Medical Policy: 07.01.60
Original Effective Date: November 2000
Reviewed: September 2019
Revised: September 2018
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
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 include generalized seizures, and it has been investigated for a range of other conditions including chronic heart failure, headaches, treatment resistant depression, essential tremor, fibromyalgia, tinnitus, obesity, upper limb impairment due to stroke and autism.
Seizures are considered paroxysomal disorders (i.e. characterized by abnormal cerebral neuronal discharge) and occur when there is errant electrical discharge activity in the brain. Seizures cause different physical symptoms depending on the location of the electrical activity in the brain. They may be mild to severe, ranging from causing slight tingling sensation or momentary confusion to causing complete loss of consciousness. Classification and subtypes of seizures are commonly diagnosed by electroencephalography (EEG). The diagnosis of seizure requires that the clinician identify that the patient has had an epileptic seizure as opposed to some other type of paroxysmal event, and then establish the type of seizure(s).
Generalized seizures are further broken down into motor and non-motor (absence) seizures. Focal seizures are further subdivided based on level of awareness (aware, impaired awareness, or unknown awareness). Additionally, focal seizures are subgrouped into motor and non-motor seizures, based on signs and symptoms at onset. Additional descriptors for both generalized and focal seizures may be added based on specific motor or nonmotor symptoms. Focal seizures can also be more clearly described based on the elemental features (cognitive, automatisms, emotional or affective, motor, autonomic, sensory, laterality).
Epilepsies can be subdivided into generalized, focal, generalized and focal and unknown (epilepsy based on seizure type).
Vagus nerve stimulation (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 new, 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 anti-seizure medications. VNS is typically used when a patient has had unsuccessful medical therapy, been intolerant of medical therapy, or has failed resective surgery.
While the mechanisms for the therapeutic effects VNS are not fully understood, the basic premise of VNS in the treatment of various conditions is that vagal visceral afferents (nerves that convey impulses from sense organs and other receptors to the brain or spinal cord) have diffuse central nervous system projection, and the activation of these pathways has a widespread effect upon neuronal excitability. aN 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. VNS may also stimulate vagal efferent pathways that innervate the heart, vocal cords, and other laryngeal and pharyngeal muscles, and provider parasympathetic innervation to the gastrointestinal tract.VNS may also stimulate vagal efferent pathways that innervate the heart, vocal cords, and other laryngeal and pharyngeal muscles, and provider parasympathetic innervation to the gastrointestinal tract. Adverse effects of VNS therapy include headache, neck pain, cough and voice alterations.
Some of the benefits of using VNS may include less-severe or shorter seizures, a reduction in seizure frequency, improved recovery periods after seizures, and a lessening of seizure clusters. Individuals undergoing VNS must be aware that seizure control improves over time, and that although VNS may reduce the frequency and magnitude of seizure activity, the need remains for ongoing, concurrent, anti-seizure medical regimen.
Vagus nerve stimulation (VNS) is an implantable, programmable electronic pulse generator that delivers stimulation to the left vagus nerve at the carotid sheath. Surgery for implantation of a vagus 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.
The stimulator is generally activated two to four weeks after implantation, although in some cases it may be activated in the operating room at the time of implantation. The physician programs the stimulator with a small hand-held computer, programming software, and a programming wand. The strength and duration of the electrical impulses are programmed. The amount of stimulation varies by case, but is usually initiated at a low level and slowly increased to a suitable level for the individual.
Patients are provided with a handheld magnet to control the stimulator at home (which must be activated by the physician to magnet mode). When the magnet is placed over the pulse generator site and then moved away, extra stimulation is delivered, regardless of the treatment schedule. Holding the magnet over the pulse generator will turn the stimulation off. Removing it will resume the stimulation cycle. This can be done by the patient, family members, friends or caregivers.
Englot et. al. (2011) conducted a meta-analysis of the literature through November 2010 assessing the efficacy of vagal nerve stimulation (VNS) and its predictors of response. VNS is considered for use in patients who are poor candidates for resection or those in whom resection has failed. The meta-analysis identified 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 non-blinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, 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 > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. The authors concluded, VNS is an effective and relatively safe adjunctive therapy in patients 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 a quarter of patients do not receive any benefit from therapy.
Ryvlin et. al. (2014) reported on an open prospective randomized long term effectiveness trial (PuLsE) on the quality of life in patients with pharmacoresistant focal epilepsy. This trial evaluated whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to best medical practice (BMP) alone in improving long-term health related quality of life (HRQoL). This was conducted at 28 sites in Europe and Canada. Adults with pharmacoresistant focal seizures (n = 112) received VNS + BMP or BMP (1:1 ratio). Medications and VNS parameters could be adjusted as clinically indicated for optimal seizure control while minimizing adverse effects. Primary endpoint was mean change from baseline HRQoL (using Quality of Life in Epilepsy Inventory-89 total score; QOLIE-89). Secondary endpoints included changes in seizure frequency, responder rate (≥50% decrease in seizure frequency), Centre for Epidemiologic Studies Depression scale (CES-D), Neurological Disorders Depression Inventory-Epilepsy scale (NDDI-E), Clinical Global Impression-Improvement scale (CGI-I), Adverse Event Profile (AEP), and antiepileptic drug (AED) load. The study was prematurely terminated due to recruitment difficulties prior to completing the planned enrollment of n = 362. Results for n = 96 who had baseline and at least one follow-up QOLIE-89 assessment (from months 3-12) were included in this analysis. Mixed model repeated measures (MMRM) analysis of variance was performed on change from baseline for the primary and secondary endpoints. Significant between-group differences in favor of VNS + BMP were observed regarding improvement in HRQoL, seizure frequency, and CGI-I score (respective p-values < 0.05, 0.03, and 0.01). More patients in the VNS + BMP group (43%) reported adverse events (AEs) versus BMP group (21%) (p = 0.01), a difference reflecting primarily mostly transient AEs related to VNS implantation or stimulation. No significant difference between treatment groups was observed for changes in CES-D, NDDI-E, AEP, and AED load. The authors concluded, VNS therapy as a treatment adjunct to BMP in patients with pharmacoresistant focal seizures was associated with a significant improvement in HRQoL compared with BMP alone.
In 2015, Panebianco et. al. updated a Cochrane systematic review and meta-analysis of vagus nerve stimulation to treat partial seizures. Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with medically refractory epilepsy. VNS consists of chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator. The majority of people given a diagnosis of epilepsy have a good prognosis, and their seizures will be controlled by treatment with a single antiepileptic drug (AED), but up to 20%-30% of patients will develop drug-resistant epilepsy, often requiring treatment with combinations of AEDs. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of vagus nerve stimulation when used as an adjunctive treatment for people with drug-resistant partial epilepsy. The following study designs were eligible for inclusion: randomized, double-blind, parallel or crossover studies, controlled trials of VNS as add-on treatment comparing high and low stimulation paradigms (including three different stimulation paradigms - duty cycle: rapid, mid and slow) and VNS stimulation versus no stimulation or a different intervention. Eligible participants were adults or children with drug-resistant partial seizures not eligible for surgery or who failed surgery. Five trials recruited a total of 439 participants and between them compared different types of VNS stimulation therapy. Baseline phase ranged from 4 to 12 weeks and double-blind treatment phases from 12 to 20 weeks in the five trials. Overall, two studies were rated as having a low risk of bias and three had an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies of VNS is difficult due to the frequency of stimulation-related side effects such as voice alteration; this may limit the validity of the observed treatment effects. Four trials compared high frequency stimulation to low frequency stimulation and were included in quantitative syntheses (meta-analyses).The overall risk ratio (95% CI) for 50% or greater reduction in seizure frequency across all studies was 1.73 (1.13 to 2.64) showing that high frequency VNS was over one and a half times more effective than low frequency VNS. For this outcome, we rated the evidence as being moderate in quality due to incomplete outcome data in one included study; however results did not vary substantially and remained statistically significant for both the best and worst case scenarios. The risk ratio (RR) for treatment withdrawal was 2.56 (0.51 to 12.71), however evidence for this outcome was rated as low quality due to imprecision of the result and incomplete outcome data in one included study. The RR of adverse effects were as follows: (a) voice alteration and hoarseness 2.17 (99% CI 1.49 to 3.17); (b) cough 1.09 (99% CI 0.74 to 1.62); (c) dyspnea 2.45 (99% CI 1.07 to 5.60); (d) pain 1.01 (99% CI 0.60 to 1.68); (e) paresthesia 0.78 (99% CI 0.39 to 1.53); (f) nausea 0.89 (99% CI 0.42 to 1.90); (g) headache 0.90 (99% CI 0.48 to 1.69); evidence of adverse effects was rated as moderate to low quality due to imprecision of the result and/or incomplete outcome data in one included study. No important heterogeneity between studies was found for any of the outcomes. The authors concluded, VNS for partial seizures appears to be an effective and well tolerated treatment in 439 included participants from five trials. Results of the overall efficacy analysis show that VNS stimulation using the high stimulation paradigm was significantly better than low stimulation in reducing frequency of seizures. Results for the outcome "withdrawal of allocated treatment" suggest that VNS is well tolerated as withdrawals were rare. No significant difference was found in withdrawal rates between the high and low stimulation groups, however limited information was available from the evidence included in this review so important differences between high and low stimulation cannot be excluded . Adverse effects associated with implantation and stimulation were primarily hoarseness, cough, dyspnea, pain, paresthesia, nausea and headache, with hoarseness and dyspnea more likely to occur on high stimulation than low stimulation. However, the evidence on these outcomes is limited and of moderate to low quality. Further high quality research is needed to fully evaluate the efficacy and tolerability of VNS for drug resistant partial seizures.
