Review

10.1586/14737175.7.12.1763 © 2007 Future Drugs Ltd ISSN 1473-7175 1763www.future-drugs.com

Vagus nerve stimulation for the treatment of intractable epilepsyArun Paul Amar

Department of Neurosurgery, 2025 Morse Avenue, Sacramento, CA 95825, USATel.: +1 916 973 6517Fax: +1 916 973 5826amar@aya.yale.edu

KEYWORDS: depression, epilepsy, neurostimulation, seizure, vagus nerve stimulation

Vagus nerve stimulation is a safe and reliable treatment adjunct for patients with medically intractable epilepsy. It is both a preventive and abortive form of therapy, potentially effective against both partial and generalized seizures in adults and children. Vagus nerve stimulation also has a number of serendipitous effects on mood, memory and attention, and has been approved for the treatment of refractory depression. Owing to its pleiotropic effects, it also holds promise for several other diseases. Its principal limitations are its unknown mechanism of action, the low likelihood of complete cure and the inability to predict which patients will derive substantial benefit. This article reviews the theoretical rationale, practical background and clinical applications of vagus nerve stimulation therapy.

Expert Rev. Neurotherapeutics 7(12), 1763–1773 (2007)

Vagus nerve stimulation (VNS) therapy, deliv-ered via an implantable device from Cyberonics,Inc. (Houston, TX, USA), has emerged as awell-established treatment adjunct for patientswith intractable epilepsy. Clinical experiencewith VNS began in 1988 with the first humanimplantation of the VNS system. Since then,more than 50,000 patients worldwide havereceived VNS therapy and more than 100,000patient-years of experience have accrued[CYBERONICS, DATA ON FILE]. This article reviewsthe theoretical rationale, practical backgroundand clinical applications of VNS. Other publi-cations offer greater detail concerning theseconsiderations [1–5], as well as the operativeprocedure for inserting the device [1,6,7].

The VNS device consists of multiple compo-nents. A pulse generator inserted in the subcuta-neous tissues of the upper left chest deliversintermittent electrical stimulation to the cervicalvagus nerve trunk via a bifurcated helical lead.The vagus nerve secondarily transmits afferent(rostral) impulses to exert widespread effects onneuronal excitability throughout the CNS.

In addition to the implantable lead and pulsegenerator, the Cyberonics system includes anumber of peripheral components, such as atelemetry wand that interrogates and programsthe pulse generator noninvasively. This

programming wand is battery powered and isinterfaced with a Dell Axim® handheld thatruns a menu-based software package furnishedby Cyberonics. The generator contains an inter-nal antenna that receives radiofrequency signalsemitted from the telemetry wand and transfersthem to a microprocessor that regulates the elec-trical output of the pulse generator. The systemalso includes a handheld magnet that patientsmay carry with them in order to alter the charac-ter of stimulation that the generator delivers.When passed briefly across the chest pocketwhere the generator resides, the magnet manu-ally triggers a train of stimulation superimposedupon the baseline output. Such on-demandstimulation can be initiated by the patient or acompanion at the onset of an aura, in an effortto diminish or even abort an impending seizure.Alternatively, if the device appears to be mal-functioning or if the patient wishes to terminateall stimulation for any other reason, the systemcan be indefinitely inactivated by applying themagnet over the generator site continuously.However, the magnet can also affect the calibra-tion of programmable ventriculoperitonealshunt valves, and symptomatic underdrainage ofcerebrospinal fluid has been reported after unin-tended adjustment of the valve by the VNSmagnet [8].

CONTENTS

Theoretical basis of VNS

Clinical utility of VNS

VNS in off-label populations

Expert commentary

Five-year view

Financial & competing interests disclosure

Key issues

References

Affiliation

For reprint orders, please contact reprints@future-drugs.com

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1764 Expert Rev. Neurotherapeutics 7(12), (2007)

The Cyberonics pulse generator is approximately the same sizeand shape as a cardiac pacemaker and is powered by a single lith-ium battery encased in a hermetically-sealed titanium module.The projected battery life of the generator varies with the stimu-lus parameters but can be as long as 6–10 years under normalconditions. Once it has expired, the generator can be replacedunder local anesthesia during a simple outpatient procedure.

The generator delivers a charge-balanced waveform character-ized by five programmable parameters: output current, signalfrequency, pulse width, signal-on time and signal-off time.These variables are titrated empirically in the outpatient setting,according to individual patient tolerance and seizure frequency.Altering the parameters of stimulation will have various conse-quences on VNS efficacy, side effects and battery life. In clinicalapplication, the most common parameters are 0.25–2.0 mAcurrent (titrated to effect and tolerance), 30 Hz frequency,500 µs pulse width and 30 s on/5 min off duty cycle. Otherparadigms, such as 7 s on and 18 s off (‘rapid cycling’) have alsobeen utilized. Regardless, the duration of VNS action isobviously longer than the periods of intermittent stimulation.

The bipolar lead is insulated by a silicone elastomer and canthus be implanted safely in patients with latex allergies. Oneend of the lead contains a connector pin that inserts directlyinto the generator, while the opposite end contains an electrodearray consisting of two discrete helical coils that wrap aroundthe vagus nerve. Another helix proximal to the electrodes servesas an integral anchoring tether that prevents excessive forcefrom being transmitted to the electrodes when the patient turnshis/her neck.

