical literature is insufficient to permit conclusions regarding the long-term effect of VNS therapy on improving health outcomes, or its effect compared with alternative therapies for TRD. Additional randomized controlled trials are needed to address the complex and unresolved issues of dose, sham control, participant blinding, and length of treatment phase to demonstrate the efficacy of VNS for TRD.

Implantable VNS as Treatment of Other Conditions

De Ferrari and colleagues (2011) conducted an open-label, phase II trial of VNS therapy utilizing the CardioFit® device (BioControl Medical, Yehud, Israel - New Hope, Minnesota) in 32 individuals with New York Heart Association (NYHA) class II-IV chronic heart failure. Improvements were reported in measures of quality of life, six-minute walk test, and left ventricular ejection fraction (from 22±7 to 29±8%, p=0.003). An international multicenter randomized clinical trial (INOVATE-HF) assessing the safety and efficacy of the CardioFit System in symptomatic individuals with heart failure is currently recruiting participants (Hauptman, 2012). To date, the CardioFit device has not received FDA clearance for VNS therapy or any other indication.

Numerous small case series and retrospective studies of short duration have investigated implantable VNS therapy as treatment for essential tremor (Handforth, 2003), enhancing cognitive deficits in Alzheimer's disease (Merrill, 2006), anxiety disorders (George, 2008), and bulimia. Other studies explore the potential use of VNS in the treatment of autism (Danielsson, 2008), addictions, coma, fibromylagia (Lange, 2011), food cravings in individuals with chronic TRD (Bordenlos, 2007), morbid/resistant obesity (Camilleri, 2008; Sarr, 2012), sleep disorders (such as narcolepsy), memory and learning deficits (Ansari, 2007), and severe refractory cluster or migraine headaches (Cecchini, 2009; Mauskop, 2005). A search of the clinicaltrials.gov database identified studies in various phases investigating the effects of implantable VNS on conditions including, but not limited to, cluster headaches, Crohn's disease, myocardial function in heart failure, enteroendocrine secretion and glucose metabolism in Type 2 diabetes-related obesity, rheumatoid arthritis, and recovery from minimally conscious or persistently vegetative states after traumatic brain injury (Shi, 2013) (U.S. National Institutes of Health, 2014). To date, the FDA has not cleared the use of any type of implantable VNS device for these indications. Well-designed, randomized clinical trials with larger sample populations are needed to demonstrate the safety and efficacy of VNS therapy as a treatment for any of these conditions.

Non Implantable VNS

The safety and effectiveness of non-implantable, transcutaneous VNS (t-VNS) therapy is being investigated for the treatment of individuals with chronic, drug-resistant epilepsy and other conditions. He and colleagues (2013) conducted a small pilot study of 14 children with intractable epilepsy using an auricular t-VNS device for 24 weeks as an adjunct to their current medication regimen. The mean reduction in seizure frequency from baseline through week 8, weeks 9 through 16, and weeks 17 through 24 was 31.8%, 54.13%, and 54.2%, respectively. The investigators found no correlation between the therapeutic efficacy of t-VNS and baseline seizure frequency reduction. In addition, age, gender, nor seizure syndrome predicted t-VNS response. In terms of reported side effects, t-VNS was well tolerated and only two participants reported mild ulceration of the skin at the stimulation area. Limitations of this study include the small sample size and lack of a control group. Stefan and colleagues (2012) evaluated t-VNS therapy in a small case series of 10 adults with drug-resistant epilepsy. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered 3 times per day for 9 months. Subjective documentation of stimulation effects was obtained from self-reported seizure diaries. An assessment of seizure frequency was evaluated with prolonged outpatient video electroencephalography (EEG) monitoring. Other evaluations included computerized testing of cognitive, affective, and emotional functions. Three participants withdrew from the study with 5 of the remaining 7 participants reporting an overall reduction of seizure frequency after 9 months of t-VNS. A major discrepancy was noted, however, between subjective reports of seizure activity and quantified video-EEG in 2 participants. One participant reported a 37% reduction of seizure frequency (baseline: 21 seizures per week; average of months 7 to 9: 13.3 seizures per week) but an increase in seizures was recorded during outpatient video-EEG monitoring. A second participant reported a significant increase in simple partial seizures with subjective signs (baseline: 1.6 seizures per week; average of months 7 to 9: 4.2 per week), but no changes were seen on EEG recording. Non-implantable t-VNS was well-tolerated with side effects limited to hoarseness, headache or obstipation. Limitations of this study include the small sample size and lack of a randomized control group.

