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 focal seizures (formerly known as partial onset seizures) who remain refractory to optimal anti-epileptic medications and/or surgical intervention (such as a lesionectomy or medial temporal lobectomy), or who have debilitating side effects from anti-epileptic medications, and who have no history of a bilateral or left cervical vagotomy.  (Note: Electronic analysis of an implanted neurostimulator pulse generator system for vagus nerve stimulation is considered medically necessary when criteria are met).

Aetna considers vagus nerve electrical stimulators medically necessary durable medical equipment (DME) for the treatment of Lennox-Gastaut syndrome in members who remain refractory to optimal anti-epileptic medications, and/or surgical intervention (such as a corpus callosotomy or lesional epilepsy surgery), or who have debilitating side effects from anti-epileptic medications, and who have no history of a bilateral or left cervical vagotomy

Aetna considers replacement/revision of a vagus nerve therapy system/handheld magnet medically necessary if the original system/magnet met criteria as medically necessary and is no longer under warranty and cannot be repaired.

Aetna considers transcutaneous vagus nerve stimulation (e.g., the Stivax device) experimental and investigational for the treatment of post-laminectomy syndrome, 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 prevention of chronic migraine attacks 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
• Alzheimer disease
• Anxiety disorders
• Atonic seizures
• Atrial fibrillation
• Autism
• Bipolar disorders
• Bulimia nervosa
• Cancer
• Cerebral palsy
• Crohn's disease
• Chronic headaches
• Cluster headaches
• Cognitive impairment associated with Alzheimer’s disease
• Coma
• Depression
• Dravet syndrome
• Eating disorders (e.g., anorexia and bulimia)
• Essential tremor
• Fibromyalgia
• Generalized motor seizures (formerly generalized tonic-clonic seizures)
• Generalized epilepsy syndromes
• Generalized treatment-resistant epilepsy
• Heart failure
• Hemicrania continua
• Impaired glucose tolerance/Pre-diabetes
• Inflammation
• Juvenile myoclonic epilepsy
• Migraine headaches
• Mood disorders
• Narcolepsy
• Obesity
• Obsessive-compulsive disorder
• Panic disorder
• Post-traumatic stress disorder
• Prader-Willi syndrome
• Rheumatoid arthritis
• Schizophrenia
• Sjogren's syndrome
• Sleep disorder
• Status epilepticus
• Stroke
• Tinnitus
• Tourette's syndrome
• Traumatic brain injury (TBI) including post-TBI pneumonia

For vagus nerve blocking for obesity, see CPB 157 - Obesity Surgery.

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 vagus nerve sends signals to the brain which stimulate the area of the brain believed to be involved in mood regulation and seizure activity; however, the exact mechanism of action is unknown. 

The NCP System, approved by the Food and Drug Administration (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.The lead electrode stimulation is performed only on the left vagal nerve, as the right vagal nerve helps control the heartbeat. 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. The pulse generator can be programmed to deliver stimulation within parameters that suit the individual’s needs. 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". 

Vagus nerve stimulation (VNS) was originally designed as a treatment option for medically refractory epilepsy or the inability to control seizure activity with antiepileptic drug therapy. However, VNS has also been proposed as adjunct therapy for treatment resistant major depression and bipolar disorder. VNS is being investigated for a broad range of indications including Alzheimer’s disease, anxiety disorders, bulimia, chronic headache/migraine, heart failure and obesity.

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 [standard error (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:

1. electroconvulsive therapy (ECT),
2. repetitive transcranial magnetic stimulation (rTMS),
3. VNS, and
4. 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.

Nonimplantable vagus nerve stimulation or transcutaneous vagus nerve stimulation devices are designed to treat medically refractory epilepsy and depression. A hand-held battery-powered stimulation unit and ear electrode combines to purportedly stimulate the auricular branch of the vagus nerve through the skin over the concha of the outer ear to deliver treatment. Stimulation treatment occurs several hours daily and is administered by the individual.

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 (odds ratio [OR] = 1.61 [95 % confidence interval [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 (2013) 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.

Straube et al (2012) stated that chronic migraine (CM) was first defined in the second edition of the International Headache Society (IHS) classification in 2004.  The definition currently used (IHS 2006) requires the patient to have headache on more than 15 days/month for longer than 3 months and a migraine headache on at least 8 of these monthly headache days and that there is no medication overuse.  In daily practice the majority of the patients with CM also report medication overuse but it is difficult to determine whether the use is the cause or the consequence of CM.  Most the patients also have other co-morbidities, such as depression, anxiety and chronic pain at other locations.  Therapy has to take this complexity into consideration and is generally multi-modal with behavioral therapy, aerobic training and pharmacotherapy.  The use of analgesics should be limited to fewer than 15 days per month and use of triptans to fewer than 10 days per month.  Drug treatment should be started with topiramate, the drug with the best scientific evidence.  If there is no benefit, onabotulinum toxin A (155 to 195 Units) should be used.  There is also some limited evidence that valproic acid and amitriptyline might be beneficial.  Moreover, the authors stated that neuromodulation by stimulation of the greater occipital nerve or vagal nerve is being tested in studies and is so far an experimental procedure only.

On behalf of the Guideline Development Subcommittee of the American Academy of Neurology (AAN), Morris et al (2013) evaluated the evidence since the 1999 assessment regarding safety and effectiveness of (VNS for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients greater than 12 years of age.  These investigators reviewed the literature and identified relevant published studies.  They classified these studies according to the AAN evidence-based methodology.  Vagal nerve stimulation is associated with a greater than 50 % seizure reduction in 55 % (95 % CI: 50 % to 59 %) of 470 children with partial or generalized epilepsy (13 Class III studies).  Vagal nerve stimulation is associated with a greater than 50 % seizure reduction in 55 % (95 % CI: 46 % to 64 %) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies).  Vagal nerve stimulation is associated with an increase in greater than or equal to 50% seizure frequency reduction rates of approximately 7 % from 1 to 5 years post-implantation (2 Class III studies).  Vagal nerve stimulation is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies).  Infection risk at the VNS implantation site in children is increased relative to that in adults (OR = 3.4, 95 % CI: 1.0 to 11.2).  Vagal nerve stimulation is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy; it may have improved efficacy over time.  The authors concluded that VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C); it may be considered to have improved efficacy over time (Level C).  Children should be carefully monitored for site infection after VNS implantation.  Moreover, these researchers noted that some reports have discussed VNS use in small numbers of patients with juvenile myoclonic epilepsy (JME); they stated that larger reports would help substantiate whether VNS is appropriate in medically refractory JME.

McClelland et al (2013) stated that eating disorders (ED) are chronic and sometimes deadly illnesses.  Existing treatments have limited proven efficacy, especially in the case of adults with anorexia nervosa.  Emerging neural models of ED provide a rationale for more targeted, brain-directed interventions.  In a systematic review, these investigators examined the effects of neuromodulation techniques on eating behaviors and body weight and assessed their potential for therapeutic use in ED.  All articles in PubMed, PsychInfo and Web of Knowledge were considered and screened against a priori inclusion/exclusion criteria.  The effects of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, VNS and deep brain stimulation (DBS) were examined across studies in ED samples, other psychiatric and neurological disorders, and animal models.  A total of 60 studies were identified.  There is evidence for ED symptom reduction following rTMS and DBS in both anorexia nervosa and bulimia nervosa.  Findings from studies of other psychiatric and neurological disorders and from animal studies demonstrated that increases in food intake and body weight can be achieved following DBS and that VNS has potential value as a means of controlling eating and inducing weight loss.  The authors concluded that neuromodulatory tools have potential for reducing ED symptomatology and related behaviors, and for altering food intake and body weight.  They stated that more research is needed to evaluate the potential of neuromodulatory procedures for improving long-term outcomes in ED.

Elliott et al (2011a) evaluated the safety and effectiveness of VNS in a consecutive series of adults and children with treatment-resistant epilepsy (TRE).  In this retrospective review of a prospectively created database of 436 consecutive patients who underwent VNS implantation for TRE between November 1997 and April 2008, there were 220 (50.5 %) females and 216 (49.5 %) males ranging in age from 1 to 76 years at the time of implantation (mean of 29.0 ± 16.5).  Thirty-three patients (7.6 %) in the primary implantation group had inadequate follow-up (less than 3 months from implantation) and 3 patients had early device removal because of infection and were excluded from seizure control outcome analyses.  Duration of VNS treatment varied from 10 days to 11 years (mean of 4.94 years).  Mean seizure frequency significantly improved following implantation (mean reduction of 55.8 %, p < 0.0001).  Seizure control greater than or equal to 90 % was achieved in 90 patients (22.5 %), greater than or equal to 75 % seizure control in 162 patients (40.5 %), greater than or equal to 50 % improvement in 255 patients (63.75 %), and less than 50 % improvement in 145 patients (36.25 %).  Permanent injury to the vagus nerve occurred in 2.8 % of patients.  The authors concluded that VNS is a safe and effective palliative treatment option for focal and generalized TRE in adults and children.  When used in conjunction with a multi-disciplinary and multi-modality treatment regimen including aggressive anti-epileptic drug regimens and epilepsy surgery when appropriate, more than 60 % of patients with TRE experienced at least a 50 % reduction in seizure burden.  Good results were seen in patients with non FDA-approved indications.  Moreover, they stated that prospective, randomized trials are needed for patients with generalized epilepsies and for younger children to potentially expand the number of patients who may benefit from this palliative treatment.  The authors also noted the following drawbacks of the study:

1. although patients were entered prospectively into the database, this study was performed via retrospective query.  Follow-up was unavailable in 8 % of patients, providing a small margin of error in the estimates of VNS efficacy.  Determination of seizure frequency and use and efficacy of magnetic swiping relied on the report of patients or caretakers and is inherently subject to error,
2. a design limitation inherent to all retrospective, non-randomized studies on VNS is the lack of a control group, and
3. a potential confound is the effect of AED (anti-epileptic drug) regimen changes on seizure frequency over time in the setting of VNS. 

Many office visits were accompanied by VNS setting changes and, much more frequently, by AED regimen adjustments (medication and/or dosage changes).  The complexity and frequency of such changes (often multiple changes in a single visit) proved too difficult to incorporate into a meaningful analysis.  The authors could not control for all of these changes but believe AED treatment plays a major role in the success of any treatment plan that includes long-term VNS therapy.  In fact, the increase in VNS efficacy over time reported by numerous centers may be due to alteration in device parameters, changes in AED regimen, or an undefined, synergistic effect of both.

