Efficacy Of Vagus Nerve Stimulation Research Articles

Case report: Vagal nerve stimulation and late onset asystole

Rohit Shankar , Victor Oluwaseyi Olotu *, Nicholas Cole , Heather Sullivan , Caryn Jory c Neuropsychiatry, Epilepsy and Memory Service, Cornwall Partnership NHS Foundation Trust, Chy Govenek, Threemilestone Industrial Estate, Threemilestone, Truro, Cornwall TR4 9LD, United Kingdom Care of the Elderly Department, Royal Cornwall Hospital NHS Trust, Treliske, Truro, Cornwall TR1 3LJ, United Kingdom c East Cornwall Resource Centre, Cornwall Partnership NHS Foundation Trust, Unit 10, Bodmin Business Centre, Harleigh Road, Bodmin, Cornwall PL31 1AH, United Kingdom

Efficacy of Vagus Nerve Stimulation (VNS) after Multiple Subpial Transections (MST) for Extra-Temporal Seizure Foci

Background: The effect of Vagus nerve stimulation (VNS) therapy following major resective surgeries has been reported. However, the effect of VNS therapy following multiple-subpial-transections (MST) has not been reported. The objective of this paper is to examine the beneficial effect of VNS therapy following MST. Methods: There are 22 patients aged 10 - 55 years. Male/female distribution is 11/11 and follow-up is 24 - 148 months (median of 120 months). Seizure foci were bilateral in 9 patients, multi-lobar (unilateral) in 12 patients and single-lobar in 1 patient. MST was performed over broad areas in and around the seizure foci. VNS implantation was done when the response to MST procedure was poor (1 patients), or there was recurrence of seizures (21 patients). Interval between MST and VNS implanttation varied from one month to three years (median of 2 years). Results: Thirteen patients (59%) are seizure free (Engel’ Class I), 8 (36.5%) have greater than 90% reduction in seizure frequency (Class II), and 1 (4.5%) has between 50% - 90% reduction in seizure frequency (Class III). Conclusion: The results show that VNS therapy produced meaningful improvement in seizure outcome in all patients with extra-temporal seizures that had inadequate response to MST.

Current and emerging treatments for absence seizures in young patients

In this report, we review the pharmacological and non-pharmacological treatments of the different absence seizure types as recently recognized by the International League Against Epilepsy: typical absences, atypical absences, myoclonic absences, and eyelid myoclonia with absences. Overall, valproate and ethosuximide remain the principal anti-absence drugs. Typical absence seizures exhibit a specific electroclinical semiology, pathophysiology, and pharmacological response profile. A large-scale comparative study has recently confirmed the key role of ethosuximide in the treatment of childhood absence epilepsy, more than 50 years after its introduction. No new antiepileptic drug has proven major efficacy against typical absences. Of the medications under development, brivaracetam might be an efficacious anti-absence drug. Some experimental drugs also show efficacy in animal models of typical absence seizures. The treatment of other absence seizure types is not supported with a high level of evidence. Rufinamide appears to be the most promising new antiepileptic drug for atypical absences and possibly for myoclonic absences. The efficacy of vagal nerve stimulation should be further evaluated for atypical absences. Levetiracetam appears to display a particular efficacy in eyelid myoclonia with absences. Finally, it is important to remember that the majority of antiepileptic drugs, whether they be old or new, may aggravate typical and atypical absence seizures.

Vagus nerve stimulation may be a sound therapeutic option in the treatment of refractory epilepsy

Refractory epilepsy accounts for 20 to 30% of epilepsy cases and remains a challenge for neurologists. Vagus nerve stimulation (VNS) is an option for palliative treatment. It was to study the efficacy and tolerability of VNS in patients implanted with a stimulator at the Curitiba Institute of Neurology (INC). A case study of six patients with refractory epilepsy submitted to a VNS procedure at the INC in the last four years was described and discussed. Mean age at time of implantation was 29 years. Mean follow-up was 26.6 months. Seizure frequency decreased in all patients (40-50% (n=2) and ≥80% (n=4)). Three patients no longer required frequent hospitalizations. Two patients previously restricted to wheelchairs started to walk, probably because of improved mood. In this population, VNS proved to be a sound therapeutic option for treating refractory epilepsy.