Other studies evaluating the effect of t-VNS include a small pilot trial combining t-VNS with sound therapy to reduce the severity of tinnitus and tinnitus-associated distress (n=10; Lehtimäki, 2013) and a small, randomized crossover study (n=48; Busch, 2013) investigating whether t-VNS may have the potential to alter pain perception and sensitivity during sustained application of painful heat. A search of the ClinicalTrials.gov database has identified trials in various phases evaluating non-implantable t-VNA for the treatment of tinnitus, pain perception in pain syndromes, schizophrenia, and evaluation of anti-inflammatory markers in individuals with juvenile idiopathic arthritis.

To date, the FDA has not granted 501(k) clearance or PMA to any non-implantable t-VNA device for any indication. Cerbomed GmbH (Erlangen, Germany) has developed a t-VNS® System with NEMOS® that received European clearance (CE mark) in 2011 for treatment of drug-resistant epilepsy. Another noninvasive VNS device called the gammaCore® (ElectroCore, LLC, Basking Ridge, NJ) is currently being investigated for the treatment of cluster/migraine headaches, severe gastroparesis, and other conditions. The gammaCore is currently unavailable for commercial distribution in the United States and has not received FDA 510(k) clearance or PMA for any indication.

Background/Overview

Description of the Conditions

The Centers for Disease Control and Prevention (CDC, 2014) estimates that about 2.3 million adults and 467,711 children (0-17 years of age) in the United States have epilepsy. Nearly 150,000 Americans develop the condition each year. New cases of epilepsy are most common among children and older adults. According to the National Institute of Neurological Disorders and Stroke (NINDS, 2014) about 70% of individuals diagnosed with epilepsy experience seizures that can be controlled with medication and surgical techniques. The American Association of Neurological Surgeons (AANS, 2013) currently classifies seizures into two basic categories: primary generalized seizures and focal seizures (previously referred to as partial seizures). Classifying the type of seizure is important in the selection of appropriate antiepileptic drug treatment. Despite advances in the medical and surgical treatment of epilepsy, 25% to 50% of individuals with epilepsy experience breakthrough seizures or suffer from debilitating adverse effects of antiepileptic drugs.

Depression is a common and debilitating illness affecting nearly 1 in 10 adults in the United States each year, and nearly twice as many women as men. Depression is characterized by changes in mood, self-attitude, cognitive functioning, sleep, appetite, and energy level. Depression may occur at any time, but on average, first appears during the late teens to mid-20s. Depression is also common in older adults (APA, 2014).

Implantable VNS

An implantable VNS device is similar to a cardiac pacemaker and includes a generator device surgically placed under the skin in the left chest area, typically below the collarbone. A nerve stimulation electrode is tunneled under the skin to the lower neck where it is placed around the left cervical vagus nerve. Using an external programmer the stimulation parameters of the device are set (or reset) to deliver preprogrammed intermittent electrical pulses to the vagus nerve, which then transmits the stimulation to the brain to create widespread antiepileptic effects. Additionally, an individual can activate the system when sensing the onset of a seizure to deliver an additional dose of stimulation by passing a magnet over the area of the chest where the device is implanted. The device is powered by a lithium thionyl chloride battery that must be replaced every 1.5-5 years depending on the stimulation parameters. Reports of adverse effects of VNS therapy have included voice alteration, headache, neck pain, and cough.