Elliott et al (2011b) analyzed the effectiveness of VNS in a large consecutive series of children 18 years of age and younger with TRE and compared the safety and effectiveness in children under 12 years of age with the outcomes in older children.  These researchers retrospectively reviewed 141 consecutive cases involving children (75 girls and 66 boys) with TRE in whom primary VNS implantation was performed by the senior author between November 1997 and April 2008 and who had at least 1 year of follow-up since implantation.  The patients' mean age at VNS insertion was 11.1 years (range of 1 to 18 years).  Eighty-six children (61.0 %) were younger than 12 years at time of VNS insertion (which constitutes off-label usage of this device).  Follow-up was complete for 91.8 % of patients and the mean duration of VNS therapy in these patients was 5.2 years (range of 25 days to 11.4 years).  Seizure frequency significantly improved with VNS therapy (mean reduction of 58.9 %, p < 0.0001) without a significant reduction in anti-epileptic medication burden (median number of anti-epileptic drugs taken 3, unchanged).  Reduction in seizure frequency of at least 50 % occurred in 64.8 % of patients and 41.4 % of patients experienced at least a 75 % reduction.  Major (3) and minor (6) complications occurred in 9 patients (6.4 %) and included 1 deep infection requiring device removal, 1 pneumothorax, 2 superficial infections treated with antibiotics, 1 seroma/hematoma treated with aspiration, persistent cough in 1 patient, severe but transient neck pain in 1 patient, and hoarseness in 2 patients.  There was no difference in efficacy or complications between children 12 years of age and older (FDA-approved indication) and those younger than 12 years of age (off-label usage).  Linear regression analyses did not identify any demographic and clinical variables that predicted response to VNS.  The authors concluded that VNS is a safe and effective treatment for TRE in young adults and children.  Over 50 % of patients experienced at least 50 % reduction in seizure burden.  Children younger than 12 years had a response similar to that of older children with no increase in complications.  Moreover, they stated that given the efficacy of this device and the devastating effects of persistent epilepsy during critical developmental epochs, randomized trials are needed to potentially expand the indications for VNS to include younger children.  Moreover, the authors stated that this study was limited by the retrospective query into a prospective database and was subject to biases inherent to such methodology.  Nearly 8 % of patients were unavailable for follow-up.  Determination of seizure frequency relied on the reports of patients or caretakers and is inherently subject to error and bias.  This limitation is common to many studies measuring seizure frequency and treatment outcomes.  These researchers tried to improve their estimates by using LVCF (last value carried forward) analysis instead of declining-n analysis, which is prone to non-responder attrition.  Detailed information on the effects of VNS on mood, quality of life, and qualitative aspects of seizures (duration, severity, clustering, postictal period, and magnet usage) were either not systematically reported or could not be derived from this retrospective analysis.  Moreover, these investigators did not determine if a mean reduction in seizures of nearly 50 % translates into caretaker and patient satisfaction and overall improvements in quality of life.  They stated that future prospective studies are needed to better ascertain baseline mood assessments, quality-of-life metrics, and caretaker satisfaction and to determine the impact of VNS on these parameters and their relation to seizure control.  Another confound concerns the unknown impact that changes in AED regimens have on seizure frequency over time in the setting of VNS.  Many office visits were accompanied by VNS setting changes and, more frequently, by AED regimen adjustments.  The authors could not control for these changes but believe AED treatment plays a major role in the success of any treatment plan, including long-term VNS therapy.  They stated that further study is needed to better understand the relative contributions of effective VNS therapy, AED regimen adjustments, and regression to the mean.

The study by Elliott et al (2011b) (effects of VNS on children) appeared to be a sub-analysis of the study by Elliott et al 2011a) (effects of VNS on adults and children).

An UpToDate review on “Vagus nerve stimulation therapy for the treatment of epilepsy” (Karceski and Schachter, 2014) states that “The Food and Drug Administration (FDA) has approved vagus nerve stimulator (VNS) therapy as adjunctive treatment for adults and adolescents over 12 years of age whose partial-onset seizures were refractory to antiepileptic drugs.  Since the approval of VNS therapy for epilepsy, clinicians have actively debated its role.  While further controlled studies are needed to more fully understand the safety, tolerability, and efficacy profile of VNS in children and in patients with generalized seizures, VNS is often used in these cases as well …. Case series suggest that VNS is also effective in generalized epilepsy syndromes.  While some studies found that symptomatic generalized epilepsy is more responsive to VNS than idiopathic syndromes, others have reported the opposite or found no difference”.

Huang et al (2014) noted that impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology.  Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure (BP).  In this pilot randomized clinical trial (RCT), these researchers compared the effectiveness of transcutaneous auricular VNS (taVNS) and sham-taVNS on patients with IGT.  A total of 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham-taVNS 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 BP, diastolic BP, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc).  A total of 100 participants completed the study and were included in data analysis.  Two female patients (1 in the taVNS group, 1 in the sham-taVNS group) dropped out of the study due to stimulation-evoked dizziness.  The symptoms were relieved after stopping treatment.  Compared with sham-taVNS, taVNS significantly reduced the 2-hour glucose tolerance (F(2) = 5.79, p = 0.004).  In addition, these investigators found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic BP over time compared with sham-taVNS.  Compared with the no-treatment control group, patients receiving taVNS 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.  The authors concluded that the findings of this study suggested that taVNS is a promising, simple, and cost-effective treatment for IGT/ pre-diabetes with only slight risk of mild side-effects.

Cai et l (2014) stated that because of its ability to regulate mechanisms well-studied in neuroscience, such as norepinephrine and serotonin release, the vagus nerve may play an important role in regulating cerebral blood flow, edema, inflammation, glutamate excito-toxicity, and neurotrophic processes.  There is strong evidence that these same processes are important in stroke pathophysiology.  These investigators reviewed the literature for the role of VNS in improving ischemic stroke outcomes by performing a systematic search for publications in Medline (1966 to 2014) with keywords "VNS AND stroke" in subject headings and key words with no language restrictions.  Of the 73 publications retrieved, these researchers identified 7 studies from 3 different research groups that met the final inclusion criteria of research studies addressing the role of VNS in ischemic stroke.  Results from these studies suggested that VNS has promising efficacy in reducing stroke volume and attenuating neurological deficits in ischemic stroke models.  Given the lack of success in phase III trials for stroke neuroprotection, it is important to develop new therapies targeting different neuroprotective pathways.  The authors concluded that further studies of the possible role of VNS, through normally physiologically active mechanisms, in ischemic stroke therapeutics should be conducted in both animal models and clinical studies.  In addition, recent advent of a non-invasive, transcutaneous VNS could provide the potential for easier clinical translation.

Hall et al (2104) stated that nosocomial infections, pneumonia in particular, are well-known complications of traumatic brain injury (TBI), which are associated with a worse neurological outcome.  These researchers explored the role of vagus nerve activity in immunomodulation as a causative factor.  A MEDLINE search revealed numerous reports published over the last decade describing the "cholinergic anti-inflammatory pathway" between the vagus nucleus and leukocyte activity.  Using a combination of lipopolysaccharide stimulation and vagotomy, it has been shown that the parasympathetic fibers terminating in the spleen reduce tumor necrosis factor (TNF) production.  Further pharmacological and receptor knockout studies have identified the α7 subtype of nicotinic receptors as the likely target for this.  Vagal activity also induces changes in neutrophil chemotaxis through altered expression of the CD11b integrin which is abolished by splenectomy.  By extrapolating this evidence these investigators suggested a possible mechanism for immunosuppression following TBI, which also has the potential to be targeted to reduce the incidence of pneumonia.  The authors concluded that while there is strong supporting evidence for the role of vagal nerve over-activity in post-TBI pneumonia, there have yet to be any clinical investigations and further study is needed.

Zhou et al (2014) noted that previous studies have shown that VNS can improve the prognosis of TBI.  These researchers examined the mechanism of the neuroprotective effects of VNS in rabbits with brain explosive injury.  Rabbits with brain explosive injury received continuous stimulation (10 V, 5 Hz, 5 ms, 20 minutes) of the right cervical vagus nerve.  Tumor necrosis factor-α, interleukin (IL)-1β and IL-10 concentrations were detected in serum and brain tissues, and water content in brain tissues was measured.  Results showed that VNS could reduce the degree of brain edema, decrease TNF-α and IL-1β concentrations, and increase IL-10 concentration after brain explosive injury in rabbits.  The authors concluded that these data suggested that VNS may exert neuroprotective effects against explosive injury via regulating the expression of TNF-α, IL-1β and IL-10 in the serum and brain tissue.

Howland (2014) noted that right cervical VNS is effective for treating heart failure in pre-clinical studies and a phase II clinical trial.  The effectiveness of various forms of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not been investigated beyond small pilot studies.  The relationship between depression, inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve.  The author concluded that VNS deserves further study for its potentially favorable effects on cardiovascular, cerebrovascular, metabolic, and other physiological biomarkers associated with depression morbidity and mortality.

Atonic Seizures

Rolston et al (2015) stated that atonic seizures are debilitating and poorly controlled with antiepileptic medications.  These investigators noted that 2 surgical options are primarily used to treat medically refractory atonic seizures:

1. corpus callosotomy (CC) and
2. VNS. 

However, given the uncertainty regarding relative effectiveness and surgical complications, the best approach for affected patients is unclear.  The PubMed database was queried for all articles describing the treatment of atonic seizures and drop attacks with either CC or VNS.  Rates of seizure freedom, greater than 50 % reduction in seizure frequency, and complications were compared across the 2 patient groups.  Patients were significantly more likely to achieve a greater than 50 % reduction in seizure frequency with CC versus VNS (85.6 % versus 57.6 %; RR: 1.5; 95 % CI: 1.1 to 2.1).  Adverse events were more common with VNS, though typically mild (e.g., 22 % hoarseness and voice changes), compared with CC, where the most common complication was the disconnection syndrome (13.2 %).  The authors concluded that both CC and VNS were well-tolerated for the treatment of refractory atonic seizures.  They noted that existing studies suggested that CC is potentially more effective than VNS in reducing seizure frequency, though a direct study comparing these techniques is needed before a definitive conclusion can be reached.