Clinical utility of vagus nerve stimulation for progressive myoclonic epilepsy

Progressive myoclonic epilepsy (PME) is a group of disorders in which myoclonus is a major component. Patients with PME typically have generalized tonic–clonic or clonic seizures, mental retardation culminating in dementia, and a neurologic syndrome that almost always includes cerebellar dysfunction. It comprises a heterogeneous group of inherited disorders. Conditions inwhich PME is seen include Unverricht–Lundborg disease, sialidosis, Gaucher’s disease, mitochondrial encephalomyelopathy with ragged-red fibers (MERRF), Lafora’s disease, neuronal ceroid lipofuscinosis, and Dentato-Rubro-Pallido Luysian Atrophy (DRPLA). The intensity of the various clinical features varies depending on the etiology. Although valproate, benzodiazepines, piracetam, zonisamide, topiramate, and levetiracetam have had a positive impact on the control of the epilepsy, the prognosis of this syndrome is poor. PME is also not responsive to open surgical resection. Among complimentary treatment options for epilepsy resistant tomedical and open surgical treatments, most patients so far have been treated by vagus nerve stimulation (VNS). VNS is a widely used neurostimulation for treatment-resistant epilepsy. Its components are a pulse generator and a bipolar vagus nerve lead. The generator is designed to be implanted in the patient’s chest on the upper left side. This pulse generator produces charge-balanced waveforms at a constant current. The effectiveness of VNS for PME has rarely been reported. The purpose of this study was to evaluate the efficacy of VNS for PME.

Efficacy of vagus nerve stimulation in posttraumatic versus nontraumatic epilepsy

In the US, approximately 500,000 individuals are hospitalized yearly for traumatic brain injury (TBI), and posttraumatic epilepsy (PTE) is a common sequela of TBI. Improved treatment strategies for PTE are critically needed, as patients with the disorder are often resistant to antiepileptic medications and are poor candidates for definitive resection. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy that results in a ≥ 50% reduction in seizure frequency in approximately 50% of patients after 1 year of therapy. The role of VNS in PTE has been poorly studied. The aim of this study was to determine whether patients with PTE attain more favorable seizure outcomes than individuals with nontraumatic epilepsy etiologies. Using a case-control study design, the authors retrospectively compared seizure outcomes after VNS therapy in patients with PTE versus those with nontraumatic epilepsy (non-PTE) who were part of a large prospectively collected patient registry. After VNS therapy, patients with PTE demonstrated a greater reduction in seizure frequency (50% fewer seizures at the 3-month follow-up; 73% fewer seizures at 24 months) than patients with non-PTE (46% fewer seizures at 3 months; 57% fewer seizures at 24 months). Overall, patients with PTE had a 78% rate of clinical response to VNS therapy at 24 months (that is, ≥ 50% reduction in seizure frequency) as compared with a 61% response rate among patients with non-PTE (OR 1.32, 95% CI 1.07-1.61), leading to improved outcomes according to the Engel classification (p < 0.0001, Cochran-Mantel-Haenszel statistic). Vagus nerve stimulation should be considered in patients with medically refractory PTE who are not good candidates for resection. A controlled prospective trial is necessary to further examine seizure outcomes as well as neuropsychological outcomes after VNS therapy in patients with intractable PTE.

Vagus nerve stimulation elevates seizure threshold in the kindling model

Vagus nerve stimulation (VNS) provides partial relief of medically refractory partial seizures in a subset of patients. The optimal pattern of stimulation and the mechanism of the antiseizure effects are uncertain. Establishing the efficacy of VNS in an animal model of epilepsy would provide an experimental preparation with which to address these questions. We sought to determine whether VNS exerted antiseizure effects in the kindling model of epilepsy. We implanted adult rats with bipolar stimulating electrodes in the right amygdala and VNS devices around the left vagus nerve. Following induction of kindling, electrographic seizure threshold (EST) was determined by quantifying the amygdala electrode current required to evoke a seizure. Once stable ESTs were established, VNS devices were programmed to deliver U.S. Food and Drug Administration (FDA)-approved, clinically used (standard) or an experimental (microburst) pattern of stimulation of variable intensity. VNS devices were programmed identically in control animals except that no current was delivered. EST was examined at 60 min and 1 week in the control and vagus nerve stimulated groups. Significant reductions of EST values were detected in control animals when tested both 60 min and 1 week following device programming. Both clinically used and experimental patterns of VNS prevented the reduction of EST evident in control animals when tested either 60 min or 1 week after device programming. These findings establish an experimental preparation with which to elucidate the antiseizure mechanisms of VNS and to determine patterns of VNS most effective at elevating seizure threshold.

