1. Aetna considers vagus nerve electrical stimulators (the NeuroCybernetic Prosthesis System) medically necessary durable medical equipment (DME) for shortening the duration or reducing the severity of seizures in members with partial onset seizures who remain refractory to optimal anti-epileptic medications and/or surgical intervention, or who have debilitating side effects from anti-epileptic medications.

2. Aetna considers electrical stimulation of the vagus nerve experimental and investigational for the treatment of all other indications, including autism, obesity, chronic headaches, addictions, anxiety disorders, bulimia, coma, essential tremor, heart failure, narcolepsy, sleep disorder, and Tourette's syndrome, refractory depression and cognitive impairment associated with Alzheimer’s disease, and obsessive-compulsive disorder because its effectiveness for these indications has not been established.

See also CPB 221 - Quantitative EEG (Brain Mapping), CPB 226 - Hospitalization for the Initiation of Ketogenic Diet for the Treatment of Intractable Seizures, CPB 279 - Magnetic Source Imaging/Magnetoencephalography, CPB 322 - Electroencephalographic (EEG) Video Monitoring, CPB 394 - Epilepsy Surgery, and CPB 425 - Ambulatory Electroencephalography.

Approximately 1.7 millions Americans suffer from epilepsy.  The vast majority of these patients can be controlled by conventional drug therapy.  Despite the availability of new anti-epileptic medications and advances in surgical therapy, more than 200,000 people remain refractory to treatment.  Vagus nerve stimulation (VNS) using the NeuroCybernetic Prosthesis (NCP) System has been shown to shorten the duration and reduce the severity of seizures in certain patients who remain refractory despite optimal drug therapy or surgical intervention or in those with debilitating side effects of anti-epileptic medications.

The NCP System, approved by the FDA on July 16, 1997, is a pacer-like device implanted under the skin in the upper left chest area.  It is connected by wire to a lead that is wrapped around the left vagus nerve in the neck.  Through the vagus nerve, it delivers intermittent electrical pulses 24 hours a day to the brain.  When a patient senses the impending onset of a seizure, he/she can activate the device through a hand-held magnet to deliver an additional dose of stimulation.  Treatment with the vagus nerve stimulator is not free of side effects.  Patients have experienced cough, hoarseness, alterations in their voice, and shortness of breath.

Recent studies have established vagus nerve stimulation to be a viable option for improving seizure control in difficult to treat pediatric patients with epilepsy (Zamponi et al, 2002; Murphy et al, 2003; Smyth et al, 2003; and Buoni et al, 2004).  An assessment of vagus nerve stimulation in children by the National Institute for Clinical Excellence (NICE, 2004) reached the following conclusion:

Current evidence on the safety and efficacy of vagus nerve stimulation for refractory epilepsy in children appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance.

It has been reported that VNS in patients with epilepsy is associated with an improvement in mood.  Approximately one-third of patients with major depressive disorder fail to experience sufficient symptom improvement despite adequate treatment.  Management of patients with treatment resistant depression (TRD) usually consists of pharmacological or non-pharmacological methods.  The former approach entails switching to another antidepressant monotherapy, and augmentation or combination with two or more antidepressants or other agents.  The latter approach includes psychotherapy, electroconvulsive therapy, and VNS.  Although VNS is associated with mood improvements in patients with epilepsy, randomized, controlled studies with long-term follow-up are needed to confirm its effect on TRD.  In this regard, Kosel and Schlaepfer (2003) stated that recent data from an open-label, multi-center pilot study involving 60 patients (Goodnick et al, 2001) suggested a potential clinical usefulness in the acute and maintenance treatment of TRD.  However, definite therapeutic effects of clinical significance remain to be confirmed in large placebo-controlled trial.  This is in agreement with the observation of George et al (2000) who noted that additional research is needed to clarify the mechanisms of action of VNS and its potential clinical utility in the management of patients with TRD.  Because of the lack of well-designed controlled clinical trials, VNS for refractory depression is considered experimental and investigational.  Long-term data regarding tolerability as well as symptomatic and functional outcomes of depressed patients receiving VNS are needed to ascertain the effectiveness of this procedure for treating refractory depression.  An assessment by the Institute for Clinical Systems Improvement (ICSI, 2004) stated that vagus nerve stimulation for depression “cannot be considered evidence-based.”