Atrial Fibrillation

Stavrakis et al (2015) stated that transcutaneous low-level tragus electrical stimulation (LLTS) suppresses atrial fibrillation (AF) in canines (Tragus is the small raised flap at the front of the ear immediately in front of the ear canal; and the vagus nerve can be activated via electrical stimulation to the ear’s tragus).  These researchers examined the anti-arrhythmic and anti-inflammatory effects of LLTS in humans.  Patients with paroxysmal AF who presented for AF ablation were randomized to either 1 hour of LLTS (n = 20) or sham control (n = 20).  Attaching a flat metal clip onto the tragus produced LLTS (20 Hz) in the right ear (50 % lower than the voltage slowing the sinus rate).  Under general anesthesia, AF was induced by burst atrial pacing at baseline and after 1 hour of LLTS or sham treatment.  Blood samples from the coronary sinus and the femoral vein were collected at those time-points and then analyzed for inflammatory cytokines, including tumor necrosis factor (TNF)-alpha and C-reactive protein (CRP), using a multiplex immunoassay.  There were no differences in baseline characteristics between the 2 groups.  Pacing-induced AF duration decreased significantly by 6.3 ± 1.9 minutes compared with baseline in the LLTS group, but not in the control subjects (p = 0.002 for comparison between groups).  Atrial fibrillation cycle length increased significantly from baseline by 28.8 ± 6.5 ms in the LLTS group, but not in control subjects (p = 0.0002 for comparison between groups).  Systemic (femoral vein) but not coronary sinus tumor necrosis factor (TNF)-alpha and CRP levels decreased significantly only in the LLTS group.  The authors concluded that LLTS suppressed AF and decreased inflammatory cytokines in patients with paroxysmal AF.  They stated that these findings support the emerging paradigm of neuromodulation to treat AF.  These preliminary findings need to be validated by well-designed studies.

Cluster Headaches

Nesbitt et al (2015) reported their initial experience with a novel device, designed to provide portable, non-invasive, transcutaneous stimulation of the vagus nerve, both acutely and preventively, as a treatment for cluster headaches.  Patients with cluster headaches (11 chronic, 8 episodic), from 2 centers, including 7 who were refractory to drug treatment, had sufficient data available for analysis in this open-label observational cohort study.  The device, known as the gammaCore, was used acutely to treat individual attacks as well as to provide prevention.  Patient-estimated effectiveness data were collected by systematic inquiry during follow-up appointments up to a period of 52 weeks of continuous use.  A total of 15 patients reported an overall improvement in their condition, with 4 reporting no change, providing a mean overall estimated improvement of 48 %.  Of all attacks treated, 47 % were aborted within an average of 11 ± 1 minutes of commencing stimulation; 10 patients reduced their acute use of high-flow oxygen by 55 % with 9 reducing triptan use by 48 %.  Prophylactic use of the device resulted in a substantial reduction in estimated mean attack frequency from 4.5/24 hours to 2.6/24 hours (p < 0.0005) post-treatment.  The authors concluded that these findings suggested that non-invasive VNS may be practical and effective as an acute and preventive treatment in chronic cluster headaches.  Moreover, they stated that further evaluation of this treatment using randomized sham-controlled trials is needed.  (This study provided Class IV evidence).

In a randomized, double-blind, sham-controlled study, Silberstein and colleagues (2016a) evaluated non-invasive VNS (nVNS) as an acute cluster headache (CH) treatment.  A total of 150 subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for less than or equal to 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 to 60 minutes).  Sub-analyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were pre-specified.  The intent-to-treat population comprised 133 subjects: 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 = 0.1).  Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2 %; sham, 10.6 %; p = 0.008) but not the cCH cohort (nVNS, 13.6 %; sham, 23.1 %; p = 0.48).  Sustained response rates were significantly higher with nVNS for the eCH cohort (p = 0.008) and total population (p = 0.04).  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.  The authors concluded that in one of the largest randomized sham-controlled studies for acute CH treatment, the response rate was not significantly different (versus sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population.  They stated that this safe and well-tolerated treatment represents a novel and promising option for eCH. The study was not powered to demonstrate independent statistical significance for the subgroup analyses, nor were the significance values adjusted for multiplicity.

The authors stated that the drawbacks of this study included the analysis of the cCH cohort as part of the primary end-point, the need for careful interpretation of sub-analyses results, challenges with blinding inherent in medical device studies, and the time to 1st measurement of response used to define the primary efficacy end-point.  Primary end-point results were significant for the eCH cohort; but were diminished overall by the cCH cohort results.  When sub-analyses results were interpreted, the lack of statistical powering and the potential for type 1 and type 2 errors (in the eCH and cCH cohorts, respectively) should be considered.  The difference in AE descriptions provided by subjects treated with the nVNS (e.g., drooping/pulling of the lip/face) and sham (e.g., burning, soreness, stinging) devices may help to explain results of the blinding analyses, which were similar to those observed in previous sham-controlled trials.  The burning sensation and other pain-related AEs reported by the sham-treated group in ACT1 may have led to a placebo effect based on impressions that the subjects were receiving active treatment.  Sham device-associated pain may have also produced a diffuse noxious inhibitory control (DNIC) effect, a phenomenon in which the application of a noxious electrical stimulus to remote body regions inhibits dorsal horn activity and attenuates the original pain.  Potential placebo and DNIC effects in the sham group may have reduced the magnitude of the therapeutic benefit associated with nVNS treatment.  Another drawback was that the time-point used to define the ACT1 primary end-point was 15 mins after treatment initiation, which has been used in other CH studies, rather than after treatment completion.  In ACT1, this 15-min interval comprised an 8-min nVNS stimulation period followed by only a 7-min period that appeared to be sufficient for significant treatment effects to become evident in the eCH cohort but not in the cCH cohort or total population.  The 15-min assessment time-point may have also contributed to the non-significant difference in average pain intensities between the nVNS and sham groups; other potential contributing factors included the combined statistical influence of the responders and non-responders as well as the assessment after all attacks (rather than after the 1st attack).  Thus, methodological implications in ACT1 regarding distinct effects among the eCH and cCH cohorts, the painful sham stimulation, and the use of a longer time to first measurement of response such as 30 mins, as used in CH studies of other therapies, should be considered for future RCTs.

Holle-Lee and Gaul (2016) noted that the effectiveness of invasive VNS as well as other invasive neuromodulatory approaches such as deep brain stimulation, occipital nerve stimulation, and ganglion sphenopalatine stimulation has been shown in the treatment of headache disorders in several studies in the past.  However, these invasive treatment options were quite costly and often associated with peri-operative and post-operative AEs, some severe.  As such, they were predominantly restricted to chronic and therapy refractory patients.  Transcutaneous VNS now offers a new, non-invasive neuromodulatory treatment approach.  Recently published studies showed encouraging results of nVNS, especially with respect to cluster headache, with high tolerability and a low rate of side effects; however, RCTs are needed to prove its effectiveness.

Goadsby et al (2018) compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH).  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 end-point 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 investigators concluded that, combing both eCH and cCH patients, nVNS was no different to sham.  For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH.

The authors stated that this study had several drawbacks, including its short duration, which did not allow for evaluation of continued/change in response with long-term nVNS therapy.  Some evidence suggested that patients who initially respond to nVNS as acute therapy for CH have a stable response with continued treatment. In epilepsy, long-term nVNS therapy has been associated with improved efficacy, which suggested possible disease-modifying effects.  Such effects have yet to be substantiated in CH.  Another drawback was the imbalance between CH subtypes, with the eCH subgroup comprising less than 30% of subjects. This imbalance was probably due, in part, to the nature of the study sites (i.e., tertiary care centers) and the recruitment of subjects throughout the year rather than specifically when attack bouts are most common among patients with eCH, such as during seasonal transition periods.  The stipulation that subjects’ preventive treatment regimens continue unchanged during the run-in and double-blind periods may have impeded enrollment of individuals with eCH, who may have opted to begin bridging therapies immediately rather than participate in the study.  During the open-label period, subjects could alter their CH treatment regimens by adding prophylactic therapies, or changing doses of existing treatments, or both.  This stipulation confounded the results, making it impossible to discern whether changes in efficacy outcomes were attributable to nVNS therapy or to other changes in treatment during this period.  In addition, there was the possible bias of multiple attack treatment that these investigators mitigated using the analytic technique, and with the secondary end-points of treated attacks on a per subject basis.  Moreover, a substantial number of attacks were treated in both arms, making multiple successful attack treatment by individuals an unlikely source of the positive outcome.

Yuan and Silberstein (2017) stated that neuromodulation is an emerging area in headache management.  Through neuro-stimulation, multiple brain areas can be modulated to alleviate pain, hence reducing the pharmacological need.  These researchers reviewed the recent development of the VNS for headache management.  Early case series from epilepsy and depression cohorts using invasive VNS showed a serendipitous reduction in headache frequency and/or severity.  Non-invasive VNS (nVNS), which stimulates the carotid vagus nerve with the use of a personal hand-held device, also demonstrated efficacy for acute migraine or cluster headache attacks.  Long-term use of nVNS appeared to exert a prophylactic effect for both chronic migraine and chronic cluster headache.  In animal studies, nVNS modulated multiple pain pathways and even lessen cortical spreading depression.  Progression in nVNS clinical efficacy over time suggested an underlying disease-modifying neuromodulation.  The authors concluded that non-invasive VNS appeared to be as effective as the invasive counterpart for many indications.  They stated that with an enormous potential therapeutic gain and a high safety profile, further development and application of nVNS is promising.

Furthermore, an UpToDate review on “Cluster headache: Treatment and prognosis” (May, 2017) stated that “When chronic cluster headache is unresponsive to medical treatments, various surgical interventions and neurostimulation techniques are potential treatment options, though none are clearly established as effective.  In such cases, it is particularly important to exclude potential causes of secondary cluster headache.  Neurostimulation techniques, including sphenopalatine ganglion stimulation and vagus nerve stimulation, appear promising but remain investigational.  Destructive surgical procedures are unproven and should be viewed with great caution”.

Gaul and colleagues (2016) noted that chronic cluster headache (CH) is a debilitating disorder for which few well-controlled studies demonstrate effectiveness of available therapies.  Non-invasive vagus nerve stimulation (nVNS) was examined as adjunctive prophylactic treatment of chronic 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 2-week baseline phase was followed by a 4-week randomized phase (SoC plus nVNS vs control) and a 4-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 versus controls (n = 48) (-5.9 versus -2.1, respectively) for a mean therapeutic gain of 3.9 fewer attacks per week (95 % CI: 0.5 to 7.2; p = 0.02).  Higher greater than or equal to 50 % response rates were also observed with SoC plus nVNS (40 % (18/45)) versus controls (8.3 % (4/48); p < 0.001).  No serious treatment-related AEs occurred.  The authors concluded that adjunctive prophylactic nVNS was a well-tolerated novel treatment for chronic CH, and may yield clinical benefits beyond those afforded by SoC treatment.