Autonomic boundary conditions for ventricular fibrillation and their implications for a novel defibrillation technique

The sympathetic and parasympathetic divisions of the autonomic nervous system modulate cardiac rhythm and the probability of arrhythmia occurrence. Both increased sympathetic drive and hypoxia increase the likelihood for ventricular fibrillation (VF). Vagus nerve stimulation (VNS) can protect from fatal arrhythmias via cholinergic and nitrergic action. We sought to determine boundary conditions for VF and defibrillation by autonomic manipulations accompanied or not by hypoxic changes in urethane-anesthetized rats. VF was induced with (1) vagotomy, (2) systemic high-dose (>15 mg/kg) isoproterenol, and (3) hypoxemia. When VNS (50 Hz) produced cardiac standstill, it converted every VF episode (59/59). A nitric oxide synthase inhibitor did not reduce VNS efficacy (13/14 episodes converted), but addition of atropine reduced VNS efficacy (11/27 episodes converted). VF can be induced by autonomic derangements only under constrained conditions, including sympathetic over-activation, reduced parasympathetic input, and hypoxemia. VNS can provide an alternative method to defibrillate via its cholinergic action.

Rationale and study design of the INcrease Of Vagal TonE in Heart Failure study: INOVATE-HF

Imbalance between the parasympathetic and sympathetic nervous systems is a recognized contributor to progression of chronic heart failure. Current therapy with beta adrenergic antagonists is designed to moderate the up-regulation of norepinephrine and sympathetic effects; however, to date, there are no therapies that specifically address the withdrawal of parasympathetic influences on cardiac function and structure. In order to evaluate the impact of vagus nerve stimulation, an international multi-center randomized clinical trial (INOVATE-HF) has been designed to assess safety and efficacy of vagus nerve stimulation in symptomatic patients with heart failure on optimal medical therapy using the CardioFit System (BioControl Medical, Yehud, Israel). Up to 650 patients from 80 sites will be recruited and randomized in a 3:2 ratio to receive active treatment or standard optimal medical therapy. Inclusion criteria include left ventricular systolic dysfunction, the presence of New York Heart Association Class III symptoms, sinus rhythm, and QRS width less than 120 milliseconds. The study is powered to detect differences in the primary efficacy end point of all-cause mortality and heart failure hospitalization and 2 safety end points. Vagal nerve stimulation with CardioFit as a treatment for symptomatic heart failure is under active investigation as a novel approach to restore balance between the sympathetic and parasympathetic nervous systems. If shown to be safe and effective in decreasing heart failure events and mortality, this novel approach will impact the treatment paradigm for heart failure.

Efficacy of Vagal Nerve Stimulation (VNS) after Multiple Subpial Transection (MST) for Extra-Temporal Seizure Foci (P01.056)

Objective: To evaluate seizure outcome with vagal nerve stimulation after multiple subpial transection in patients with extra temporal seizure foci. Background Though there are reports on seizure outcome of vagal stimulation (VNS) following failed major resective surgeries there are no studies on its effect following multiple subpial transections (MST). Design/Methods: 24 patients between the ages of 10-55 years were followed up for 24-148 months (median of 115 months). Seizure foci were bilateral in 11 patients, multi-lobar (unilateral) in 12 patients and single-lobar(unilateral) in 1 patient. MST was performed over broad areas in and around the seizure foci. Minimal topectomies were done in areas in which intra-operative EEG recording showed epileptogenic activity after 2-3 MST passes. VNS implant was done when the response from first surgery was poor (2 patients) or there was recurrence of seizures (24 patients). The interval between MST and VNS was 1 month-3years (median of 2 years). Results: There were no complications from VNS implant. The seizure outcome after VNS implant is: 15/24(62.5%) Engle9s class I, 8/24 (33.3%) class II and 1/24 (4%) class III. Conclusions: The results show that VNS improves seizure outcome in patients who have previously had MST. Based on literature search these results are better than those reported in patients who had VNS implant alone (with a 50 % responder rate in 30-40 percent); or had VNS implant after major resective surgery (with no significant benefit) or those who had major resective surgery alone. This difference may be because MST is performed over a large area of the brain; so that satellite foci in distant areas also get treated. Furthermore, it is possible that the pruning of the inter-neuronal connections that occurs in MST makes VNS signals reaching the cortical neurons more intense (and therefore more effective) by reducing its peripheral spread. Disclosure: Dr. Patil has nothing to disclose. Dr. Antony has nothing to disclose. Dr. Andrews has nothing to disclose.

Pretreatment cerebral metabolic activity correlates with antidepressant efficacy of vagus nerve stimulation in treatment-resistant major depression: A potential marker for response?

Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD). Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥ 50% reduction in HDRS from baseline. Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n=11) from nonresponders (n=4) and correlated with HDRS change (r=.64, p=.01). In a regression analysis, lower anterior insular cortex CMRGlu (p=.004) and higher orbitofrontal cortex CMRGlu (p=.047) together predicted HDRS change (R(2)=.58, p=.005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r=.78, p=.001). Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled. This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.

Long-Term Vagus Nerve Stimulation for Severe Refractory Depression: A Case Study With a Six-Year Follow-Up

Long-Term Vagus Nerve Stimulation for Severe Refractory Depression: A Case Study With a Six-Year Follow-Up

Vagus nerve stimulation has a positive effect on mood in patients with refractory epilepsy

BackgroundPreliminary research on the efficacy of vagus nerve stimulation (VNS) indicated additional effects on neuropsychological variables like mood and quality of life (QOL). ObjectivesThe objectives of this prospective longitudinal observational cohort study were to assess the effects of VNS on mood, QOL and cognition in patients with refractory epilepsy and to determine whether these effects occur dependent of seizure control. MethodsWe included 41 patients with refractory epilepsy; treated with VNS as part of usual patient care. A neuropsychological battery was performed during baseline and repeated after 6 months of VNS in order to compare neuropsychological variables before and after VNS. All patients completed seizure diaries. ResultsSignificant improvements were observed for both mood and QOL after 6 months of VNS; based on the results in the POMS and QOLIE-89 questionnaires (p<0.05). There was no significant change in cognition. Mean percentage change in seizure frequency was −9.0%, while 20% of the patients achieved a seizure frequency reduction of 50% or more. No significant correlation was found between changes in seizure frequency and improvements in mood or QOL. ConclusionsVNS is associated with improvements in both mood and QOL in patients with refractory epilepsy. Since these improvements appeared to be independent of seizure control, the results of this study indicate an additional antidepressant effect of VNS, which can be of extra value in view of the high co-morbidity of mood disturbances in patients with epilepsy.

Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: Variable results based on study designs

PurposeTo determine the efficacy of vagus nerve stimulation (VNS) for treatment of depression. MethodsWe conducted a systematic review and meta-analysis of analytical studies. Efficacy was evaluated according to severity of illness and percentage of responders. ResultsWe identified 687 references. Of these, 14 met the selection criteria and were included in the review. The meta-analysis of efficacy 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 randomised control trial which covered a sample of 235 patients with depression, reported no statistically significant differences between the active intervention and placebo groups (OR=1.61 [95%CI 0.72 to 3.62]; P=0.25). To study the cause of this heterogeneity, a meta-regression was performed. The adjusted coefficient of determination (R2Adj) 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). ConclusionCurrently, 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.

Safety and Efficacy of Vagus Nerve Stimulation in Fibromyalgia: A Phase I/II Proof of Concept Trial

We performed an open-label Phase I/II trial to evaluate the safety and tolerability of vagus nerve stimulation (VNS) in patients with treatment-resistant fibromyalgia (FM) as well as to determine preliminary measures of efficacy in these patients. Of 14 patients implanted with the VNS stimulator, 12 patients completed the initial 3-month study of VNS; 11 patients returned for follow-up visits 5, 8, and 11 months after start of stimulation. Therapeutic efficacy was assessed with a composite measure requiring improvement in pain, overall wellness, and physical function. Loss of both pain and tenderness criteria for the diagnosis of FM was added as a secondary outcome measure because of results found at the end of 3 months of stimulation. Side effects were similar to those reported in patients treated with VNS for epilepsy or depression and, in addition, dry mouth and fatigue were reported. Two patients did not tolerate stimulation. At 3 months, five patients had attained efficacy criteria; of these, two patients no longer met widespread pain or tenderness criteria for the diagnosis of FM. The therapeutic effect seemed to increase over time in that additional participants attained both criteria at 11 months. Side effects and tolerability were similar to those found in disorders currently treated with VNS. Preliminary outcome measures suggested that VNS may be a useful adjunct treatment for FM patients resistant to conventional therapeutic management, but further research is required to better understand its actual role in the treatment of FM.

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.

