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Clinical Policy Bulletin:
Vagus Nerve Stimulation
Number: 0191


Policy

Aetna considers vagus nerve electrical stimulators 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.  (Note: Electronic analysis of an implanted neurostimulator pulse generator system for vagus nerve stimulation is considered medically necessary when criteria are met).

Aetna considers transcutaneous vagus nerve stimulation experimental and investigational for the treatment of seizures and all other indications (see below) because the effectiveness of this approach has not been established.

Aetna considers vagus nerve electrical stimulators and transcutaneous vagus nerve stimulation experimental and investigational for the treatment of all other indications because its effectiveness for these indications has not been established (not an all inclusive list):

  • Addictions
  • Anxiety disorders
  • Autism
  • Bipolar disorders
  • Bulimia
  • Cerebral pals
  • Chronic headaches
  • Cognitive impairment associated with Alzheimer’s disease
  • Coma
  • Depression
  • Essential tremor
  • Fibromyalgia
  • Heart failure
  • Hemicrania continua
  • Mood disorders
  • Narcolepsy
  • Obesity
  • Obsessive-compulsive disorder
  • Sleep disorder
  • Tinnitus
  • Tourette's syndrome

See also CPB 0221 - Quantitative EEG (Brain Mapping)CPB 0226 - Hospitalization for the Initiation of Ketogenic Diet for the Treatment of Intractable SeizuresCPB 0279 - Magnetic Source Imaging/MagnetoencephalographyCPB 0322 - Electroencephalographic (EEG) Video MonitoringCPB 0394 - Epilepsy SurgeryCPB 0425 - Ambulatory Electroencephalography, and CPB 0406 - Tinnitus Treatments.



Background

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 VNS 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 1/3 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 anti-depressant monotherapy, and augmentation or combination with 2 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 VNS 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, 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 2 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 2 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).  Vagal nerve stimulation 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.

An Agency for Healthcare Research and Quality's review (Gaynes et al, 2011) reported that there is insufficient evidence to evaluate whether non-pharmacological treatments are effective for TRD.  The review summarized evidence of the effectiveness of 4 non-pharmacological treatments: (i) electroconvulsive therapy (ECT), (ii) repetitive transcranial magnetic stimulation (rTMS), (iii) VNS, and (iv) cognitive behavioral therapy (CBT) or interpersonal psychotherapy.  With respect to maintaining remission (or preventing relapse), there were no direct comparisons (evidence) involving ECT, rTMS, VNS, or CBT.  With regard to indirect evidence, there were 3 fair trials compared rTMS with a sham procedure and found no significant differences, however, too few patients were followed during the relapse prevention phases in 2 of the 3 studies (20-week and 6-month follow-up) and patients in the 3rd study (3-month follow-up) received a co-intervention providing insufficient evidence for a conclusion.  There were no eligible studies for ECT, VNS. or psychotherapy. 

The review concluded that that comparative clinical research on non-pharmacologic interventions in a TRD population is early in its infancy, and many clinical questions about efficacy and effectiveness remain unanswered.  Interpretation of the data is substantially hindered by varying definitions of TRD and the paucity of relevant studies.  The greatest volume of evidence is for ECT and rTMS.  However, even for the few comparisons of treatments that are supported by some evidence, the strength of evidence is low for benefits, reflecting low confidence that the evidence reflects the true effect and indicating that further research is likely to change our confidence in these findings.  This finding of low strength is most notable in 2 cases: ECT and rTMS did not produce different clinical outcomes in TRD, and ECT produced better outcomes than pharmacotherapy.  No trials directly compared the likelihood of maintaining remission for non-pharmacologic interventions.  The few trials addressing adverse events, subpopulations, subtypes, and health-related outcomes provided low or insufficient evidence of differences between non-pharmacologic interventions.  The most urgent next steps for research are to apply a consistent definition of TRD, to conduct more head-to-head clinical trials comparing non-pharmacologic interventions with themselves and with pharmacologic treatments, and to delineate carefully the number of treatment failures following a treatment attempt of adequate dose and duration in the current episode.

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 esophago-gastric 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.