The authors stated that this study’s drawbacks included the lack of a placebo/sham device, an open-label study design, the short treatment duration (2.5 months) and the use of patient-reported outcomes.  No placebo-arm was incorporated into the study because a suitable placebo/sham device had not yet been designed.  In lieu of a placebo/sham-arm, SoC was deemed the most appropriate control treatment that was reflective of a real-world clinical scenario.  The open-label study design and short treatment duration may have contributed to a placebo effect in both treatment groups.  The 16.7 % response rate in the control group during the extension phase may partially reflect a placebo response to nVNS.  The initial response experienced in the control group during the randomized phase may have also impacted the capacity for a meaningful response to nVNS during the extension phase.  Additionally, fewer individuals in the control arm (50 %) than in the nVNS arm (64.4 %) were highly adherent (greater than or equal to 80 %) to prophylactic nVNS, which may have further confounded response rates and reductions in abortive medication use in this group.  Only patients with chronic, treatment-refractory CH were included because of their stable CH attack frequency and intensity.  A 2.5-month study duration was deemed sufficient to observe a treatment effect . Treatment response in favor of nVNS was consistent across ITT, mITT and per-protocol populations (per-protocol population was defined as participants in the mITT population who had greater than or equal to 12 days of observation in the randomized phase and no major protocol violation).  Because no CH-specific QOL instruments exist, the EQ-5D-3L and HIT-6 measures were considered most appropriate, and nVNS prophylaxis resulted in meaningful improvements for both measures.  The apparent lack of effect of acute nVNS therapy on CH duration or severity was consistent with findings in the chronic CH population that were reported in a recent study of acute nVNS therapy for CH.  The nVNS adherence rates in this study (50 % to 64 %) were consistent with those reported for prophylactic non-invasive neuromodulation in migraine and were considered meaningful given that twice-daily nVNS requires more effort and participation than a conventional oral medication regimen.

Gaul and associates (2017) stated that in the PREVA study, attack frequency reductions from baseline were significantly more pronounced with nVNS + SoC than with SoC alone.  Given the intensely painful and frequent nature of chronic CH attacks, additional patient-centric outcomes, including the time to and level of therapeutic response, were evaluated in a post-hoc analysis of the PREVA study.  After a 2-week baseline phase, a total of 97 patients with chronic CH entered a 4-week randomized phase to receive nVNS + SoC (n = 48) or SoC alone (n = 49).  All 92 patients who continued into a 4-week extension phase received nVNS + SoC.  Compared with SoC alone, nVNS + SoC led to a significantly lower mean weekly attack frequency by week 2 of the randomized phase; the attack frequency remained significantly lower in the nVNS + SoC group through week 3 of the extension phase (p < 0.02).  Attack frequencies in the nVNS + SoC group were significantly lower at all study time-points than they were at baseline (p < 0.05).  Response rates were significantly greater with nVNS + SoC than with SoC alone when response was defined as attack frequency reductions of greater than or equal to 25 %, greater than or equal to 50 %, and greater than or equal to 75 % from baseline (greater than or equal to 25 % and greater than or equal to 50 %, p < 0.001; greater than or equal to 75 %, p = 0.009).  The 100 % response rate was 8 % with nVNS + SoC and 0 % with SoC alone.  The authors concluded that prophylactic nVNS led to rapid, significant, and sustained reductions in chronic CH attack frequency within 2 weeks after its addition to SoC and was associated with significantly higher greater than or equal to 25 %, greater than or equal to 50 %, and greater than or equal to 75 % response rates than SoC alone.  The authors concluded that the rapid decrease in weekly attack frequency justified a 4-week trial period to identify responders to nVNS, with a high degree of confidence, among patients with chronic CH.

Marin and co-workers (2018) noted that evidence supports the use of nVNS (gammaCore) as a promising therapeutic option for patients with CH.  These researchers conducted this audit of real-world data from patients with CH, the majority of whom were treatment refractory, to explore early United Kingdom clinical experience with nVNS used acutely, preventively, or both.  They retrospectively analyzed data from 30 patients with CH (29 chronic, 1 episodic) who submitted individual funding requests for nVNS to the National Health Service.  All patients had responded to adjunctive nVNS therapy during an evaluation period (typical duration, 3 to 6 months).  Data collected from patient interviews, treatment diaries, and physician notes were summarized with descriptive statistics.  Paired t-tests were used to examine statistical significance.  The mean (SD) CH attack frequency decreased from 26.6 (17.1) attacks/week before initiation of nVNS therapy to 9.5 (11.0) attacks/week (p < 0.01) afterward.  Mean (SD) attack duration decreased from 51.9 (36.7) mins to 29.4 (28.5) mins (p < 0.01), and mean (SD) attack severity (rated on a 10-point scale) decreased from 7.8 (2.3) to 6.0 (2.6) (p < 0.01).  Use of abortive treatments also decreased.  Favorable changes in the use of preventive medication were also observed.  No serious device-related AEs were reported.  The authors concluded that significant decreases in attack frequency, severity, and duration were observed in these patients with CH who did not respond to or were intolerant of multiple preventive and/or acute treatments.  These real-world findings complemented evidence from clinical trials demonstrating the safety and efficacy of nVNS in CH.

The authors stated that drawbacks of this study include its small sample size (n = 30) and inherent inclusion bias.  By definition, this was a responder study, and patient responses were unlikely representative of the CH population as a whole.  Use of an evaluation period appeared to be a feasible and practical method for assessing response to nVNS in patients with CH, especially if one considers the mild side effect profile of nVNS and practicality of this therapy.  Furthermore, the current study sample comprising 63 % women was unusual considering that CH is more common among men.

Generalized Motor Seizures (Generalized Tonic-Clonic Seizures)

The AAN guidelines on “Vagus nerve stimulation for the treatment of epilepsy” (Morris et al., 2013) did not mention  of the use of VNS system in this subset of patients with generalized tonic-clonic seizures.

Status Epilepticus

Zeiler et al (2015) performed a systematic review of the literature on the insertion of VNS for refractory status epilepticus (RSE) and its impact on the control of RSE.  All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform, clinicaltrials.gov (inception to June 2014), reference lists of relevant articles, and gray literature were searched.  The strength of evidence was adjudicated using both the Oxford and GRADE methodology by 2 independent reviewers.  Overall, 17 studies were identified, with 7 manuscripts and 10 meeting abstracts.  A total of 28 patients were treated.  In those with generalized RSE, 76 % displayed cessation of RSE with VNS insertion.  In cases of focal RSE, 25 % responded to VNS insertion.  Few adverse effects related to VNS insertion were described.  The authors concluded that they currently cannot recommend the use of VNS for RSE; Oxford level 4, GRADE D evidence exists to suggest improvement in seizure control with the use of urgent VNS in generalized RSE.  They stated that no comments can be made on the utility of VNS in focal RSE; further prospective study is needed.

Prevention and Treatment of Chronic Migraine Attacks

In a prospective, multi-center, double-blind, sham-controlled pilot study, Silberstein and colleagues (2016b) evaluated the feasibility, safety, and tolerability of nVNS for the prevention of chronic migraine (CM) attacks.  Adults with CM (greater than or equal to 15 headache days/month) entered the baseline phase (1 month) and were subsequently randomized to nVNS or sham treatment (2 months) before receiving open-label nVNS treatment (6 months).  The primary end-points were safety and tolerability; effectiveness end-points in the intent-to-treat population included change in the number of headache days per 28 days and acute medication use.  A total of 59 participants (mean age of 39.2 years; mean headache frequency, 21.5 days/month) were enrolled.  During the randomized phase, tolerability was similar for nVNS (n = 30) and sham treatment (n = 29).  Most AEs were mild/moderate and transient.  Mean changes in the number of headache days were -1.4 (nVNS) and -0.2 (sham) (Δ = 1.2; p = 0.56); 27 participants completed the open-label phase.  For the 15 completers initially assigned to nVNS, the mean change from baseline in headache days after 8 months of treatment was -7.9 (95 % CI: -11.9 to -3.8; p < 0.01).  The authors concluded that therapy with nVNS was well-tolerated with no safety issues; persistent prophylactic use may reduce the number of headache days in CM.  Moreover, they stated that larger sham-controlled studies larger studies using modified stimulation parameters and longer open-label periods are needed.  This study provided Class II evidence that for patients with CM, nVNS was safe, was well-tolerated, but did not significantly change the number of headache days.  This pilot study lacked the precision to exclude important safety issues or benefits of nVNS.  The main drawbacks of this study were its small sample size (27 completed the open-label phase; n = 15 in the nVNS group), blinding challenges, and high discontinuation rate (only 46 % of subjects completed the open-label phase)).

In an open-label study, Grazzi and colleagues (2016) evaluated the safety, effectiveness, and tolerability of nVNS for the prophylactic treatment of menstrual migraine/menstrually related migraine.  A total of 56 enrolled subjects (menstrual migraine, 9 %; menstrually related migraine, 91 %), 33 (59 %) of whom were receiving other prophylactic therapies, entered a 12-week baseline period; 51 subjects subsequently entered a 12-week treatment period to receive open-label prophylactic nVNS adjunctively (31/51; 61 %) or as monotherapy (20/51; 39 %) on day-3 before estimated onset of menses through day +3 after the end of menses.  The number of menstrual migraine/menstrually related migraine days per month was significantly reduced from baseline (mean ± standard error, 7.2 ± 0.7 days) to the end of treatment (mean ± SE, 4.7 ± 0.5 days; p < 0.001) (primary end-point).  Of all subjects, 39 % (95 % CI: 26 %, 54 %) (20/51) had a greater than or equal to 50 % reduction (secondary end-point).  For the other secondary end-points, clinically meaningful reductions in analgesic use (mean change ± SE, -3.3 ± 0.6 times per month; p < 0.001), 6-item Headache Impact Test score (mean change ± SE, -3.1 ± 0.7; p < 0.001), and Migraine Disability Assessment score (mean change ± SE, -11.9 ± 3.4; p < 0.001) were observed, along with a modest reduction in pain intensity (mean change ± SE, -0.5 ± 0.2; p = 0.002).  There were no safety/tolerability concerns.  The authors concluded that these findings suggested that nVNS is an effective treatment that reduces the number of menstrual migraine/menstrually related migraine days and analgesic use without safety/tolerability concerns in subjects with menstrual migraine/menstrually related migraine; they stated that RCTs are needed.

