Version May 2024
INTRODUCTION — Antiseizure medications are the most often used treatment for patients with epilepsy. However, in approximately one-third of people with epilepsy, medications do not completely control seizures [1]. The seizures that occur in these patients are referred to as refractory or drug-resistant.
In patients with refractory epilepsy, various combinations of antiseizure medications may be tried. Although combination therapy may help to reduce the total number of seizures, polypharmacy often leads to an increased number of side effects. Nonpharmacologic options are therefore an important component of the overall therapeutic approach to refractory epilepsy. One such option is vagus nerve stimulation (VNS) therapy; others include epilepsy surgery, ketogenic diet, and responsive neurostimulation. Among these, epilepsy surgery is the only potentially curative option. Neuromodulatory options, including VNS, are appropriate to consider in patients who are not candidates for resective epilepsy surgery.
This topic reviews the relevant anatomy, possible mechanisms of action, and clinical results of VNS in patients with epilepsy. Other aspects of epilepsy treatment in both children and adults are discussed separately. (See "Overview of the management of epilepsy in adults" and "Evaluation and management of drug-resistant epilepsy" and "Surgical treatment of epilepsy in adults" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Seizures and epilepsy in children: Refractory seizures" and "Ketogenic dietary therapies for the treatment of epilepsy".)
MECHANISM OF EFFECT — The precise mechanisms by which vagus nerve stimulation (VNS) therapy achieves seizure reduction are not well established. A variety of nonexclusive mechanisms have been proposed and are partially supported by animal and human studies, including:
●Afferent vagal projections through the pontine parabrachial nucleus and thalamus to seizure generating regions in the basal forebrain and insular cortex [2,3]
●Effects on the locus ceruleus, which receives vagal afferent signals from the nucleus tractus solitarius [4,5]
●Desynchronization of hypersynchronized cortical activity (ie, seizure activity), dependent on stimulus frequency and the strength of the electrical current [6-8]
●Cortical inhibition secondary to release of inhibitory neurotransmitters, such as glycine and gamma-aminobutyric acid (GABA) [9,10]
●Increased blood flow and neural activity in the thalamus, limbic system, and multiple cortical regions [11-21]
In animal models, a variety of antiseizure properties of VNS have been demonstrated, including abortion of an ongoing seizure, prophylaxis against acute seizure-inducing insults, reduction in chronic seizure frequency in epilepsy models, and inhibition of epileptogenesis in models of seizure kindling [22-29].
PATIENT SELECTION — In general, vagus nerve stimulation (VNS) therapy is considered a valid treatment option for children and adults with well-documented medically refractory seizures who are opposed to intracranial surgery, are not candidates, or whose medically refractory seizures were not substantially improved by prior intracranial epilepsy surgery [30,31]. (See "Evaluation and management of drug-resistant epilepsy" and "Surgical treatment of epilepsy in adults".)
The US Food and Drug Administration (FDA) has approved VNS therapy as adjunctive treatment for patients 4 years of age and older with focal seizures that are refractory to antiseizure medications. The approval was based largely on two pivotal randomized trials in this patient population (see 'Focal epilepsy' below). In Europe, VNS is approved, unrestricted by age, as adjunctive therapy for patients whose epileptic disorder is dominated by focal seizures (with or without secondary generalization) or generalized seizures that are refractory to antiseizure medications.
Although there are limited randomized studies in other age groups and seizure types, observational studies reviewed below suggest that the benefits of VNS may extend to a broad range of seizure types [32,33]. The effectiveness of VNS does not appear to vary significantly based on age, neurologic comorbidity, cause of epilepsy, location of the brain from which seizure arise, or epilepsy syndrome.
Identification of factors that accurately predict a clinical response to VNS has been elusive [34-37]. Although VNS is effective for seizures that originate from any lobe of the brain, one study found that seizures arising from the frontal lobes responded better than seizures arising from the temporal region [38]. Other studies have suggested that VNS may be more effective in patients who have had epilepsy for a shorter period of time [39] and in patients with seizures beginning after one year of age [32,40,41]. Earlier age of epilepsy onset is also a predictor of medical intractability [42]. Further studies are needed to identify predictive factors associated with a response to VNS.
Focal epilepsy — Two multicenter, blinded, randomized trials in patients 12 years of age and older with refractory focal epilepsy (more than six seizures per month) have found that active, high-intensity VNS stimulation improves seizure outcomes compared with low-intensity control stimulation [43-48]. In both trials, patients were treated with a mean of two antiseizure medications at study entry; these were not adjusted during the study period. The primary efficacy measure was the percentage change in seizure frequency during VNS treatment (measured over 12 weeks, two weeks after implantation) compared with a 12-week preimplantation baseline.
●In the E03 study, 114 patients with predominantly focal seizures were enrolled [46]. The high-stimulation group experienced a greater mean reduction in seizure frequency compared with the low-stimulation group (24.5 versus 6.1 percent). More patients in the high-stimulation group experienced a greater than 50 percent reduction in seizures (31 versus 13 percent).
●In the E05 study, 199 patients with complex partial or secondarily generalized seizures were enrolled [47]. The mean reduction in seizure frequency was greater in the high-stimulation group (28 versus 15 percent). A greater than 75 percent reduction in seizures was achieved in more patients in the high-stimulation group (11 versus 2 percent).
Patients in both studies, as well as 124 other patients who received VNS on a compassionate-use basis, were followed for an additional 12 months [49-51]. All patients received high-stimulation VNS. Median seizure reductions compared with baseline appeared even greater than in the controlled portion of the studies: 34 percent at three months and 45 percent at 12 months. At 12 months, 20 percent of patients achieved seizure reduction of greater than 75 percent.
These and other open-label studies suggest that the efficacy of VNS may improve over time [34,52-58]. However, these results should be interpreted with some caution; there were no control groups in these studies. Further, antiseizure medication adjustments, permitted during some of these observational studies, may have contributed to improved seizure control.
A third study, referred to as the PULSE trial, was stopped early due to slow recruitment after 112 out of a planned 362 patients were enrolled [59]. PULSE was an open-label randomized trial comparing VNS plus best medical practice (BMP) with BMP alone in adults with refractory focal seizures. In 96 analyzed patients, there were significant between-group differences in favor of VNS plus BMP on measures of quality of life and seizure frequency. Although a greater number of patients in the VNS plus BMP group reported adverse events (43 versus 21 percent), the adverse effects were mostly transient and related to VNS implantation or stimulation. (See 'Side effects and complications' below.)
In addition to randomized trials [48], multiple large case series have reported responder rates (>50 percent reduction of seizures) of 50 to 64 percent in patients implanted with VNS with a follow up time ranging from one to five years [34,37,39,60,61].
Generalized epilepsies — Case series suggest that VNS is also effective in generalized epilepsy syndromes [32,37,41,55,60,62]. While some studies have found that symptomatic generalized epilepsy is more responsive to VNS than idiopathic syndromes, others have reported the opposite or found no difference [32,55,63,64]. In one of the early randomized trials of VNS, 24 patients had refractory idiopathic generalized epilepsy, and there was a 46 percent median reduction of seizures in this group after three months of treatment [32].
A relatively large accumulation of clinical experience with VNS in patients with Lennox-Gastaut syndrome is due in part to the fact that seizures are often medically intractable, and surgical treatment options are limited [62-73]. VNS appears to be very effective in this patient group, leading to a greater than 50 percent reduction in seizure frequency in approximately two-thirds of patients, shortened seizure duration, and a median reduction of one prescribed antiseizure medication [73]. VNS may be particularly effective at reducing atonic and tonic seizures in these patients. (See "Lennox-Gastaut syndrome".)
Other refractory epilepsies with onset in childhood also appear to respond to VNS in uncontrolled case series; these include epileptic encephalopathies (eg, Landau Kleffner syndrome), Dravet syndrome (ie, severe myoclonic epilepsy of infancy), tuberous sclerosis complex, and atypical absence epilepsy [32,40,55,62-69,74-78].
Children — In addition to small studies reviewed above in children with specific epilepsy syndromes such as Lennox-Gastaut syndrome, one randomized study and multiple observational studies have examined the efficacy and tolerability of VNS in children.
In the only randomized study to date, 41 children (mean age 11 years, range 3 to 17 years), most with intractable focal epilepsy, were randomized to high-output stimulation versus low-output (control) stimulation and followed for 20 weeks [79]. At the end of the blinded randomized treatment phase, the proportion of patients achieving 50 percent or greater reduction in seizure frequency was similar between groups (16 percent in the high-stimulation group versus 21 percent in the low-stimulation group). After a 19-week unblinded add-on phase during which 34 children all received high-output stimulation, 26 percent of patients achieved a 50 percent or greater reduction in seizure frequency and 94 percent of parents or guardians reported positive qualitative effects of treatment.
These results contrast with many prior observational studies that suggested that VNS was similarly effective in children compared with adolescents and adults [37,40,41,62,80,81]. A 2021 systematic review and meta-analysis included 98 observational studies, one randomized controlled trial, and 3474 children with drug-resistant epilepsy who were treated with VNS; at last follow-up (mean 2.5 years), the responder rate (>50 percent seizure reduction) associated with VNS was 56 percent, and the pooled seizure freedom rate was 11 percent [82].
There are several possible explanations for the discrepancy between the randomized and observational data in children. Some have suggested that the randomized study was under-powered or too short to see the full impact of VNS, since data in adults suggest that improvement may only be seen after a year or longer of stimulation [83]. Alternatively, differences in electrophysiology and incomplete maturation of the vagus nerve in children compared with adults could impact the effectiveness of stimulation [84]. In other reports, VNS has been used with success in children as young as 11 months.
Older adults — Experience with VNS in older patients with epilepsy is limited. The subset of 45 patients in the EO3 and EO5 trials reviewed above who were 50 years of age or older experienced a benefit similar to the population as a whole [85]. However, only eight of these patients were older than 60 years. (See "Seizures and epilepsy in older adults: Treatment and prognosis", section on 'Other treatments'.)
Previous epilepsy surgery — VNS treatment has been reported to be successful in patients with previous epilepsy surgery [34,40,62,63,86,87]. In a VNS registry study, the response was favorable but somewhat less so in the 591 surgical patients compared with the 2382 nonsurgical patients; median reduction in seizure frequencies at 3 and 12 months were 43 versus 47 percent and 46 versus 60 percent [88]. While some case series have suggested that the outcomes with VNS may be more favorable in the post-callosotomy group, the VNS registry data suggest that at 12 months, response rates are similar in these two groups.
CONTRAINDICATIONS — Baseline cardiac conduction disorders are generally considered a contraindication to vagus nerve stimulation (VNS) therapy, given the potential for efferent conduction through the vagus nerve, particularly on the right, to worsen cardiac conduction abnormalities. (See 'Bradycardia' below.)
Sleep apnea is a relative contraindication for VNS (see 'Sleep apnea' below). Prior to VNS implantation, possible sleep apnea-related symptoms and physical signs should be sought on history and physical examination, and if found, should be pursued by testing to determine whether the patient does have clinically significant sleep apnea. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and "Evaluation of suspected obstructive sleep apnea in children" and "Central sleep apnea: Risk factors, clinical presentation, and diagnosis".)
There are reports that programmable shunt valves can be affected by use of the VNS magnet [89]. VNS stimulation using the magnet should probably be avoided in individuals with programmable shunts.
DEVICE SELECTION — Vagus nerve stimulation (VNS) is a battery-powered device similar to a cardiac pacemaker. In most models, stimulating leads are surgically placed around the left vagus nerve in the carotid sheath and are connected to an infraclavicular subcutaneous programmable pacemaker (figure 1).
Because the right vagus nerve provides more innervation to the cardiac atria than the left vagus nerve, electrical stimulation of the left vagus nerve is generally used in clinical practice to avoid adverse cardiac effects [90]. However, right-sided VNS has been reported safe in at least one case series, and in animal studies it appears equally effective against seizures as left-sided stimulation [91,92].
Responsive devices — A VNS model that provides responsive stimulation to increases in heart rate that are often associated with seizures was approved by the US Food and Drug Administration (FDA) in 2015 [93]. The responsive stimulation occurs in addition to the automatic intermittent stimulation and in addition to the on-demand stimulation when the patient uses the magnet. It is not yet known whether responsive models are more effective than non-responsive models, and the design of the trials that have been performed does not allow for direct comparison.
The rationale for the model is the observation that up to 80 percent of patients experience an acceleration of heart rate when a seizure occurs [94]. The automated stimulation function of this VNS model detects these heart rate changes and automatically responds by sending a programmed stimulation to the vagus nerve. Both seizure-related and non-seizure related increases in heart rate may trigger stimulation.
In a multicenter unblinded trial of 20 patients with refractory focal epilepsy who underwent placement of heart-rate responsive VNS, a total of 89 seizures occurred while patients were continuously monitored over three to five days in an epilepsy monitoring unit [95]. Overall, 43 percent of seizures were associated with ≥20 percent rise in heart rate, 35 percent of seizures received automated stimulation, and 21 percent of seizures stopped during automated stimulation (median duration from stimulation to seizure end, 35 seconds). Responder rates (≥50 percent reduction in seizures per month compared with baseline) at 3, 6, and 12 months were 20, 35, and 50 percent, respectively. The mean duty cycle increased from 11 to 16 percent at six months, which represents approximately five additional stimulations per hour compared with standard, non-responsive settings.
The device is relatively new, and selection criteria and predictors of benefit have not been established. Pending further data and clinical experience, a heart rate-responsive VNS model may be considered in patients who have documented tachycardia at the onset of seizures and who are not expected to be able to apply on-demand stimulation with the magnet.
Noninvasive systems — An entirely noninvasive, transcutaneous vagal nerve stimulator has been in use in Europe. The device stimulates the auricular branch of the vagus nerve via a small earphone-like stimulator. Although no randomized studies have been done in patients with epilepsy, it appears promising in one pilot study [96].
Other emerging technologies — A variety of additional technologies related to VNS are under development. These include:
●A system that combines stimulation and recording of the vagus nerve
●A stimulator that provides unidirectional (ie, afferent-only) stimulation
STIMULATION PARAMETERS
Initial settings — Typical initiation stimulation parameters are outlined in the table (table 1). Baseline active stimulation consists of a 30 Hz stimulus delivered for 30 seconds every five minutes.
More research is needed to determine whether any initiation stimulation settings provide more benefit than standard initial settings [97,98].
Adjustments over time — Baseline VNS settings can be adjusted over time at outpatient follow up visits to maximize efficacy and minimize side effects (table 1). Adjustments that may improve efficacy include decreasing off time and increasing the output current. In a retrospective study of 50 children with drug-resistant epilepsy treated with VNS, switching to a rapid duty cycle (off time ≤1.1 minute, keeping the duty cycle less than 50 percent) was associated with an increased response to VNS and was well tolerated [99]. The significance of this finding is uncertain given that prospective studies have shown that efficacy from VNS can increase over time independent of parameter changes.
Adjustments that may improve tolerability include decreasing the frequency of the stimulus and decreasing the pulse width.
On-demand stimulation — For some patients who experience auras, on-demand stimulation with the supplied magnet can be an effective adjunct to chronic stimulation for attenuating or interrupting seizures [80].
In one of the initial randomized trials (E03), patients receiving high-stimulation (active) treatment also received an active magnet, while patients in the control group received an inactive magnet [100]. Use of the active magnet terminated more seizures than the inactive magnet (21 versus 12 percent). Similar efficacy was seen in patients with generalized epilepsy. One case series in children reported that 19 of the 27 patients were able to abort or attenuate at least some of their seizures [41].
SIDE EFFECTS AND COMPLICATIONS
Voice alteration and other common side effects — In the EO3 study, the most commonly reported side effects of high-stimulation vagus nerve stimulation (VNS) were [46]:
●Hoarseness (37 percent)
●Throat pain (11 percent)
●Coughing (7 percent)
●Shortness of breath (6 percent)
●Tingling (6 percent)
●Muscle pain (6 percent)
Among these, hoarseness was the only side effect that occurred significantly more often with high stimulation than with low stimulation. In the E05 study, shortness of breath and pharyngitis, as well as voice alteration, occurred significantly more often in the high-stimulation group than in the low-stimulation group [47].
Lowering the pulse width of stimulation can alleviate symptoms and allow for higher stimulation intensities [101]. Lowering the frequency can also attenuate side effects related to VNS stimulation (table 1). (See 'Adjustments over time' above.)
Long-term studies of VNS generally show improved tolerability over time [56]. Among 444 patients who continued VNS after participating in a clinical study, the most commonly reported side effects at the end of the first year post-implantation were voice alteration (29 percent), tingling (12 percent), dyspnea (8 percent), and cough (8 percent); at the end of two years, the prevalence of these complaints was 19, 4, 3, and 6 percent, and at three years, each of these was present in less than 3 percent. High retention rates (>70 percent) may be an indicator of how well VNS is tolerated.
Implantation site infection — Infection of the subcutaneous pocket that holds the VNS generator, usually with Staphylococcus aureus, complicates surgery in 2 to 7 percent of cases [37,102-105]. The risk of infection may be higher in children compared with adults [30]. Systemic antibiotics along with explantation of the device and/or open wound debridement is usually required. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
Other surgical complications associated with VNS are infrequent. Early reports of electrode failure and lead fracture appear to be largely resolved with improvements in the device and enhancements in surgical techniques and postoperative care [106-109].
Bradycardia — Physiologic studies have generally found no clinically relevant effects of chronic VNS on cardiorespiratory function [110-112]. However, bradycardia followed by transient asystole lasting up to 45 seconds has been reported in association with the lead test conducted during VNS implantation (the initial lead test, which is performed in the operating room when the VNS is being implanted for the first time) in approximately 0.1 percent of cases [113-115]. These cases occurred with the earliest VNS devices when a 1.0 milliamps test stimulus was given. Changes in the programming now allow for testing at 0.25 milliamps; there have been no reported cases of asystole in the operating room in association with contemporary testing parameters.
Complete heart block due to atrioventricular nodal block has been documented in three patients with no reported adverse effects [116]. In some cases, a rechallenge stimulus is uneventful, and the VNS has been implanted successfully without adverse consequences. In general, baseline cardiac conduction disorders are considered a contraindication to VNS.
Two case reports describe VNS-induced episodes of bradycardia and asystole occurring two and nine years after device implantation [117,118].
Vocal cord paralysis — Unilateral vocal cord paralysis occurs in approximately 1 percent of cases, and is attributed to intraoperative manipulation of the recurrent laryngeal nerve [37,46,60]. Most of these recover. Two cases of delayed permanent vocal cord paralysis occurring several weeks after implantation appeared to be self-inflicted by patients who manipulated the device externally, presumably placing traction on the recurrent laryngeal nerve [119]. This phenomenon appears analogous to the "twiddler's syndrome" described in individuals with cardiac pacemakers. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Twiddler's syndrome'.)
Aspiration — There are some reports that children with severe developmental delay on assisted feeding may aspirate. This seems to occur if the child is fed during the time that the VNS is delivering its programmed stimulation [62,108,120,121]. However, the association between aspiration and VNS has been disputed [120]. Nonetheless, there are reports that using the magnet to inactivate the VNS during mealtime controls this problem.
Sleep apnea — Sleep apnea is a relative contraindication for VNS (see 'Contraindications' above) based on observations that VNS can induce or aggravate a sleep apnea syndrome [122-125]. VNS is associated with more frequent apnea and hypopnea episodes in sleep, but this appears clinically relevant mainly in those with preexisting sleep apnea.
Lowering stimulus frequency can ameliorate VNS-related apnea and hypopnea [123]. Continuous positive airway pressure (CPAP) may be required for some cases [124]. Botulinum toxin was reported to be helpful in one case of VNS-induced laryngospasm [126].
Other rare side effects
●Aside from recurrent laryngeal nerve palsy, other cranial nerve palsies that can complicate VNS implant include Horner syndrome and facial paralysis [127].
●Pneumothorax has been described in at least one patient [37].
●Some patients experience uncomfortable spasms of the left chest wall, which has been demonstrated to be due to collateral spread of stimulation to phrenic nerve, causing contraction of the left hemidiaphragm [128]. Contraction of the left anterior sternocleidomastoid muscle may also occur as a result of current stimulating adjacent structures [129]. These symptoms are often precipitated by assumption of certain postures or movement and are relieved by changing position.
●While gastrointestinal side effects might be expected with VNS, reports of this are infrequent. One patient experienced chronic diarrhea after VNS implant, but this is exceptional [130]. One case series documented clinically significant weight loss in 17 of 27 patients who had received VNS [131]. This observation requires further confirmation.
●Forced normalization refers to a phenomenon of psychiatric disturbances that emerge in some patients with long-standing, high-frequency seizures when their seizures are dramatically reduced. This has been described with VNS, usually with reduction in seizure frequency of greater than 75 percent [132,133]. Some, but not all, of these patients exhibited psychiatric symptoms, including psychosis prior to VNS implantation. Psychosis in these cases usually responds to psychotropic medication; in some cases, lowering the potency of antiseizure treatment is required.
●Patients are cautioned by the manufacturer not to undergo short-wave, microwave, or therapeutic ultrasound diathermy, which in theory could cause the VNS generator or lead to heat up and cause thermal tissue damage. There are no documented cases of this complication in VNS-treated patients.
OTHER PRACTICAL ISSUES
MRI compatibility — The presence of any implanted pacemaker is widely regarded as a contraindication to magnetic resonance imaging (MRI). Potential problems include considerable heating at the lead tip, which has been documented in animal experiments, and programming changes of pacing parameters [134]. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging", section on 'Assessing implants, devices, or foreign bodies for MRI'.)
However, MRI is safe using 1.5 Tesla (T) or 3 T scanners for patients with an implanted VNS if performed according to guidelines from the VNS manufacturer. Clinicians should refer to online MRI safety guidelines and downloadable MRI Physician’s Manual from the manufacturer to determine specific MRI scan conditions for patients with an implanted VNS (or incompletely explanted VNS, as many patients cannot have complete removal of the leads).
Use of MRI outside the limits outlined by the manufacturer cannot be considered safe and is not recommended. VNS remains contraindicated in 7 T MRI environments.
A 2021 systematic review, with a total of 216 patients, found that cranial MRI of patients with an implanted VNS system can be completed and is tolerable and safe using 1.5 T or 3 T MRI when performed in adherence to guidelines from the VNS manufacturer [135]. An earlier ex vivo study of temperature changes associated with different MRI conditions found no clinically significant temperature changes under the guidelines outlined by the manufacturer [136]. Excessive heating was observed with the use of body coil during imaging of the neck and shoulder but not of the lumbar spine; however, the number of experiments in the latter case was limited. VNS device function was not affected by the MRI procedure.
Of note, hospitals and imaging centers may have their own safety committees that may at times be more conservative than manufacturer recommendations. For this reason, it is often wise to obtain a 3 T brain MRI prior to the insertion of VNS in patients who have not previously had high-resolution brain imaging, so that surgical resective options may be revisited if appropriate after VNS.
Battery life — As the VNS generator battery is expended, seizure frequency may increase in some patients [137,138]. Others may note decreased or irregular perception of stimulation [138]. Fortunately, the end of battery service can be predicted with the current VNS model, allowing for elective generator replacement before the battery is fully depleted.
A reason for re-implanting a new battery before the old one is depleted is that a small number of patients who initially responded to VNS reportedly did not regain seizure control with VNS reimplant after a period of seizure-worsening associated with an expended battery [137]. As a result of these cases, it is generally agreed that patients who experience efficacy with VNS should have the generator battery replaced before it is expended.
Cost — There is an initial cost to implanting a VNS (estimated USD $15,000 to $25,000). Due to concerns about medical costs, there have been several studies which have tried to assess the economic impact of adding VNS to the patient’s existing therapy. In these studies, economic analyses suggest that VNS reduces doctor visits, hospitalizations, and other epilepsy-related direct medical care costs when these are averaged over the lifespan of the generator [139-142].
In one study that included over 1600 epilepsy patients enrolled in Medicaid (mean age 29 years), VNS was associated with decreased resource utilization and epilepsy-related clinical events that resulted in a net cost savings by 1.5 years post-implantation [143]. Similar cost savings have been found in children [144].
NONSEIZURE OUTCOMES
Quality of life — Quality of life measures improve in most studies of vagus nerve stimulation (VNS) in both children and adults [40,41,62,72,145-149]. While this effect is greatest in those who achieve the highest reduction in seizures, there appears to be an effect that is independent of reduction in seizure frequency, and may relate to independent effects of VNS on mood, alertness, and other factors. As with seizure reduction, improvement in quality of life measures also appear to increase over time.
Mood symptoms — Evidence indicating that VNS may improve mood and other depressive symptoms in patients with epilepsy is inconclusive [150-152]. In some but not all studies, a positive effect of VNS on mood appeared to correlate with reduction in seizures. VNS is under investigation as a treatment for major depression in nonepileptic patients. Although open-label studies suggest that the intervention may have some efficacy, a randomized trial found no benefit compared with sham stimulation over a 10-week treatment phase [153]. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Vagus nerve stimulation'.)
Daytime sleepiness — VNS may improve daytime alertness and vigilance and reduce daytime sleepiness despite its potential to exacerbate sleep apnea (see 'Sleep apnea' above) [68,146,154,155]. In one series, this was documented by longer mean sleep latency times and improved scores on a daytime sleepiness scale. Improved alertness occurred even in patients without significant reduction in seizure frequency [155]. Vagal stimulation of brainstem centers known to promote alertness (eg, parabrachial nucleus, locus ceruleus) may mediate this effect.
There appears to be a differential effect of high- versus low-intensity stimulus on sleep and alertness. Low-intensity stimulation (<1.5 mA) more consistently improves daytime alertness than higher intensity stimulation [146,155]. In one study, higher intensity stimulation was associated with reduced rapid eye movement (REM) sleep [154].
Behavior — Children with autism and intellectual disability have demonstrated improved behavioral outcomes with VNS treatment of their epilepsy. Benefits include improved alertness, mental age, and performance on functional measures and some cognitive tests, as well as reduced autistic behaviors [40,64,70,74,76,145,156]. In some cases, these improvements appear to be independent of seizure control. In adult patients, cognition does not appear to be positively or negatively affected by VNS treatment [157,158].
Reduction in antiseizure medications — Reduction of antiseizure medications can be of primary benefit to patients and may also affect the quality of life outcomes discussed above. In most cases, patients with VNS continue to require medical treatment [159]. However, some patients are able to reduce one or more drugs and/or doses, and a few patients are seizure free with VNS and no antiseizure medication treatment [32,160].
There is limited information regarding the frequency of this outcome. Larger series indicate that most patients remain on the same number of antiseizure medications after VNS, without specifically discussing dose alterations [40,56,159]. Smaller case series report higher percentages of antiseizure medication dose or medication reductions, perhaps reflecting a more aggressive effort of the clinicians involved in achieving this goal [160].
Mortality — Neither sudden death nor overall mortality rates appear to be increased in patients receiving VNS compared with expected rates in the refractory epilepsy population.
In fact, there is evidence that VNS may reduce the rates of sudden unexplained death in epilepsy (SUDEP): in a cohort of 1819 individuals with VNS followed for >3000 person-years from VNS implantation, the SUDEP rate was 5.5 per 1000 over the first two years, but only 1.7 per 1000 thereafter [161]. By contrast, a smaller retrospective study with longer median follow up observed a trend towards decreased overall mortality rates in the years following VNS implantation, but no change in the SUDEP rate over time [162]. (See "Sudden unexpected death in epilepsy".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults" and "Society guideline links: Seizures and epilepsy in children".)
SUMMARY AND RECOMMENDATIONS
●Surgical evaluation is recommended for patients with refractory focal seizures (Grade 1A). Eligible patients with medically refractory epilepsy are more likely to achieve seizure remission with epilepsy surgery than with other treatment modalities. (See "Surgical treatment of epilepsy in adults".)
●Vagus nerve stimulation (VNS) is a battery-powered device similar to a cardiac pacemaker. Stimulating leads are surgically placed around the left vagus nerve in the carotid sheath (figure 1). VNS has multiple antiseizure properties, but the exact mechanisms of effect remain unclear. (See 'Mechanism of effect' above.)
●VNS is a valid treatment option for patients with medically refractory epilepsy. This includes patients who are not candidates for resective surgery, those who opt not to undergo brain surgery, and those whose seizures persist after resective epilepsy surgery. (See 'Patient selection' above.)
●Controlled trials in individuals greater than 12 years of age with focal epilepsy indicate that 30 to 40 percent achieve a greater than 50 percent reduction in seizure frequency. Open-label studies suggest that these benefits may increase over time and adjustment of parameter settings. (See 'Focal epilepsy' above.)
●There are conflicting data on the efficacy of VNS in younger children. Most open-label studies suggest that younger children and individuals with other seizure types and epilepsy syndromes (eg, Lennox-Gastaut syndrome) can benefit from VNS. However, a single, small, randomized study found no benefit of VNS compared with low-stimulation control in patients 3 to 17 years in age. (See 'Generalized epilepsies' above and 'Children' above.)
●Side effects that occur during stimulation in a minority of patients are usually mild to moderate in severity and diminish with time or reduction in stimulation intensity. These include voice alteration and tingling. (See 'Voice alteration and other common side effects' above.)
●Serious adverse events are rare and include infections, cardiac arrhythmias, and aspiration. Infections may be more common in children than adults. (See 'Side effects and complications' above.)
●Magnetic resonance imaging (MRI) in patients with VNS is limited to brain MRI under specific conditions outlined by the manufacturer. (See 'MRI compatibility' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven Karceski, MD, who contributed to an earlier version of this topic review.
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