Non-Implantable VNS

A non-implantable VNS device (also referred to as transcutaneous VNS [t-VNS] or n-VNS) requires no surgical procedure and uses a combined stimulation unit and ear electrode to stimulate the auricular branch of the vagus nerve via skin over the concha of the ear. Device users self-administer electric stimulation for several hours a day per parameters agreed upon by the prescribing physician. Side effects of t-VNS are similar to those reported with an implantable VNS device, in addition to local skin irritation at the site of application.

Definitions

Focal seizure: A seizure that begins with an electrical discharge in a relatively small area (called the focus) of the brain; previously referred to as a partial or localization-related seizure. In most cases, the cause is unknown, but may be related to a brain infection, head injury, stroke, or a brain tumor.

Medically refractory seizures: Seizures that occur despite treatment with therapeutic levels of antiepileptic drugs or seizures that cannot be treated with therapeutic levels of antiepileptic drugs because of intolerable adverse side effects.

Refractory depression: A major depressive disorder that fails to demonstrate an adequate response to an adequate treatment trial of antidepressant medications (i.e. sufficient intensity of treatment for sufficient duration); also referred to as treatment-resistant depression (TRD). Potential factors contributing to apparent non-response include trial adequacy, individual compliance, differential diagnosis, and treatable comorbid conditions.

Vagus nerve: A nerve that controls both motor and sensory functions of the gastrointestinal tract, heart and larynx; also referred to as the 10th cranial nerve.

Coding

The following codes for treatments and procedures applicable to this document 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 policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services may be Medically Necessary when specified as vagus nerve stimulator and criteria are met:

CPT 
61885Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array
64553Percutaneous implantation of neurostimulator electrode array; cranial nerve
64568Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator
64569Revision or replacement of cranial nerve (eg, vagus nerve) neurostimulator electrode array, including connection to existing pulse generator
95974-95975Electronic analysis of implanted neurostimulator pulse generator system; complex cranial nerve neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming, with or without nerve interface testing
  
HCPCS 
C1767Generator, neurostimulator (implantable), nonrechargeable
L8679Implantable neurostimulator, pulse generator, any type
L8680Implantable neurostimulator electrode, each
L8685Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686Implantable neurostimulator pulse generator, single array, nonrechargeable, includes extension
  
ICD-9 Procedure[For dates of service prior to 10/01/2015]
04.92Implantation or replacement of peripheral neurostimulator
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2015]
345.00-345.91Epilepsy
  
ICD-10 Procedure[For dates of service on or after 10/01/2015]
00HE0MZInsertion of neurostimulator lead into cranial nerve, open approach
00HE3MZInsertion of neurostimulator lead into cranial nerve, percutaneous approach
00HE4MZInsertion of neurostimulator lead into cranial nerve, percutaneous endoscopic approach
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2015]
G40.001-G40.919Epilepsy and recurrent seizures

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when specified as vagus nerve stimulator when criteria are not met or for all other diagnoses (including but not limited to those listed below), or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

ICD-9 Diagnosis[For dates of service prior to 10/01/2015]
 All other diagnoses, including, but not limited to:
278.00-278.03Overweight and obesity
296.00-296.99Episodic mood disorders
298.0Depressive type psychosis
299.00-299.01Autistic disorder
307.51Bulimia nervosa
327.00-327.8Organic sleep disorders
331.0Alzheimer's disease
333.1Essential and other specified forms of tremor
339.00-339.02Cluster headaches
343.0-343.9Infantile cerebral palsy
346.00-346.93Migraine
347.00-347.11Cataplexy and narcolepsy
428.0-428.9Heart failure
783.6Polyphagia
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2015]
 All other diagnoses, including, but not limited to:
E66.01-E66.9Overweight and obesity
F30.10-F39Mood (affective) disorders
F50.2Bulimia nervosa
F84.0Autistic disorder
G25.0-G25.2Essential and other specified forms of tremor
G30.0-G30.9Alzheimer's disease
G43.001-G43.919Migraine
G43.A0-G43.D1Migraine
G44.001-G44.029Cluster headaches
G47.00-G47.9Organic sleep disorders
G80.0-G80.9Cerebral palsy
I50.1-I50.9Heart failure
R63.2Polyphagia