Rosenberg et al (2009) stated that treatment of mood disorders is one of the most challenging territories in the elderly.  Effectiveness of different treatment strategies could be related to age, sex and physical conditions.  The side effect profile in this population also affects pharmacological interventions.  These investigators reviewed the neurostimulative treatment strategies in this population of patients.  However, possible treatment strategies such as electroconvulsive therapy, transcranial magnetic stimulation (TMS), VNS and deep brain stimulation (DBS) were less studied in the elderly.  Electroconvulsive therapy was found to be an effective treatment procedure in mood disorders.  Few double-blind sham controlled studies were conducted and demonstrated effectiveness of TMS; and DBS has lack of double-blind studies.  Electroconvulsive therapy appears to be the golden standard for the treatment resistant elderly patients despite its side effects.  The authors stated that double-blind, sham, controlled studies with larger samples are needed to confirm preliminary results with transcranial direct current stimulation, magnetic seizure therapy, DBS as well as VNS.

Jaseja (2008) stated that cerebral palsy (CP) continues to pose a cause for major socio-economic concern and medical challenge worldwide.  It is associated with a multi-faceted symptomatology warranting a multi-dimensional management-approach.  Recent recognition of neurocognitive impairment and its hopefully possible treatment has opened up a new dimension in its management to the neurologists.  Vagal nerve stimulation technique is presently emerging as an effective alternative anti-epileptic therapeutic measure in intractable epilepsy. Vagus nerve stimulation has recently been shown to possess a suppressive effect also on interictal epileptiform discharges (IEDs) that are now being widely accepted as established associates of neurocognitive impairment.  The author proposed VNS technique implantation in CP patients on account of its dual therapeutic effectiveness, i.e., anti-epileptic and IED-suppression.  These 2 effects are likely to control seizures that are quite often drug-resistant and also improve neurocognition in CP patients, thus hoping for a better overall prognostic outcome and an improved quality of life of the CP patients by VNS.

Kraus et al (2007) stated that direct VNS has proved to be an effective treatment for seizure disorder.  However, since this invasive technique implies surgery, with its side-effects and relatively high financial costs, a non-invasive method to stimulate vagal afferences would be a great step forward.  These researchers studied effects of non-invasive electrical stimulation of the nerves in the left outer auditory canal in healthy subjects (n = 22), aiming to activate vagal afferences transcutaneously (tVNS).  Short-term changes in brain activation and subjective well-being induced by tVNS were investigated by functional magnetic resonance imaging (fMRI) and psychometric assessment using the adjective mood scale (AMS), a self-rating scale for current subjective feeling.  Stimulation of the ear lobe served as a sham control.  Functional MRI showed that robust tVNS induced blood oxygenation level dependent (BOLD)-signal decreases in limbic brain areas, including the amygdala, hippocampus, para-hippocampal gyrus and the middle and superior temporal gyrus.  Increased activation was seen in the insula, precentral gyrus and the thalamus.  Psychometric assessment revealed significant improvement of well-being after tVNS.  Ear lobe stimulation as a sham control intervention did not show similar effects in either fMRI or psychometric assessment.  No significant effects on heart rate, blood pressure or peripheral microcirculation could be detected during the stimulation procedure.  The authors concluded that these findings showed the feasibility and beneficial effects of tVNS in the left auditory canal of healthy subjects.

Dietrich and colleagues (2008) stated that left cervical VNS using the implanted NCP can reduce epileptic seizures.  To address a disadvantage of this device, the use of an alternative transcutaneous electrical nerve stimulation technique, designed for muscular stimulation, was studied.  Functional MRI has been used to test non-invasively access nerve structures associated with the vagus nerve system.  The results and their impact were unsatisfying due to missing brainstem activations.  These activations, however, are mandatory for reasoning, higher subcortical and cortical activations of vagus nerve structures.  The objective of this study was to test a new parameter setting and a novel device for performing specific tVNS at the inner side of the tragus.  This study showed the feasibility of these and their potential for brainstem and cerebral activations as measured by BOLD fMRI.  In total, 4 healthy male adults were scanned inside a 1.5-Tesla MR scanner while undergoing tVNS at the left tragus.  These investigators ensured that their newly developed tVNS stimulator was adapted to be an MRI-safe stimulation device.  In the experiment, cortical and brainstem representations during tVNS were compared to a baseline.  A positive BOLD response was detected during stimulation in brain areas associated with higher order relay nuclei of vagal afferent pathways, the left locus coeruleus, the thalamus, the left prefrontal cortex, the right and the left postcentral gyrus, the left posterior cingulated gyrus and the left insula, respectively.  Deactivations were found in the right nucleus accumbens and the right cerebellar hemisphere.  The authors concluded that this method and device are feasible and appropriate for accessing cerebral vagus nerve structures.