In a multi-center, double-blind, randomized, sham-controlled trial (the PRESTO Study), Tassorelli and colleagues (2018) evaluated the safety, efficacy, and tolerability of nVNS (gammaCore; electroCore, LLC, Basking Ridge, NJ).  A total of 248 participants with episodic migraine with/without aura were randomized to receive nVNS or sham within 20 mins from pain onset.  Participants were to repeat treatment if pain had not improved in 15 mins.  nVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 mins (12.7 % versus 4.2 %; p = 0.012) and 60 mins (21.0 % versus 10.0 %; p = 0.023); but not at 120 mins (30.4 % versus 19.7 %; p = 0.067; primary end-point; logistic regression) after the 1st treated attack.  A post-hoc repeated-measures test provided further insight into the therapeutic benefit of nVNS through 30, 60, and 120 mins (OR 2.3; 95 % CI: 1.2 to 4.4; p = 0.012).  nVNS demonstrated benefits across other end-points including pain relief at 120 mins and was safe and well-tolerated.  The authors concluded that this randomized, sham-controlled trial supported the abortive efficacy of nVNS as early as 30 mins and up to 60 mins after an attack.  They stated that these findings also suggested effective pain relief, tolerability, and practicality of nVNS for the acute treatment of episodic migraine.

The authors stated that the drawbacks of this study included the selection of an appropriate sham device, which was a consistent challenge in neuromodulation studies.  The sham device in this study had an active signal that was strong enough to be perceived but was not intended to stimulate the vagus nerve, as recommended in published literature.  The apparent strength of the sham signal helped to maintain blinding but could have conceivably elevated the effects of sham treatment across all end-points, limiting the ability of clinically meaningful active therapeutic gains to achieve statistical superiority.  These researchers hypothesized that the higher-than-expected sham results could represent either a psychobiological placebo effect, or a physiologically active response potentially related to an unanticipated low-level of vagal or other activity generated by an active sham signal being applied to the neck.  It should be noted that this study was funded by electroCore.

Grazzi and associates (2018) examined additional data from the PRESTO Study to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication.  Patients recorded pain intensity for treated migraine attacks on a 4-point scale.  Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity.  These investigators also assessed the percentage of attacks that needed rescue medication and pain-free rates stratified by pain intensity at treatment initiation.  A significantly higher percentage of patients who used acute nVNS treatment (n = 120) versus sham (n = 123) reported a greater than or equal to 1-point decrease in pain intensity at 30 mins (nVNS, 32.2 %; sham, 18.5 %; p = 0.020), 60 mins (nVNS, 38.8 %; sham, 24.0 %; p = 0.017), and 120 mins (nVNS, 46.8 %; sham, 26.2 %; p = 0.002) after the first attack.  Similar significant results were seen when assessing the benefit in all attacks.  The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3 %; sham, 41.9 %; p = 0.013) and all attacks (nVNS, 52.3 %; sham, 37.3 %; p = 0.008).  When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 mins (all attacks: nVNS, 37.0 %; sham, 21.2 %; p = 0.025) and 120 mins (first attack: nVNS, 50.0 %; sham, 25.0 %; p = 0.018; all attacks: nVNS, 46.7 %; sham, 30.1 %; p = 0.037).  The authors concluded that this post-hoc analysis showed that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use.  These clinical benefits provided guidance in the optimal use of nVNS in everyday practice, which could potentially reduce use of acute pharmacologic medications and their associated AEs.

The authors stated that a limiting factor of the PRESTO Study was that the sham device, which delivered an appreciable electrical signal, appears to have had some level of vagal activation.  The design of sham devices for neuromodulation studies is inherently difficult because a compromise must be reached between maintaining blinding with a noticeable stimulation and minimizing an active effect.  A sham device that produces an active signal could obscure the actual effects of the verum device, thus reducing the opportunity to demonstrate therapeutic benefits above that of the sham device.  These researchers believed that the sham signal in the PRESTO Study likely provided a detectable degree of active treatment effects that potentially masked some of the differences between the nVNS and sham groups in the current analysis.

Martelletti and co-workers (2018) reported additional pre-defined secondary and other end-points from the PRESTO Study that demonstrated the consistency and durability of nVNS efficacy across a broad range of outcomes.  After a 4-week observation period, 248 patients with episodic migraine with/without aura were randomly assigned to acute treatment of migraine attacks with nVNS (n = 122) or a sham device (n = 126) during a double-blind period lasting 4 weeks (or until the patient had treated 5 attacks).  All patients received nVNS therapy during the subsequent 4-week/5-attack open-label period.  The intent-to-treat population consisted of 243 patients.  The nVNS group (n = 120) had a significantly greater percentage of attacks treated during the double-blind period that were pain-free at 60 (p = 0.005) and 120 mins (p = 0.026) than the sham group (n = 123) did.  Similar results were seen for attacks with pain relief at 60 (p = 0.025) and 120 mins (p = 0.018).  For the first attack and all attacks, the nVNS group had significantly greater decreases (versus sham) in pain score from baseline to 60 mins (p = 0.029); the decrease was also significantly greater for nVNS at 120 mins for the first attack (p = 0.011).  Results during the open-label period were consistent with those of the nVNS group during the double-blind period.  The incidence of AEs and adverse device effects was low across all study periods, and no serious AEs occurred.  The authors concluded that these results further demonstrated that nVNS is an effective and reliable acute treatment for multiple migraine attacks, which can be used safely while preserving the patient's option to use traditional acute medications as rescue therapy, possibly decreasing the risk of medication overuse.  Together with its practicality and optimal tolerability profile, these findings suggested nVNS has value as a front-line option for acute treatment of migraine.

The authors stated that this study had several drawbacks.  The selection of an appropriate sham device in neuromodulation studies was challenging.  In accordance with previous recommendations to ensure maintenance of the study blind, the sham device used in PRESTO produced an active signal that could be perceived by the user but was not designed to stimulate the vagus nerve; recent data suggest that the strength of the sham device’s signal may have inadvertently activated the vagus nerve and could have inflated the responses to sham treatment across all end points.  This phenomenon, which merited further investigation, may have been related to a psychobiological placebo effect; but more likely resulted from the unanticipated physiologically active signal that may have decreased the difference in therapeutic gain seen between the nVNS and sham groups.  During both the double-blind and open-label periods, the mean number of acute medications used per migraine attack was substantially lower than that seen during the observational period.  Such a decrease in medication use could be interpreted as evidence of treatment efficacy; however, these results must be interpreted with caution, as patients were encouraged to refrain from using acute medications for 120 mins after stimulation with the study device.  This study limitation most likely contributed to decreases in acute medication use in both the nVNS and sham groups during the double-blind period and may partially explain the lack of significance between treatment groups for this end-point.

Vecchio and colleagues (2018) examined the potential effect of nVNS in the modulation of spontaneous and pain related bioelectrical activity in a subgroup of migraine patients enrolled in the PRESTO trial by using resting-state EEG and trigeminal laser-evoked potentials (LEPs), which were recorded for 27 migraine patients who received active or sham nVNS over the cervical vagus nerve.  These researchers measured power values for frequencies between 1 to 100 Hz in a resting-state condition and the latency and amplitude of N1, N2, and P2 components of LEPs in a basal condition during and after active or sham VNS (T0, T1, T2).  The P2 evoked by the right and the left trigeminal branch was smaller during active nVNS.  The sham device also attenuated the P2 amplitude evoked by the left trigeminal branch at T1 and T2, but this attenuation did not reach significance.  No changes were observed for N1 amplitude, N1, N2, P2 latency, or pain rating. The authors concluded that nVNS induced an increase of EEG power in both slow and fast rhythms, but this effect was not significant as compared to the sham device.  These researchers stated that these findings suggested that nVNS acted on the cortical areas that are responsible for trigeminal pain control and pave the ground for future studies aimed at confirming the possible correlations with clinical outcomes, including the effect on symptoms that are directly correlated with trigeminal pain processing and modulation.

Lendvai and associates (2018) noted that cervical nVNS emerged as an adjunctive neuromodulation approach for primary headache disorders with limited responsiveness to pharmacologic and behavioral treatment.  These researchers evaluated the safety and efficacy of invasive and non-invasive peripheral nerve stimulation of the cervical branch of the vagal nerve (afferent properties) for primary headache disorders (episodic/chronic migraine [EM/CM] and cluster headache [ECH/CCH]) and provided a brief summary of the pre-clinical data on the possible mechanism of action of cervical VNS and trigemino-nociceptive head pain transmission.  They carried out a systematic search of published data in PubMed for RCTs and prospective cohort clinical studies assessing the safety/efficacy and cost-effectiveness of cervical VNS in primary headache disorders and related pre-clinical studies.  A total of 3 RCTs were identified for ECH/CCH (ACT-1, ACT-2 and PREVA), 1 RCT for migraine (EVENT) and several prospective cohort studies and retrospective analyses for both headache disorders.  In ACT-1, a significantly higher response rate, a higher pain-free rate and a decrease in mean attack duration were found in nVNS-treated ECH/CCH patients compared to sham stimulation.  ACT-2 confirmed these findings (e.g., significantly higher pain-free attacks, pain severity decline and increased responder-rate [defined as greater than or equal to 50 % reduction]).  The PREVA study demonstrated the superiority of adjunctive nVNS to standard care alone and observed a significantly higher attack reduction (p = 0.02) and responder rate (defined as greater than or equal to 50 % reduction).  For CM, the EVENT study assessed a significantly higher frequency of decline in the open-label phase.  Mostly transient mild/moderate AEs were recorded, and no severe device-related AEs occurred.

The authors concluded that currently published clinical nVNS data demonstrated promising clinical effects for the abortive use in episodic migraine and cluster headache.  The interpretation of the findings in this narrative review may be hindered due to several considerations.  Although, most of the abortive and preventive trials have been determined as Class I to IV studies (Class I studies for the acute treatment and Class II to IV studies for the preventive use), comparative and reproducible conclusions were limited by the different stimulation protocols and/or outcome parameter measures.  Secondly, a more systematic review-based approach including multiple comparative correlation analysis of primary and secondary end-point classified as significantly different or nearly-significant should re-examine the positive findings of this narrative review.  So far, the episodic subtypes of migraine and cluster headache have responded superiorly compared to the chronic forms.  Due to its non-invasive character along with the reported tolerability, cervical nVNS may be justified in the pre-refractory state of migraine and cluster headache, and probably in a migraine subpopulation with limited available options (e.g., adolescents with migraine, menstruation-associated migraine).  The afferent properties of the vagus nerve are well-connected via the ncl. tractus solitarii to the locus coeruleus, the dorsal raphe nucleus, the parabrachial plexus, the paraventricular nucleus of the hypothalamus and directly to the TNC and the cervical spinal cord.  Given these anatomic reciprocal projections of the vagus nerve, electrical non-invasive modulation of the cervical vagal afferents may impact trigemino-vascular nociceptive transmission.  These researchers strongly believe that VNS constitutes an emerging issue of ongoing headache treatment and research.