When services are also Investigational and Not Medically Necessary:

CPT 
0312TVagus 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
0313TVagus nerve blocking therapy (morbid obesity); laparoscopic revision or replacement of vagal trunk neurostimulator electrode array, including connection to existing pulse generator
0314TVagus nerve blocking therapy (morbid obesity); laparoscopic removal of vagal trunk neurostimulator electrode array and pulse generator
0315TVagus nerve blocking therapy (morbid obesity); removal of pulse generator
0316TVagus nerve blocking therapy (morbid obesity); replacement of pulse generator
0317TVagus nerve blocking therapy (morbid obesity); neurostimulator pulse generator electronic analysis, includes reprogramming when performed
  
HCPCS 
E1399Durable medical equipment, miscellaneous [when specified as a transcutaneous (non-implantable) VNS device]
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2015]
 All diagnoses
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2015]
 All diagnoses
  
References

Peer Reviewed Publications:

  1. Aaronson ST, Carpenter LL, Conway CR, et al. Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects. Brain Stimul. 2013; 6(4):631-640.
  2. Alexopoulos AV, Kotagal P, Loddenkemper T, et al. Long-term results with vagus nerve stimulation in children with pharmacoresistant epilepsy. Seizure. 2006; 15(7):491-503.
  3. Ansari S, Chaudhri K, Al Moutaery K. Vagus nerve stimulation: indications and limitations. Acta Neurochir Supp. 2007; 97(2):281-286.
  4. Bajbouj M, Merkl A, Schlaepfer TE, et al. Two-year outcome of vagus nerve stimulation in treatment-resistant depression. J Clin Psychopharmacol. 2010; 30(3):273-281.
  5. Benifla M, Rutka JT, Logan W, Donner EJ. Vagal nerve stimulation for refractory epilepsy in children: indications and experience at The Hospital for Sick Children. Childs Nerv Syst. 2006; 22(8):1018-1026.
  6. Bodenlos JS, Kose S, Borckardt JJ, et al. Vagus nerve stimulation acutely alters food craving in adults with depression. Appetite. 2007; 48(2):145-153.
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  13. De Ferrari GM, Crijns HJ, Borggrefe M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011; 32(7):847-855.
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  16. 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. 2011b; 20(1):57-63.
  17. 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. 2011c; 7(5):491-450.
  18. Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. J Neurosurg. 2011; 115(6):1248-1255.
  19. George MS, Nahas Z, Borckardt JJ, et al. Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders. Expert Rev Neurotherapeutics. 2007; 7(1):63-74.
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  21. Ghaemi K, Elsharkawy AE, Schulz R, et al. Vagus nerve stimulation: outcome and predictors of seizure freedom in long-term follow-up. Seizure. 2010; 19(5):264-268.
  22. Handforth A, Ondo WG, Tatter S, et al. Vagus nerve stimulation for essential tremor: a pilot efficacy and safety trial. Neurology. 2003; 61(10):1401-1405.
  23. Hauptman PJ, Schwartz PJ, Gold MR, et al. Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J. 2012; 163(6):954-962.
  24. He W, Jing X, Wang X, et al. Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial. Epilepsy Behav. 2013; 28(3):343-346.
  25. Healy S, Lang J, Te Water Naude J, et al. Vagal nerve stimulation in children under 12 years old with medically intractable epilepsy. Childs Nerv Syst. 2013; 29(11):2095-2099.
  26. 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.
  27. Kabir SM, Rajaraman C, Rittey C, et al. Vagus nerve stimulation in children with intractable epilepsy: indications, complications and outcome. Childs Nerv Syst. 2009; 25(9):1097-1100.
  28. Klinkenberg S, Aalbers MW, Vles JS, et al. Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. Dev Med Child Neurol. 2012; 54(9):855-861.
  29. Kostov K, Kostov H, Taubøll E. Long-term vagus nerve stimulation in the treatment of Lennox-Gastaut syndrome. Epilepsy Behav. 2009; 16(2):321-324.
  30. Kostov H, Larsson PG, Roste GK. Is vagus nerve stimulation a treatment option for patients with drug-resistant idiopathic generalized epilepsy? Acta Neurol Scand Suppl. 2007; 187:55-58.