Xiong et al (2009) stated that post-operative cognitive dysfunction (POCD) is a decline in cognitive function for weeks or months after surgery.  It may affect the patients' length of hospital stay, quality of life, the rehabilitation process, and work performance.  Prolonged POCD occurs frequently after cardiac surgery, and the risk of POCD increases with age.  The pathophysiology of POCD is not well-understood.  However, emerging evidences indicate that various inflammatory mediators are involved in the pathophysiology of POCD and inflammatory response may be a potential pathogenic factor.  Vagus nerve stimulation has been shown to decrease production and release of pro-inflammatory cytokines through the cholinergic anti-inflammatory pathway (CAP) in both animal model and human.  Considering that inflammation plays a definite role in the pathogenesis of POCD and the vagus nerve can mediate inflammation via CAP, these researchers hypothesized that transcutaneous VNS may attenuate POCD by reducing inflammatory response in elderly patients.

Hemicrania continua is a rare, relentless, constant, 1-sided headache that is accompanied at times by mild symptoms related to dysfunction of the autonomic nervous system in the face -- small pupil, drooping eyelid, red or watering eye, stuffy or runny nose -- similar to the symptoms of a cluster headache, but much less dramatic.  The pain is usually dull but can wax and wane in severity.  These headaches often subside entirely with prescription anti-inflammatory medication.

Magis et al (2011) stated that cluster headache is well known as one of the most painful primary neurovascular headache.  Since 1 % of chronic cluster headache patients become refractory to all existing pharmacological treatments, various invasive and sometimes mutilating procedures have been tried in the last decades.  Recently, neurostimulational approaches have raised new hope for drug-resistant chronic cluster headache patients.  The authors reviwed the evidence on stimulation of the great occipital nerve, which has been the best evaluated peripheral nerve stimulation technique in drug-resistant chronic cluster headache, providing the most convincing results so far.  Other peripheral nerve stimulation approaches used for this indication were also reviewed in detail.  They noted that "[a]lthough available studies are limited to a relatively small number of patients and placebo-controlled trials are lacking ....  More studies are needed to evaluate the usefulness of supraorbital nerve stimulation and of vagus nerve stimulation in management of cluster headaches".

Martin and Martin-Sanchez (2012) evaluated the effectiveness of VNS for treatment of depression.  These researchers conducted a systematic review and meta-analysis of analytical studies.  Effectiveness was evaluated according to severity of illness and percentage of responders.  They identified 687 references.  Of these, 14 met the selection criteria and were included in the review.  The meta-analysis of effectiveness 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 controlled trial that 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 co-efficient 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 concluded that currently, insufficient data are 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.

In a pilot study, Lehtimaki et al (2012) examined if transcutaneous VNS (tVNS) combined with sound therapy (ST) would reduce the severity of tinnitus and tinnitus-associated distress.  The objectives were to study whether tVNS has therapeutic effects on patients with tinnitus and, additionally, if tVNS has effects on acoustically evoked neuronal activity of the auditory cortex.  The clinical efficacy was studied by a short-term tVNS plus ST trial in 10 patients with tinnitus using disease-specific and general well-being questionnaires.  Transcutaneous VNS was delivered to the left tragus.  The acute effects of tVNS were evaluated in 8 patients in the MEG study in which the N1m response was analyzed in terms of source level amplitude and latency in the presence or absence of tVNS.  The treatment with tVNS plus ST produced improved mood and decreased tinnitus handicap scores, indicating reduced tinnitus severity.  The application of tVNS decreased the amplitude of auditory N1m responses in both hemispheres.  The results of this pilot study need to be validated by well-designed studies.