The evidence for the efficacy of vagus nerve stimulation (VNS) for generalized seizures in adults is primarily from observational data, including registries and small cohort studies.
In 2013, Garcia-Navarrete et. al. evaluated the long term effects of vagus nerve stimulation (VNS) at 18 months of follow-up in a prospective study on epileptic patients who have been on unchanged antiepileptic medication. Forty-three patients underwent a complete epilepsy preoperative evaluation protocol, and were selected for VNS implantation. After surgery, patients were evaluated on a monthly basis, increasing stimulation 0.25mA at each visit, up to 2.5mA. Medication was unchanged for at least 18 months since the stimulation was started. The outcome was analyzed in relation to patients' clinical features, stimulation parameters, epilepsy type, magnetic resonance imaging (MRI) results, and history of prior brain surgery. Of the 43 operated patients, 63% had a similar or greater than 50% reduction in their seizure frequency. Differences in the responder rate according to stimulation intensity, age at onset of epilepsy, duration of epilepsy before surgery, previous epilepsy surgery and seizure type, did not reach statistical significance. Most side effects were well tolerated. The authors concluded, 62.8% of our series of 43 medication-resistant epileptic patients experienced a significant long-term seizure reduction after VNS, even in a situation of on unchanged medical therapy. Patient characteristics predictive of VNS responsiveness remain subject to investigation. Controlled studies with larger sample sizes, on VNS for patients with medication-resistant epilepsy on unchanged medication, are necessary to confirm VNS efficacy for drug-resistant epilepsy, and to identify predictive factors.
Englot et. al. (2016) examined freedom from seizure rates and predictors across 5554 patients enrolled in the vagus nerve stimulation (VNS) therapy Patient Outcome Registry, and also performed a systematic review of the literature including 2869 patients across 78 studies. Registry data revealed a progressive increase over time in seizure freedom after VNS therapy. Overall, 49% of patients responded to VNS therapy 0 to 4 months after implantation (≥50% reduction seizure frequency), with 5.1% of patients becoming seizure-free, while 63% of patients were responders at 24 to 48 months, with 8.2% achieving seizure freedom. On multivariate analysis, seizure freedom was predicted by age of epilepsy onset >12 years (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.38-2.58), and predominantly generalized seizure type (OR, 1.36; 95% CI, 1.01-1.82), while overall response to VNS was predicted by non-lesional epilepsy (OR, 1.38; 95% CI, 1.06-1.81). Systematic literature review results were consistent with the registry analysis: At 0 to 4 months, 40.0% of patients had responded to VNS, with 2.6% becoming seizure-free, while at last follow-up, 60.1% of individuals were responders, with 8.0% achieving seizure freedom. The authors concluded response and seizure freedom rates increase over time with VNS therapy, although complete seizure freedom is achieved in a small percentage of patients.
The evidence for vagus nerve stimulation for pediatric seizures consists of a variety of small non-comparator trials, prospective observational studies, and retrospective case series. Some studies have defined pediatric patients as less than 12 years of age and other have defined them as less than 18 years and may have included patients as young as 2 to 3 years of age. Study populations may have had prior failed respective surgery. Complete freedom from seizures is the exception, and the primary reported end point is 50% or more reduction in seizure frequency, determined over varying lengths of follow-up. There is an overlap of authors for multiple studies suggesting utilization of vagus nerve stimulation (VNS) is specialized clinical care environments. Multiple studies have some form of innovate device company sponsorship.
In 2012 Klinkenberg et. al. conducted a randomized controlled trial to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity in terms of tolerability and safety. In this study, 41 children (23 males; 18 females; mean age at implantation 11y 2mo, SD 4y 2mo, range 3y 10mo-17y 8mo) were included. Thirty-five participants had localization-related epilepsy (25 symptomatic; 10 cryptogenic), while six participants had generalized epilepsy (four symptomatic; two idiopathic). During a baseline period of 12 weeks, seizure frequency and severity were recorded using seizure diaries and the adapted Chalfont Seizure Severity Scale (NHS3), after which the participants entered a blinded active controlled phase of 20 weeks. During this phase, half of the participants received high-output VNS (maximally 1.75mA) and the other half received low-output stimulation (0.25mA). Finally, all participants received high-output stimulation for 19 weeks. For both phases, seizure frequency and severity were assessed as during the baseline period. Overall satisfaction and adverse events were assessed by semi-structured interviews. At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high-output stimulation group and in 21% of the low-output stimulation group (p=1.00). There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. Overall, VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add-on phase The overall seizure severity also improved (p<0.001). The authors concluded, VNS is safe and well-tolerated adjunctive treatment of epilepsy in children. The results suggest that the effect of VNS on seizure frequency in children is limited. However, the possible reduction in seizure severity and improvement in well-being makes this treatment worth considering in individual children with intractable epilepsy.
Cukiert et. al. (2013) reported on the outcome after vagus nerve stimulation (VNS) in children with generalized epilepsy. Twenty-four consecutive children with Lennox-Gastaut or Lennox-like syndrome under the age of 12 years by the time of surgery, who were implanted with a vagus nerve stimulator and had at least two years of post-implantation follow-up, were prospectively included in the study. The generator was turned on using 0.25 mA, 30 Hz, 500 μsec, 30 sec "on," 5 min "off" stimuli parameters; current was then increased by 0.25 mA every two weeks, until 3.5 mA was reached or adverse effects were noted. Magnetic resonance imaging was normal or showed atrophy in 13 children. Six children got an end-of-study (24 months) post-implantation video-electroencephalogram, and their findings were similar to those before VNS. Quality of life and health measures improved in up to 50% (mean = 25%) in 20 children. Attention was noted to improve in 21 out of the 24 children. Final intensity parameters ranged from 2 to 3.5 mA (mean = 3.1 mA). An implantation effect was noted in 14 out of the 24 children, and lasted a mean of 20.2 days. There were 47 seizure types among the 24 children. An at least 50% seizure frequency reduction was noted in 35 seizure types and 17 seizure types disappeared after VNS. Atypical absence, myoclonic and generalized tonic-clonic seizures were significantly reduced by VNS; tonic and atonic seizures did not improve. Transient seizure frequency worsening was noted in ten of the 24 children, at a mean of 3.1 mA. The authors concluded, our study showed that VNS was effective in reducing atypical absence, generalized tonic-clonic, and myoclonic seizures (but not atonic or tonic seizures) in children with Lennox-Gastaut or Lennox-like syndrome. A concomitant improvement in attention level and quality of life and health also was noted. Secondary generalized epilepsy represents a subset of good candidates for VNS.