The leads come in two sizes, measured by the internal diame-ter of each helix. Although most patients can be fitted with the2-mm coil, a 3-mm version is available. The spiral configura-tion permits the electrodes to maintain optimum mechanicalcontact with the nerve. The electrode is intended to fit snuglyaround the nerve while avoiding compression, thus allowing itto shift with the nerve and minimizing abrasion from relativemovement of the nerve against the electrode. Damage to thenerve is greatly reduced by the self-sizing, open helical design ofthe VNS electrode array, which permits body fluid interchangewith the nerve. Thus, compared with cuff electrodes, mechani-cal trauma and ischemia to the nerve are also minimized. Histo-logical examination of the vagus nerve following VNS hasrevealed no axonal loss, demyelination, lymphocytic infiltrationor other evidence of permanent damage resulting from electricalstimulation [1]. Other observations have confirmed the safety ofchronic nerve stimulation when the duty cycle (the fraction oftime the nerve undergoes stimulation) is less than 50%.

Theoretical basis of VNSAs with many other anticonvulsant therapies, informationregarding the neural mechanisms underlying VNS lags behindthe appreciation of its clinical efficacy. The exact means by whichVNS modulates seizure activity and its locus of action in thebrain remain uncertain despite investigations of EEG, functionalimaging, neurotransmitter analysis and other approaches [1].

The suggestion that afferent stimulation may modulate seizureactivity dates back at least 2000 years to the teachings of Pelops,the master of Galen. He described a technique using ligaturesapplied to the limb in which partial seizures began as a means ofaborting the progression of a focal seizure or preventing its gener-alization. More recent studies have confirmed that stimulationof cutaneous afferent fibers and other sensory pathways, includ-ing direct stimulation of the cervical vagus nerve, can affectEEG synchronization and sleep cycles. Since highly synchro-nized patterns are characteristic of electrographic seizures, thesestudies of EEG rhythmicity form the neuroanatomic and neuro-physiologic foundations for the hypothesis that appropriatelytimed stimulation of the vagus nerve might prevent or abortparoxysmal epileptiform activity.

Although the vagus nerve carries efferent projections that inner-vate the striated muscle of the larynx and provide parasympatheticcontrol of the heart, lungs and gastrointestinal tract, over 80% ofits fibers are special visceral and general somatic afferents leadingtowards the brain [9]. While it was initially suspected that VNSworks by recruiting afferent C-fibers and A-δ fibers, this conten-tion has been challenged recently by observations that VNSretains its antiepileptic effects even after selective destruction ofthese small unmyelinated fibers by capsaicin treatment [10].

Vagal afferent fibers originate from receptors in the visceraand terminate in diffuse areas of the CNS, many of which arepotential sites of epileptogenesis. These include the cerebellum,diencephalon, amygdala, hippocampus, insular cortex and mul-tiple brainstem centers. Some of these projections relay throughthe nucleus tractus solitarius (NTS), while others form direct,monosynaptic connections with their targets. Although itremains unclear which of these pathways underlie the mecha-nism of VNS action, the locus coeruleus (LC) and dorsal raphenucleus (DRN) appear to be key intermediaries. The basal firingrates of neurons within the LC and DRN are significantlyincreased after long-term treatment with VNS [11]. LC firingrates increase earlier than those of the DRN, and since the LChas an excitatory influence on DRN, it is possible that theincreased firing rate in the latter is secondary to the initialincrease in LC firing rates [11]. Furthermore, bilateral chemicallesions of these centers abolish the seizure-suppressing effects ofVNS therapy in animal models [12].

These results imply that norepinephrine and serotonin, whichare diffusely released by the LC and raphe DRN, respectively, maymediate the anticonvulsant actions of VNS. Indeed, these twoneurotransmitters are known to modulate seizure threshold insome parts of the brain by inducing interneurons to releaseGABA, leading to widespread inhibition of neuronal excitabilitythroughout the brain. However, the levels of GABA and serotoninmetabolites in the cerebrospinal fluid of patients undergoing VNSappears to be inversely correlated with the efficacy of treatment,and the neurotransmitter systems that mediate the antiepilepticactions of VNS remain uncertain [1]. Since noradrenergic and ser-otonergic pathways are also implicated in the pathogenesis ofdepression, the effects of VNS on these neurotransmitters mayalso underlie its proposed utility as an antidepressant treatment.

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At the stimulation parameters typically used for humanapplication, VNS has no effect on background EEG rhythms.Most patients have a decrease in the number and duration ofinterictal epileptiform discharges (IED) [13]. However, no corre-lation between IED and VNS efficacy has been reported. Vagalstimulation induces evoked responses from regions as disparateas the cerebral cortex, hippocampus, brainstem, thalamus andcerebellum, and many authors have proposed that its anti-epileptic actions relate to effects on the brainstem reticular-acti-vating system, which then projects to these forebrain structures[2]. However, PET experiments measuring regional cerebralblood flow (rCBF) in response to VNS reveal changes confinedto more circumscribed regions, such as the ipsilateral anteriorthalamus and cingulate gyrus, contralateral thalamus and ipsi-lateral cerebellum, or bilateral activation of the hypothalamicand insular cortices [1,2]. The reasons for this disparity in acti-vated rCBF patterns from study to study are not immediatelyapparent but may relate to differences in stimulation parame-ters, individual patient variation and other factors [1]. Inconsist-encies between PET studies acquired during the acute versuslong-term phases of VNS may reflect chronic adaptation tocentral processing, which attenuates responses to individualtrains of VNS. Furthermore, PET studies have been con-founded by multiple methodological limitations, such as sei-zures occurring during PET acquisition, the effects of prior cra-nial surgery [1]. In any case, the central consequences of VNSon rCBF are not as diffuse as might be expected were its effectsmediated through the brainstem reticular substance [2].

Right- versus left-sided vagal stimulation is equally effectivein controlling seizures in animal models, and bilateral stimula-tion produces no measurably greater effect than unilateral stim-ulation [1]. Using techniques such as EEG and immunolabelingagainst fos, a nuclear protein expressed under conditions ofhigh neuronal activity, these studies suggest that unilateralafferent vagal impulses generate bilaterally symmetric responsesin the cerebral cortex and subcortical structures [1].

By contrast, vagal efferent innervation appears asymmetric. Insome species, the right vagus nerve innervates the sinoatrialnode, while the left one preferentially supplies the atrio-ventricular node [1]. Canine studies have shown that stimulationof the right vagus nerve produces greater cardiac slowing thansimilar stimulation of the left vagus. For these reasons, the VNSsystem is generally inserted on the left side. Anecdotal experi-ence shows that right-sided VNS in humans has been well toler-ated. In patients who developed device infections that precludedrepeat left-sided VNS, the device has been reinserted on theright vagus nerve. In these patients, no cardiac side effectsoccurred, though some did experience reactive airway diseaseand respiratory compromise [14]. In some patients, a differentialbenefit occurred when the left-sided VNS was replaced by right-sided VNS, raising the possibility that those who fail left-sidedVNS may benefit from a trial of contralateral stimulation.

Some animal studies have shown that cardiac and respiratoryfunction are adversely affected by VNS while others have not,depending on the species used, the stimulation parameters

applied and other variables [1]. Such side effects do not gener-ally occur in humans because stimulation can be performed dis-tant from the site at which the cardiac branches originate fromthe cervical vagus trunk [6,7]. In fact, VNS exerts central cardio-inhibition through its afferent effects without vasodepression ornegative chronotropic effect of efferent vagal stimulation, lead-ing some to propose VNS as a potential cardioprotective strat-egy in high-risk patients with ischemic heart disease due tounrestrained sympathoexcitation [15]. Rarely, however, vagally-induced bradyarrhythmia, perfectly correlated with periods ofstimulation, has been described even years after uneventfulVNS therapy in some patients [16].

Clinical utility of VNSSince 1988, more than 1000 patients have participated in sevencorporate-sponsored clinical trials throughout 26 countries,and over 3000 patient-years of data have been accrued. Five ofthese studies (E01–E05) have been conducted in the USA. TheE01 and E02 trials were nonrandomized pilot studies in smallgroups of patients with partial onset seizures, designed to inves-tigate the safety and feasibility of VNS therapy. An importantobservation was the fact that patients can perceive the onset ofstimulation as a tingling sensation in the throat. In order tocompensate for this phenomenon, subsequent controlled, rand-omized, double-blinded studies (E03 and E05) had to incorpo-rate an ‘active control’ group rather than a true placebo. In thelatter studies, this was accomplished by comparing high (pre-sumably therapeutic) versus low (presumably less therapeutic)parameters of stimulation. The E04 trial was an open-label,compassionate-use study that examined the potential efficacy ofVNS in patient populations that were not studied in the otherfour trials, namely those with generalized-onset epilepsy,patients younger than 12 years, patients with less than six sei-zures per month and so forth. This study was important forconfirming the potential efficacy of VNS in these other patientgroups, but the scientific validity of its results cannot attain tothose of the two randomized trials. E05 was the largest control-led clinical trial and included comprehensive safety monitoring;this study was pivotal in obtaining US FDA approval 6 monthsafter its completion.

Collectively, these studies confirm the long-term safety, effi-cacy, feasibility and tolerability of VNS, as well as the durabil-ity of the device [1,3,17]. VNS gained approval for the treatmentof medically refractory epilepsy by the FDA in 1997. Post-marketing experience validates the earlier clinical trials, and in1999, the Therapeutics and Technology subcommittee of theAmerican Association of Neurology declared VNS to be “safeand effective”, based on a preponderance of class I evidence[18]. Although VNS requires a large initial investment due tothe price of the device itself, as well as its surgical insertion,cost–benefit analysis suggests that the expense of VNS is recov-ered within 2 years of follow-up [19]. Positive effects have beendocumented for both the utilization of healthcare services andthe time spent on epilepsy-related tasks. In one study, statisti-cally significant reductions in the number of emergency

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department visits, hospitalizations and hospital lengths of stayoccuring within the first fiscal quarter after VNS implantation,and the average numbers of days on which patients could notwork because of health-related concerns also decreased afterinitiation of VNS therapy [20].

No accepted standard exists for reporting the outcome ofVNS in clinical trials. A novel classification scheme has beenproposed recently, which incorporates measures of both sei-zure frequency and ictal or postictal severity, as well as consid-erations unique to VNS therapy, such as the efficacy of magnetusage [21]. However, most papers merely report the percentreduction in seizure frequency, expressed as the average for theentire cohort of patients. The response to VNS is not normallydistributed. Usually, the histogram depicting response rates isskewed to the left, reflecting the disproportionate influence ofthe few patients who derive no benefit from therapy. Thus, themost valid summary statistic of central tendency for this non-parametric data is the median reduction in baseline seizurefrequency rather than the mean.

Patients who enter clinical trials of new antiepileptic therapies,such as VNS, generally have the most intractable form of the dis-ease. As they are often pharmacoresistant, such patients are notexpected to become completely seizure free by the addition of anew investigational agent. Furthermore, many are predicted tofail completely. Therefore, the primary outcome measure ofmost antiepileptic medication trials has been the 50% responderrate (the proportion of patients who achieve a 50% or greaterreduction in seizure frequency). Although complete eradicationof seizure activity always remains the goal of therapy, even 50%reductions can dramatically improve the quality of patients’ lives.

In addition to seizure control, quality of life (QoL) alsodepends on the side effects and toxicity of the treatment ren-dered. Improvements in cognitive function and mood not relatedto seizure frequency per se are also reflected in these latter indices.

A meta-analysis was performed of the 454 patients enrolled inone of five controlled, multicenter clinical trials (two double-blind and three open-label studies) conducted in the USA [17].For the study population as a whole, the median reduction inseizure frequency was 35% at 1 year, 43% at 2 years and 44% at3 years. These results were obtained using a ‘last visit carried for-ward’ analysis, which minimizes selection bias by extrapolatingdata from nonresponders who exit the trial, thus tending tounderestimate efficacy among responders. For patients persistingin the trial (declining N analysis), sustained efficacy was evengreater. An important observation is that the response to VNS ismaintained during prolonged stimulation, and unlike the casewith chronic medication therapy, seizure control actuallyimproves with time.

The response of individual patients to VNS varies widely.While rare subjects enjoy complete seizure cessation, othersderive no benefit; the remainder experience intermediateresults. In the collective study experience, the proportion ofpatients who sustained a 50% reduction in baseline seizure fre-quency was approximately 23% at 3 months [17]. Although thisfigure is similar to the initial results of many new drug trials, the

50% responder rate also showed substantial increases with time,reaching 43% after 2 years [17]. These improvements occurredin a highly refractory population of patients who typically hadan average of 1.7 seizures per day despite administration ofmore than two antiepileptic medications.

Clinical results since FDA approval have generally surpassedthose in the company-sponsored trials. In some cases, this mayreflect more aggressive titration of stimulation parameters. Inother instances, the more favorable results reflect the trend ofimproved seizure control with time. For instance, in one study,the median reduction in seizure frequency at 3 months was 45%and that at 12 months 58% [22]. In another, mean seizure reduc-tion at 1–6 years was 14, 25, 29, 29, 43 and 50%,respectively [23]. In yet another, the median reduction in seizurefrequency improved from 28% at 12 months to 72% at follow-up 5–7 years after implantation. Some patients in the latter studywhose seizure frequency was not reduced during the initial12 months of VNS therapy experienced significant reductionduring the follow-up period [24]. Some postmarket trials havereported 50% responder rates of nearly 60% and seizure-freedomrates of up to 10% [25].

A potential confounding effect in the interpretation of thesedata is the fact that many published trials of VNS for epilepsyhave permitted simultaneous alterations in antiepileptic drugregimens, making it difficult to know which treatment variablewas most relevant in any given patient.

Despite the well-known functions of the vagus nerve as theprincipal efferent component of the parasympathetic nervoussystem, VNS has not been shown to adversely effect any aspectof physiological function in a consistent fashion, including car-diac rhythm (as assessed by ECG and ambulatory Holter mon-itoring), pulmonary function, gastrointestinal motility andsecretion [26]. Moreover, unlike many antiepileptic medications,VNS therapy does not impair cognition, balance or emotionduring extensive testing. Plasma concentrations of antiepilepticmedications remain unchanged.

However, some adverse effects do occur with VNS. At3 months of therapy during the acute phase studies, hoarseness,cough, paresthesia and other symptoms were common, occur-ring in up to half of patients. These effects were rated as mild ormoderate 99% of the time [26]. They tend to occur concomi-tant with stimulus delivery and not throughout the day, unlikethe side effects of antiepileptic medications. Furthermore, theside effects of VNS are generally transient and their long-termincidence is much lower. The most common complaints after1 year of treatment were hoarseness (28%) and paresthesias(12%) [17]. At 2 years, they were hoarseness (19.8%) and head-ache (4.5%); after 3 years shortness of breath (3.2%) was theprincipal side effect [17]. Surgical complications are rare butinclude infection requiring explantation (1.1%), transient vocalcord injury (<1%) and temporary lower facial paresis (<1%)[BRUCE, UNPUBLISHED DATA]. Device failures are also uncommon.

The true incidence of recurrent laryngeal nerve injury isunknown, as most reports of transient vocal changes are basedon perceptual observations by the patients only. Using a strict

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protocol employing laryngeal electromyography (EMG), videolaryngoscopy and quantitative assessments of voice, one studydemonstrated that perioperative vocal cord paresis occurs inalmost half of patients within 2 weeks of surgery [27]. LaryngealEMG performed before implantation of the VNS devicestrongly predicted which patients were at risk for more pro-longed vocal cord abnormalities [27]. Such information shouldbe considered before patients undergo anterior cervical discec-tomy, right-sided VNS or other procedures that could result inbilateral vocal cord paresis.

More serious adverse events are rare. Although some deathshave occurred among the 454 study patients receiving VNS,none were definitely attributed to VNS itself [17]. In fact, somestudies suggest that the incidence of sudden unexplaineddeath in epilepsy patients is actually lower after treatmentwith VNS [28].

Patient satisfaction with VNS therapy is generally high.One way to quantify this parameter is to measure the percent-age of patients who continue their therapy after completingthe acute phase of a clinical trial. Continuation rates in thecollective study experience were 97, 85 and 72% after 1, 2and 3 years of therapy, respectively [17]. A related measure ofpatient satisfaction is the percentage of patients who opt toundergo replacement of the generator after the battery hasexpired. With a previous model of the VNS device, batteryexpiration typically occurred 4–5 years after initiating ther-apy, and approximately three-quarters of patients elected tochange it at that time [17]. Long-term continuation ratesreflect the unique profile of safety, efficacy and tolerabilitythat VNS provides.

An additional measure of patient satisfaction is assessmentof overall QoL. In randomized controlled trials, improve-ments in QoL were independently documented by thepatient, the blinded physician and the patient’s companionusing a visual analog scale (VAS) [17,26]. Some patients who donot experience any reduction in seizure frequency still reportimprovements in overall wellbeing. Even among populationswith a low intelligence quotient who live in long-term carefacilities, the improved QoL during VNS therapy can enhanceattention, language, balance and activities of daily living [29].The basis of the enhanced QoL parameters, especially amongpatients without any improvements in seizure control,remains uncertain and reinforces the enigma of how VNSactually works. Most studies documenting improved QoLhave relied on relatively crude measures, such as VAS, ratherthan comprehensive neuropsychological testing.

VNS in off-label populationsPresently, VNS is only approved by the FDA “as an adjunctivetherapy in reducing the frequency of seizures in adults and ado-lescents over 12 years of age with partial onset seizures whichare refractory to antiepileptic medications.” However, the VNSdevice has been used successfully in children younger than12 years of age, as well as patients who suffer primarily fromseizures of generalized onset.

Subgroup analysis of the children and adolescents treated inone of the five multicenter prospective VNS trials conductedprior to FDA approval suggests that they derived substantialbenefit from VNS, achieving median reductions in seizure fre-quency and 50% responder rates at least as favorable as thosein adults. A total of 60 pediatric patients were treated in thiscohort [30]. Children aged 12–18 years were included in thedouble-blind, controlled trials, while patients as young as3.5 years old were studied in the open-label, compassionate-use protocol. After 3 months of stimulation, the medianreduction in seizure frequency among these 60 patients was23%. Using a last visit carried forward analysis, this figureimproved to 31% at 6 months, 37% at 12 months and 44% at18 months. At 12 months, the 50% responder rate was 29%.These results are similar to those achieved by adults in thesame trials.

Since FDA approval, small uncontrolled studies studyingpediatric patients exclusively have confirmed the safety and effi-cacy of VNS in children. The results of these latter trials appeareven more salutary than those in the older populations [4].Infants less than 1 year old have been treated successfully [31].As in adults, the response to VNS improves with time. In onestudy, the mean reduction in total seizures was 39% at3 months, 38% at 6 months, 49% at 12 months, 61% at24 months and 71% at 36 months [32]. In another, the reduc-tion was 56% at 3 months, 50% at 6 monhts, 63% at12 months, 83% at 24 months and 74% at 36 months [33].Nearly 40% of children achieve at least 90% reductions in sei-zure frequency [34,35] and up to 10% are seizure free [33]. As inthe adult population, improvements in QoL parameters such asmemory, mood, behavior, alertness, achievement and verbalskills, have been documented in children [36,37].

Analysis of seizures by type failed to identify any classificationthat is consistently more responsive to VNS than others in chil-dren. Stratification into symptomatic versus idiopathic epilepsywas likewise unrevealing, since children with both typesappeared to benefit from VNS in some cases [30,37]. Atonic sei-zures generally respond well [31], whereas myoclonic seizures,which frequently accompany mitochondrion electron-transportchain disorders, tend to respond poorly [38].

Adverse events in children were also similar to those in adultsin the company-sponsored trials and none of them necessitatedtermination of therapy [30,39]. Serious complications includedaspiration pneumonia and necrosis of the skin overlying thegenerator site, each occurring in one child. Postmarketingapproval studies have revealed rare instances of both central andobstructive patterns of sleep apnea [40–43].

Although approved only for partial-onset seizures, VNS hasbeen successfully applied for the off-label treatment of patientssuffering from generalized-onset seizures, such as those withLennox Gastaut syndrome [4]. In some studies, VNS is an evenmore effective therapy for idiopathic generalized epilepsy thanfor partial epilepsy [44]. Even the most refractory patient popu-lations, such as those with persistent seizures after failed cranialsurgery, derive significant benefit from VNS [5].

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In summary, VNS appears to offer several advantages overpharmacotherapy and other surgical modalities. VNS avoidscerebral toxicity and the attendant impairments of cognition,emotion and coordination that often complicate antiepilepticmedication. The preprogrammed, computer-controlled charac-teristic of the system permits complete and involuntary treat-ment compliance. VNS is potentially reversible, unlike cerebralsurgery. Unlike the case with many medications, the effective-ness of VNS is maintained during prolonged therapy and, infact, overall seizure frequency diminishes with time. Further-more, there are no adverse drug interactions. The improvedcognitive function perceived by patients during VNS trials is atestimony to this unique combination of efficacy and favorableside-effect profile. In addition, the ability to initiate stimulationduring an aura restores an element of sovereignty to patients’lives, which are severely disrupted by the unpredictability ofepilepsy. Thus, VNS is both a preventive and abortive therapy.This attests to a mechanism of action that is of longer durationthan the periods of intermittent stimulation.

Expert commentaryLimitations of VNSVNS remains a promising therapy for a population of patientswho have failed prior medication trials and have no other surgi-cal option. However, several limitations pertain to this therapy.These include the low likelihood of complete seizure eradicationand the inability to predict who will respond favorably. Suchmodest gains will curtail the widespread application of VNS.

An area of active investigation is the prognostication of possi-ble benefit from VNS therapy. As reported previously, atonic sei-zures tend to respond favorably whereas myoclonic seizures donot. Some studies suggest better outcomes among patientswhere the onset of seizure activity occurs in the temporal area,while patients with frontal or frontocentral seizures have thepoorest outcomes [45]. Seizure semiology does not seem to havepredictive value.

As stressed earlier, it is important to consider that the stimula-tion parameters for VNS are empiric. Some studies have shownno differences between patients who were placed on standardversus rapid cycling or changed from standard to rapid para-digms during the crossover phase [22]. Similarly, in a randomizedtrial of three unique modes of VNS, which varied by duty cycle,all three were equally effective [46]. However, individual patientswho fail to demonstrate benefit from one paradigm may improvesubstantially as stimulation parameters are titrated over time.

Patient selectionEpilepsy affects up to 1% of the general population and is thesecond most common neurological disorder. Despite recentadvances in our understanding of the molecular and cellularbasis of epilepsy and the development of several new medica-tions targeted against these mechanisms, satisfactory seizurecontrol remains elusive in 30–40% of patients. In the USAalone, there are at least 300,000 people with medically refrac-tory seizures of partial onset. Although there is disagreement as

to which of these patients should undergo cerebral surgery, it isestimated that only 30,000–100,000 patients are appropriatecandidates for temporal lobectomy, focal cortical resection, cal-losotomy, hemispherectomy, subpial transection and otherextant procedures [1].

The selection criteria for insertion of the VNS system remainin evolution and reflect current governmental standards, as wellas institutional biases and general guidelines from prior clinicaltrials. As noted, the off-label use of VNS to treat children lessthan 12 years of age or those with primarily generalized epilepsyhas been rewarding, although these patient groups were notstudied in randomized, controlled trials. Patients with both idio-pathic epilepsy and seizures of structural etiology are consideredappropriate candidates.

The definition of medical intractability varies from center tocenter. Standards from previous studies commonly required afrequency of at least six seizures per month and a seizure-freeinterval of no longer than 2–3 weeks despite therapy with mul-tiple medications. However, seizure frequency, seizure type,severity of attacks, drug toxicity and overall impact on QoLmust all be considered before a patient is deemed refractory topharmacotherapy.

As noted previously, the response to VNS is highly variableand previous clinical trials have failed to characterize the demo-graphic factors that predict a favorable outcome. Furthermore,VNS is rarely curative (<10%). Although reductions in seizurefrequency can dramatically improve patients’ QoL, residual sei-zures may still preclude them from driving a car, maintainingemployment or other basic functions. Therefore, we do not con-sider the VNS device an alternative to conventional methods ofepilepsy surgery that may offer a higher likelihood of seizure ces-sation, and we generally reserve VNS for patients in whom suchoperations are not indicated. These include those patientswhose seizure focus is bilateral, not associated with a structuralabnormality or cannot be completely resected owing to overlapwith functional cortex. Extensive work-up, including invasivemonitoring when indicated, should precede the decision to optfor VNS before resective surgery is excluded

For obvious reasons, the VNS system cannot be inserted inpatients who have undergone a prior left cervical vagotomy.Furthermore, the safety of VNS has not been tested in severalconditions in which impairment of vagus nerve function mightproduce deleterious effects. Thus, relative contraindicationsinclude progressive neurologic or systemic diseases, pregnancy,cardiac arrhythmia, asthma, chronic obstructive pulmonary dis-ease, active peptic ulcer disease and insulin-dependent diabetesmellitus. Patients with prior anterior cervical discectomy orother neck surgery should undergo video laryngoscopy or EMGto assess the possibility of preexisting vocal cord paresis.

Five-year viewAlternative uses of VNSIn the course of studying VNS for the treatment of epilepsy, anumber of serendipitous observations have occurred. Manypatients report an improvement in mood, cognition and wellbeing

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not related to seizure control per se [1,17,26]. Stimulation of thevagus nerve has been shown to enhance retention in verballearning tasks, confirming the hypothesis that vagus nerve acti-vation modulates memory formation similarly to arousal. Inaddition, VNS has been shown to exert an antinociceptiveeffect [47].

As a result of these fortuities, VNS has been proposed as a pos-sible treatment for a number of diverse neurologic conditions [48].One of the potential applications that has received much atten-tion, both within the medical community and among patientgroups and the lay press, is depression. Several lines of evidencesupport this practice [49]. First is the clinical observation of sub-stantial improvements in mood during VNS trials for epilepsythat were not attributable to seizure control alone. Second,neuroanatomic studies of vagal afferent connections suggest thatthe NTS and LC project to the amygdala, stria terminalis andother limbic structures involved in mood regulation [9]. In VNStrials for epilepsy, for instance, PET studies have shown decreasedblood flow to the hippocampus, amygdala and cingulate gyrusreminiscent of the effects of selective serotonin reuptake inhibi-tors and other antidepressant drugs [49]. In addition, many anti-convulsant medications have mood-stabilizing effects and areuseful treatments for the depressive phase of bipolar affective dis-order [49]. Conversely, electroconvulsive therapy (ECT) – themost effective antidepressant therapy currently available – haspotent anticonvulsant effects. Furthermore, VNS alters the CNSconcentrations of norepinephrine, serotonin, glutamate andother monoamine neurotransmitters implicated in the patho-genesis of major depression. Finally, it is well established thatdepressed patients have autonomic system dysfunction that ismediated by the vagus nerve. If depressed patients have abnor-malities in brain regions that control the vagus nerve from thetop down, then perhaps stimulating the vagus nerve mightengage this dysfunctional circuit from the bottom up [49].

A corporate-sponsored, nonrandomized clinical trial of VNSfor depression has been conducted [50]. In this open-label pilotstudy, 30 patients with treatment-resistant depression wereenrolled. All had failed at least two pharmacological trials andmore than half had also failed ECT. Following a baseline periodwith stable medication regimens, patients underwent insertionof the VNS device. A 2-week single-blind recovery period wasfollowed by a 10-week period of active stimulation, usingparameters similar to those employed for epilepsy. Functionalstatus was assessed by several scales, with response defined by a50% or greater reduction in baseline scores.

For both the 28-item Hamilton Depression Rating Scale(Hamilton-D-28) and the Clinical Global Impressions–Improve-ment index, the response rate was 40%. For the Mont-gomery–Asberg Depression Rating Scale, the response rate was50%. In total, 17% of patients had complete remission. Sympto-matic responses and functional improvements have been sustainedduring follow-up as long as 9 months [50].

The promising results of the pilot study have been replicatedin larger company-sponsored studies, including the pivotal ran-domized, controlled acute-phase trial that enrolled 235

patients [51]. Furthermore, the durability of the treatment effecthas been confirmed. In follow-up of the patients in the pilottrial, for instance, 72 and 61% of the early responders (thosewith a 50% reduction in symptom scores by 3 months of ther-apy) were still responders at 12 and 24 months, respectively,and nearly 80% of the later responders (those achieving a 50%reduction by 12 months) were still responders at 24 months[52]. For the pivotal trial, analogous numbers were 63, 77 and61% [52]. As with VNS for epilepsy, a trend towards greaterefficacy was observed over time. In the pilot study, for instance,Hamilton-D-28 response rates were 31% at 3 months, 44%after 1 year and 42% after 2 years based on last visit carried for-ward analysis [53]. Remission rates for similar time periods were15, 27 and 22% [53].

Based on these and other studies, the VNS device gained FDAapproval in July 2005 “for the adjunctive long-term treatment ofchronic or recurrent depression for patients 18 years of age orolder who are experiencing a major depressive episode and havenot had an adequate response to four or more adequate anti-depressant treatments”. As with VNS for epilepsy, cost analysissuggests that, compared with other treatment modalities, such asmaintenance ECT (M-ECT) at frequent intervals, VNS fordepression is associated with a cost savings. The cost of VNS isestimated at US$3900 annually ($31,000 cumulative total forsurgery, device and office visits, prorated over 8 years) asopposed to M-ECT at $1,000 per treatment [54].

However, despite the suggestion of clinical efficacy and thepotential cost savings, the Centers for Medicare and MedicaidServices recently issued a noncoverage decision applying to VNStherapy for refractory depression. Since third-party insurers willprobably issue similar policies, the future of VNS for depressionlooks bleak. Furthermore, the validity of the scientific data insupport of VNS for the treatment of depression has been ques-tioned recently. Some patient advocacy groups, and even somephysicians, have requested that the FDA repeat its review ofVNS for depression and repeal its approval for this indication.

As with VNS for epilepsy, the locus of effect and mode ofaction of VNS for depression remains uncertain. PET studieshave shown VNS induced increases in rCBF in the bilateralorbitofrontal cortex, bilateral anterior cingulated cortex, andright superior and medial frontal cortices. Decreases were foundin the bilateral temporal cortex and right parietal regions. Theseareas of change are consistent with brain structures associatedwith depression and the afferent pathways of the vagus nerve [55].More recently, functional MRI using blood oxygenation level-dependent signal as the dependent variable has revealed that, overtime, VNS therapy is associated with ventromedial prefrontalcortex deactivation, an effect similar to that of other antidepres-sant treatments [56]. Also, as with VNS for epilepsy, it is difficultto predict which patients will respond to VNS for depression andwhich will not. However, in one study auditory event-relatedpotentials demonstrated some prognostic value, as enhancementof the P300 peak distinguished VNS responders from non-responders 10 weeks after therapy onset [57]. The P300 peak alsocorrelated with Hamilton-D scores.

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Other hints suggest that VNS may have utility for additionalneuropsychiatric illnesses. For instance, several theories of anx-iety purport faulty or erratic interpretation of peripheral infor-mation that flows into the CNS [49]. By affecting the flux ofthis information, VNS might have therapeutic potential intreating anxiety disorders. Similarly, the vagus nerve is knownto transmit signals pertaining to hunger, satiety and pain. Forthose reasons, potential applications for obesity, addiction andpain syndromes seem plausible.

The effects of VNS on feeding behavior were investigated ina canine model [REDDY, UNPUBLISHED OBSERVATIONS]. Six dogsunderwent bilateral VNS at parameters similar to those usedfor epilepsy. Feeding times, amount consumed and weightwere serially monitored and compared with baseline. Inresponse to VNS, feeding behavior changed following a varia-ble period of latency. Both the rate of consumption and theamount consumed decreased, leading to weight loss. Whenstimulation was suspended, eating returned to baseline in3–5 days, but resuming the stimulation reproduced the initialdietary changes. Similarly, in a pig model, low-frequency vagusnerve pacing produced continuous decreases in food intakeand body weight gain over 8 weeks of experimentation [58].

In humans treated with VNS for refractory depression, sig-nificant, gradual weight loss despite the lack of any inten-tional change in diet or exercise has been another serendipi-tous observation [59]. Weight loss did not correlate withchanges in mood symptoms. In another study of patientsundergoing VNS for depression, acute device activationresulted in a significant change in cravings ratings for sweetfoods [60]. A Phase I clinical trial of the effects of VNS onobesity is currently in progress.

In rodent models, VNS has been shown to enhance long-term potentiation and human studies suggest a favorableimpact on recognition memory [61]. Based on these observa-tions, a pilot study for the treatment of Alzheimer’s diseasebeen conducted [62]. In this trial of 17 patients, seven (42%)and 12 (70%) demonstrated improved Alzheimer's DiseaseAssessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) scores, respectively, after1 year of stimulation. Furthermore, there was a median reduc-tion of cerebrospinal fluid tau protein, a marker of Alzheimer’sdisease severity, by 4.8% (p = 0.057) after 1 year [62].

Seizures are a common comorbidity of the autism spec-trum disorders and occur in as many as 30% of patients [63].Preliminary results in patients suffering from both epilepsyand autism or Asperger’s syndrome suggest that VNS mayexert beneficial effects in treatment of the latter conditionsalone [63,64].

Moreover, the NTS sends fibers to the dorsal raphe andother areas of the reticular formation known to control levelsof consciousness [9]. Thus, VNS has been considered as apotential treatment for disorders of sleep or alertness, such asnarcolepsy and coma. VNS is also a possible treatment foradditional conditions, such as movement disorders. Forinstance, a patient with medically refractory epilepsy and

concurrent Tourette syndrome underwent VNS and experi-enced improvements of his tics [65]. However, VNS does notappear to be helpful in the treatment of essential tremor [66].

Electrical stimulation of vagal afferents inhibits spinalnociceptive reflexes and transmission, resulting in alteredpain perception and thresholds. Changes in the activity ofspinal trigeminal nucleus neurons may underlie thiseffect [47]. These findings provide the impetus for studyingVNS in the treatment of chronic headache, intractablemigraines and cluster headache.

Through mechanisms that remain to be clarified, VNS fol-lowing experimental traumatic brain injury enhances recov-ery of motor and cognitive function. Attenuation of cerebraledema may underlie this effect [67], and further study maydisclose additional applications for VNS in the treatment ofthis condition.

Finally, it is important to recall that the VNS device per-mits delivery of stimulation at different amplitudes, frequen-cies, pulse widths and duty cycles [1]. At present, these set-tings are titrated empirically according to the desired effectand tolerability. Although stimulation paradigm (standardversus rapid cycle) and output current do not correlate withthe effectiveness of VNS for seizure control [22], it is possiblethat varying these parameters in different combinations mayaffect different regions of the brain, thereby influencing dis-tinct pathologic conditions and producing pleiotropiceffects. As more becomes known regarding the physiology ofafferent autonomic stimulation, the utility of VNS willprobably broaden.

Alternatives to direct VNSThe success of directly stimulating the vagus nerve via animplantable device has prompted interest in less invasivemethods of afferent cranial nerve activation. Building uponearly experiments of transcutaneous electrical stimulation ofthe recurrent laryngeal nerve as a diagnostic aid in laryngo-scopy and as a therapeutic tool in controlling the glottic aper-ture [68], more recent studies have focused on the potential oftranscutaneous stimulation of the vagus nerve for control ofpartial onset seizures [69] and potentially other conditions. Forinstance, transcutaneous electrical stimulation of the sensoryauricular branch of the vagus nerve innervating parts of theouter ear results in sensory evoked potentials originating invagus nuclei within the brainstem [70]. In one application ofthis approach, vagal branches of the left outer auditory canalwere simulated, followed by functional MRI and psychometricassessments of mood [71]. Transcutaneous VNS produced brainactivation patterns in limbic and other areas reminiscent ofinvasive VNS and also caused significant improvements inoverall feelings of wellbeing [71].

Similarly, the trigeminal nerve (the fifth cranial nerve) isknown to converge upon many of the same brainstem nucleias the vagus nerve. The safety and preliminary efficacy ofafferent trigeminal nerve stimulation for epilepsy was evalu-ated recently in a pilot feasibility study of transcutaneous

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stimulation of the infraorbital and supraorbital branches ofthe trigeminal nerve [72]. In this study, trigeminal nerve stim-ulation was well tolerated, and four of seven (57%) subjectswho completed 3 or more months of stimulation experienceda 50% or greater reduction in seizure frequency. It is there-fore conceivable that, in the future, direct (invasive) VNS forthe treatment of epilepsy or other disorders will be sup-planted by transcutaneous or less invasive methods of afferentcranial stimulation.

Financial & competing interests disclosureThe author has no relevant affiliations or financial involvementwith any organization or entity with a financial interest in orfinancial conflict with the subject matter or materials discussed inthe manuscript. This includes employment, consultancies, hono-raria, stock ownership or options, expert testimony, grants or patentsreceived or pending, or royalties.

No writing assistance was utilized in the production of thismanuscript.

Key issues

• Vagus nerve stimulation (VNS) therapy is a safe and effective treatment for patients with medically refractory epilepsy. A pulse generator inserted in the chest delivers intermittent electrical stimulation to the cervical vagus nerve trunk, which secondarily transmits afferent (rostral) impulses to exert widespread effects on neuronal excitability throughout the CNS.

• VNS therapy is approved by the US FDA as “an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures which are refractory to antiepileptic medications.” However, VNS also has proven utility in other populations, including children as young as 1 year old and patients suffering from generalized seizures. Results in these patients appear as good as, or even better than, those in the approved patient group.

• The exact means by which VNS modulates seizure activity and its locus of action in the brain remain uncertain. Over 80% of the fibers within the vagus nerve are special visceral and general somatic afferents leading towards the brain. Vagus nerve fibers project to the cerebellum, diencephalon, amygdala, hippocampus, insular cortex and multiple brainstem centers. The locus coeruleus appears to be a key intermediary in VNS mechanism of action.

• Although VNS is typically applied to the left cervical vagus nerve trunk, anecdotal experience with right-sided VNS supports its potential safety and efficacy.

• The response to VNS is variable. The rate of cure is only approximately 2–10%. The reported median reduction in seizure frequency ranges from 40 to 70%. Approximately a third of patients derive no significant benefit.

• The response to VNS is maintained during prolonged stimulation, and unlike the case with chronic medication therapy, seizure control actually improves with time.

• VNS has a well-tolerated safety profile. Common side effects include mild hoarseness, cough and paresthesia. VNS does not adversely affect any aspect of physiological function, including cardiac rhythm, pulmonary function, gastrointestinal motility and secretion.

• Limitations of VNS therapy include the low likelihood of complete seizure eradication and the inability to predict which patients will respond favorably.

• Serendipitous observations of improved mood among epilepsy patients undergoing VNS therapy led to its study for treatment-resistant depression. Results of these studies are promising and VNS is now approved “for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.” However, the Centers for Medicare and Medicaid Services has issued a noncoverage determination for the use of VNS in treatment-resistant depression, which limits reimbursement for the device and its insertion.

• Based on its pleiotropic effects, VNS has been proposed as a potential treatment for a wide spectrum of diseases, including chronic pain, headache, coma, Alzheimer’s disease, movement disorders, autism and others. As more becomes known regarding the physiology of afferent autonomic stimulation, the utility of VNS will probably broaden.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Affiliation

• Arun Paul Amar, MD

Department of Neurosurgery, 2025 Morse Avenue, Sacramento, CA 95825, USATel.: +1 916 973 6517Fax: +1 916 973 5826amar@aya.yale.edu