|Subject:||Vagus Nerve Stimulation|
|Policy #:||SURG.00007||Current Effective Date:||04/05/2016|
|Status:||Revised||Last Review Date:||02/04/2016|
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.
Note: The use of vagal nerve blocking for the treatment of morbid obesity is addressed in the following document:
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 conditions, including, but not limited to:
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 6 partial onset seizures per month reduces seizure frequency by approximately 25% after 3 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; Yu, 2014). 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 three blinded, randomized controlled trials (Class I evidence); two nonblinded, randomized controlled trials (Class II evidence); ten 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 [CI], 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.
Orosz and colleagues (2014) conducted the largest retrospective multicenter study to date to gain insight into the long-term impact of VNS therapy in children with drug-resistant epilepsy. A total of 347 records of children, aged 6 months to 17.9 years (at the time of implant), were assessed for change in seizure frequency following VNS device implantation from baseline to 24 months of follow-up. At 6-, 12-, and 24 months after implantation, 32.5%, 37.6%, and 43.8% of children, respectively, had ≥ 50% reduction in baseline seizure frequency of the predominant seizure type. A subgroup of children who had no change in antiepileptic drugs during the study had a higher response rate. Favorable changes in secondary outcomes were reported in seizure duration, ictal severity, postictal severity, quality of life, clinical global impression of improvement, and safety measurements. A post hoc analysis demonstrated a statistically significant correlation between VNS total charge delivered per day and an increase in response rate. The study did not identify any new safety issues with use of VNS therapy in this group of children.
Ryvlin and colleagues (2014) published a randomized controlled trial reporting long-term quality of life outcomes for 112 individuals with drug-resistant focal seizures, which supports the beneficial effects of VNS for this group.
In a Cochrane review, Panebianco and colleagues (2015) systematically reviewed the available evidence in the peer-reviewed medical literature for the efficacy and tolerability of VNS when used as an adjunctive treatment for individuals with drug-resistant partial epilepsy. In five trials which included 439 participants, VNS appeared to be effective and well tolerated for the treatment of partial seizures. Results of the overall efficacy analysis showed that VNS using a high stimulation paradigm was significantly better than low stimulation in reducing frequency of seizures. In addition, results for the outcome "withdrawal of allocated treatment" suggested that VNS was well tolerated as withdrawals were rare. The authors reported no significant difference was found in withdrawal rates between the high and low stimulation groups; however, limited information was available, so important differences between high and low stimulation could not be excluded. Adverse effects associated with implantation and stimulation included hoarseness, cough, dyspnea, pain, paresthesia, nausea and headache, with hoarseness and dyspnea more likely to occur on high stimulation than low stimulation. The authors suggest, however, that further high quality research is needed to fully evaluate the long-term efficacy and tolerability of VNS for drug resistant partial seizures.
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 guideline states that VNS may be considered for seizures (both partial and generalized) in children, for LGS-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 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 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 4 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 United 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. A total of 7 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 (2007) subsequently initiated a national coverage analysis (NCA) to reconsider resistant depression as an additional indication for implantable VNS. 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 (Gelenberg, 2010) 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
Treatment of Chronic Heart Failure
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, 6-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.
Zannad and colleagues (2014) reported results from an industry-sponsored randomized, sham-controlled trial (NECTAR-HF) with outcomes from VNS in individuals with severe left ventricular (LV) dysfunction despite optimal medical interventions. A total of 96 participants implanted with VNS were randomized 2:1 to VNS ON or 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. A total of 59 of the 63 participants randomized to the intervention had paired pre-post data available; 28 of 32 participants randomized to control had paired data available. Analysis of trial data was a modified intention-to-treat. There were no significant differences between groups for the primary end point of change in left ventricular end systolic diameter (LVESD) from baseline to 6 months (p=0.60 between-group difference in LVESD change). Other secondary efficacy end points related to LV remodeling parameters, LV function, and circulating biomarkers of heart failure, did not differ between groups with the exception of a 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). A major limitation of this study includes flaws in the blinding of participants, which may have biased the subjective outcome data reporting.