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.
 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
61885
64553
64568
64569
64570
95970
95974
+ 95975
CPT codes not covered for indications listed in the CPB:
0312T
0313T
0317T
64550
Other CPT codes related to the CPB:
0314T Vagus nerve blocking therapy (morbid obesity); laparoscopic removal of vagal trunk neurostimulator electrode array and pulse generator
0315T Vagus nerve blocking therapy (morbid obesity); removal of pulse generator
0316T Vagus nerve blocking therapy (morbid obesity); replacement of pulse generator
HCPCS codes covered if selection criteria are met:
C1767 Generator, neurostimulator (implantable), nonrechargeable
C1778 Lead, neurostimulator (implantable)
C1816 Receiver and/or transmitter, neurostimulator (implantable)
C1883 Adaptor/ extension, pacing lead or neurostimulator lead (implantable)
L8680 Implantable neurostimulator electrode, each
L8681 Patient programmer (external) for use with implantable programmable neurostimulator pulse generator, replacement only
L8682 Implantable neurostimulator radiofrequency receiver
L8683 Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8685 Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686 Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687 Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688 Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689 External recharging system for battery (internal) for use with implanted neurostimulator, replacement only
L8695 External recharging system for battery (external) for use with implantable neurostimulator, replacement only
ICD-9 codes covered if selection criteria are met:
345.40 - 345.41 Localization-related (focal) (partial) epilepsy and epileptic syndromes with complex partial seizures [not covered for transcutaneous vagus nerve stimulation]
345.50 - 345.51 Localization-related (focal) (partial) epilepsy and epileptic syndromes with simple partial seizures [not covered for trancutaneous vagus nerve stimulation]
ICD-9 codes not covered for indications listed in the CPB:
278.00 - 278.01 Obesity
291.82 Alcohol-induced sleep disorders
292.85 Drug-induced sleep disorders
296.00 - 296.99 Episodic mood disorders
299.00 - 299.01 Autistic disorder
300.00 - 300.09 Anxiety states
300.3 Obsessive-compulsive disorders
300.4 Dysthymic disorder
303.00 - 303.93 Alcohol dependence syndrome
304.00 - 304.93 Drug dependence
305.00 - 305.93 Nondependent abuse of drugs
307.23 Tourette's disorder
307.40 - 307.49 Specific disorders of sleep of nonorganic origin
307.81 Tension headache
311 Depressive disorder, not elsewhere classified
327.30 - 327.39 Circadian rhythm sleep disorder
327.40 - 327.49 Organic parasomnia
327.51 - 327.59 Organic sleep related movement disorders
327.8 Other organic sleep disorders
331.0 Alzheimer's disease
333.1 Essential and other specified forms of tremor
339.41 Hemicrania continua
343.0 - 343.9 Infantile cerebral palsy
345.00 - 345.3
345.60 - 345.91
Epilepsy [other than partial onset]
346.00 - 346.93 Migraine
347.00 - 347.11 Cataplexy and narcolepsy
388.30 - 388.32 Tinnitus
398.91 Rheumatic heart failure (congestive)
402.01 Hypertensive heart disease, malignant, with heart failure
402.11 Hypertensive heart disease, benign, with heart failure
402.91 Hypertensive heart disease, unspecified, with heart failure
404.01 Hypertensive heart and chronic kidney disease, malignant, with heart failure and with chronic kidney disease stage I through stage IV, or unspecified
404.03 Hypertensive heart and chronic kidney disease, malignant, with heart failure and chronic kidney disease stage V or end stage renal disease
404.11 Hypertensive heart and chronic kidney disease, benign, with heart failure and with chronic kidney disease stage I through stage IV, or unspecified
404.13 Hypertensive heart and chronic kidney disease, benign, with heart failure and chronic kidney disease stage V or end stage renal disease
404.91 Hypertensive heart and chronic kidney disease, unspecified, with heart failure and with chronic kidney disease stage I through stage IV, or unspecified
404.93 Hypertensive heart and chronic kidney disease, unspecified, with heart failure and chronic kidney disease stage V or end stage renal disease
428.0 - 428.9 Heart failure
729.1 Myalgia and myositis, unspecified [fibromyalgia]
780.01 Coma
780.39 Other convulsions [seizure NOS]
780.50 - 780.59 Sleep disturbances
783.6 Polyphagia
784.0 Headache