In an acute phase pilot study (n = 59), Nahas et al (2005) evaluated the safety and effectiveness of VNS for patients with treatment-resistant major depressive episode (MDE).  They examined the effects of adjunctive VNS over 24 months in this patient population.  Adult outpatients with chronic or recurrent major depressive disorder or bipolar (I or II) disorder and experiencing a treatment-resistant, non-psychotic MDE (DSM-IV criteria) received 2 years of VNS.  Changes in psychotropic medications and VNS stimulus parameters were allowed only after the first 3 months.  Response was defined as greater than or equal to 50 % reduction from the baseline 28-item Hamilton Rating Scale for Depression (HAM-D-28) total score, and remission was defined as a HAM-D-28 score less than or equal to 10.  Based on last observation carried forward analyses, HAM-D-28 response rates were 31% (18/59) after 3 months, 44% (26/59) after 1 year, and 42% (25/59) after 2 years of adjunctive VNS.  Remission rates were 15% (9/59) at 3 months, 27% (16/59) at 1 year, and 22% (13/59) at 2 years.  By 2 years, 2 deaths (unrelated to VNS) had occurred, 4 participants had withdrawn from the study, and 81% (48/59) were still receiving VNS.  Longer-term VNS was generally well tolerated.  These investigators concluded that their findings suggest that patients with chronic or recurrent, treatment-resistant depression (TRD) may show long-term benefit when treated with VNS.

George et al (2005) stated that previous reports had described the effects of VNS plus treatment as usual (VNS+TAU) during open trials of patients with TRD.  To better understand these effects on long-term outcome, these researchers compared 12-month VNS+TAU outcomes with those of a comparable TRD group.  Admission criteria were similar for those receiving VNS+TAU (n = 205) or only TAU (n = 124).  In the primary analysis, repeated-measures linear regression was used to compare the VNS+TAU group (monthly data) with the TAU group (quarterly data) according to scores of the 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR(30)).  The two groups had similar baseline demographic data, psychiatric and treatment histories, and degrees of treatment resistance, except that more TAU participants had at least 10 prior major depressive episodes, and the VNS+TAU group had more electroconvulsive therapy before study entry.  The VNS+TAU group was associated with greater improvement per month in IDS-SR(30) than the TAU group across 12 months (p < 0.001).  Response rates according to the 24-item Hamilton Rating Scale for Depression (last observation carried forward) at 12 months were 27% for the VNS+TAU group and 13% for the TAU group (p < 0.011).  Both groups received similar TAU (drugs and electroconvulsive therapy) during follow-up.  These investigators concluded that this comparison of two similar but non-randomized TRD groups showed that VNS+TAU was associated with a greater anti-depressant benefit over 12 months.  These preliminary findings by Nahas et al (2005) as well as George as et (2005) need to be validated by prospective, randomized placebo-controlled studies.

In a randomized controlled 10-week study, Rush and colleagues (2005a) compared adjunctive VNS with sham treatment in 235 outpatients with non-psychotic major depressive disorder (n = 210) or non-psychotic, depressed phase, bipolar disorder (n = 25).  Subjects had not responded adequately to between 2 to 6 research-qualified medication trials.  A 2-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation.  Medications were kept stable.  Primary efficacy outcome among 222 evaluable participants was based on response rates (greater than or equal to 50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]).  At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0 % for the sham (n = 110) groups (p = 0.251).  Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = 0.032).  VNS was well tolerated; 1% (3/235) of subjects left the study because of adverse events.  These investigators concluded that this study did not yield definitive evidence of short-term effectiveness of adjunctive VNS in TRD.

Rush et al (2005b) described follow-up of outpatients with non-psychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham VNS (n = 95).  The initial active group received another 9 months, while the initial sham group received 12 months of VNS.  Participants received anti-depressant treatments and VNS, both of which could be adjusted.  The primary analysis (repeated measures linear regression) revealed a significant reduction in HRSD(24) scores (average improvement, .45 points [SE = .05] per month (p < 0.001).  At exit, HRSD(24) response rate was 27.2% (55/202); remission rate (HRSD(24) less than or equal to 9) was 15.8% (32/202).  Montgomery Asberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0 % [68/200]) showed similar response rates.  Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events.  These researchers concluded that these 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in TRD, albeit in the context of changes in depression treatments.  Comparative long-term data are needed to determine whether these benefits can be attributed to VNS.