The Correlation Between Vagus Nerve Stimulation Efficacy and Partial Onset Epilepsies

To evaluate the correlation between vagus nerve stimulation (VNS) efficacy and partial seizures originating from different brain regions. The authors retrospectively analyzed the data of 46 subjects with medically intractable epilepsy who had insertion of VNS between April 1999 and July 2005. The clinical outcome was assessed with Engel classification. Subjects were divided into group A (Engel I, II, and III) and group B (Engel IV) for statistical analysis. Group A was referred as a satisfactory outcome. The statistical analysis of the data was assessed whether these parameters such as age, type of seizure, age at insertion of VNS, and lengths of follow-up affect the outcome. Nineteen patients (41.3%) had a satisfactory outcome (Engel II, III). The analysis of VNS efficacy demonstrated that 65% of the patients with frontal lobe epilepsy and only 15% of the patients with temporal lobe epilepsy (TLE) had a satisfactory outcome. There was a statistically significant difference between these types of epilepsyand VNS outcomes (Fisher exact test, P = 0.004). VNS is more effective in frontal lobe epilepsy than in temporal lobe epilepsy. Further studies are warranted to verify our findings and the correlation between types of epilepsy and VNS outcome.

Novel attempts to optimize vagus nerve stimulation parameters on serotonin neuronal firing activity in the rat brain

Vagus nerve stimulation (VNS) is indicated for treatment-resistant epilepsy and depression. Electrophysiologic recordings in the rat brain have shown that VNS promptly increases the firing rate of NE neurons and subsequently that of 5-HT neurons. Thus far, it appears that the standard stimulation parameters currently used in depressed patients produce an optimal activation of 5-HT neurons. This study was therefore aimed at investigating additional alterations of stimulation parameters to optimize VNS efficacy to further increase 5-HT neuronal activity. Rats were implanted with a VNS device and stimulated for 14 days using standard (0.25 mA/20 Hz/500 microseconds/30 seconds ON-5 minutes OFF, continuously) or various stimulation parameters: extension of the OFF period (30 seconds ON every 10 to 30 minutes), the OFF and ON periods, discontinuous stimulation (12 hours per day using standard parameters), and burst stimulation modes. Rat dorsal raphe 5-HT neurons were recorded under chloral hydrate anesthesia. Both 12-hour stimulation periods for 14 days, and the 30-second stimulation every 10 or 15 minutes significantly increased the firing activity of 5-HT neurons to the same extent as standard parameters while the 30-minute intervals were ineffective. Stimulations in a burst mode and the pseudo-one-pulse stimulations also significantly increased 5-HT neuronal activity. These results indicate that less stimulation is sufficient to achieve the same VNS efficacy on 5-HT neuronal firing. These data may be relevant for patients using VNS because these new parameters could minimize or prevent side effects and increase battery life of the stimulator.

Impact of Failed Intracranial Epilepsy Surgery on the Effectiveness of Subsequent Vagus Nerve Stimulation

Using the Cyberonics registry, Amar and colleagues reported poorer efficacy of vagus nerve stimulation (VNS) in patients who failed intracranial epilepsy surgery (IES). To study the impact of failed IES and other surrogate marker of severe epilepsy on VNS effectiveness in a large cohort with treatment-resistant epilepsy (TRE). We retrospectively reviewed 376 patients (188 female patients; 265 adults; mean age, 29.4 years at implantation) with TRE who underwent VNS implantation between 1997 and 2008 and had at least 1 year of follow-up. One hundred ten patients (29.3%) had failed ≥ 1 prior craniotomies for TRE, and 266 (70.7%) had no history of IES. The mean duration of VNS therapy was 5.1 years. Patients with prior IES were more commonly male and adult, had a greater number of seizure types, and more commonly had focal or multifocal vs generalized seizures (P < .05). There was no significant difference in the mean percentage seizure reduction between patients with and without a history of IES (59.1% vs 56.5%; P = .42). There was no correlation between type of failed IES (callosotomy vs resection) and seizure reduction with VNS therapy. Failed IES did not affect the response to VNS therapy. Unlike prior reports, patients with callosotomy did not respond better than those who had resective surgery. Nearly 50% of patients experienced at least 50% reduction in seizure frequency. For patients with TRE, including patients who failed cranial epilepsy surgeries, VNS should be considered a palliative treatment option.

Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases

The authors undertook this study to analyze the efficacy of vagus nerve stimulation (VNS) in a large consecutive series of children 18 years of age and younger with treatment-resistant epilepsy and compare the safety and efficacy in children under 12 years of age with the outcomes in older children. The authors retrospectively reviewed 141 consecutive cases involving children (75 girls and 66 boys) with treatment-resistant epilepsy 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 vagus nerve stimulator insertion was 11.1 years (range 1-18 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 25 days-11.4 years). Seizure frequency significantly improved with VNS therapy (mean reduction 58.9%, p < 0.0001) without a significant reduction in antiepileptic medication burden (median number of antiepileptic 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. Vagus nerve stimulation is a safe and effective treatment for treatment-resistant epilepsy 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. 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.