Healy et. al. (2013) assessed the efficacy and safety of vagal nerve stimulation (VNS) in children less than 12 years of age. This was a retrospective review of patients undergoing VNS insertion, over a 3 year period. All children had a minimum follow-up period of 2 years. Sixteen patients were identified via the pediatric epilepsy surgery database. A case note review and telephone evaluation as conducted. Seizure frequency using the McHugh classification was the primary outcome measure, with anti-epileptic drug (AED) use as a secondary outcome measure. There were 10 males and 6 females. The mean time with epilepsy prior to surgery was 5.7 years and the mean age at the time of surgery was 7.6 years. Overall, nine (56%) children experienced a reduction in their seizure frequency of 50 % or more. Of these, four (25%) had a reduction of more than 80%. Seven children (44%) had no reduction in their seizure frequency, although two of these patients reported benefit regarding seizure control and post-ictal recovery. The VNS system was removed in two patients due to infection and no benefit, respectively. Half of the cohort (50%) reduced the number of anti-epileptic drugs post-surgery, and there was an overall mean reduction of AED of 0.5. The authors concluded, this study suggests VNS is a safe and effective adjuvant therapy in children under 12 years of age, with over half reporting significant benefit. Further studies are needed to enable preoperative selection of patients in order to maximize the potential benefit.
In 2014 Terra et. al. reported on a case control prospective study of children with refractory epilepsy submitted to vagal nerve stimulator (VNS) implantation and a control group with epilepsy treated with antiepileptic drugs. Patients under 18 years of age who underwent clinical or surgical treatment because of pharmacoresistant epilepsy from January 2009 to January 2012 were followed and compared with an age-matched control group at final evaluation. Statistically significant differences were observed considering age at epilepsy onset (VNS group - 1.33±1.45years; controls - 3.23±3.11; p=0.0001), abnormal findings in neurological examination (p=0.01), history of previous ineffective epilepsy surgery (p=0.03), and baseline seizure frequency (p=0.0001). At long-term follow-up, 55.4% of the patients in the VNS group had at least 50% reduction of seizure frequency, with 11.1% of the patients presenting 95% reduction on seizure frequency. Also, a decrease in traumas and hospitalization due to seizures and a subjective improvement in mood and alertness were observed. The control group did not show a significant modification in seizure frequency during the study. In this series, VNS patients evolved with a statistically significant reduction of the number of seizures, a decreased morbidity of the seizures, and the number of days in inpatient care. In accordance with the current literature, VNS has been proven to be an effective alternative in the treatment of pediatric patients with drug-resistant epilepsy.
Yu et. al. evaluated the efficacy of vagus nerve stimulation (VNS) in pediatric patients with medically refractory epilepsy in a retrospective single center experience case review. Medical records were reviewed of 252 consecutive patients who underwent VNS implantation at a single center over a 5-year period. Patients with complete 6- and 12-month follow-up data were included. Analysis was also done across various subgroups including gender, age at implantation, seizure type, abnormal MRI findings pre-implantation, number of medications at baseline, history of side effects (SE), and duration of epilepsy. Complete follow-up data were available for 69 patients. Median seizure reduction for these patients was 50% (Q1: 0%; Q3: 73%) at 6 months and 40% (Q1: -25%; Q3: 75%) at 12 months. When stratified by baseline seizure frequency, there was a significant reduction from baseline of 61% at 6 months and 69% at 12 months for patients in the high-baseline frequency group. There were no significant reductions at month 6 or 12 months for the lower-baseline frequency group. Adverse events were reported in 40.6% (28 out of 69 patients). Six patients had the VNS removed for reasons including lack of efficacy and side effects and were excluded from the study group. The authors concluded, VNS provides significant seizure reduction, in particular in pediatric patients with higher baseline seizure frequency.
The evidence on the efficacy of vagus nerve stimulation (VNS) for treatment of medically refractory seizures consists of randomized controlled trials (RCTs) at the time of initial U.S. Food and Drug Administration approval of the marketed device, two recent meta-analysis, 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 and case series have consistently reported reductions of clinical significance, defined as a 50% or more reduction in seizure frequency in both adults and children over almost 2 decades of publications. Interpretation of all outcomes and results were limited by the variety of comparators (when used), variability in length of follow-up, limited published data on antiepileptic medication requirements, mixed seizure etiologies, and history of prior failed resective surgery. Multiple studies have some form of innovator device company sponsorship.
Interest in the application of vagus nerve stimulation (VNS) for treatment of treatment resistant depression is related to reports of improvement in depressed mood among epileptic patients undergoing VNS. TEC Assessments by BlueCross and BlueShield Association (BCBSA) written in 2005 and updated in 2006 concluded the evidence was insufficient to permit conclusions about the effect of VNS therapy on depression. The available evidence included study groups assembled by the manufacturer of the device (Cyberonics) and have since been reported on in various publications. Analyses from these study groups were presented for Food and Drug Administration review (summary of safety and effectiveness data), and consisted of case series of 60 patients receiving VNS, a short term (i.e. 3 month) sham-controlled randomized trial of 221 patients, and an observational study comparing 205 patients on VNS therapy with 124 patients receiving ongoing treatment for depression. Patients who responded to sham treatment in the short-term randomized controlled trial (RCT) 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. Improvement in depression symptoms may allow reduction of pharmacologic therapy for depression, with a reduction in adverse events related to that form of treatment. In the studies evaluating VNS therapy, the four 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).
In 2012, Martin et. al. conducted a systematic review and meta-analysis of vagus nerve stimulation (VNS) in the treatment of depression. The efficacy was evaluated according to severity of illness and percentage of responder. They identified 687 references, and of these 14 met selection criteria and were included in the review. The meta-analysis of efficacy for uncontrolled studies showed a significant reduction in scores at the Hamilton Depression Rating Scale endpoint, and the percentage of responders was 31.8% ([23.2% to 41.8%], P<0.001). However, the randomized control trial (RCT) which covered a sample of 235 patients with depression, reported no statistically significant differences between the active intervention and placebo groups (OR=1.61 [95%CI 0.72 to 3.62]; P=0.25). To study the cause of this heterogeneity, a meta-regression was performed. The adjusted coefficient of determination (R2(Adj)) was 0.84, which implies that an 84% variation in effect size across the studies was explained by baseline severity of depression (P<0.0001). The authors concludes, there was insufficient data available to describe VNS as effective in the treatment of depression. In addition, it cannot be ruled out that the positive results observed in the uncontrolled studies might have been mainly due to a placebo effect.
Berry et. al (2013) reported on the results from a meta-analysis evaluating vagus nerve stimulation (VNS) therapy for treatment resistant depression. The objective of the study was to compare response and remission rates in depressed patients with chronic treatment resistant depression (TRD) treated with vagus nerve stimulation therapy plus treatment as usual (VNS + TAU) or TAU alone. Six outpatient, multicenter, clinical trials that have evaluated VNS + TAU or TAU in TRD, including two single-arm studies of VNS + TAU (n = 60 and n = 74), a randomized study of VNS + TAU versus TAU (n = 235), a randomized study of VNS + TAU comparing different VNS stimulation intensities (n = 331), a nonrandomized registry of VNS + TAU versus TAU (n = 636), and a single-arm study of TAU (n = 124) to provide longer-term, control data for comparison with VNS-treated patients. Response was based on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions scale's Improvement subscale (CGI-I), as these were the two clinician-rated measures common across all or most studies. Remission was based on the MADRS. Outcomes were compared from baseline up to 96 weeks of treatment with VNS + TAU (n = 1035) versus TAU (n = 425). The MADRS response rate for VNS + TAU at 12, 24, 48, and 96 weeks were 12%, 18%, 28%, and 32% versus 4%, 7%, 12%, and 14% for TAU. The MADRS remission rate for VNS + TAU at 12, 24, 48, and 96 weeks were 3%, 5%, 10%, and 14% versus 1%, 1%, 2%, and 4%, for TAU. Adjunctive VNS Therapy was associated with a greater likelihood of response (odds ratio [OR] = 3.19, 95% confidence interval [CI]: 2.12, 4.66) and remission (OR = 4.99, CI: 2.93, 7.76), compared with TAU. For patients who had responded to VNS + TAU at 24 weeks, sustained response was more likely at 48 weeks (OR = 1.98, CI: 1.34, 3.01) and at 96 weeks (OR = 3.42, CI: 1.78, 7.31). Similar results were observed for CGI-I response. The authors concluded that adjunctive VNS was associated with a greater likelihood of treatment response, however, the meta-analysis did not have systematic study selection criteria, limiting the conclusions that can be drawn from it.