Jancic and associates (2018) stated that migraine and epilepsy are classified as chronic paroxysmal neurologic disorders sharing many clinical features, as well as possible therapeutic options.  This review highlighted the similarities between migraine and epilepsy in pediatrics, focusing on epidemiologic, pathophysiological, genetic, clinical, and pharmacologic aspects.  Despite the fact that several syndromes share symptoms of both migraine and epilepsy, further research is needed to clarify the pathophysiological and genetic basis of their co-morbidity.  Drugs used for prophylactic therapy of migraine and epilepsy have similar pharmacologic properties.  The role of epileptic pharmacotherapy in the prophylaxis of migraine is assessed, including the use of conventional anti-epileptic drugs, calcium channel blockers, and non-pharmacologic methods such as dietary therapy, supplements, and VNS.  The authors concluded that further RCTs assessing pharmacologic and non-pharmacologic methods for the treatment of both disorders are needed to initiate new therapeutic approaches.

Starling (2018) provided an overview of the currently available non-invasive neuromodulation devices for the treatment of migraine and cluster headache.  Over the past 10 years, several non-invasive devices have undergone development and clinical trials to evaluate safety and efficacy.  Based on this body of work, single-pulse transcranial magnetic stimulation, transcutaneous supra-orbital neuro-stimulation, and nVNS devices have been cleared by the FDA and are available for clinical use for the treatment of primary headache disorders.  The author concluded that these novel non-invasive devices appear to be safe, well-tolerated, and have demonstrated promising results in clinical trials in both migraine and cluster headache.

Furthermore, UpToDate reviews on “Acute treatment of migraine in adults” (Bajwa and Smith, 2018a) and “Preventive treatment of migraine in adults” (Bajwa and Smith, 2018b) do not mention vagus nerve stimulation as a therapeutic / prophylactic option.

Treatment of Crohn's disease

Bonaz et al (2016a) noted that the VN is a link between the brain and the gut.  The VN is a mixed nerve with anti-inflammatory properties through the activation of the hypothalamic-pituitary-adrenal (HPA) axis by its afferents and by activating the cholinergic anti-inflammatory pathway through its efferent fibers.  These investigators have previously shown that VNS improves colitis in rats and that the vagal tone is blunted in Crohn's disease (CD) patients.  Thus, they performed a pilot study of chronic VNS in patients with active CD.  A total of 7 patients who received VNS were followed-up for 6 months with a primary end-point to induce clinical remission and a secondary end-point to induce biological (CRP and/or fecal calprotectin) and endoscopic remission and to restore vagal tone (heart rate variability).  The authors concluded that VNS was feasible and well-tolerated in all patients.  Among the 7 patients, 2 were removed from the study at 3 months for clinical worsening and 5 evolved toward clinical, biological, and endoscopic remission with a restored vagal tone.  They stated that these results provided the first evidence that VNS is feasible and appears as an effective tool in the treatment of active CD.  These preliminary findings need to be validated by well-designed studies.

Treatment of Rheumatoid Arthritis

Koopman and associates (2016) noted that symptomatic relief of rheumatoid arthritis (RA) can be achieved in up to 50 % of patients using biological agents that inhibit tumor necrosis factor (TNF), a pro-inflammatory cytokine, or other mechanisms of action, but there are no universally effective therapies.  Recent advances in basic and pre-clinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models.  One well-characterized cytokine-inhibiting mechanism, termed the "inflammatory reflex", is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats.  It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production.  These researchers showed that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6; VNS (up to 4 times daily) in RA patients significantly inhibited TNF production for up to 84 days.  Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly.  Together, these results establish that VNS targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans.  The authors concluded that these findings suggested that it is possible to use mechanism-based neuro-modulating devices in the experimental therapy of RA and possibly other autoimmune and auto-inflammatory diseases.

Bonaz et al (2016b) stated that brain and viscera interplay within the autonomic nervous system where the VN, containing approximately 80 % afferent and 20 % efferent fibers, plays multiple key roles in the homeostatic regulations of visceral functions.  Recent data have suggested the anti-inflammatory role of the VN.  This vagal function is mediated through several pathways, some of them still debated.  The 1st one is the anti-inflammatory HPA axis that is stimulated by vagal afferent fibers and leads to the release of cortisol by the adrenal glands.  The 2nd one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibers that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages; ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of TNFα.  The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve.  Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the β2 adrenergic receptor of splenic lymphocytes that release ACh.  Finally, ACh inhibits the release of TNFα by spleen macrophages through α-7-nicotinic ACh receptors.  The authors concluded that understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNFα-related diseases such as inflammatory bowel disease and RA.  Among others, VNS, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation.

Treatment of Schizophrenia

Hasan et al (2015) stated that despite many different available pharmacological and psychosocial therapeutic options, an optimal control of symptoms is only partly possible for most schizophrenia patients.  In particular, persistent auditory hallucinations, negative symptoms and cognitive impairment are difficult to treat symptoms.  Several non-invasive brain stimulation techniques are increasingly being considered as new therapeutic add on options for the management of schizophrenia, targeting these symptom domains.  The technique that has been available for the longest time and that is best established in clinical care is ECT.  New stimulation techniques, such as rTMS and transcranial direct current stimulation (tDCS) allow a more pathophysiological-based approach.  These researchers discussed various non-invasive brain stimulation techniques and recent treatment studies on schizophrenia.  In total, the novel brain stimulation techniques discussed can be considered relevant add on therapeutic approaches for schizophrenia.  In this context, the best evidence is available for the application of rTMS for the treatment of negative symptoms and persistent auditory hallucinations; however, negative studies have also been published for both indications.  The authors concluded that studies using other non-invasive brain stimulation techniques showed promising results but further research is needed to establish the clinical effectiveness.  They stated that based on a growing pathophysiological knowledge, non-invasive brain stimulation techniques provide new treatment perspectives for patients with schizophrenia; and VNS is one of the keywords listed in this review.

Lennox-Gastaut Syndrome

Lancman et al (2013) stated that Lennox-Gastaut syndrome (LGS) is an epileptogenic disorder that arises in childhood and is typically characterized by multiple seizure types, slow spike-and-wave complexes on electroencephalography (EEG) and cognitive impairment.  If medical treatment fails, patients can proceed to one of two palliative surgeries:

1. vagus nerve stimulation (VNS), or
2. corpus callosotomy (CC). 

Their relative seizure control rates in LGS have not been well studied.  These researchers compared seizure reduction rates between VNS and CC in LGS using meta-analyses of published data.  A systematic search of PubMed, Ovidsp, and Cochrane was performed to find articles that met the following criteria:

1. prospective or retrospective study,
2. at least 1 patient diagnosed with LGS, and
3. well-defined measure of seizure frequency reduction. 

Seizure reduction rates were divided into seizure subtypes, as well as total seizures, and categorized as 100 %, greater than 75 %, and greater than 50 %.  Patient groups were compared using Chi-square tests for categorical variables and t-test for continuous measures.  Pooled proportions with 95 % confidence interval (95 % CI) of seizure outcomes were estimated for total seizures and seizure subtypes using random effects methods.  A total of 17 VNS and 9 CC studies met the criteria for inclusion; CC had a significantly better outcome than VNS for greater than 50 % atonic seizure reduction (80.0 % [67.0 to 90.0 %] versus 54.1 % [32.1 to 75.4 %], p < 0.05) and for greater than 75 % atonic seizure reduction (70.0 % [48.05 to 87.0 %] versus 26.3 % [5.8 to 54.7 %], p < 0.05).  All other seizure types, as well as total number of seizures, showed no statistically significant difference between VNS and CC.  The authors concluded that CC may be more beneficial for LGS patients whose predominant disabling seizure type is atonic.  For all other seizure types, VNS offered comparable rates to CC.

Cukiert et al (2013) noted that there is currently no resective (potentially curative) surgical option that is useful in patients with LGS.  Palliative procedures such as CC, VNS or deep brain stimulation (DBS) have been offered.  These investigators compared the outcomes after CC or VNS in 2 consecutive prospective cohorts of patients with generalized epilepsy.  A total of 24 patients underwent CC from 2006 to 2007 (Group 1); 20 additional patients were submitted to VNS from 2008 to 2009 (Group 2).  They had generalized epilepsy of the Lennox-Gastaut or Lennox-like type.  They were submitted to a neurological interview and examination, inter-ictal and ictal video-EEG, high resolution 1.5T MRI, and cognitive and quality of life (QOL) evaluations.  The 2-year post-operative follow-up results were evaluated for each patient.  The final mean stimuli intensity was 3.0 mA in the Group 2 patients.  Seizure-free patients accounted for 10 % in Group 1 and none in Group 2; 10 % and 16 % of the Group 1 and 2 patients, respectively, were non-responders.  Improvements in attention and QOL were noted in 85 % of both Group 1 and 2 patients.  Rupture of the secondary bilateral synchrony was noted in 85 % of Group 1 patients; there was no EEG modification after VNS in Group 2.  Both procedures were effective regarding the control of atypical absences and generalized tonic-clonic seizures.  Both procedures were not effective in controlling tonic seizures; CC was very effective in reducing the frequency of atonic seizures, but VNS was ineffective.  In contrast, CC was not effective in reducing myoclonic seizures, whereas VNS was.  The authors concluded that CC might be preferred as the primary treatment in children with LGS, and no specific findings on MRI if atonic seizures prevail in the patient's clinical picture; when myoclonic seizures prevail, the same might hold true in favor of VNS.  When atypical absence or generalized tonic-clonic seizures are the main concern, although both procedures carried similar effectiveness, VNS might be considered a good option as an initial approach, taking into account the adverse event (AE) profile.  Patients should be advised that both procedures are not very effective in the treatment of tonic seizures.