Premchand and colleagues (2014) evaluated the use of a novel autonomic regulation therapy (ART) using either left or right VNS in 60 individuals with heart failure with reduced ejection fraction. In the ANTHEM-HF study, VNS was randomly assigned to right- or left-sided implantation (n=29 and 31, respectively). Participants followed from baseline to 6-month follow-up experienced improvements in LV ejection fraction by 4.5% (95% CI, 2.4 to 6.6), LV end systolic volume (LVESV) by -4.1 mL (95% CI, -9.0 to 0.8), LVESD by -1.7 mm (95% CI, -2.8 to -0.7), heart rate variability by 17 ms (95% CI, 6.5 to 28), and 6-minute walk distance by 56 m (95% CI, 37 to 75). Limitation of this study include the modest sample size, wide CIs of the estimated differences between left- and right-side VNS (clinically important differences could not be ruled out), and at least some of the clinical improvements were due to the placebo effect, especially in more subjective assessments. Further investigation is needed in a larger randomized controlled trial to confirm the results of this preliminary study.
Treatment of Other Conditions
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 review articles and studies explore the potential use of VNS in the treatment of acute asthma exacerbation (Miner, 2012; Yuan, 2015), autism (Danielsson, 2008), addictions, coma, pain syndromes (such as fibromylagia) (Lange, 2011), obesity-related food cravings in individuals with chronic TRD (Bodenlos, 2007), 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, active Crohn's disease despite treatment with a tumor necrosis factor (TNF) antagonist drug, 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 [NIH], 2015). 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 Transcutaneous VNS (t-VNS)
t-VNS for Pharmacoresistant Epilepsy
The safety and effectiveness of non-implantable, 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 2 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.
Aihua and colleagues (2014) reported results from a case series of 60 individuals with pharmacoresistant epilepsy treated with a t-VNS device. A total of 60 participants were equally randomized to receive either stimulation over the earlobe (control group) or the Ramsay-Hunt zone, which includes the external auditory canal and the conchal cavity and is considered to be the somatic sensory territory of the vagus nerve. Four participants from the treatment group and 9 participants from the control group were excluded from analysis due to loss to follow-up (n=3, treatment group; n=2, control group); adverse effects (n=1, treatment group), or increase or lack of decrease in seizures or other reasons (n=7, control group). Compared with baseline, the median monthly seizure frequency in the treatment group 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. However, the median seizure frequency in the treatment group was not significantly lower than that in the control group until 12-months of treatment (4.0 vs. 8.0; p<0.001). Limitations of this study include the small sample size, potential for unblinding in the control group as participants brought the instruments home for daily use and may have realized that they were in sham stimulation, and the study focused on seizure frequency with no comparison of different seizure syndromes.
t-VNS for Other Conditions
Hasan and colleagues (2015) conducted a bicentric randomized, sham-controlled, double-blind pilot study of the safety and efficacy of t-VNS in 20 individuals with stable schizophrenia. Participants in the active t-VNS group received daily active stimulation of the left auricle for 26 weeks. The sham t-VNS group received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. The primary outcome was defined as a change in the Positive and Negative Symptom Scale (PANSS) total score between baseline and week 12. In the intention-to-treat analysis from week 12 to week 26, the PANSS total scores were reduced by 8.5 (± 5.3) in the active t-VNS group and 5.1 (± 3.7) in the sham t-VNS group (switched to active treatment after week 12), with no significant differences between groups (p=0.52). The treatment was well tolerated with no significant adverse effects associated with use of the t-VNS device beyond local skin irritation or mild pain. The investigators concluded that "neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups"; however, further study of overall patterns of symptom change with use of t-VNS may be warranted in the treatment of individuals with schizophrenia.