In 2013, Aaronson et. al. reported on results from randomized controlled trial in which 331 patients with a history of chronic or recurrent bipolar disorder or major depressive disorder, with a current diagnosis of major depressive episode, were randomized to 1 of 3 VNS current doses (high, medium, low). 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 were no statistically significant differences between the dose groups for the study’s primary outcome, change in IDS score from baseline. However, mean IDS scores 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 no-treatment control group. Approximately 20% of patients included had a history of bipolar disorder; as such, the result might not be representative of most patients with treatment-resistant unipolar depression.
Liu et. al. (2014) conducted a systematic review of brain stimulation treatments, including deep brain stimulation, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS), for late life mental illnesses excluding unipoloar nonpsychotic depression in adults 65 years and older. The search identified 1,181 publications, of which 43 met the inclusion criteria: 24 were related to the treatment of non-unipolar depression (ECT: 21; rTMS: 2; ECT and rTMS: 1), 14 related to dementia (ECT: 7[2 of these studies were also related to depression]; vagal nerve stimulation: 2; rTMS: 4; deep brain stimulation: 1), and 7 to schizophrenia (ECT: 7). These studies reported a high degree of variability in efficacy and safety with promising results in general, particularly in the treatment of dementia and schizophrenia. Most publications were limited by small sample sizes, lack of control conditions, and lack of randomization. Large studies with a randomized controlled design or other designs such as crossover or off-on-off-on are needed.
Several cases series do not substantially strengthen the evidence supporting VNS therapy for treatment resistant depression.
The randomized controlled trial (RCT) evaluating the efficacy of vagus nerve stimulation (VNS) therapy for treatment resistant depression reported only short-term results and found no significant improvement in 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 groups. Further large randomized controlled studies are needed. 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 treatment resistant depression.
Vagus nerve stimulation (VNS) therapy has been investigated for the treatment of chronic heart failure.
In a 2011 case series De Ferrari et. al. assessed safety and tolerability of chronic vagal nerve stimulation (VNS) in symptomatic congestive heart failure (CHF) patients. The secondary goal was to obtain preliminary data on clinical efficacy. The multi-center open label phase II two staged study (8-patient feasibility phase plus 24-patient safety and tolerability phase) enrolled 32 New York Heart Association (NYHA) class II-IV patients [age 56 ± 11 years, LV ejection fraction (LVEF) 23 ± 8%]. Right cervical VNS with CardioFit (BioControl Medical) implantable system started 2-4 weeks after implant, slowly raising intensity; patients were followed 3 and 6 months thereafter with optional 1-year follow-up. Overall, 26 serious adverse events (SAEs) occurred in 13 of 32 patients (40.6%), including three deaths and two clearly device-related AEs (post-operative pulmonary edema, need of surgical revision). Expected non-serious device-related AEs (cough, dysphonia, and stimulation-related pain) occurred early but were reduced and disappeared after stimulation intensity adjustment. There were significant improvements (P < 0.001) in NYHA class quality of life, 6-minute walk test (from 411 ± 76 to 471 ± 111 m), LVEF (from 22 ± 7 to 29 ± 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year. The authors concluded, this open label study shows that chronic VNS in CHF patients with severe systolic dysfunction may be safe and tolerable and may improve quality of live and left ventricular (LV) function. A controlled clinical trial appears warranted.
The ANTHEM-HF trial (2014 Premchand et. al.) is another case series, which a evaluated automonic regulation therapy (ART) via either left or right vagus nerve stimulation (VNS) in patients with heart failure (HF) and reduced ejection fraction. Sixty subjects (New York Heart Association [NYHA] functional class II-III, left ventricular ejection fraction (LVEF) ≤ 40%, left ventricular end-diastolic diameter ≥ 50 mm to < 80 mm) receiving optimal pharmacologic therapy were randomized at 10 sites. VNS systems were randomly implanted on the left (n = 31) or right (n = 29) side. All patients were successfully implanted and 59 were titrated over 10 weeks to a well-tolerated stimulation intensity. One patient died 3 days after an embolic stroke that occurred during implantation. Common device-related adverse events after VNS titration were transient mild dysphonia, cough, and oropharyngeal pain, which were similar for left- and right-side VNS. After 6 months of ART, the adjusted left-right differences in LVEF, left ventricular end-systolic volume (LVESV), and left ventricular end-systolic diameter (LVESD) were 0.2% (95% CI -4.4 to 4.7), 3.7 mL (95% CI -7.0 to 14.4), and 1.3 mm (95% CI -0.9 to 3.6), respectively. In the combined population, absolute LVEF improved by 4.5% (95% CI 2.4-6.6), LVESV improved by -4.1 mL (95% CI -9.0 to 0.8), and LVESD improved by -1.7 mm (95% CI -2.8 to -0.7). Heart rate variability improved by 17 ms (95% CI 6.5-28) with minimal left-right difference. Six-minute walk distance improved an average of 56 m (95% CI 37-75); however, improvement was greater for right-side ART (77 m [95% CI 49-105]). NYHA functional class improved in 77% of patients (baseline to 6 months). The authors concluded, chronic open-loop ART via left or right VNS is feasible and well tolerated in reduced ejection fraction patients. Safety and efficacy measures are encouraging and warrant further study.
In 2015, Zannad et. al. reported on results from NECTAR-HF which was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodeling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy. Patients were randomized in a 2:1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-hour holter, and circulating biomarkers. Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was -0.04 ± 0.25 cm in the therapy group compared with -0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group. The authors concluded, vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodeling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement. Additional clinical research still needs to be performed to determine if alternative translation methods can become an effective heart failure therapy.
Dawson et. al. (2016) conducted a randomized controlled clinical pilot study of vagus nerve stimulation (VNS) paired with rehabilitation on upper-limb function after ischemic stroke. Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl-Meyer Assessment-Upper Extremity). Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl-Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, -0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl-Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6). There were limitations to the study to consider. This study was not blinded to either the physiotherapies delivering the therapy or the participant, and there was no sham stimulation group. Furthermore, the study was small leading to impression in some of the efficacy assessments. The authors concluded, VNS paired with rehabilitation therapy is feasible in adult with arm weakness ≥ 6 months after ischemic stroke. It also seems to be acceptably safe for further study.
Vagus nerve stimulation (VNS) has been investigated with small pilot studies evaluating the mechanism of disease for several conditions. These conditions include essential tremor, fibromyalgia, headaches, and tinnitus. The utility of VNS added to behavioral management of autism and autism spectrum disorders has been suggested, but there are no randomized controlled trials. None of these studies are sufficient to draw conclusions on the effect of VNS on these conditions.
In other conditions evaluated with randomized controlled trials (RCTs) (heart failure, upper-limb impairment), the trials failed to show the efficacy of vagus nerve stimulation (VNS) for the primary outcome. Other conditions (essential tremor, headache, fibromyalgia, tinnitus, autism) have only been investigated with case series, which are not sufficient to draw conclusions on the effect of vagus nerve stimulation (VNS).
Vagus nerve stimulation (VNS) has been studied in the treatment of obesity and it has been suggested that VNS might affect food cravings of individuals. However, limitations in studies include small sample size, lack of randomization and heterogeneity of groups that prevented conclusions about impact of VNS on eating behavior. Study findings need to be validated in large, well designed controlled studies to evaluate the impact of VNS on eating behavior and obesity.