Morris et al (2013) evaluated the evidence since the 1999 assessment regarding safety and effectiveness of VNS for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients greater  than 12 years.  These researchers reviewed the literature and identified relevant published studies.  They classified these studies according to the American Academy of Neurology (AAN) evidence-based methodology.  VNS is associated with a greater than 50 % seizure reduction in 55 % (95 % CI: 50 % to 59 %) of 470 children with partial or generalized epilepsy (13 Class III studies).  VNS is associated with a greater than 50 % seizure reduction in 55 % (95 % CI: 46 % to 64 %) of 113 patients with LGS (4 Class III studies).  VNS is associated with an increase in greater than or equal to 50 % seizure frequency reduction rates of approximately 7 % from 1 to 5 years post-implantation (2 Class III studies).  VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies).  Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio [OR] 3.4, 95 % CI: 1.0 to 11.2).  VNS was possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy.  VNS may have improved efficacy over time.  The authors recommended VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C).  VNS may be considered to have improved efficacy over time (Level C).  Children should be carefully monitored for site infection after VNS implantation.

Mastrangelo (2017) stated that LGS is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age.  Functional neuroimaging studies recently introduced the concept of Lennox-Gastaut as "secondary network epilepsy" resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, cortico-reticular connections, and thalamus).  These dysfunctions are produced by different disorders including hypoxic-ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors.  The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization (CGH) associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2.  Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, CC, and VNS in the treatment of epileptic manifestations.  The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning.  The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients.

Asadi-Pooya (2018) noted that LGS is considered an epileptic encephalopathy and is defined by a triad of multiple drug-resistant seizure types, a specific EEG pattern showing bursts of slow spike-wave complexes or generalized paroxysmal fast activity, and intellectual disability.  The prevalence of LGS is estimated between 1 and 2 % of all patients with epilepsy.  The etiology of LGS is often divided into 2 groups:

1. identifiable (genetic-structural-metabolic) in 65 to 75 % of the patients, and
2. LGS of unknown cause in others.  Lennox-Gastaut syndrome may be considered as secondary network epilepsy. 

The seizures in LGS are usually drug-resistant, and complete seizure control with resolution of intellectual and psychosocial dysfunction is often not achievable.  Reduction in frequency of the most incapacitating seizures (e.g., drop attacks and tonic-clonic seizures) should be the major objective.  Valproate, lamotrigine, and topiramate are considered to be the first-line drugs by many experts.  Other effective anti-epileptic drugs include levetiracetam, clobazam, rufinamide, and zonisamide.  The ketogenic diet is an effective and well-tolerated therapeutic option.  For patients with drug resistance, a further therapeutic option is surgical intervention; CC is a palliative surgical procedure that aims at controlling the most injurious seizures.  Finally, VNS offers reasonable seizure improvement.  The long-term outcome for patients with LGS is generally poor.  This syndrome is often associated with long-term AEs on intellectual development, social functioning, and independent living.

Furthermore, an UpToDate review on “Epilepsy syndromes in children” (Wilfong, 2017) states that “Vagus nerve stimulation also appears to be effective in some patients with LGS, leading to a greater than 50 % reduction in seizure frequency (particularly for atonic and tonic seizures), as well as shortened seizure duration and reduced number of anti-seizure drugs prescribed.  Other surgical options, including corpus callosotomy or lesional epilepsy surgery in patients with hypothalamic hamartoma, may be considered in some refractory cases”.

Dravet Syndrome

Dibue-Adjei and colleagues (2017) noted that Dravet Syndrome (DS) is a severe epileptic encephalopathy of childhood involving intractable seizures, recurrent status epilepticus and cognitive decline.  Because DS is a rare disease, available data is limited and evidence-based treatment guidelines are lacking; VNS is an established neurostimulation treatment for intractable epilepsy, however little evidence is published on its efficacy in patients with DS.  These investigators performed a meta-analysis of all peer-reviewed English language studies reporting seizure outcomes of patients with DS treated with adjunctive VNS.  The primary and secondary outcome measures were greater than or equal to 50 % reduction of seizures or of the most-debilitating seizure type and seizure reduction per patient.  A total of 13 studies comprising 68 patients met the inclusion criteria of which 11 were single-center retrospective case series, 1 was a multi-center retrospective analysis and 1 was a case report; 52.9 % of patients experienced a greater than or equal to 50 % reduction of seizures and the average seizure reduction, which could only be assessed in 28 patients was 50.8 %; 7 out of 13 studies reported additional benefits of VNS, however this could not be assessed systematically.  The authors concluded that VNS appeared to reduce seizure frequency in patients with DS.  They stated that based on this preliminary analysis, controlled trials of VNS in this rare condition using patient-centric outcome measures are needed.

Inflammation

Kwan and associates (2017) stated that VNS has been used since 1997 for treatment of drug-resistant epilepsy.  More recently, an off-label use of VNS has been explored in animal models and clinical trials for treatment of a number of conditions involving the innate immune system.  The underlying premise has been the notion of the cholinergic anti-inflammatory pathway (CAP), mediated by the vagus nerves.  While the macro-anatomic substrate -- the vagus nerve -- is understood, the physiology of the pleiotropic VNS effects and the "language" of the vagus nerve, mediated brain-body communication, remain an enigma.  Tackling this kind of enigma is precisely the challenge for and promise of bio-electronic medicine.  These researchers reviewed the state of the art of this emerging field as it pertains to developing strategies for use of the endogenous CAP to treat inflammation and infection in various animal models and human clinical trials.  This was a systematic PubMed review for the MeSH terms "vagus nerve stimulation AND inflammation".  They reported the diverse profile of currently used VNS anti-inflammatory strategies in animal studies and human clinical trials.  This review provided a foundation and calls for devising systematic and comparable VNS strategies in animal and human studies for treatment of inflammation.  The authors concluded that this review revealed the nascent stage in which the field of VNS treatment of inflammation finds itself 16 years since its inception.  The results of the animal studies are very promising and call for a theoretical modeling of vagus code accounting for all levels of organization, from systems biology to systems physiology; a more systematic approach to experimental design and reporting; consideration of the gender effect on inflammation developmental stages; and more diverse animal models (to better gauge the putative species diversity in the vagus code) to ultimately harness the salutary potential of this treatment modality.  They stated that such framework has the potential to lead to the development of truly personalized VNS regimens; and concerted and well-funded efforts are needed to devise non-invasive alternatives to VNS to translate this therapeutic approach into widely used clinical experimentation, and eventually practice, to benefit patients.. 

Vagus Nerve Stimulation in Psychiatry

Cimpianu and colleagues (2017) stated that invasive and non-invasive VNS is a promising add-on treatment for treatment-refractory depression, but is also increasingly evaluated for its application in other psychiatric disorders, such as dementia, schizophrenia, somatoform disorder, and others.  These investigators performed a systematic review aiming to give a detailed overview of the available evidence of the efficacy of VNS for the treatment of psychiatric disorders.  Data derived from animal models, experimental trials without health-related outcomes, case reports, single-session studies, and reviews were excluded.  From a total of 1,292 publications, 33 records were included for further analyses: 25 focused on VNS as treatment of unipolar or bipolar major depressive disorder and 1 investigated the neurocognitive improvement after VNS in major depressive disorder; 7 focused on the improvement of cognitive function in Alzheimer´s disease, improvement of schizophrenia symptoms, treatment of obsessive compulsive disorder (OCD), panic disorder (PD) and post-traumatic stress disorder (PTSD), treatment resistant rapid-cycling bipolar disorder, treatment of fibromyalgia, and Prader-Willi syndrome.  A total of 29 studies used invasive VNS, while 4 studies used non-invasive, transcutaneous VNS.  Only 7 out of 33 studies investigated conditions other than affective disorders.  The authors concluded that the efficacy data of VNS in affective disorders is promising, whereas more in controlled and naturalistic studies are needed.  In other conditions like schizophrenia, Alzheimer's disease, OCD, PD, PTSD, and fibromyalgia, either no effects or preliminary data on efficacy were reported.  They noted that at this point, no final conclusion can be made regarding the efficacy of VNS to improve symptoms in psychiatric disorders other than in affective disorders.

LivaNova VNS Therapy System

On June 29, 2017, LivaNova PLC announced the FDA approval of its VNS Therapy system, indicated for use as an adjunctive therapy in reducing the frequency of seizures in persons four years of age and older with partial onset seizures that are refractory to antiepileptic medications. LivaNova, a London-based medical device manufacturer, merged with Cyberonics, Inc. of Houston, Texas, to which original FDA Premarket Approval was granted for VNS Therapy system as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years old. On June 23, 2017, VNS Therapy system received a Premarket Approval expansion (P970003/S207) to  include persons 4 years of age and older. Contraindications include vagotomy and diathermy.

Stroke

In a pilot study, Kimberley and colleagues (2018) evaluated the safety, feasibility, and potential effects of VNS paired with rehabilitation for improving arm function after chronic stroke.  These researchers performed a randomized, multi-site, double-blinded, sham-controlled study.  All subjects were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program.  Randomization was to active VNS (n = 8) or control VNS (n = 9) paired with rehabilitation.  Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy.  All participants completed the course of therapy.  There were 3 serious AEs related to surgery.  Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI: -1.8 to 6.4; p = 0.20).  At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI: -1.4 to 11.5; p = 0.055).  The clinically meaningful response rate of FMA-UE at day 90 was 88 % with active VNS and 33 % with control VNS (p < 0.05).  The authors concluded that VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke; a pivotal study of this therapy is justified.

Kilgard and associates (2018) noted that recent studies indicated that VNS paired with rehabilitation could enhance neural plasticity in the primary sensory and motor cortices, improve forelimb function after stroke in animal models and improve motor function in patients with arm weakness after stroke.  These researchers attempted to gain "first-in-man" experience of VNS paired with tactile training in a patient with severe sensory impairment after stroke.  During the long-term, follow-up phase of a clinical trial of VNS paired with motor rehabilitation, a 71-year old man who had made good motor recovery had ongoing severe sensory loss in his left hand and arm.  He received VNS paired with tactile therapy in an attempt to improve his sensory function.  During 20 2-hr sessions, each passive and active tactile event was paired with a 0.5-second burst of 0.8 mA VNS.  Sensory function was measured before, halfway through, and after this therapy.  The patient did not report any side effects during or following VNS+Tactile therapy.  Quantitative measures revealed lasting and clinically meaningful improvements in tactile threshold, proprioception, and stereognosis.  After VNS+Tactile therapy, the patient was able to detect tactile stimulation to his affected hand that was 8 times less intense, identify the joint position of his fingers in the affected hand 3 times more often, and identify everyday objects using his affected hand 7 times more often, compared to baseline.  The authors concluded that sensory function significantly improved in this man following VNS paired with tactile stimulation.  These researchers stated that this approach merits further study in controlled clinical trials.