  31. Lange G, Janal MN, Maniker A, et al. Safety and efficacy of vagus nerve stimulation in fibromyalgia: a phase I/II proof of concept trial. Pain Med. 2011; 12(9):1406-1413.
  32. Lehtimäki J, Hyvärinen P, Ylikoski M, et al. Transcutaneous vagus nerve stimulation in tinnitus: a pilot study. Acta Otolaryngol. 2013; 133(4):378-382.
  33. Marangell LB, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for major depressive episodes: one-year outcomes. Biol Psychiatry. 2002; 51(4):280-287.
  34. Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalgia. 2005; 25(2):82-86.
  35. Merrill CA, Jonsson MAG, Minthon L, et al. Vagus nerve stimulation in patients with Alzheimer's disease: additional follow-up results of a pilot study through one year. J Clin Psychiatry. 2006; 67(1):1171-1178.
  36. Morris GL, Meuller WM. Long term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology. 1999; 53(8):1731-1735.
  37. Murphy JV. Left vagal nerve stimulation in children with medically refractory epilepsy. J Pediat. 1999; (5)134:563-566.
  38. Nahas Z, Marangell LB, Hussain MM, et al. Two year outcome of VNS for treatment of major depressive episodes. J Clin Psychiatry. 2005; 66(9):1097-1104.
  39. Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: a multicenter study. Biol Psychiatry. 2000; 47(4):276-286.
  40. 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.
  41. 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.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Blue Cross Blue Shield Association Technology Evaluation Center. Vagus nerve stimulation for the treatment of resistant depression. August, 2006. TEC Bulletin, 2006: 21(7).
  2. Centers for Medicare and Medicaid Services (CMS). National Coverage Determinations. Vagus nerve stimulation. NCD #160.18. Effective May 4, 2007. Available at: http://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=160.18&ncd_version=2&basket=ncd%3A160%2E18%3A2%3AVagus+Nerve+Stimulation+for+Treatment+of+Seizures. Accessed on June 27, 2014.
  3. Fisher RS, Handforth A. Reassessment: vagus nerve stimulation for epilepsy. A Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1999; 53:666-669.
  4. Gaynes BN, Lux L, Lloyd S, et al. Nonpharmacologic interventions for treatment-resistant depression in adults [Internet]. 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 on June 27, 2014.
  5. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Work Group on Major Depressive Disorder. American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. 3rd Edition. Am J Psychiatry. 2010; 167(10S).
  6. Kennedy SH, Milev R, Giacobbe P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults: IV. Neurostimation therapies. J Affect Disord. 2009; 117 Suppl 1:S44-53.
  7. Morris GL III, 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.
  8. National Institute for Clinical Excellence (NICE). VNS for refractory epilepsy in children. March 16, 2004. Available at: http://www.nice.org.uk/Guidance/IPG50/Guidance/pdf/English. Accessed on June 27, 2014.
  9. U.S. Food and Drug Administration (FDA). Summary of Safety and Effectiveness Data. Stimulator, vagus nerve. Available at: http://www.fda.gov/ohrms/dockets/dockets/05m0283/05m-0283-aav0001-03-SSED-vol1.pdf. Accessed on June 27, 2014.
  10. U.S. National Institutes of Health (NIH). Clinical trials: vagus nerve stimulation. Available at: http://www.clinicaltrials.gov. Accessed on June 27, 2014.
Websites for Additional Information
  1. American Academy of Neurology (AAN). Available at: http://www.aan.com/. Accessed on June 27, 2014.
  2. American Association of Neurological Surgeons (AANS). Available at: http://www.aans.org/. Accessed on June 27, 2014.
  3. American Psychiatric Association (APA). Available at: http://www.psychiatry.org/mental-health/depression. Accessed on June 27, 2014.
  4. Centers for Disease Control and Prevention (CDC. Diseases and conditions. Available at: http://www.cdc.gov/DiseasesConditions/. Accessed on June 27, 2014.
  5. Epilepsy Foundation. Available at: http://www.epilepsyfoundation.org/. Accessed on June 27, 2014.
  6. National Institute of Neurological Disorders and Stroke (NINDS). Disorder index. NINDS information pages. Available at: http://www.ninds.nih.gov/disorders/disorder_index.htm. Accessed on June 27, 2014.
    • Epilepsy. Updated April 28, 2014.
    • Lennox-Gastaut Syndrome. Updated April 16, 2014.
Index

CardioFit
gammaCore
t-VNS System with NEMOS
VBLOC® Vagal Blocking Therapy
VNS Therapy

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
StatusDateAction
Revised08/14/2014Medical Policy & Technology Assessment Committee (MPTAC) review. Expanded scope of document, adding a separate investigational and not medically necessary statement for non-implantable VNS for all behavioral health and medical indications. Clarified investigational and not medically necessary statement for implantable VNS. Updated Description, Rationale, Background, Coding, References, Websites for Additional Information, and Index sections.
Revised08/08/2014Behavioral Health Subcommittee review. Expanded scope of document, adding a separate investigational and not medically necessary statement for non-implantable VNS for all behavioral health and medical indications. Clarified investigational and not medically necessary statement for implantable VNS. Updated Description, Rationale, Background, Coding, References, Websites for Additional Information, and Index sections.
 01/01/2014Updated Coding section with 01/01/2014 HCPCS changes.
Revised08/08/2013MPTAC review. Added treatment of heart failure to the VNS investigational and not medically necessary indications and clarified electronic analysis statement. Updated Rationale, Background, Definitions, Coding, References, Websites for Additional Information, and Index sections.
 01/01/2013Updated Coding section with 01/01/2013 CPT changes.
Reviewed08/09/2012MPTAC review.
Reviewed08/03/2012Behavioral Health Subcommittee review. Updated Rationale, Background, References, and Websites for Additional Information.
Reviewed11/17/2011MPTAC review. Updated Rationale, References, and Websites for Additional Information.
Revised11/18/2010MPTAC review. Clarified statement for electronic analysis of an implanted VNS device, that it is medically necessary for monitoring of an appropriately implanted device. Updated the Rationale, Background, Definitions, References, Websites for Additional Information and Index.  Updated Coding section to include 01/01/2011 CPT changes; removed 64573 deleted 12/31/2010.
Revised11/19/2009MPTAC review. Added medically necessary statement addressing analysis of an implanted neurostimulator pulse generator system for VNS when criteria are met. Clarified and expanded investigational and not medically necessary statements:  added specific medical conditions and separate statement to address when analysis of an implanted neurostimulator pulse generator system for VNS is investigational and not medically necessary. Updated Description, Rationale, Background, and References. Updated Coding section with 01/01/2010 HCPCS changes.
Reviewed11/20/2008MPTAC review. Rationale, Definitions, and References updated.
 10/01/2008Updated Coding section with 10/01/2008 ICD-9 changes.
Reviewed11/29/2007MPTAC review. Clarified Position Statement. Rationale, Background, Coding and References updated. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary."
Reviewed12/07/2006MPTAC review. Background/Overview updated. 
Reviewed09/14/2006MPTAC review. References updated. Coding update: removed HCPCS E0752, E0754, E0756 deleted 12/31/05.
 01/01/2006Updated Coding section with 01/01/2006 CPT/HCPCS changes
Revised12/01/2005MPTAC review.
 11/22/2005Added reference for Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD).
Revised09/22/2005MPTAC review.
Revised07/14/2005MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger OrganizationsLast Review DateDocument NumberTitle 
Anthem, Inc.01/28/2004SURG.00007Vagus Nerve Stimulation Therapy
WellPoint Health Networks, Inc.04/28/20052.10.05Vagus Nerve Stimulation