Transcutaneous vagus nerve stimulation (tVNS) is being investigated as a noninvasive alternative to surgery for implantable vagus nerve stimulation (VNS) and is being investigated for a number of indications including but not limited to headaches (migraine and cluster), psychiatric disorders (depression, schizophrenia), epilepsy, traumatic brain injury (TBI) and impaired glucose tolerance.
A non-implantable transcutaneous vagus nerve stimulation (tVNS) (gammaCore®) is a hand held battery powered stimulation unit that sends gentle, patented stimulation through the skin to activate the vagus nerve. The stimulation treatment is administered by the individual for several hours per day.
A non-implantable transcutaneous vagus nerve stimulation (tVNS) hand held battery powered stimulation units may also include an ear electrode to stimulate the auricular branch of the vagus nerve through the skin over the concha of the outer ear to deliver treatment.
Vagus nerve stimulation (VNS) is being investigated to augment recovery from traumatic brain injury. It is proposed that early stimulation of the vagus nerve accelerates the rate and extent of behavioral and cognitive recovery after fluid percussion brain injury in rats. Shi et. al. (2013) received FDA approval to conduct a pilot prospective randomized trial to demonstrate objective improvement in clinical outcome by placement of VNS in individuals who are recovering from severe traumatic brain injury. If this study demonstrates that VNS can be safely and positively impact outcome, then a larger randomized prospective crossover trial will be proposed.
There is currently an ongoing clinical trial NCT02974959, single center prospective randomized (1:1), double blind, sham controlled parallel arm pilot study to provide initial evidence of the use of the noninvasive vagus nerve stimulator (VNS) for treatment in patients recovering from concussion and moderate traumatic brain injury to improve clinical recovery. The study is comparing the safety and effectiveness of an active gammaCore treatment against sham treatment. This is a Phase I study, looking to recruit 30 participants with an estimated completion date of June 2019.
The FDA approval for gammaCore® was based on subgroup analyses from two clinical trials for the Acute Treatment of Cluster Headache (ACT1 and ACT2). Both trials were prospective, double-blind, placebo controlled, randomized controlled trials (RCTs) evaluating the use of gammaCore® (non-invasive VNS [nVNS]) versus sham treatment.
Gaul et. al. (2016) conducted a randomized controlled study (PREVA) on non-invasive vagus nerve stimulation (nVNS) as adjunctive prophylactic treatment of chronic cluster headache (CH). PREVA was a prospective, open-label, randomized study that compared adjunctive prophylactic nVNS (n = 48) with standard of care (SoC) alone (control (n = 49)). A two-week baseline phase was followed by a four-week randomized phase (SoC plus nVNS vs control) and a four-week extension phase (SoC plus nVNS). The primary end point was the reduction in the mean number of CH attacks per week. Response rate, abortive medication use and safety/tolerability were also assessed. During the randomized phase, individuals in the intent-to-treat population treated with SoC plus nVNS (n = 45) had a significantly greater reduction in the number of attacks per week vs controls (n = 48) (-5.9 vs -2.1, respectively) for a mean therapeutic gain of 3.9 fewer attacks per week (95% CI: 0.5, 7.2; p = 0.02). Higher ≥50% response rates were also observed with SoC plus nVNS (40% (18/45)) vs controls (8.3% (4/48); p < 0.001). No serious treatment-related adverse events occurred. The study lacked a sham placebo control group, which might have resulted in placebo response in the tVNS group.
Silberstein et. al. (2016) evaluated non-invasive vagus nerve stimulation (nVNS) for the acute treatment of cluster headaches in a randomized, double-blind, shame controlled ACT1 study. One hundred fifty individuals were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double-blind phase; completers could enter a 3-month nVNS open-label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15-60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified. The intent-to-treat population comprised 133 individuals: 60 nVNS treated (eCH, n = 38; cCH, n = 22) and 73 sham-treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS-treated subjects and 15.1% of sham-treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double-blind phase and 18/128 subjects in the open-label phase. No serious ADEs occurred. Importantly, the study was not powered to demonstrate independent statistical significance for the subgroup analyses, nor were the P values adjusted for multiple comparisons. The authors concluded the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected the results in the total population. This represents a novel and promising option for eCH.
In 2018, Goadsby et. al. reported on a randomized, double-blind, sham controlled ACT2 study for non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). Methods After completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%; p < 0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup. The authors concluded, combining both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy but not in cCH. These results confirm extended previous findings regarding the efficacy, safety, and tolerability of nVNS for the treatment of eCH.
Noninvasive transcutaneous vagus nerve stimulation (nVNS) has been investigated for episodic cluster headaches in three randomized controlled trials (RCTs). One RCT assessing cluster headache showed a reduction in headache frequency but did not have a sham treatment group. Two randomized, double-blinded, sham-controlled studies (ACT1 and ACT2) showed efficacy in achieving pain-free status within 15 minutes of treatment with t-VNS. However, the ACT1 and ACT2 studies had small episodic cluster headache subgroups 85 (38 treated, 45 sham) and 27 (14 treated, 13 sham) respectively. Additional studies with larger cohorts of patients with episodic cluster headache are required given the small sample sizes evaluated in these trials.
Goadsby et. al. (2014) reported on results from an open label pilot study to assess noninvasive vagus nerve stimulation (nVNS) for acute treatment of migraine. Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain. Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching (n = 1), raspy voice (n = 1) and redness at the device site (n = 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%).
In 2017, Tso et. al. evaluated the records of 15 patients treated with noninvasive vagus nerve stimulation (nVNS) (gammaCore) for paroxysmal hemicrania (n=6) or hemicrania continue (n=9) as primary treatment or as an adjunct to indomethacin. Symptom related outcomes included reduction of pain severity and reduced frequency of attacks: for the first, 7 hemicrania continua patients saw improvement with tVNS therapy, as did 3 patients with paroxysmal hemicranias. The frequency of attacks was reduced for 2 hemicrania continua patients and 2 paroxysmal hemicranias patients. Some adverse events were reported in all patients, although not detailed. The authors concluded, the initial experience suggests that nVNS may be an important alternative or adjunctive therapy for patients with these indomethacin sensitive TACs (trigeminal autonomic cephalgias) who are unable to tolerate indomethacin. Conducting a prospective, randomized, and sham-controlled study seems warranted, although given the rarity of the problem, this will be a considerable challenge.
Two small case series were identified using transcutaneous vagus nerve stimulation (t-VNS) for treatment of medication refractory seizures.
Stefan et. al. (2012) reported on a proof of concept trial on transcutaneous vagus nerve stimulation (t-vns) in pharmacoresistant epilepsies. t-VNS was applied to 10 patients with pharmacoresistant epilepsies. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered three times per day for 9 months. Subjective documentation of stimulation effects was obtained from patients' seizure diaries. For a more reliable assessment of seizure frequency, prolonged outpatient video-electroencephalography (EEG) monitoring was carried out. In addition, computerized testing of cognitive, affective, and emotional functions was performed. Three patients aborted the study. Of the remaining seven patients, an overall reduction of seizure frequency was observed in five patients after 9 months of t-VNS. The authors concluded, t-VNS stimulation might be an alternative treatment option for patients with epilepsy.
In 2013, He et. al. investigated in a pilot trial the safety and efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of pediatric epilepsy. Fourteen pediatric patients with intractable epilepsy were treated by ta-VNS of the bilateral auricular concha using an ear vagus nerve stimulator. The baseline seizure frequency was compared with that after 8weeks, from week 9 to 16 and from week 17 to the end of week 24, according to the seizure diaries of the patients. One patient dropped out after 8weeks of treatment due to lack of efficacy, while the remaining 13 patients completed the 24-week study without any change in medication regimen. The mean reduction in seizure frequency relative to baseline was 31.83% after week 8, 54.13% from week 9 to 16 and 54.21% from week 17 to the end of week 24. The responder rate was 28.57% after 8weeks, 53.85% from week 9 to 16 and 53.85% from week 17 to the end of week 24. No severe adverse events were reported during treatment. The authors concluded, transcutaneous auricular VNS (ta-VNS) may be a complementary treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy and should be further studied.
One randomized controlled trial (RCT) was identified. Aihua et. al. (2014) explored the efficacy and safety of transcutaneous vagus nerve stimulation (t-VNS) in patients with pharmacoresistant epilepsy in a controlled trial. A total of 60 patients were randomly divided into two groups based on the stimulation zone: the Ramsay-Hunt zone (treatment group) and the earlobe (control group). Before and after the 12-month treatment period, all patients completed the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Liverpool Seizure Severity Scale (LSSS), and the Quality of Life in Epilepsy Inventory (QOLIE-31). Seizure frequency was determined according to the patient's seizure diary. During the study, the antiepileptic drugs were maintained at a constant level in all subjects. After 12 months, the monthly seizure frequency was lower in the treatment group than in the control group (8.0 to 4.0; P=0.003). This reduction in seizure frequency was correlated with seizure frequency at baseline and duration of epilepsy (both P>0.05). Additionally, all patients showed improved SAS, SDS, LSSS, and QOLIE-31 scores that were not correlated with a reduction in seizure frequency. The side effects in the treatment group were dizziness (1 case) and daytime drowsiness (3 cases), which could be relieved by reducing the stimulation intensity. In the control group, compared with baseline, there were no significant changes in seizure frequency (P=0.397), SAS, SDS, LESS, or QOLIE-31. There were also no complications in this group.
Hein et. al. (2013) reported on results of a randomized controlled pilot study on auricular transcutaneous electrical nerve stimulation in the treatment of major depressive disorder. A total of 37 patients suffering from major depression were included in two randomized sham controlled add-on studies. Patients were stimulated five times a week on a daily basis for the duration of 2 weeks. On days 0 and 14, the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI) were assessed. In contrast to sham-treated patients, electrically stimulated persons showed a significantly better outcome in the BDI. Mean decrease in the active treatment group was 12.6 (SD 6.0) points compared to 4.4 (SD 9.9) points in the sham group. HAMD score did not change significantly in the two groups. An antidepressant effect of a new transcutaneous auricular nerve stimulation technique has been shown for the first time in this controlled pilot study. Regarding the limitations of psychometric testing, the risk of unblinding for technical reasons, and the small sample size, further studies are necessary to confirm the present results and verify the practicability of tVNS in clinical fields.
In 2014, Shiozawa et. al. conducted a systematic review of studies evaluating trigeminal nerve stimulation (TNS) and transcutaneous vagus nerve stimulation (t-VNS). They found 4 studies addressing t-VNS for psychiatric disorders (total N=84 subjects). Overall the studies assessed were limited by small size and poor generalizability.
Hasan et. al. (2015) reported on a bicentric randomized controlled pilot study for transcutaneous noninvasive vagus nerve stimulation (t-VNS) in the treatment of schizophrenia. The objective of the study was to investigate the feasibility, safety and efficacy. This bicentric randomized, sham-controlled, double-blind trial was conducted from 2010 to 2012. Twenty schizophrenia patients were randomly assigned to one of two treatment groups. The first group (active tVNS) received daily active stimulation of the left auricle for 26 weeks. The second group (sham tVNS) received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. Primary outcome was defined as change in the Positive and Negative Symptom Scale total score between baseline and week 12. Various other secondary measures were assessed to investigate safety and efficacy. The intervention was well tolerated with no relevant adverse effects. They did not observe a statistically significant difference in the improvement of schizophrenia psychopathology during the observation period. Neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups. Application of tVNS was well tolerated, but did not improve schizophrenia symptoms in the 26-week trial. While unsatisfactory compliance questions the feasibility of patient-controlled neurostimulation in schizophrenia, the overall pattern of symptom change might warrant further investigations in this population.
In 2014, Huang et. al. conducted pilot randomized clinical trial comparing the efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) and sham ta-VNS on patients with impaired glucose tolerance (IGT)-. Seventy-two participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham ta-VNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc). One hundred participants completed the study and were included in data analysis. Two female patients (one in the ta-VNS group, one in the sham ta-VNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham ta-VNS, ta-VNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, ta-VNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham ta-VNS. Compared with the no-treatment control group, patients receiving ta-VNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period. There were several limitations in this study: treatments in this study were self-administered by the patients, thus patient compliance may have influenced the observed results; the treatment was only 12 weeks in duration, therefore the results obtained only represent its short or mid-term effect, further study is warranted to evaluate the long-term effects of this treatment option; blood glucose levels were measured at three time points (baseline, after 6 weeks, and after 12 weeks) for statistic analysis, since blood glucose levels may be affected by food intake of the previous day a more frequent measurement in the future study may provide more reliable information for the influence of treatment on blood glucose levels; and no treatment control group was not included in the randomization scheme, as were the other two treatment groups. The authors concluded that this pilot study demonstrates that ta-VNS can reduce two hour glucose tolerance and systolic blood pressure, however, further studies are warranted to include longer follow-up to evaluate the long-term effects of this treatment option.
The evidence for transcutaneous vagal nerve stimulation (t-VNS) in individuals who have epilepsy, depression, schizophrenia, headache (episodic cluster headaches and migraines), traumatic brain injury or impaired glucose tolerance includes small randomized trials, case series and systematic review. Studies are all small and have various methodologic problems. None show definitive efficacy of transcutaneous vagal nerve stimulation (t-VNS) in improving outcomes among patients. Current studies are limited by lack of a comparator and small sample sizes. Further studies are needed to determine the safety and efficacy. The evidence is insufficient to determine the effects of this technology on net health outcomes.
For individual who have seizures refractory to medical treatment that have received vagus nerve stimulation (VNS), the evidence includes randomized controlled trials (RCTs) and multiple observational studies. The RCTs have reported significant reductions in seizure frequency for patients with partial-onset seizures. The uncontrolled studies have consistently reported large reductions in a broader range of seizure types in both adults and children. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have treatment resistant depression who receive vagus nerve stimulation (VNS), the evidence includes randomized controlled trial (RCT), nonrandomized comparative studies, and case series. The RCT only reported short-term results and found no significant improvement in the primary outcome. Other available studies are limited by small sample sizes, potential selection bias, and lack of a control groups in the case series. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have chronic heart failure who receive vagus nerve stimulation (VNS), the evidence includes RCTs and case series. The RCTs evaluating chronic heart failure did not show significant improvements in the primary outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have upper-limb impairment due to stroke who receive vagus nerve stimulation (VNS), the evidence includes a single pilot study. This pilot study has provided preliminary support for improvement in functional outcomes. However, the evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have other neurologic conditions (e.g. essential tremor, headache, fibromyalgia, tinnitus, autism) who receive vagus nerve stimulation (VNS), the evidence includes case series. Case series are insufficient to draw conclusions regarding efficacy. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals in the treatment of obesity who receive vagus nerve stimulation, the evidence is limited and has small sample size, lack of randomization and heterogeneity of groups that prevented conclusions about impact of VNS on eating behavior. Study findings need to be validated in large, well designed controlled studies to evaluate the impact of VNS on eating behavior and obesity. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals with episodic cluster headaches who receive transcutaneous vagus nerve stimulation (t-VNS), the evidence includes three randomized controlled trials (RCTs). One RCT showed a reduction in headache frequency but did not include a sham treatment group. Two randomized, double-blind, sham-controlled studies showed efficacy of achieving pain free status within 15 minutes of treatment with noninvasive VNS in patients with episodic cluster headaches but not in patients with chronic cluster headaches. The RCTs for episodic cluster headaches are promising, however, additional studies with larger relevant populations are required to establish the treatment efficacy. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals with neurologic, psychiatric, or metabolic disorders (e.g. epilepsy, depression, schizophrenia, non-cluster headaches (migraines), traumatic brain injury and impaired glucose tolerance) who receive transcutaneous vagus nerve stimulation (t-VNS), the evidence includes RCTs and case series for some of the conditions. The RCTs are small and have various methodologic problems. None showed definitive efficacy of transcutaneous vagus nerve stimulation (t-VNS) in improving patient outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes.
More than one-third (36.5%) of U.S. adults have obesity which is defined as a body max index (BMI) 30.0 or higher (based on the U.S. Centers for Disease Control and Prevention). Obesity is a major cause of premature death and is linked to serious illnesses including heart disease, type 2 diabetes, stroke, sleep apnea, osteoarthritis, and certain types of cancer. Lifestyle interventions, especially changes to diet and exercise are the first line treatment of obesity. These interventions can be enhanced by participating in a structured weight loss program and/or by psychological interventions. There are also prescription weight loss medications available which have limited evidence of efficacy and there are adverse effects associated with their use. Weight loss (bariatric) surgery is another potential option for patients who have failed conservative treatments.
Vagus nerve blocking therapy is being investigated as another potential treatment option for obese patients. The vagus nerve consists of 2 long cranial nerves that extend from the brain to the viscera. The vagus nerve winds through the abdomen and has branches that come into contact with the heart, lung, stomach, and other body parts. The vagus nerves plays a major role in autonomic and sympathetic nervous system functioning, including regulation of heartbeat and breathing. It is also involved in regulation of the digestive system, although its exact role in controlling appetite and feelings of satiety is unknown. Vagus nerve blocking therapy involves intermittent blocking of signals to the intra-abdominal vagus nerve, with the intent of disrupting hunger sensations and inducing feelings of satiety.
In January 2015, the U.S. Food and Drug Administration (FDA) approved a medical device specifically designed to provide vagal nerve blocking therapy for regulation of weight in obese patients. This device, the Maestro Rechargeable system, includes neuroblocking pulse generator that is implanted subcutaneously on the thoracic sidewall and flexible leads approximately 47 cm in length that are placed on the abdominal anterior and posterior vagal nerve trunks. External components include mobile charge, a transmit coil, a programmable microprocessor, and customized software. The system delivers high-frequency pulses of electrical current to vagus nerve trunks; therapy parameters and the treatment schedule can be customized by a clinician. Like other surgical interventions, there is the potential for adverse effects. In addition, there may be other unintended consequences of disrupting signals to a particular portion of the vagus nerve.
The published literature on vagus nerve blocking for obesity consists of two ra ndomized controlled trials (RCTs) (EMPOWER and ReCharge), both of which were industry sponsored, multicenter, double-blind and sham-controlled. Although both trials included a sham treatment group, protocols differed. In the 2012 EMPOWER trial, all participants had devices implanted and leads placed. However, external controllers were programmed differently such that if the controllers were worn for 10 hours a day, total charge delivered was 3.9 coulombs (C) to patients in the treatment and a negligible amount (0.0014 C), to the sham group. In the 2014 ReCharge trial, all participants had devices implanted, but no leads were placed in the sham group.
Sarr et. al. (2012) conducted a randomized, prospective, double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity, the EMPOWER study. This controlled trial was conducted in the U.S. and Australia. Five hundred three subjects were enrolled at 15 centers. After informed consent, 294 subjects were implanted with the vagal blocking system and randomized to the treated (n = 192) or control (n = 102) group. Main outcome measures were percent excess weight loss (percent EWL) at 12 months and serious adverse events. Subjects controlled duration of therapy using an external power source; therapy involved a programmed algorithm of electrical energy delivered to the subdiaphragmatic vagal nerves to inhibit afferent/efferent vagal transmission. Devices in both groups performed regular, low-energy safety checks. Data are mean ± SEM (standard error of the mean). Study subjects consisted of 90 % females, body mass index of 41 ± 1 kg/m(2), and age of 46 ± 1 years. Device-related complications occurred in 3 % of subjects. There was no mortality. 12-month percent EWL was 17 ± 2 % for the treated and 16 ± 2 % for the control group. Weight loss was related linearly to hours of device use; treated and controls with ≥ 12 h/day use achieved 30 ± 4 and 22 ± 8 % EWL, respectively. The authors concluded, VBLOC therapy to treat morbid obesity was safe, but weight loss was not greater in treated compared to controls; clinically important weight loss, however, was related to hours of device use. Post-study analysis suggested that the system electrical safety checks (low charge delivered via the system for electrical impedance, safety, and diagnostic checks) may have contributed to weight loss in the control group.
Ikramuddin et. al. (2014) conducted a randomized, double-blind, sham-controlled clinical trial to evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment, the ReCharge study. This trial was conducted at 10 sites in the U.S. and Australia between May and December 2011. The 12 month blinded portion of the 5 year study was completed in January 2013. The trial involved 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition. One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. The co-primary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%. In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity. The authors concluded, among patients with morbid obesity, the use of vagal nerve block therapy compared with sham control device did not meet wither of the prescribed co-primary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective.
The primary efficacy outcomes were not met in either RTC. The difference in mean percent excess weight loss (EWL) was the sole primary efficacy outcome in the EMPOWER study and a co-primary outcome in the ReCharge study. This outcome was evaluated in both trials using a superiority margin of 10% (i.e. the efficacy objective would be met only if there was > 10% difference between groups in EWL). U.S. Food and Drug Administration (FDA) documents (Summary of Safety and Effectiveness Data [SEED]) have indicated that the unattained 10% margin was considered to indicate a clinically meaningful difference in weight loss between active and sham treatment groups.
The outcome used in these studies was percent EWL, and modest changes in this outcome may translate to a relatively small amount of weight loss relative to total weight for patients with morbid obesity. Mean initial body weight in the ReCharge trial was 113 kilograms (249 pounds) in the active treatment group and 116 kilograms (255 pounds) in the sham group. Mean excess body weight was 44 kilograms (97 pounds) in the treatment group and 45 kilograms (99 pounds) in the sham group. A difference of 10% EWL, used in the primary analyses, represents a difference of only about 5 kilograms (10 pounds) in absolute weight loss and a 4% difference in absolute body weight.
Additional information on the ReCharge trial design and findings has been reported in FDA documents (Summary of Safety and Effectiveness Data [SEED]). The trial was designed to evaluate primary end points at 12 months and to follow patients for 5 years post implant. Patients were blinded until 12 months and unblinding began once all patients had completed the 12 month follow-up. After the 12 month follow-up, sham patients had the option to cross over into the active treatment group. At 18 months, follow-up data (n=159) were reported for 117 (72%) patients initially assigned to the active treatment group and 42 (55%) assigned to the sham treatment group. The number of patients in the sham group who crossed over to active treatment and the timing of unblinding were not reported. At 18 months, the mean percent EWL (excess weight loss) was 25.3% in the active treatment group and 11.7% in sham group; the mean between group difference was 13.5% (95% CI, 5.7% to 21.3%). In this analysis, the treatment group maintained the weight loss they achieved at 12 months, and the control group gained weight. Nearly half of the patients initially randomized to the sham group were not included in the 18 month analysis, which limits ability to draw conclusions about these data. In addition, the 18 month analysis could have been biased by unblinding, which occurred after all patients completed the 12 month follow-up. In the 12 month sham intervention phase of the trial, patients in both groups experienced decreased hunger, increased cognitive restraint, and decreased food intake. It is likely that unblinding could have had an impact on these factors. FDA documents also reported longer term safety data. Analyses of data up to 48 months from the EMPOWER trial and 18 month data from the ReCharge trial did not identify any deaths or unanticipated serious adverse events. There were 13 surgical explants through 12 months (5 in active treatment group, 8 in sham group) and an additional 16 explantations between 12 and 18 months. Reasons for explant included patient decision, pain, and need for MRI.