Transcutaneous Vagal Nerve Stimulation (The Stivax Device)

The Stivax device is a single-use, battery-powered, electrical nerve stimulator.  It is indicated for complementary therapy to increase the transcutaneous oxygen partial pressure, and  treatment to reduce the intensity of acute pain.

Akbas et al (2016) noted that spinal cord stimulation (SCS) as treatment of chronic low back pain via neuromodulation has been frequently performed in recent years.  The dorsal column is stimulated by an electrode placed at the epidural region.  In the case presently described, subcutaneous lead was implanted in a patient with failed back syndrome after SCS was inadequate to treat back and gluteal pain.  A 65-year old man had undergone surgery to treat lumbar disc herniation, after which he received physical therapy and multiple steroid injections due to unrelieved pain.  He was admitted to the pain clinic with pain radiating to right gluteal muscle and leg; SCS was performed and, as pain was not relieved, subcutaneous lead was applied to the right cluneal nerve distribution.  Following treatment, the patient scored 1 to 2 on visual analog scale (VAS).  Pain had been reduced by over 80 %.  Octad electrode was placed between T8 and T10 vertebrae after Tuohy needle was introduced to intervertebral area between L1 and L2.  Paresthesia occurred in the right extremity.  Boundaries were determined by area of right gluteal region in which paresthesia did not occur.  Octad electrode was placed subcutaneously after vertical line was drawn from center point.  Paresthesia occurred throughout the region.  Pulse wave was 390 to 450 msec; frequency was 10 to 30 Hz.  The authors concluded that subcutaneous electrode replacement was an effective additional therapy when pain was not relieved by SCS.

Furthermore, reviews on “Pain management using interventionist techniques for lumbar post-laminectomy syndrome” (Robaina Padron 2007 and 2008) did not mention vagal nerve stimulation as a management tool.

Vagal Nerve Stimulation for Patients With Cancers

Reijmen and colleagues (2018) stated that accumulating evidence points to a beneficial effect of vagus nerve activity in tumor development.  The vagus nerve is proposed to slow tumorigenesis because of its anti-inflammatory properties mediated through acetylcholine (ACh) and the alpha-7 nicotinic acetylcholine receptor (α7nAChR).  Since α7nAChRs are widely expressed by many types of immune cells, these researchers hypothesized that the vagus nerve affects the tumor micro-environment and anti-cancer immunity.  They found direct evidence in studies using animal cancer models that VNS altered immunological responses relevant to the tumor micro-environment.  Furthermore, studies in pathologies other than cancer suggested a role for the vagus nerve in altering immunological responses relevant to anti-cancer immunity.  The authors concluded that these results provided a rationale to expect that VNS, in combination with conventional cancer treatments, may improve the prognosis of cancer patients by promoting anti-cancer immunity.

Vagal Nerve Stimulation for Patients With Primary Sjogren's Syndrome

Tarn and colleagues (2018) stated that primary Sjogren's syndrome (pSS) sufferers have rated chronic fatigue as the most important symptom needing improvement.   Emerging data suggested that VNS could modulate immunological responses.  The gammaCore device (electroCore), developed to stimulate the cervical vagus nerve non-invasively, was used to assess the effects of vagus nerve activation on immune responses and clinical symptoms of pSS.  A total of 15 female pSS subjects used the nVNS device twice-daily in a 26-day period.  At baseline, blood was drawn before and after application of the gammaCore device for 90 seconds over each carotid artery.  The following fatigue-related outcome measures were collected at baseline, day 7 and day 28: EULAR patient reported outcome index, profile of fatigue (Pro-F), visual analog scale (VAS) of abnormal fatigue, and Epworth sleepiness scale (ESS).  Whole blood samples were stimulated with 2 ng/ml lipopolysaccharide (LPS) and the supernatant levels of gamma interferon (IFNγ), interleukin 12 (IL12)-p70, tumor necrosis factor- alpha (TNFα), macrophage inflammatory protein-1 alpha (MIP-1α), alpha IFN (IFNα), IL-10, IL-1β, IL-6, and IFNγ-induced protein 10 (IP-10) were measured at 24 hours.  In addition, clinical hematology and flow cytometric profiles of whole blood immune cells were analyzed.  Pro-F and ESS scores were significantly reduced across all 3 visits.  LPS-stimulated production of IL-6, IL-1β, IP-10, MIP-1α, and TNFα were significantly reduced over the study period.  Patterns of NK- and T-cell subsets also altered significantly over the study period.  Interestingly, lymphocyte counts at baseline visit correlated to the reduction in fatigue score.  The authors concluded that vagus nerve may play a role in the regulation of fatigue and immune responses in pSS and nVNS may reduce clinical symptoms of fatigue and sleepiness.  However, a sham-controlled follow-up study with a larger sample size is needed to confirm these findings.

Appendix

Exclusion Criteria for VNS Therapy of Focal Seizures (formerly known as 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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
61885	Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array
64553	Percutaneous implantation of neurostimulator electrodes; cranial nerve
64568	Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator
64569	Revision or replacement of cranial nerve (eg, vagus nerve) neurostimulator electrode array, including connection to existing pulse generator
64570	Removal of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator
95970	Electronic analysis of implanted neurostimulator pulse generator system (e.g., rate, pulse amplitude and duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple or complex brain, spinal cord, or peripheral (i.e., cranial nerve, peripheral nerve, autonomic nerve, neuromuscular) neurostimulator pulse generator/transmitter, without reprogramming
95976	Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with simple cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional
CPT codes not covered for indications listed in the CPB:
Transcutaneous vagal nerve stimulation - no specific code :
0312T	Vagus nerve blocking therapy (morbid obesity); laparoscopic implantation of neurostimulator electrode array, anterior and posterior vagal trunks adjacent to esophagogastric junction (EGJ), with implantation of pulse generator, includes programming
0313T	Vagus nerve blocking therapy (morbid obesity); laparoscopic revision or replacement of vagal trunk neurostimulator electrode array, including connection to existing pulse generator
0317T	Vagus nerve blocking therapy (morbid obesity); neurostimulator pulse generator electronic analysis, includes reprogramming when performed
64550	Application of surface (transcutaneous) neurostimulator [not covered for transcutaneous vagus nerve stimulation]
Other CPT codes related to the CPB:
61534	Craniotomy with elevation of bone flap; for excision of epileptogenic focus without electrocorticography during surgery
61536	for excision of epileptic focus, with electrocorticography during surgery
61537	for lobectomy, temporal lobe, without electrocorticography during surgery
61538	for lobectomy with electrocorticography during surgery, temporal lobe
61541	Craniotomy with elevation of bone flap; for transection of corpus callosum
61543	for partial or subtotal hemispherectomy
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
HCPCS codes not covered if selection criteria are met:
E0770	Functional electrical stimulator, transcutaneous stimulation of nerve and/or muscle groups, any type, complete system, not otherwise specified
ICD-10 codes covered if selection criteria are met:
G40.001 - G40.019	Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable/not intractable, with/without status epilepticus
G40.101 - G40.219	Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable/not intractable, with/without status epilepticus
G40.811 - G40.814	Lennox-Gastaut syndrome
ICD-10 codes not covered for indications listed in the CPB:
C00.0 - C96.9	Malignant neoplasm [not covered for vagus nerve electrical stimulation]
E66.01 - E66.9	Overweight and obesity
F10.20, F10.220 - F10.229, F10.230 - F10.239, F10.250 - F10.259, F10.26, F10.27, F10.280 - F10.288, F10.29	Alcohol related disorders
F11.10 - F11.99	Opiod related disorders
F12.10 - F12.99	Cannabis related disorders
F13.10 - F13.99	Sedative, hypnotic, or anxiolytic related disorders
F14.10 - F14.99	Cocaine related disorders
F15.10 - F15.99	Other stimulant related disorders
F16.10 - F16.99	Hallucinogen related disorders
F18.10 - F18.99	Inhalent related disorders
F19.10 - F19.99	Other psychoactive substance related disorders
F20.0 - F20.9	Schizophrenia
F30.10 - F39	Mood [affective] disorders
F32.9	Major depressive disorder, single episode, unspecified
F34.1	Dysthymic disorder
F41.0 - F41.9	Other anxiety disorders
F42.2 - F42.9	Obsessive-compulsive disorder
F43.10 - F43.12	Post-traumatic stress disorder (PTSD)
F50.00 - F50.9	Eating disorders
F51.01 - F51.9	Sleep disorders not due to substance or known physiological condition
F84.0 - F89	Pervasive developmental disorders
F95.2	Tourette's disorder
G25.0 - G25.2	Essential, drug-induced and other specified forms of tremor
G30.0 - G30.9	Alzheimer's disease
G40.301 - G40.919	Epilepsy [other than partial onset]
G43.001 - G43.919	Migraine
G44.001 - G44.029	Cluster headaches
G44.201 - G44.229	Tension-type headache
G44.51	Hemicrania continua
G47.00 - G47.9	Sleep disorders
G80.0 - G80.9	Cerebral palsy
H93.11 - H93.19	Tinnitus
H93.A1 - H93.A9	Pulsatile tinnitus
I09.81	Rheumatic heart failure
I11.0 - I11.9	Hypertensive heart disease
I13.0 - I13.2	Hypertensive heart and chronic kidney disease
I48.0 - I48.2, I48.91	Atrial fibrillation
I50.1 - I50.9	Heart failure
I63.30 - I63.9	Cerebral infarction [stroke]
I66.01 - I66.9	Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction [stroke]
J12.0 - J18.9	Pneumonia [post-TBI pneumonia]
K50.00 - K50.919	Crohn’s disease
M05.00 - M06.9	Rheumatoid arthritis
M35.00 - M35.09	Sicca syndrome [Sjogren]
M79.7	Fibromyalgia
M96.1	Postlaminectomy syndrome, not elsewhere classified. [not covered for transcutaneous vagal nerve stimulation]
Q87.1	Congenital malformation syndromes predominantly associated with short stature [Prader-Willi syndrome]
R40.20 - R40.4	Coma
R51	Headache
R56.00 - R56.9	Convulsions, not elsewhere classified [seizure NOS]
R63.2	Polyphagia
R73.01 - R73.09	Abnormal glucose
S02.0xx+ - S02.92x+	Fracture of skull and facial bones [traumatic brain injury]
S06.0X0+ - S06.9X9+	Intracranial injury [traumatic brain injury]
T79.8xx+	Other early complications of trauma [post-TBI pneumonia]

The above policy is based on the following references: