Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Vagus Nerve Stimulation Page 1 of 22 Medical Policy Title: An independent licensee of the Blue Cross Blue Shield Association Vagus Nerve Stimulation Professional Original Effective Date: June 1, 1997 Revision Date(s): November 1, 1997; July 1, 1998; January 1, 2006; September 1, 2006; October 26, 2010; March 3, 2011; January 1, 2012; August 24, 2012; June 26, 2013; November 24, 2015; April 25, 2016 Current Effective Date: November 24, 2015 Institutional Original Effective Date: April 1, 2007 Revision Date(s): November 29, 2010; March 3, 2011; January 1, 2012; August 24, 2012; June 26, 2013; November 24, 2015; April 25, 2016 Current Effective Date: November 24, 2015 State and Federal mandates and health plan member contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. To verify a member's benefits, contact Blue Cross and Blue Shield of Kansas Customer Service. The BCBSKS Medical Policies contained herein are for informational purposes and apply only to members who have health insurance through BCBSKS or who are covered by a self-insured group plan administered by BCBSKS. Medical Policy for FEP members is subject to FEP medical policy which may differ from BCBSKS Medical Policy. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents of Blue Cross and Blue Shield of Kansas and are solely responsible for diagnosis, treatment and medical advice. If your patient is covered under a different Blue Cross and Blue Shield plan, please refer to the Medical Policies of that plan. Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 2 of 22 Populations Individuals: With seizures refractory to medical treatment Interventions Interventions of interest are: Vagus nerve stimulation Comparators Comparators of interest are: Standard of care Individuals: With treatment-resistant depression Interventions of interest are: Vagus nerve stimulatio Comparators of interest are: Standard of car Individuals: With chronic heart failure With upper-limb impairment due to stroke Individuals: With essential tremor, obesity headache, fibromyalgia, or tinnitus Individuals: With epilepsy, depression, schizophrenia, headache, or impaired glucose tolerance Interventions of interest are: Vagus nerve stimulation Comparators of interest are: Standard of car Interventions of interest are: Vagus nerve stimulation Comparators of interest are: Standard of care Interventions of interest are: Transcutaneous vagus nerve stimulatio Comparators of interest are: Standard of car Outcomes Relevant outcomes include: Symptoms Change in disease status Functional outcomes Relevant outcomes include: Symptoms Change in disease status Functional outcomes Relevant outcomes include: Symptoms Change in disease status Functional outcomes Relevant outcomes include: Symptoms Change in disease status Functional outcomes Relevant outcomes include: Symptoms Change in disease status Functional outcomes DESCRIPTION Stimulation of the vagus nerve can be performed by means of an implantable stimulator within the carotid artery sheath. This technique has been proposed as a treatment for refractory seizures, depression and other disorders. There are also devices available that are implanted at different areas of the vagus nerve. This evidence review also addresses devices that stimulate the vagus nerve transcutaneously. Background Vagus Nerve Stimulation (VNS) was initially investigated as a treatment alternative in patients with medically refractory partial-onset seizures for whom surgery is not recommended or for whom surgery has failed. Over time, the use of VNS has expanded to generalized seizures, and it has been investigated for a range of other conditions. While the mechanisms for the therapeutic effects of VNS are not fully understood, the basic premise of VNS in the treatment of various conditions is that vagal visceral afferents have a diffuse central nervous system projection, and activation of these pathways has a widespread effect on neuronal excitability. Electrical stimulus is applied to axons of the vagus nerve, which have their cell bodies in the nodose and junctional ganglia and synapse on the nucleus of the solitary tract in the brainstem. From the solitary tract nucleus, vagal afferent pathways project to multiple areas of the brain. There are also vagal efferent pathways that innervate the heart, vocal cords, and other laryngeal and pharyngeal muscles, and provide parasympathetic innervation to the gastrointestinal tract that may also be stimulated by VNS. The type of VNS device addressed in this policy consists of an implantable, programmable electronic pulse generator that delivers stimulation to the left vagus nerve Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 3 of 22 at the carotid sheath. The pulse generator is connected to the vagus nerve via a bipolar electrical lead. Surgery for implantation of a vagal nerve stimulator involves implantation of the pulse generator in the infraclavicular region and wrapping 2 spiral electrodes around the left vagus nerve within the carotid sheath. The programmable stimulator may be programmed in advance to stimulate at regular intervals or on demand by patients or family by placing a magnet against the subclavicular implant site. Various types of devices that stimulate the vagus nerve transcutaneously have been developed as well. One device made by Cerbomed stimulates the auricular branch of the vagus nerve. Some devices used in studies are not well characterized as to the specific manufacturer or type of device used. The U.S. Food and Drug Administration has not approved any transcutaneous VNS devices. Other types of implantable vagus nerve stimulators are also available. The Maestro® System (EnteroMedics, St. Paul, MN) consists of a subcutaneously implanted pulse generator and electrodes that are placed in contact with the trunks of the vagus nerve at the gastroesophageal junction. These types of stimulators differ in the location of the pulse generator and electrodes and the stimulation programming settings, and are not addressed in this evidence review. VNS was originally approved for the treatment of medically refractory epilepsy. Significant advances have been made since then in the surgical and medical treatment of epilepsy, and newer, more recently approved medications are available. Despite these advances, however, 25% to 50% of patients with epilepsy experience breakthrough seizures or suffer from debilitating adverse effects of antiepileptic drugs. For patient such as these, VNS therapy has been used as an alternative to or adjunct to epilepsy surgery or medications. Based on observations that patients treated with VNS experience improvements in mood, VNS has been evaluated for the treatment of refractory depression. VNS has been investigated for multiple other conditions which may be affected by either the afferent or efferent stimulation of the vagus nerve, including headaches, tremor, obesity, heart failure, fibromyalgia, tinnitus, and traumatic brain injury. Regulatory Status In 1997, the NeuroCybernetic Prosthesis (NCP®) System (Cyberonics), a vagus nerve stimulation (VNS) device, was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval (PMA) process for use in conjunction with drugs or surgery “…as an adjunctive treatment of adults and adolescents over 12 years of age with medically refractory partial onset seizures.” On July 15, 2005, Cyberonics received PMA supplement approval by FDA for the VNS Therapy™ System “…for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 4 of 22 episode and have not had an adequate response to four or more adequate antidepressant treatments.” Cerbomed has developed a transcutaneous VNS (t-VNS®) system that uses a combined stimulation unit and ear electrode to stimulate the auricular branch of the vagus nerve, which supplies the skin over the concha of the ear. Patients self-administer electric stimulation for several hours a day; no surgical procedure is required. The device received the CE mark in Europe in 2011, but has not been FDA approved for use in the United States. ElectroCore Medical has developed a noninvasive VNS system (gammaCore®) that is currently being investigated for headache; the device has not been FDA approved. POLICY A. Vagus nerve stimulation may be considered medically necessary as a treatment of medically refractory seizures. B. Vagus nerve stimulation is considered experimental / investigational as a treatment of other conditions, including but not limited to heart failure, fibromyalgia, depression, essential tremor, obesity, headaches, tinnitus, and traumatic brain injury. C. Nonimplantable vagus nerve stimulation devices are considered experimental / investigational for all indications. Policy Guidelines Medically refractory seizures are defined as seizures that occur in spite of therapeutic levels of antiepileptic drugs or seizures that cannot be treated with therapeutic levels of antiepileptic drugs because of intolerable adverse effects of these drugs. RATIONALE The most recent update covered the period through January 20, 2016. The review of evidence in the first several sections will pertain to implantable vagus nerve stimulators. The evidence on transcutaneous vagus nerve stimulators will be discussed separately in the last section. Treatment of Seizures Vagus Nerve Stimulation for Adult Partial-Onset Seizures The evidence review on treatment of seizures has expanded the indications over time, but was originally based, in part, on a 1998 TEC Assessment that offered the following conclusions.1 Published evidence from 2 large, well-designed multicenter randomized trials involving over 300 patients demonstrates that the use of vagus nerve stimulation (VNS) as an adjunct to optimal use of antiepileptic drugs in the treatment of medically refractory Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 5 of 22 patients with at least 6 partial-onset seizures/month reduces seizure frequency by approximately 25% after 3 months of treatment. In patients who achieve an initial reduction in seizure frequency, the beneficial treatment effect appears to be maintained and may increase with time. Adverse effects are mild and consist primarily of hoarseness or voice change during “on” periods of stimulation. There is limited information about the use of VNS in patients with other types of seizure disorders. Based on this TEC Assessment, earlier versions of this evidence review supported the use of VNS for partial-onset seizures for patients older than 12 years of age. A randomized controlled trial (RCT) published in 2014 reported long-term quality of life outcomes for 112 patients with pharmaco-resistant focal seizures, which supported the beneficial effects of VNS for this group.2 VNS for Adult Generalized Seizures Tecoma and Iragui observed in a 2006 review that since the approval of VNS for partial-onset seizures, a number of case series including patients with generalized seizures have been published. These series report seizure reduction rates similar to or greater than those reported in partial epilepsy and note that “…this body of evidence suggests that VNS has broad antiepileptic efficacy.”3 The authors suggest that these results may be particularly important since resective epilepsy surgery is generally not feasible in these patients. Other reports published since the review by Tecoma and Iragui are consistent with the authors’ observations. In a French study of 50 consecutive refractory adolescents and adults who were not eligible for surgery, 11 of whom had generalized epilepsy, 58% were classified as responders to VNS at 3 year follow-up.4 Generalized epilepsy was predictive of a better outcome than partial epilepsy. Seizure reduction of 61% was also reported in a case series of 12 patients with drugresistant idiopathic generalized epilepsy.5 Garcia-Navarrete et al evaluated outcomes after 18 months of follow-up for a prospectively followed cohort of 43 patients with medication-resistant epilepsy who underwent VNS implantation.6 Subjects’ seizure types were heterogeneous, but 52% had generalized epilepsy. Pharmacotherapy was unchanged during the course of the study. Twenty-seven subjects (63%) were described as “responders,” defined as having a 50% or greater reduction in seizure frequency compared with the year prior to VNS implantation. The difference in reduction of seizure frequency was not statistically significant between subjects with generalized and focal epilepsy. VNS for Childhood Seizures Since publication of the 1998 TEC assessment, there has been interest in expanding the use of VNS to younger patients. Several studies have reported results that support the safety and efficacy of the device in children with refractory seizures.7 For example, 60 pediatric patients were treated as part of the double-blind clinical trials conducted to support the U.S. Food and Drug Administration (FDA) application.8 At 18 months, the median reduction in seizure frequency with VNS was 50%, similar to the results achieved in adults. Adverse events were also similar to those recently reported in adults,9 and none resulted in termination of stimulation. Hornig et al reported on a case series of 19 pediatric patients, with observation periods ranging up to 30 months.10 Overall, 50% of patients had a 50% reduction in seizure frequency. Patwardhan et al reported that among 38 patients aged 11 months to 16 years with medically refractory seizures, both generalized and partial-onset, 29% had a greater than 90% reduction in seizure frequency Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 6 of 22 after VNS implantation, while 39% had 50% to 90% reduction.11 Healy et al reported that among 16 patients younger than 12 years of age who underwent VNS implantation at a single center, 9 (56%) experienced a reduction in their seizure frequency of 50% or more.12 Results from an addon study to an RCT designed to compare high-output with low-output VNS stimulation among 41 children with medically refractory epilepsy suggest that VNS does not have adverse effects on cognitive or psychosocial outcomes.13 Other studies of pediatric patients that included patients with generalized and partial-onset seizures have supported the use of VNS in reducing seizure frequency. These have included a series of 41 children treated with VNS, randomized to a highor low-dose stimulation protocol,14 a retrospective case-control study with 36 patients treated with VNS compared with 72 age- and sex-matched controls with refractory epilepsy not treated with VNS,15 a retrospective cohort study including 252 pediatric patients with a variety of seizure types treated with VNS,16 and a retrospective cohort study of 347 children with a variety of seizure types treated with VNS followed for up to 2 years.17 Similar to studies in adults, pediatric studies suggest that VNS improves seizure frequency in generalized epilepsy syndromes. In a multicenter study of 28 children with refractory seizures, You et al reported that 15 (53.6%) children showed a greater than 50% reduction in seizure frequency and 9 (32.1%) had a greater than 75% reduction, and there were no significant differences when groups were compared by seizure type or etiology.18 Tecoma and Iragui cite a multicenter retrospective analysis of 50 children with Lennox-Gastaut syndrome (LGS) treated with VNS.3 Median seizure reduction at 6 months was 88% for tonic seizures and 81% for atypical absence seizures. You et al compared VNS and total corpus callosotomy for LGS.19 Of the 14 patients who underwent a corpus callosotomy, 9 (64%) had a greater than 50% reduction in seizure frequency and 5 (36%) had a greater than 75% reduction. Of the 10 patients who underwent VNS implantation, 7 (70%) had a greater than 50% reduction in seizure frequency and 2 (20%) had a greater than 75% reduction. For 24 children with LGS or LGS-like syndrome who underwent VNS implantation, Cukiert et al reported that at least a 50% seizure frequency decrease was seen for 35 different seizure types.20 VNS generally does not completely eliminate seizures, and it is not possible to predict which patients will respond. One meta-analysis that included 74 retrospective and prospective studies assessing VNS efficacy in seizures found that predictors of efficacy included generalized epilepsy or mixed seizure types (compared with partial-onset seizures) and age younger than 18 years.21 In 2014, Arya et al reported results of a single-center retrospective chart review that included 43 pediatric patients who underwent VNS implantation over a 5-year period; the authors found that absence of a lesion on MRI predicted a good outcome.22 These studies support the use of VNS in children, in patients with generalized epilepsy, and in those who are not candidates for surgery. Section Summary: Treatment of Seizures The evidence on the efficacy of VNS for treatment of medically refractory seizures consists of 2 RCTs and numerous uncontrolled studies. The RCTs both reported a significant reduction in seizure frequency with VNS for patients with partial-onset seizures. The uncontrolled studies have consistently reported large reductions for a broader range of seizure types in both adults and children. The large reduction in seizures includes substantial numbers of patients who achieve a greater than 50% reduction in seizure frequency. Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 7 of 22 Treatment-Resistant Depression Interest in the application of VNS for treatment of treatment-resistant depression is related to reports of improvement in depressed mood among epileptic patients undergoing VNS.23 TEC Assessments written in 2005 and updated in 2006 concluded that evidence was insufficient to permit conclusions of the effect of VNS therapy on depression.24,25 The available evidence for these TEC Assessments included study groups assembled by the manufacturer of the device (Cyberonics) and have since been reported on in various publications.26,27 Analyses from these study groups were presented for FDA review and consisted of a case series of 60 patients receiving VNS (study D-01), a short-term (ie, 3-month) sham-controlled RCT of 221 patients (study D-02), and an observational study comparing 205 patients on VNS therapy with 124 patients receiving ongoing treatment for depression (study D-04).28 Patients who responded to sham treatment in the short-term RCT (10%) were excluded from the long-term observational study. The primary outcome evaluated was the relief of depression symptoms that can usually be assessed by any one of many different depression symptom rating scales. A 50% reduction from baseline score is considered to be a reasonable measure of treatment response. An improvement in depression symptoms may allow reduction of pharmacologic therapy for depression, with a reduction in adverse effects related to that form of treatment. In the studies evaluating VNS therapy, the 4 most common instruments used were the Hamilton Rating Scale for Depression, Clinical Global Impression, Montgomery and Asberg Depression Rating Scale, and the Inventory of Depressive Symptomatology (IDS). Several case series published before the randomized trial showed rates of improvement with VNS, as measured by a 50% improvement in depression score, of 31% at 10 weeks to greater than 40% at 1 to 2 years, but there are some losses to follow-up.29-31 Natural history, placebo effects, and patient and provider expectations make it difficult to infer efficacy from case series data. The randomized study (D-02) that compared VNS therapy with a sham control (implanted but inactivated VNS) showed a nonstatistically significant result for the principal outcome.27,28 Fifteen percent of VNS subjects responded versus 10% of control subjects (p=0.31). The Inventory for Depressive Symptomatology Systems Review (IDS-SR) score was considered a secondary outcome and showed a difference in outcome that was statistically significant in favor of VNS compared with sham treatment (17.4% vs 7.5%, respectively, p=0.04). The observational study that compared patients participating in the RCT and a separately recruited control group (D-04 vs D-02, respectively) evaluated VNS therapy out to 1 year and showed a statistically significant difference in the rate of change of depression score.26,28 However, issues such as unmeasured differences among patients, nonconcurrent controls, differences in sites of care between VNS therapy patients and controls, and differences on concomitant therapy changes raise concern about this observational study. Analyses performed on subsets of patients cared for in the same sites, and censoring observations after treatment changes, generally showed diminished differences in apparent treatment effectiveness of VNS and almost no statistically significant differences.28 Patient selection for the randomized trial and the observational comparison trial may be of concern. VNS is intended for treatment-refractory depression, but the entry criteria of failure of 2 drugs and a 6-week trial of therapy may not be a strict enough definition of treatment resistance. Treatment-refractory depression should be Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 8 of 22 defined by thorough psychiatric evaluation and comprehensive management. It is important to note that patients with clinically significant suicide risk were excluded from all VNS studies. Given these concerns about the quality of the observational data, these results did not provide strong evidence for the effectiveness of VNS therapy. In addition to the results of the TEC Assessments, several systematic reviews and meta-analyses have addressed the role of VNS in treatment-resistant depression. A systematic review of the literature for VNS of treatment-resistant depression identified the randomized trial previously described among the 18 studies that met the study’s inclusion criteria.32 VNS was found to be associated with a reduction in depressive symptoms in the open-label studies. However, results from the only double-blind trial were considered to be inconclusive.27,28 Daban et al concluded that further clinical trials are needed to confirm efficacy of VNS in treatment-resistant depression. In a meta-analysis that included 14 studies, Martin and Martin-Sanchez reported that among the uncontrolled studies included in their analysis, 31.8% of subjects responded to VNS treatment.33 However, results from a meta-regression to predict each study’s effect size suggested that 84% of the observed variation across studies was explained by baseline depression severity. Berry et al34 reported results from a meta-analysis of 6 industry-sponsored studies of safety and efficacy for VNS in treatment-resistant depression, which included the D-01, D-02, Bajbouj et al35 (D-03), D-04, and Aaronson et al (D-21) study results.36 In addition, the meta-analysis used data from a registry of patients with treatment-resistant depression (335 patients receiving VNS and treatment as usual and 301 patients receiving treatment as usual only) that were unpublished at the time of the meta-analysis publication (NCT00320372). The authors report that adjunctive VNS was associated with a greater likelihood of treatment response (odds ratio, 3.19; 95% confidence interval [CI], 2.12 to 4.66). However, the meta-analysis did not have systematic study selection criteria, limiting the conclusions that can be drawn from it. In 2014, Liu et al conducted a systematic review of brain stimulation treatments, including deep brain stimulation, electroconvulsive therapy, transcranial magnetic stimulation, and VNS, for mental illnesses other than nonpsychotic unipolar depression in adults aged 65 years or older.37 The authors identified 2 small studies that evaluated the effect of VNS on cognition in patients with Alzheimer disease, 1 with 10 subjects and 1 with 17 subjects, which were mixed in demonstrating clinical improvements. In 2013, Aaronson et al reported results from an active-controlled trial in which 331 patients with a history of chronic or recurrent bipolar disorder or major depressive disorder, with a current diagnosis of a major depressive episode, were randomized to 1 of 3 VNS current doses (high, medium, low).36 Patients had a history of failure to respond to at least 4 adequate dose/duration of antidepressant treatment trials from at least 2 different treatment categories. After 22 weeks, the current dose could be adjusted in any of the groups. At follow-up visits at weeks 10, 14, 18, and 22 after enrollment, there was no statistically significant difference between the dose groups for the study’s primary outcome, change in IDS score from baseline. However, the mean IDS score improved significantly for each group from baseline to the 22-week follow-up. At 50-week follow-up, there were no significant differences between the treatment dose groups for any of the depression scores used. Most patients completed the study; however, there was a high rate of reported adverse events, including voice alteration in 72.2%, dyspnea in 32.3%, and pain in 31.7%. Interpretation of the IDS improvement over time is limited by the lack of a no-treatment control group. Approximately 20% of the patients included had a history of bipolar disorder; as Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 9 of 22 such, the results may not be representative of most patients with treatment-resistant unipolar depression. Other case series do not substantially strengthen the evidence supporting VNS. A case series by Bajbouj et al that followed patients for 2 years showed that 53.1% (26/49) patients met criteria for a treatment response and 38.9% (19/49) met criteria for remission.35 A small study of 9 patients with rapid-cycling bipolar disorder showed improvements in several depression rating scales over 40 weeks of observation.38 Another case series by Cristancho et al that followed patients for 1 year showed that 4 of 15 responded and 1 of 15 remitted according to the principal response criteria.39 In a 2014 case series that included 27 patients with treatment-resistant depression, 5 patients demonstrated complete remission after 1 year and 6 patients were considered responders.40 Adverse effects of VNS therapy included voice alteration, headache, neck pain, and cough, which are known from prior experience with VNS therapy for seizures. Regarding specific concerns for depressed patients (eg, those with mania, hypomania, suicide, or worsening depression), there does not appear to be a greater risk of these events during VNS therapy.28 Section Summary: Treatment-Resistant Depression There is 1 RCT evaluating the efficacy of VNS for treatment-resistant depression. This study reported only short-term results and found no significant improvement for the primary outcome with VNS. Other available studies, which include nonrandomized comparative studies and case series, are limited by relatively small sample sizes and the potential for selection bias; the case series are further limited by the lack of a control group. Given the limitations of this literature, combined with the lack of substantial new clinical trials, the scientific evidence is considered to be insufficient to permit conclusions on the effect of this technology on major depression. Other Conditions Treatment of Chronic Heart Failure VNS has been investigated for treatment of chronic heart failure in some case series. A case series phase 2 trial of VNS therapy for chronic heart failure reported improvements in New York Heart Association class quality of life, 6-minute walk test, and left ventricular (LV) ejection fraction.41 The ANTHEM-HF study is also a case series study, but patients were randomized to either right- or left-sided vagus nerve implantation (but there was no control group).42 Overall, from baseline to 6-month follow-up, LV ejection fraction improved by 4.5% (95% CI, 2.4 to 6.6), LV end systolic volume improved by -4.1 mL (95% CI, -9.0 to 0.8), LV end-diastolic diameter (LVESD) improved by -1.7 mm (95% CI, -2.8 to -0.7), heart rate variability improved by 17 milliseconds (95% CI, 6.5 to 28), and 6-minute walk distance improved by 56 meters (95% CI, 37 to 75). In 2015, Zannand et al reported results from the NECTAR-HF trial, a randomized, shamcontrolled trial, with outcomes from VNS in patients with severe LV dysfunction, despite optimal medical therapy.43 Ninety-six patients were implanted with a vagal nerve stimulator and randomized in a 2:1 manner to active therapy (VNS ON) or control (VNS OFF) for 6 months. Programming of the generator was performed by a physician unblinded to treatment assignment, while all other investigators and site study staff involved in end point data collection were blinded to randomization. Sixty-three patients were randomized to the intervention, of whom 59 had Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 10 of 22 paired pre-post data available, while 32 were randomized to control, of whom 28 had paired data available. The analysis was a modified intention-to-treat. For the primary end point of change in LVESD from baseline to 6 months, there were no significant differences between groups (p=0.60 between-group difference in LVESD change). Other secondary efficacy end points related to LV remodeling parameters, ie, LV function and circulating biomarkers of heart failure, did not differ between groups, with the exception of 36-Item Short-Form Health Survey Physical Component score, which showed greater improvement in the VNS ON group than in the control group (from 36.3 to 41.2 in the VNS ON group vs from 37.7 to 38.4 in the control group; p=0.02). Subject blinding was found to be imperfect, which may have biased the subjective outcome data reporting. Treatment of Upper-Limb Impairment Due to Stroke Dawson et al conducted a randomized pilot trial of VNS in patients with upper-limb dysfunction after ischemic stroke.44 Twenty-one subjects were randomized to VNS plus rehabilitation or rehabilitation alone. Mean change in the outcome as assessed by a functional assessment score was +8.7 in the VNS group versus +3.0 in the control group (p=0.064). Six patients in the VNS group achieved clinically meaningful response versus 4 in the control group (p=0.17). Essential Tremor, Obesity, Headache, Fibromyalgia, and Tinnitus VNS has been investigated with small pilot studies or studies evaluating mechanism of disease for several conditions. These conditions include essential tremor,45 obesity,46 fibromyalgia,47 headache,48,49 and tinnitus.50 None of these studies are sufficient to make conclusions on the effect of VNS on these conditions. Only conditions for which at least 1 randomized trial has been reported will be detailed. Section Summary: Other Conditions In other conditions evaluated with RCTs (heart failure, upper-limb impairment), the trials did not show efficacy of VNS for the primary outcome. Other conditions (essential tremor, obesity, headache, fibromyalgia, tinnitus) have only been investigated with case series, which are not sufficient to make conclusions on the effect of VNS. Transcutaneous VNS Only conditions for which there is at least 1 RCT will be discussed, as case series are inadequate to determine the effect of the technology. Transcutaneous VNS for Epilepsy Aihua et al reported results from a series of 60 patients with pharmaco-resistant epilepsy treated with a transcutaneous VNS (t-VNS) device, who were randomly assigned to receive stimulation over the earlobe (control group) or the Ramsay-Hunt zone (treatment group), which includes the external auditory canal and the conchal cavity and is considered to be the somatic sensory territory of the vagus nerve.51 Thirty patients were randomized to each group; 4 subjects from the treatment group were excluded from analysis due to loss to follow-up (n=3) or adverse effects (n=1), while 9 subjects from the control group were excluded from analysis due to loss to follow-up (n=2) or increase or lack of decrease in seizures or other reasons (n=7). In the treatment group, compared with baseline, the median monthly seizure frequency was significantly reduced after 6 months (5.5 vs 6.0; p<0.001) and 12 months (4.0 vs 6.0; p<0.001) of t-VNS therapy. At 12-month follow-up, t-VNS group subjects had a significantly lower median monthly seizure frequency compared with the control group (4.0 vs 8.0; p<0.001). Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 11 of 22 Two small case series were identified that used a t-VNS device for treatment of medicationrefractory seizures. In a small case series of 10 patients with treatment-resistant epilepsy, Stefan et al reported that 3 patients withdrew from the study, while 5 of 7 patients reported a reduction in seizure frequency.52 In another small case series, He et al reported that among 14 pediatric patients with intractable epilepsy who were treated with bilateral t-VNS, of the 13 patients who completed follow-up, mean reduction in self-reported seizure frequency was 31.8% after 8 weeks, 54.1% from week 9 to 16, and 54.2% from week 17 to 24.53 Transcutaneous VNS for Psychiatric Disorders Hein et al reported results of 2 pilot RCTs of a t-VNS device for the treatment of depression, 1 which included 22 subjects and 1 with 15 subjects.54 In the first study, 11 subjects each were randomized to active or sham t-VNS. At 2 weeks follow-up, Beck Depression Inventory (BDI) selfrating scores in the active-stimulation group decreased from 27.0 to 14.0 points (p<0.001), while the sham-stimulated patients did not show significant reductions in the BDI (31.0 to 25.8 points). In the second study, 7 patients were randomized to active t-VNS and 8 patients were randomized to sham t-VNS. In this study, BDI self-rating scores in the active stimulation group decreased from 29.4 to 17.4 points (p<0.05) after 2 weeks, while the sham-stimulated patients did not show significant change in BDI (28.6 to 25.4 points). The authors do not report direct comparisons in BDI change between the sham- and active-stimulation groups. Hasan et al reported a randomized trial of t-VNS for the treatment of schizophrenia.55 Twenty patients were assigned either to active t-VNS or to sham treatment for 12 weeks. There was no statistically significant difference in the improvement of schizophrenia status during the observation period. Shiozawa et al conducted a systematic review of studies evaluating the evidence related to transcutaneous stimulation of the trigeminal or vagus nerve for psychiatric disorders.56 They found 4 studies that addressed t-VNS for psychiatric disorders and included a total of 84 subjects. Three of the 4 studies evaluated physiologic parameters in healthy patients and 1 evaluated pharmaco-resistant epilepsy (Stefan et al, previously described52). The authors also include a fifth study in a data table, although not in their text or reference list (Hein et al, previously described54) Overall, the studies included were limited by small size and poor generalizability. Transcutaneous VNS for Headache Gaul et al reported the results of a randomized open-label study of t-VNS for the treatment of chronic cluster headache.57 Forty-eight patients with chronic cluster headache were randomized to either t-VNS or to individualized standard of care. Transcutaneous VNS was to be used twice daily with the option of additional treatment during headaches. At 4 weeks, the t-VNS group had a greater reduction in the number of headaches than the control group, resulting in a mean therapeutic gain of 3.9 fewer headaches per week (p=0.02). In terms of response rate, defined as a 50% or more reduction in headaches, the t-VNS group had a 40% response rate versus 8.3% in the control group (p<0.001). The study lacked a sham placebo control group, which may result in placebo response in the t-VNS group. Goadsby et al reported results from an open-label pilot study of t-VNS for the treatment of migraine with or without aura.58 Eighty migraine attacks were self-treated by 27 patients, of an initial sample of 30 patients (2 patients treated no migraine attacks with the device, 1 patient Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 12 of 22 treated only an aura). Of 54 moderate or severe attacks treated, 12 subjects (22%) were painfree at 2 hours posttreatment. Thirteen subjects reported adverse events, which were all considered mild or moderate. Transcutaneous VNS for Impaired Glucose Tolerance Huang et al reported results of a pilot RCT of a t-VNS device that provides stimulation to the auricle for the treatment of impaired glucose tolerance.59 The study included 70 patients with impaired glucose tolerance who were randomized to active or sham t-VNS, along with 30 controls who received no t-VNS treatment. After 12 weeks of treatment, patients who received active tVNS were reported to have significantly lower 2-hour glucose tolerance test results than those who received sham t-VNS (7.5 mmol/L vs 8 mmol/L; p=0.004). Section Summary: Transcutaneous VNS Transcutaneous VNS has been investigated with small randomized trials for several conditions. Some evidence for the efficacy of t-VNS for epilepsy comes 1 small RCT, which reported lower seizure rates for active t-VNStreated patients compared with sham controls; however, the high dropout rates in this study are problematic. In the study of depression, 1 small RCT that compared treatment with t-VNS with sham stimulation demonstrated some improvements in depression scores with t-VNS; however, the lack of comparisons between groups limits conclusions that may be drawn. An RCT for cluster headache showed a reduction in headache frequency, but did not have a sham treatment group. A sham-controlled pilot RCT for impaired glucose tolerance showed some effect on glucose tolerance tests. Ongoing and Unpublished Clinical Trials Some currently unpublished trials that might influence this review are listed in Table 1. Table 1. Summary of Key Trials NCT No. Ongoing NCT02089243 Unpublished NCT01958125a NCT01792817a Trial Name Planned Completion Enrollment Date Prospective Randomized Controlled Study of Vagus Nerve Stimulation Therapy in the Patients With Medically Refractory Medial Temporal Lobe Epilepsy; Controlled Randomized Vagus Nerve Stimulation Versus Resection (CoRaVNStiR) 40 Jul 2017 A Randomized, Multicentre, Double-blind, Parallel, Sham-controlled Study of GammaCore®, a Noninvasive Neurostimulator Device for the Acute Relief of Episodic and Chronic Cluster Headache. Non-invasive Neurostimulation of the Vagus Nerve With the GammaCore Device for the Treatment of Cluster Headache 120 Jan 2015 150 Oct 2014 NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial. Summary of Evidence The evidence for vagus nerve stimulation (VNS) in individuals who have seizures refractory to medical treatment includes randomized controlled trials (RCTs) and multiple observational studies. Relevant outcomes are symptoms, change in disease status, and functional outcomes. Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 13 of 22 The RCTs reported a significant reduction in seizure frequency for patients with partial-onset seizures. The uncontrolled studies have consistently reported large reductions for a broader range of seizure types in both adults and children. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for VNS in individuals who have treatment-resistant depression includes 1 RCT and other nonrandomized comparative studies and case series. Relevant outcomes are symptoms, change in disease status, and functional outcomes. The RCT reported only short-term results and found no significant improvement for the primary outcome. Other available studies are limited by small sample sizes, potential selection bias, and lack of a control group in the case series. The evidence is insufficient to determine the effects of the technology on health outcomes. The evidence for VNS in individuals who have chronic heart failure or upper-limb impairment due to stroke includes RCTs and case series. Relevant outcomes are symptoms, change in disease status, and functional outcomes. The RCTs for both conditions did not show significant improvements in the primary outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes. The evidence for VNS in individuals who have essential tremor, obesity, headache, fibromyalgia, or tinnitus includes case series. Relevant outcomes are symptoms, change in disease status, and functional outcomes. Case series are insufficient to make conclusions regarding efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes. The evidence for transcutaneous VNS stimulation in individuals who have epilepsy, depression, schizophrenia, headache, or impaired glucose tolerance includes at least 1 RCT and case series for some of the conditions. Relevant outcomes are symptoms, change in disease status, and functional outcomes. The RCTs are all small and have various methodologic problems. None shows definitive efficacy of transcutaneous VNS in improving outcomes among patients. The evidence is insufficient to determine the effects of the technology on health outcomes. Practice Guidelines and Position Statements American Academy of Neurology In 1999, the American Academy of Neurology (AAN) released a consensus statement on the use of VNS in adults that stated, “VNS is indicated for adults and adolescents over 12 years of age with medically intractable partial seizures who are not candidates for potentially curative surgical resections, such as lesionectomies or mesial temporal lobectomies.”60 AAN released an update to these guidelines in 2013 that stated, “VNS may be considered for seizures in children, for LGS [Lennox-Gastaut syndrome]-associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C).”61 American Psychiatric Association The American Psychiatric Association guidelines on the treatment of major depressive disorder in adults, updated in November 2010, includes the following statement on the use of VNS: “Vagus nerve stimulation (VNS) may be an additional option for individuals who have not responded to at least four adequate trials of antidepressant treatment, including ECT [electroconvulsive therapy],” with a level of evidence III (may be recommended on the basis of individual circumstances).62 Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation Page 14 of 22 European Headache Federation In 2013, the European Headache Federation issued a consensus statement on neuromodulation treatments for chronic headaches, which makes the following statement about the use of VNS: “Due to the lack of evidence, VNS should only be employed in chronic headache sufferers using a randomized, placebo controlled trial design.”63 U.S. Preventive Services Task Force Recommendations Not applicable. CODING The following codes for treatment and procedures applicable to this policy are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement. Please refer to the member's contract benefits in effect at the time of service to determine coverage or noncoverage of these services as it applies to an individual member. CPT/HCPCS 61885 61886 64553 64568 64569 64570 95974 95975 L8680 L8681 L8685 L8686 Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to 2 or more electrode arrays Percutaneous implantation of neurostimulator electrode array; cranial nerve Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator Revision or replacement of cranial nerve (eg, vagus nerve) neurostimulator electrode array, including connection to existing pulse generator Removal of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude and duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); complex cranial nerve neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming, with or without nerve interface testing, first hour Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude and duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); complex cranial nerve neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming, each additional 30 minutes after first hour (List separately in addition to code for primary procedure) Implantable neurostimulator electrode, each Patient programmer (external) for use with implantable programmable neurostimulator pulse generator, replacement only Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation L8687 L8688 L8689 Page 15 of 22 Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension External recharging system for battery (internal) for use with implantable neurostimulator, replacement only VNS requires not only the surgical implantation of the device, but also subsequent neurostimulator programming, which occurs intraoperatively and typically during additional outpatient visits. There are CPT codes that specifically describe the neurostimulator programming and analysis of cranial nerve stimulation (ie, vagus nerve) as follows: 95974, 95975. ICD-9 Diagnoses 345.00-345.91 Epilepsy, code range ICD-10 Diagnoses (Effective October 1, 2015) G40.001 G40.009 G40.011 G40.019 G40.101 G40.109 G40.111 G40.119 G40.201 G40.209 G40.211 G40.219 G40.301 G40.309 G40.311 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, with status epilepticus Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, without status epilepticus Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, with status epilepticus Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, without status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, with status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, without status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, with status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, without status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, with status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, without status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, with status epilepticus Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, without status epilepticus Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus Generalized idiopathic epilepsy and epileptic syndromes, not intractable, without status epilepticus Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status epilepticus Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation G40.319 G40.401 G40.409 G40.411 G40.419 G40.501 G40.509 G40.801 G40.802 G40.811 G40.812 G40.813 G40.814 G40.821 G40.822 G40.823 G40.824 G40.A01 G40.A09 G40.A11 G40.A19 G40.B01 G40.B09 G40.B11 G40.B19 Page 16 of 22 Generalized idiopathic epilepsy and epileptic syndromes, intractable, without status epilepticus Other generalized epilepsy and epileptic syndromes, not intractable, with status epilepticus Other generalized epilepsy and epileptic syndromes, not intractable, without status epilepticus Other generalized epilepsy and epileptic syndromes, intractable, with status epilepticus Other generalized epilepsy and epileptic syndromes, intractable, without status epilepticus Epileptic seizures related to external causes, not intractable, with status epilepticus Epileptic seizures related to external causes, not intractable, without status epilepticus Other epilepsy, not intractable, with status epilepticus Other epilepsy, not intractable, without status epilepticus Lennox-Gastaut syndrome, not intractable, with status epilepticus Lennox-Gastaut syndrome, not intractable, without status epilepticus Lennox-Gastaut syndrome, intractable, with status epilepticus Lennox-Gastaut syndrome, intractable, without status epilepticus Epileptic spasms, not intractable, with status epilepticus Epileptic spasms, not intractable, without status epilepticus Epileptic spasms, intractable, with status epilepticus Epileptic spasms, intractable, without status epilepticus Absence epileptic syndrome, not intractable, with status epilepticus Absence epileptic syndrome, not intractable, without status epilepticus Absence epileptic syndrome, intractable, with status epilepticus Absence epileptic syndrome, intractable, without status epilepticus Juvenile myoclonic epilepsy, not intractable, with status epilepticus Juvenile myoclonic epilepsy, not intractable, without status epilepticus Juvenile myoclonic epilepsy, intractable, with status epilepticus Juvenile myoclonic epilepsy, intractable, without status epilepticus REVISIONS 10-08-2008 Revised title from Vagal Nerve Stimulator to Vagus Nerve Stimulation Added Rationale section In Coding section: ▪ Added L8689 Added Revisions section 10-26-2010 Description section updated In Policy section: ▪ Policy language liberalized from: "Vagal nerve stimulation is medically necessary for: 1. Patient not responding to anticonvulsant medications with multiple medications tried 2. Patient not a candidate for a surgical procedure 3. Medically refractory seizures (i.e. Lennox-Gastaut) in children under 12 years" Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation 03-03-2011 01-01-2012 08-24-2012 Page 17 of 22 to: "A. Vagus nerve stimulation may be considered medically necessary as a treatment of medically refractory seizures. ▪ Policy language liberalized from: "Vagal nerve stimulation is experimental / investigational because effectiveness has not been established for all other indications including: 1. Autism, 2. Obesity, 3. Refractory depression, 4. Obsessive-compulsive disorder, 5. Cognitive impairment associated with Alzheimer’s disease, and 6. Depression" to: "B. Vagus nerve stimulation is considered experimental / investigational as a treatment of other conditions." with the reference to indications being removed as the list was not all inclusive. Added Policy Guidelines section and the following wording: ▪ "Medically refractory seizures are defined as seizures that occur in spite of therapeutic levels of antiepileptic drugs or seizures that cannot be treated with therapeutic levels of antiepileptic drugs because of intolerable adverse effects of these drugs." Updated Rationale section In Coding section: ▪ Updated wording for CPT/HCPCS codes: 61886, L8681, L8689 Updated References section In Coding section: ▪ Added CPT codes: 64568, 64569, 64570 Rationale section updated. Reference section updated. In Coding section: Revised CPT nomenclature for the following code: 64553 Removed CPT code: 64573 Removed the following CPT guidelines: “95974: Electronic analysis of implanted neurostimulator pulse generator system (e.g., rate, pulse amplitude and duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance, and patient compliance measurements); complex cranial nerve neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming, with or without nerve interface testing, first hour. 95975: complex cranial nerve neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming, with or without nerve interface testing, each additional 30 minutes.” Added the following CPT guidelines: “95974: use modifier 52, if less than 31 minutes in duration.” Description section updated. In the Policy section: In Item B, added "including, but not limited to heart failure, fibromyalgia, depression, essential tremor, obesity, and headaches." to read "Vagus nerve stimulation is considered experimental / investigational as a treatment of other conditions, including, but not limited to heart failure, fibromyalgia, Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation 06-26-2013 11-24-2015 04-25-2016 Page 18 of 22 depression, essential tremor, obesity, and headaches." Rationale section updated. Reference section updated. Rational section updated. In Coding section: Added ICD-10 Diagnoses (Effective October 1, 2014) Description section updated In Policy section: In Item B removed “and” and added “tinnitus, and traumatic brain injury” to read, “Vagus nerve stimulation is considered experimental / investigational as a treatment of other conditions, including but not limited to heart failure, fibromyalgia, depression, essential tremor, obesity, headaches, tinnitus, and traumatic brain injury.” Rationale section updated In Coding section: Updated Coding notations. References updated Description section updated Rationale section updated References updated REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Chronic vagus nerve stimulation for treatment of seizures. TEC Assessments. 1998;Volume 13 Tab 9. Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia. Jun 2014;55(6):893-900. PMID 24754318 Tecoma ES, Iragui VJ. Vagus nerve stimulation use and effect in epilepsy: what have we learned? Epilepsy Behav. Feb 2006;8(1):127-136. PMID 16376157 Montavont A, Demarquay G, Ryvlin P, et al. Long-term efficiency of vagus nerve stimulation (VNS) in non-surgical refractory epilepsies in adolescents and adults article in French. Rev Neurol (Paris). 2007;163(12):1169-1177. 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;187:5558. PMID 17419830 Garcia-Navarrete E, Torres CV, Gallego I, et al. Long-term results of vagal nerve stimulation for adults with medication-resistant epilepsy who have been on unchanged antiepileptic medication. Seizure. Jan 2013;22(1):9-13. PMID 23041031 Amar AP, Levy ML, McComb JG, et al. Vagus nerve stimulation for control of intractable seizures in childhood. Pediatr Neurosurg. Apr 2001;34(4):218-223. PMID 11359116 Murphy JV. Left vagal nerve stimulation in children with medically refractory epilepsy. The Pediatric VNS Study Group. J Pediatr. May 1999;134(5):563-566. PMID 10228290 Morris GL, 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology. Nov 10 1999;53(8):1731-1735. PMID 10563620 Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. Page 19 of 22 Hornig GW, Murphy JV, Schallert G, et al. Left vagus nerve stimulation in children with refractory epilepsy: an update. South Med J. May 1997;90(5):484-488. PMID 9160063 Patwardhan RV, Stong B, Bebin EM, et al. Efficacy of vagal nerve stimulation in children with medically refractory epilepsy. Neurosurgery. Dec 2000;47(6):1353-1357; discussion 1357-1358. PMID 11126906 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. Nov 2013;29(11):2095-2099. PMID 23681311 Klinkenberg S, van den Bosch CN, Majoie HJ, et al. Behavioural and cognitive effects during vagus nerve stimulation in children with intractable epilepsy - a randomized controlled trial. Eur J Paediatr Neurol. Jan 2013;17(1):82-90. PMID 22878130 Klinkenberg S, Aalbers MW, Vles JS, et al. Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. Dev Med Child Neurol. Sep 2012;54(9):855-861. PMID 22540141 Terra VC, Furlanetti LL, Nunes AA, et al. Vagus nerve stimulation in pediatric patients: Is it really worthwhile? Epilepsy Behav. Feb 2014;31:329-333. PMID 24210463 Yu C, Ramgopal S, Libenson M, et al. Outcomes of vagal nerve stimulation in a pediatric population: A single center experience. Seizure. Feb 2014;23(2):105-111. PMID 24309238 Orosz I, McCormick D, Zamponi N, et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. Epilepsia. Oct 2014;55(10):1576-1584. PMID 25231724 You SJ, Kang HC, Kim HD, et al. Vagus nerve stimulation in intractable childhood epilepsy: a Korean multicenter experience. J Korean Med Sci. Jun 2007;22(3):442-445. PMID 17596651 You SJ, Kang HC, Ko TS, et al. Comparison of corpus callosotomy and vagus nerve stimulation in children with Lennox-Gastaut syndrome. Brain Dev. Mar 2008;30(3):195-199. PMID 17825516 Cukiert A, Cukiert CM, Burattini JA, et al. A prospective long-term study on the outcome after vagus nerve stimulation at maximally tolerated current intensity in a cohort of children with refractory secondary generalized epilepsy. Neuromodulation. Nov 2013;16(6):551-556. PMID 23738578 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. PMID 21838505 Arya R, Greiner HM, Lewis A, et al. Predictors of response to vagus nerve stimulation in childhood-onset medically refractory epilepsy. J Child Neurol. Dec 2014;29(12):1652-1659. PMID 24309242 Elger H, Hoppe C, Falkai P, et al. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000;42(3-Feb):203-210. Blue Cross and Blue Shield Assocation Technology Evaluation Center (TEC). Vagus nerve stimulation for treatment-resistant depression. TEC Assessments. 2006;Volume 21, Tab 7. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Vagus nerve stimulation for treatment-resistant depression. TEC Assessments. 2005;Volume 21, Tab 7. 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):364373. Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. Page 20 of 22 Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. Sep 1 2005;58(5):347-354. PMID 16139580 U.S. Food and Drug Administration Center for Devices and Radiological Health. Summary of Safety and Effectiveness Data for the Vagus Nerve Stimulation (VNS) Therapy System. http://www.fda.gov/ohrms/dockets/ac/04/briefing/4047b1_02_Summary%20of%20Safety %20and%20Effectiveness.pdf. Accessed January 12, 2015. Marangell LB, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes. Biol Psychiatry. Feb 15 2002;51(4):280-287. PMID 11958778 Rush AJ, George MS, Sackheim HA, et al. Vagus nerve stimulation (VNS) for treatmentresistant depression: a multicenter study. Biol Psychiatry. 2000;47(4):276-286. Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatmentresistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology. Nov 2001;25(5):713-728. PMID 11682255 Daban C, Martinez-Aran A, Cruz N, et al. Safety and efficacy of Vagus Nerve Stimulation in treatment-resistant depression. A systematic review. J Affect Disord. Sep 2008;110(1-2):115. PMID 18374988 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. Apr 2012;27(3):147-155. PMID 22137776 Berry SM, Broglio K, Bunker M, et al. A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckl). 2013;6:17-35. PMID 23482508 Bajbouj M, Merkl A, Schlaepfer TE, et al. Two-year outcome of vagus nerve stimulation in treatment-resistant depression. J Clin Psychopharmacol. Jun 2010;30(3):273-281. PMID 20473062 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. Jul 2013;6(4):631-640. PMID 23122916 Liu AY, Rajji TK, Blumberger DM, et al. Brain stimulation in the treatment of late-life severe mental illness other than unipolar nonpsychotic depression. Am J Geriatr Psychiatry. Mar 2014;22(3):216-240. PMID 23891366 Marangell LB, Suppes T, Zboyan HA, et al. A 1-year pilot study of vagus nerve stimulation in treatment-resistant rapid-cycling bipolar disorder. J Clin Psychiatry. Feb 2008;69(2):183189. PMID 18211128 Cristancho P, Cristancho MA, Baltuch GH, et al. Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. J Clin Psychiatry. 2011;72(10):1376-1382. Tisi G, Franzini A, Messina G, et al. Vagus nerve stimulation therapy in treatment-resistant depression: a series report. Psychiatry Clin Neurosci. Aug 2014;68(8):606-611. PMID 25215365 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. Apr 2011;32(7):847855. PMID 21030409 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. Nov 2014;20(11):808-816. PMID 25187002 Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. Page 21 of 22 Zannad F, De Ferrari GM, Tuinenburg AE, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial. Eur Heart J. Feb 14 2015;36(7):425-433. PMID 25176942 Dawson J, Pierce D, Dixit A, et al. Safety, feasibility, and efficacy of vagus nerve stimulation paired with upper-limb rehabilitation after ischemic stroke. Stroke. Jan 2016;47(1):143-150. PMID 26645257 Handforth A, Ondo WG, Tatter S, et al. Vagus nerve stimulation for essential tremor: a pilot efficacy and safety trial. Neurology. Nov 25 2003;61(10):1401-1405. PMID 14638963 Bodenlos JS, Kose S, Borckardt JJ, et al. Vagus nerve stimulation acutely alters food craving in adults with depression. Appetite. Mar 2007;48(2):145-153. PMID 17081655 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. Sep 2011;12(9):1406-1413. PMID 21812908 Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia. Feb 2005;25(2):82-86. PMID 15658944 Cecchini AP, Mea E, Tullo V, et al. Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: preliminary data. Neurol Sci. May 2009;30 Suppl 1(suppl 1):S101-104. PMID 19415436 De Ridder D, Vanneste S, Engineer ND, et al. Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case series. Neuromodulation. Feb 2014;17(2):170-179. PMID 24255953 Aihua L, Lu S, Liping L, et al. A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy. Epilepsy Behav. Oct 2014;39:105-110. PMID 25240121 Stefan H, Kreiselmeyer G, Kerling F, et al. Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia. Jul 2012;53(7):e115118. PMID 22554199 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. Sep 2013;28(3):343-346. PMID 23820114 Hein E, Nowak M, Kiess O, et al. Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J Neural Transm. May 2013;120(5):821-827. PMID 23117749 Hasan A, Wolff-Menzler C, Pfeiffer S, et al. Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study. Eur Arch Psychiatry Clin Neurosci. Oct 2015;265(7):589-600. PMID 26210303 Shiozawa P, Silva ME, Carvalho TC, et al. Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review. Arq Neuropsiquiatr. Jul 2014;72(7):542-547. PMID 25054988 Gaul C, Diener HC, Silver N, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia. Sep 21 2015. PMID 26391457 Goadsby PJ, Grosberg BM, Mauskop A, et al. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. Oct 2014;34(12):986-993. PMID 24607501 Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information Vagus Nerve Stimulation 59. 60. 61. 62. 63. 64. Page 22 of 22 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. PMID 24968966 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. Sep 11 1999;53(4):666-669. PMID 10489023 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. Oct 15 2013;81(16):1453-1459. PMID 23986299 Association AP. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 2010; 3rd ed.:http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd. pdf. Accessed January 12, 2015. Martelletti P, Jensen RH, Antal A, et al. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J Headache Pain. Oct 21 2013;14(1):86. PMID 24144382 National Coverage Determination (NCD) for VAGUS Nerve Stimulation (VNS) (160.18). http://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?NCDId=230&ncdver=2&CoverageSelection=National&KeyWord=vagus&KeyWo rdLookUp=Title&KeyWordSearchType=And&where=%252520index&nca_id=%252520195& bc=gAAAABAAAAAAAA%3d%3d&. Accessed January 12, 2015. Other References: 1. Blue Cross and Blue Shield of Kansas Behavioral Health Liaison Committee, June 2006. 2. Blue Cross and Blue Shield of Kansas Behavioral Health Liaison Committee, June 2007. Current Procedural Terminology © American Medical Association. All Rights Reserved. Contains Public Information