The above policy is based on the following references:
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  3. The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology. 1995;45(2):224-230.
  4. Salinsky MC, Uthman BM, Ristanovic RK, et al. Vagus nerve stimulation for the treatment of medically intractable seizures. Results of a 1-year open-extension trial. Vagus Nerve Stimulation Study Group. Arch Neurol. 1996;53(11):1176-1180.
  5. Clarke BM, Upton AR, Griffin H, et al. Seizure control after stimulation of the vagus nerve: Clinical outcome measures. Can J Neurol Sci. 1997;24(3):222-225.
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  7. Alberta Heritage Foundation for Medical Research (AHFMR). Vagus nerve stimulation for refractory epilepsy. Technote TN 19. Edmonton, AB: AHFMR; 1998.
  8. George MS, Sackeim HA, Marangell LB, et al. Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr Clin North Am. 2000;23(4):757-783.
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  14. Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: Efficacy, side effects, and predictors of outcome. Neuropsychopharmacology. 2001;25(5):713-728.
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  27. Buoni S, Mariottini A, Pieri S, et al. Vagus nerve stimulation for drug-resistant epilepsy in children and young adults. Brain Dev. 2004;26(3):158-163.
  28. National Institute for Clinical Excellence (NICE). Vagus nerve stimulation for refractory epilepsy in children. Interventional Procedure Guidance 50. London, UK: NICE; March 2004. Available at: http://www.nice.org.uk. Accessed June 15, 2004.
  29. National Institute for Clinical Excellence (NICE), Interventional Procedures Programme. Interventional procedure overview of vagus nerve stimulation for refractory epilepsy in children. London, UK: NICE; October 2002. Available at: http://www.nice.org.uk/page.aspx?o=66545. Accessed June 15, 2004.
  30. Elger G, Hoppe C, Falkai P, et al. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000;42(2-3):203-210.
  31. Carpenter LL, Friehs GM, Price LH. Cervical vagus nerve stimulation for treatment-resistant depression. Neurosurg Clin N Am. 2003;14(2):275-282.
  32. National Institute for Clinical Excellence (NICE), National Collaborating Centre for Primary Care. The epilepsies. The diagnosis and management of the epilepsies in adults and children in primary and secondary care. Clinical Guideline 20. London, UK: NICE; October 2004.
  33. Klein N, Sacher J, Wallner H, et al. Therapy of treatment resistant depression: Focus on the management of TRD with atypical antipsychotics. CNS Spectr. 2004;9(11):823-832.
  34. Husted DS, Shapira NA. A review of the treatment for refractory obsessive-compulsive disorder: From medicine to deep brain stimulation. CNS Spectr. 2004;9(11):833-847.
  35. Pallanti S, Hollander E, Goodman WK. A qualitative analysis of nonresponse: Management of treatment-refractory obsessive-compulsive disorder. J Clin Psychiatry. 2004;65 Suppl 14:6-10.
  36. Institute for Clinical Systems Improvement (ICSI). Major depression in adults for mental health care. ICSI Health Care Guideline. Bloomington, MN: ICSI; May 2004.
  37. Institute for Clinical Systems Improvement (ICSI). Major depression in adults in primary care. ICSI Health Care Guideline. 10th ed. Bloomington, MN: ICSI; May 2007.
  38. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of epilepsy in adults. A national clinical guideline. SIGN Publication No. 70. Edinburgh, Scotland: SIGN; April 2003.
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  40. George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58(5):364-373.
  41. Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial. Biol Psychiatry. 2005a;58(5):347-354.
  42. Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: A naturalistic study. Biol Psychiatry. 2005b;58(5):355-363.
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  46. United States Senate, Committee on Finance. Review of the FDA's approval process for the vagus nerve stimulation therapy system for treatment-resistant depression. Committee Staff Report to the Chairman and Ranking Member. 109th Congress, 2nd Session. S. Prt. 109-45.  Washington, DC: U.S. Government Printing Office; 2006. Available at: http://finance.senate.gov/press/Gpress/02_2006%20report.pdf. Accessed June 12, 2006.
  47. Aggressive Research Intelligence Facility (ARIF). Vagus nerve stimulation. Persistent severe depression. Requests for Information -- Completed. Birmingham, UK: University of Birmingham; October 2005. Available at: http://www.bham.ac.uk/arif/tvt.htm. Accessed January 29, 2007.
  48. California Technology Assessment Forum (CTAF). Vagus nerve stimulation for treatment resistant depression. Technology Assessment. San Francisco, CA: CTAF; February 15, 2006.  Available at: http://ctaf.org/ass/viewfull.ctaf?id=65198186099. Accessed June 6, 2006.
  49. George MS, Nahas Z, Borckardt JJ, et al. Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders. Expert Rev Neurother. 2007;7(1):63-74.
  50. Centers for Medicare & Medicaid Services (CMS). Decision memo for vagus nerve stimulation for treatment of resistant depression (TRD) (CAG-00313R). Baltimore, MD: CMS; May 4, 2007. Available at: http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=195. Accessed May 14, 2007.
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  54. Diamond A, Kenney C, Jankovic J. Effect of vagal nerve stimulation in a case of Tourette's syndrome and complex partial epilepsy. Mov Disord. 2006;21(8):1273-1275.
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  57. Fitzgerald PB, Daskalakis ZJ. The use of repetitive transcranial magnetic stimulation and vagal nerve stimulation in the treatment of depression. Curr Opin Psychiatry. 2008;21(1):25-29.
  58. Camilleri M, Toouli J, Herrera MF, et al. Intra-abdominal vagal blocking (VBLOC therapy): Clinical results with a new implantable medical device. Surgery. 2008;143(6):723-731.
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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