Shiozawa and colleagues (2015) published the result of a systematic review of the peer-reviewed medical literature through 2013 evaluating the clinical utility of t-VNS and trigeminal nerve stimulation (TNS). Three t-VNS clinical trials assessed physiological features (that is, brain activation patterns and pain thresholds) in healthy volunteers and one trial evaluated use in individuals with pharmacoresistant epilepsy. One study was a crossover design and the remaining trials were open-label studies. This analysis was limited in drawing conclusions due to lack of standardization of study design and small study populations (n=84). The authors concluded that controlled trials measuring long-term outcomes are required before drawing conclusions concerning the clinical utility of t-VNS to improve health outcomes for any condition.
Goadsby and colleagues (2014) performed an open-label pilot study of portable t-VNS for the treatment of acute migraine with or without aura. A total of 27 from an initial sample size of 30 participants self-treated 80 migraine attacks (2 participants treated no migraine attacks with the device; 1 participant treated only an aura). Of the 54 moderate or severe attacks treated, 12 participants (22%) were pain-free at 2 hours post treatment. Adverse events reported by 13 participants were all considered mild or moderate.
Kreuzer and colleagues (2014) reported the results of a single-arm pilot study of t-VNS with 2 different devices for the treatment of tinnitus. A total of 48 participants were included in the primary intention-to-treat analysis. The primary outcome was a change in mean Tinnitus Questionnaire (TQ) score from baseline to 6-month follow-up, for the 24 participants in the first phase of the study who used an earlier generation t-VNS device (Cerbomed, Erlangen, Germany). For these participants, the TQ total score decreased by 3.7 points (p=0.036). A total of 9 participants (37.5%) were considered responders. In the second phase of the study, 24 participants who used the next generation t-VNS device reported a decrease by 2.8 points (p=0.014) in the mean TQ score. Eleven participants were considered responders (45.8%). A per-protocol analysis of 28 participants who received treatment reported no significant improvement in TQ scores. The authors concluded that t-VNS treatment did not result in clinically significant improvement in tinnitus complaints.
Huang and colleagues (2014) reported results of a pilot randomized controlled trial of a t-VNS device that provided stimulation to the auricle for the treatment of impaired glucose tolerance. A total of 70 participants were randomized to active or sham t-VNS, along with 30 controls who received no t-VNS treatment. After 12 weeks of treatment, participants who received active t-VNS were reported to have significantly lower 2-hour glucose tolerance test results than those who received sham t-VNS (7.5 vs. 8 mmol/L; p=0.004).
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 cluster headaches, 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-VNS device for any indication. Cerbomed GmbH 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.
Description of the Conditions
The Centers for Disease Control and Prevention (CDC, 2015) estimates about 2.4 million adults (aged 18 years or older) and 460,000 children (0-17 years of age) in the United States population in 2013 had active epilepsy. New cases of epilepsy are most common among children and older adults. According to the National Institute of Neurological Disorders and Stroke (NINDS, 2015) 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).
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.
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.
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.
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:
|61885||Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array|
|64553||Percutaneous implantation of neurostimulator electrode array; cranial nerve|
|64568||Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator|
|64569||Revision or replacement of cranial nerve (eg, vagus nerve) neurostimulator electrode array, including connection to existing pulse generator|
|95974-95975||Electronic 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|
|C1767||Generator, neurostimulator (implantable), nonrechargeable|
|L8679||Implantable neurostimulator, pulse generator, any type|
|L8680||Implantable neurostimulator electrode, each|
|L8685||Implantable neurostimulator pulse generator, single array, rechargeable, includes extension|
|L8686||Implantable neurostimulator pulse generator, single array, nonrechargeable, includes extension|
|00HE0MZ||Insertion of neurostimulator lead into cranial nerve, open approach|
|00HE3MZ||Insertion of neurostimulator lead into cranial nerve, percutaneous approach|
|00HE4MZ||Insertion of neurostimulator lead into cranial nerve, percutaneous endoscopic approach|
|G40.001-G40.919||Epilepsy 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.
|All other diagnoses, including, but not limited to:|
|E66.01-E66.9||Overweight and obesity|
|F30.10-F39||Mood (affective) disorders|
|G25.0-G25.2||Essential and other specified forms of tremor|
|G47.00-G47.9||Organic sleep disorders|
|G89.0||Central pain syndrome|
|G89.4||Chronic pain syndrome|
|K50.00-K50.919||Crohn's disease (regional enteritis)|
When services are also Investigational and Not Medically Necessary:
|E1399||Durable medical equipment, miscellaneous [when specified as a transcutaneous (non-implantable) VNS device]|
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
t-VNS System with NEMOS
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.
|Revised||02/04/2016||Medical Policy & Technology Assessment Committee (MPTAC) review. Added use of implantable VNS as investigational and not medically necessary for the treatment of asthma and pain syndromes. Added headaches (including cluster and migraine headaches), pain syndromes, schizophrenia, and tinnitus to the investigational and not medically necessary statement for use of non-implantable VNS.|
|Revised||01/29/2016||Behavioral Health Subcommittee review. Updated cross-reference in the Description. Added use of implantable VNS as investigational and not medically necessary for the treatment of asthma and pain syndromes. Added headaches (including cluster and migraine headaches), pain syndromes, schizophrenia, and tinnitus to the investigational and not medically necessary statement for use of non-implantable VNS. Updated Rationale, Coding, References, and Websites for Additional Information sections.|
|Revised||11/05/2015||MPTAC review. Updated Description, adding a cross-reference to SURG.00024 Surgery for Clinically Severe Obesity which addresses the use of vagal nerve blocking therapy (VBLOC) for the treatment of morbid obesity. Added use of VNS as investigational and not medically necessary for the treatment of Crohn's disease. Clarified use of VNS therapy as investigational and not medically necessary for obesity-related food cravings. Updated Rationale, Background, References, Websites for Additional Information, and Index sections. Updated Coding section to remove codes 0312T-0317T no longer addressed in this document, and removed ICD-9 codes.|
|Reviewed||01/30/2015||Behavioral Health Subcommittee review. Minor format changes and updates to Rationale, References and Websites for Additional Information sections.|
|Revised||08/14/2014||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.|
|Revised||08/08/2014||Behavioral 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.|
|01/01/2014||Updated Coding section with 01/01/2014 HCPCS changes.|
|Revised||08/08/2013||MPTAC 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.|
|01/01/2013||Updated Coding section with 01/01/2013 CPT changes.|
|Reviewed||08/03/2012||Behavioral Health Subcommittee review. Updated Rationale, Background, References, and Websites for Additional Information.|
|Reviewed||11/17/2011||MPTAC review. Updated Rationale, References, and Websites for Additional Information.|
|Revised||11/18/2010||MPTAC 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.|
|Revised||11/19/2009||MPTAC 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.|
|Reviewed||11/20/2008||MPTAC review. Rationale, Definitions, and References updated.|
|10/01/2008||Updated Coding section with 10/01/2008 ICD-9 changes.|
|Reviewed||11/29/2007||MPTAC 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."|
|Reviewed||12/07/2006||MPTAC review. Background/Overview updated.|
|Reviewed||09/14/2006||MPTAC review. References updated. Coding update: removed HCPCS E0752, E0754, E0756 deleted 12/31/05.|
|01/01/2006||Updated Coding section with 01/01/2006 CPT/HCPCS changes|
|11/22/2005||Added reference for Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD).|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
|Pre-Merger Organizations||Last Review Date||Document Number||Title|
|Anthem, Inc.||01/28/2004||SURG.00007||Vagus Nerve Stimulation Therapy|
|WellPoint Health Networks, Inc.||04/28/2005||2.10.05||Vagus Nerve Stimulation|