Furthermore, the BlueCross BlueShield TEC assessment on VNS for TRD (2005) stated that this method does not meet the TEC criteria.  The TEC assessment stated that the available evidence is insufficient to permit conclusions of the effect of VNS therapy on health outcomes.  According to the TEC assessment, “the available evidence consists of a case series of 60 patients receiving VNS, a short-term (i.e., 3-month) randomized, sham-controlled clinical trial of 221 patients, and an observational study comparing 205 patients on VNS therapy compared to 124 patients receiving ongoing treatment for depression.  Patients who responded to sham treatment in the short-term randomized, controlled trial (approximately 10%) were excluded from the long-term observational study.  Patient selection was a concern for all studies.  VNS is intended for treatment-refractory depression, but the entry criteria of failure of 2 drugs and a 6-week trial of therapy may not be a strict enough definition of treatment resistance.  Treatment-refractory depression should be defined by thorough state-of-the-art psychiatric evaluation and management”.

The BlueCross BlueShield Association updated their assessment in August 2006, and concluded that VNS does not meet the TEC criteria. The assessment explained that, "[s]ince the last TEC Assessment, there have been no studies reporting clinical outcomes on any new or different patients. Data from the case series and clinical trials have been reanalyzed to show what proportions of patients who respond at one time are still responders at a subsequent time point. However, this information by itself does not provide evidence of the efficacy of VNS beyond that provided by the original observational comparison of VNS versus treatment as usual."

An assessment of VNS for severe depression by the Aggressive Research Intelligence Facility (ARIF, 2005) stated: "To conclude, this is an experimental and as yet unproven method of treatment for severe depression.  If this treatment is utilized, patients should be advised of the experimental nature of the treatment and should be assessed by an expert in the field, who is familiar with the treatment.  The treatment should ideally be given as part of a robust evaluation of clinical effectiveness and safety in order to add to the current evidence base".  Furthermore, an assessment by the California Technology Assessment Forum (CTAF, 2006) concluded that the use of VNS for the treatment of resistant depression does not meet CTAF's technology assessment criteria for safety, effectiveness, and improvement in health outcomes.

George et al (2007) stated that VNS is a new approach in treating neuropsychiatric diseases within the class of brain-stimulating devices known as neuromodulators.  Although VNS has received FDA approval for the treatment of medication-resistant depression. there is a lack of Class I evidence of effectiveness in treating depression.  The authors concluded that much more research is needed regarding exactly how to refine and deliver the electrical pulses and how this differentially affects brain function in health and disease.

The Centers for Medicare & Medicaid Services (CMS, 2007) stated that there is sufficient evidence to conclude that VNS is not reasonable and necessary for the treatment of resistant depression.  Thus, CMS has announced a national non-coverage determination for this indication.

In a systematic review on the safety and effectiveness of VNS in the management of patients with TRD, Daban and colleagues (2008) concluded that VNS seems to be an interesting new approach to treating TRD.  However, despite the promising results reported mainly in open studies, further clinical trials are necessary to confirm its effectiveness in major depression.  Moreover, studies on its mechanism of action and cost-effectiveness are also needed to better understand and develop VNS therapy for affective disorder.  This is in agreement with the observation of Fitzgerald and Daskalakis (2008) who stated that given the invasive nature of VNS and potential side effects, further research on its use for the treatment of depression is urgently needed.  This should include the development of predictors of clinical response and definition of stimulation parameters with enhanced effectiveness.

Recently, VNS has been used to treat patients with autism, obesity, Alzheimer’s disease, and obsessive-compulsive disorder.  Results from pilot studies suggested that VNS might induce weight loss in obese individuals and improve cognitive function in patients with Alzheimer’s disease.  However, these findings need to be validated in large randomized placebo-controlled studies with long-term outcomes.

In an open-label study, Camilleri and associates (2008) evalauted the effects of vagal blocking by means of a new medical device that uses high-frequency electrical algorithms to create intermittent vagal blocking (VBLOC therapy) on excess weight loss (EWL).  Electrodes were implanted laparoscopically on both vagi near the esophagogastric junction to provide electrical block.  Patients (obese subjects with body mass index [BMI] of 35 to 50 kg/m(2)) were followed for 6 months for body weight, safety, electrocardiogram, dietary intake, satiation, satiety, and plasma pancreatic polypeptide (PP) response to sham feeding.  To specifically assess device effects alone, no diet or exercise programs were instituted.  A total of 31 patients (mean BMI, 41.2 +/- 1.4 kg/m(2)) received the device.  Mean EWL at 4 and 12 weeks and 6 months after implant was 7.5 %, 11.6 %, and 14.2 %, respectively (all p < 0.001); 25 % of patients lost over 25 % EWL at 6 months (maximum, 36.8 %).  There were no deaths or device-related serious adverse events (AEs).  Calorie intake decreased by greater than 30 % at 4 and 12 weeks and 6 months (all p < or = 0.01), with earlier satiation (p < 0.001) and reduced hunger (p = 0.005).  After 12 weeks, plasma PP responses were suppressed (20 +/- 7 versus 42 +/- 19 pg/ml).  Average percent EWL in patients with PP response  less than 25 pg/ml was double that with PP response greater than 25 pg/ml (p = 0.02).  Three patients had serious AEs that required brief hospitalization, 1 each for lower respiratory tract, subcutaneous implant site seroma, and clostridium difficile diarrhea.  The authors concluded that VBLOC therapy is associated with significant EWL and a desirable safety profile.  They noted that these findings have resulted in the design and implementation of a randomized, double-blind, prospective, multi-center trial in an obese subject population.

Vagal nerve stimulation is also being studied for treating chronic headaches; however, its value for this indication has yet to be established.  Mauskop (2005) reported that VNS was implanted in 4 men and 2 women with disabling chronic cluster and migraine headaches.  In 1 man and 1 woman with chronic migraines, VNS produced dramatic improvement with restoration of ability to work.  Two patients with chronic cluster headaches had significant improvement of their headaches.  Treatment was well-tolerated in 5 patients, while 1 developed nausea even at the lowest current strength.  The author concluded that VNS may be an effective therapy for intractable chronic migraine and cluster headaches and deserves further trials.

Ansari et al (2007) noted that a possible role of VNS in the treatment of severe refractory headache, intractable chronic migraine and cluster headache has been suggested.  Clinical trials are ongoing to examine VNS as a potential treatment for essential tremor, cognitive deficits in Alzheimer's disease, anxiety disorders, and bulimia.  Furthermore, VNS has also been studied in the treatment of resistant obesity, addictions, sleep disorders, narcolepsy, coma, as well as memory and learning deficits.

In a review on current and future treatments for chronic migraine, Mathew (2009) stated that larger and more accurate studies are needed to further evaluate the usefulness of VNS as a preventive migraine treatment.

In a pilot study, Schwartz et al (2008) examined the feasibility and safety and tested possible efficacy of chronic VNS in patients with heart failure (HF).  A total of 8 patients (mean age of 54 years) were included in this study.  CardioFit (BioControl Medical), a vagal stimulation implantable system delivering pulses synchronous with heart beats through a multiple contact bipolar cuff electrode, was used.  Vagus nerve stimulation was started 2 to 4 weeks after implant, slowly raising intensity; patients were followed 1, 3 and 6 months thereafter.  All procedures were successful: as sole surgical side effect, 1 patient had transient hoarseness.  Vagal stimulation was well-tolerated, with only mild side effects (cough and sensation of electrical stimulation).  There was a significant improvement in NYHA class, Minnesota quality of life (from 52 +/- 14 to 31 +/- 18, p < 0.001), left ventricular end-systolic volume (from 208 +/- 71 to 190 +/- 83 ml, p = 0.03), and a favorable trend toward reduction in end-diastolic volume.  The authors concluded that this novel approach in treating patients with HF is feasible, and appears safe and tolerable.  They stated that the preliminary efficacy results appear promising, and that these findings suggest the opportunity to proceed with a larger multi-center study.

Appendix

Exclusion Criteria for VNS Therapy of Partial Onset Seizures:

• VNS can not be used in persons with left or bilateral cervical vagotomy
• VNS is not indicated for persons with other types of seizures.