In 2015, Shikora et. al. published the 18 month follow-up data from the ReCharge trial. They reported on a larger proportion of the patient population than that discussed in the FDA documents: in addition to the 159 (67%) of 239 randomized patients who completed the 18 month follow-up, the 2015 analysis included 30 patients who missed the 18 month analysis but had a visit at 16 or 17 months. The additional patients included 11 from the active treatment group and 19 from the sham group, comprising 188 patients (79% of those originally randomized). At 18 months, the mean percent EWL noted was 23.5% (95% CI, 20.8% to 26.3%) in the active treatment group and 10.2% (95% CI, 6.0% to 14.4%) in the sham group. The mean between group difference in percent EWL was 13.4% (95% CI, 8.4% to 18.4%). The authors also evaluated the potential impact of blinding on outcomes and found no statistically significant effect; their findings were similar to the analysis restricted to patients who remained blinded at 18 months. The percentages of EWL at 18 months in this 2015 analysis of ReCharge trial data were also similar to those previously reported in FDA documents, although this sample size was larger, reducing potential bias from missing data. The authors concluded, follow-up through 18 months of the ReCharge study showed sustained weight loss with intermittent vagal nerve block but not with sham surgery and device intervention. vBloc therapy continued to be safe and well tolerated. Additional long-term data and continued follow-up of the ReCharge study are needed to further characterize the safety and effectiveness profile of vBloc therapy.
Apovian et. al. (2017) published two year outcomes of vagal nerve blocking (vBloc) for the treatment of obesity in the ReCharge trial. Participants with body mass index (BMI) 40 to 45 kg/m2, or 35 to 40 kg/m2 with at least one comorbid condition were randomized to either vBloc therapy or sham intervention for 12 months. After 12 months, participants randomized to vBloc continued open-label vBloc therapy and are the focus of this report. Weight loss, adverse events, comorbid risk factors, and quality of life (QOL) will be assessed for 5 years. The investigators noted that the sham arm was no longer a valid comparator at 24 months due to crossovers, dropouts, and patient unblended at 12 months. Participants who presented at 24 months (n = 103) had a mean excess weight loss (EWL) of 21 % (8 % total weight loss [TWL]); 58 % of participants had ≥5 % TWL and 34 % had ≥10 % TWL. Among the subset of participants with abnormal preoperative values, significant improvements were observed in mean LDL (-16 mg/dL) and HDL cholesterol (+4 mg/dL), triglycerides (-46 mg/dL), HbA1c (-0.3 %), and systolic (-11 mmHg) and diastolic blood pressures (-10 mmHg). QOL measures were significantly improved. Heartburn/dyspepsia and implant site pain were the most frequently reported adverse events. The primary related serious adverse event rate was 4.3 %. The analysis lacked a blinded comparison group, and, like the 18 month data, was post hoc.
For individuals with obesity who receive vagus nerve blocking therapy, the evidence includes 2 sham-controlled randomized trials. The primary efficacy outcome (at least a 10% difference between groups at 12 months) was not met for either trial. In the first trial (EMPOWER), the observed differences in excess weight loss (EWL) between groups at 12 months was 1%. In the more recent trial (ReCharge), the observed difference in excess weight loss (EWL) between groups at 12 months was 8.5%; a post hoc analysis found this difference statistically significant, but the magnitude of change may not be viewed as clinically significant according to investigators original trial decisions. Post hoc analysis of longer term data have been published and are subject to various biases, including missing data and unblinding at 12 months. Based on the trials the treatment was well tolerated, having met the primary safety objective. Additional studies are needed to compare effectiveness of vagal nerve blocking therapy with other obesity treatments and to assess long-term durability of weight loss and safety. The evidence is insufficient to determine the effects of the technology on net health outcomes.
In 2013, the American Academy of Neurology (AAN) issued an evidence based guideline update on vagus nerve stimulation for the treatment of epilepsy, that stated:
The American Psychiatric Association guidelines on treatment of major depressive disorder in adults, updated in November 2010, includes the following statement on the use of VNS: “electroconvulsive therapy (ECT) remains the treatment of best established efficacy against which other stimulation treatments (e.g. vagus nerve stimulation (VNS), deep brain stimulation, transcranial magnetic stimulation, other electromagnetic stimulation therapies) should be compared. 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, with a level of evidence III (May be recommended on the basis of individual circumstances).”
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 suffers using a randomized placebo controlled trial design.”
In 2014, the American Headache Society issued information regarding stimulators for the treatment of headache and stated the following regarding vagal nerve stimulation (VNS): “Stimulation of the vagal nerve has been described as a means to treat both migraine and cluster headache in patients who have not responded to conventional treatment. A hand held device was developed to make this far more convenient and less dangerous than implanted stimulators. The device is called a noninvasive vagal nerve stimulator (nVNS). The device is held by the patient to the neck on the same side as the pain, and a low level electrical stimulation is discharged. This can be used preventatively or at onset of pain. However, it is important to state that no scientific studies with placebo have been published on the nVNS as of early 2014, and the evidence for its safety and effectiveness is merely the reports of the less than 50 patients who have used it and reported its effects. nVNS does not have FDA approval for use in the United States at this time.”
In 2016, the American Society for Metabolic and Bariatric Surgery published a position statement that included the following conclusions and recommendations on vagus nerve blocking therapy for the treatment of obesity:
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 adjunctive treatment for adults and children 12 years of age and older with medically refractory partial onset seizures.
July 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 episode and have not had an adequate response to four or more adequate antidepressant treatments.
Cerbomed has developed a transcutaneous vagal nerve stimulator (tVNS) 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 electrical stimulation for several hours a day; no surgical procedure is required. The device received European clearance (CE mark) in 2011, but has not been FDA approved for use in the United States.
January 2015 Maestro Rechargeable System (EnteroMedics, St. Paul, MN) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process for use in adults aged 18 years and older who have a body mass index (BMI) of 40 to 45 kg/m2 or a BMI of 35 to 39.9 kg/m2 with 1 or more obesity related conditions such as high blood pressure or high cholesterol and have failed at least 1 supervised weight management program within the past 5 years. Implantable components are incompatible with magnetic resonance imaging. Additional contraindications to use of the device include conditions such as cirrhosis of the liver, portal hypertension and clinically significant hiatal hernia, and the presence of a previously implanted medical device. FDA product code: PIM.
April 2017, the U.S. Food and Drug Administration (FDA) approved gammaCore Non-invasive Vagus Nerve Stimulator ( ElectroCore LLC, Basking Ridge, New Jersey) intended to provide non-invasive vagus nerve stimulation (nVNS) on the side of the neck. The gammaCore device is indicated for the acute treatment of pain associated with episodic cluster headache in adult patients.
Implantable vagus nerve stimulation (VNS) may be considered medically necessary when all of the following criteria are met:
Note: 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.
Replacement or revisions of an implantable vagus nerve stimulator and/or leads is considered medically necessary in an individual that meets the above criteria and the existing generator/lead/electrodes/programmer is no longer under warranty and/or cannot be repaired.
Vagus Nerve Stimulation (VNS) is considered investigational as treatment of all other conditions, including but not limited to the following:
Based on peer reviewed literature the use of vagus nerve stimulation has been examined for additional indications. The evidence includes randomized controlled trials, nonrandomized comparative studies and case series. Randomized controlled trials reported short term results, and found no significant improvement in the primary outcomes. Other available studies are limited by small sample sizes, potential selection bias, and lack of a control group in the case series. Additional larger prospective randomized sham-controlled studies are needed to determine safety and effectiveness. The evidence is insufficient evidence to determine the effectiveness of the technology on net health outcomes.
Transcutaneous vagus nerve stimulation (tVNS) devices are considered investigational for all indications, including but not limited to the following:
The evidence for transcutaneous vagal nerve stimulation (tVNS) includes small randomized trias, case series and systematic review. Studies are all small and have various methodologic problems. The evidence is insufficient in showing definitive efficacy of transcutaneous vagal nerve stimulation (tVNS) in improving outcomes among patients. Current studies are limited by lack of a comparator and small sample sizes. Further studies are needed. The evidence is insufficient to determine the effects of this technology on net health outcomes.
Intra-abdominal vagus nerve blocking therapy is considered investigational for all indications, including but not limited to the treatment of obesity.
Based on the peer reviewed medical literature the evidence includes two sham-controlled randomized trials in which the primary efficacy outcome was not met for either trial. Additional studies are needed to compare effectiveness of vagal nerve blocking therapy with other obesity treatments and to assess long-term durability of weight loss and safety. The evidence is insufficient to determine the effects of this technology on net health outcomes.
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